Graphical Model-Based Vertebra Identification from X-Ray Image(s)

Automated identification of vertebrae from X-ray image(s) is an important step for various medical image computing tasks such as 2D/3D rigid and non-rigid registration. In this chapter we present a graphical model-based solution for automated vertebra identification from X-ray image(s). Our solution does not ask for a training process using training data and has the capability to automatically determine the number of vertebrae visible in the image(s). This is achieved by combining a graphical model-based maximum a posterior probability (MAP) estimate with a mean-shift based clustering. Experiments conducted on simulated X-ray images as well as on a low-dose low quality X-ray spinal image of a scoliotic patient verified its performance.

A stereotaxic, population-averaged T1w ovine brain atlas including cerebral morphology and tissue volumes

Standard stereotaxic reference systems play a key role in human brain studies. Stereotaxic coordinate systems have also been developed for experimental animals including non-human primates, dogs, and rodents. However, they are lacking for other species being relevant in experimental neuroscience including sheep. Here, we present a spatial, unbiased ovine brain template with tissue probability maps (TPM) that offer a detailed stereotaxic reference frame for anatomical features and localization of brain areas, thereby enabling inter-individual and cross-study comparability. Three-dimensional data sets from healthy adult Merino sheep (Ovis orientalis aries, 12 ewes and 26 neutered rams) were acquired on a 1.5 T Philips MRI using a T1w sequence. Data were averaged by linear and non-linear registration algorithms. Moreover, animals were subjected to detailed brain volume analysis including examinations with respect to body weight (BW), age, and sex. The created T1w brain template provides an appropriate population-averaged ovine brain anatomy in a spatial standard coordinate system. Additionally, TPM for gray (GM) and white (WM) matter as well as cerebrospinal fluid (CSF) classification enabled automatic prior-based tissue segmentation using statistical parametric mapping (SPM). Overall, a positive correlation of GM volume and BW explained about 15% of the variance of GM while a positive correlation between WM and age was found. Absolute tissue volume differences were not detected, indeed ewes showed significantly more GM per bodyweight as compared to neutered rams. The created framework including spatial brain template and TPM represent a useful tool for unbiased automatic image preprocessing and morphological characterization in sheep. Therefore, the reported results may serve as a starting point for further experimental and/or translational research aiming at in vivo analysis in this species.

Registration And Visualisation Of Deformation Maps From Terrestrial Radar Interferometry Using Photogrammetry And Structure From Motion

This paper describes a general workflow for the registration of terrestrial radar interferometric data with 3D point clouds derived from terrestrial photogrammetry and structure from motion. After the determination of intrinsic and extrinsic orientation parameters, data obtained by terrestrial radar interferometry were projected on point clouds and then on the initial photographs. Visualisation of slope deformation measurements on photographs provides an easily understandable and distributable information product, especially of inaccessible target areas such as steep rock walls or in rockfall run-out zones. The suitability and error propagation of the referencing steps and final visualisation of four approaches are compared: (a) the classic approach using a metric camera and stereo-image photogrammetry; (b) images acquired with a metric camera, automatically processed using structure from motion; (c) images acquired with a digital compact camera, processed with structure from motion; and (d) a markerless approach, using images acquired with a digital compact camera using structure from motion without artificial ground control points. The usability of the completely markerless approach for the visualisation of high-resolution radar interferometry assists the production of visualisation products for interpretation.

A Neuromonitoring Approach to Facial Nerve Preservation During Image-guided Robotic Cochlear Implantation.

