International Migration, Integration and Social Cohesion online publications
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From beads to bedside:Standardizing extracellular vesicle concentration measurements
Get PDFExtracellular vesicles (EVs) are cell-derived particles with a phospholipid bilayer that are present in body fluids, such as blood and urine. Concentrations of EVs in body fluids are potential disease biomarkers and can be measured with flow cytometers (FCMs). To explore the biomarker potential of EV concentrations, reliable and reproducible measurements of EVs are needed. At present, however, measured EV concentrations are incomparable between instruments and institutes. The aim of this thesis is to improve reliability and comparability of EV concentration measurements with flow cytometry by 1) identifying current challenges faced in EV flow cytometry, 2) developing a robust methodology for reliable and comparable EV concentration measurements, and 3) evaluating the developed methodology in an interlaboratory comparison study. In this thesis, we present a filtration procedure to remove residual platelets from blood plasma, thereby improving the quality of plasma for EV research. Furthermore, we introduce a novel methodology to generate reliable and comparable EV concentration measurements by flow cytometry. The newly developed methodology includes a plasma EV test sample and reference materials to calibrate all parameters of an FCM influencing measured EV concentrations. The methodology was evaluated in a global interlaboratory comparison study including 38 FCMs from 24 laboratories. Emphazising the clinical relevance of the developed methodology, we applied the methodology to determine the first-ever reference ranges of cell-type specific EV concentrations in human blood plasma of healthy volunteers. The methodology presented in this thesis opens the door to explore EV concentrations as potential biomarkers for disease
Teaching historical empathy:Perspective taking in past and present using eyewitnesses
No full textThe aim of this dissertation is to provide history teachers insights and tools on how they can foster students’ empathy in history lessons by using eyewitnesses. The central research question is: How can history teachers promote empathy in history lessons by incorporating eyewitnesses? This thesis aims to provide insights for history teachers to address citizenship competencies through the teaching of historical empathy. The overall approach in this thesis has characteristics of educational design research in which design principles and lessons based on them are developed and tested on the basis of theoretical and empirical exploration. From the literature and interviews with history teachers and students, design principles were derived that can be considered principles for promoting empathy in the context of a history class. These design principles were used to design lesson series on Israel-Palestine in which two eyewitnesses acted as guest speakers in class and a lesson unit in which eyewitnesses were included in a documentary. These outcomes were used to organize a Professional Learning Community for history teachers on historical empathy. It can be concluded that history education, particularly focusing on historical empathy, can offer valuable opportunities for students to practice empathy by exploring the perspectives of individuals from the past and present. The combination of working with eyewitnesses and seven design principles has the potential to provide teachers with concrete tools to promote empathy in history class, allowing teachers to add emphases and make choices depending on their own preferences in teaching and their goals
Colorectal anastomotic leakage:Unraveling a multifaceted complication
Get PDFColorectal anastomotic leakage (CAL) is a serious and potentially life-threatening complication following colorectal surgery. This thesis addresses the challenges in defining, predicting, diagnosing, and understanding the pathophysiology of CAL.In Part 1, the definition of CAL is refined using a modified Delphi analysis. Part 2 focuses on improving preoperative prediction of CAL by investigating various factors, including preoperative fecal microbiome profiles, plasma biomarkers, and body composition metrics. Part 3 describes the IMARI study, a protocol aimed at enhancing CAL prevention, early diagnosis, and treatment through multi-step interventions such as mechanical bowel preparation, splenic flexure mobilization, and routine CRP measurements. Finally, Part 4 explores the physiological processes of normal and disturbed anastomotic healing in a rat model. Furthermore, we investigate the effect of butyrate on intestinal anastomotic healing in animal models.This research advances CAL management by refining its definition, assessing predictive factors, testing new diagnostic approaches, and elucidating the underlying processes of intestinal healing and leakage, providing a comprehensive framework for improved colorectal cancer surgical care
Electron-phonon coupling in organic semiconductors
