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Economic evaluation of risks to producers who use milk residue testing programs.

OBJECTIVE: To evaluate the decision to test for milk antimicrobial residues in milk from dairy cows treated with procaine penicillin G (PPG). DESIGN: Economic-decision analysis after stochastic simulation. SAMPLE POPULATION: 1,000 computer-simulated cows/model. PROCEDURE: Meta-analysis of the Food Animal Residue Avoidance Databank was used to generate PPG disappearance curves for cows given single PPG treatments, IM, of 6,600 U/kg (3,000 U/lb) of body weight or 26,400 U/kg (12,000 U/lb), and multiple treatments at 26,400 U/kg (12,000 U/lb), IM. These curves were entered into 1,000-replication stochastic pharmacokinetic models, generating population-level milk PPG profiles for each treatment group for each day after treatment, which were subjected to economic-decision analyses of feasibility of residue testing. The model was evaluated for changes in herd size, proportion of herd available for testing, milk production, test price, test sensitivity/specificity, and withdrawal periods. RESULTS: For both single-treatment groups, a 2-day withdrawal period avoided violative residues. However, nearly two thirds of the cows risked false identification for violative residues. For the multiple-treated group, nearly 40% had violative residues after a 5-day withdrawal period, and an additional 10 to 15% risked false identification for violative residues. Economic analysis yielded a decision against testing; mean cost was $2 (ie, 5% more than the mean cost of not testing). CLINICAL IMPLICATIONS: Complex dynamics of current milk residue tests discourage practitioners from recommending procedures to clients. In general, increases in herd size, milk production, proportion of a herd available for testing, or milk price will increase the value of testing. Increasing test sensitivity decreases its desirability to producers.

Animals↗

Power of a score test for quantitative trait linkage analysis of relative pairs.

The score test of Dudoit and Speed [(2000) Biostatistics 1:1-26] to detect linkage between a trait locus and a marker locus, using identity by descent data on sib pairs, is extended to other types of relative pairs (grandparent/grandchild, avuncular, and half-sib relationships). The test is based on the likelihood of the recombination fraction theta between trait and marker loci, conditional on phenotypes of the relatives. We present results of simulation studies characterizing power and robustness properties of this linkage score test, and compare the power of the score test to that of the classical and modified Haseman-Elston tests. The score test has considerable power, particularly under sampling schemes where selection is on double probands. Use of a generic additive model [Goldstein et al., submitted] with allele frequency p = 0.2, heritability H = 0.3, and a moderate residual correlation of rho = 0.2 resulted in a very good overall performance across a wide range of trait-generating models.

Computer Simulation↗

The determination of equilibrium constants for heterogeneous macromolecular interactions. Systems forming 2:1 complexes.

In developing a method for analyzing the heterogeneous association nA + mB in equilibrium AnBm, we have specifically investigated the case of n = 2, m = 1 for both the specific case of no appreciable intermediates and the more general case allowing intermediates. Computer-simulated three-dimensional surfaces of the 2:1 model generated from total concentrations of species A and B and the resulting weight-average molecular weights were analyzed with a Gauss-Newton nonlinear least-squares minimization routine. The surfaces generated included normalized random error of varying standard deviations imposed upon both the concentrations and weight-average molecular weights. For comparison purposes, these surfaces were analyzed not only by using the correct 2:1 model, but also by an incorrect (1:1) model and by the other (incorrect) 2:1 model. Except for those situations where the 'experimental' noise was consistently higher than the concentration of one of the species, correct K values were obtained and the correct model was easily distinguished from the incorrect model. The computer routine similarly distinguished between data correctly described as 1:1 and the same data incorrectly analyzed as either 2:1 model. For those cases in which a microscopic Ki value predicts an association such that all species involved for that particular Ki are in appreciable amounts, the Ki value is returned correctly. Correct overall equilibrium constants are also converged upon as long as adequate amounts of A2B, B and A are present.

Kinetics↗

A novel non-stochastic quadratic fingerprints-based approach for the 'in silico' discovery of new antitrypanosomal compounds.

A non-stochastic quadratic fingerprints-based approach is introduced to classify and design, in a rational way, new antitrypanosomal compounds. A data set of 153 organic chemicals, 62 with antitrypanosomal activity and 91 having other clinical uses, was processed by a k-means cluster analysis to design training and predicting data sets. Afterwards, a linear classification function was derived allowing the discrimination between active and inactive compounds. The model classifies correctly more than 93% of chemicals in both training and external prediction groups. The predictability of this discriminant function was also assessed by a leave-group-out experiment, in which 10% of the compounds were removed at random at each time and their activity predicted a posteriori. In addition, a comparison with models generated using four well-known families of 2D molecular descriptors was carried out. As an experiment of virtual lead generation, the present TOMOCOMD approach was finally satisfactorily applied on the virtual evaluation of 10 already synthesized compounds. The in vitro antitrypanosomal activity of this series against epimastigotes forms of Trypanosomal cruzi was assayed. The model was able to predict correctly the behaviour of these compounds in 90% of the cases.

