Genetic obesity:Disorders and diagnostics

Obesity is a common disease with serious consequences for the health and well-being of patients. In a small proportion of people with excessive weight, a change in genetic material is the main cause of the obesity. In this thesis, the results of genetic testing for these rare obesity disorders are described. Because of the high prevalence of obesity, it is currently impossible to perform genetic diagnostics in all people with obesity. An improved insight in the clinical phenotype of patients with a genetic obesity disorder is therefore needed to determine which patients should undergo genetic testing. Moreover, the impact of diagnosing these disorders is described in this thesis. Increased knowledge about the underlying mechanisms offers great opportunities for the development of novel drug therapy for obesity

UNDERSTANDING CHASSIS INPUTS FROM THE REAR SUSPENSION OF A SNOWMOBILE

Today’s snowmobile industry faces great challenges in the field of noise & vibration. The area of main concern is the pass-by noise restriction defined by the Society of Automotive Engineers (SAE) test standard J192, with a maximum sound pressure level of 78 dB(A) being required by many states and national parks. To continue meet or beat this requirement without effecting machine performance, a deeper understanding of the sound transfer paths is required. This thesis examines the transfer paths created by the tunnel, rear suspension, drive shaft, and rubber composite track, with the primary source being suspension input through the ground. Using a combination of field experiments and analytical modeling, perspective was gained on which suspension and drive elements create the primary transfer paths. With further understanding of these paths, industry can tailor and fine-tune the approaches taken in to control overall noise output

Extensive Phenotyping for Potential Weight-Inducing Factors in an Outpatient Population with Obesity

Background: Obesity has been associated with miscellaneous weight-inducing determinants. A comprehensive assessment of known obesity-related factors other than diet and physical activity within one cohort is currently lacking. Objectives: To assess the prevalence of potential contributors to obesity and self-reported triggers for marked weight gain in an adult population with obesity and between obesity classes. Methods: In this observational cohort study, we assessed 408 persons with obesity (aged 41.3 ± 14.2 years, BMI 40.5 ± 6.2) visiting our obesity clinic. They were evaluated for use of weight-inducing drugs, hormonal abnormalities, menarcheal age, (high) birth weight, sleep deprivation, and obstructive sleep apnea syndrome (OSAS). We additionally assessed self-reported triggers for marked weight gain and performed genetic testing in patients suspected of genetic obesity. Results: Nearly half of the patients were using a potentially weight-inducing drug, which was also the most reported trigger for marked weight gain. For the assessed hormonal conditions, a relatively high prevalence was found for hypothyroidism (14.1%), polycystic ovary syndrome (12.0%), and male hypogonadism (41.7%). A relatively low average menarcheal age (12.6 ± 1.8 years) was reported, whereas there was a high prevalence of a high birth weight (19.5%). Sleep deprivation and OSAS were reported in, respectively, 14.5 and 13.7% of the examined patients. Obesity class appeared to have no influence on the majority of the assessed factors. Of the genetically analyzed patients, a definitive genetic diagnosis was made in 3 patients (1.9%). Conclusions: A thorough evaluation of patients with obesity yields a relatively high prevalence of various potentially weight-inducing factors. Diagnostic screening of patients with obesi

IMPROVE 2022 International Meeting on Pathway‐Related Obesity: Vision of Excellence

Nearly 90 clinicians and researchers from around the world attended the first IMPROVE 2022 International Meeting on Pathway-Related Obesity. Delegates attended in person or online from across Europe, Argentina and Israel to hear the latest scientific and clinical developments in hyperphagia and severe, early-onset obesity, and set out a vision of excellence for the future for improving the diagnosis, treatment, and care of patients with melanocortin-4 receptor (MC4R) pathway-related obesity. The meeting co-chair Peter Kühnen, Charité Universitätsmedizin Berlin, Germany, indicated that change was needed with the rapidly increasing prevalence of obesity and the associated complications to improve the understanding of the underlying mechanisms and acknowledge that monogenic forms of obesity can play an important role, providing insights that can be applied to a wider group of patients with obesity. World-leading experts presented the latest research and led discussions on the underlying science of obesity, diagnosis (including clinical and genetic approaches such as the role of defective MC4R signalling), and emerging clinical data and research with targeted pharmacological approaches. The aim of the meeting was to agree on the questions that needed to be addressed in future research and to ensure that optimised diagnostic work-up was used with new genetic testing tools becoming available. This should aid the planning of new evidence-based treatment strategies for the future, as explained by co-chair Martin Wabitsch, Ulm University Medical Center, Germany

DLG4-related synaptopathy: a new rare brain disorder

PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.Genetics of disease, diagnosis and treatmen

Micron-scale experimental-numerical characterization of metal-polymer interface delamination in stretchable electronics interconnects

