Scientific guidelines for preclinical research on potentised preparations manufactured according to current pharmacopoeias-the PrePoP guidelines.

OBJECTIVE: Pharmacopoeias regulate the manufacture of potentised pharmaceutical preparations used in different branches of complementary and integrative medicine. The physicochemical properties and biological activity of these preparations are often investigated in preclinical research, yet no guidelines for experimental research currently exist in this area. The present PrePoP guidelines aim to provide recommendations to promote high-quality, statistically sound, and reproducible preclinical research on potentised preparations. METHODS: Input was gathered from researchers nominated by the relevant scientific societies using a simplified Delphi consensus approach covering the most relevant aspects of basic research methodology in the field including appropriate controls, sample preparation and handling, and statistics. After three rounds of feedback, a consensus was finally reached on the most important aspects and considerations for conducting high-quality research on potentised preparations. RESULTS: We present a series of recommendations on a range of topics including experimental controls, system stability, blinding and randomisation, environmental influences, and procedures for the preparation of potentised samples and controls, and we address some specific challenges of this research field. CONCLUSION: This expert consensus process resulted in a robust set of methodological guidelines for research on potentised preparations and provides a valuable framework that will inform and improve the quality of subsequent research in this emerging field. PLEASE CITE THIS ARTICLE AS: Tournier AL, Bonamin LV, Buchheim-Schmidt S, Cartwright S, Dombrowsky C, Doesburg P, Holandino C, Kokornaczyk MO, van de Kraats EB, López-Carvallo JA, Nandy P, Mazón-Suástegui JM, Mirzajani F, Poitevin B, Scherr C, Thieves K, Würtenberger S, Baumgartner S. Scientific guidelines for preclinical research on potentised preparations manufactured according to current pharmacopoeias-the PrePoP guidelines. J Integr Med. 2024; Epub ahead of print.

Image-guided vascular neurosurgery based on three-dimensional rotational angiography. Technical note.

Three-dimensional rotational angiography is capable of exquisite visualization of cerebral blood vessels and their pathophysiology. Unfortunately, images obtained using this modality typically show a small region of interest without exterior landmarks to allow patient-to-image registration, precluding their use for neuronavigation purposes. The aim of this study was to find an alternative technique to enable 3D rotational angiography-guided vascular neurosurgery. Three-dimensional rotational angiograms were obtained in an angiographic suite with direct navigation capabilities. After image acquisition, a navigated pointer was used to touch fiducial positions on the patient's head. These positions were located outside the image volume but could nevertheless be transformed into image coordinates and stored in the navigation system. Prior to surgery, the data set was transferred to the navigation system in the operating room, and the same fiducial positions were touched again to complete the patient-to-image registration. This technique was tested on a Perspex phantom representing the cerebral vascular tree and on two patients with an intracranial aneurysm. In both the phantom and patients, the neuronavigation system provided 3D images representing the vascular tree in its correct orientation, that is, the orientation seen by the neurosurgeon through the microscope. In one patient, tissue shift was clearly observed without significant changes in the orientation of the structures. Results in this study demonstrate the feasibility of using 3D rotational angiography data sets for neuronavigation purposes. Determining the benefit of this type of navigation should be the subject of future studies.

Navigation with three-dimensional rotational radiographic data for transpedicular percutaneous needle introduction: feasibility and comparison with fluoroscopic guidance.

PURPOSE: To investigate the feasibility of navigation with three-dimensional (3D) rotational radiographic data for transpedicular percutaneous needle introduction and to compare navigation with 3D rotational radiographic data with conventional fluoroscopic guidance. MATERIALS AND METHODS: A navigation system was coupled to a 3D rotational radiographic imaging system. In a cadaver study, 60 biopsy needles were introduced into vertebral bodies with fluoroscopic guidance or navigation with 3D rotational radiographic data by two interventionalists with different levels of experience in percutaneous procedures. Radiation exposure, fluoroscopy and introduction times, and needle position were evaluated and compared. RESULTS: For 3D rotational radiographic navigation, the needle position was equivalent for both interventionalists (7 mm). For fluoroscopic guidance, the interventionalist with less experience in percutaneous procedures had significantly more pedicle cortex violations than the other interventionalist (eight vs one). Radiation exposure measured at the operators' hand was lower for 3D rotational radiography-guided needle introductions. Radiation exposure measured at the body wall of the cadaver was equivalent between modalities (9 mGy). CONCLUSIONS: Navigation with 3D rotational radiographic image data is feasible for transpedicular percutaneous needle introduction and has two advantages compared with fluoroscopic guidance: it poses less strict requirements on the expertise of the interventionalist, and it reduces radiation exposure to the interventionalist.