Animals↗

Development of an integrated CAD-FEA process for below-knee prosthetic sockets.

BACKGROUND: Computer-aided design and manufacturing has been successfully used in prosthetic applications since 1980s. It simplifies the socket rectification process and improves reproducibility but does not introduce any new principle into socket design. Integrating finite element analysis to CAD will provide a more objective assessment of socket fit and improve the chance of a successful first fitting. METHODS: Current study aims to establish a finite element model generation technique directly from geometrical information of commercial prosthetic CAD workstation. A program developed in-house automatically performs meshing of the stump geometry and assigns suitable material properties, load and boundary conditions to the model. The model was validated by comparing predicted pressure with experimentally measured values for one amputee subject. FINDINGS: The predicted pressure distribution has an root-mean-square error of 8.8 kPa compared to experimental values at 10%, 25% and 50% of the gait cycle. INTERPRETATION: Current method was able to develop a finite element model to predict interface pressure reasonably well and can be integrated with prosthetic CAD system to provide quantitative feedback to the prosthetist in an automated process.

Artificial Limbs↗

Dynamic interaction between Leishmania infection in mice and Th1-type CD4+ T-cells: complexity in outcome without a requirement for Th2-type responses.

The interaction between Leishmania parasites and Th1 cells is investigated using a simple mathematical model of immunological responses and parasite population growth within the host. The model generates patterns of resistance and susceptibility to infection that mirror observed trends in experimental infections of mice and of humans exposed to infection in areas of endemic transmission. The heterogeneity in outcome predicted by the model can arise either through differences in the values of the parameters that characterize the genetic background of the host or as a consequence of differences in the size of the infecting inoculum of the parasite. Detailed analyses of equilibrium states and of the time course of infection within a host suggest that a limitation in the availability of precursor T-cells, as a consequence of high levels of recruitment into the activated pool, may play a significant role in the progression of infection in susceptible hosts. A brief discussion is presented of the implications of model prediction for therapeutic intervention.

Animals↗

Carcinoma extent in prostate needle biopsy tissue in the prediction of whole gland tumor volume in a screening population.

Increasing prostate tumor volume has been shown to correlate with numerous adverse prognostic indicators for patients with prostate carcinoma The ability to predict tumor volume from pretreatment parameters is potentially critical in the stratification of patients for different management strategies. We assessed the capacity of preoperative variables to predict tumor volume in 100 men diagnosed with prostate cancer in a prostate-specific antigen (PSA)-based screening program. Preoperative information included total serum PSA concentration and needle biopsy tissue variables, including Gleason score, number of positive cores, linear extent of carcinoma in millimeters, greatest percentage of carcinoma (in a single core), total percentage of carcinoma (all cores), presence of perineural invasion, and percentage of high-grade carcinoma. The postoperative end point was total tumor volume in radical prostatectomy tissue, calculated by image analysis. We determined independently significant factors and generated a predictive modelfor whole gland tumor volume. Total tumor volume was related significantly in multivariate analysis to 3 preoperative variables: linear extent of carcinoma, exponential number of positive cores, and serum PSA. A predictive model generated based on these 3 variables accounted for only 65% of the natural deviance of the data owing to data-point scatter for individual patients, suggesting that additional variables are needed to more accurately predict tumor volume. Findings highlight the importance of reporting quantitative measures of tumor amount in prostate needle biopsy specimens; several measures of tumor extent (vs 1 measure) provide maximal information on prostate cancer size.

Adenocarcinoma↗

Interpretation of current-voltage relationships for "active" ion transport systems: I. Steady-state reaction-kinetic analysis of class-I mechanisms.

