Medicine and Health Sciences

Public defences 2022

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

Exploring paths forward for mood disorder research: Embracing heterogeneity, complexity and idiography - Kaat Hebbrecht (30/1/2022)

Kaat Hebbrecht

  • 30 November 2022
  • Time: 5.00 PM - 7.00 PM.
  • Venue: aula De Tichelrij, congres building De Kleiput, campus Duffel, Stationsstraat 22c, 2570 Duffel 
  • PhD defence
  • Supervisors: Em.Prof. B. Sabbe and prof. E. Giltay

Abstract

Sleeping towards Synucleinopathies - the Polysomnography Progression Marker Initiative - Femke Dijkstra (28/10/2022)

Femke Dijkstra

  • 28 October 2022
  • Time: 4.15 PM - 6.15 PM.
  • Venue: CDE, building R, room R.101
  • PhD defence
  • Supervisors: Prof. D. Crosiers and prof. P. Cras

Abstract

Multi-country economic evaluations of interventions against Respiratory Syncytial Virus (RSV) and influenzalike- illness (ILI) - Xiao Li (27/10/2022)

Xiao Li

  • 27 October 2022
  • Time: 9 AM - 11 AM.
  • Venue: CDE, building R, room R.101
  • PhD defence
  • Supervisors: Prof. P. Beutels, Prof. M. Jit, dr. L. Willem and Prof. J. Bilcke

Abstract

Development, characterization and application of luminescent human iPSC-derived neurospheroids in ischemic stroke research - Elise Van Breedam (10/10/2022)

Elise Van Breedam

  • 10 October 2022
  • Time: 3:00 PM - 5:00 PM.
  • PhD defence 
  • Supervisor: Prof. P. Ponsaerts

Abstract

Although stroke is one of the world’s leading causes of death and disability, and more than a thousand candidate neuroprotective drugs have been proposed based on extensive in vitro and animal-based research, an effective neuroprotective/restorative therapy for ischemic stroke patients is still missing. Especially the high attrition rate of neuroprotective compounds in clinical studies should make us question the ability of in vitro stroke models currently used for ischemic stroke research to recapitulate human ischemic responses with sufficient fidelity. The ischemic stroke field would greatly benefit from the implementation a physiologically relevant human in vitro stroke model.

In a first part, a luminescent human iPSC-derived neurospheroid model enabling the real-time read-out of neural viability after ischemia-like conditions was developed and characterized. By depriving neurospheroids from oxygen and glucose, the ability of the applied bioluminescent system to detect neurotoxicity was demonstrated. Moreover, differences in behaviour after oxygen-glucose deprivation between different ages of neurospheroids were observed, whereby 1-week-old but not 4-week-old neurospheroids displayed spontaneous recovery. This underscores the need for more mature neurospheroids in in vitro stroke research that more faithfully recapitulate the in vivo adult situation. Furthermore, evaluation of the pan-caspase inhibitor Z-VAD-FMK in the established model demonstrated its inability to increase overall neural survival in neurospheroids in contrast to a 2D culture of the same hiPSC-derived neural stem cells, where neuroprotection was observed. This exemplifies how the increased complexity of spheroid models can result in a different outcome when testing neuroprotective compounds.

In a second part, the foundation was laid to further increase the complexity and predictivity of the developed human neurospheroid model by generating more mature, multicellular neurospheroids. In a first set of explorative experiments, culture conditions were optimized in order to obtain neurospheroids with increased maturity and the presence of astrocytes. Hereby, increasing the culture time of the neurospheroids markedly increased neuronal maturity as well as the spontaneous development of astrocytes. It was also noted that culture of neurospheroids in selected differentiation media did not give rise to astrocytes for the evaluated time points despite their ability to display faster differentiation and maturation. In a second set of explorative experiments, the integration of hematopoietic progenitors cells into neurospheroids was explored for the future creation of an immune-competent, microglia-enriched neurospheroid model for ischemic stroke. Comparison of different time points for the addition of hematopoietic progenitor cells to neurospheroids, showed higher integration efficiency when added to pre-established neurospheroids.

From nodding syndrome to onchocerciasis associated epilepsy: epidemiological studies in Uganda - Nolbert Gumisiriza (05/10/2022)

Nolbert Gumisiriza:

  • 5 October 2022
  • Time: 5:00 PM - 7:00 PM.
  • Online PhD defence 
  • Supervisor: Em.Prof. R. Colebunders

Abstract

Nodding syndrome (NS) is a type of epilepsy that appears in previously healthy children between the ages of 3-18 years and is characterised by repetitive, involuntary head drops to the chest. At the beginning of this PhD work, NS was largely an enigmatic disease, considered to occur only in onchocerciasis endemic areas in Tanzania, Uganda and South Sudan. A variety of potential etiologies were proposed, including onchocerciasis. However, most researchers did not consider onchocerciasis as the cause of NS because, at that time, NS was only observed in onchocerciasis endemic areas in three countries and because O. volvulus worms have not been detected in the cerebrospinal fluid. There was a significant frequency of epilepsy in Cameroon's onchocerciasis endemic regions. Despite this, NS was assumed to be unconnected to epilepsy in Cameroon because of its unusual clinical presentation. This PhD research is part of a multi-country study to identify the cause of NS, the NSETHIO project. In this context, I investigated the association between onchocerciasis and NS in Uganda.
A first study was conducted in Kitgum and Pader districts, located in an onchocerciasis-endemic zone of northern Uganda. These districts witnessed an NS outbreak and a general rise in epilepsy in the early 2000s. We carried out an epilepsy survey in 2017 and compared our findings to those of a study performed in 2012 in the same area. We observed that new cases of epilepsy decreased after the introduction of annual ivermectin distribution, and that NS stopped appearing after the implementation of biannual ivermectin distribution and ground larviciding of rivers.
A second study was performed in Kabende, in western Uganda. In 1991, in this onchocerciasis endemic region, a high prevalence of epilepsy and cases of NS had been reported. Onchocerciasis transmission had been interrupted by 2004 and was later eradicated with the combination of annual ivermectin distribution and river ground larviciding. In 2018, during an epilepsy survey in the same area, we observed that new cases of NS had stopped appearing since the eradication of onchocerciasis and that the overall prevalence and incidence of epilepsy also had dropped significantly.
We also conducted a case-control study to identify risk factors for NS and other forms of epilepsy in northern Uganda. We observed that Onchocerca volvulus seropositivity was associated with both NS and other forms of epilepsy. Preterm delivery was also identified as a probable risk factor for NS in the study. In contrast to earlier findings, we discovered that being born in an IDP camp was not a risk factor for NS or other diseases.
These three studies confirmed the association between onchocerciasis and epilepsy, NS in particular. Since we started our studies in Uganda, NS has also been reported during surveys in several additional onchocerciasis-endemic locations in Cameroon, the Democratic Republic of Congo, and the Central African Republic. In these studies, persons with NS were frequently found to have siblings with epilepsy without nodding seizures but with similar characteristics to NS. Therefore, NS should be considered as one of the phenotypic presentations of onchocerciasis-associated epilepsy, including the onset of seizures in previously healthy children between the ages of 3-18 years. Despite the epidemiological evidence for the association between onchocerciasis and epilepsy, the pathophysiological mechanism by which the O. volvulus parasite causes epilepsy remains unidentified. The scale of the disease burden caused by onchocerciasis-associated epilepsy needs to be internationally acknowledged. A delay in applying sufficient onchocerciasis elimination measures will result in the continued development of NS and other forms of epilepsy among children in onchocerciasis with high ongoing transmission.