Understanding the mechanical behavior and failure mechanisms of stretchable electronics is key in developing reliable and long-lasting devices. In this work a micron-scale stretchable system consisting of an aluminum serpentine patterned interconnect adhered to a polyimide substrate is studied. In-situ experiments are performed where the stretchable sample is elongated, while the surface topography is measured using a confocal microscope. From the resulting height profiles the microscopic three-dimensional deformations are extracted using an adaptive isogeometric digital height correlation algorithm. The displacement information is compared to realistic numerical simulations, in which the interface behavior is described by cohesive zone elements. It is concluded that despite fitting the traction separation law parameters, the model fails to correctly capture the distinct out-of-plane buckling (with magnitude of a few micron) of the interconnect. The model is updated with residual stresses resulting from processing and crystal plasticity induced behavior (decreased yield strength) in the aluminum layer, but both measures are not resulting in the experimentally observed deformations. Finally, mixed-mode cohesive zones are implemented, in which the properties are different in the shear and normal direction. After fitting the corresponding parameters to the experimental data, the model shows realistic in-plane and out-of-plane deformations. Also a predictive simulation for a different geometry results in the correct experimentally measured behavior. It is concluded that the aluminum-polyimide interface mode-angle dependency explains the observed microscopic failure mode of local delamination and buckle formation

The narrative of a patient with leptin receptor deficiency: personalized medicine for a rare genetic obesity disorder

Leptin receptor deficiency is a rare genetic disorder that affects the body’s ability to regulate appetite and weight. For patients and their families, the disorder seriously disrupts daily life, however, little is published about this impact. We here report the experiences of a 10.5-year-old girl with leptin receptor deficiency and her family. The diagnosis of this rare genetic obesity had deep impact on the live of the child and her family. It led to a better understanding of the cause of the impaired appetite regulation and early-onset obesity with subsequently less judgement by others and improved cooperation of their social network and school on maintaining a healthy lifestyle for this girl. A strict eating regimen and lifestyle measures resulted in the first year after diagnosis in a significantly decreased BMI, followed by BMI stabilization, still categorized as obesity class three. However, the troublesome challenge on how to manage the disrupting behaviour due to hyperphagia remained. Eventually, due to treatment with targeted pharmacotherapy, i.e., melanocortin-4 receptor agonists, her BMI continued to decrease due to resolving hyperphagia. The daily routine of the family and the atmosphere at home positively changed, as it was no longer dominated by the food-focused behaviour of the child and the adherence to the strict eating regimen. This case report demonstrates the importance and impact of a rare genetic obesity disorder diagnosis in a family. Additionally, it highlights the value of genetic testing in patients with a high suspicion of a genetic obesity disorder as it can eventually lead to personalized treatment, such as guidance by specialized healthcare professionals and educated caregivers or targeted pharmacotherapy

Mechanical shape correlation: a novel integrated digital image correlation approach

Mechanical Shape Correlation (MSC) is a novel integrated digital image correlation technique, used to determine the optimal set of constitutive parameters to describe the experimentally observed mechanical behavior of a test specimen, based on digital images taken during the experiment. In contrast to regular digital image correlation techniques, where grayscale speckle patterns are correlated, the images used in MSC are projections of the sample contour. This enables the analysis of experiments for which this was previously not possible, because of restrictions due to the speckle pattern. For example, analysis becomes impossible if parts of the specimen move or rotate out of view as a result of complex and three-dimensional deformations and if the speckle pattern degrades due to large deformations. When correlating on the sample outline, these problems are overcome. However, it is necessary that the outline is large with respect to the structure volume and that its shape changes significantly upon deformation, to ensure sufficient sensitivity of the images to the model parameters. Virtual experiments concerning stretchable electronic interconnects, which because of their slender wire-like structure satisfy the conditions for MSC, are executed and yield accurate results in the objective model parameters. This is a promising result for the use of the MSC method for tests with stretchable electronics and other (micromechanical) experiments in general

Self-adaptive isogeometric global digital image correlation and digital height correlation

This work explores the full potential of isogeometric shape functions for global digital image correlation. To this end, a novel DIC and DHC (digital height correlation) methodology have been developed based on adaptive refinement of isogeometric shape functions. Non-Uniform Rational B-Spline (NURBS) shape functions are used employed of their flexibility and versatility, which enables a wide range of kinematic descriptions. In the adaptive refinement algorithm, the shape functions are automatically adjusted to be able to describe the kinematics of the sought (2D or 3D) displacement field with an optimized number of degrees of freedom. Both methods show high accuracy as demonstrated by various virtual experiments with predefined, highly localized (2D and 3D) displacement field. For adaptive iso-GDIC, real tensile tests of complex sample geometries demonstrate its effectiveness in practice, showing local refinement at the areas of localization, without the need of making problem-specific choices regarding the structure of the shape functions. For adaptive iso-GDHC, the correlation of surface height profiles of deforming stretchable electronics structures shows successful autonomous refinement at two localized buckles, thereby strongly reducing the 3D residual, while also analytical differentiation of the C1-continuous 3D displacement field yields the curvature field of the deforming stretchable interconnect