Medicine and Health Sciences

Public defences 2021

Attend a phd defence or find the archive of concluded doctoral research

New insights in the immuno- and molecular biology of soft tissue and bone tumors with therapeutic implications - Vasiliki Siozopoulou (19/10/2021)

Vasiliki Siozopoulou

  • 19 October 2021
  • Time: 5 PM - 7 PM.
  • Public defence
  • Supervisors: prof. P. Pauwels, prof. E. Smits and dr E. Marcq

Exercise training in cardiovascular disease: focus on epigenetics and sex differences - Isabel Witvrouwen (30/09/2021)

Isabel Witvouwen

  • 30 September 2021
  • Time: 3.30 PM - 5.30 PM.
  • PhD defence
  • Supervisors: Prof. H. Heidbuchel and prof. E. Van Craenenbroeck

Tinnitus and temporomandibular disorders. A study on the effectiveness of conservative temporomandibular treatment on tinnitus - Annemarie van der Wal (27/09/2021)

Annemarie van der Wal

  • 27 September 2021
  • Time: 3 PM - 5 PM.
  • Public defence
  • Supervisors: Prof. W. De Hertogh, em.prof. P. Van de Heyning and prof. S. Michiels


Harms and pitfalls of intravenous fluid therapy in the hospital - Niels Van Regenmortel (23/09/2021)

Niels Van Regenmortel

  • 23 September 2021
  • Time: 5 PM - 7 PM.
  • Public defence CDE aula O8
  • Supervisors: Prof. P. Jorens and prof. T. Van den Wyngaert


Pain science education after breast cancer surgery - Elien Van der Gucht (22/09/2021)

Elien Van der Gucht

  • 22 September 2021
  • Time: 6 PM - 8 PM.
  • Joint PhD defence
  • Supervisors: Prof. N. Devoogdt, prof M. Meeus and prof. A. De Groef

Abstract

The Belgian Cancer Registry reported 10,905 new female breast cancer patients in 2018. Although successful screening, early intervention and enhanced treatment options have improved breast cancer survival, 90% of survivors suffer lifelong sequelae, which substantially impair daily life functioning and quality of life. One of the most frequently reported side effects of breast cancer treatments is pain, possibly affecting all aspects of functioning, including physical activity, upper limb use and return to work. As a result, adequate pain management during the early stages of breast cancer treatment is essential for resolving and preventing these issues, both in the short and long term.

Over the last few decades, there has been a greater understanding of the important role of educational interventions in the management of pain. However, they mainly focus on tissue injury as the source of pain and are often restricted to biomedical pain management instructions. Only recently, increased knowledge on pain mechanisms has resulted in a more modern educational approach, also known as pain science education (PSE). During the sessions, the patient is explained that pain is not always a true representation of the actual state of the tissues, but that it is the brain’s interpretation of the threat of the injury, which is influenced by a variety of psychosocial factors. By zooming out of the purely biomedical vision on pain, PSE aims for a reconceptualization from a biomedical or structural model to an actual biopsychosocial one. Patients who understand that tissue damage is not the only cause of pain, but that stress, sleep, social interactions and physical activity, among other things, can all influence the pain experience, may be more likely to engage in activities they previously avoided due to pain. This, in turn, may lead to improved functioning.

The existing evidence for the potential benefits of PSE in non-cancer pain populations, along with the lack in methodologically strong studies in breast cancer patients, led us to the main research objective of this PhD research project, which was to investigate the effectiveness of PSE in improving functioning after breast cancer surgery.

In conclusion, this work provides deeper insights into the follow-up of pain-related disability after breast cancer surgery, as well as the clinical application of PSE in this population and recommendations for further research. At first glance, our findings suggest that PSE does not ensure more favorable outcomes compared to biomedical pain education. However, several concerns were raised about the PSE intervention’s cookie-cutter approach, leading to the conclusion that the question should not be whether educational interventions are necessary, but rather how the delivery method, timing and other factors could be refined to achieve a change in behavior and, as a result, improved functioning. The complexity of educational interventions combined with a health care system that is entirely biomedical in nature will require years of efforts to optimize these interventions through a variety of mechanisms.

Cardiovascular disease prevention in Mukono and Buikwe districts in Uganda: evidence to implementation - Rawlance Ndejjo (22/09/2021)

Rawlance Ndejjo

  • 22 September 2021
  • Time: 3:30 PM - 5:30 PM.
  • Public defence
  • Supervisors: Prof. H. Bastiaens, dr. G. Musinguzi and Prof. R. Wanyenze

Abstract

Cardiovascular disease (CVD), the number one cause of death globally, disproportionately affects low- and middle- income countries (LMICs) creating a new burden for their unprepared health systems amidst resource constraints. Community-wide interventions targeting CVD risk factors can support CVD prevention and control efforts in LMICs. However, there is need for more evidence on the effectiveness of community-based interventions for CVD prevention and an exploration of their implementation processes in real-world settings.

The objectives of this research were to synthesise evidence and examine the implementation process of a community CVD prevention programme in Mukono and Buikwe districts in Uganda to inform scale-up in a low-income context. We employed a mixed methods study design to answer the research questions. Besides a systematic review that was conducted to synthesise evidence on effectiveness of community-based interventions for CVD prevention among adults in LMICs, the remaining objectives were answered using primary data collected in Mukono and Buikwe districts in Uganda using quantitative and qualitative approaches.

Results from the systematic review revealed that community-based interventions successfully improved population knowledge on CVD and risk factors and influenced physical activity and dietary practices for CVD prevention. However, evidence was inconsistent for smoking cessation and reduced alcohol consumption. The most effective interventions involved health education, community mobilisation and lifestyle counselling (Paper I). To inform the community CVD prevention programme, we collected baseline data from 4372 respondents and found that only 776 (17.7%) were knowledgeable on CVD prevention with several associated factors (Paper II). Mapping of the prevalence of selected CVD risk factors using the baseline data indicated substantial gender and small area geographic heterogeneity which was masked on aggregate analysis (Paper III). Evidence on effective interventions together with gaps identified in knowledge and CVD risk practices informed the design of our intervention which was acceptable to both CHWs and community members (Paper IV). The barriers of implementation included complexity, low CVD knowledge and CHW competing demands. The facilitators were availability of inputs and protective equipment, being trained, frequent support supervision (Paper V). Following implementation, we found variations in uptake of healthy lifestyle practices for CVD prevention with most changes reported for dietary behaviour and physical activity than alcohol consumption, smoking behaviours, and stress reduction like our review findings (Paper VI).

Evidence-based, acceptable, and well-designed community-based interventions led by community health workers can support uptake of healthy lifestyles that are key for CVD prevention. These interventions hold promise for LMICs to deal with CVD.