Combined targeting of the epidermal growth factor receptor and the innate immune system: a novel therapeutic approach for the treatment of head and neck cancer - Hasan Baysal (26/09/2022)

Hasan Baysal

  • 26 September 2022
  • Time: 4 PM - 6 PM.
  • Venue: CDE, building R, room R.3
  • PhD defence
  • Supervisors: Prof. F. Lardon, Prof. A. Wouters, Dr. J. De Waele

Abstract

Head and neck squamous cell carcinomas (HNSCC) are a group of malignancies that despite preventative measures and advances in cancer treatments, have a detrimental impact on patients’ outcome and quality of life. Targeted therapies and immunotherapies, being at the forefront of personalized cancer medicine, aim to fulfil the dire need for effective treatment strategies. However, despite promising clinical results, the effectiveness of these modalities is severely limited due to the heterogeneous nature of HNSCC and the presence of multiple resistance and immune evasion mechanisms. In this dissertation, our goal was to investigate whether these shortcomings could be overcome through combined targeting of the epidermal growth factor receptor (EGFR) together with immunotherapeutic modalities that focus on reinvigorating natural killer (NK) cells. We showed that treatment of different HNSCC cell lines with the anti-EGFR antibody, cetuximab, in co-culture with NK cells was capable of inducing antibody-dependent cellular cytotoxicity (ADCC) independent of basal EGFR levels. Characterization of the immune signature of HNSCC patients indicated an inflamed tumor environment. NK cell presence was largely restricted to peritumoral stroma but strongly associated with improved survival. Increased expression of CD276 and CD155 were identified as negative prognostic factors and regarded as potential novel immunotherapeutic targets. Combined with the idea that chemo- and targeted therapies may influence the immune landscape, we investigated the immunomodulatory effects of cetuximab in vitro. Differences in expression of immune checkpoint ligands between various HNSCC cell lines based on their cetuximab sensitivity were limited in size but observable. Based on the overall high expression of CD155, CD276 and CD47 across all cell lines, these were suggested as interesting targets for therapeutic intervention. Investigating the complimentary receptors of these ligands on NK cells showed a clear presence of TIGIT and DNAM-1 on both healthy and patient-derived NK cells. Thus, the TIGIT/CD155-signaling axis was interrupted as a means to enhance the antitumor activity of NK cells towards our panel of HNSCC cell lines. Combined targeting of CD155 with cetuximab synergistically enhanced the antitumor activity of NK cells compared to single agent treatments in all cell lines, especially the intrinsically resistant cells. In conclusion, the data presented in this dissertation support the rationale for combining cetuximab with CD155 inhibition to enhance the NK cell antitumor activity and overcome cetuximab resistance.

Assessing brand-specific influenza vaccine effectiveness in Europe - Experiences from the DRIVE project - Anke Stuurman (20/09/2022)

Anke Stuurman

  • 20 September 2022
  • Time: 4 PM - 6 PM.
  • Venue: CDE, building Q, Promotiezaal 
  • PhD defence
  • Supervisor: prof. P. Beutels

Novel outcome measures for cystic fibrosis in a changing world: functional respiratory imaging and computer aided lung sound analysis - Eline Lauwers (15/09/2022)

Eline Lauwers

  • 15 September 2022
  • Time: 5 PM - 7 PM.
  • Venue: UZA, G. Kinsbergen auditorium
  • PhD defence
  • Supervisors: prof. S. Verhulst, prof. K. Ides and prof. K. Van Hoorenbeeck

Abstract

Cystic fibrosis is a life-threatening genetic disease, characterized by an early onset of progressive lung disease. Over the past decade CF care has evolved at a rapid pace having a great impact on the therapeutic approach and follow-up of patients. In this new world of advanced therapies and technological developments, the need for objective and sensitive methods to identify regional abnormalities in the lungs becomes increasingly important. The overall aim of this PhD project was to explore the role of two novel outcome measures in CF research: Functional Respiratory Imaging (FRI) and Computer Aided Lung Sound Analysis (CALSA).
FRI comprises quantitative CT analysis combined with computational fluid dynamics (CFD), which results in a set of structural and functional biomarkers on a lobar level. This technology has been studied in various pulmonary diseases, but research in the field of CF is scarce. Two studies were conducted to examine the added value of FRI in CF research. Results showed that structural FRI outcomes have the potential to complement findings derived from conventional outcome measures as an alternative to visual CT scores. Moreover, an interventional study suggested that multiple FRI outcomes are more sensitive than conventional outcomes to detect short-term therapeutic effects.
In the second part of this thesis, a novel approach for automated CALSA was evaluated in a real-world clinical setting. Our research focused on the development of automated algorithms that result in continuous output values, which can be used to indicate the severity level of a patient’s disease or to quantify treatment effects. The approach was proposed in collaboration with CoSys-Lab (Faculty of Applied Engineering, UAntwerp) and Sonavi Labs (Baltimore, USA). A cross-sectional study comparing digital lung sound characteristics to imaging outcomes offered a first clinical validation of the approach. A second interventional study demonstrated the responsiveness of sound characteristics to the short-term effects of airway clearance techniques.
Overall, both FRI and CALSA are suggested to be valuable outcome measures for CF. The added value of FRI focuses on the sensitivity of the technique and its potential to be used in clinical trials with a small number of patients and/or patients with mild lung disease. CALSA, on the other hand, has the advantage that it is suitable for frequent assessment in settings with minimal infrastructure. However, research regarding CALSA is still in an early stage and improvements to the methodology should be made before its implementation in clinical practice.

Roadblocks on the tissue-engineering path towards conjunctival restoration: The hidden truth behind the in vitro functionality of cultured goblet cells and the ancient pterygium pathology - Sara Van Acker (14/09/2022)

Sara Van Acker

  • 14 September 2022
  • Time: 5 PM - 7 PM.
  • Venue: CDE, building O, room O6
  • PhD defence
  • Supervisors: Prof. C. Koppen, Prof. N. Zakaria and Dr. I. Pintelon

Abstract

Many consider the cornea the window of the eye, making the neighboring conjunctiva to be often overlooked. However, correct conjunctival functioning is indispensable for the maintenance of ocular surface homeostasis and, consequently, for creating an optimal environment for corneal epithelial cell renewal. It is therefore not surprising that a wide range of ocular surface pathologies are characterized by conjunctival damage or compromised performances. Standard practice of care includes the surgical removal of the affected conjunctiva and covering the open 'wound' to avoid structural alterations and permanent scar formation related to secondary healing.

The most optimal conjunctival substitute for this 'wound' coverage is yet to be defined. The emerging field of tissue engineering in ophthalmology offers the possibility to address the limitations of the current conjunctival substitutes, opening new horizons in treatment options for those with severe cicatrizing conjunctivitis as well as other pathologies such as pterygium, bleb leaks following trabeculectomy, and extensive nevi. The end-point of this development road would be an appropriate tissue-engineered graft, potentially adaptable to a specific disease location, damage type, or patient population. However, considerable roadblocks are to be addressed before conjunctival tissue engineering can be implemented as a treatment option.

In this PhD thesis, two different types of roadblocks were investigated. The first obstacle relates to a proper cell characterization of the cultured conjunctival epithelium, which is currently lacking. Ex vivo expanded conjunctival cultures were established in a serum-free environment using an explant culture technique. To ensure short- and long-term rehabilitation, the cultured epithelium should consist of barrier-forming squamous epithelial cells, gel-forming mucin secreting goblet cells, and self-renewing stem cells. A marker panel for the immunocytochemical identification of these three cultured conjunctival cell types has been drafted. However, the contradicting results obtained with the state-of-the-art markers for conjunctival goblet cells led us to re-evaluate their characterization as well as their ex vivo functionality. The second hurdle corresponds to the path that is undeniably intertwined with the development of a tissue-engineered graft and could be summarized as the unwavering need to understand the underlying pathology as novel approaches are drafted. During this thesis, patients suffering from pterygium have been taken as a patient group that would significantly benefit from a conjunctival reconstruction. To further improve the treatment strategy, questions surrounding its origin, pathophysiology, and recurrence have therefore been addressed.

