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Towards computing with proteins.

Can proteins be used as computational devices to address difficult computational problems? In recent years there has been much interest in biological computing, that is, building a general purpose computer from biological molecules. Most of the current efforts are based on DNA because of its ability to self-hybridize. The exquisite selectivity and specificity of complex protein-based networks motivated us to suggest that similar principles can be used to devise biological systems that will be able to directly implement any logical circuit as a parallel asynchronous computation. Such devices, powered by ATP molecules, would be able to perform, for medical applications, digital computation with natural interface to biological input conditions. We discuss how to design protein molecules that would serve as the basic computational element by functioning as a NAND logical gate, utilizing DNA tags for recognition, and phosphorylation and exonuclease reactions for information processing. A solution of these elements could carry out effective computation. Finally, the model and its robustness to errors were tested in a computer simulation.

Adenosine Triphosphate↗

Characterization of four basic models of indirect pharmacodynamic responses.

Four basic models of indirect pharmacodynamic responses were characterized in terms of changing dose, Imax or Smax, and IC50 or SC50 to examine the effects of these fundamental drug properties on response profiles. Standard pharmacokinetic parameters were used for generating plasma concentration, and response-time profiles using computer simulations. Comparisons to theoretical expectations were made. In all four models, the maximum response (Rmax) (inhibition or stimulation) and the time of its occurrence (TRmax) were dependent on the model, dose, Imax or Smax, and IC50 or SC50 values. An increase in dose or a decrease in IC50 or SC50 by the same factor produced, as theoretically expected, identical and superimposable pharmacodynamic response patterns in each of the models. Some parameters (TRmax, ABEC) were nearly proportional to log dose, while others (Rmax, CRmax) were nonlinear. Assessment of expected response signature patterns as demonstrated in this report may be helpful in experimental designs and in assigning appropriate models to pharmacodynamic data.

Computer Simulation↗

Effects of rotational myocardial anisotropy in forward potential computations with equivalent heart dipoles.

Rotating fibers in the heart lead to a myocardium of inhomogeneous anisotropic conductivity. Besides affecting the activation isochrones, this anisotropy modifies the equivalent dipoles used in calculating extracardiac potentials, rendering them oblique rather than normal to the activation wavefront due to an added axial dipole component oriented along the fibers. Herein, however, consequences of the assumption usually made in forward potential calculations that the equivalent dipoles act in a myocardium that is homogeneous and isotropic are examined. A layered inner block representing the heart was placed inside an outer block representing an isotropic volume conductor. Fiber direction in the inner block rotated uniformly from layer to layer. Current dipoles of different orientations were placed in the inner block and the potentials calculated everywhere. Effects of the anisotropy of the inner block were gauged by computing an equivalent dipole that best fit the outer block surface potentials. For volume conductor conductivities close to that of the torso, the anisotropy diminished dipoles oriented along the fibers. Since the intraventricular blood masses in the heart also diminish such dipoles, these reductions of the axial component may explain the success of heart model simulations that ignore this component.

Anisotropy↗

Performance evaluation of a multi-slice CT system with 16-slice detector and increased gantry rotation speed for isotropic submillimeter imaging of the heart.

BACKGROUND: 4-slice CT scanners have shown limitations in clinical application for noninvasive coronary CT angiography (CTA). We evaluate advances in ECG-gated scanning of the heart and the coronary arteries with recently introduced 16-slice CT equipment (SOMATOM Sensation 16, Siemens, Forchheim, Germany). MATERIALS AND METHODS: The technical principles of ECG-gated cardiac scanning, scan parameters, and detector design of the new scanner are presented. ECG-gated scan and image reconstruction techniques and ECG-controlled dose modulation ("ECG pulsing") for a reduction of the patient dose are described, key parameters for image quality and simulation results presented, and phantom studies and initial patient experience discussed. The impact of reduced gantry rotation time (0.42 s) on temporal resolution and initial estimations of the patient dose are presented. RESULTS: Extensions of ECG-gated reconstruction algorithms used for 4-slice CT provide adequate image quality for up to 16 slices. For each detector collimation different slice widths are available for retrospective reconstruction with well-defined slice sensitivity profiles (SSPs). For coronary CTA the heart can be covered with 0.75 mm collimation within a 20-s breathhold. The best possible spatial resolution is 0.5 x 0.5 x 0.6 mm. For 0.42 s gantry rotation time, temporal resolution reaches its optimum (105 ms) at a heart rate of 81 bpm. Effective patient dose for coronary CTA is 4-5 mSv using ECG-pulsed acquisition. CONCLUSION: The clinical performance of coronary CTA by means of spatial resolution, temporal resolution and scan time is substantially improved with the evaluated 16-slice CT scanner. Also, display of smaller coronary segments and instent visualization are substantially improved.

