International Migration, Integration and Social Cohesion online publications
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Precision medicine in respiratory diseases:A translational journey from biomarker discovery to validation
Full text linkRespiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and post COVID condition pose significant global health challenges due to their complexity, heterogeneity, and burden on patients and healthcare systems. This thesis explored innovative approaches for improved understanding, diagnoses, and management of these conditions through systems biology and biomarker research.The thesis starts with providing an introduction on prevalence, impact, and shared biological mechanisms of respiratory diseases. The chapter emphasizes on the roles of inflammation, oxidative stress, and metabolic disruptions. The following section of the work is related to exhaled metabolites. In a systematic review the association of volatile organic compounds (VOCs) in exhaled breath with asthma and COPD risk factors is addressed, the results advocate for careful interpretation and exclusion of risk factor-driven VOCs. Subsequent chapters investigated the potential of VOCs as noninvasive biomarkers for asthma control, COPD exacerbations, and pediatric post COVID condition, demonstrating their utility in diagnosis/prognosis, monitoring, and patient stratification. The closing chapter before the general discussion reports on the integration of multi-omics approaches, incorporating salivary microbiome and serum inflammatory markers to enhance prediction of asthma attacks in children.The general discussion synthesized key findings, addressing methodological challenges, the necessity for standardization, and the importance of external validation in biomarker research. By leveraging omics technologies and advanced analytical tools, this work contributes to the advancement of precision medicine in respiratory diseases. It underscores the potential for noninvasive diagnostic and monitoring strategies to improve early detection, potential personalized treatment, and overall patient outcomes
The ileal pouch in IBD:Unraveling the complexities
Full text linkApproximately 10% of ulcerative colitis patients undergo a proctocolectomy within ten years of their diagnosis. An ileal pouch-anal anastomosis is the gold standard for restoring bowel continuity. While pouch patients generally experience a good quality of life, both short- and long-term complications are common.The first part of this dissertation focuses on various outcomes and complications of the pouch, including chronic pouchitis, pre-pouch ileitis, Crohn’s-like disease of the pouch (CDP), and solitary pouch ulcers. Establishing the correct diagnosis is challenging due to the lack of clear definitions and overlapping clinical and endoscopic parameters. Patients presenting with pre-pouch ileitis or structural issues such as strictures, fistulas, or a chronic sinus are often diagnosed with CDP, even in the absence of preoperative evidence of Crohn’s disease. Our study found that nearly half of the patients diagnosed with CDP had a fistula or sinus closely associated with the anastomosis, which is indicative of (late) anastomotic leakage. As a result, these patients were incorrectly treated with medication instead of surgery. A MRI one year after surgery or at the initiation of step-up therapy is recommended to rule out postoperative complications.The second part of the dissertation examines the effect of tofacitinib in patients with ulcerative colitis as well as those with chronic pouchitis. In our pilot study on chronic pouchitis patients, 31% achieved clinical remission, and 54% showed a clinical response after eight weeks of treatment with tofacitinib. However, endoscopic and histological scores did not significantly improve. In patients with ulcerative colitis who still had their colon in situ, tofacitinib was also investigated, with 38% showing histo-endoscopic improvement. Gene expression analysis confirmed the effect of tofacitinib on the JAK-STAT signaling pathway, and CLC (Charcot-Leyden Crystal) was identified as a potential biomarker for predicting response to tofacitinib
Pulsed Dye Laser in psoriasis:A nerve-wrecking event?
