A new type of model-based Roentgen stereophotogrammetric analysis for solving the occluded marker problem

Roentgen stereophotogrammetric analysis (RSA) measures micromotion of an orthopaedic implant with respect to its surrounding bone. A problem in RSA is that the markers are sometimes overprojected by the implant itself. This study describes the so-called Marker Configuration Model-based RSA (MCM-based RSA) that is able to measure the pose of a rigid body in situations where less than three markers could be detected in both images of an RSA radiograph. MCM-based RSA is based on fitting a Marker Configuration model (MC-model) to the projection lines from the marker projection positions in the image to their corresponding Roentgen foci. An MC-model describes the positions of markers relative to each other and is obtained using conventional RSA. We used data from 15 double examinations of a clinical study of total knee prostheses and removed projections of the three tibial component markers, simulating occlusion of markers. The migration of the tibial component with respect to the bone, which should be zero, for the double examination is a measure of the accuracy of algorithm. With the new algorithm, it is possible to estimate the pose of a rigid body of which one or two markers are occluded in one of the images of the RSA radiograph with high accuracy as long as a proper MC-model of the markers in the rigid body is available. The new algorithm makes RSA more robust for occlusion of markers. This improves the results of clinical RSA studies because the number of lost RSA follow-up moments is reduced.     

Digital automated RSA compared to manually operated RSA

The accuracy of digital Roentgen stereophotogrammetric analysis (RSA) was compared to the accuracy of a manually operated RSA system. For this purpose, we used radiographs of a phantom and radiographs of patients. The radiographs of the patients consisted of double examinations of 12 patients that had a tibial osteotomy and of double examinations of 12 patients that received a total hip prosthesis. First, the radiographs were measured manually with an accurate measurement table. Subsequently, the images were digitized by a film scanner at 150 DPI and 300 DPI resolutions and analyzed with the RSA-CMS software. In the phantom experiment, the manually operated system produced significantly better results than the digital system, although the maximum difference between the median values of the manually operated system and the digital system was as low as 0.013 mm for translations and 0.033° for rotations. In the radiographs of the patients, the manually operated system and the digital system produced equally accurate results: no significant differences in translations and rotations were found. We conclude that digital RSA is an accurate, fast, and user friendly alternative for manually operated RSA. Currently, digital RSA systems are being used in a growing number of clinical RSA-studies.     

Handling modular hip implants in model-based RSA: combined stem-head models

Migration measurements of hip prostheses using marker-based Roentgen stereophotogrammetric analysis (RSA) require the attachment of markers to the prostheses. The model-based approach, which does not require these markers, is, however, less precise. One of the reasons may be the fact that the spherical head has not been modelled. Therefore, we added a 3D surface model of the spherical head and estimated the position and orientation of the combined stem-head model. The new method using a combined stem-head model was compared in a phantom study on five prostheses (of different types) and in a clinical study using double examinations of implanted hip prostheses, with two existing methods: a standard model-based approach and one using elementary geometrical shapes. The combined model showed the highest precision for the rotation about the longitudinal axis in the phantom experiments. With a standard deviation of 0.69 degrees it showed a significant improvement (p=0.02) over the model-based approach (0.96 degrees ) on the phantom data, but no improvement on the clinical data. Overall, the use of elementary geometrical shapes was worse with respect to the model-based approach, with a standard deviation of 1.02 degrees on the phantom data and 0.79 degrees on the clinical data. This decrease in precision was significant (p<0.01) on the clinical data. With relatively small differences in the other migration directions, these results demonstrate that the new method with a combined stem-head model can be a useful alternative to the standard model-based approach.     

Development of an RSA calibration system with improved accuracy and precision

In this study, a new radiostereometric analysis (RSA) calibration cage was developed with the aim of improving the accuracy and precision of RSA. This development consisted of three steps: a numerical simulation technique was first used to design the new cage; a synthetic imaging method was then implemented to predict the performance of the designed cage before it was actually fabricated; and an experimental phantom test was finally conducted to verify the actual performance of the new cage and compare with two currently widely used cages. Accuracy was calculated as the 95% prediction intervals from regression analyses between the measured and actual displacements, and precision was defined as the standard deviation of repeated measurements. The final experimental phantom tests showed that the accuracy and precision of the new calibration cage were improved by about 40% over an existing biplanar cage and by about 70% compared to a uniplanar cage design. This new cage can be used with any skeletal joints, in either static or kinematic examination, which is helpful for the standardization of the RSA application.     

