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Deformation models and correlation analysis in elastography.

Cross-correlation functions are derived with the purpose of determining how strain inhomogeneities affect the displacement estimates used in ultrasound-based elastography. Variations in the strain profile occur in most imaging situations and are caused by fluctuations in the stress field or elastic modulus of the sample. An analytical framework for developing signal processing strategies in elastography is described, and the limitations of correlation-based methods for measuring displacements in tissuelike media caused by static compression are emphasized. This paper includes (1) an accurate approximation for an inverse coordinate transformation that release pre- and postcompression reflectivity profiles of the media, (2) a derivation of the echo-signal cross-correlation function in media with deterministic or stochastic strain profiles; (3) mathematical and graphical descriptions of the consequences that nonuniformities in the strain profile impose upon the uncertainty of displacement estimation; and (4) a demonstration of the advantages of echo signal conditioning and ultrasonic-pulse shaping to reduce the nonstationary effects that attenuate the cross-correlation peak and reduce the signal-to-noise ration for displacement estimation.

Elasticity↗

Pharmacoeconomic analysis of fondaparinux versus enoxaparin for the prevention of thromboembolic events in orthopedic surgery patients.

INTRODUCTION: Fondaparinux is a novel synthetic antithrombotic that has been evaluated for the prevention of venous thromboembolism (VTE). In four large trials in patients who underwent major hip or knee surgery, fondaparinux was found to have a good safety profile and be more effective than enoxaparin. To generate Canadian pharmacoeconomic data for fondaparinux, an internationally developed cohort deterministic model was used to estimate the costs and consequences of prophylaxis with fondaparinux compared with enoxaparin in the Canadian orthopedic surgical setting. DESIGN AND SETTING: A health economic advisory group was assembled to guide the pharmacoeconomic evaluation. Efficacy and safety data for fondaparinux relative to enoxaparin were abstracted from a meta-analysis of four randomized trials. Canadian cost data to populate the model were obtained from a resource-use survey of four large Canadian hospitals, from the Canadian Institute for Health Information (CIHI), and from the Canadian economic literature. Case-mix information obtained from CIHI was incorporated into the cohort deterministic model, which predicted the number of VTEs and bleeds following prophylaxis with fondaparinux or enoxaparin within 90 days of surgery, and the associated overall cost difference. The stability of the base-case findings was evaluated with sensitivity analyses. STUDY PERSPECTIVE: Canadian healthcare system perspective. MAIN OUTCOME MEASURES AND RESULTS: Assuming a case mix of 50,693 major hip or knee surgeries performed in Canada in 1999/2000 (as reported by CIHI), the model predicted that prophylaxis with fondaparinux would avoid an additional 16 symptomatic VTEs per 1000 patients over the first 90 days, with an average cost savings of Can 55 dollars per patient. These findings were stable when key economic and clinical parameters were varied, including bleeding events. CONCLUSIONS: Our results suggest that in Canada, prophylactic fondaparinux compared with enoxaparin avoids VTEs and is associated with lower costs in patients who undergo major hip or knee surgery.

Anticoagulants↗

Probabilistic Monte Carlo based mapping of cerebral connections utilising whole-brain crossing fibre information.

A methodology is presented for estimation of a probability density function of cerebral fibre orientations when one or two fibres are present in a voxel. All data are acquired on a clinical MR scanner, using widely available acquisition techniques. The method models measurements of water diffusion in a single fibre by a Gaussian density function and in multiple fibres by a mixture of Gaussian densities. The effects of noise on complex MR diffusion weighted data are explicitly simluated and parameterised. This information is used for standard and Monte Carlo streamline methods. Deterministic and probabilistic maps of anatomical voxel scale connectivity between brain regions are generated.

Algorithms↗

The impact of a resident's seniority on operative time and length of hospital stay for laparoscopic appendectomy: outcomes used to measure the resident's laparoscopic skills.