A Contact-Based Modelling Framework For Contagious Disease Dynamics - Andrea Torneri (21/09/2021)

Andrea Torneri

  • 21 September 2021
  • Time: 3:30 PM - 5:30 PM.
  • Online defence
  • Supervisor: Prof. N. Hens

Delay in toilet training in healthy toddlers: investigating possible influencing factors and implementing a new toilet training method - Tinne Van Aggelpoel (09/09/2021)

Tinne Van Aggelpoel

  • 9 September 2021
  • Time: 3 PM - 5 PM.
  • Online defence
  • Supervisors: Prof. A. Vermandel and Prof. S. De Wachter

Abstract

TT is a universal issue for children and one of the most important first steps toward independence. Researchers emphasize the importance of starting TT at the moment the child is ready and shows certain developmental skills and characteristics. But at the same time, parents tend to initiate TT at a later age, leading to a delayed acquisition of volitional bladder and bowel control. Delay in TT can lead to several disadvantageous consequences, both for the child and for their environment.The main objectives of this thesis were to address four factors contributing to the postponement of TT: 1. parents’ perception; 2. diverse information; 3. stool problems ; and 4. time.In chapter 2 the perception of 832 parents on TT was investigated by means of a questionnaire. 50% of parents initiated TT because the child would soon be attending school and parents seem to rely on external factors to start training, rather than taking into account the maturity or readiness of the child, although the latter group ended toilet training significantly sooner.Chapter 3 highlighted the diverse information on TT that is available nowadays and the insecurity of parents on how and when to initiate TT. Six focus group discussions (FGD), involving 37 participants, were used to explore parents' experiences on TT. The findings of this qualitative study show that reputable agencies, family, friends, daycare workers and nursery school64teachers were considered trustworthy sources. TT information should be easily understandable and not contain scientific terms. A colourful and illustrated brochure sent by regular mail seems to be preferred.A prospective, observational study was performed in Chapter 4 to explore the occurrence of postprandial defecation in 40 healthy infants not yet toilet trained. We observed a bowel movement within the first hour after a meal in 75% of the children. Of them, 37% would defecate within 15 minutes and 72% within half an hour. Fifty-nine percent of all children defecated in the morning, 54% at noon and 28% in the evening.We believe the implementation of the gastrocolic reflex in TT, as scheduled toilet seats 15–30 minutes after a meal, might help a child in his learning process to defecate on the potty.In Chapter 5 we addressed the problems of the growing population of children in daycare that needed to be toilet trained and parents that are insecure about the right timing and manner or lack initiative and time to start TT. In a prospective clustered randomized controlled trial 55 children in total (16 boys and 39 girls) were trained: 27 children in 11 different daycares in the intervention group and 28 in 11 other daycares in the control group. Innovative aspects of this toilet training method were a 2-hour intensive training on two consecutive days, carried out in small groups in daycare centres.The intervention had a significant influence on the duration of toilet training in healthy children, with a median duration of 2 weeks, compared to 5 weeks in control groups. The hazard of being clean during the following 6 weeks was twice as high in the intervention group compared to control groups.Education of parents and daycare workers on the assessment of the child’s readiness and evidence based guidelines for conducting TT could be the first steps in tackling the postponement of TT in healthy children.

Analysis of blood and urine nucleic acids: the value of liquid biopsy to improve diagnosis, follow-up and monitoring of treatment response of lung cancer and pancreatic cancer patients - Elien Augustus (31/08/2021)

Elien Augustus

  • 31 August 2021
  • Time: 5:15 PM - 7:15 PM.
  • Public defence
  • Supervisors: Prof. P. Pauwels, prof. M. Peeters and prof. G. Roeyen

Abstract

In order to provide cancer patients with a personalized treatment, molecular understanding of the tumor is indispensable. Today, tissue biopsies are often used to characterize the tumor. However, tissue biopsies face some limitations. Circulating cell-free DNA (cfDNA) in liquid biopsies might overcome these issues. Analyzing cfDNA is a cost-effective, minimal invasive technique that enables repetitive sampling and gives real-time information on the tumor characteristics The first objective of this thesis was to establish some standardized guidelines on the use of urine samples for cfDNA analysis in the management of cancer patients. We collected urine samples from 39 healthy volunteers and 14 cancer patients. Based on our results, we advise to: (i) isolate cfDNA from the whole urine sample; (ii) store fresh urine samples at 4°C and centrifuge them with a two-step centrifugation protocol as soon as possible after sample collection; (iii) supplement urine samples with a preservative in case the samples cannot be processed immediately after collection, store these samples at room temperature and centrifuge them with a short one-step centrifugation protocol at high speed. The second objective was to investigate the prognostic value of cfDNA in 10 non-small cell lung cancer (NSCLC) patients receiving immunotherapy. We found that NSCLC patients without detectable levels mutated cfDNA in their liquid biopsy samples, had a better clinical outcome compared to patients with detectable levels. We also compared the performance of next-generation sequencing (NGS) for genomic alterations in tissue samples with liquid biopsy samples. We were able to detect gene amplifications in the blood-derived cfDNA of the included NSCLC patients. Furthermore, we identified a resistance mechanism against alectinib in a blood sample of one NSCLC patient. The third objective was to study the role of liquid biopsy for the follow-up of PDAC patients. We studied the cfDNA derived from matched plasma and urine samples of 47 pancreatic ductal adenocarcinoma (PDAC) patients who underwent surgery and 26 metastatic PDAC patients. According to our results, plasma might be a more suitable body fluid than urine when evaluating the levels cfDNA to monitor PDAC patients. Secondly, our data show that the sensitivity of a liquid biopsy test can be increased by combining multiple tumor markers. We also found that cfDNA analysis enables the detection of disease progression in patients whose total tumor volume (primary tumor and metastases) increases. However, the detection of small primary tumors or new metastases can be challenging when using liquid biopsy.


New Insights in the Vitreolenticular Interface of Pediatric Cataracts - Jan Van Looveren (09/07/2021)

Jan Van Looveren

  • 9 July 2021
  • Time: 5 PM - 7 PM.
  • PhD defence
  • Supervisors: Prof. C. Koppen and Em. Prof. MJ. Tassignon

Abstract

Despite tremendous efforts in recent years to increase the understanding of pediatric cataract formation and to refine its surgical approach, pediatric cataract is still the number one cause of childhood blindness and is in many cases still classified to be of unknown origin. When operating pediatric cataracts using the bag-in-the-lens implantation technique the presence of an abnormal Berger’s space was observed with adhesions between the posterior lens capsule and the anterior hyaloid membrane in many of these idiopathic cases. The anomaly of Berger’s space in these pediatric cataracts was defined as anterior vitreolenticular interface dysgenesis (AVLID). A strong correlation was found between AVLID and unilateral cataract and when confronted with a posterior capsular plaque after lens removal. Based on the proteins found in these plaques they are speculated to be the result of an epithelial-mesenchymal transformation. Congenital cataracts associated with AVLID are more challenging to cataract surgeons.  Intraoperative optical coherence tomography of the lens proved to be a supplementary and objective tool for early AVLID detection and to anticipate surgical difficulties. Increasing knowledge on AVLID will help to find the best surgical approach in these peculiar pediatric cataracts and maybe one day prevent them to occur.

Collaboration with a practice nurse in Belgian general practice. Current and potential roles of practice nurses - Evi Matthys (08/07/2021)

Evi Matthys

  • 8 July 2021
  • Time: 5 PM - 7 PM.
  • Online defence
  • Supervisors: Prof. P. Van Bogaert and prof. R. Remmen

Abstract

Een vergrijzende populatie, met een stijging van het aantal niet-overdraagbare aandoeningen, heeft geleid tot een toename van de complexe zorgnoden in de eerste lijn in Vlaanderen. Om tegemoet te kunnen komen aan de veranderende zorgnoden, is er nood aan meer beschikbare zorgverleners, maar ook aan een meer geïntegreerd zorgaanbod. Gezond ouder worden kan immers enkel gerealiseerd worden wanneer ook preventie, gezondheidspromotie, educatie en welzijn deel uitmaken van zorgverlening.