Three-dimensional computer simulation of radiostereometric analysis (RSA) in distal radius fractures

Physical phantom models have conventionally been used to determine the accuracy and precision of radiostereometric analysis (RSA) in various orthopaedic applications. Using a phantom model of a fracture of the distal radius it has previously been shown that RSA is a highly accurate and precise method for measuring both translation and rotation in three-dimensions (3-D). The main shortcoming of a physical phantom model is its inability to mimic complex 3-D motion. The goal of this study was to create a realistic computer model for preoperative planning of RSA studies and to test the accuracy of RSA in measuring complex movements in fractures of the distal radius using this new model. The 3-D computer model was created from a set of tomographic scans. The simulation of the radiographic imaging was performed using ray-tracing software (POV-Ray). RSA measurements were performed according to standard protocol. Using a two-part fracture model (AO/ASIF type A2), it was found that for simple movements in one axis, translations in the range of 25microm-2mm could be measured with an accuracy of +/-2microm. Rotations ranging from 16 degrees to 2 degrees could be measured with an accuracy of +/-0.015 degrees . Using a three-part fracture model the corresponding values of accuracy were found to be +/-4microm and +/-0.031 degrees for translation and rotation, respectively. For complex 3-D motion in a three-part fracture model (AO/ASIF type C1) the accuracy was +/-6microm for translation and +/-0.120 degrees for rotation. The use of 3-D computer modelling can provide a method for preoperative planning of RSA studies in complex fractures of the distal radius and in other clinical situations in which the RSA method is applicable.     

Accuracy and repeatability of Roentgen stereophotogrammetric analysis (RSA) for measuring knee laxity in longitudinal studies

Roentgen stereophotogrammetric analysis (RSA) can be used to assess temporal changes in anterior-posterior (A-P) knee laxity. However, the accuracy and precision of RSA is dependent on many factors and should be independently evaluated for a particular application. The objective of this study was to evaluate the use of RSA for measuring A-P knee laxity. The specific aims were to assess the variation or "noise" inherent to RSA, to determine the reproducibility of RSA for repeated A-P laxity testing, and to assess the accuracy of these measurements. Two experiments were performed. The first experiment utilized three rigid models of the tibiofemoral joint to assess the noise and to compare digitization errors of two independent examiners. No differences were found in the kinematic outputs of the RSA due to examiner, repeated trials, or the model used. In a second experiment, A-P laxity values between the A-P shear load limits of +/-60 N of five cadaver goat knees were measured to assess the error associated with repeated testing. The RSA laxity values were also compared to those obtained from a custom designed linkage system. The mean A-P laxity values with the knee 30 degrees, 60 degrees, and 90 degrees of flexion for the ACL-intact goat knee (+/-95% confidence interval) were 0.8 (+/-0.25), 0.9 (+/-0.29), and 0.4 (+/-0.22) mm, respectively. In the ACL-deficient knee, the A-P laxity values increased by an order of magnitude to 8.8 (+/-1.39), 7.6 (+/-1.32), and 3.1 (+/-1.20)mm, respectively. No significant differences were found between the A-P laxity values measured by RSA and the independent measurement technique. A highly significant linear relationship (r(2)=0.83) was also found between these techniques. This study suggests that the RSA method is an accurate and precise means to measure A-P knee laxity for repeated testing over time.     

Evaluation of a new body composition phantom for quality control and cross-calibration of DXA devices.

This study evaluated a new body composition phantom and its use for quality control and cross-calibration of dual-energy X-ray absorptiometry (DXA) instruments for measurements of body composition. We imaged the variable composition phantom (Lunar, Madison, WI) on eight different DXA devices. Deviations of up to 7% fat were observed when we compared the percent fat values measured by the different devices with the nominal values provided by the manufacturer. Absolute precision error of percent fat measurements for the phantom ranged from 0.6 to 0.8%. The phantom's percent fat values were also compared with whole body composition measurements from 130 female and male volunteers. The phantom detected differences in percent fat values that were similar to those found by comparing in vivo measurements with values from different DXA scanner models from the same manufacturer. When comparing different models of scanners from different manufacturers, such as the Hologic QDR-4500 and the Lunar DPX-IQ, the phantom showed a different relationship than was seen for patients. Therefore, corrections or comparisons based on the phantom data alone would be incorrect. In conclusion, the Lunar variable composition phantom is capable of accurately measuring the fat calibration of DXA devices and may be suitable for cross-sectional cross-calibration between scanners from the same manufacturer; however, for comparison of DXA scanners from different manufacturers, in vivo cross-calibration is still the only accurate method. The phantom may be used in longitudinal quality control to verify an instrument's temporal stability.     