Get PDFThis thesis investigates the charge transport in organic semiconductors using terahertz (THz) spectroscopy. The flexible nature and the optoelectronic properties of organic semiconductors make them excellent candidates for the next generation of flexible conductive materials. However, their electronic mobility remains lower than inorganic semiconductors, due to the relatively weak intermolecular electronic coupling and strong electron-vibration interactions originating from their soft and disordered structure. The recent developments in polymer chemistry have enabled the synthesis of small molecular crystalline organic semiconductors, with a mobility reaching approximately 10 cm2/Vs. These values are higher than the charge mobility observed in conventional polymers (approximately 1 cm2/Vs). Our temperature-dependent measurements conducted on two small molecular semiconductors (DNTT and its alkylated derivative, C8-DNTT-C8), revealed that charges undergo transient localization due to the large motion of their soft lattice. The scattering of charges with low-frequency vibrations around 10 meV and 16 meV limits the conductivity of DNTT and C8-DNTT-C8, respectively. Understanding the factors that limit electron mobility in these systems allows for better semiconductor design to enhance their electrical performance. In the same material system, we have also investigated how the interaction between electron-hole pairs and vibrations affects their optical and optoelectronic properties. Finally, we explored an alternative approach to control conductivity by cavity. In this designed experiment, we measured the photoresponse of an inorganic-organic semiconductor perovskite whose THz vibrations were coupled with a THz cavity. Despite the apparent polariton formation under strong electron-phonon coupling, the cavity-coupled material properties remained unaffected. By tuning the interaction between the cavity and the phonon, the terahertz response of the integral perovskite-cavity system can be modulated, offering potential benefits for integrated photonic devices.In conclusion, our findings provide insights into the control and understanding of electron-phonon coupling in organic semiconductors
Molecular stool testing for colorectal cancer:Improving screening and surveillance strategies
Get PDFColorectal cancer (CRC) is a highly prevalent disease and chances of survival are dependent on CRC stage at diagnosis. Unfortunately, symptoms often only arise at late stages of the disease. Therefore, CRC screening and surveillance strategies have been introduced. The introduction of these strategies has helped to reduce the global burden of CRC. This because CRC is more often detected at an early and curable stage, or even prevented due to the detection and resection of its advanced precursor lesions. Nevertheless, the benefit-to-harm ratio of these strategies can be improved. In this thesis several opportunities to improve the benefit-to-harm ratio of CRC screening and post-polypectomy surveillance were investigated. The studies focused on non-invasive strategies based on molecular stool testing for CRC. One important milestone was the development and prospective validation of a new non-invasive molecular stool test for CRC screening, the multitarget fecal immunochemical test (mtFIT).The results of this thesis pave the way towards an increased benefit-to-harm ratio of CRC screening and surveillance, by presenting different strategies with potential to be implemented in CRC screening or post-polypectomy surveillance
A kick in the guts:Insulin resistance, gut microbiota and cardiometabolic diseases
Get PDFIn this thesis we show that bacteria in the gut are associated to many aspects of metabolism in prediabetes, diabetes and cardiovascular diseases. We identified changes in metabolism associated to insulin resistance in individuals with the metabolic syndrome, which were previously unknown. In particular certain proteins related to inflammation were strongly associated to insulin resistance. Previous studies have indicated that compounds produced by bacteria in the gut can have beneficial or detrimental effects on health. One metabolite called Imidazole propionate (ImP) from histidine metabolism has been shown to result in insulin resistance when injected to mice. This is of importance, because histidine is abundant in proteins such as nuts and meat and typically individuals with diabetes get recommendations to consume less sugars and simple carbohydrates and more proteins. Therefore, the questions we wanted to answer was: (1) is dietary histidine resulting in higher levels of ImP and (2) is supplementation of histidine detrimental for insulin resistance? We found that histidine supplementation increased ImP levels but that histidine supplementation also improved blood sugar levels, indicating an improvement in insulin resistance. Finally, we show that bacteria in the gut are associated to cardiovascular diseases in a multi ethnic study. We find a trophic network of bacteria to be inversely associated to cardiovascular diseases and triglyceride levels. We hypothesize that gut microbiota might influence cardiovascular diseases by affecting blood lipid levels. However, future studies should confirm our findings in a randomized trial
Algorithms in colorectal cancer screening
Get PDFScreening individuals for colorectal cancer (CRC) leads to a reduction in disease-related morbidity and mortality. In Europe, screening is mostly performed using the faecal immunochemical test (FIT). Individuals with a positive FIT result are referred for colonoscopy, where cancer or precursor lesion can be detected and/or resected. FIT is not optimal, as it lacks the ability to accurately detect precursor lesions. Algorithms may improve the yield of screening by combining FIT with other risk factors. The studies in this thesis aimed to develop and evaluate these algorithms while using readily available data that have low additional operational costs, such as age, sex, and data derived from questionnaires. Another drawback of FIT is the high number of individuals who receive a false-positive test. This thesis also describes work on an add-on test designed to reduce the number of individuals undergoing an unnecessary colonoscopy. Finally, this thesis proposes several potential avenues for the development of algorithms in CRC screening
