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Duchenne Muscular Dystrophy (DMD) is a severe muscle disorder caused by lack of dystrophin. Predictive biomarkers able to anticipate response to the therapeutic treatments aiming at dystrophin re-expression are lacking. The objective of this study is to investigate Matrix Metalloproteinase-9 (MMP-9) as predictive biomarker for Duchenne. Two natural history cohorts were studied including 168 longitudinal samples belonging to 66 patients. We further studied 1536 samples obtained from 3 independent clinical trials with drisapersen, an antisense oligonucleotide targeting exon 51: an open label study including 12 patients; a phase 3 randomized, double blind, placebo controlled study involving 186 patients; an open label extension study performed after the phase 3. Analysis of natural history cohorts showed elevated MMP-9 levels in patients and a significant increase over time in longitudinal samples. MMP-9 decreased in parallel to clinical stabilization in the 12 patients involved in the open label study. The phase 3 study and subsequent extension study clarified that the decrease in MMP-9 levels was not predictive of treatment response. These data do not support the inclusion of serum MMP-9 as predictive biomarker for DMD patients., QC 20180111

This paper introduces SEMM: a method based on Frequency Based Substructuring (FBS) techniques that enables the construction of hybrid dynamic models. With System Equivalent Model Mixing (SEMM) frequency based models, either of numerical or experimental nature, can be mixed to form a hybrid model. This model follows the dynamic behaviour of a predefined weighted master model. A large variety of applications can be thought of, such as the DoF-space expansion of relatively small experimental models using numerical models, or the blending of different models in the frequency spectrum. SEMM is outlined, both mathematically and conceptually, based on a notation commonly used in FBS. A critical physical interpretation of the theory is provided next, along with a comparison to similar techniques; namely DoF expansion techniques. SEMM's concept is further illustrated by means of a numerical example. It will become apparent that the basic method of SEMM has some shortcomings which warrant a few extensions to the method. One of the main applications is tested in a practical case, performed on a validated benchmark structure; it will emphasize the practicality of the method., Accepted Author Manuscript, Dynamics of Micro and Nano Systems

This paper introduces SEMM: a method based on Frequency Based Substructuring (FBS) techniques that enables the construction of hybrid dynamic models. With System Equivalent Model Mixing (SEMM) frequency based models, either of numerical or experimental nature, can be mixed to form a hybrid model. This model follows the dynamic behaviour of a predefined weighted master model. A large variety of applications can be thought of, such as the DoF-space expansion of relatively small experimental models using numerical models, or the blending of different models in the frequency spectrum. SEMM is outlined, both mathematically and conceptually, based on a notation commonly used in FBS. A critical physical interpretation of the theory is provided next, along with a comparison to similar techniques; namely DoF expansion techniques. SEMM's concept is further illustrated by means of a numerical example. It will become apparent that the basic method of SEMM has some shortcomings which warrant a few extensions to the method. One of the main applications is tested in a practical case, performed on a validated benchmark structure; it will emphasize the practicality of the method., Accepted Author Manuscript, Dynamics of Micro and Nano Systems

Transfer Path Analysis (TPA) designates the family of test-based methodologies to study the transmission of mechanical vibrations. Since the first adaptation of electric network analogies in the field of mechanical engineering a century ago, a multitude of TPA methods have emerged and found their way into industrial development processes. Nowadays the TPA paradigm is largely commercialised into out-of-the-box testing products, making it difficult to articulate the differences and underlying concepts that are paramount to understanding the vibration transmission problem. The aim of this paper is to derive and review a wide repertoire of TPA techniques from their conceptual basics, liberating them from their typical field of application. A selection of historical references is provided to align methodological developments with particular milestones in science. Eleven variants of TPA are derived from a unified framework and classified into three categories, namely classical, component-based and transmissibility-based TPA. Current challenges and practical aspects are discussed and reference is made to related fields of research., Precision and Microsystems Engineering, Mechanical, Maritime and Materials Engineering