BACKGROUND: Laparoscopic appendectomy (LA) frequently is performed by residents during calls. This study aimed at evaluating residents' surgical skills using parameters of operating time, length of hospital stay (LOS), and conversion rate in correlation with the operating team's level of seniority. In addition, this study compared the operating time for LA with that for open appendectomy performed by the same teams, and identified deterministic factors that have an impact on such parameters. METHODS: All records of patients undergoing appendectomy performed by residents alone during a 32-month period were reviewed retrospectively. Eight residents were assigned to two levels of seniority: juniors 3 years (S). Operating time and LOS were compared between the three surgical teams, namely, J/J, J/S, and S/J as operating and assistant surgeons, respectively. Operating time, conversion rates, and LOS were compared for the same team combinations. RESULTS: Residents alone performed 341 (151 laparoscopic and 190 open) appendectomies during on-call hours. Four of the residents had been 3 years or less in residency (J), and four had been in residency more than 3 years (S). The overall mean operating time was 1.33 +/- 0.48 h for LA and 1.2 +/- 0.5 h for open appendectomy (p = 0.016). The operating time correlated with the level of training for both LA (J/J, 1.6 +/- 0.38 h; J/S, 1.41 +/- 0.37 h; S/J, 1. 25 +/- 0.4 h; p = 0.03, ANOVA) and open appendectomy (J/J, 1.53 +/- 0.89 h; J/S, 1.4 +/- 0.63 h; S/J, 0.86 +/- 0.45 h; p = 0.023, ANOVA). The mean LOS was 2.9 +/- 3.1 days for open appendectomy and 2.1 +/- 2.8 days for LA (p = 0.065), and was not different after operation by any of the teams (J/J, J/S, S/J) for either the open or the laparoscopic procedure. CONCLUSIONS: There is a distinct difference in the surgical skills of residents according to level of seniority, as primarily reflected by operating time. Laparoscopic appendectomy requires longer time to perform in a teaching setting, but the most deterministic factor that dictates operating time is the composition of the surgical team rather than the laparoscopic approach.

Adolescent↗

Non-linear time series analysis of intracranial EEG recordings in patients with epilepsy--an overview.

Deterministic chaos offers a striking explanation for apparently irregular behavior, a characteristic feature of brain electrical activity. The framework of the theory of non-linear dynamics provides new concepts and powerful algorithms to analyze such time series. However, different influencing factors render the use of non-linear measures in a strict sense problematic. Nevertheless, if interpreted with care, particularly the correlation dimension or the Lyapunov-exponents provide a means to reliably characterize different states of normal and pathological brain function. This overview summarizes recent findings applying this concept in the field of epileptology that promise to be important for clinical practice. Non-linear measures extracted from the intra-cranially recorded EEG allow (a) localization of epileptogenic areas in different cerebral regions even during seizure-free intervals, (b) investigation of the influence of anticonvulsive drugs and (c) detection of features predictive of imminent seizure activity. Moreover, particularly the dimensional complexity proves a valuable parameter reflecting spatially distributed neuronal activity during verbal learning and memory processes. Specific changes in time of this non-linear measure allow the prediction of memory performance and, in addition, represent an estimate of the recruitment potency in the anterior mesial temporal lobes. Thus, the application of non-linear time series analysis to brain electrical activity offers new information about the dynamics of the underlying neuronal networks.

Electroencephalography↗

[A simulation method for studying scintillation camera collimators].

This paper presents a computer simulation of photon interaction with collimator septa, which allows the point spread function of scintillation camera collimators to be calculated. The method simulates photon attenuation along their propagation direction in a determinist way. Using this simulation, the spatial resolution, geometric efficiency and penetration index of collimators may be easily assessed. Results obtained with this method are presented and compared with those obtained from standard formulae. We show the usefulness of the simulation which precisely accounts for effects of septum penetration. Measurements performed on two collimators with 131I and 99Tcm point sources provide results consistent with those obtained from the simulation method. In conclusion we show that this method is an accurate tool to assist conception of collimators for nuclear medicine.

Computer Simulation↗

Similia similibus obscurantur: the pharmacological clinical activity bias I. A prototype model to correct a disease-drug interaction leading to misestimations of drug-attributable side effects.