HYPOTHESIS A multielectrode probe in combination with an optimized stimulation protocol could provide sufficient sensitivity and specificity to act as an effective safety mechanism for preservation of the facial nerve in case of an unsafe drill distance during image-guided cochlear implantation. BACKGROUND A minimally invasive cochlear implantation is enabled by image-guided and robotic-assisted drilling of an access tunnel to the middle ear cavity. The approach requires the drill to pass at distances below 1 mm from the facial nerve and thus safety mechanisms for protecting this critical structure are required. Neuromonitoring is currently used to determine facial nerve proximity in mastoidectomy but lacks sensitivity and specificity necessaries to effectively distinguish the close distance ranges experienced in the minimally invasive approach, possibly because of current shunting of uninsulated stimulating drilling tools in the drill tunnel and because of nonoptimized stimulation parameters. To this end, we propose an advanced neuromonitoring approach using varying levels of stimulation parameters together with an integrated bipolar and monopolar stimulating probe. MATERIALS AND METHODS An in vivo study (sheep model) was conducted in which measurements at specifically planned and navigated lateral distances from the facial nerve were performed to determine if specific sets of stimulation parameters in combination with the proposed neuromonitoring system could reliably detect an imminent collision with the facial nerve. For the accurate positioning of the neuromonitoring probe, a dedicated robotic system for image-guided cochlear implantation was used and drilling accuracy was corrected on postoperative microcomputed tomographic images. RESULTS From 29 trajectories analyzed in five different subjects, a correlation between stimulus threshold and drill-to-facial nerve distance was found in trajectories colliding with the facial nerve (distance <0.1 mm). The shortest pulse duration that provided the highest linear correlation between stimulation intensity and drill-to-facial nerve distance was 250 μs. Only at low stimulus intensity values (≤0.3 mA) and with the bipolar configurations of the probe did the neuromonitoring system enable sufficient lateral specificity (>95%) at distances to the facial nerve below 0.5 mm. However, reduction in stimulus threshold to 0.3 mA or lower resulted in a decrease of facial nerve distance detection range below 0.1 mm (>95% sensitivity). Subsequent histopathology follow-up of three representative cases where the neuromonitoring system could reliably detect a collision with the facial nerve (distance <0.1 mm) revealed either mild or inexistent damage to the nerve fascicles. CONCLUSION Our findings suggest that although no general correlation between facial nerve distance and stimulation threshold existed, possibly because of variances in patient-specific anatomy, correlations at very close distances to the facial nerve and high levels of specificity would enable a binary response warning system to be developed using the proposed probe at low stimulation currents.

Image-Guided Orthopaedic Surgery

Image-guided surgery systems are increasingly being used during orthopaedic interventions. The aim of this chapter is to present the basic elements of these image-guided orthopaedic surgery (IGOS) devices and to review examples of preoperative or intra-operative imaging modalities, of trackers for navigation systems, of different surgical robots, and of methods for registration as well as referencing. IGOS modules that have been realised for different surgical procedures will be presented.

Retinal slit lamp video mosaicking

Purpose To this day, the slit lamp remains the first tool used by an ophthalmologist to examine patient eyes. Imaging of the retina poses, however, a variety of problems, namely a shallow depth of focus, reflections from the optical system, a small field of view and non-uniform illumination. For ophthalmologists, the use of slit lamp images for documentation and analysis purposes, however, remains extremely challenging due to large image artifacts. For this reason, we propose an automatic retinal slit lamp video mosaicking, which enlarges the field of view and reduces amount of noise and reflections, thus enhancing image quality. Methods Our method is composed of three parts: (i) viable content segmentation, (ii) global registration and (iii) image blending. Frame content is segmented using gradient boosting with custom pixel-wise features. Speeded-up robust features are used for finding pair-wise translations between frames with robust random sample consensus estimation and graph-based simultaneous localization and mapping for global bundle adjustment. Foreground-aware blending based on feathering merges video frames into comprehensive mosaics. Results Foreground is segmented successfully with an area under the curve of the receiver operating characteristic curve of 0.9557. Mosaicking results and state-of-the-art methods were compared and rated by ophthalmologists showing a strong preference for a large field of view provided by our method. Conclusions The proposed method for global registration of retinal slit lamp images of the retina into comprehensive mosaics improves over state-of-the-art methods and is preferred qualitatively.