Evaluating developments in rectal cancer care in routine clinical practice
Get PDFThe aim of this thesis was to evaluate developments in the multidisciplinary treatment of primary rectal cancer on a national level. Part I focused on the new consensus definition of rectal cancer in the multidisciplinary team meetings, based on the sigmoid take-off landmark. Online training has the potential to improve implementation and unambiguous assessment. By using the sigmoid take-off, 11% of the prior diagnosis of rectal cancer were redefined as sigmoid cancer, with substantial inter-hospital variation and potential implications for multimodality and prognostic value. In part II new developments in the treatment of rectal cancer were evaluated. When comparing two national cohorts with patients with a resection for rectal cancer in 2011 and 2016, an absolute 50% reduction in radiotherapy use for non-locally advanced rectal cancer was observed. This change in neoadjuvant therapy did not compromise cancer-related outcomes and even an improvement in overall survival from 79.6% to 86.4% was observed. Permanent stoma rate and stoma-related complications were evaluated in the two national cohorts. Remarkable hospital variability in permanent stoma rate was observed. Stoma complications were most often observed after a Hartmann’s Procedure (23%), still requiring a significant number of reinterventions even after one year. No beneficial influence of transanal or robot-assisted laparoscopy was found on the permanent stoma rate. Part III addresses the prognostic implications of lateral lymph nodes. Results of an online survey showed vast variation in the awareness, definition of suspicious lateral lymph nodes in rectal cancer and different treatment approaches
Paediatric inflammatory bowel disease:Moving towards tailored diagnostic and treatment approaches
Get PDFPaediatric inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic disorder with relapsing-remitting inflammation of the gastrointestinal tract, affecting around 8% of patients before the age of 18. While the exact cause remains unclear, the interplay of gut microbiota, genetics, environment, and immune factors is hypothesised. The diagnostic work-up of paediatric IBD involves clinical symptoms along with laboratory, radiologic, endoscopic, and histologic findings. However, current biomarkers, with faecal calprotectin as the most commonly used marker, lack specificity. The first part of this thesis investigates the potential of faecal gut microbiota and metabolomics as non-invasive diagnostic biomarkers. Findings suggest altered metabolomic profiles in children with IBD, with specific amino acids showing promise for differentiation between IBD and controls. The second part focuses on optimising treatment with thiopurines and infliximab and evaluating surveillance strategies. It was shown that accelerated infliximab infusions without an intrahospital observation period were safe. Additionally, we observed variability in surveillance practices for colorectal cancer in paediatric UC patients among Dutch gastroenterologists, proposing the need for standardised guidelines. The third part aims to establish a shared research agenda, involving patients, caregivers, and healthcare professionals. The top 10 research priorities are identified, covering aspects including the cause and management of fatigue, IBD pathophysiology, non-invasive diagnostic strategies, and coping support
Targeting data in armed conflict:Interpreting international humanitarian law’s fundamental notions of ‘attack’, ‘object(ive)’ & ‘damage’ against the effects of cyber operations
Get PDFThis thesis aimed to clarify the extent to which cyber operations directed against data during armed conflict could be subjected to the targeting principles and rules concerning attack (art. 49 Protocol Additional to the Geneva Conventions of 12 August 1949, and relating to the Protection of Victims of International Armed Conflicts, 8 June 1977. Hereafter API.), military objectives (art. 52(2) API) and damage (art. 57 API). Findings indicated that cyber operations leading to ‘violent effects’ such as the termination of combat action of an adversary, enforced or coercive changes and severe illness and mental suffering amongst the civilian population, are subjected to the targeting rules and principles of API, in so far as the targeted data fulfilled the criteria of Art. 52(2) API to constitute a military objective. If the data in question does not fulfil those criteria but can be understood to consist of data that is susceptible to damage or destruction, and has a key-position in civilian life, that data could be interpreted evolutively as a civilian object in the sense of Art. 52(2) API. Lastly, damage and more specifically collateral damage, interpreted evolutively, consists of physical and non-physical effects brought about through cyber operations which either impact functionality in a serious manner or, that in the contextual circumstances of a specific situation, would lead to the type of human suffering which API intends to minimise