Identifying and clarifying alcohol use patterns in community-dwelling older adults - Yannic van Gils (07/09/2022)

Yannic van Gils

  • 7 September 2022
  • Time: 4 PM - 6 PM.
  • Venue: CDE, building O, aula O5
  • Joint PhD defence UA and VUB
  • Supervisors: prof. E. Franck, prof. E. Dierckx, prof. G. Dom and prof B. van Alphen

De gustibus (non) disputandum est: Taste steering as a complex intervention for chemotherapy-induced taste alterations - Marleen Corremans (31/08/2022)

Marleen Corremans

  • 31 August 2022
  • Time: 5 PM - 7 PM.
  • Venue: CDE, building Q, Promotiezaal 
  • PhD defence
  • Supervisors: Prof. B. Geurden and prof. D. Mortelmans

Ways to mitigate the public health problem caused by onchocerciasis-associated epilepsy - Alfred Dusabimana (23/08/2022)

Alfred Dusabimana

  • 23 August 2022
  • Time: 4 PM - 76PM.
  • Venue: CDE, building Q, Promotiezaal 
  • PhD defence
  • Supervisors: Em.Prof. R. Colebunders, prof. S. Coenen and prof. S. Abrams

Abstract

Onchocerciasis, known as river blindness, is a neglected tropical diseases caused by a filarial worm Onchocerca volvulus (O. volvulus) and is transmitted by blackflies through the repeated bites of the genus Simulium. In onchocerciasis-endemic areas mainly in sub-Saharan Africa, a high epilepsy prevalence of 2−8% has been  documented, which is considerably higher than the median prevalence of epilepsy in Africa of 1.4%. Recent data suggest that onchocerciasis is linked with epilepsy, so-called onchocerciasis-associated epilepsy (OAE). OAE affect children between 3 to 18 years. OAE affected children present, in addition to epilepsy, often cognitive impairment, severe stunting and delayed puberty. This PhD research aimed to better understand the link between onchocerciasis and epilepsy and to investigate ways to mitigate the public health impact caused by OAE.

Despite many years of onchocerciasis elimination efforts with mass drug administration of ivermectin treatment, there is still high ongoing onchocerciasis transmission in certain areas. We found that a higher intensity of O. volvulus infection was associated  with a lower parasitological ivermectin response. Moreover, our findings suggest that the high ongoing onchocerciasis transmission in certain areas may be the consequence of sub-optimal functioning of the onchocerciasis-elimination programme.

We demonstrated that onchocerciasis antibody positivity among 6-10-year-old children (a proxy for ongoing O. volvulus transmission), epilepsy prevalence and incidence, and ivermectin therapeutic coverage in an onchocerciasis endemic area could be used to identify areas where onchocerciasis-elimination programmes need to be strengthened or introduced.

We also showed that a community-based epilepsy treatment programme in an onchocerciasis endemic areas in Ituri, in the Democratic Republic of Congo was able to  positively change the communities’ perceptions and attitudes towards persons with epilepsy and empowered the local health care workers to manage epileptic seizures.

Our studies show that the current high prevalence of OAE is a consequence of sub-optimal performance of onchocerciasis-elimination programmes. Onchocerciasis elimination programs should prioritize their efforts towards onchocerciasis-endemic regions with a high epilepsy prevalence and incidence.

Evaluation of optimized strategies for the detection and treatment of asymptomatic malaria infections in the Peruvian Amazon - Diamantina Moreno Gutierrez (20/07/2022)

Diamantina Moreno Gutierrez

  • 20 July 2022
  • Time: 4 PM - 6 PM.
  • Venue: UCL, Maisin et du Hall Maisin E auditorim
  • Joint PhD defence UCL and UA
  • Supervisors: Prof. P. Beutels, prof. N. Van Speybroeck and prof. A. Rosas-Aguirre

Abstract

Malaria remains a public health problem in the Peruvian Amazon. To understand malaria transmission in riverine communities of Mazan district in the Peruvian Amazon, combined parasitological, entomological, and environmental observations. Despite heterogeneity across communities, the prevalence of submicroscopic malaria infections was high and mainly due to Plasmodium vivax. Furthermore, housing with incomplete walls was the main risk factor for malaria, and communities in Mazan basin had higher entomological indicators, prevalence, and incidence rates than communities in the Napo basin. In that scenario and considering that routine malaria surveillance is based on passive case detection (PCD) using light microscopy (LM) for malaria diagnosis, we conducted two cross-sectional studies to estimate the economic costs associated with passive case detection (PCD) and management of uncomplicated malaria episodes and explore whether healthcare-seeking behaviours significantly influence those costs. Although malaria case management was free, there was a delay in seeking care, and the costs of uncomplicated malaria incurred by families were mainly indirect costs due to loss of working days. Since the Peruvian Ministry of Health (MoH) improved routine malaria surveillance by the addition of an optimized strategy recommended by the World Health Organization (WHO) known as active case detection (ACD) to overcome the limitations of the routine malaria surveillance based on PCD using LM for detecting both asymptomatic infected individuals and symptomatic individuals that do not attend the health services, a population-based cohort study was conducted to assess the effectiveness of this optimized strategy based on ACD using light microscopy (LM) compared with quantitative real-time polymerase chain reaction (qPCR). The optimized ACD-strategy using LM had less effectiveness than qPCR. Furthermore, qPCR results confirmed that most malaria infections were asymptomatic, submicroscopic, and mainly due to P. vivax.

As asymptomatic and submicroscopic malaria infections are common, undetected, and untreated using a standard diagnostic test such as light microscopy due to low effectiveness, optimized strategies based on ACD using molecular tests added to PCD could reduce the malaria burden in the Peruvian Amazon. However, to ensure optimal allocation of resources for malaria elimination, Peruvian stakeholders should consider implementing mass drug administration (MDA) with a single treatment using artemisinin-based combination therapy (ACT) plus primaquine or tafenoquine for uncomplicated malaria by both P. falciparum and P. vivax infections. Furthermore, high heterogeneity in malaria transmission creates opportunities for targeted control interventions such as MDA in clusters of high malaria prevalence.

Biomarkers and molecular immunopathology of pneumonia - Fien De Winter (01/07/22)

Fien De Winter

  • 1 July 2022
  • Time: 4 PM - 6 PM
  • Venue: CDE, building Q, promotiezaal, room Q.002
  • PhD defence
  • Supervisor: prof. S. Kumar-Singh, Councelor: Dr. A. Hotterbeekx

Abstract

Pneumonia remains worldwide the single largest infectious cause of death both in children and adults, as well as in hospitalised patients. One of the most important bacterial causes of hospital-related mortality is Pseudomonas aeruginosa (PA), which is high on the WHO priority list of pathogenic organisms. This is because of PA’s substantial ability to rapidly gain resistance against antibiotics, partly because of protective biofilm formation, and cause mortality in immunocompromised patients including patients on mechanical ventilation (MV). We studied the effect of MV on innate immune factors such as cytokines and its relation to development of ventilator-associated pneumonia (VAP). We showed both in a rat VAP model as well as in VAP patients that the pro-inflammatory Th17-related cytokines are substantially dampened. We concluded that this form of immune modulation caused by MV can be an important cause of VAP. We further elucidated how inducing dispersal of bacteria from a biofilm causes an increased in vivo dissemination and mortality in mice, thereby suggesting that biofilm dispersion as a potential anti-PA therapy should be treaded carefully. While performing these studies, we also identified a knowledge gap regarding temporal evolution of immune responses in animal infection models. We showed distinct temporal expression profiles of cytokines and, importantly, demonstrated that serum levels are representative of the local lung immune response in mice. We believe that these studies will have an important impact on pre-clinical research utilizing these rodent pneumonia models. With the emergence of SARS-CoV-2, the focus of this thesis shifted on COVID-19 pneumonia. In the search for biomarkers of disease severity, we first developed a model based on the cytokine, chemokine, and growth factors (CCG) to predict development of acute respiratory distress syndrome already at the time of hospital admission. This research also elucidated a significant role of TGF-β in COVID-19 whose function is linked both with normal healing, as with fibrosis seen in COVID-19 patients. Lastly, we showed in a SARS-CoV-2 exposed cancer population long-term alterations in levels of inflammatory CCGs, some of which are also tumour-promoting factors. These data prompt for increased vigilance in SARS-CoV-2-exposed cancer patients and long-COVID management. The work performed in this thesis has provided useful insights in our understanding of the molecular pathology of pneumonia and will form the basis for future translational research in development of early diagnostic tools as well as for new therapies directed towards the immune system targeting bacterial and viral pneumonia.