This paper develops a simple reaction-kinetic model to describe electrogenic pumping and co- (or counter-) transport of ions. It uses the standard steady-state approach for cyclic enzyme- or carrier-mediated transport, but does not assume rate-limitation by any particular reaction step. Voltage-dependence is introduced, after the suggestion of Läuger and Stark (Biochim. Biophys. Acta 211:458-466, 1970), via a symmetric Eyring barrier, in which the charge-transit reaction constants are written as k12 = ko12 exp(zF delta psi/2RT) and k21 = ko21 exp(-zF delta psi/2RT). For interpretation of current-voltage relationships, all voltage-independent reaction steps are lumped together, so the model in its simplest form can be described as a pseudo-2-state model. It is characterized by the two voltage-dependent reaction constants, two lumped voltage-independent reaction constants (k12, k21), and two reserve factors (ri, ro) which formally take account of carrier states that are indistinguishable in the current-voltage (I-V) analysis. The model generates a wide range of I-V relationships, depending on the relative magnitudes of the four reaction constants, sufficient to describe essentially all I-V datas now available on "active" ion-transport systems. Algebraic and numerical analysis of the reserve factors, by means of expanded pseudo-3-, 4-, and 5-state models, shows them to be bounded and not large for most combinations of reaction constants in the lumped pathway. The most important exception to this rule occurs when carrier decharging immediately follows charge transit of the membrane and is very fast relative to other constituent voltage-independent reactions. Such a circumstance generates kinetic equivalence of chemical and electrical gradients, thus providing a consistent definition of ion-motive forces (e.g., proton-motive force, PMF). With appropriate restrictions, it also yields both linear and log-linear relationships between net transport velocity and either membrane potential or PMF. The model thus accommodates many known properties of proton-transport systems, particularly as observed in "chemiosmotic" or energy-coupling membranes.

Animals↗

Modeling the bioconcentration factors and bioaccumulation factors of polychlorinated biphenyls with posetic quantitative super-structure/activity relationships (QSSAR).

During bioconcentration, chemical pollutants from water are absorbed by aquatic animals via the skin or a respiratory surface, while the entry routes of chemicals during bioaccumulation are both directly from the environment (skin or a respiratory surface) and indirectly from food. The bioconcentration factor (BCF) and the bioaccumulation factor (BAF) for a particular chemical compound are defined as the ratio of the concentration of a chemical inside an organism to the concentration in the surrounding environment. Because the experimental determination of BAF and BCF is time-consuming and expensive, it is efficacious to develop models to provide reliable activity predictions for a large number of chemical compounds. Polychlorinated biphenyls (PCBs) released from industrial activities are persistent pollutants of the environment that produce widespread contamination of water and soil. PCBs can bioaccumulate in the food chain, constituting a potential source of exposure for the general population. To predict the bioconcentration and bioaccumulation factors for PCBs we make use of the biphenyl substitution-reaction network for the sequential substitution of H-atoms by Cl-atoms. Each PCB structure then occurs as a node of this reaction network, which is some sort of super-structure, turning out mathematically to be a partially ordered set (poset). Rather than dealing with the molecular structure via ordinary QSAR we use only this poset, making different quantitative super-structure/activity relationships (QSSAR). Thence we developed cluster expansion and splinoid QSSARs for PCB bioconcentration and bioaccumulation factors. The predictive ability of the BAF and BCF models generated for 20 data sets (representing different conditions and fish species) was evaluated with the leave-one-out cross-validation, which shows that the splinoid QSSAR (r between 0.903 and 0.935) are better than models computed with the cluster expansion (r between 0.745 and 0.887). The splinoid QSSAR models for BAF and BCF yield predictions for the missing PCBs in the investigated data sets.

Animals↗

Modelling functional integration: a comparison of structural equation and dynamic causal models.

The brain appears to adhere to two fundamental principles of functional organisation, functional integration and functional specialisation, where the integration within and among specialised areas is mediated by effective connectivity. In this paper, we review two different approaches to modelling effective connectivity from fMRI data, structural equation models (SEMs) and dynamic causal models (DCMs). In common to both approaches are model comparison frameworks in which inferences can be made about effective connectivity per se and about how that connectivity can be changed by perceptual or cognitive set. Underlying the two approaches, however, are two very different generative models. In DCM, a distinction is made between the 'neuronal level' and the 'hemodynamic level'. Experimental inputs cause changes in effective connectivity expressed at the level of neurodynamics, which in turn cause changes in the observed hemodynamics. In SEM, changes in effective connectivity lead directly to changes in the covariance structure of the observed hemodynamics. Because changes in effective connectivity in the brain occur at a neuronal level DCM is the preferred model for fMRI data. This review focuses on the underlying assumptions and limitations of each model and demonstrates their application to data from a study of attention to visual motion.

Algorithms↗

The how and why of what went where in apparent motion: modeling solutions to the motion correspondence problem.