De integratie van praktijkverpleegkundigen in de Vlaamse huisartsenpraktijken kan bijdragen aan het tegemoetkomen van bestaande zorgnoden. De multiprofessionele samenwerking tussen huisartsen en praktijkverpleegkundigen wordt geassocieerd met tal van verbeterde patiëntenuitkomsten, in het bijzonder bij patiënten gediagnosticeerd met een chronische aandoening. Daarnaast wordt de samenwerking zowel door patiënten, als door huisartsen en praktijkverpleegkundigen als positief ervaren.

De voornaamste barrières ten aanzien van de integratie van een praktijkverpleegkundige in de huisartsenpraktijk zijn het huidige betalingssysteem, het onduidelijke profiel en het onduidelijk ethisch kader van praktijkverpleegkundigen. Wanneer huisartsen een samenwerking initiëren, wordt deze keuze voornamelijk gemotiveerd door de ervaren behoefte om meer kwalitatieve zorg te kunnen verlenen. Momenteel zijn het de early adopters die een geïntegreerde samenwerking met een praktijkverpleegkundige realiseren.

Praktijkverpleegkundigen nemen een breed takenpakket op in de huisartsenpraktijken, waarbij de taken zich situeren binnen zeven domeinen. Verpleegtechnische zorgen, administratieve taken, preventietaken, chronische zorgen, evidence-based praktijkvoering, coördinerende taken en welzijnszorg. Het belang van een postgraduaatopleiding voor praktijkverpleegkundigen en van zorgprotocollen in de huisartsenpraktijk, om een geïntegreerde samenwerking te kunnen realiseren, wordt door zowel praktijkverpleegkundigen als huisartsen erkend.

Aanbevelingen ten aanzien van huisartsenpraktijken, huisartsen en praktijkverpleegkundigen, maar ook ten aanzien van onderwijs en beleidsmakers, worden gedaan. Dit om de verdere integratie van praktijkverpleegkundigen in de Vlaamse huisartsenpraktijken mogelijk te maken, en bijgevolg om tegemoet te kunnen komen aan de veranderende zorgnoden van de eerstelijnspopulatie.

Helicobacter suis: further characterization of the agent and its possible impact on the course of Parkinson's disease - Helena Berlamont (06/07/2021)

Helena Berlamont

  • 6 July 2021
  • Time: 4 PM - 6 PM.
  • Online joint PhD defence
  • Supervisors: Prof. F. Haesebrouck (UGent), Prof. R. Vandenbroucke (UGent) and Prof. A. Smet (UAntwerpen)

Abstract

Non-Helicobacter pylori Helicobacter (NHPH) species naturally colonize the stomach of animals, but some of them can also infect the human stomach. The most prevalent NHPH species in the human stomach is Helicobacter suis (H. suis), which naturally colonizes the stomach of pigs and non-human primates. Transmission of H. suis from pigs to humans might occur through direct or indirect contact or through the food chain. NHPH infections have been associated with gastritis, gastric and duodenal ulcers, and MALT lymphoma in humans.

We first investigated the potential virulence factors of H. suis and H. heilmannii (another zoonotically important cat-/dog-associated NHPH) playing a role in the adherence to the human gastric mucosa. Using RNA sequencing, we identified bacterial genes that are differentially expressed in a H. suis (HS1) and H. heilmannii (ASB1) strain when adhered to the human gastric epithelial cell line MKN7 in comparison to non-adhered H. suis and H. heilmannii bacteria. Our study suggests that the porcine H. suis strain HS1 and the feline H. heilmannii strain ASB1 use distinct pathways when adhering to human gastric epithelial cells.

Mounting evidence suggests a potential role of H. suis in Parkinson’s disease (PD). To investigate this further, a 6-hydroxydopamine (6-OHDA) PD mouse model was used. Two animal experiments with H. suis-infected mice (acute and chronic H. suis infection) were performed whereby 6-OHDA was stereotactically injected in the left brain striatum 1 week prior to euthanasia. Remarkably, a lower % loss of dopaminergic neurons was seen in the H. suis–6-OHDA groups compared to the control–6-OHDA groups. This potential protective effect of H. suis against 6-OHDA-induced toxicity needs further elucidation.

Diagnosis of NHPH infections is difficult and most techniques used for H. pylori diagnosis lack sensitivity and/or are not able to discriminate between different gastric Helicobacter species. Therefore, we investigated whether MALDI-TOF MS might constitute a potential tool for future diagnosis of NHPH infections. While our study showed that MALDI-TOF MS allows rapid differentiation between gastric Helicobacter species, further research to enable its use in clinical practice is needed.

To improve treatment strategies of H. suis infections in humans, we determined the in vitro susceptibility of 35 H. suis isolates (i.e. 20 porcine isolates and 15 non-human primate isolates) to 15 antibiotics. Our study indicates that acquired resistance occasionally occurs in H. suis isolates and that porcine isolates may be intrinsically less susceptible to aminopenicillins and tetracyclines than primate isolates.

Building a European laboratory network to combat bacterial resistance by boosting the clinical development of anti-infectives - Tomislav Kostyanev (01/07/2021)

Tomislav Kostyanev 

  • 1 July 2021
  • Time: 4 PM - 6 PM.
  • Online defence
  • Supervisor: Prof. H. Goossens


Effects of Constraint Induced Movement Therapy on Outcomes after Stroke - Auwal Abdullahi ( 29/06/2021)

Auwal Abdullahi

  • 29 June 2021
  • Time: 5 PM - 7 PM.
  • Online defence
  • Supervisors: Prof. W. Saeys and prof. S. Truijen

Towards patient-tailored treatment in multiple sclerosis: a dendritic cell-based vaccine for the treatment of multiple sclerosis - Barbara Willekens (25/06/2021)

Barbara Willekens

  • 25 June 2021
  • Time: 5 PM - 7 PM.
  • Online defence
  • Supervisors: Prof. P. Cras and prof. N. Cools

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) in which an autoimmune T cell response towards myelin peptides plays an important role. Despite the availability of more than ten approved drugs for the treatment of MS, there still is a significant unmet need for novel therapeutic approaches. The holy grail is to find a treatment that leads to restoration of immune tolerance towards myelin peptides while leaving other immune effector functions intact. Dendritic cells (DC) are potent antigen-presenting cells and function as gatekeepers of the immune system, directing both T cell immunity and tolerance. Previously, we have demonstrated that dendritic cells of MS patients are in a hyperactivated state and show increased migratory capacity towards the CNS. Furthermore, we have developed antigen-specific tolerogenic dendritic cells, that have the capacity to downregulate autoreactive myelin-specific T cell responses in vitro and in vivo in an EAE-model. In a systematic review and meta-analysis on tolerance inducing cell-based therapies in autoimmune diseases, including MS, neuromyelitis optica, rheumatoid arthritis, Crohn’s disease, diabetes type I and organ transplantation, we demonstrated that tolerogenic dendritic cells, mesenchymal stem cells and regulatory T-cells are safe in the short term.
We aimed to demonstrate that tolerogenic cell-based therapy is safe and feasible in a first-in-man study in active MS patients. Hence, a harmonized study protocol of two dose-escalation phase I clinical trials, aiming to compare two ways of administration of tolDC (intradermal and intranodal) was designed. In this thesis, the interim results of the phase I clinical trial to assess safety and feasibility of intradermal tolDC administration in Antwerp, Belgium are discussed.  The baseline and follow-up data of the first two dose cohorts, receiving 5 and 10 million tolDC per injection, show that it is safe and feasible to administer tolDC in active MS patients. The third dose cohort, receiving 15 million tolDC per injection is ongoing.
Furthermore, we took the first steps into development of a biomarker for measuring efficacy of myelin-specific T cell responses in MS patients. A longitudinal study in which interferon-gamma EliSPOT was used to measure myelin-specific T-cell reactivity in the peripheral blood of stable MS patients demonstrates that myelin specific T cell responses show intra- and interindividual variation over time.  This PhD thesis describes the first steps in the clinical translation and development of a tolerance-inducing dendritic cell-based treatment in MS, paving the way towards a phase II clinical trial.