Longontsteking of pneumonie blijft wereldwijd de grootste infectieuze doodsoorzaak, zowel bij kinderen, volwassenen als bij gehospitaliseerde patiënten. Een van de belangrijkste bacteriële oorzaken van ziekenhuissterfte is Pseudomonas aeruginosa (PA), een bacterie hoog geplaatst op de WHO-prioriteitenlijst van pathogene organismen. Dit komt door het substantiële vermogen van PA om snel resistentie tegen antibiotica op te bouwen, onder andere vanwege de vorming van biofilm, alsook sterfte te veroorzaken bij immuun-gecompromitteerde patiënten zoals patiënten die mechanische ventilatie (MV) ondergaan. Wij bestudeerden het effect van MV op immuunfactoren zoals cytokines en de relatie ervan met de ontwikkeling van ventilator-geassocieerde pneumonie (VAP), en demonstreerden zowel in een rat-VAP-model als in VAP-patiënten dat de pro-inflammatoire Th17-gerelateerde cytokines substantieel afgeremd worden. We concludeerden dat deze vorm van immuunmodulatie veroorzaakt door MV een belangrijke oorzaak van VAP kan zijn. Verder hebben we toegelicht hoe het induceren van verspreiding van bacteriën uit biofilm een verhoogde in vivo verspreiding en mortaliteit bij muizen veroorzaakt, en suggereerden daarmee dat biofilmverspreiding als een potentiële anti-PA-therapie met voorzichtigheid moet worden behandeld. Tijdens het uitvoeren van deze onderzoeken identificeerden we ook een kenniskloof met betrekking tot de tijdelijke evolutie van immuunresponsen in dierinfectiemodellen. We toonden verschillende temporele expressieprofielen van cytokines en, belangrijker nog, bewezen dat serumniveaus representatief zijn voor de lokale longimmuunrespons bij muizen. Wij zijn van mening dat deze onderzoeken een belangrijke impact zullen hebben op preklinisch onderzoek waarbij gebruik wordt gemaakt van deze pneumonie knaagdiermodellen. Met de opkomst van SARS-CoV-2 verschoof de focus van dit proefschrift op COVID-19-pneumonie. Bij de zoektocht naar biomerkers voor de ernst van de ziekte ontwikkelden we eerst een model op basis van cytokines, chemokines en groeifactoren (CCG) om de ontwikkeling van acute longinsufficiëntie (ARDS) al op het moment van ziekenhuisopname te voorspellen. Dit onderzoek toonde ook een significante rol van TGF-β in COVID-19 wiens functie zowel in verband staat met normale genezing als met fibrose die wordt gezien bij COVID-19-patiënten. Ten slotte lieten we in een aan SARS-CoV-2 blootgestelde kankerpopulatie langdurige veranderingen in niveaus van inflammatoire CCG's zien, waarvan sommige ook tumorbevorderende factoren zijn. Deze resultaten vragen om verhoogde waakzaamheid bij aan SARS-CoV-2 blootgestelde kankerpatiënten en behandeling van post-acute-COVID. Het werk uitgevoerd in dit proefschrift leverde nuttige inzichten op in ons begrip van de moleculaire pathologie van pneumonie en zal de basis vormen voor toekomstig translationeel onderzoek naar de ontwikkeling van diagnostische hulpmiddelen en nieuwe therapieën gericht op het immuunsysteem, zowel voor bacteriële als voor virale pneumonie.

Anatomical and pharmacological strategies to improve treatment outcome in patients with obstructive sleep apnea - Eli Van de Perck (29/06/2022)

Eli Van de Perck

  • 29 June 2022
  • Time: 5 PM - 7 PM.
  • Venue: CDE, building Q, Promotiezaal 
  • PhD defence
  • Supervisors: Prof. O. Vanderveken, em.prof. M. Braem and prof. J. Verbraecken

Abstract

The field of obstructive sleep apnea (OSA) is moving from a one-size-fits-all to an individualized approach. Although continuous positive airway pressure clearly has a place as highly efficacious treatment, there are several opportunities to tailor therapy to the individual patient. This thesis aimed to improve treatment outcome in patients with OSA by combining anatomical and pharmacological strategies. The first part focused on endoscopic techniques. It explored the value of office-based nasopharyngoscopy as screening tool for oral appliance therapy and provided recommendations for drug-induced sleep endoscopy (DISE) scoring. Second, we applied an innovative method based on specific flow parameters to identify the site(s) of upper airway collapse during DISE. Last, this thesis assessed the potential of acetazolamide, a carbonic anhydrase inhibitor, as adjunct therapy for upper airway surgery and determined its lowest effective dose. Overall, these findings may promote a personalized management approach in patients with  OSA.

Genomics and innovative induced pluripotent stem cell (iPSC) modeling to improve understanding of pathomechanisms underlying Brugada syndrome (BrS) - Aleksandra Nijak (29/06/22)

Aleksandra Nijak:

  • 29 June 2022
  • Time: 5 PM - 7 PM.
  • Venue: CDE, building O, room O3
  • PhD defence 
  • Supervisors: prof. B. Loeys, prof. M. Alaerts and prof. A. Labro

Abstract

Brugada syndrome (BrS) is an inherited cardiac arrhythmia disorder that predisposes patients to ventricular fibrillation and sudden cardiac death. This event mainly occurs in young adults, who often do not experience any prior symptoms. Over 20 genes have so far been reported to be involved in BrS development, but contemporary knowledge about the pathomechanisms underlying BrS is limited and about 70% of the patients remain genetically undiagnosed. Also, no suitable pharmacological therapies exist. Identification of novel genes underlying BrS can contribute important knowledge on disease mechanisms and reveal potential therapeutic targets, and as such formed the general aim of this thesis.

While heterologous expression models remain a gold standard in studies of single causal mutations for cardiac arrhythmias, iPSC models provide a solution to study more complex cases, where a sum of multiple factors is at play for the expression of the phenotype. In this thesis, evaluation of the applicability of iPSC-derived cardiomyocytes (iPSC-CM) in BrS studies was performed by modeling a known BrS SCN5A Belgian founder mutation (c.4813+3_4813+6dupGGGT). The previously reported variant loss-of-function effect on a single channel level observed in a heterologous expression model, was observed in the generated iPSC-CMs. Nevertheless, there was variability in the observed results, suggesting immaturity of the cell model and existence of other factors which modulate the expression of the observed phenotypes.

In the Cardiogenetics clinic at the Antwerp University Hospital, extensive phenotypic information was collected on BrS families in which genetic screening with an in-house developed cardiac arrhythmia gene panel did not yield any result. Three of those families became the basis for this project, in which a combined linkage analysis and whole-genome sequencing approach was used to look for potential disease-causing variants. The applied genetic screening identified a significantly linked region on Chromosome 2 in one of the families, however without identification of a clear candidate variant. Also in the other unresolved families no strong candidate variant was identified. Next, BrS modeling was performed in iPSC-CMs from two patients and one unaffected relative of the family showing linkage, to gain insights on the disease mechanism. While in literature reports iPSC-CM models of genotype-negative BrS patients did not show phenotypical changes, in this PhD project the patient-derived iPSC-CMs displayed a BrS phenotype with either sodium current reduction and/or calcium handling abnormalities, encouraging further investigation. The obtained results suggest different underlying disease mechanisms within one family, which underscores the complex nature of BrS.

