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Summary Background The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure. Methods The RAPID study was a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial of A1PI treatment in patients with α1 antitrypsin deficiency. We recruited eligible non-smokers (aged 18–65 years) in 28 international study centres in 13 countries if they had severe α1 antitrypsin deficiency (serum concentration Findings Between March 1, 2006, and Nov 3, 2010, we randomly allocated 93 (52%) patients A1PI and 87 (48%) placebo, analysing 92 in the A1PI group and 85 in the placebo group. The annual rate of lung density loss at TLC and FRC combined did not differ between groups (A1PI −1·50 g/L per year [SE 0·22]; placebo −2·12 g/L per year [0·24]; difference 0·62 g/L per year [95% CI −0·02 to 1·26], p=0·06). However, the annual rate of lung density loss at TLC alone was significantly less in patients in the A1PI group (−1·45 g/L per year [SE 0·23]) than in the placebo group (−2·19 g/L per year [0·25]; difference 0·74 g/L per year [95% CI 0·06–1·42], p=0·03), but was not at FRC alone (A1PI −1·54 g/L per year [0·24]; placebo −2·02 g/L per year [0·26]; difference 0·48 g/L per year [–0·22 to 1·18], p=0·18). Treatment-emergent adverse events were similar between groups, with 1298 occurring in 92 (99%) patients in the A1PI group and 1068 occuring in 86 (99%) in the placebo group. 71 severe treatment-emergent adverse events occurred in 25 (27%) patients in the A1PI group and 58 occurred in 27 (31%) in the placebo group. One treatment-emergent adverse event leading to withdrawal from the study occurred in one patient (1%) in the A1PI group and ten occurred in four (5%) in the placebo group. One death occurred in the A1PI group (respiratory failure) and three occurred in the placebo group (sepsis, pneumonia, and metastatic breast cancer). Interpretation Measurement of lung density with CT at TLC alone provides evidence that purified A1PI augmentation slows progression of emphysema, a finding that could not be substantiated by lung density measurement at FRC alone or by the two measurements combined. These findings should prompt consideration of augmentation treatment to preserve lung parenchyma in individuals with emphysema secondary to severe α1 antitrypsin deficiency. Funding CSL Behring.

The traditional Hessian-related vessel filters often suffer from the problem of handling non-cylindrical objects. To remedy the shortcoming, we present a shape-tuned strain energy density function to measure vessel likelihood in 3D images. Based on the tensor invariants and stress-strain principle in mechanics, a new shape discriminating and vessel strength measure function is formulated. The synthetical and clinical data experiments verify the performance of our method in enhancing complex vascular structures including branches, bifurcations, and feature details.

Contrast-enhanced CT Angiography has become an accepted diagnostic tool for detecting Pulmonary Embolism (PE). The CT obstruction index proposed by Qanadli, which is based on the number of obstructed arterial segments, enables the quantification of PE severity. Because the required manual identification of twenty arterial segments is time consuming, we propose a method for automated labeling of the pulmonary arterial tree to identify the arterial segments. Assuming that the peripheral parts of the arterial tree contain most relevant information for labeling, we propose a bottom-up labeling algorithm exploiting the spatial information of the peripheral arteries. A model of reference positions of the arterial segments was trained using manually labeled trees of 9 patients. To improve accuracy, the arterial tree was partitioned into sub-trees enabling an iterative labeling technique that labels each sub-tree separately. The accuracy of the labeling technique was evaluated using manually labeled trees of 10 patients. Initially an accuracy of 74% was obtained, whereas the iterative approach improved accuracy to 85%. The labeling errors had minor effects on the calculated Qanadli index. Therefore, the presented labeling approach is applicable in automated PE quantification.

Rheumatoid arthritis (RA) is a disease of the synovium that involves the small joints of hands and feet. The focus in RA-research, however, has primarily been on involvement of the hands. In this thesis we studied involvement of the forefoot. Throughout this thesis we found that synovitis in the rheumatoid foot affects more than just the joints. In an anatomic study we revealed that the tendon-sheaths in the forefoot also possess a synovial layer. Inflammation of this, detected by MRI that is referred to as tenosynovitis, was an important aspect of RA involvement in the forefoot. In addition, intermetatarsal bursae also detected by MRI are also often inflamed due to disease-involvement. These extra-articular involvements of the synovium that are found in RA importantly contribute to joint swelling and walking disability, and are therefore clinically relevant. Therefore we believe that it is essential for the clinician to pay attention to the forefeet of patients with RA to have a complete idea of disease activity

In this thesis, we developed methods focusing on quantifying pulmonary vascular diseases and assessing treatment effects, based on CT images. A lung vessel segmentation method was proposed in Chapter 2, as accurately extracting lung vessels is an essentialstep for pulmonary vessel analysis. An automatic method for pulmonary vessel quantification was developed in Chapter 3, where two imaging biomarkers were proposed for quantifying the vascular morphology. In Chapter 4, the relation between these imaging biomarkers and pulmonary function were investigated in a selected SSc patient group, who had reductions in gas transfer but did not have fibrosis. The densitometry changes in pulmonary vasculature and parenchyma were studied by comparing CTPA scans before and after treatment for CTEPH patients treated with BPA, in Chapter 5. A vascular tree matching method was proposed for matching pulmonaryvasculature trees, for quantifying changes in vascular morphology for CTEPH patients in Chapter 6.