Cultured human mast cells: application in immediate drug hypersensitivity - Jessy Elst (23/06/2021)

Jessy Elst

  • 23 June 2021
  • Time: 5 PM - 7 PM.
  • Online PhD defence
  • Supervisors: Prof. D. Ebo, prof. V. Sabato and prof. M. Hagendorens

An investigation of the prevalence of Oral and Oropharyngeal Human Papillomavirus in selected South African population groups and tissue specimens - Neil Wood (22/06/2021)

Neil Wood

  • 22 June 2021
  • Time: 5 PM - 7 PM.
  • Online joint PhD defence with Sefako Makgatho Health Sciences University
  • Supervisors: Prof. R. Lebelo, Prof. S. Boy, Prof. JP. Bogers and Prof. O. Vanderveken 

Genotype-Phenotype correlation study in p.Pro51Ser variant carriers in COCH causing DFNA9 - Sebastien Janssens de Varebeke (18/06/2021)

Sebastien Janssens de Varebeke

  • 18 June 2021
  • Time: 5 PM - 7 PM.
  • Online defence
  • Supervisors: Prof. V. Van Rompaey and prof. G. Van Camp

Abstract

DFNA9 is an autosomal dominant hereditary hearing disorder associated with vestibular deterioration with a late onset of symptoms. Many variants in COCH have been identified, however, the c.151C>T, p.Pro51Ser is highly prevalent in the Low Countries. The clinical characteristics of this condition were based on genetic linkage studies of some 15 years ago. However, nowadays, new clinical vestibular tools permit more detailed observation of the progression of the vestibular deterioration at different compartments and at different frequency range of the vestibular organ. Since the last several years, tremendous efforts are being displayed to develop new therapeutic options, such as vestibular implants and genetic therapy, for which a better knowledge of the natural course of DFNA9 has become essential to define the most optimal therapeutic window. A prospective multi-centric cross-sectional study, conducted in Antwerp and Hasselt, including 111 Belgian & Dutch p.Pro51Ser variant carriers, showed the following results: 1) the hearing thresholds at 8 kHz were already beyond age-referenced limits in the youngest age group (18-25 years), 2) this was followed by the decline of caloric response (35 years on average) and C-VEMPs (31 years). 3) The hearing frequencies higher than 2 kHz all started to deteriorate at about 34-38 years of age, whereas the lower frequencies started their decline ten years later. 4) The vestibulo-ocular reflexgains, which are obtained with high angular acceleration video head impulse test (vHIT), were the last to deteriorate (end of 4th & early 5th decade). Imaging of DFNA9 patients showed typical features like focal sclerosis or T2-weighted signal loss in semicircular canals (SCC) of p.Pro51Ser carriers that had reached advanced stages of oto-vestibular deterioration. These lesions seemed to correlate with lower caloric and vHIT function. These findings suggest an (auto)immune reaction as a result of accumulation of misfolded mutant cochlin in the inner ear and ampullae of the SCC, with fibrosis and late-onset calcification. Until 2018, all known COCH variants had autosomal dominant trait, however, we identified a new COCH variant with an autosomal recessive trait, causing congenital hearing loss (DFNB110). Since adult heterozygous carriers in that family all showed normal hearing and balance function, this suggests haploinsufficiency is not the cause of hearing disorder, but rather the dominant negative trait of these new variants. These new insights are useful in future research for new treatment options in DFNA9 patients.

Breaching the barrier - Targeting dendritic cell migration in the treatment of multiple sclerosis - Maxime De Laere (11/06/2021)

Maxime De Laere

  • 11 June 2021
  • Time: 4 PM - 6 PM.
  • Online defence
  • Supervisors: Prof. Z. Berneman and prof. N. Cools

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). It has been shown that the accumulation of dendritic cells (DC) in the CNS is a rate-limiting factor for neuroinflammation in both early stages as well as during established disease. Indeed, the presence and number of DC in the inflamed CNS correlates with disease severity. The presence of tolerogenic (tol)DC in the CNS, on the other hand, has been shown to downmodulate ongoing inflammation in experimental animal models.

Different routes of entry exist for DC to reach the CNS, but most of the DC-inherent molecular pathways and mechanisms underlying their migration to the inflamed CNS remain elusive. In this thesis, we aimed to elucidate the molecular mechanisms underlying DC trafficking across the blood-brain barrier (BBB) in the context of MS pathogenesis, in view of identifying targets and approaches to modulate DC migration, either by interfering with inflammatory DC trafficking or by enhancing tolDC homing to the inflamed CNS.

Using an in vitro BBB model, we studied gene expression patterns of migrating and non-migrating DC from relapsing-remitting MS patients, progressive MS patients, and healthy controls. We identified a transcriptional program driven by the transcription factor EGR-1, which could be the driving force behind the elevated chemokine-induced migration observed in MS-derived DC. Moreover, a series of proinflammatory genes with elevated expression in MS-derived migrating DC were identified, providing increased insight into how these cells contribute to local inflammatory processes within the CNS. Compared to DC of healthy controls, migrating DC of untreated MS patients are characterized by the expression of genes driving inflammatory responses, including several genes which have been shown to be associated with a Type 1 and Type 17 T helper cell bias when activated in DC. Remarkably, expression of specific anti-inflammatory markers was also found to be upregulated in MS-derived DC, pointing towards the existence of a delicate immunomodulatory balance in DC functioning and/or between DC subsets in MS.

Next, we investigated the CCR5-driven inflammatory migratory capacity of in vitro generated Vitamin D3-stimulated tolDC, which proved to be minimal. This limitation could be overcome by inducing de novo CCR5 expression by means of mRNA electroporation. Importantly, the tolerogenic phenotype and function of tolDC was not impacted by mRNA electroporation. These data provide proof-of-concept for the possibility of generating so-called ‘designer’ tolDC, i.e. tolDC in which specific properties have been introduced artificially to increase their clinical potential.

Revisional and future techniques in bariatric surgery - Ben Gys (02/06/2021)

Ben Gys

  • 2 June 2021
  • Time: 5.15 PM - 7.15 PM.
  • Online defence
  • Supervisors: Prof. G. Hubens and prof. N. Komen

Abstract

Bariatrische chirurgie evolueert snel en is sterk aanwezig in de huidige chirurgische praktijk. Niet alleen door de complexe procedures, maar ook door de noodzaak van zeer intensieve preoperatieve patiëntenscreening en postoperatieve follow-up, is het één van de meest uitdagende niches binnen de abdominale chirurgie geworden.

De nood aan revisionele chirurgie is altijd aanwezig geweest vanwege complicaties op korte of lange termijn. Het omgaan met deze complicaties is een grote uitdaging en moet in een multidisciplinaire setting worden georganiseerd. Historische kennis van bariatrische technieken is van het allergrootste belang, evenals een patiëntgerichte aanpak bij de keuze voor de juiste revisionele procedure. Keuzes moeten met de patiënt worden besproken in meerdere consultaties om aan de verwachtingen tegemoet te komen.