An ultrasensitive NanoLuc-based luminescence system for monitoring Plasmodium berghei throughout its life cycle

BACKGROUND: Bioluminescence imaging is widely used for cell-based assays and animal imaging studies, both in biomedical research and drug development. Its main advantages include its high-throughput applicability, affordability, high sensitivity, operational simplicity, and quantitative outputs. In malaria research, bioluminescence has been used for drug discovery in vivo and in vitro, exploring host-pathogen interactions, and studying multiple aspects of Plasmodium biology. While the number of fluorescent proteins available for imaging has undergone a great expansion over the last two decades, enabling simultaneous visualization of multiple molecular and cellular events, expansion of available luciferases has lagged behind. The most widely used bioluminescent probe in malaria research is the Photinus pyralis firefly luciferase, followed by the more recently introduced Click-beetle and Renilla luciferases. Ultra-sensitive imaging of Plasmodium at low parasite densities has not been previously achieved. With the purpose of overcoming these challenges, a Plasmodium berghei line expressing the novel ultra-bright luciferase enzyme NanoLuc, called PbNLuc has been generated, and is presented in this work. RESULTS: NanoLuc shows at least 150 times brighter signal than firefly luciferase in vitro, allowing single parasite detection in mosquito, liver, and sexual and asexual blood stages. As a proof-of-concept, the PbNLuc parasites were used to image parasite development in the mosquito, liver and blood stages of infection, and to specifically explore parasite liver stage egress, and pre-patency period in vivo. CONCLUSIONS: PbNLuc is a suitable parasite line for sensitive imaging of the entire Plasmodium life cycle. Its sensitivity makes it a promising line to be used as a reference for drug candidate testing, as well as the characterization of mutant parasites to explore the function of parasite proteins, host-parasite interactions, and the better understanding of Plasmodium biology. Since the substrate requirements of NanoLuc are different from those of firefly luciferase, dual bioluminescence imaging for the simultaneous characterization of two lines, or two separate biological processes, is possible, as demonstrated in this work.

Carbohydrate Estimation by a Mobile Phone-Based System Versus Self-Estimations of Individuals With Type 1 Diabetes Mellitus: A Comparative Study

Background: Diabetes mellitus is spreading throughout the world and diabetic individuals have been shown to often assess their food intake inaccurately; therefore, it is a matter of urgency to develop automated diet assessment tools. The recent availability of mobile phones with enhanced capabilities, together with the advances in computer vision, have permitted the development of image analysis apps for the automated assessment of meals. GoCARB is a mobile phone-based system designed to support individuals with type 1 diabetes during daily carbohydrate estimation. In a typical scenario, the user places a reference card next to the dish and acquires two images using a mobile phone. A series of computer vision modules detect the plate and automatically segment and recognize the different food items, while their 3D shape is reconstructed. Finally, the carbohydrate content is calculated by combining the volume of each food item with the nutritional information provided by the USDA Nutrient Database for Standard Reference. Objective: The main objective of this study is to assess the accuracy of the GoCARB prototype when used by individuals with type 1 diabetes and to compare it to their own performance in carbohydrate counting. In addition, the user experience and usability of the system is evaluated by questionnaires. Methods: The study was conducted at the Bern University Hospital, “Inselspital” (Bern, Switzerland) and involved 19 adult volunteers with type 1 diabetes, each participating once. Each study day, a total of six meals of broad diversity were taken from the hospital’s restaurant and presented to the participants. The food items were weighed on a standard balance and the true amount of carbohydrate was calculated from the USDA nutrient database. Participants were asked to count the carbohydrate content of each meal independently and then by using GoCARB. At the end of each session, a questionnaire was completed to assess the user’s experience with GoCARB. Results: The mean absolute error was 27.89 (SD 38.20) grams of carbohydrate for the estimation of participants, whereas the corresponding value for the GoCARB system was 12.28 (SD 9.56) grams of carbohydrate, which was a significantly better performance ( P=.001). In 75.4% (86/114) of the meals, the GoCARB automatic segmentation was successful and 85.1% (291/342) of individual food items were successfully recognized. Most participants found GoCARB easy to use. Conclusions: This study indicates that the system is able to estimate, on average, the carbohydrate content of meals with higher accuracy than individuals with type 1 diabetes can. The participants thought the app was useful and easy to use. GoCARB seems to be a well-accepted supportive mHealth tool for the assessment of served-on-a-plate meals.

Cognitive-Behavioural Analysis System of Psychotherapy (CBASP), a drug, or their combination: differential therapeutics for persistent depressive disorder: a study protocol of an individual participant data network meta-analysis.