Three-dimensional rotational X-ray navigation for needle guidance in percutaneous vertebroplasty: an accuracy study.

STUDY DESIGN: The position of a needle tip displayed on a navigation system after transpedicular introduction into a vertebral body is compared with the real position of the needle tip when using a direct navigation coupling between a three-dimensional rotational X-ray (3DRX) system and a navigation system. OBJECTIVES: To assess whether the needle tip position displayed by the navigation system corresponds to the real needle position and to quantitatively determine needle navigation accuracy in a clinically relevant setting. SUMMARY OF BACKGROUND DATA: Image-guided navigation has reportedly increased the accuracy and safety of pedicle screw insertion and decreased complication rates. In former studies, the result of image-guided navigation was mainly compared qualitatively with the result of conventional fluoroscopy-guided procedures. Previously, a direct navigation coupling between a 3DRX system and a standard navigation system was introduced that bypasses the need for explicit patient-to-image registration necessary for image-guided orthopedic surgery. In a phantom experiment, the reported accuracy of navigation with the coupling to a 3DRX system was approximately 1 mm. However, in a clinical setting, additional errors can be introduced. METHODS: Twenty-three needles were placed transpedicularly into vertebral bodies of embalmed human trunks using 3DRX-guided navigation. The navigated needle tip positions were compared with the real needle tip positions manually extracted from 3DRX volumes acquired after completion of the introduction. RESULTS: The average distance between the navigated needle tip and the real position of the needle tip extracted from a postprocedure 3DRX volume was 2.5 +/- 1.5 mm. CONCLUSIONS: Accuracy of 3DRX-guided navigation is 2.5 +/- 1.5 mm in a clinically relevant setting, which is less than the accuracy determined in phantom experiments.

Accuracy evaluation of direct navigation with an isocentric 3D rotational X-ray system.

Minimally invasive interventions are often performed under fluoroscopic guidance. Drawbacks of fluoroscopic guidance are the fact that the presented images are 2D projections and that both the patient and the clinician are exposed to radiation. Image-guided navigation using pre-interventionally acquired 3D MR or CT data is an alternative. However, this often requires invasive anatomical landmark-based, marker-based or surface-based image-to-patient registration. In this paper, a coupling between an image-guided navigation system and an intraoperative C-arm X-ray device with 3D imaging capabilities (3D rotational X-ray (3DRX) system) that enables direct navigation without invasive image-to-patient registration on 3DRX volumes, is described and evaluated. The coupling is established in a one-time preoperative calibration procedure. The individual steps in the registration procedure are explained and evaluated. The acquired navigation accuracy using this coupling is approximately one millimeter.

Direct navigation on 3D rotational x-ray data acquired with a mobile propeller C-arm: accuracy and application in functional endoscopic sinus surgery.

Recently, three-dimensional (3D) rotational x-ray imaging has been combined with navigation technology, enabling direct 3D navigation for minimally invasive image guided interventions. In this study, phantom experiments are used to determine the accuracy of such a navigation set-up for a mobile C-arm with propeller motion. After calibration of the C-arm system, the accuracy is evaluated by pinpointing divots on a special-purpose phantom with known geometry. This evaluation is performed both with and without C-arm motion in between calibration and registration for navigation. The variation caused by each of the individual transformations in the calibration and registration process is also studied. The feasibility of direct navigation on 3D rotational x-ray images for functional endoscopic sinus surgery has been evaluated in a cadaver navigation experiment. Navigation accuracy was approximately 1.0 mm, which is sufficient for functional endoscopic sinus surgery. C-arm motion in between calibration and registration slightly degraded the registration accuracy by approximately 0.3 mm. Standard deviations of each of the transformations were in the range 0.15-0.31 mm. In the cadaver experiment, the navigation images were considered in good correspondence with the endoscopic images by an experienced ENT surgeon. Availability of 3D localization information provided by the navigation system was considered valuable by the ENT surgeon.