Toekomstige technieken in bariatrische heelkunde zijn ontwikkeld in de laparoscopie (zoals hechtdraden met weerhaakjes) en endoscopie (zoals NOTES). Op dit moment worden veel open en laparoscopische technieken uit het verleden endoscopisch nagebootst (LAGB en TERIS, VBG en TOGa®, LGCP en ESG / POSE™, RYGB en endoluminele bypass / mucosale resurfacing, BDP-DS / JIB en IMAS / IAS). Sommigen van deze technieken zijn echter om verschillende redenen reeds lang geleden verlaten.

De beste manier om toekomstige technieken in te schatten, is door terug te kijken naar het verleden en kennis op te doen over de motieven waarom soortgelijke interventies zijn mislukt.

Toekomstig onderzoek naar de niet-conservatieve behandeling van morbide obesitas, inclusief de noodzaak voor revisionele chirurgie, moet worden uitgevoerd door middel van studies die zijn gebaseerd op de piramide van wetenschappelijk bewijs.

Tijdens de voorbereiding van dit proefschrift werd een overvloed aan laagkwalitatieve publicaties waargenomen. Er is dringend behoefte aan RCTs en meta-analyses om de indicatie en plaats van toekomstige (en revisionele) bariatrische technieken in de huidige praktijk te bepalen. De behoefte aan onderzoek is van het allergrootste belang omdat dit zal leiden tot de ontwikkeling van officiële en reproduceerbare richtlijnen die op het moment van schrijven ontbreken.

Peer Distribution of HIV Self-Test Kits to Men having Sex with Men in Uganda - Stephen Okoboi (26/05/2021)

Okoboi Stephen

  • 26 May 2021
  • Time: 4 PM - 6 PM.
  • Online defence
  • Supervisors: Prof. JP. Van geertruyden and dr. B. Castelnuovo

Abstract

Key populations defined as groups, which, due to specific high-risk behaviors, are at increased risk of HIV, irrespective of the epidemic type or local context.  Furthermore, in 2018, key populations and their sexual partners accounted for 54% of new HIV infections globally, and 25% of new HIV infections in Eastern and Southern Africa. They often have healthcare stigma and discrimination due to their behaviors that increase their vulnerability to HIV infection. Globally, the risk of HIV acquisition is 23 times higher among men who have sex with men (MSM) than heterosexual men. In 2012, HIV prevalence among MSM (13.2%) in Uganda was twice that of heterosexual men (6.4%). A mathematical model suggests that the biggest reductions in HIV incidence in Sub-Saharan Africa (SSA) will occur with increased coverage of HIV testing, linkage of newly diagnosed persons to antiretroviral therapy, and sustained viral suppression among people with HIV. HIV testing uptake is sub-optimal (55%) among MSM in Uganda, a setting where same sex behavior is criminalized. The Uganda Anti-Homosexuality Act was passed by parliament in 2014, but was subsequently overturned by the Constitutional Court. However, cultural and healthcare stigma and discrimination still hamper the scale up of HIV services for MSM, despite the fact that the Uganda Ministry of Health prohibits discrimination of MSM during healthcare delivery.

HIV self-testing (HIVST), a process by which a person performs an HIV test on himself or herself to know their HIV sero-status, is an accessible evidence-based self-controlled tool that can empower MSM to overcome healthcare stigma and discrimination, and increase access to HIV testing.  Peer delivered HIV self-testing through MSM networks could be synergistic to existing HIV prevention programs in a high-burden population unconnected to conventional health systems. A peer is defined as a non-clinically trained person with similar background characteristics to the beneficiary population. The World Health Organization (WHO) recommends peer approaches to improve the uptake of HIV testing - the entry point to HIV care and timely linkage to care after testing. Combining HIVST with peer network delivery offers a unique opportunity to reach MSM with user-friendly technology in their community. However, these strategies have not been combined to extend the reach of HIV testing services into African MSM social and sexual networks, and no study has estimated the cost and cost-effectiveness of peer delivery of HIVST kits in Sub-Saharan Africa.

In this thesis, we examine:

·        acceptability of HIVST among MSM and health care workers,

·        preliminary effectiveness of the MSM peer HIVST kit distribution in identifying undiagnosed HIV infection compared with standard of care HIV testing,

·        the cost and cost-effectiveness of the peer HIVST kit distribution compared to standard of care HIV testing among MSM.

We used:

·        a qualitative design to assess acceptability of HIVST,

·        a non-randomized study to evaluate the preliminary effectiveness of peer distribution regarding the HIV self-testing (HIVST) kits compared with standard of care in identifying undiagnosed HIV infection, and

·        the provider perspective to estimate cost and cost-effectiveness of the peer distribution of the HIV self-testing (HIVST) kit compared with the standard of care in identifying undiagnosed HIV infection at The AIDS Support Organization (TASO) centers in Entebbe and Masaka.

Key results

We observed that peer-delivered HIV self-testing in MSM networks was highly acceptable. MSM participants further described HIV self-testing as a mechanism that would facilitate the uptake of HIV testing in a rapid, efficient, confidential, non-painful, and non-stigmatizing manner. MSM participants were also willing to distribute HIV self-test kits to their sexual and social networks. Health care workers were supportive of HIV self-test kit distribution through MSM peers.

Out of 297 participants included in the non-randomized study, 150 received HIVST (intervention) and 143 received standard of care HIV testing within three months. We observed that 95% of the MSM completed HIVST, of which 32% had never tested for HIV, while 100% completed SOC testing. A total of 12 participants were diagnosed with HIV: eight in the intervention arm, and four in the SOC group [5.6% versus 2.7%, respectively; P=0.02]. All participants newly diagnosed using HIVST received confirmatory HIV testing and were linked to care by the peers, who provided pre and post- test HIV counselling.

The provider cost for the MSM peer distribution strategy (intervention arm) was $2,276 compared with $1,827 for SOC in the three-month study period. Overall, the MSM peer strategy resulted in higher HIV positivity yield (4.9% vs. 1.4%) and averted more HIV infections per year (0.364 vs. 0.104) compared with SOC. The cost per person tested was higher for the MSM peer strategy compared to SOC ($15.90 vs $12.40). Importantly, the cost per new HIV diagnosis ($324 vs. $914) and cost per transmission averted ($6,253 vs. $17,567) were lower for the peer distribution approach relative to SOC. The incremental cost per HIV transmission averted by the self-testing program was $1,727. The incremental cost to providers per additional HIV-positive person identified by the intervention was $112.3.

Conclusions

The distribution of HIVST kits by MSM peers is an acceptable strategy that can promote access and uptake to HIV testing. HIVST was perceived by participants as beneficial: it would address many barriers that affect their acceptance of HIV testing such as healthcare stigma. However, a combined approach that includes peer support for confirmatory HIV testing and immediate, linkage to HIV treatment, and prevention services is needed for effective epidemic control. Peer distribution of HIVST through MSM networks is feasible, effective, diagnoses more new HIV infections than SOC approach.

Using a costeffectiveness threshold set at US $2,129.10, peer distribution of HIVST kits was cost-effective, averted more HIV transmissions and identified more undiagnosed HIV infections than SOC hotspot testing. Peer HIVST distribution programs should be scaled up among hard to reach populations, with the aim of diagnosing 95% of all persons with HIV by 2030 (UNAIDS first 95 -95-95 target).