RSA wear measurements with or without markers in total hip arthroplasty

Novel algorithms for radiostereometric (RSA) measurements of the femoral head and metal-backed, hemi-spherical cups of a total hip replacement are presented and evaluated on phantom images and clinical double examinations of 20 patients. The materials were analysed with classical RSA and three novel algorithms: (1) a dual-projection head algorithm using the outline of the femoral head together with markers in the cup; (2) a marker-less algorithm based on measurements of the outline of the femoral head, the cup shell and opening circle of the cup; and (3) a combination of both methods. The novel algorithms improve current, marker-based, RSA measurements, as well as allows studies without marked cups. This opens the possibility of performing wear measurements on larger group of patients, in clinical follow-ups, even retrospective studies. The novel algorithms may help to save patient data in current RSA studies lost due to insufficiently marked cups. Finally, the novel algorithms simplify the RSA procedure and allow new studies without markers, saving time, money, and reducing safety concerns. Other potential uses include migration measurements of re-surfacing heads and measuring spherical sections as implant landmarks instead of markers.     

Radiostereometric analysis using clinical radiographic views: Development of a universal calibration object

Radiostereometric analysis (RSA) is a highly accurate technique used to provide three-dimensional (3D) measurements of orthopaedic implant migration for clinical research applications, yet its implementation in routine clinical examinations has been limited. Previous studies have introduced a modified RSA procedure that separates the calibration examinations from the patient examinations, allowing routine clinical radiographs to be analyzed using RSA. However, in order to calibrate the wide range of clinical views, a new calibration object is required. In this study, a universal, isotropic calibration object was designed to calibrate any pair of radiographic views used in the clinic for RSA. A numerical simulation technique was used to design the calibration object, followed by a phantom validation test of a prototype to verify the performance of the novel object, and to compare the measurement reliability to the conventional calibration cage. The 3D bias for the modified calibration method using the new calibration object was 0.032 ± 0.006 mm, the 3D repeatability standard deviation was 0.015 mm, and the 3D repeatability limit was 0.042 mm. Although statistical differences were present between the universal calibration object and the conventional cage, the differences were considered to be not clinically meaningful. The 3D bias and repeatability values obtained using the universal calibration object were well under the threshold acceptable for RSA, therefore it was successfully validated. The universal calibration object will help further the adoption of RSA into a more routine practice, providing the opportunity to generate quantitative databases on joint replacement performance.     

Validation of radiostereometric analysis in six degrees of freedom for use with reverse total shoulder arthroplasty

A phantom study was conducted to determine bias in motion and bias at zero motion of radiostereometric analysis (RSA) for evaluating implant relative displacement in reverse total shoulder arthroplasty (RTSA). A Sawbones shoulder phantom was fitted with a RTSA implant set and 13 tantalum markers. The model was fixed to a manual micrometer, providing controlled movements though fifteen known increments in translation and twelve increments in rotation (0.02–5.00 mm and 0.1–6.0°), along each translation and rotation axis. Movement between the glenoid and humerus was assessed using beads vs. beads (B/B), model vs. beads (M/B), and model vs. model (M/M) measurement methods in a model-based RSA environment. Bias in motion and bias at zero motion were defined as the difference between measured and accepted reference values, and the difference between double examinations with a theoretical displacement of zero, respectively. Bias in motion ranged from 0.054 ± 0.010 to 0.129 ± 0.014 mm and 0.076 ± 0.025 to 0.126 ± 0.025° (B/B), 0.023 ± 0.009 to 0.126 ± 0.016 mm and 0.111 ± 0.033 to 0.794 ± 0.251° (M/B), and 0.029 ± 0.010 to 0.135 ± 0.030 mm and 0.243 ± 0.088 to 0.384 ± 0.153° (M/M). Bias at zero motion ranged from 0.120 to 0.156 mm and 0.075 to 0.206° (B/B), 0.074 to 0.149 mm and 0.067 to 1.953° (M/B), and 0.069 to 0.259 mm and 0.284 to 1.273° (M/M). This is the first RSA for RTSA study, with results comparable to those validating the use of RSA for hip and knee arthroplasties (accepted as 0.05–0.50 mm and 0.15–1.15°), justifying the potential use of RSA as a tool for measuring implant displacement in the shoulder.     