Transfer Path Analysis (TPA) designates the family of test-based methodologies to study the transmission of mechanical vibrations. Since the first adaptation of electric network analogies in the field of mechanical engineering a century ago, a multitude of TPA methods have emerged and found their way into industrial development processes. Nowadays the TPA paradigm is largely commercialised into out-of-the-box testing products, making it difficult to articulate the differences and underlying concepts that are paramount to understanding the vibration transmission problem. The aim of this paper is to derive and review a wide repertoire of TPA techniques from their conceptual basics, liberating them from their typical field of application. A selection of historical references is provided to align methodological developments with particular milestones in science. Eleven variants of TPA are derived from a unified framework and classified into three categories, namely classical, component-based and transmissibility-based TPA. Current challenges and practical aspects are discussed and reference is made to related fields of research., Precision and Microsystems Engineering, Mechanical, Maritime and Materials Engineering

QC 20150107

This thesis deals with new methods, which can determine the dynamic response of a complex system identified in operation, based on the knowledge of its subsystem dynamics and excitation. In the first part of this thesis, the identification of component excitation and its transmission into the total system will be addressed. The identification of the internal component excitation is performed on a test bench, on which equivalent forces at the component interface to the test setup are measured. The total system’s response is calculated on the knowledge of its dynamic properties from the component interface onwards. It is shown that physically correct responses for the systems in front of the component’s interface can be calculated. A compensation technique is also outlined to eliminate possible test bench influences. In this thesis, this first approach is called the Gear Noise Propagation (GNP) method, which can be seen as a special class of the well known Transfer Path Analysis (TPA) method. The method could be partially validated on the vibration propagation of a Rear Axle Differential (RAD) in a vehicle, also showing that test bench influences can be minimized in real life applications. In the second part, a new experimental strategy is developed, which enables the identification of systems in operation. In this thesis the method is referred to as the Operational System Identification (OSI) method. It is shown that the signal processing involved yields better FRF estimates than the classical Cross Power Spectrum (CPS) and Auto Power Spectrum (APS) averaging technique. In addition the method has been successfully validated by comparison with the Principle Component Analysis (PCA) method on a test object. Application of the method to an operating vehicle reveals some interesting dependencies of its system dynamics on temperature and applied engine torque. The third part of this thesis deals with methods which improve coupling results in experimental Dynamic Substruct, PME, Mechanical, Maritime and Materials Engineering

This thesis deals with new methods, which can determine the dynamic response of a complex system identified in operation, based on the knowledge of its subsystem dynamics and excitation. In the first part of this thesis, the identification of component excitation and its transmission into the total system will be addressed. The identification of the internal component excitation is performed on a test bench, on which equivalent forces at the component interface to the test setup are measured. The total system’s response is calculated on the knowledge of its dynamic properties from the component interface onwards. It is shown that physically correct responses for the systems in front of the component’s interface can be calculated. A compensation technique is also outlined to eliminate possible test bench influences. In this thesis, this first approach is called the Gear Noise Propagation (GNP) method, which can be seen as a special class of the well known Transfer Path Analysis (TPA) method. The method could be partially validated on the vibration propagation of a Rear Axle Differential (RAD) in a vehicle, also showing that test bench influences can be minimized in real life applications. In the second part, a new experimental strategy is developed, which enables the identification of systems in operation. In this thesis the method is referred to as the Operational System Identification (OSI) method. It is shown that the signal processing involved yields better FRF estimates than the classical Cross Power Spectrum (CPS) and Auto Power Spectrum (APS) averaging technique. In addition the method has been successfully validated by comparison with the Principle Component Analysis (PCA) method on a test object. Application of the method to an operating vehicle reveals some interesting dependencies of its system dynamics on temperature and applied engine torque. The third part of this thesis deals with methods which improve coupling results in experimental Dynamic Substruct, PME, Mechanical, Maritime and Materials Engineering