Full text linkThis thesis investigates the mechanisms and effects of Pulsed Dye Laser (PDL) therapy in the treatment of psoriasis, aiming to clarify the underlying mechanisms of PDL's therapeutic effects. The research encompasses a range of experimental approaches, including in vitro, ex vivo, in silico, and in vivo studies. The first chapters focus on the impact of hyperthermia on various cell types, while the later chapters present clinical patient studies that explore the detailed morphology of the perivascular network in the skin and the changes it undergoes following PDL treatment. The original hypothesis of the work that PDL destructs perivascular nerves in psoriasis could not be confirmed, yet 3D histological sections suggested that PDL may inflict damage upon the CD3+ immune cell clusters right below the dermo-epidermal junction. Thus, PDL may cause thermal damage that leads to a functional, but not morphological, alteration of nerve fibers and possibly also cause thermal damage to immune cell clusters around the vasculature of the skin
Optimising PROTACs against integral membrane proteins
No full textIntegral membrane proteins (IMPs) play a critical role in the pathophysiology of a range of diseases. Resistance mechanisms to conventional IMP-targeted therapeutics have driven the need for novel modalities. While PROteolysis TArgeting Chimeras (PROTACs) have shown significant potential for degrading cytosolic proteins, their use in the targeted degradation of IMPs remains challenging due to structural complexity and limited accessibility of IMPs. This thesis explored novel approaches to support the development of IMP-targeted PROTACs. First, potential reasons underlying the complexity of targeting IMPs for PROTAC-mediated degradation were discussed. These included the strong IMP-lipid bilayer interaction and poor understanding of the mechanism of degradation. Next, we addressed current limitations in traditional immunoblotting, which has low throughput and lacks spatial resolution. We proposed an immunofluorescence-based protocol, which provides increased accuracy, a qualitative and quantitative insight into degradation efficacy and a critical distinction between cell membrane-localised and intracellular IMP protein pools. To address the underutilisation of the E3 ligase repertoire, we also developed a ligand-independent E3 ligase recruitment system, integrated with an imaging-based assay, to identify putative E3 ligase candidates. Lastly, we integrated machine learning with proteome-profiling to characterise off target effects of androgen receptor-targeted PROTACs. We demonstrated a link between observed mitochondrial toxicity and the respiratory chain complex I and provided an analytical framework for the proteome-guided rational PROTAC development. Overall, the body of work conducted as part of the PhD thesis provides novel insights into more effective drug development for the targeted degradation of IMPs
Direct oral anticoagulants for atrial fibrillation:On comparing apples and oranges
No full textAtrial fibrillation is the most common sustained cardiac arrhythmia. It increases the risk of thromboembolism, which oral anticoagulants reduce effectively. For decades, vitamin K antagonists were the only class of oral anticoagulants available, but their narrow therapeutic window and need for close monitoring limited their use. Direct oral anticoagulants (DOACs) offered safer, more convenient alternatives, backed by robust phase III trials. This thesis examines key concerns that arose after their approval and widespread use in clinical practice.Part I reviews nonadherence and treatment patterns. Tracing the history of anticoagulant trials, we see how DOACs became the preferred agents. Large cohort studies reveal a clinician preference for factor Xa inhibitors, show that switching and serious nonadherence are relatively uncommon, and identify candidate predictors for both outcomes.Part II focuses on higher-risk patients and off-label dosing. We found sex differences in how clinicians assess frailty using clinical judgment alone. Patients with atrial fibrillation and atherosclerotic disease in routine practice show better cardiovascular health and fewer events than those in original trials — likely due to patient selection, improved care, or tailored treatment. We critique flawed off-label dosing studies and recommend integrating clinical judgment into DOAC dosing decisions for higher-risk individuals. Finally, we show that higher event rates seen with apixaban in daily practice mainly reflect patients’ underlying risk, not off-label dosing.Part III is on drug-level monitoring. We updated DOAC on-therapy ranges to aid interpretation of measured levels, and we found that a single apixaban measurement may help personalize dose selection.<br/
Developing digital health interventions for falls prevention:An innovative user-centered design approach