Standardized evaluation methodology for 2-D-3-D registration.

In the past few years, a number of two-dimensional (2-D) to three-dimensional (3-D) (2-D-3-D) registration algorithms have been introduced. However, these methods have been developed and evaluated for specific applications, and have not been directly compared. Understanding and evaluating their performance is therefore an open and important issue. To address this challenge we introduce a standardized evaluation methodology, which can be used for all types of 2-D-3-D registration methods and for different applications and anatomies. Our evaluation methodology uses the calibrated geometry of a 3-D rotational X-ray (3DRX) imaging system (Philips Medical Systems, Best, The Netherlands) in combination with image-based 3-D-3-D registration for attaining a highly accurate gold standard for 2-D X-ray to 3-D MR/CT/3DRX registration. Furthermore, we propose standardized starting positions and failure criteria to allow future researchers to directly compare their methods. As an illustration, the proposed methodology has been used to evaluate the performance of two 2-D-3-D registration techniques, viz. a gradient-based and an intensity-based method, for images of the spine. The data and gold standard transformations are available on the internet (http://www.isi.uu.nl/Research/Databases/).

Bone displacement and the role of longitudinal ligaments during balloon vertebroplasty in traumatic thoracolumbar fractures.

STUDY DESIGN: In a human cadaveric burst fracture model with and without longitudinal ligament damage, the amount of anterior and posterior bone displacement (ABD, PBD) during balloon vertebroplasty after pedicle-screw instrumentation was investigated quantitatively. OBJECTIVES: To investigate, in a burst fracture model with and without longitudinal ligament damage, the amount of ABD, PBD, and cement leakage at various phases during balloon vertebroplasty in combination with pedicle-screw instrumentation. SUMMARY OF BACKGROUND DATA: The role of intact longitudinal ligaments in traumatic spine fractures, for prevention of bone retropulsion and subsequent reduction, has been discussed in several studies but is still up for debate. In a recent human cadaveric burst fracture study, inflatable bone tamps and calcium phosphate cement were used for the augmentation of the anterior column after pedicle-screw instrumentation. The additional balloon vertebroplasty procedure was found to be feasible and safe, but no data pertaining to unwarranted bone displacement or cement leakage during the procedure are available for burst fractures with damaged longitudinal ligaments. METHODS: Ten thoracic and 10 lumbar burst fractures, with rotation or flexion components, were created, and balloon vertebroplasty with calcium phosphate cement was performed after pedicle-screw instrumentation. Volumetric datasets (using the 3-dimensional (3D) rotational x-ray imaging technique) of the fractures were obtained during the following phases: intact, fractured, after reduction and stabilization with pedicle-screws, after inflation of the balloons, after deflation and removal of the balloons, and after injection of the cement. The amount of ABD and PBD was measured on reconstructed sagittal images and recorded together with the presence of extracorporal cement leakage. The continuity of the longitudinal ligaments was assessed after anatomic dissection. RESULTS: During the balloon vertebroplasty procedure, a significant (P < 0.05) increase of ABD (at both thoracic and lumbar level) and PBD (thoracic level) occurred after inflation of the balloons. After deflation and subsequent injection of the cement, however, the ABD and PBD returned to the preinflation levels. The absolute amount of ABD and PBD (<1 mm) during inflation was considered of little clinical importance. No differences in ABD or PBD were observed for specimens with or without continuity of the corresponding longitudinal ligament, irrespective of the level, at any of the phases during the experiment (P > 0.5 in all cases). A small amount of cement leakage was observed in the psoas compartment of one specimen with intact longitudinal ligaments. CONCLUSIONS: It is suggested that balloon vertebroplasty after pedicle-screw instrumentation may safely be used, in terms of bone displacement and cement leakage, in fracture types where damage to longitudinal ligaments is to be expected.

The reduction of endplate fractures during balloon vertebroplasty: a detailed radiological analysis of the treatment of burst fractures using pedicle screws, balloon vertebroplasty, and calcium phosphate cement.