The precision of radiostereometric measurements. Manual vs. digital measurements.

The precision of digital vs. manual radiostereometric measurements in total hip arthroplasty was evaluated using repeated stereoradiographic exposures with an interval of 10-15 min. Ten Lubinus SP2 stems cemented into bone specimens and 12 patients with the same stem design were used to evaluate the precision of stem translations and rotations. The precision of translations and rotations of the cup and femoral head penetration was studied in 12 patients with whole polyethylene cups.The use of a measurement method based on digitised radiographs improved the precision for some of the motion parameters, whereas many of them did not change. A corresponding pattern was observed for both the intra- and interobserver error. Of the wear parameters, the most pronounced improvements were the 3D wear and in the proximal-distal direction, although the anterior-posterior precision was also improved. The mean errors of rigid body and elliptic fitting decreased in all evaluations but one, consistent with a more reproducible identification of the markers centres and the edge of the femoral head.Increased precision of radiostereometric measurements may be used to increase the statistical power of future randomised studies and to study new fields in orthopaedics requiring higher precision than has been available with RSA based on manual measurements.     

The robustness and accuracy of in vivo linear wear measurements for knee prostheses based on model-based RSA

Accurate in vivo measurements methods of wear in total knee arthroplasty are required for a timely detection of excessive wear and to assess new implant designs. Component separation measurements based on model-based Roentgen stereophotogrammetric analysis (RSA), in which 3-dimensional reconstruction methods are used, have shown promising results, yet the robustness of these measurements is unknown. In this study, the accuracy and robustness of this measurement for clinical usage was assessed. The validation experiments were conducted in an RSA setup with a phantom setup of a knee in a vertical orientation. 72 RSA images were created using different variables for knee orientations, two prosthesis types (fixed-bearing Duracon knee and fixed-bearing Triathlon knee) and accuracies of the reconstruction models. The measurement error was determined for absolute and relative measurements and the effect of knee positioning and true seperation distance was determined. The measurement method overestimated the separation distance with 0.1mm on average. The precision of the method was 0.10mm (2*SD) for the Duracon prosthesis and 0.20mm for the Triathlon prosthesis. A slight difference in error was found between the measurements with 0° and 10° anterior tilt. (difference=0.08mm, p=0.04). The accuracy of 0.1mm and precision of 0.2mm can be achieved for linear wear measurements based on model-based RSA, which is more than adequate for clinical applications. The measurement is robust in clinical settings. Although anterior tilt seems to influence the measurement, the size of this influence is low and clinically irrelevant.     

Validation of a low-dose hybrid RSA and fluoroscopy technique: Determination of accuracy, bias and precision

Analyzing skeletal kinematics with radiostereometric analysis (RSA) following corrective orthopedic surgery allows the quantitative comparison of different implant designs. The purpose of this study was to validate a technique for dynamically estimating the relative position and orientation of skeletal segments using RSA and single plane X-ray fluoroscopy. Two micrometer-based in vitro phantom models of the skeletal segments in the hip and knee joints were used. The spatial positions of tantalum markers that were implanted into each skeletal segment were reconstructed using RSA. The position and orientation of each segment were determined in fluoroscopy images by minimizing the difference between the markers measured and projected in the image plane. Accuracy was determined in terms of bias and precision by analyzing the deviation between the applied displacement protocol and measured pose estimates. Measured translational accuracy was less than 100 microm parallel to the image plane and less than 700 microm in the direction orthogonal to the image plane. The measured rotational error was less than 1 degrees . Measured translational and rotational bias was not statistically significant at the 95% level of confidence. The technique allows real-time kinematic skeletal measurements to be performed on human subjects implanted with tantalum markers for quantitatively measuring the motion of normal joints and different implant designs.     