No full textDigital health interventions are promising for improving the efficiency and quality of care delivery, but their broader adoption remains limited due to design approaches that often do not adequately address user needs. This dissertation aimed to enhance the iterative cycle of User-Centered Design (UCD) and applied this improved cycle for the development of two digital falls prevention interventions for use by health care professionals (HCPs), namely an online multifactorial falls risk assessment tool (i.e., Fall Analysis 2.0) and a medication-related clinical decision support system (i.e., ADFICE_IT CDSS). Chapters 2 and 3 detail the construction of theory-driven personas and journey maps to foster user-focused thinking and guide design and implementation requirements for the Fall Analysis 2.0. Chapter 4 demonstrates how interdisciplinary collaboration supported the development of the ADFICE_IT CDSS. Chapter 5 introduces a novel approach to usability problem prioritization, emphasizing severity based on the problem’s potential negative impact on the secondary (patient) rather than primary (HCP) user experience. In chapter 6, the effectiveness, user experience, and implementation of the Fall Analysis 2.0 is examined in Dutch primary care, revealing that the UCD developed tool positively influenced HCPs falls risk management behavior by facilitating fully completed multifactorial falls risk assessments in older adults at high risk of falling. Together, the findings set new standards for the development and testing of UCD-driven digital health interventions for HCPs, both within and beyond the context of falls prevention. The final chapter discusses the implications of these findings for research and (clinical) practice
Quantitative MRI in pancreatic and liver diseases:From technical optimization to clinical application
No full textQuantitative MRI techniques provide non-invasive biomarkers of tissue properties, with potential to inform personalized treatment strategies. This thesis investigates the optimization, validation, and clinical application of multiple quantitative MRI methods in pancreatic and liver diseases.In pancreatic ductal adenocarcinoma (PDAC), MR elastography (MRE) was optimized and shown to reliably quantify pancreatic stiffness and viscosity, revealing increased values in tumors compared to non-tumorous tissue. Furthermore, dynamic contrast-enhanced MRI (DCE-MRI) acquisition and reconstruction were systematically optimized for abdominal applications. Phantom and in vivo scans demonstrate that tailored protocols enable accurate pharmacokinetic parameter estimation while maintaining image quality. Histopathological validation of quantitative MRI techniques in PDAC revealed that microvascular density correlated with intravoxel-incoherent motion diffusion-weighted (IVIM-DWI) and T2* metrics, while collagen density correlated with T2*, supporting their value as tissue biomarkers.Clinical utility of these techniques in PDAC patients is shown in a multicenter phase I/II clinical trial evaluated combined chemotherapy and LDE225 in metastatic PDAC patients. Quantitative MRI demonstrated treatment-induced increases in diffusion and perfusion parameters, with IVIM-DWI showing prognostic potential for overall survival. Beyond pancreatic cancer, quantitative MRI was applied to metabolic dysfunction-associated steatotic liver disease (MASLD). In a cohort of 91 patients, quantitative MRI parameters, particularly when combined with laboratory markers, differentiated disease activity, fibrosis, and severity stages with strong correlation to histopathology.The findings of this thesis underscore the value of quantitative MRI for characterizing tissue microenvironments in pancreatic and liver diseases. While technical and translational challenges remain, optimized protocols and histopathological validation advance the clinical integration of these techniques
Indulging in Paradise?:EU law and policy of holiday air travel through the lens of practice theory
No full textIn his doctoral thesis Yannick van den Berg researches how EU (consumer) law and policy have failed to reduce emissions from holiday air travel. In his thesis he argues that taking a social practice theoretical approach to holiday air travel can yield valuable insights into EU law and policy on sustainable consumption, in particular by giving new ways to frame problems of sustainability. Instead of focusing on individual choice, behaviour and green technologies, the thesis shows how it can be more fruitful to understand the problem of emissions of holiday air travel as one that requires us to recraft air travel to become more sustainable, substitute air travel by rail travel and finally to see how air travel can become less ‘locked in’ to other practices like holidaying. Taking a practice approach, Van den Berg also sheds a light on the limitations of law (and policy) in addressing unsustainable social practices