STUDY DESIGN: In a human cadaveric burst fracture model, the amount of endplate fracture reduction after posterior instrumentation and balloon vertebroplasty was investigated quantitatively. OBJECTIVES: To assess, in a burst fracture model, the vertebral body and adjacent disc heights, in parallel sagittal planes with 3-dimensional (3D) rotational x-ray imaging, at various phases during pedicle screw fixation and subsequent balloon vertebroplasty. SUMMARY OF BACKGROUND DATA: In recent human cadaveric thoracolumbar fracture studies, it was found that vertebral body height could be restored significantly with inflatable bone tamps. However, limited quantitative data exist on the amount of fracture reduction that can be achieved and how much of the reduction will be lost after deflation and removal of the bone tamps before the cement is injected. METHODS: Twenty burst fractures were created and balloon vertebroplasty with calcium phosphate cement was performed after pedicle screw instrumentation. A 3D dataset was obtained during the following phases: intact, fractured, after reduction and stabilization with pedicle screws, after inflation of the balloons, after deflation and removal of the balloons, after injection of the cement. The fractured vertebral body and adjacent disc heights were measured from five reconstructed sagittal images and compared for the six phases of the procedure. Furthermore, the difference between the vertebral body height centrally and peripherally was calculated. RESULTS: The mean vertebral body height at the thoracic level was Tintact = 19.5 +/- 2.2 mm, Tfractured = 14.6 +/- 3.8 mm, Treduction = 17.3 +/- 2.2 mm, Tinflation = 20.1 +/- 2.0 mm, Tdeflation = 18.0 +/- 2.0 mm, and Tcement = 17.8 +/- 1.8 mm. The overall change in vertebral body height between these phases was significant (P < 0.001). At the lumbar level the mean vertebral body height was Tintact = 23.2 +/- 3.8 mm, Tfractured = 14.7 +/- 3.0 mm, Treduction = 18.4 +/- 2.5 mm, Tinflation = 23.2 +/- 3.5 mm, Tdeflation = 19.3 +/- 2.3 mm, and Tcement = 20.2 +/- 2.8 mm. The overall change in MCVBH between these phases was also significant (P < 0.001). The increase in vertebral body height resulted in a decrease of the adjacent disc height. No difference was found for the amount of endplate reduction in the center or at the periphery. No leakage of cement was detected in the spinal canal. CONCLUSIONS: Reduction of endplate fractures, both in the center and at the periphery, seems feasible and safe with combined fracture reduction and balloon vertebroplasty. The endplate fracture reduction that was gained by inflation of the bone tamps could not be maintained after deflation.

The role of 3-D rotational x-ray imaging in spinal trauma.

The most widely used imaging devices in trauma spine surgery are fluoroscopy and computed tomography. Both techniques have their specific pros and cons and expose both patient and operating staff to considerable radiation during image acquisition. Three-dimensional-rotational x-ray imaging (3-DRX) is a relatively new technique in which a C-arm is moved around the patient to allow for an "acquisition run" during which multiple fluoroscopy images are obtained. The images can subsequently be processed on a workstation into a 3-D volume, which can then be manipulated in a similar way to 3-D computed tomography data. The 3-DRX technique combines the advantages of both fluoroscopy and computed tomography: fast visual feedback and high resolution multiplanar reformatted images, respectively, and could be used in an intraoperative setting. In this paper some technical aspects of 3-DRX imaging and its potential role in spinal trauma treatment are presented.

Three-dimensional rotational X-ray imaging for spine surgery: a quantitative validation study comparing reconstructed images with corresponding anatomical sections.

STUDY DESIGN: A validation study was done in which reconstructed three-dimensional rotational x-ray images were quantitatively compared with corresponding anatomic sections. OBJECTIVES: To assess the accuracy of reconstructed images acquired on a three-dimensional rotational x-ray imaging device. SUMMARY OF BACKGROUND DATA: Minimally invasive procedures have proven quite successful as alternatives for a multitude of open treatments. An unfavorable property of this type of procedure is a lack of direct vision of the operating area. Three-dimensional rotational x-ray imaging may be able to merge the advantages of computed tomography and fluoroscopy: real-time two-dimensional projections for fast visual feedback and three-dimensional reconstructions for detailed volumetric imaging of complex anatomy. METHODS: Twenty traumatic thoracolumbar burst fractures were created and underwent pedicle screw instrumentation and balloon vertebroplasty. Subsequently, a three-dimensional dataset was obtained, and the midsagittal image was reconstructed. The specimens were sliced, and photographs were obtained. Multiple parameters on the reconstructed images and photographs were measured two times by two observers using a graphical method. The differences and standard deviations were calculated for the corresponding parameters and for the intraobserver data. RESULTS: The mean difference between the corresponding values ranged between -1.1 and 2.1 mm for all parameters. The standard deviation for the differences per parameter ranged between 1.2 and 3.2 mm. The intraobserver differences ranged from -0.8 to 1.4 mm, and the standard deviation varied between 0.4 and 2.4 mm. CONCLUSIONS: The reconstructed midsagittal images were accurate in all measured parameters. The three-dimensional rotational x-ray technique may prove to be valuable for less invasive spine surgery.