Accuracy and precision of a method to study kinematics of the temporomandibular joint: combination of motion data and CT imaging

The purpose of the study was to test the precision and accuracy of a method used to track selected landmarks during motion of the temporomandibular joint (TMJ). A precision phantom device was constructed and relative motions between two rigid bodies on the phantom device were measured using optoelectronic (OE) and electromagnetic (EM) motion tracking devices. The motion recordings were also combined with a 3D CT image for each type of motion tracking system (EM+CT and OE+CT) to mimic methods used in previous studies. In the OE and EM data collections, specific landmarks on the rigid bodies were determined using digitization. In the EM+CT and OE+CT data sets, the landmark locations were obtained from the CT images. 3D linear distances and 3D curvilinear path distances were calculated for the points. The accuracy and precision for all 4 methods were evaluated (EM, OE, EM+CT and OE+CT). In addition, results were compared with and without the CT imaging (EM vs. EM+CT, OE vs. OE+CT). All systems overestimated the actual 3D curvilinear path lengths. All systems also underestimated the actual rotation values. The accuracy of all methods was within 0.5mm for 3D curvilinear path calculations, 0.05mm for 3D linear distance calculations and 0.2 degrees for rotation calculations. In addition, Bland-Altman plots for each configuration of the systems suggest that measurements obtained from either system are repeatable and comparable.     

The effect of patient positioning on the precision of model-based radiostereometric analysis

A repeatable method for in vivo and in vitro measurement of polyethylene wear in total knee replacement (TKA) is needed. This research examines the model-based radiostereometric analysis’ (MBRSA) in vitro precision under different patient-radiograph orientations and flexion angles of the knee using a TKA phantom. Anterior–posterior and medial–lateral imaging orientations showed the highest precision; better than 0.036 mm (3-dimensional translation) and 0.089° (3-dimensional rotation). Flexion of the knee did not affect MBRSA precision. Medial–lateral imaging is advantageous as it allows for flexion of the knee joint during an RSA examination, thus providing greater information for wear measurement.     

Implementation and validation of an implant-based coordinate system for RSA migration calculation

An in vitro radiostereometric analysis (RSA) phantom study of a total knee replacement was carried out to evaluate the effect of implementing two new modifications to the conventional RSA procedure: (i) adding a landmark of the tibial component as an implant marker and (ii) defining an implant-based coordinate system constructed from implant landmarks for the calculation of migration results. The motivation for these two modifications were (i) to improve the representation of the implant by the markers by including the stem tip marker which increases the marker distribution (ii) to recover clinical RSA study cases with insufficient numbers of markers visible in the implant polyethylene and (iii) to eliminate errors in migration calculations due to misalignment of the anatomical axes with the RSA global coordinate system. The translational and rotational phantom studies showed no loss of accuracy with the two new measurement methods. The RSA system employing these methods has a precision of better than 0.05 mm for translations and 0.03° for rotations, and an accuracy of 0.05 mm for translations and 0.15° for rotations. These results indicate that the new methods to improve the interpretability, relevance, and standardization of the results do not compromise precision and accuracy, and are suitable for application to clinical data.     

Model-based Roentgen stereophotogrammetry of orthopaedic implants

Attaching tantalum markers to prostheses for Roentgen stereophotogrammetry (RSA) may be difficult and is sometimes even impossible. In this study, a model-based RSA method that avoids the attachment of markers to prostheses is presented and validated. This model-based RSA method uses a triangulated surface model of the implant. A projected contour of this model is calculated and this calculated model contour is matched onto the detected contour of the actual implant in the RSA radiograph. The difference between the two contours is minimized by variation of the position and orientation of the model. When a minimal difference between the contours is found, an optimal position and orientation of the model has been obtained. The method was validated by means of a phantom experiment. Three prosthesis components were used in this experiment: the femoral and tibial component of an Interax total knee prosthesis (Stryker Howmedica Osteonics Corp., Rutherfort, USA) and the femoral component of a Profix total knee prosthesis (Smith & Nephew, Memphis, USA). For the prosthesis components used in this study, the accuracy of the model-based method is lower than the accuracy of traditional RSA. For the Interax femoral and tibial components, significant dimensional tolerances were found that were probably caused by the casting process and manual polishing of the components surfaces. The largest standard deviation for any translation was 0.19mm and for any rotation it was 0.52 degrees. For the Profix femoral component that had no large dimensional tolerances, the largest standard deviation for any translation was 0.22mm and for any rotation it was 0.22 degrees. From this study we may conclude that the accuracy of the current model-based RSA method is sensitive to dimensional tolerances of the implant. Research is now being conducted to make model-based RSA less sensitive to dimensional tolerances and thereby improving its accuracy.     