Drugs have side effects that manifest as signs or symptoms which are sometimes undistinguishable from signs or symptoms of active disease. The conventional approximation of the rate of side effects of drugs is by subtracting the rate of signs and symptoms in the placebo group from that in the drug group. This measures net side effects and is adequate in studies with healthy volunteers, in which no interaction between drug and disease exists. For ethical and practical reasons, however, volunteer studies cannot be large and the frequency of non-rare side effects must be estimated in large-scale clinical trials. In the latter, biasing drug disease interactions may occur. We report on such a hitherto undescribed interaction: the pharmacological clinical activity bias. If one is interested in estimating not the net, but the direct or intrinsic, ie, drug-attributable side effects, the conventional approximation is biased whenever, in clinical trials, both of two conditions apply. The first is that the variable on the scale of which a sign or symptom is recorded as a putative side effect, is also in the absence of drug affected by uncontrolled disease. The second is that the drug has pharmacological clinical activity (A) on that sign or symptom, thus reducing the contribution of disease (D) to what is measured. In this case the drug affects the variable under study both directly, through its intrinsic side effect, and indirectly, through its clinical activity, and the rate of attributable side effects differs from the rate of net side effects as calculated by the conventional approximation. We present a simple deterministic model, which assumes that disease remains stable if untreated, additivity of the relative contributions of drug, placebo and disease to the total rate of the sign or symptom, and no other interaction between intrinsic properties of the drug and active disease than pharmacological clinical activity. This theoretical model quantifies the bias as DO(Ad-Ap), in which DO is the baseline frequency of the sign or symptom in the studied patients, and Ad and Ap are the intrinsic clinical activities of drug and placebo, respectively, on the sign or symptom under study. The model confirms that the conventional approximation of drug side effects is unbiased only in healthy volunteers or with drugs devoid of clinical activity. Without correction by such a model, any clinical activity of the drug or manifestation of active disease will cause the conventional approximation of side effects to be biased. This may manifest as artifacts such as attribution of a side effect when there is none, and as under- or overestimation, pseudotachyphylaxis, or pseudo-delayedness of attributable side effects.

Disease↗

The effectiveness and cost-effectiveness of pimecrolimus and tacrolimus for atopic eczema: a systematic review and economic evaluation.

OBJECTIVES: To consider the effectiveness and cost-effectiveness of pimecrolimus for mild to moderate atopic eczema and tacrolimus for moderate to severe atopic eczema compared with current standard treatment in adults and children. DATA SOURCES: Electronic databases. Experts and the manufacturers of these agents were also approached for information. REVIEW METHODS: The systematic review was carried out using standard methodological guidelines and a stringent quality assessment strategy. A state transition (Markov) model was developed to estimate cost--utility of tacrolimus and pimecrolimus separately, compared with current standard practice with topical corticosteroids, (a) as first-line treatment and (b) as second-line treatment. Pimecrolimus was also compared to emollients only. RESULTS: The pimecrolimus trial reports were of varying quality; however when compared with a placebo (emollient), pimecrolimus was found to be more effective and to provide quality of life improvements. There is very little evidence available about pimecrolimus compared with topical corticosteroids. Compared with a placebo (emollient), both 0.03% and 0.1% tacrolimus were found to be more effective. Compared with a mild corticosteroid, 0.03% tacrolimus is more effective in children as measured by a 90% or better improvement in the Physician's Global Evaluation (PGE). Compared with potent topical corticosteroids, no significant difference in effectiveness is seen with 0.1% tacrolimus as measured by a 75% or greater improvement in the PGE. Minor application site adverse effects are common with tacrolimus. However, this did not lead to increased rates of withdrawal from treatment in trial populations. The PenTag economic model demonstrates a large degree of uncertainty, which was explored in both deterministic and stochastic analyses. This is the case for the cost-effectiveness of pimecrolimus and tacrolimus in first- or second-line use compared with topical steroids. In all cases immunosuppressant regimes were estimated to be more costly than alternatives and differences in benefits to be small and subject to considerable uncertainty. CONCLUSIONS: There is limited evidence from a small number of randomised controlled trials (RCTs) that pimecrolimus is more effective than placebo treatment in controlling mild to moderate atopic eczema. Although greater than for pimecrolimus, the evidence base for tacrolimus in moderate to severe atopic eczema is also limited. At both 0.1% and 0.03% potencies, tacrolimus appears to be more effective than the placebo treatment and mild topical corticosteroids. However, these are not the most clinically relevant comparators. Compared with potent topical corticosteroids, no significant difference was shown. Short-term adverse effects with both immunosuppressants are relatively common, but appear to be mild. Experience of long-term use of the agents is lacking so the risk of rare but serious adverse effects remains unknown. No conclusions can be confidently drawn about the cost-effectiveness of pimecrolimus or tacrolimus compared with active topical corticosteroid comparators. Areas for further research should focus on the effectiveness and safety of the treatments through good-quality RCTs and further economic analysis.