Algorithms↗

[Fluoroscopy based surgical navitation vs. mechanical guidance system for percutaneous interventions. A controlled prospective study exemplified by distal locking of intramedullary nails].

The aim of this study was to directly compare mechanically based targetting and surgical navigation when applied for percutaneous osteosynthesis. The distal locking procedure of intramedullary nails was used as the clinical model for a controlled prospective study. A total of 50 patients were included in two groups. In group 1, the distal locking was done with a mechanical aiming device while in group 2 this was done using a fluoroscopy based surgical navigation system. The target parameters were the precision attained, the necessary operation and fluoroscopy times as well as the number and severity of intra-operative problems. The drill-bit failed to pass through the interlocking hole in one patient with mechanical guidance and in two patients with surgical navigation. The average procedure time for distal locking with mechanical guidance was 6.9 minutes compared with 37.6 minutes with surgical navigation. An additional 44 minutes were required before skin incision and after skin closure as setup time for the navigation system. There was no significant difference in the fluoroscopy time or in the number of intra-operative technical problems. Surgical navigation increased the demand for resources but failed to improve the precision of distal locking compared with mechanical guidance. Further clinical studies are required to determine to what degree these results, using a special model, relate to other applications.

Aged↗

[Navigated reposition of transverse acetabulum fractures. A precision analysis].

Up to now navigated reduction control based on computed tomography (CT) image data could not be used commercially. With newly developed software, a transverse fracture of the acetabulum was reduced with navigation control in a laboratory test. The results were compared to visual and tactile control in a foam pelvis and specimen. Measurements were done with another magnet-based navigation system. The residual dislocation was measured with translation (mm) and rotation (degrees). Compared with visually controlled reduction, navigated reduction led to a residual dislocation of 0.7 mm and 0.9 degrees. Navigated reduction based on CT image data is also accurate for reduction of joint fractures under laboratory conditions. Further improvements of the software are planned for later in vivo use.

Acetabulum↗

[CT-free image guided acetabulum navigation in clinical routine].

After experimental and preclinical evaluation (HAP Paul Award 2001) of the CT-free image-guided surgical navigation system for acetabular cup placement (SurgiGATE C-arm cup" by Medivision, Switzerland), the system was introduced into clinical routine. The computation of the angular orientation of the cup is based on reference coordinates from the anterior pelvic plane concept. A hybrid strategy for pelvic landmark acquisition has been introduced involving percutaneous pointer-based digitization with the noninvasive biplanar landmark reconstruction using multiple registered fluoroscopy images. From January 2001 to December 2002, a total of 256 consecutive patients with primary osteoarthrosis (mean age 69 years, 161 male, 95 female, 132 left, and 124 right hip joints) were operated on with the hybrid CT-free navigation system. During each operation the angular orientation of the inserted implant was recorded. To determine the placement accuracy of the acetabular components, 50 consecutive patients underwent a CT scan 7-10 days postoperatively to analyze the cup position related to the anterior pelvic plane. This was all done blinded by the same investigator with the planning software of the CT-based navigation system of Medivision. There was no significant learning curve observed for the use of the system. The mean value for postoperative inclination was 43 degrees (SD 3.0, range: 37 degrees -49 degrees ) and for anteversion 19 degrees (SD 3.9, range: 10 degrees -28 degrees ). The resulting system accuracy, i.e., the difference between intraoperatively calculated cup orientation and postoperatively measured implant position showed a mean error of 1.5 degrees for the inclination (maximum 5 degrees, SD 1.1) and 2.4 degrees for the anteversion (maximum 6 degrees, SD 1.3). An accuracy of better than 5 degrees inclination and 6 degrees anteversion was achieved under clinical conditions, which implies that there is no significant difference in performance from the established CT-based navigation methods. Image-guided CT-free cup navigation provides a reliable solution for future THA.

Acetabulum↗

[CT-based and CT-free navigation in knee prosthesis implantation. Results of a prospective study].