Indirect allorecognition: the quest to monitor chronic allograft rejection - Eytan Breman (12/05/2021)

Eytan Breman

  • 12 May 2021
  • Time: 5 PM - 7 PM.
  • Online defence
  • Supervisors: Prof. D. Abramowicz and em.prof. F. Claas

Abstract

T-cell mediated rejection and especially chronic rejection, is a major risk for the survival of transplanted organs. Recognition of donor antigens can occur through three separate pathways: The direct pathway of allorecognition - recognition of non-self HLA (class I or II) and/or a peptide in the context of non-self HLA on donor Antigen presenting cell (APCs). This direct pathway of allorecognition has an important role in the phase after transplantation. As time progresses donor APCs will be depleted by either apoptosis or necrosis and donor antigens will be taken up by the recipient APCs where they will be processed and presented to CD4 T-cells in the context of self HLA-II. This indirect pathway of allorecognition has been shown to be correlated with chronic rejection. The third pathway (semi-direct) is not well understood but involves the recognition of non-self HLA on recipient APCs.

In this thesis, we have assessed methods to measure indirect alloreactive T-cells and investigated the optimal routes of alloantigen processing and presentation by different APCs. We discovered that using cellular material as alloantigens leads largely to recognition through the semi-direct pathway of allorecognition and not indirect allorecognition when using monocytes and dendritic cells (DCs) as APCs. Indirect allorecognition was achieved in all APCs assessed when proteins or long synthetic peptides were used. Interestingly, even plasmacytoid DCs could induce indirect allorecognition upon specific secondary signals of stimulation. Utilizing the optimized conditions, we measured the contribution of indirect allorecogtive T-cells in a patient cohort of renal transplant recipients. The results suggested the activation of T-cells under certain patients, but as no alloantibodies could be detected in the patients they could not be validated. Therefore, a second retrospective study was conducted in a cohort of women that have delivered children and developed alloantibodies against the children. Unfortunately the material was of tool quality and quantity to allow for a proper analysis of indirect alloreactive T-cells, and was inconclusive.
In conclusion, methods have been developed to allow for the assessment of indirect alloreactive T-cells in a clinical setting although validation is still required, and additional technological features can be included to allow for a more through characterization of indirect alloreactive T-cells.

Advances in keratoconus care - Elke Kreps (12/05/2021)

Elke Kreps

  • 12 May 2021
  • Time: 5 PM
  • Online defence
  • Supervisors: Prof. C. Koppen, Prof I. Claerhout (UGent) and prof. B. Leroy (UGent)

Abstract

The cornea is the dome-shaped ‘window’ located at the very front of the eye that helps to focus light rays on the retina. In keratoconus, the normal regular shape of the cornea is progressively lost: the cornea thins, steepens and takes on the shape of a cone. The main objective of this thesis was to gain insight in how diagnostic and therapeutic advances of the past two decades impact the care for patients with keratoconus.

Modern day corneal imaging devices allow very detailed analysis of the cornea. In our first paper, we investigated the inherent variability of repeated measurements in eyes with varying degrees of keratoconus. This variability is clinically relevant and needs to be taken into account when assessing eyes with keratoconus for corneal crosslinking. This technique allows to strengthen the cornea, and thus stop keratoconus progression without markedly improving vision. In our second paper, we discussed the current diagnostic and referral patterns of keratoconus, illustrating the difficulty of early diagnosis of keratoconus at the primary eye care level. In our third paper, we presented the results of a school-based screening study, which allowed detection of both keratoconus and inadequately corrected refractive errors.  Further research is needed regarding cost-effectiveness of this screening strategy.

Several types of specialty contact lenses are available nowadays to improve vision in keratoconus. We investigated the role of scleral lenses, large-diameter rigid lenses that rest on the sclera (white tissue surrounding the clear cornea). Fitting of these lenses was found to significantly improve both visual acuity and vision-related quality of life in patients with keratoconus. In two subgroups that typically require corneal transplant surgery, very advanced keratoconus and post-hydrops keratoconus, scleral lenses allowed for satisfactory vision in the majority of patients and considerably reduced the need for corneal transplant surgery. The role of hybrid lenses, consisting of a central rigid lens and a soft skirt, in the correction of keratoconus was studied in the seventh paper. In clinical practice, the outcome of these lenses still remains suboptimal.

The advent of corneal crosslinking and innovations in contact lens care have both shifted the desired timing of diagnosis and treatment to earlier in the disease and have reduced the need for corneal graft surgery.

Characterization of pathogen-specific human CD4 T cells after natural infection and vaccination - George Elias (26/04/2021)


George Elias

  • 26 April 2021
  • Time: 1 PM - 3 PM.
  • Online defence
  • Supervisors: Prof. V. Van Tendeloo and prof. B. Ogunjimi

Proteinopathies of frontotemporal lobar degeneration: investigating the impact of vascular contributions - Anne Sieben (22/04/2021)


Anne Sieben

  • 22 April 2021
  • Time: 6 PM
  • Online joint PhD defence
  • Supervisors: Prof. P. Boon (UGent), prof. P. De Deyn (UA) and prof. P. Santens (UGhent)

​Abstract

In the last decade, evidence showed that dementia syndromes such as Alzheimer’s disease (AD) and vascular dementia can be delayed or even prevented by changes in lifestyle and reduction of cardiovascular risk factors. For less prevalent dementia syndromes, such as frontotemporal dementia (FTD) and its neuropathological correlate frontotemporal lobar degeneration (FTLD) this information is lacking.

This thesis covers the neuropathological evaluation of a young onset FTLD cohort, with specific interest in vascular and other age-related alterations. In a review paper, the different FTLD syndromes and their genetics were described.

A first study included the creation of a cohort of young onset FTLD cases from the brain bank of the Institute Born-Bunge. The study resulted in 106 well characterized cases of which FTLD with TDP-43 pathology was most prevalent. A semi-quantitative rating of cerebrovascular pathology was also included.

In a next study the cerebrovascular pathology was assessed in a 9 members of the Belgian progranulin gene (GRN) founder family. The neuropathological analysis in all cases showed FTLD-TDP type A, combined with mild AD, age-related tauopathy or Lewy body disease. Additionally, cerebrovascular disease (CVD) was found and scored in every case.

Next to TDP-43 proteinopathies, our FTLD cohort also consisted of cases with tauopathies. As progressive supranuclear paralysis (PSP) is the most common tauopathy, 7 PSP cases and 7 age matched control cases were neuropathologically examined to assess other comorbidities, including cerebrovascular pathology. A tendency of a higher CVD load was found in the PSP cases compared to the control cases.

Hippocampal sclerosis (HS) is a common finding in elderly patients, often associated with TDP-43, but also with CVD. In a next study, we confirmed the strong relation between HS and hippocampal TDP-43 pathology, and showed an additional  association between HS and vascular changes in the deep white matter and basal ganglia. We hypothesize that both conditions act as a double hit on vulnerable hippocampal neurons and suggest that both conditions affect each other, driving neurodegeneration and the degradation of the blood-brain barrier, leading to sclerosis and neuronal loss.

We conclude that FTLD is clinically, neuropathologically and genetically heterogeneous with plenty of overlap between the neurodegenerative mechanisms and the clinical expression thereof. This thesis demonstrates that proteinopathies are not isolated events in the aging brain. Other factors such as cerebrovascular pathology and with that the involvement of the blood-brain barrier should also be considered. We propose a multi-cellular disease concept in FTLD.