Adrenal Cortex Hormones↗

Two mathematically defined expressive language structures in humans and chimpanzees.

Two expressive language structures have been identified mathematically in humans and chimpanzees. The first was found by measuring the waiting times between the invocation of new words or symbols, which consistently yielded individually characteristic rate constants and descending exponential curves that reflect a stochastically lawful Poisson process. The second was discovered by calculating the cumulative informational complexity (entropy) of word usage, which in all cases was a deterministically lawful logarithmic function of the number of words used to a given point in a communicative sequence. Individual and species differences in how this law is obeyed also characterized the sample. The results from the apes resembled those from the works of human poets like Shakespeare. The findings speak for deep, natural, unlearned expressive language structures in apes that are comparable to those seen in humans.

Animals↗

[Ergonomical studies about the superposition of control activity and mechanical vibration (author's transl)].

The effects of combined stresses due to control activity and vertical mechanical vibration on man are analysed. In the first part, the processes in the human being at those superposed stresses are shown in a deterministic way, starting from morphological and physiological facts, which leads to a division of the organismic data processing in the fields of information reception, central information processing and information output. Hypothesis of the effects of vibration in the parts of information reception and information output as well as indications to measurable variables at laboratory experiments can be deduced from the model formulation. In the experimental part about factorized laboratory experiments with combined stresses consisting of an ideal-typical compensatory-tracking-task and mechanical vibration is reported, which can be divided into short-time experiments with measurement of the statistical control-factor and perseverance experiments with additional measurements of physiological variables. As established in the first part, influences of vibration in the regions of information reception and information output were found as well as thresholds for the performance-reducing effects of mechanical vibrations. The magnitudes of the thresholds are dependent on the task difficulty.

Ergonomics↗

Uncertainty assessment for management of soil contaminants with sparse data.

In order for soil resources to be sustainably managed, it is necessary to have reliable, valid data on the spatial distribution of their environmental impact. However, in practice, one often has to cope with spatial interpolation achieved from few data that show a skewed distribution and uncertain information about soil contamination. We present a case study with 76 soil samples taken from a site of 15 square km in order to assess the usability of information gleaned from sparse data. The soil was contaminated with cadmium predominantly as a result of airborne emissions from a metal smelter. The spatial interpolation applies lognormal anisotropic kriging and conditional simulation for log-transformed data. The uncertainty of cadmium concentration acquired through data sampling, sample preparation, analytical measurement, and interpolation is factor 2 within 68.3 % confidence. Uncertainty predominantly results from the spatial interpolation necessitated by low sampling density and spatial heterogeneity. The interpolation data are shown in maps presenting likelihoods of exceeding threshold values as a result of a lognormal probability distribution. Although the results are not deterministic, this procedure yields a quantified and transparent estimation of the contamination, which can be used to delineate areas for soil improvement, remediation, or restricted area use, based on the decision-makers' probability safety requirement.

Data Collection↗

Predicted steady-state cell size distributions for various growth models.