Standardized ultrasound evaluation of carotid stenosis for clinical trials: University of Washington Ultrasound Reading Center

Introduction

Serial monitoring of patients participating in clinical trials of carotid artery therapy requires noninvasive precision methods that are inexpensive, safe and widely available. Noninvasive ultrasonic duplex Doppler velocimetry provides a precision method that can be used for recruitment qualification, pre-treatment classification and post treatment surveillance for remodeling and restenosis. The University of Washington Ultrasound Reading Center (UWURC) provides a uniform examination protocol and interpretation of duplex Doppler velocity measurements.

Methods

Doppler waveforms from 6 locations along the common carotid and internal carotid artery path to the brain plus the external carotid and vertebral arteries on each side using a Doppler examination angle of 60 degrees are evaluated. The UWURC verifies all measurements against the images and waveforms for the database, which includes pre-procedure, post-procedure and annual follow-up examinations. Doppler angle alignment errors greater than 3 degrees and Doppler velocity measurement errors greater than 0.05 m/s are corrected.

Results

Angle adjusted Doppler velocity measurements produce higher values when higher Doppler examination angles are used. The definition of peak systolic velocity varies between examiners when spectral broadening due to turbulence is present. Examples of measurements are shown.

Discussion

Although ultrasonic duplex Doppler methods are widely used in carotid artery diagnosis, there is disagreement about how the examinations should be performed and how the results should be validated. In clinical trails, a centralized reading center can unify the methods. Because the goals of research examinations are different from those of clinical examinations, screening and diagnostic clinical examinations may require fewer velocity measurements.     

Comparison of titration results of diphtheric antitoxic antibodies obtained by means of Jensen's method and the methods of tissue cultures and haemagglutination.

In 33 human sera the determination of diphtheric antitoxic antibodies was performed in a double blind test using Jensen's method, the method of tissue cultures and the haemagglutination method. In the method of tissue cultures the antibody levels in the sera were determinated in the first and second experiment with the precision of +/- half dilution of the geometrical progression. In Jensen's method, the difference between the first and second measurements slightly exceeded +/- 1 dilution. In the haemagglutination method the error considerably exceeded the binary step dilution. In most cases, the determination fluctuated up to seven times the actual value. Differences among the mean values of examination results obtained by Jensen's method and the method of the tissue cultures are statistically insignificant. The differences between the haemagglutination method and both the other methods are statistically significant.     

Time-resolved fluorescence of the single tryptophan residue in rat alpha-fetoprotein and rat serum albumin: analysis by the maximum-entropy method.

The time-resolved fluorescence emissions of the lone tryptophan residues in rat alpha-fetoprotein (RFP) and rat serum albumin (RSA) were studied. The total fluorescence intensity decays in both proteins were multiexponential. Analysis of the data by nonlinear least squares as a sum of discrete exponentials showed that four exponentials were needed for a satisfactory fit for both proteins. Analysis by the maximum entropy method using 150 logarithmically equally spaced exponentials yielded four well-resolved excited-state lifetime classes with barycenters and relative amplitudes values (ci) that corresponded to those obtained from the nonlinear least-squares method. Changing the temperature affected the relative amplitudes of the lifetime classes but had little effect on the lifetime values themselves. This suggests that the four classes reflect local conformational substates that exchange slowly with respect to the time window of observation defined by the longest lifetime. The internal rotational dynamics of the tryptophan in each protein was monitored by fluorescence anisotropy decay measurements. The mobility of the tryptophan appeared to be larger and faster in RFP than in RSA. The nonlinear least-squares analysis suggests the existence of three rotational correlation times of 0.1, 3, and 55 ns for this protein. As a function of temperature, the long correlation time did not follow the Perrin's law expected for a rigid rotating body. This suggests that this correlation time may reflect not only the Brownian rotation of the whole protein but also the flexibilities of domains in the protein. For RSA a two-component model with correlation times of 0.4 and 31 ns was sufficient to describe the data.(ABSTRACT TRUNCATED AT 250 WORDS)