Pancreatic Neuroendocrine Neoplasms: from Genetics to Everolimus Resistance - Timon Vandamme (20/04/2021)


Timon Vandamme

  • 20 April 2021
  • Time: 1 PM - 2 PM.
  • Online joint PhD defence
  • Supervisors: Prof. L. Hofland (Erasmus University Rotterdam), Prof. M. Peeters, Prof. P. Pauwels and prof. K. Op de Beeck

Abstract

Pancreatic neuroendocrine neoplasms (pNENs) comprise only 1-2% of all pancreatic neoplasms, with an incidence of about 0.48 per 100,000 person years. Recent advances in next-generation sequencing (NGS) has led to a better understanding of the genetic constitution of pNENs, uncovering the role of the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mTOR signalling in these tumors. Surgical resection is the primary treatment in locoregional pNENs, and the only curative treatment option. However, more than 50% of cases present with unresectable disease at time of diagnosis. For these advanced pNENs, the mTOR-inhibitor everolimus, a so-called rapalog, has demonstrated to improve progression-free survival. However, primary and acquired resistance to everolimus, may limit its efficacy as single treatment modality. In acquired resistance, patients who initially respond to everolimus, later relapse and develop resistance, whereas in primary resistance, patients do not respond at all. To allow in vitro study of pNEN, the BON-1 and QGP-1 human cell lines have been developed. In this thesis, we characterize the genetic make-up of both cell lines and compare it to patient samples. In addition, we establish a model for acquired everolimus resistance and use this to uncover everolimus resistance mechanisms.

Identification of gait deviations in patients with Dravet Syndrome - Lore Wyers (19/04/2021)


Lore Wyers

  • 19 April 2021
  • Time: 5 PM - 7 PM.
  • Online joint PhD defence
  • Supervisors: Prof. A. Hallemans, Prof. P. Van de Walle and prof. K. Desloovere

Abstract

Dravet Syndrome (DS) is a developmental and epileptic encephalopathy, characterised by severe epilepsy and cognitive and motor impairments. Patients with Dravet syndrome are often confronted with walking problems. As a comorbidity in the broad clinical picture of this syndrome, walking problems form a disabling factor. Studying gait deviations provides insight into the pathological processes that underlie walking problems. Research on gait in patients with DS is, however, still limited. This makes it difficult to formulate clinical advice for the evaluation and treatment of walking problems.

This PhD project aimed to characterise the main gait deviations in patients with DS. First, the state-of-the-art regarding motion analysis and gait deviations in patients with intellectual disabilities (ID) and DS is established. To this end, two review studies are conducted. Thereafter, three empirical studies document biomechanical aspects of gait in children, adolescents and young adults with DS.

Literature often described gait deviations as crouch gait in patients with DS as well as in the general population with ID. The results of the current research project confirmed that increased knee flexion increased the lower limb support moment in stance, reducing the efficiency of the gait pattern. Based on knee extensor moments and trunk lean, three kinetic strategies to maintain stance limb stability were identified. Moreover, foot function seemed impaired, as half of the participants did not consistently perform heel strikes and showed deviations in plantar pressure measures. Even though feasibility of strength measurements was low in this population, indications of dereased muscle strength were observed.

An overall inefficient gait pattern was identified, mainly characterised by increased knee flexion and diverse neurologic, motor and musculoskeletal deviations. Two main hypotheses are formulated to explain the observed gait deviations in patients with DS. First, the musculoskeletalhypothesis suggests that in DS, decreased muscle strength and lever arm dysfunction only partly explain the gait deviations. Second, the motor control hypothesis states that the contribution of impaired neuromotor control and delayed psychomotor development to gait deviations in patients with DS should not be underestimated

Developing experimental therapeutic strategies for impaired gastrointestinal permeability, bacterial translocation, intestinal inflammation, and adhesiogenesis during sepsis - Philip Plaeke (30/03/2021)

Philip Plaeke

  • 30 March 2021
  • Time: 4 PM - 6 PM.
  • Online defence
  • Supervisors: Prof. G. Hubens and prof. B. De Winter

Abstract

Sepsis is a severe inflammatory disorder that affects the whole body and remains one of the leading causes of mortality worldwide. A highly important mechanism in sepsis is the loss of the intestinal barrier which leads to the influx of proinflammatory and pathogenic molecules and micro‐organisms into the body. As such, intestinal barrier impairment has been recognized as a driving force for sepsis. In this dissertation we discuss the effects of intestinal alkaline phosphatase, protease inhibitors such as nafamostat mesylate and UAMC‐00050, and gelatin tannate on the intestinal barrier during sepsis. Moreover, during sepsis of abdominal origin an intraperitoneal adhesiogenic response is often observed. These adhesions, also often seen in patients that underwent abdominal surgery, can have severe clinical implications frequently leading to urgent surgical interventions. In the second part of this dissertation, we discuss how proteases play a crucial role in several pathways responsible for adhesion formation and how protease inhibitors can interfere with the adhesiogenesis.

Gadolinium Retention And DEposition (GRADE): effects and technical considerations - Carlo Augusto Mallio (11/03/2021)


Carlo Augusto Mallio

  • 11 March 2021
  • Time: 2 PM - 4 PM.
  • Online defence
  • Supervisors: Prof. P. Parizel and prof. C. Quatrocchi

Abstract

In this project we have investigated current evidence and illustrated future landscapes in the field of gadolinium deposition and safety. Even if what really counts is whether or not retained gadolinium in the brain and body is harmful, and to date no proven causation with permanent severe adverse effects has been reported in patients, we should keep investigating the topic and, if the current standard practice can be outperformed using different strategies, we should definitely go for it.

Urinary extracellular vesicles as source of biomarkers for the diagnosis and follow up of bladder cancer patients - Eline Oeyen (09/03/2021)

Eline Oeyen

  • 9 March 2021
  • Time: 5 PM - 7 PM.
  • Online defence
  • Supervisors: Prof. I. Mertens, prof. S. De Wachter and prof. G. Baggerman

Abstract

Bladder cancer is the 4th most common cancer in men and the 8th most common in women in the Western world. Approximately 550,000 new cases occur yearly worldwide. The current gold standard methods to diagnose a bladder tumour are cystoscopy and urine cytology. However, limitations exist. Early detection is required to avoid cystectomy. Due to the high risk of relapse, intensive follow-up of bladder cancer patients is recommended. A non-invasive and inexpensive diagnostic method to detect bladder cancer in an early stage and monitor the patient to detect relapse will reduce the costs and is beneficial for the patient.

Urine biomarkers are an attractive alternative for the detection of a bladder cancer tumour. However, no urinary biomarkers are used in daily clinical practice yet due to the lack of sensitivity or specificity or negative predictive value. Recently, it was demonstrated that small extracellular vesicles (<200 nanometres), that are present in different types of liquid biopsies, are a potential source of biomarkers for cancer diagnosis. Tumour-derived vesicles have a role in cancer development and therefore a potential source of biomarkers with high sensitivity and specificity. The ultimate goal of this dissertation was to explore the cargo of urinary small extracellular vesicles to identify biomarker candidates for the initial diagnosis and recurrence diagnosis of bladder cancer patients.

Optimisation of the separation of small extracellular vesicles from urine was performed. Next, a variation analysis was performed on the isolated proteins to obtain insights into the interbiological variation and a sample size calculation was performed. Mass spectrometry was used to identify protein biomarker candidates in the urinary sEV isolates for (1) the diagnosis of an initial bladder cancer tumour and (2) the follow-up of patients to detect a bladder cancer relapse. Protein biomarkers allow the easy and fast diagnosis of biomarkers in antibody-based assays.This resulted in a list of 1,226 identified and quantified proteins and respectively 69 and 2 proteins were differentially detected based on high quality raw data. Although this study was promising, extra training cohorts are required. Ultimately, further verification and validation steps of the biomarker candidates are required to investigate the sensitivity, specificity and predictive values of the final biomarker panel and compare them with the current diagnostic standards to develop inexpensive and non-invasive tests.

