Assessment by doppler ultrasound of entheseal lesions in spondyloarthritis : a longitudial study to determine structural damage and disease activity lesions

RESUMO: Enthesitis is the hallmark of spondyloarthritis (SpA), and is observed in all subtypes. Wide information on SpA abnormalities, including synovitis, tendinitis and enthesitis, can be efficiently perceived by Doppler ultrasound. Furthermore, several studies on imaging of enthesis showed that imaging techniques are better than clinical examination to detect enthesis alterations; and vascularized enthesitis detected by Doppler ultrasound appears to be a valuable diagnostic tool to confirm SpA diagnosis. However, data published until now concerning entheseal elementary alterations that characterize SpA enthesitis (enthesis inflammatory activity) or enthesopathy (permanent structural changes) reflect rather the authors’ empiric opinion than a methodological validation process. In this sense it seems crucial to identify elementary entheseal lesions associated with activity or damage, in order to improve monitoring and treatment response in SpA patients. The development of better assessment tools is today a challenge and a need in SpA. The first study of this thesis focused on the analysis of the reliability of inter-lector and inter-ultrasonography equipment of Madrid sonography enthesitis index (MASEI). Fundamental data for the remaining unrolling project validity. In the second and third studies we concerned about two entheseal elemental lesions: erosions and bursa. In literature erosions represent a permanent structural damage, being useful for monitoring joint injury, disease activity and therapeutic response in many rheumatic diseases; and to date, this concept has been mostly applied in rheumatoid arthritis (RA). Unquestionably, erosion is a tissue-related damage and a structural change. However, the hypothesis that we decided to test was if erosions represent a permanent structural change that can only grow and worsen over time, as occurs in RA, or a transitory alteration. A longitudinal study of early SpA patients was undertaken, and the Achilles enthesis was used as a model. Our results strongly suggested that previously detected erosions could disappear during the course of the disease, being consistent with the dynamic behavior of erosion over time. Based on these striking results it seems reasonable to suggest that the new-bone formation process in SpA could be associated with the resolution of cortical entheseal erosion over time. These results could also be in agreement with the apparent failure of anti-tumor necrosis factor (TNF) therapies to control bone proliferation in SpA; and with the relation of TNF-α, Dickkopf-related protein 1 (Dkk-1) and the regulatory molecule of the Wnt signaling pathway in the bone proliferation in SpA. In the same model, we then proceeded to study the enthesis bursa. Interestingly, the Outcome Measures in Rheumatology Clinical Trials (OMERACT) enthesopathy definition does not include bursa as an elementary entheseal lesion. Nonetheless, bursa was included in 46% of the enthesis studies in a recently systematic literature review, being in agreement with the concept of “synovio-entheseal complex” that includes the link between enthesitis and osteitis in SpA. It has been clarified in recent data that there is not only a close functional integration of the enthesis with the neighboring bone, but also a connection between enthesitis and synovitis. Therefore, we tried to assess the prevalence and relevance of the bursa-synovial lesion in SpA. Our findings showed a significant increase of Achilles bursa presence and thickness in SpA patients compared to controls (healthy/mechanical controls and RA controls). These results raise awareness to the need to improve the enthesopathy ultrasonographic definition. In the final work of this thesis, we have explored new perspectives, not previously reported, about construct validity of enthesis ultrasound as a possible activity outcome in SpA. We performed a longitudinal Achilles enthesis ultrasound study in patients with early SpA. Achilles ultrasound examinations were performed at baseline, six- and twelve-month time periods and compared with clinical outcome measures collected at basal visit. Our results showed that basal erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are higher in patients with Doppler signal in enthesis, and even that higher basal ESR, CRP and Ankylosing Spondylitis Disease Activity Score (ASDAS) predicted a higher Doppler signal (an ultrasound alteration accepted as representative of inflammation) six months later. Patients with very high disease activity assessed by ASDAS (>3.5) at baseline had significantly higher Achilles total ultrasound score verified at the same time; and ASDAS <1.3 predicted no Doppler signal at six and twelve months. This seems to represent a connection between classical biomarkers and clinical outcomes associated with SpA activity and Doppler signal, not only at the same time, but also for the following months. Remarkably, patients with inactive disease (ASDAS < 1.3) at baseline had no Doppler signal at six and twelve months. These findings reinforce the potential use of ultrasound related techniques for disease progression assessment and prognosis purposes. Intriguingly, Ankylosing Spondylitis Disease Activity Index (BASDAI) didn’t show significant differences between different cut-offs concerning ultrasound lesions or Doppler signal, while verified with ASDAS. These results seem to indicate that ASDAS reflects better than BASDAI what happens in the enthesis. The work herein discussed clearly shows the potential utility of ultrasound in enthesis assessment in SpA patients, and can be important for the development of ultrasound activity and structural damage scores for diagnosis and monitoring purposes. Therefore, local promotion of this technique constitutes a medical intervention that is worth being tested in SpA patients for diagnosis, monitoring and prognosis purposes.

Structural transformation in the product space: Patterns and implications

Product fundamentals are essential in explaining heterogeneity in the product space. The scope for adapting and transferring capabilities into the production of different goods determines the speed and intensity of the structural transformation process and entails dissimilar development opportunities for nations. Future specialization patterns become then partly determined by the current network of products’ relatedness. Building on previous literature, this paper explicitly compares methodological concepts of product connectivity to conclude in favor of the density measure we propose combined with the Revealed Relatedness Index (RRI) approach presented by Freitas and Salvado (2011). Overall, RRI specifications displayed more consistent behavior when different time horizons are equated.