INTRODUCTION: Accurate leg alignment is one important factor for long-term survival in total knee arthroplasty (TKA). The classical surgeon-controlled technique is associated with a deviation of the leg axis of more than 3 degrees in up to 30% of cases, regardless of the surgeon's experience. The aim of this study was to test the efficiency of a CT-based and CT-free navigation system in restoration of the leg axis. METHOD: 100 TKA (PFC-Sigma, DePuy) were implanted either using the CT-based or CT-free module of the Vector-Vision navigation System (BrainLAB). There were no significant differences between the groups in preoperative leg deformity. Accuracy of implantation was determined on postoperative long-leg coronal and lateral X-rays. RESULTS: A postoperative leg axis between 3 degrees varus and 3 degrees valgus was obtained in 46 patients (92%) in the CT-based group (A) and in 48 patients (96%) in the CT-free group (B). No significant differences were found for varus / valgus orientation (+/-3 degrees ) of the femoral (A=96%; B=94%) and tibial (A and B each 98%) components. CONCLUSION: The use of the CT-based and CT-free Vector-Vision system allows a significant improvement in the accuracy of implantation in TKA. The CT-based module has the advantage of precise preoperative planning. On the other hand there are additional costs and time-consuming logistics. The advantages of the CT-free module are the intraoperative visualisation of the leg axis, the ligament balancing and joint kinematics. Cutting errors can be detected and corrected with both modules.

Adult↗

[CT analysis of leg alignment after conventional vs. navigated knee prosthesis implantation. Initial results of a controlled, prospective and randomized study].

INTRODUCTION: Correct alignment of the leg is one of the significant factors for the outcome after TKA. Previous studies have shown that the use of a navigation system can improve the alignment. However, for the positioning of the femoral component no validated data are available. This article presents the first results of a controlled, prospective and randomised trial comparing navigation versus free-hand implantation in TKA with special reference to the rotation of the femoral component. METHODS: Since January 2003, all patients with primary arthrosis of the knee admitted to our hospital for TKA have been followed prospectively. For this first analysis, data were collected over a period of 5 months. Apart from the usual clinical evaluations, all patients had CT of the leg prior to the operation and 1 week postoperatively. Measurement of axis and rotation was performed by staff members of the X-ray department who had no knowledge of the operation technique (navigation vs. free-hand). RESULTS: Twenty five sets of CT scans have been analysed, from 12 navigated operations and 13 freehand procedures. All 12 of the navigated knees were within the interval of +/-3 degrees varus/valgus deviation, but only 8 of the 13 non-navigated knees met this criteria. The analysis of the rotation position of the femoral component revealed no difference between the two groups. CONCLUSION: By using an intraoperative navigation system, the accuracy of the alignment in TKA can be improved. Long-term studies will have to be carried out to verify whether this will lead to a lasting benefit for the patient. Concerning the rotation position of the femoral implant, no conclusion can be made regarding the recommended rotation position at this point of the study.

Adult↗

A two-dimensional immune algorithm for resolution of overlapping two-way chromatograms.

A two-dimensional immune algorithm is proposed for resolving the multicomponent overlapping two-way data matrices. The method is a development of the one-dimensional immune algorithm proposed elsewhere. When the inner product of vectors is expanded to the similar operation on matrices, the 1D immune algorithm can be expanded to the 2D algorithm which is suitable for the analysis of two-way data matrices. Both simulated and experimental two-way data sets were investigated by the method, and the results prove that the 2D immune algorithm is an effective tool for resolving the overlapping two-way signals. The effect of noise on the recoveries is also discussed.

Algorithms↗

Optimization of diffusion-tensor MR imaging data acquisition parameters for brain fiber tracking using parallel imaging at 3 T.

The purpose of this study was to optimize the parameters of diffusion-tensor magnetic resonance imaging (DT MRI) for brain fiber tracking using a slice thickness of 2 mm, a resolution advantage allowed by the high signal-to-noise ratio at 3 T, combined with an 8-channel phased-array head coil. The b-factor, number of motion probing gradient (MPG) directions, and number of averages were varied, and the results of brain fiber tracking for the pyramidal tract and trigeminal nerve were compared qualitatively and quantitatively. The DT MRI data sufficient for brain fiber tracking in healthy subjects can be obtained in <2 min with a 2-mm slice thickness, 700-s/mm2 b-factor, 6 MPG directions, and no averaging (number of averages=1).

Adult↗

The computerization of the Cardiff Births Survey.

The Cardiff Births Survey (CBS) is a major ongoing study of childbirth in a well defined population, and has formed the basis for a number of important investigations in its field. It started at a time when computers were about to become readily available in United Kingdom universities, and it has made use of them from its earliest days. The changing ways in which this has been done over the years are here described in parallel with the changes that have taken place to the survey itself. Conclusions are drawn concerning the characteristics of other studies to which similar methods might be applied, and the inherent advantages and limitations of these methods are considered. Finally brief discussion is made of future prospects for the use of computers in the Cardiff Births Survey itself.