A model that is capable of maintaining the identities of individuated elements as they move is described. It solves a particular problem of underdetermination, the motion correspondence problem, by simultaneously applying 3 constraints: the nearest neighbor principle, the relative velocity principle, and the element integrity principle. The model generates the same correspondence solutions as does the human visual system for a variety of displays, and many of its properties are consistent with what is known about the physiological mechanisms underlying human motion perception. The model can also be viewed as a proposal of how the identities of attentional tags are maintained by visual cognition, and thus it can be differentiated from a system that serves merely to detect movement.

Attention↗

Risk adjustment using automated ambulatory pharmacy data: the RxRisk model.

OBJECTIVES: Develop and estimate the RxRisk model, a risk assessment instrument that uses automated ambulatory pharmacy data to identify chronic conditions and predict future health care cost. The RxRisk model's performance in predicting cost is compared with a demographic-only model, the Ambulatory Clinical Groups (ACG), and Hierarchical Coexisting Conditions (HCC) ICD-9-CM diagnosis-based risk assessment instruments. Each model's power to forecast health care resource use is assessed. DATA SOURCES: Health services utilization and cost data for approximately 1.5 million individuals enrolled in five mixed-model Health Maintenance Organizations (HMOs) from different regions in the United States. STUDY DESIGN: Retrospective cohort study using automated managed care data. SUBJECTS All persons enrolled during 1995 and 1996 in Group Health Cooperative of Puget Sound, HealthPartners of Minnesota and the Colorado, Ohio and Northeast Regions of Kaiser-Permanente. MEASURES RxRisk, an algorithm that classifies prescription drug fills into chronic disease classes for adults and children. RESULTS: HCCs produce the most accurate forecasts of total costs than either RxRisk or ACGs but RxRisk performs similarly to ACGs. Using the R(2) criteria HCCs explain 15.4% of the prospective variance in cost, whereas RxRisk explains 8.7% and ACGs explain 10.2%. However, for key segments of the cost distribution the differences in forecasting power among HCCs, RxRisk, and ACGs are less obvious, with all three models generating similar predictions for the middle 60% of the cost distribution. CONCLUSIONS: HCCs produce more accurate forecasts of total cost, but the pharmacy-based RxRisk is an alternative risk assessment instrument to several diagnostic based models and depending on the nature of the application may be a more appropriate option for medical risk analysis.

Adolescent↗

Automated finite element analysis of excised human femora based on precision -QCT.

The creation of 3-D finite element (FE) models of bone and implant-bone systems is a labor-intensive task due to the need to model different cases and variations, to perform patch tests and to account for the nonhomogeneous material properties with an acceptable amount of work. In this study, we developed an interface between a precision QCT and a FE system and applied it to a specimen bone. With the new method, the time necessary for model generation was reduced substantially. Furthermore, the elastic properties for each element were automatically derived from the corresponding CT-values. In order to demonstrate the importance of taking into account inhomogeneity, a comparison between the nonhomogeneous model and a homogeneous, "averaged" model was performed.

Biomechanical Phenomena↗

Guidelines for the microbiological quality of treated wastewater used in agriculture: recommendations for revising WHO guidelines.

Three different approaches for establishing guidelines for the microbiological quality of treated wastewater that is reused for agriculture are reviewed. These approaches have different objectives as their outcomes: the absence of faecal indicator organisms in the wastewater, the absence of a measurable excess of cases of enteric disease in the exposed population and a model-generated estimated risk below a defined acceptable risk. If the second approach (using empirical epidemiological studies supplemented by microbiological studies of the transmission of pathogens) is used in conjunction with the third approach (using a model-based quantitative risk assessment for selected pathogens) a powerful tool is produced that aids the development of regulations. This combined approach is more cost-effective than the first approach and adequately protects public health. The guideline limit for faecal coliform bacteria in unrestricted irrigation (< or = 1000 faecal coliform bacteria/ 100 ml) is valid, but for restricted irrigation < or = 10(5) faecal coliform bacteria/100 ml is recommended when adult farmworkers are exposed to spray irrigation. A limit of < or = 10(3) faecal coliform bacteria/100 ml is recommended if flood irrigation is used or children are exposed. The guideline limit for nematode eggs for both types of irrigation is adequate except when conditions favour the survival of nematode eggs and where children are exposed; in these cases it should be reduced from < or = 1 egg/l to < or = 0.1 egg/l.

Adult↗

Evaluation of predictive formulae for determining metabolic rate during cold water immersion.