The delayed preshaped-breast principle after nipple-sparing mastectomy: A safe two-staged breast reconstruction in the anatomically challenging breast - Thierry Tondu (28/06/2022)

Thierry Tondu:

  • 28 June 2022
  • Time: 4:30 PM - 6:30 PM.
  • Venue: CDE, building Q, Promotiezaal
  • PhD defence 
  • Supervisors: prof. W. Hubens, prof. W. Tjalma, prof. V. Verhoeven and prof. P. Blondeel

Classification and functional approach of emotion disorders: psychomotor symptoms and personality pathology - Lieve Beheydt (27/06/2022)

Lieve Beheydt:

  • 27 June 2022
  • Time: 5:15 PM - 7:15 PM.
  • Venue: De Leuze, Congrescentrum UPC Duffel. Stationsstraat 22c, 2570 Duffel
  • PhD defence 
  • Supervisors: Em.prof. B. Sabbe, prof. P. Luyten and prof. D. Schrijvers

Abstract

Evaluating the severity of symptoms is not enough as severity assessment in depression treatment. The well-known 5 R's complicate assessment of severity: lack or delay of Response, incomplete Remission, Relapse, permanent impairment (Recovery), and recurrent episodes (Recurrence). These five disruptive factors in recovery from depression occur with two 'trait' features, the psychomotor cluster of symptoms and disturbed personality functioning. These belong, however, to two different clinical perspectives: the perspective of classification of diseases and the perspective of exploration of normal developmental processes. This study tries to connect those perspectives in a two-pronged approach and make that connection recognizable to the clinician to provide indications for better-tailored therapy.

In the first part, we closely examine different dimensions of psychomotor retardation in the elderly with and without depression. We show that psychomotor retardation in the elderly is manifest in the elderly, not only by the depressive state but also due to the interaction between aging and depression. Furthermore, recovery of psychomotor retardation appears to be more delayed and slower than the recovery of mood complaints, which is typical of the older population.

In a second part, we investigated personality functioning as a developmental process of the dimensions of identity and relationships with others, determining the presence and severity of a personality disorder. In addition, we investigated whether distinguishing disturbed personality functioning from the burden of clinical distress is possible. In a student population, we obtained indications for a cut-off point of a sufficient level of personality functioning. The 'sufficient' functioning meant no  association with symptoms. In contrast, in a psychiatric population with emotional disorders, controlling for the influence of mood symptoms and dissociation revealed divergent associations between personality disorders and the level of personality functioning. This finding led to an investigation of the possible impact of a general psychopathology factor that could explain these differences. We explored the separate contribution of extreme style and overall vulnerability to psychopathology in personality disorders. The general factor for psychopathology was manifest in all personality disorders but in very different proportions with style. This functional unraveling offers tools for targeted therapy. Distinguishable targets for emotional disorders include cognitive modeling in thought disorders, treatment of biological psychiatric symptoms, stress coping, adaptive skills for extreme styles, and a focus on relational functioning (empathy and intimacy) or self-functioning (identity and autonomy)  for further personality development.

Family planning knowledge and use by people living in fishing communities of Lake Victoria in Uganda - Annet Nanvubya (17/06/2022)

Annet Nanvubya:

  • 17 June 2022
  • Time: 5:15 PM - 7:15 PM.
  • Venue: CDE, building R, room R.003
  • PhD defence 
  • Supervisors: prof. JP. Van geertruyden and dr. R. Wanyenze


Therapeutic inertia in the management of hypertensive patients in general practice - Jean-Pierre Lebeau (17/06/2022)

Jean-Pierre Lebeau:

  • 17 June 2022
  • Time: 4:00 PM - 6:00 PM.
  • Venue: CDE, building O, aula O5
  • PhD defence 
  • Supervisors: em.prof. E. Vermeire, em.prof. K. Hendrickx and prof. R. Remmen

Questions and Answers about Quality of Colonoscopy in Belgium - Elisabeth Macken (14/06/2022)

Elisabeth Macken:

  • 14 June 2022
  • Time: 4:00 PM - 6:00 PM.
  • Venue: CDE, building O, aula O4
  • PhD defence 
  • Supervisors: Prof. G. Van Hal and prof. S. Van Dongen

Primary mast cell disorders: from biomolecular profiles to clinical perspectives - Leander De Puysseleyr (10/06/2022)

Leander De Puysseleyr:

  • 10 June 2022
  • Time: 5:00 PM - 7:00 PM.
  • Venue: CDE, building O, aula O5 or online
  • PhD defence 
  • Supervisors: Prof.  V. Sabato, prof. D. Ebo and prof. M. Hagendorens

Immunosuppressive impact of the CD73-adenosine pathway in colorectal cancer liver metastasis: a paradigm shift towards immune-based prognostication - Nouredin Messaoudi (10/06/2022)

Nouredin Messaoudi:

  • 10 June 2022
  • Time: 3:00 PM - 5:00 PM.
  • Venue: CDE, Q.002 (promotiezaal)​
  • PhD defence 
  • Supervisors: Prof.  D. Ysebaert, Prof. S. Turcotte, Prof. P. Vermeulen 

Abstract

​Colorectal cancer (CRC) constitutes the third most frequent type of cancer worldwide. Approximately 50% of all patients with CRC develop liver metastases (CRLMs) in the course of their disease. Liver resection in combination with systemic chemotherapy is regarded as the most effective and potentially curative treatment strategy for CRLMs, with a 5-year survival rate surpassing 50%. Despite the advent of modern chemotherapy and broadened surgical indications for liver resection, the majority of patients develop recurrent disease within 2 years after hepatectomy.
Although current risk assessment tools based on clinicopathological factors have been generally informative, they have however failed to incorporate the prognostic relevance of immune evasion as an important hallmark of cancer growth and progression. Moreover, immune checkpoint blockade has not yet been effective in patients with mismatch repair proficient metastatic CRC. New targeting immunosuppressive metabolic pathways are therefore being explored as a novel immunotherapeutic approach. As such, the CD73-adenosine axis represents a promising target in immuno-oncology. Extracellular adenosine is a potent immunosuppressive metabolite of ATP released by cancer and immune cells in the tumor microenvironment. The membrane-bound and soluble homodimer nucleotidase CD73 is the rate-limiting enzyme in the ATP to adenosine degradation pathway. CD73 is also an adhesive and signaling molecule that has been associated with cancer proliferation, invasion, metastasis, neovascularization and drug resistance.
In this thesis, we focus on the prognostic value of CD73 expression in CRLMs, claiming that high intratumoral CD73 levels, measured by immunofluorescence, may be
useful in predicting a subgroup of patients with poor pathological features, shorter recurrence time and worse survival, independently from other clinico-pathological variables. This groundwork defines the biological relevance and potential rationale of targeting CD73 in now-designed clinical immune-oncology trials using blocking antibodies or inhibiting the adenosine A2A receptor in patients with CRLMs.
While histopathology and immune scoring of primary CRC are well studied, comparatively little is known about metastatic CRC lesions. We therefore address in this thesis associations between histopathological growth patterns (HGPs) of CRLMs and three adaptive immune features, representing effector T cells (CD3), antigen presentation (MHC-I), and immunosuppression within the tumor microenvironment (CD73). After validating the prognostic value of HGPs, our main contribution is to find that CD73 expression was the immune marker best able to further stratify patients. This thesis advocates however that no single biomarker can accurately predict outcome, but that models integrating clinical, histological, immune and other parameters are needed to guide clinical decision making in CRLM patients.

Ill during the weekend: to the General Practitioner or to the Emergency Department? - Stefan Morreel (07/06/2022)

Stefan Morreel:

  • 7 June 2022
  • Time: 4:30 PM - 6:30 PM.
  • Venue: CDE, building O, aula O6. Registration required.
  • PhD defence 
  • Supervisors: Prof. V. Verhoeven, prof. H. Philips and prof. K. Monsieus

Abstract

When confronted with an illness during out-of-hours care, patients can consult primary care (organised in General Practice Cooperatives, GPCs) or an Emergency Departments (EDs). Up to 40% of those who choose the ED have complaints suitable for primary care. One solution to this problem is to help patients to make this choice by triage, a quick examination to determine the priority of need and proper place of treatment.