The question of how an individual bacterial cell grows during its life cycle remains controversial. In 1962 Collins and Richmond derived a very general expression relating the size distributions of newborn, dividing and extant cells in steady-state growth and their growth rate; it represents the most powerful framework currently available for the analysis of bacterial growth kinetics. The Collins-Richmond equation is in effect a statement of the conservation of cell numbers for populations in steady-state exponential growth. It has usually been used to calculate the growth rate from a measured cell size distribution under various assumptions regarding the dividing and newborn cell distributions, but can also be applied in reverse--to compute the theoretical cell size distribution from a specified growth law. This has the advantage that it is not limited to models in which growth rate is a deterministic function of cell size, such as in simple exponential or linear growth, but permits evaluation of far more sophisticated hypotheses. Here we employed this reverse approach to obtain theoretical cell size distributions for two exponential and six linear growth models. The former differ as to whether there exists in each cell a minimal size that does not contribute to growth, the latter as to when the presumptive doubling of the growth rate takes place: in the linear age models, it is taken to occur at a particular cell age, at a fixed time prior to division, or at division itself; in the linear size models, the growth rate is considered to double with a constant probability from cell birth, with a constant probability but only after the cell has reached a minimal size, or after the minimal size has been attained but with a probability that increases linearly with cell size. Each model contains a small number of adjustable parameters but no assumptions other than that all cells obey the same growth law. In the present article, the various growth laws are described and rigorous mathematical expressions developed to predict the size distribution of extant cells in steady-state exponential growth; in the following paper, these predictions are tested against high-quality experimental data.

Bacteria↗

Analytical model of susceptibility-induced MR signal dephasing: effect of diffusion in a microvascular network.

A deterministic analytical model that describes the time course of magnetic resonance signal relaxation due to magnetic field inhomogeneity induced by a vascular network is developed. Both static and diffusion dephasing are taken into account. The contribution of the diffusion dephasing is calculated for relatively large vessels (R>10 microm) or short measurement times when the diffusion length is smaller than the vessel radius. The signal is found to possess the following features: a) an initial deviation from the monoexponential relaxation which is more pronounced for the imaginary part of the signal; b) a deviation from monoexponential relaxation at short echo times for the spin-echo (SE) signal measured as a function of the echo time; c) the echo maximum of the SE signal shifted from the nominal echo time to a shorter time; and d) a diffusion effect much stronger for the SE than for the free induction decay experiment. The model presented agrees within its validity domain with a known Monte Carlo simulation.

Brain↗

Ultradian rhythms and the lux-gene reporter system.

'Noisy' bioluminescence of an unstirred and exposed-to-air microculture of lux -gene fused Escherichia coli was interpreted, assuming two oscillatory processes: cyclic induction of the lac promoter, resulting in oscillatory reporter lux -gene expression, and oscillatory respiration in the culture. Biological support for the theoretical argument, that two rhythms can interact in cells to produce additional rhythms, is provided. These results, along with previously obtained data on oscillatory bioluminescence, indicate the deterministic nature of observed noise-like fluctuations and promising perspectives of lux gene reporter systems in investigations of ultradian rhythm.

Bacteria↗

The three modes of the science of psychoanalysis.

Three modes of the science of psychoanalysis are identified: (1) the domain mode is established when claim is laid for investigation of a distinctive area of nature for investigation. For psychoanalysis, this territory involves human adaptation, mentation, and communication in the emotional arena. This mode essentially is one in which a scientific spirit is central and gross, qualitative observation the source of data and theory; (2) the statistical mode is characterized by quantification (measurement), prediction, controlled study, and global correlational or probability methods. In general, this mode of science serves to confirm, refute, or revise postulates derived from domain-mode observations. An advanced aspect of this mode is termed stochastics, a form of science that deals with events that are both random and deterministic, and which introduces post hoc mathematical equations that are probabilistic in nature. (3) the formal mode is grounded in moment-to-moment observations (time-series data); its results are defined entirely through mathematical treatments of quantified data. The unique quest in this mode is for laws of nature. Each mode of the science of psychoanalysis is discussed for its actual and potential contributions to the field and for its limitations and pitfalls. Finally, the paper discusses aspects of recent research that has, we believe, established a heretofore absent formal mode of science for the field of psychoanalysis.

Female↗

Modelling the long term cost effectiveness of clopidogrel for the secondary prevention of occlusive vascular events in the UK.