INTRODUCTION Despite important advances in psychological and pharmacological treatments of persistent depressive disorders in the past decades, their responses remain typically slow and poor, and differential responses among different modalities of treatments or their combinations are not well understood. Cognitive-Behavioural Analysis System of Psychotherapy (CBASP) is the only psychotherapy that has been specifically designed for chronic depression and has been examined in an increasing number of trials against medications, alone or in combination. When several treatment alternatives are available for a certain condition, network meta-analysis (NMA) provides a powerful tool to examine their relative efficacy by combining all direct and indirect comparisons. Individual participant data (IPD) meta-analysis enables exploration of impacts of individual characteristics that lead to a differentiated approach matching treatments to specific subgroups of patients. METHODS AND ANALYSIS We will search for all randomised controlled trials that compared CBASP, pharmacotherapy or their combination, in the treatment of patients with persistent depressive disorder, in Cochrane CENTRAL, PUBMED, SCOPUS and PsycINFO, supplemented by personal contacts. Individual participant data will be sought from the principal investigators of all the identified trials. Our primary outcomes are depression severity as measured on a continuous observer-rated scale for depression, and dropouts for any reason as a proxy measure of overall treatment acceptability. We will conduct a one-step IPD-NMA to compare CBASP, medications and their combinations, and also carry out a meta-regression to identify their prognostic factors and effect moderators. The model will be fitted in OpenBUGS, using vague priors for all location parameters. For the heterogeneity we will use a half-normal prior on the SD. ETHICS AND DISSEMINATION This study requires no ethical approval. We will publish the findings in a peer-reviewed journal. The study results will contribute to more finely differentiated therapeutics for patients suffering from this chronically disabling disorder. TRIAL REGISTRATION NUMBER CRD42016035886.

Na 1 Nachlass Max Horkheimer, 708 - "Image de la France. Un sondage de L'opinion publique allemande" Band I und II (p. IX 185.1 Bd. I - IX 185.1 Bd. II)

1. "Image de la France. Un sondage de l'opinion publique allemande (République fédérale)", 1954. Als Typoskript vervielfältigt, in drei Bänden gebunden, 441 Blatt;

Na 1 Nachlass Max Horkheimer, 709 - "Image de la France. Un sondage de l'opinion publique allemande" Band III (p. IX 185.1 Bd. III)

"Image de la France. Un sondage de l'opinion publique allemande (République fédßerale)", 1954. Als Typoskript vervielfältigt, in 3 Bänden gebunden, 441 Blatt;

Na 1 Nachlass Max Horkheimer, 711 - Zu "Image de la France. Un sondage de l'opinion publique allemande" und "Enquête sur l'écoute et les conditions d'efficacité des émissions en langue allemande de la Radiodiffusion Francais à destination de l'Allemangne" sowie "The Effectiveness of Candid versus Evasive German-Language Broadcasts of the Voice of America. Final Report" (p. IX 185.3-22 - IX 186)