In two precursory studies concerning 1733 telephone triage, we found that this system was not ready for implementation, telephone triage alone was not the solution. A pilot studying a campaign promoting the GPC at an ED, resulted in the save diversion of 5% of the patients from the ED to the GPC.

The TRIAGE trial was an unblinded randomised controlled trial with weekends serving as clusters. The intervention was triage by a nurse using a new tool assigning low-risk patients to the GPC. During intervention weekends, patients were encouraged to follow this assignment while it was not communicated during control weekends (all patients remained at the ED).

Out of the included patients, 9.5% were diverted to the GPC. This proportion was influenced by the reason for encounter, age of the patient, and the nurse on duty. Out of the diverted patients, 4% were referred back to the ED. The trial was randomised for the secondary outcome: the proportion of patients assigned to the GPC. In the intervention group, this proportion was 13%, in the control group 25%. This discrepancy was due to differences in the use of the studied tool.

Using semi-structured interviews with healthcare workers we found a high enthusiasm. Risk aversion of some nurses, possible language barriers and the non-adapted ED infrastructure were the main barriers to implementation. One quarter of the patients who received an assignment to the GPC refused to comply and stayed at the ED. This proportion was influenced by the nurse on duty and the patient’s socio-economic status. The intervention reduces costs for patients but slightly increased cost for the government.

Overall, the intervention of the TRIAGE trial was evaluated positive, albeit some methodological limitations and a low efficiency. It helps patients to choose the most appropriate caregiver. An integrated approach which includes self- and telephone triage is required for further implementation.

Tumor vessel co-option at single-cell resolution - Laure-Anne Teuwen (31/05/2022)

Laure-Anne Teuwen

  • 31 May 2022
  • Time: 5 PM - 7 PM.
  • Location: KUL, 02.21
  • PhD defence
  • Supervisors: Prof. S. Van Laere, Dr. P. Vermeulen, Prof. P. Carmeliet
    Counselor: Dr. L. Dirix

Abstract: 

Tumors depend on blood vessels to survive, grow and metastasize. They can ensure access to
blood vessels through angiogenesis, which means they induce the sprouting of new blood
vessels from existing ones by releasing growth factors into the environment. Decades ago,
the discovery of tumor angiogenesis led to the concept of "anti-angiogenic therapy", with the
idea that blocking a tumor's blood supply, would starve the tumor to death. Since 2004, this
therapy has been introduced for several tumor types, but has only a limited effect, due to
intrinsic or acquired resistance.
One important resistance mechanism to anti-angiogenic therapy is "tumor vessel cooption",
a process in which tumors use the already existing blood vessels from the organ in
which they are growing. Vessel co-option occurs frequently, but has been poorly studied,
which results in insufficient knowledge to develop an effective therapy. To improve this, it is
essential to generate insight into the role of the different cell types involved in vessel cooption.
In the first part of this thesis, I present an optimized protocol to isolate endothelial
cells, the cells that line the inside of blood vessels, from different types of organs. This is of
great importance, since high quality cells are necessary to perform reliable analyses. These
protocols can also be used, with minor modifications, for the isolation of other cell types from
normal and tumor tissue.
In the second part of this thesis, I show that blood vessels in vessel co-option share
similar characteristics with healthy blood vessels, both in terms of endothelial cells and
pericytes, the cells that surround blood vessels and provide stability. I describe a population
of cancer cells with invasive properties, which they require to move forward along blood
vessels, and likely forms an important mechanism that enables vessel co-option. I also
describe two types of macrophages, a type of immune cell, that might play a role in vessel cooption
by dismantling and assembling the matrix of tissues so cancer cells can move through,
and by potentially sending signals to pericytes to remain in a resting state.
The results I describe in this thesis may prompt further research into different cell
types that play an active role in vessel co-option, as well as their interactions with each other.
This may bring us one step closer to developing a therapy against vessel co-option, with the
ultimate goal to improve the survival of patients with cancer.

Improving antibiotic prescribing in out-of-hours primary care through participatory action research - Annelies Colliers (25/05/2022)

Annelies Colliers

  • 25 May 2022
  • Time: 6 PM - 8 PM.
  • Venue: CDE - building Q - Promotiezaal 
  • Registration
  • PhD defence
  • Supervisors: Prof. S. Coenen, prof. S. Anthierens and prof. H. Philips


A novel combination strategy of anti-CD70 immunotherapy and chemotherapy in non-small cell lung cancer: the right partners in crime? - Tal Flieswasser (24/05/2022)

Tal Flieswasser

  • 24 May 2022
  • Time: 2 PM - 4 PM.
  • Location: D.Q.002, Promotiezaal
  • PhD defence
  • Supervisors: Prof.E. Smits, Prof. P. Pauwels, Prof. J. Jacobs

Abstract:

This PhD dissertation focused on the immune checkpoint protein CD70, as an attractive immunotherapeutic target to exploit in non-small cell lung cancer (NSCLC). First, we evaluated CD70 expression using one validated method, which showed that anti-CD70 therapy could be explored in a broad range of tumor types, including NSCLC. When CD70 binds to its unique receptor CD27 (present on tumor-infiltrating lymphocytes), the soluble form of CD27 (sCD27) is released and can be found in body fluids. In line with this notion, we evaluated the potential use of sCD27 as a blood-based surrogate marker for CD70 expression on the tumor cells, which would provide a less invasive method to decide upon anti-CD70 therapy. Here, we did not find a correlation between patient-matched sCD27 serum levels and CD70 expression on tumor specimens in the NSCLC patient population. In addition, we found that 31% of the NSCLC specimens were CD70 positive, pointing out the potential of anti-CD70 therapy in a considerable subset of NSCLC patients. To further improve the treatment efficacy, we further assessed a combination strategy of anti-CD70 therapy and chemotherapy. Different clinically relevant chemotherapies were evaluated for their ability to induce immunogenic cell death (ICD), a type of cell death that can enhance the anti-tumor immune response. Here, we observed that the chemotherapeutic regimen of docetaxel and cisplatin was the most ideal partner for anti-CD70 therapy in terms of its ability to induce ICD. Moreover, we observed increased CD70 expression on the tumor cells after treatment with this chemotherapeutic regimen, suggesting this combination could be used to broaden the therapeutic window of anti-CD70 as well. Finally, the effects of anti-CD70 therapy as single agent or in combination with chemotherapy on NSCLC killing and the anti-tumor immune response were evaluated. We observed that the sequential treatment schedule of chemotherapy and anti-CD70 therapy resulted in significantly improved overall survival and a delay in tumor growth in Lewis lung carcinoma-bearing mice. Chemotherapy increased the numbers of dendritic cells in the tumor-draining lymph nodes, suggesting its ability to enable responsiveness to anti-CD70 therapy. Furthermore, the sequential treatment schedule showed increased intratumoral T and NK cell numbers, and increased ratios of CD8+ T cells over regulatory T cells, which could explain the enhanced anti-tumor effects after sequential therapy in this in vivo NSCLC model. The superior effect of the sequential combination therapy on improved survival was further validated in a more humanized in vivo model.

Unravelling the Role of Cochlin in the Innate Immune Response of the Cochlea: Impact of Noise Exposure and Pathogenic Variants in the Coch allele - Dorien Verdoodt (23/05/2022)

Dorien Verdoodt

  • 23 May 2022
  • Time: 4 PM - 6 PM.
  • Location: D.Q.002, Promotiezaal​
  • PhD defence
  • Supervisors: Prof. V. Van Rompaey, Prof. P. Ponsaerts, Prof. G. Van Camp

Abstract: 

The main topic of this doctoral thesis is the COCH gene and the protein which it encodes, cochlin. This protein is mainly expressed in the spiral ligament of the inner ear. The function of cochlin is not fully understood but there is a growing body of evidence that it plays an important role in the innate immune system of the cochlea. Furthermore, cochlin has a role in maintaining the structure and function of the extracellular matrix of the inner ear. One of the disorders caused by mutations in the COCH gene is DFNA9, which is a dominant hereditary disorder characterized by progressive hearing loss and vestibular dysfunction. Different heterozygous mutations can cause DFNA9. Dependent on the exact location of the mutation in the COCH gene, a slightly different phenotype and pathology is observed between DFNA9 patients harbouring different pathogenic variants. A Coch knockout mouse model has been used to investigate the role of cochlin in the inner ear. These mice do not express cochlin as exon 7 to exon 12 of the COCH gene is removed. Both Coch knockout mice and Coch wildtype mice were exposed to noise in order to investigate the role of cochlin after noise exposure.