EFFECT – Efficient finite element code

The theme of this dissertation is the finite element method applied to mechanical structures. A new finite element program is developed that, besides executing different types of structural analysis, also allows the calculation of the derivatives of structural performances using the continuum method of design sensitivities analysis, with the purpose of allowing, in combination with the mathematical programming algorithms found in the commercial software MATLAB, to solve structural optimization problems. The program is called EFFECT – Efficient Finite Element Code. The object-oriented programming paradigm and specifically the C ++ programming language are used for program development. The main objective of this dissertation is to design EFFECT so that it can constitute, in this stage of development, the foundation for a program with analysis capacities similar to other open source finite element programs. In this first stage, 6 elements are implemented for linear analysis: 2-dimensional truss (Truss2D), 3-dimensional truss (Truss3D), 2-dimensional beam (Beam2D), 3-dimensional beam (Beam3D), triangular shell element (Shell3Node) and quadrilateral shell element (Shell4Node). The shell elements combine two distinct elements, one for simulating the membrane behavior and the other to simulate the plate bending behavior. The non-linear analysis capability is also developed, combining the corotational formulation with the Newton-Raphson iterative method, but at this stage is only avaiable to solve problems modeled with Beam2D elements subject to large displacements and rotations, called nonlinear geometric problems. The design sensitivity analysis capability is implemented in two elements, Truss2D and Beam2D, where are included the procedures and the analytic expressions for calculating derivatives of displacements, stress and volume performances with respect to 5 different design variables types. Finally, a set of test examples were created to validate the accuracy and consistency of the result obtained from EFFECT, by comparing them with results published in the literature or obtained with the ANSYS commercial finite element code.

Hydric behavior of earth materials and the effects of their stabilization with cement or lime: study on repair mortars for historical rammed earth structures

Earthen building materials bear interesting environmental advantages and are the most appropriate to conserve historical earth constructions. To improve mechanical properties, these materials are often stabilized with cement or lime, but the impact of the stabilizers on the water transport properties, which are also critical, has been very rarely evaluated. We have tested four earth-based repair mortars applied on three distinct and representative rammed earth surfaces. Three mortars are based on earth collected from rammed earth buildings in south of Portugal and the fourth mortar is based on a commercial clayish earth. The main objective of the work was over the commercial earth mortar, applied stabilized and not stabilized on the three rammed earth surfaces to repair, to assess the influence of the stabilizers. The other three earth mortars (not stabilized) were applied on each type of rammed earth, representing the repair only made with local materials. The four unstabilized earth materials depicted nonlinear dependence on t1/2 during capillary suction. This behaviour was probably due to clay swelling. Stabilization with any of the four tested binders enabled the linear dependence of t1/2 expected from Washburn's equation, probably because the swelling did not take place in this case. However, the stabilizers also increased significantly the capillary suction and the capillary porosity of the materials. This means that, in addition to increasing the carbon footprint, stabilizers like cement and lime have functional disadvantages that discourage its use in repair mortars for raw earth construction.

The antecedents of post-initial adoption behavior in a S-D logic context

Repercussions of innovation adoption and diffusion studies have long been imperative to the success of novel introductions. However, perceptions and deductions of current innovation understandings have been changing over time. The paradigm shift from the goods-dominant (G-D) logic to the service-dominant (S-D) logic potentially makes the distinction between product (goods) innovation and service innovation redundant as the S-D logic lens views all innovations as service innovations (Vargo and Lusch, 2004; 2008; Lusch and Nambisan, 2015). From this perspective, product innovations are in essence service innovations, as goods serve as mere distribution mechanisms to deliver service. Nonetheless, the transition to such a broadened and transcending view of service innovation necessitates concurrently a change in the underlying models used to investigate innovation and its subsequent adoption. The present research addresses this gap by engendering a novel model for the most crucial period of service diffusion within the S-D logic context – the post-initial adoption phase, which demarcates an individual’s behavior after the initial adoption decision of a service. As a wellfounded understanding of service diffusion and the complementary innovation adoption still lingers in its infancy, the current study develops a model based on interdisciplinary domains mapping. Here fore, knowledge of the relatively established viral source domain is mapped to the comparatively undetermined target domain of service innovation adoption. To assess the model and test the importance of the explanatory variables, survey data from 750 respondents of a bank in Northern Germany is scrutinized by means of Structural Equation Modeling (SEM). The findings reveal that the continuance intention of a customer, actual usage of the service and the customer influencer value all constitute important postinitial adoption behavior that have meaningful implications for a successful service adoption. Second, the four constructs customer influencer value, organizational commitment, perceived usefulness and service customization are evidenced to have a differential impact on a iv customer’s post-initial adoption behavior. Third, this study indicates that post-initial adoption behavior further underlies the influence of a user’s age and besides that is also provoked by the internal and external environments of service adoption. Finally, this research amalgamates the broad view of service innovation by Nambisan and Lusch (2015) with the findings ensuing this enquiry’s model to arrive at a framework that it both, generalizable and practically applicable. Implications for academia and practitioners are captured along with avenues for future research.