3. "Plan d'ensemble d'une enquête sur les attitudes generales de la population allemande a l'egard de la France et leurs consequences en ce qui concerne l'orientation des emissions en langue allemande de la radiodiffusion francaise", 18.05.1953. Typoskript, 7 Blatt; 4. "Note" Über Methode, Forschungsrichtung und Reichweite der Ergebnisse der Untersuchung; 18.05.1953; Typoskript, 7 Blatt; 5. "Note" Über Geschichte und Tätigkeit des Instituts für Sozialforschung; 18.05.1953; Typoskript, 5 Blatt; 6. Memorandum des Instituts zu Verfahren und ergebnissen der Untersuchung; 1954 [?]; Typoskript, 2 Blatt; 7.-17. Décamps, Jacques: Memoranden; 7. Memorandum, 12.09.1953; Typoskript, 1 Blatt; 8. "Memorandum re: Besprechung in Bad Godesberg in Bezug auf die französische Studie, am 04.September 1953", 10.09.1953. Typoskript, 1 Blatt; 9. "Memorandum re: Vorhaben des 'Centre d'Etudes Sociologiques, Paris', eine deutsch-französische Arbeitsgemeinschft für die Durchführung von Gemeindestudien zu gründen", 15.06.1953. Typoskript, 1 Blatt; 10. "Memorandum über den Besuch von M. Jean L. Pelosse, Centre d'Etudes sociologiques Paris", 12.06.1953. Typoskript, 3 Blatt; 11. "Bericht über die 'Journées d'Etudes eurropéennes sur la Population' Paris, 21., 22. und 23. Mai 1953", 01.06.1953; 12. "Bericht über den Stand der Verhandlungen mit dem Französischen Auswärtigen Amt und dem französischem Rundfunk. Besprechungen in Paris am 27. und 28. Mai 1953", 01.06.1953. Typoskript, 2 Blatt; 13. Angaben für Max Horkheimer zur Übergabe von Memoranden, Projektbeschreibungen und Briefentwürfen, Mai 1953; Typoskript, 1 Blatt; 14. "Bericht über das 'Institut National d'Etudes Démographiques'", 07.05.1953. Typoskript, 4 Blatt; 15. "Memorandum re: Methode der Gruppendiskussion", 04.05.1953. Typoskript, 1 Blatt; 16. "Besprechung im 'Institut francaise d'Opinion Publique, Paris' und bei der hohen Behörde Luxemburg" 30.04.1953; 17. "Besprechung im Auswärtigen Amt und bei dem französischen Rundfunk", 29.04.1953. Typoskript, 6 Blatt; 18. Horkheimer, Max: 1 Brief an den französischen Botschafter in der Bundesrepublik Deutschland, ohen Ort, ohne Datum; Typoskript, 1 Blatt; 19. Radiodiffusion-Télévision Francaise, le Directeur: 1 Briefabschrift an Jacques Décamps, Paris, 09.03.1954; 1 Blatt; 20. Plessner, Helmuth: 1 Brief an den französischen Außenminister, ohne Ort, 18.05.1953; 1 Blatt; 21. Plessner, Helmuth: 1 Brief an Radiodiffusion Francaise, ohne Ort, 18.05.1953; 1 Blatt; 22. Plessner, Helmuth: 1 Brief an den Ministerialrat der Sektion "Agences et Radio" im französischem Außenministerium, ohne Ort, 18.05.1953; 1 Blatt; "The Effectiveness of Candid versus Evasive German-Language Broadcasts of the Voice of America. Final Report", 1953. Typoskript, gebunden, 432 Blatt;

Improved Techniques for Acquisition and Analysis of Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Detecting Vascular Permeability in the Central Nervous System

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a noninvasive technique for quantitative assessment of the integrity of blood-brain barrier and blood-spinal cord barrier (BSCB) in the presence of central nervous system pathologies. However, the results of DCE-MRI show substantial variability. The high variability can be caused by a number of factors including inaccurate T1 estimation, insufficient temporal resolution and poor contrast-to-noise ratio. My thesis work is to develop improved methods to reduce the variability of DCE-MRI results. To obtain fast and accurate T1 map, the Look-Locker acquisition technique was implemented with a novel and truly centric k-space segmentation scheme. In addition, an original multi-step curve fitting procedure was developed to increase the accuracy of T1 estimation. A view sharing acquisition method was implemented to increase temporal resolution, and a novel normalization method was introduced to reduce image artifacts. Finally, a new clustering algorithm was developed to reduce apparent noise in the DCE-MRI data. The performance of these proposed methods was verified by simulations and phantom studies. As part of this work, the proposed techniques were applied to an in vivo DCE-MRI study of experimental spinal cord injury (SCI). These methods have shown robust results and allow quantitative assessment of regions with very low vascular permeability. In conclusion, applications of the improved DCE-MRI acquisition and analysis methods developed in this thesis work can improve the accuracy of the DCE-MRI results.