Multispectral MR to X-ray registration of vertebral bodies by generating CT-like data.

A new method for MR to X-ray registration is presented. Based on training data, consisting of registered multispectral MR and CT data, a function is defined that maps multispectral MR data to CT-like data. For new subjects for which multispectral MR data have been acquired, the mapping function is used to generate a corresponding CT-like dataset. The CT-like image is subsequently used for registration to X-ray data, using gradient-based registration. Preliminary experiments indicate that MR to X-ray registration using this method is more accurate and has a larger capture range than gradient-based registration applied directly to MR data.

Noninvasive magnetic resonance to three-dimensional rotational x-ray registration of vertebral bodies for image-guided spine surgery.

STUDY DESIGN: Magnetic resonance (MR) and three-dimensional rotational x-ray (3DRX) images of cadaveric spinal segments were registered using a conventional point-based technique and a noninvasive technique called maximization of mutual information (MMI). OBJECTIVES: To assess the feasibility and accuracy of MMI-based registration in comparison with point-based registration as a new noninvasive image-to-patient registration technique for use in minimally invasive image-guided spine surgery. SUMMARY OF BACKGROUND DATA: In image-guided orthopedic surgery, correspondence between before surgery acquired images and the patient is required. Currently, this necessitates an invasive registration step, in which anatomic landmarks on the bone surface have to be physically touched by a pointer. To overcome this invasive procedure, we propose using a calibrated 3DRX system, a modality that can visualize high contrast objects intraoperatively and that provides a direct correspondence between the image data and the patient. A noninvasive voxel-based technique is used to register the intraoperative 3DRX image to a before surgery acquired MR image. METHODS: Cadaveric thoracic and lumbar spine segments were implanted with markers, which were used as landmarks. The accuracy of the landmark-based registration was compared with MMI-based registration using the residual errors on the marker positions. RESULTS: The errors made using the point-based registration technique were compared with the errors made with MMI. The results show a statistically significant lower error (P < 0.01) for the proposed MMI method. CONCLUSIONS: Noninvasive MMI registration of intraoperative 3DRX images to preoperative MR images is more accurate than point-based registration in cadaveric spine segments. It is therefore a promising technique for replacing the invasive landmark-based registration that is currently used in image-guided spine surgery.

Three-dimensional guide-wire reconstruction from biplane image sequences for integrated display in 3-D vasculature.

Using three-dimensional rotational X-ray angiography (3DRA), three-dimensional (3-D) information of the vasculature can be obtained prior to endovascular interventions. However, during interventions, the radiologist has to rely on fluoroscopy images to manipulate the guide wire. In order to take full advantage of the 3-D information from 3DRA data during endovascular interventions, a method is presented that yields an integrated display of the position of the guide wire and vasculature in 3-D. The method relies on an automated method that tracks the guide wire simultaneously in biplane fluoroscopy images. Based on the calibrated geometry of the C-arm, the 3-D guide-wire position is determined and visualized in the 3-D coordinate system of the vasculature. The method is evaluated in an intracranial anthropomorphic vascular phantom. The influence of the angle between projections, distortion correction of the projection images, and accuracy of geometry knowledge on the accuracy of 3-D guide-wire reconstruction from biplane images is determined. If the calibrated geometry information is used and the images are corrected for distortion, a mean distance to the reference standard of 0.42 mm and a tip distance of 0.65 mm is found, which means that accurate guide-wire reconstruction from biplane images can be performed.