Five models predicting shivering thermogenesis on the basis of steady state skin and core temperature were evaluated: Hayward et al., Stolwijk and Hardy,; Nadel et al.,; Timbal et al., and Brown and Brengelmann, using the empirical data derived from a cold water immersion study by Morrison et al. A residual analysis indicated that all models generated substantial errors of prediction. The best overall predictors were expressions suggested by Hayward et al., while the predictive equation of Nadel et al. ranked second. Derivation of personal coefficients significantly improved the prediction of all models and a subsequent modification of the standard models, adding temperature derivative terms, further reduced the magnitude of the error. An analysis of the residuals indicated that peripheral and core temperatures should be weighted according to the characteristics of thermosensitive neural structures in these regions.

Body Temperature Regulation↗

Force generation by cytoskeletal filament end-tracking proteins.

Force generation in several types of cell motility is driven by rapidly elongating cytoskeletal filaments that are persistently tethered at their polymerizing ends to propelled objects. These properties are not easily explained by force-generation models that require free (i.e., untethered) filament ends to fluctuate away from the surface for addition of new monomers. In contrast, filament end-tracking proteins that processively advance on filament ends can facilitate rapid elongation and substantial force generation by persistently tethered filaments. Such processive end-tracking proteins, termed here filament end-tracking motors, maintain possession of filament ends and, like other biomolecular motors, advance by means of 5'-nucleoside triphosphate (NTP) hydrolysis-driven affinity-modulated interactions. On-filament NTP hydrolysis/phosphate release yields substantially more energy than that required for driving steady-state assembly/disassembly of free filament ends (i.e., filament treadmilling), as revealed by an energy inventory on the treadmilling cycle. The kinetic and thermodynamic properties of two simple end-tracking mechanisms (an end-tracking stepping motor and a direct-transfer end-tracking motor) are analyzed to illustrate the advantages of an end-tracking motor over free filament-end elongation, and over passive end-trackers that operate without the benefit of NTP hydrolysis, in terms of generating force, facilitating rapid monomer addition, and maintaining tight possession of the filament ends. We describe an additional cofactor-assisted end-tracking motor to account for suggested roles of cofactors in the affinity-modulated interactions, such as profilin in actin-filament end-tracking motors and EB1 in microtubule end-tracking motors.

Actins↗

Airway mechanics, gas exchange, and blood flow in a nonlinear model of the normal human lung.

A model integrating airway/lung mechanics, pulmonary blood flow, and gas exchange for a normal human subject executing the forced vital capacity (FVC) maneuver is presented. It requires as input the intrapleural pressure measured during the maneuver. Selected model-generated output variables are compared against measured data (flow at the mouth, change in lung volume, and expired O2 and CO2 concentrations at the mouth). A nonlinear parameter-estimation algorithm is employed to vary selected sensitive model parameters to obtain reasonable least squares fits to the data. This study indicates that 1) all three components of the respiratory model are necessary to characterize the FVC maneuver; 2) changes in pulmonary blood flow rate are associated with changes in alveolar and intrapleural pressures and affect gas exchange and the time course of expired gas concentrations; and 3) a collapsible midairway segment must be included to match airflow during a forced expiration. Model simulations suggest that the resistances to airflow offered by the collapsible segment and the small airways are significant throughout forced expiration; their combined effect is needed to adequately match the inspiratory and expiratory flow-volume loops. Despite the limitations of this lumped single-compartment model, a remarkable agreement with airflow and expired gas concentration measurements is obtained for normal subjects. Furthermore, the model provides insight into the important dynamic interactions between ventilation and perfusion during the FVC maneuver.

Adult↗

Looked but didn't see: inattentional blindness and yes-bias confabulation in vision-language models.

Previous work showed that many participants fail to notice a gorilla in a video of people playing basketball. Another study found that 83% of trained radiologists failed to report a gorilla figure inserted into a chest CT nodule-search task, even though eye-tracking revealed that most observers had foveated the figure. We ask whether a similar phenomenon exists in contemporary vision-language models (VLMs). We find that (i) VLMs are capable of spotting the gorilla in both still-frame images and videos of lung CT scans; (ii) models display inattentional blindness, which varies according to model generation and type of stimulus presented; (iii) Gemini-3.1-Pro outperforms most other flagship and open-weight VLMs at identifying the presence or absence of the gorilla. We additionally ran a segmentation experiment utilizing two different model classes: a generalist (SAM 3), which found the gorilla but produced little to no results for anatomy-based prompts; a medical specialist (BiomedParse), which produced more promising anatomy-based results but flagged "gorilla" on gorilla-free control videos on 82% of frames. The behavioral signature of inattentional blindness reproduces in VLMs, but a unique confabulation failure mode means that any "did the model see X" claim requires signal-detection analysis with a matched-control false-alarm baseline.

Journal Article↗