Inflammatory arthritis comprises a group of diseases in which the immune system attacks the body’s own tissues. Two prevalent types of inflammatory arthritis are rheumatoid arthritis (RA) and spondyloarthritis (SpA). Clinical research points to the importance of early diagnosis, as treatment in early disease stages increases chances of better outcome and improved quality of life for patients. To this end, the diagnostic potential of imaging modalities sensitive to local inflammation, such as magnetic resonance imaging (MRI), is of great interest. The goal of this thesis was to develop computer-aided methods for assessment of MRI-detected inflammation with the aim of aiding early diagnosis of inflammatory arthritis. In particular, we focused on the tasks of comparative visualization, automatic quantification, and feature selection. The presented studies showcase the potential of comparative visualization and automatic quantification to overcome the limitations of visual scoring and lay out a fertile ground for future improvements. Additionally, the understanding of the diagnostic role of individual inflammatory features in prediction of RA development is further advanced. Collectively, these findings can help facilitate the use of MRI for early diagnosis of inflammatory arthritis and potentially increase chances of better outcome and quality of life for patients.

The primary aim of this work was to develop novel model-based mJSW measurement methods using a 3D reconstruction and compare the accuracy and precision of these methods to conventional mJSW measurement. This thesis contributed to the development, validation and clinical application of model-based mJSW measurements for the natural knee and for total knee prostheses. The majority of this work focusses on measuring linear wear of the total knee protheses by estimating the remaining insert thickness with the mJSW. Both in vivo and in vitro research shows that the application of model-based techniques can give a large improvement in measurement accuracy and precision. This applies for measurements based on both Röntgen Stereogrammetric Analysis (RSA) and standard radiographs. Secondary, this work investigated volumetric wear measurement and the effect of patient positioning on the measurement outcome. In conclusion, this work presents convincing evidence that the mJSW measurement accuracy and precision is improved using model-based measurement techniques in RSA images as well as in standard AP radiographs. The next steps towards clinical application are to improve the measurement software and to conduct further research on the influence of knee flexion and implant design on the reliability of mJSW as surrogate for the insert thickness.

Model-based shape matching is commonly used, for example to measure the migration of an implant with Roentgen stereophotogrammetric analysis (RSA) or to measure implant kinematics with fluoroscopy. The aim of this thesis was to investigate the general usability of shape matching and to improve the reliability of shape matching for RSA and fluoroscopy. Several improvements were made to the usability and reliability of model-based shape matching for RSA and fluoroscopy. An automatic contour detection approach was proposed, integrating directly into the estimation of position and orientation of the implant. The accuracy of such estimation was also improved by taking the relation between implant parts into account. The robustness of model-based shape matching was assessed when it is applied fully automatically, demonstrating that manual supervision remains necessary. The standardization of validating new fluoroscopic methods could be a welcome addition to the biomechanical field, making it a lot easier to compare results between methods and experiments. As the technology of fluoroscopy advances, the amount of high quality data is getting larger, and may soon grow beyond the capabilities of manual, supervised pose estimation methods. It is therefore imperative that fully automatic unsupervised methods are developed.

We hypothesized that shoulder pain, caused by rheumatoid arthritis (RA), can lead to disuse of the affected shoulder joint. In addition to the structural changes caused by rotator cuff tears, tendonitis or synovitis disuse may play an important role in the aetiology of fatty degeneration (FD) of the rotator cuff muscles. This FD may induce proximal migration due to shoulder muscle force imbalance, causing even more pain due to subacromial impingement. FD is thought irreversible, even when the underlying pathology was treated. Early referral and treatment of shoulder involvement of rheumatoid disease may protect the rheumatoid shoulder from this downward spiral. It is of great importance to screen rheumatoid arthritis patients for shoulder joint involvement at an early stage. The use of the Upward migration Index to assess proximal migration can be used reliably to screen for the presence of rotator degeneration. In order to quantify fatty degeneration we advocate using the Mean Muscle Density measured on CT-images. We underline the importance of these measurements as they were strongly correlated to shoulder pain and functional loss. Measurement of proximal migration in an early stage can therefore play an important role in the initiation of functional and medicinal treatment of RA and may present patients with better possible outcome providing that shoulder surgery is indicated.