The first section of this thesis focuses on the optimization of hearing and vestibular assessment in mice. To evaluate hearing function, ABR and DPOAE measurements were performed. These quantitative measurements assess inner and outer hair cell function respectively and require the mice to be under anaesthesia during the tests. A test battery based on observation of behaviour and different reflexes was performed to evaluate vestibular function semi-quantitatively in mice. Two different anaesthetics are commonly used to perform these measurements: isoflurane (an inhalation anaesthetic) and a mixture of ketamine and xylazine (a parenteral anaesthetic). In the first section of this PhD thesis, the effect of both anaesthesia methods on hearing thresholds in mice was evaluated. Furthermore, allylnitrile was administered to mice to obtain a total loss of hearing function. This allowed us to assess whether our set-up could differentiate between deaf mice and mice with a normal hearing function.

The second part of this doctoral thesis describes the function and physiology of the spiral ligament fibrocytes. The spiral ligament forms the outer wall of the cochlea and consists of five different types of fibrocytes. Cochlin is an important protein in the spiral ligament and plays a key role in maintaining the ion homeostasis in the endolymph, the regulation of the cochlear blood flow and immune response in the cochlea. In addition, section two outlines the pathology observed in the spiral ligament of DFNA9 patients and the different pathogenic variants present in the COCH gene and their effect on hearing loss and vestibular dysfunction.

In section three of this doctoral thesis, Coch knockout and Coch wildtype mice were exposed to noise. Noise exposure can induce hearing loss by causing damage to different cochlear cells. In addition, an inflammatory response and oxidative stress in the inner ear enhance hearing loss. The inferior region of the spiral ligament, where COCH expression is most abundant, is the most sensitive to noise exposure. Therefore, in the third section of this doctoral dissertation, investigating the role of cochlin after noise exposure was performed by exposing both Coch knockout and Coch wildtype mice to broadband noise.

Finally, the fourth part of this dissertation focuses on the use of an adeno-associated viral vector to deliver gene therapy into the inner ear. Gene therapy can have the potential to prevent otovestibular loss originating from pathogenic variants in several genes. Even though AAV are the most frequently used viral vectors to deliver gene therapy into the cochlea, little is known regarding their transduction efficiency in different cochlear cell types and the possible induction of an immune response. This part gives an overview of the transduction efficiency of several AAV serotypes in different cochlear cell types as well as the best method to inject AAV in the inner ear, the optimal AAV concentration and the possible risk regarding an immune response in the cochlea.


Exploring the neural activity underlying tinnitus perception and its therapeutic exploitation - Emilie Cardon (20/05/2022)

Emilie Cardon

  • 20 May 2022
  • Time: 5 PM - 7 PM.
  • PhD defence
  • Venue: CDE - building O - aula O6
  • Supervisors: Prof. V. Van Rompaey, prof. A. Gilles and em.prof. P. Van de Heyning

Abstract

Tinnitus, the perception of sound in the absence of an external sound source, occurs in ten to fifteen percent of the general adult population. The phantom sound can be accompanied by several nonspecific symptoms, including hearing loss, anxiety, depression, and concentration difficulties. There currently is no cure for tinnitus, partially due to an incomplete understanding of its pathophysiology. Although tinnitus is often associated with hearing loss, there is no straightforward causal relationship between both symptoms. A cascade of neural alterations may lead to a pattern of modified activity and connectivity in several brain areas, ultimately leading to the perception of a phantom sound. So far, it has proven difficult to target this neural activity, and a lack of biomarkers hampers the search for successful treatments. Therefore, this thesis explores neurobehavioral measures that may function as biomarkers for the perception of tinnitus, and examines whether the neural activity underlying tinnitus can be targeted therapeutically.

In a first chapter, we investigate whether tinnitus can be characterized using auditory evoked potentials, electrophysiological responses to auditory stimuli. A meta-analysis revealed that the P300 component, a response to unexpected but relevant stimuli, is diminished in patients with tinnitus. The second chapter of this thesis exposes subtle deficits in cognitive performance, confirming the impact of tinnitus on the executive control of attention. These neural and behavioral measures are combined in a third chapter, which uses novel analytic techniques to further illuminate the neural alterations underlying tinnitus. This chapter culminates in the development of a model to detect the presence of tinnitus, based on an integration of neural and neurobehavioral measures.

A second part of this thesis focuses on the use of high-definition transcranial direct current stimulation (HD-tDCS) as a treatment for tinnitus. Although tinnitus severity decreased over time in both the active treatment and the sham control group, we report no beneficial effect of active HD-tDCS over sham treatment. In a final chapter, we present a machine learning model that is able to predict treatment response.

The work presented in this dissertation confirms the role of the P300 response as an objective read-out of tinnitus-related cortical activity. Novel measures can provide insight into the pathophysiology of tinnitus and may also be used as biomarkers to facilitate research into experimental treatments. Furthermore, we offer recommendations for future randomized controlled trials in tinnitus populations. Lastly, this thesis demonstrates the appeal of machine learning models for treatment prediction.

Integrated management of patients with atrial fibrillation Full care pathway and insights in several of its components - Michiel Delesie (18/05/2022)

Michiel Delesie

  • 18 May 2022
  • Time: 4 PM - 6 PM.
  • Venue: CDE - building O - aula O5 or online
  • Joint PhD defence with UHasselt
  • Supervisors: prof H. Heibuchel, prof L. Desteghe and prof P. Dendale

Abstract

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide and creates a significant burden on patients, physicians and healthcare systems. To reduce the AF burden by delivering optimized AF care, AF guidelines propose a patient-centered, multidisciplinary and structured integrated care approach. This integrated AF care concept consists of different components, but it remains unknown which elements are beneficial or may be redundant. In addition, several elements of the integrated AF care concept itself contain specific knowledge gaps.

Firstly, the ongoing AF-EduCare study is introduced, which is a large multicenter randomized clinical trial based on the integrated AF care model consisting of (i) targeted AF education, (ii) improving patients’ lifestyle, (iii) optimizing adherence to oral anticoagulants (OAC) and (iv) continuity of care for AF patients in case of AF related problems. The main aim of this trial is to improve several (clinical) outcomes for AF patients. The characteristics of the assessed AF population for this study (n=1232) and its eventual participants are also discussed, providing insights in the current AF management in Flanders. In contrast to prior integrated AF trials, the AF-EduCare study incorporates all types of AF patients.

In the second part, specific building blocks of the integrated AF care model were further investigated. Appropriateness of non-vitamin K antagonist oral anticoagulants (NOAC) dosing in ambulatory care was assessed. This study found a relatively high proportion of AF patients receiving an inappropriate NOAC dose according to different NOAC dosing algorithms. Furthermore, an electronic medication event monitoring system (MEMS) for optimizing OAC adherence is investigated in the AF-EduCare study. A first analysis showed a high mean adherence >90% for all OAC therapy. Future results and additional analysis will provide more insights into the use of the MEMS and its influence on improving adherence to OAC therapy. Tools for the detection of obstructive sleep apnea (OSA), a highly underrecognized AF risk factor, were evaluated as screening options in AF patients. The use of OSA screening questionnaires/scoring systems for the detection of clinically relevant OSA was highly questionable, but polygraphy devices combined with an automated algorithm can be used as reliable OSA detection tools in selected AF patients. Lastly, motivation for weight reduction in overweight AF patients and associated factors were investigated. One-third of the participants did not realize that being overweight is an AF risk factor. Tailored (home-based) weight reduction programs should be developed and validated to address this prevalent AF risk factor.