The development and validation of tools to improve the efficacy of sacral neuromodulation and understanding of its action - Donald Vaganée (02/03/2021)


Donald Vaganée

  • 2 March 2021
  • Time: 5 PM - 7 PM.
  • Online defence
  • Supervisor: Prof. S. De Wachter

Abstract

Sacral neuromodulation is a longstanding, minimally invasive treatment for patients with overactive bladder syndrome, non-obstructive urinary retention and fecal incontinence, refractory to conservative treatments. The treatment consists of placement of a tined lead with four stimulation electrodes through the third or fourth sacral foramen in order to stimulate in the vicinity of the sacral spinal nerves. Lead placement can occur under general or local anaesthesia. Correct lead position with respect to the sacral spinal nerves is determined guided by adequate pelvic floor motor and/or genital/peri-anal sensory responses after electrical stimulation. With the lead positioned, the electrodes are “programmed”, meaning that one or more electrode(s) are chosen as stimulation point(s) and an electrode as reference point. The current measurement techniques to record the motor and sensory responses during lead placement and electrode programming, are highly subject to subjectivity (visual inspection of contraction of the pelvic floor and verbal inquiry, respectively). For the motor and sensory response are considered the best indicators of optimal nerve stimulation, good tools to objectively record these responses are paramount (i.e. to improve the efficacy of sacral neuromodulation). In this thesis a multiple array electromyography probe and a pelvic chart are presented as tools to record the motor and sensory response. The validity, reliability and feasibility of these tools are assessed. Subsequently, their usefulness in clinical practice is investigated.

A listening ear. Psychotherapeutic interventions in the treatment of chronic, subjective tinnitus - Tine Luyten (15/01/2021)

Tine Luyten

  • 15 January 2021
  • Time: 5 PM - 7 PM
  • Supervisors: Em.Prof P. Van de Heyning, Em.Prof M. De Bodt and Prof A. Gilles
  • Language: Dutch

Abstract

The perception of tinnitus, known as an internal sound in the absence of external auditory input, can be extremely bothersome and debilitating. Worldwide, tinnitus sounds raise awareness in 8 – 20% of the population and become chronic. For about 1 – 3 %, tinnitus is distressing and therapeutic intervention is needed.

Currently, psychotherapeutic tinnitus interventions commonly consist of psychoeducation, Tinnitus Retraining Therapy (TRT) and / or Cognitive Behavioral Therapy (CBT). The tinnitus population is frequently represented with comorbid complaints such as insomnia, anxiety and depression. For this reason, there is no treatment-fits-all and thus personalized treatment options are recommended, however, to date effective treatment options are scarce. Tinnitus is known as phantom percept and recent research on Eye Movement Desensitization Reprocessing (EMDR) and phantom pain has shown promising results.

This doctoral thesis was performed in order to gain insight in the value of EMDR as treatment for chronic subjective tinnitus, to examine whether this psychotherapeutic intervention can be applied as effective tinnitus treatment, and to explore the influence of personality traits on treatment outcome.

The first part of this dissertation investigated the existence of relevant EMDR - studies. This was the first systematic review on EMDR as treatment for tinnitus resulting in an overview of the currently existing scientifically proven studies assessed by the Platinum Standard, giving support to the effectiveness of EMDR.

Consequently, in the second part of the thesis the study protocol for a prospective, randomized controlled trial with blind evaluator was represented. A total of 166 patients with chronic, subjective, non-pulsatile tinnitus were screened and 91 patients were randomized in two treatment groups: TRT/CBT versus TRT/EMDR. Data from 89 patients were assessed at three time-points i.e. before treatment, after treatment, and at three month follow up. The focus was on analyzing the Tinnitus Functional Index (TFI) as primary outcome measurement, and the Tinnitus Questionnaire (TQ), Hyperacusis Questionnaire (HQ), Hospital Anxiety and Depression Scale (HADS), Visual Analogue Scale for tinnitus loudness (VASLoudness), and Global Perceived Effect (GPE) as secondary outcomes, after psychotherapeutic treatment.

Both bimodal therapies resulted in significant reduction of tinnitus distress, tinnitus related complaints, tinnitus loudness, hypersensitivity to sound, anxiety, and depressive symptoms and led to significant increase of quality of life. Assessments indicated a stable effect of these improvements after three months. The present study provides evidence for the effectiveness of both treatment protocols showing no superiority of TRT/EMDR over TRT/CBT.

In the third part, the influence of specific personality traits in therapeutic outcome was investigated. Data from the RCT were employed to identify correlations between self-report outcome measures and Big Five Inventory (BFI) personality traits. K-means cluster analysis revealed four distinct personality clusters containing a specific combination of traits.

In conclusion, these empirical findings highlight the effectiveness of both bimodal therapies showing no different efficacy and underline the significant influence of personality traits in psychotherapeutic treatments.

New insights in connective tissue and growth disorders - Silke Peeters (14/01/2021)


Silke Peeters

  • 14 January 2021
  • Time: 3 PM - 5 PM.
  • Online defence
  • Supervisors: Prof. G. Mortier and prof. W. Van Hul

Abstract

The primary purpose of this thesis was to gain more insights in the genetic architecture and disease mechanisms underlying connective tissue and growth disorders. The first and main project focused on carpal tunnel syndrome (CTS). Although CTS is common and widely recognized, its precise etiology still remains largely unknown. In this project, we were able to delineate a new fibrillino-2-pathy by studying a family in whom CTS occurred in three subsequent generations at an unusually young age. Additional clinical features included brachydactyly and short Achilles tendons. Using exome sequencing, we identified a heterozygous pathogenic variant (p.Phe1670Cys) in the fibrillin-2 (FBN2) gene that co‐segregated with the phenotype in the family. We found evidence that the mutant protein affects normal integrin-mediated cell adhesion in the ECM and observed increased TGF-β signaling, resulting in fibrosis of the carpal tissues with entrapment of the median nerve as a consequence. A variant burden test in a large cohort of sporadic CTS patients revealed a significantly increased frequency of rare (6.7% versus 2.5-3.4%, p<0.001) and high-impact (6.9% versus 2.7%, p<0.001) FBN2 variants in patient alleles compared to controls. These findings strongly suggest a role of FBN2 in the pathogenesis of CTS.

The second project of this thesis focused on children born small-for-gestational age (SGA) with persisting growth failure. In a significant proportion of SGA children, the etiology of the growth failure remains unclear after routine diagnostic work-up. In this project, we investigated whether an extensive analysis of the (epi)genome can unravel the (epi)genetic cause of growth failure in a well-defined group of 20 SGA children.

We identified (likely) pathogenic variants in two siblings and two additional probands using exome sequencing. Furthermore,

SNP array analysis in all children and their parents revealed a rare, pathogenic de novo copy number variation (CNV) in two other unrelated probands. In almost all children with a genetic diagnosis, we observed an “above average” response to growth hormone treatment. These results question the relevance of the exclusion of syndromic SGA patients from growth hormone treatment. In a subgroup of 10 children, we performed a genome-wide DNA methylation assay. This analysis revealed multi-locus imprinting disturbances in two additional children. Furthermore, in the child harboring the NSD1-containing microduplication, we identified a novel DNA methylation signature. The conclusion of this second project is that a more advanced approach with deep genotyping can unravel unexpected (epi)genomic alterations in SGA children with persistent growth failure.