OBJECTIVE: To assess the long term cost effectiveness of clopidogrel monotherapy compared with acetylsalicylic acid (aspirin; ASA) monotherapy in patients at risk of secondary occlusive vascular events (OVEs) in the UK. DESIGN: Cost utility analysis based on clinical data from CAPRIE (a multicentre randomised controlled trial, involving 19185 patients); long-term effects were extrapolated beyond the trial period using a Markov model populated with data from UK observational studies. Health economic evaluation carried out from the perspective of the UK National Health Service. PARTICIPANTS: A representative cohort of 1000 UK patients aged 60 years (approximate mean age of the CAPRIE population), with the qualifying diagnoses of myocardial infarction, ischaemic stroke and peripheral arterial disease, who are at risk of secondary OVEs (non-fatal myocardial infarction, non-fatal stroke or vascular death). INTERVENTIONS: Patients were assumed to receive treatment with either clopidogrel (75 mg/day) for 2 years followed by ASA (325 mg/day, average) for their remaining lifetime, or ASA alone (325 mg/day, average) for life. MAIN OUTCOME MEASURES: Incremental cost per life year gained and incremental cost per quality-adjusted life year (QALY) gained. RESULTS: In the base case, the incremental cost effectiveness of clopidogrel versus ASA in this population is estimated at 18888 pounds per life year gained and 21 489 pounds per QALY gained. Multiple deterministic and probabilistic sensitivity analyses suggest the model is robust to variations in a wide range of input parameters. CONCLUSION: Two years of treatment with clopidogrel can be considered a cost effective intervention in patients at risk of secondary OVEs in the UK.

Aged↗

Deterministic pressure-induced dissociation of vicilin, the 7S storage globulin from pea seeds: effects of pH and cosolvents on oligomer stability.

A thermodynamic characterization of subunit association of vicilin, a storage protein from pea seeds, was performed using a combination of hydrostatic pressure and fluorescence spectroscopy. Application of pressure up to 2.4 kbar caused dissociation of vicilin subunits, as revealed by (1) size-exclusion PPLC of pressurized samples, (2) fluorescence anisotropy measurements of a dansyl-vicilin conjugate under pressure, and (3) quenching of the intrinsic fluorescence of vicilin. Pressure dissociation data were well described by a model for dissociation of a trimer. This enabled calculation of the standard molar volume change of association (delta Vo) and the equilibrium dissociation constant at atmospheric pressure (Ko); at pH 10 these were found to be delta Vo = 146 mL/mol and Ko = 2.2 x 10(-15) M2, respectively, corresponding to C1/2 (the concentration of protein at 50% dissociation at atmospheric pressure) = 18 nM and a stabilization free energy of -19.6 kcal/mol for the oligomer. Vicilin exhibited an anomalously low dependence on protein concentration for pressure dissociation. This appeared related to conformational changes in the dissociated subunits, which caused a loss of ca. 5 kcal/mol in the free energy of association and to structural/energetic heterogeneity in the population of oligomers. Pressure dissociation was markedly pH-dependent, with a stabilization free energy loss of 3.4 kcal/mol upon raising pH from 9 to 10. Circular dichroism and intrinsic fluorescence lifetime measurements at atmospheric pressure showed that the structure of vicilin was largely unaffected by pH in the range investigated. These results suggest that the effect of pH may involve deprotonation of lysine residues participating in salt bridges between vicilin subunits. Pressure dissociation of vicilin was significantly inhibited by addition of salts (NaCl, KCl, LiCl) or glycerol. Dissociation curves obtained in the presence of salts enabled calculation of the free energies of stabilization (ranging from ca. -1.2 to -2.4 kcal/mol) of the vicilin oligomers by these cosolvents. The similar effects of salts or glycerol suggest a common mechanism of stabilization of the oligomer involving exclusion of the cosolvents from the protein interface and preferential hydration of the protein.

Fabaceae↗

Nonlinear dynamics of the blood flow studied by Lyapunov exponents.

In order to gain an insight into the dynamics of the cardiovascular system throughout which the blood circulates, the signals measured from peripheral blood flow in humans were analyzed by calculating the Lyapunov exponents. Over a wide range of algorithm parameters, paired values of both the global and the local Lyapunov exponents were obtained, and at least one exponent equaled zero within the calculation error. This may be an indication of the deterministic nature and finite number of degrees of freedom of the cardiovascular system governing the blood-flow dynamics on a time scale of minutes. A difference was observed in the Lyapunov dimension of controls and athletes.

Algorithms↗