Design, Synthesis and Development of Transporter Targeting Agents for Image-guided Therapy and Drug Delivery

The purpose of this study was to design, synthesize and develop novel transporter targeting agents for image-guided therapy and drug delivery. Two novel agents, N4-guanine (N4amG) and glycopeptide (GP) were synthesized for tumor cell proliferation assessment and cancer theranostic platform, respectively. N4amG and GP were synthesized and radiolabeled with 99mTc and 68Ga. The chemical and radiochemical purities as well as radiochemical stabilities of radiolabeled N4amG and GP were tested. In vitro stability assessment showed both 99mTc-N4amG and 99mTc-GP were stable up to 6 hours, whereas 68Ga-GP was stable up to 2 hours. Cell culture studies confirmed radiolabeled N4amG and GP could penetrate the cell membrane through nucleoside transporters and amino acid transporters, respectively. Up to 40% of intracellular 99mTc-N4amG and 99mTc-GP was found within cell nucleus following 2 hours of incubation. Flow cytometry analysis revealed 99mTc-N4amG was a cell cycle S phase-specific agent. There was a significant difference of the uptake of 99mTc-GP between pre- and post- paclitaxel-treated cells, which suggests that 99mTc-GP may be useful in chemotherapy treatment monitoring. Moreover, radiolabeled N4amG and GP were tested in vivo using tumor-bearing animal models. 99mTc-N4amG showed an increase in tumor-to-muscle count density ratios up to 5 at 4 hour imaging. Both 99mTc-labeled agents showed decreased tumor uptake after paclitaxel treatment. Immunohistochemistry analysis demonstrated that the uptake of 99mTc-N4amG was correlated with Ki-67 expression. Both 99mTc-N4amG and 99mTc-GP could differentiate between tumor and inflammation in animal studies. Furthermore, 68Ga-GP was compared to 18F-FDG in rabbit PET imaging studies. 68Ga-GP had lower tumor standardized uptake values (SUV), but similar uptake dynamics, and different biodistribution compared with 18F-FDG. Finally, to demonstrate that GP can be a potential drug carrier for cancer theranostics, several drugs, including doxorubicin, were selected to be conjugated to GP. Imaging studies demonstrated that tumor uptake of GP-drug conjugates was increased as a function of time. GP-doxorubicin (GP-DOX) showed a slow-release pattern in in vitro cytotoxicity assay and exhibited anti-cancer efficacy with reduced toxicity in in vivo tumor growth delay study. In conclusion, both N4amG and GP are transporter-based targeting agents. Radiolabeled N4amG can be used for tumor cell proliferation assessment. GP is a potential agent for image-guided therapy and drug delivery.

A dual resonance, image -guided, volume localization technique for magnetic resonance spectroscopy

An interleaved, dual resonance, volume localization technique for $\sp1$H/$\sp{31}$P magnetic resonance spectroscopy has been designed, implemented on a 2 T imager/spectrometer, and verified with phantom studies.^ Localization techniques, including several single voxel techniques and spectroscopic imaging, were implemented, and studies were performed to compare the efficiency of each sequence of $\sp1$H/$\sp{31}$P spectral acquisitions. The sequence chosen was a hybrid of the stimulated echo single voxel technique and the spectroscopic imaging technique.^ Water suppression during the $\sp1$H spectral acquisitions was accomplished by the use of three narrow bandwidth RF saturation pulses in combination with three spoiler gradients. The spoiler gradient amplitudes were selected on the basis of a numerical solution of the Bloch equations. A post-acquisition water suppression algorithm was used to minimize any residual water signal.^ For interleaved $\sp1$H/$\sp{31}$P acquisitions, a dual resonance RF coil was constructed and interfaced to the existing RF detection system via a custom-designed dual resonance transcoupler and switching system. Programmable attenuators were incorporated to allow for changes in receiver and transmitter attenuation "on the fly".^ To provide the rapidly switched gradient fields required for the $\sp1$H/$\sp{31}$P acquisitions, an actively screened gradient coil system was designed and implemented. With this system, gradient field rise times on the order of 100 $\mu$s were obtained. These rapid switching times were necessary for minimizing intrasequence delays and for improving localization quality and water suppression efficiency.^ The interleaved $\sp1$H/$\sp{31}$P volume localization technique was tested using a two-compartment phantom. Analysis of the data showed that the spectral contamination was less than three percent. One-to-one spatial correspondence of the $\sp1$H and $\sp{31}$P spectra was verified and allowed for direct correlation of the spectral data with a standard magnetic resonance image. ^