Birth Rate↗

Improved methods of estimating survival probabilities applied to renal transplant data.

In the evaluation of clinical studies of different kinds with survival time as the response variable to be analysed the estimation of survival probabilities plays an important role. The ordinary procedure in survival data analysis for estimating survival probabilities is the Kaplan-Meier product-limit estimator. However, in the case of heavy censoring or if the largest observed failure times are censored the product-limit method is known to be a biased estimator of the survival function. Recently, two improved methods of estimating survival functions, a semiparametric procedure and an approach using splines, were proposed (Klein JP, Lee SC and Moeschberger ML, Biometrics, 46 (1990) 795-811; Whittemore AS and Keller JB, Biometrics, 42 (1986) 495-506). These new methods are less biased than the product-limit estimator, especially for heavily censored data. A computer program based on the integrated statistical and graphical software package RS/1 was developed for the calculation and graphical representation of the new estimators. Their improved properties are illustrated by the application to renal transplant data.

Computer Graphics↗

A dynamic model for finger interphalangeal coordination.

In this paper a dynamic model to investigate interphalangeal coordination in the human finger is proposed. Suitable models which describe the relationship between the tendon displacement and the joint angles have been chosen and incorporated into the skeletal dynamic model. A kinematic and kinetic model for interphalangeal coordination is suggested. Digital computer simulations are carried out to study interphalangeal (IP) flexion. Moreover, the effect of two different optimization methods is contrasted. The two optimization algorithms are employed to obtain a set of feasible values for the forces in the tendons or muscles of the finger.

Biomechanical Phenomena↗

Energy-optimized structure of antifreeze protein and its binding mechanism.

A combination of Monte Carlo simulated annealing and energy minimization was utilized to determine the conformation of the antifreeze protein from the fish winter flounder. It was found from the energy-optimized structure that the hydroxyl groups of its four threonine residues, i.e. Thr2, Thr13, Thr24, Thr35, are aligned on almost the same line parallel to the helix axis and separated successively by 16.1, 16.0 and 16.2 A, respectively, very close to the 16.6 A repeat spacing along [0112] in ice. Based on such a space match, a zipper-like model is proposed to elucidate the binding mechanism of the antifreeze protein to ice crystals. According to the current model, the antifreeze protein may bind to an ice nucleation structure in a zipper-like fashion through hydrogen bonding of the hydroxyl groups of these four Thr residues to the oxygen atoms along the [0112] direction in ice lattice, subsequently stopping or retarding the growth of ice pyramidal planes so as to depress the freeze point. The calculated results and the binding mechanism thus derived accord with recent experimental observations. The mechanistic implications derived from such a special antifreeze molecule might be generally applied to elucidate the structure-function relationship of other antifreeze proteins with the following two common features: (1) recurrence of a Thr residue (or any other polar amino acid residue whose side-chain can form a hydrogen bond with water) in an 11-amino-acid period along the sequence concerned; and (2) a high percentage of Ala residue component therein. Further experiments are suggested to test the ice binding model.

Amino Acid Sequence↗

Computer simulation of fluid resuscitation in trauma. I. Description of an extensive pathophysiological model and its first validation.

Computer-based 'patient simulators' are of a potential value in diagnosis, monitoring and therapy of the severely ill patient with trauma. An extensive pathophysiological model is described and documented in full detail. The model makes it possible to calculate and predict clinically important state variables on the basis of fluid input and fluid losses. Sample runs are presented for illustrations in hemorrhage, fluid and salt loading.

Animals↗

Strategies for graphical threshold determination.

Determining a threshold for a quantitative variable (arising in biological measurements for instance) is a common problem in medical decision making. We define seven commonly used strategies: each one leads to an optimal determination. To these strategies correspond relevant empirical curves: the ROC curve for strategies involving the sensitivity or the specificity, the predictive ROC curve (P-ROC curve) for strategies involving the positive and negative predicting values, and the well classified frequencies curve (WCF curve) for classification strategies where all misclassifications have the same importance. For one of the considered strategies, there also exists a theoretical formula for the optimal threshold, elicited within a classical probabilistic model, which gives a considerable advantage to this strategy. These strategies are applied to a stimulated example containing 702 cases, where we see that they lead to different optimal threshold values. Finally, we briefly review a practical application in the determination of thresholds for glycemia measurements, leading to the choice of one of them as the optimal one to consider in the gestational diabetes mellitus prediction.

Diagnosis, Computer-Assisted↗