Optimizing the treatment for anorectal disease:Surgical and patient-reported outcomes
Full text linkThis thesis focuses on optimizing treatment strategies for two prevalent benign anorectal conditions: hemorrhoidal disease and cryptoglandular perianal fistulas. It emphasizes the importance of integrating surgical outcomes with patient-reported experiences to improve clinical decision-making and personalized care.Part I evaluates the management of hemorrhoidal disease. The HOLLAND trial compared rubber band ligation (RBL) with hemorrhoidectomy for grade III hemorrhoids, revealing that hemorrhoidectomy provided superior long-term symptom relief, improved quality of life, and lower recurrence, though it was associated with higher morbidity and costs. A cost-effectiveness analysis highlighted that its value depends on willingness-to-pay thresholds. Additionally, the thesis critically assessed the Goligher classification, revealing its limitations and advocating for symptom-based alternatives that better reflect disease burden.Part II explores the prevention and treatment of cryptoglandular perianal fistulas. The ATLAS trial investigates the role of postoperative antibiotics in preventing fistula formation following surgical drainage of a perianal abscess. Novel use of 3D high-resolution anorectal manometry (3D-HRAM) was explored, though its clinical utility in predicting continence outcomes after fistula surgery remains inconclusive. Long-term follow-up studies of sphincter-sparing techniques (LIFT and advancement flap) demonstrated high recurrence and continence deterioration, underscoring the need for careful patient selection and informed counseling. A pilot study of the Semiflex catheter showed potential for integration in multimodal strategies, though feasibility targets were not fully met.Altogether, this thesis advocates for patient-centered, evidence-based approaches in anorectal disease management, highlighting the need for standardized outcome measures and pragmatic trial designs to guide future research and clinical practice
Identità e contesti nella committenza del cardinale di Senigallia Marco Vigerio (1505-1516)
Full text linkLa tesi ricerca analizza il contesto di committenza artistica e culturale gravitante attorno alla corte del cardinale Marco Vigerio (1505-1516). Nonostante l'importanza del personaggio, Vigerio ha ricevuto scarsa attenzione storiografica, sia per l'assenza di una tradizione storiografica relativa alla famiglia Vigerio, originaria di Savona, sia per la sua marginalizzazione operata dagli storici della Controriforma, che ne hanno restituito un'immagine scialba e parziale. La ricerca mette radicalmente in discussione questo orientamento critico. Le informazioni recuperate attraverso l’individuazione, lo studio e l’interpretazione delle fonti letterarie e archivistiche mettono a fuoco, in primo luogo, il ruolo di primo piano ricoperto dal cardinale, personalità di spicco, tra Quattro e Cinquecento, dello stretto entourage familiare del pontefice Giulio II, e figura di raccordo tra le reti internazionali dell’ordine francescano e i circoli umanistici e intellettuale italiani ed europei. La tesi prende quindi in esame gli interessi figurativi e la committenza artistica del prelato. Se lo studio dei suoi scritti teologici rivela l’interesse del personaggio rispetto a teorie e pratiche artistiche, l’analisi stilistica, iconografica e sociologica delle opere mette in luce la capacità del cardinale di utilizzare la committenza artistica come veicolo delle proprie istanze religiose e culturali, come mezzo di promozione personale, nonché come strumento funzionale al consolidamento della propria rete di clientela e alla promozione delle strategie propagandistiche del papato. Infine, viene preso in esame il ruolo rivestito da Vigerio nelle strategie artistiche di Giulio II. Il cardinale, impegnato nell’organizzazione della propaganda pontificia e principale promotore del Concilio Lateranense, è coinvolto nel piano di riassetto urbano avviato da Giulio II e nei cantieri artistici e architettonici promossi dal pontefice. Sulla base di questi elementi, la ricerca avanza l’ipotesi che l’insigne teologo francescano sia da riconoscere nell’intellettuale in dialogo con Raffaello per l’elaborazione del programma iconografico dell’affresco raffigurante la Disputa del Sacramento. Elaborato sotto il profilo iconografico alla stregua di un’Apocalisse, il tema teologico della Rivelazione, soggetto dell’affresco vaticano, viene pertanto interpretato alla luce della funzione escatologica assegnatagli dalla teologia francescana. L’iconografia dell’affresco trova in questo modo una sua coerente collocazione all’interno della retorica profetica utilizzata dalla propaganda pontificia