In conclusion, the results of these investigated components contribute to the optimization of integrated AF management. In addition, based on the future outcome results of our large AF-EduCare trial, we can hopefully obtain an effective blueprint for a structured AF care approach and add extra evidence to the integrated AF concept.

Physiological Basis for Revascularization of Left Main Coronary Artery Lesions and Chronically Occluded Coronary Arteries - Peter Kayaert (9/05/2022)

Peter Kayaert:

  • 9 May 2022
  • Time: 5 PM - 7 PM.
  • Venue: muziekcentrum De Bijloke, Bijlokekaai 9, 9000 Gent. Registration required.
  • Joint PhD defence with UGhent
  • Supervisors: Prof. S. Haine, prof. S. Gevaert and prof. M. De Pauw

Abstract

This thesis sought evidence from coronary physiology that selected patients with a left main coronary artery (LM) lesion or a chronic total occlusion (CTO) of a coronary artery may benefit from myocardial revascularization (MR) and that physiological assessments may assist in guiding and/or optimizing treatment.

In the first part, we investigated the subset of patients with a LM lesion. 

We first showed by analyzing the nationwide Quality-oriented Electronic Registration of Medical Implant Devices (QERMID) registry data, that patients undergoing LM percutaneous coronary intervention (PCI) had a significant risk of short- and long-term mortality. ST-elevation myocardial infarction (STEMI) patients presenting in cardiogenic shock and undergoing LM PCI also had a higher mortality compared to that in the whole group of cardiogenic shock patients.

Second, we reviewed the current evidence on physiology-based revascularization of LM lesions. We concluded that the recommended physiological assessment techniques, fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR), have only been studied relatively limitedly in the setting of LM disease and are probably insufficient on their own to correctly predict the prognosis of the individual patient.

Third, we presented the first results of the Prospective Left Main Physiology (PHYNAL) registry that was established to collect more physiological, imaging and outcome data on this type of patients. Physiological measurements yielded contradictory results in more than a quarter of patients and even more so if concomitant downstream disease is present.

In the second part, we investigated the subset of patients with a CTO.

First, we looked at the evidence underlying CTO PCI. Most proven today is its potential to better reduce ischemic symptoms compared to optimal medical treatment alone.

Next, we showed our analysis of the Belgian Working Group on CTO (BWGCTO) registry, illustrating that today CTO PCI can be performed with a high success rate and few complications.

Finally, we presented the DISTAL CTO study results. We were able to demonstrate with physiological assessments that CTO patients do indeed have ischemic myocardium and that PCI can alleviate this, which may explain symptomatic improvement. We also showed that residual ischemia can persist in up to 30% of patients. To improve the clinical outcomes of CTO PCI, one should strive to optimize PCI results as best as possible, and our findings suggest that physiological assessment can help with that.

Postpartum lifestyle, weight and body composition - Margriet Bijlholt (26/04/2022)

Margriet Bijlholt

  • 26 April 2022
  • Time: 4 PM - 6 PM.
  • Joint PhD defence
  • Supervisors: Prof. A. Bogaerts (UA) and prof. R. Devlieger (KULeuven)

The role of differentially active T-cell subsets in the pathogenesis of non-alcoholic steatohepatitis - Mikhaïl Van Herck (19/04/2022)

Mikhaïl Van Herck

  • 19 April 2022
  • Time: 5 PM - 7 PM.
  • PhD defence
  • Supervisors: prof. S. Francque, prof. L. Vonghia, prof. T. Vanwolleghem
    Mentor: prof. D. Ebo

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disease states characterized by hepatic steatosis, which includes the more active disease state called non-alcoholic steatohepatitis (NASH). NAFLD is a highly prevalent condition, reaching a prevalence of 25-30% in the general population of the Western world. The pathogenesis of NASH is complex and entails multiple parallel hits, involving both the liver and the adipose tissue, with a critical role for the immune system. The aim of this research work was to further explore the involvement of the cell-mediated component of the adaptive immune system, specifically cytotoxic T (Tc) cells, regulatory T (Treg) cells, T helper 1 (Th1) cells, and T helper 17 (Th17) cells, both at the level of the liver and the adipose tissue, in a high-fat high-fructose diet (HFHFD) mouse model.

In a first experiment, we used the HFHFD mouse model to elicit NASH and study the above-mentioned T-cell subsets in multiple involved tissues. We demonstrated an expansion of Th17 cells in the liver, whereas both Tc cells and Th17 cells were increased in the visceral adipose tissue (VAT). Conversely, Treg cells were shown to be reduced in the VAT.

In a second experiment, we used a diet reversal from HFHFD to control diet to elicit weight loss and NASH resolution. Remarkably, in contrast to the marked phenotypical improvement, the above-described T-cell alterations in the liver and VAT did not revert to normal.

In a third experiment, we used anti-CD8a and anti-IL-17A antibodies, respectively inhibiting Tc and Th17 cell functionality. The treatment with anti-CD8a antibodies resulted in an attenuation of the NASH, both histologically and biochemically. Conversely, the anti-IL-17A antibodies had a less marked effect, although they did result in the attenuation of hepatic inflammation.

In a fourth and last experiment, we used an adoptive cell transfer of Treg cells from healthy donor mice to HFHFD-fed mice. Unexpectedly, this resulted in an exacerbation of the NASH, both histologically and biochemically. We formulated multiple hypotheses for this finding, including migration of the transferred Treg cells to the subcutaneous rather than the visceral adipose tissue, a reduction in Th1 cells and a role for peroxisome proliferator-activated receptor γ (PPARγ).

In conclusion, our research work presents longitudinal and mechanistic data that support a profound role for the differentially active T-cell subsets Tc, Treg, and Th17 in the liver and the adipose tissue in the pathogenesis of NASH, representing a promising therapeutic target.

Cross-cultural analysis of motivational determinants among people at risk of or with type two diabetes: A translational study of self-determination theory - Jeroen De Man (31/03/2022)

Jeroen De Man

  • 31 March 2022
  • Time: 6 PM - 8 PM.
  • Online PhD defence
  • Supervisors: Prof. R. Remmen, prof. E. Wouters, prof. J. van Olmen and prof. D. Guwattude

Abstract

Type 2 diabetes (T2D) belongs to the world’s biggest killers and is a leading cause of disability. The burden of T2D is increasing rapidly, not least in Sub-Saharan Africa, and disadvantaged populations are disproportionally affected. A healthy lifestyle such as engaging in regular physical activity and a healthy diet are key in the prevention and management of T2D, but are a challenge to implement. Understanding motivational determinants of health behavior is essential to guide implementation, but evidence is lacking for disadvantaged populations and people living in low- and middle-income countries. The aim of this study is to confirm the validity of Self-determination Theory in maintaining a healthy diet and regular physical activity among disadvantaged populations with, or at risk of diabetes.

Using structural equation modeling, we assessed the validity of a motivational process model across a rural Ugandan sample and disadvantaged samples with high proportions of immigrants in urban South Africa and Sweden.

Associations between motivational constructs and behavioral outcomes were consistent with the hypothesized Self-determination theory process model for both lifestyle behaviors. Proxy measures of perceived competence and perceived relatedness were associated with autonomous motivation for both behaviors. Findings suggested that different types of motivation regulate different domains and intensities of physical activity. We also found that it was possible to compare motivational constructs across settings, but the motivational process model was not consistent across settings.

Our findings support the use of Self-determination Theory for the implementation of a healthy lifestyle among disadvantaged populations. Our findings are relevant for health promotion at public health level, for health workers, but also for people living with type two diabetes themselves and their significant others. We recommend future research to focus on the role of perceived autonomy and to address the methodological challenges of our studies, including the cross-sectional design, the sampling strategy and the quality of the measures.

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Posttraumatic stress disorder following traumatic brain injury in civilians - Dominique Van Praag (14/03/2022)

Dominique Van Praag

  • 14 March 2022
  • Time: 5 PM - 7 PM.
  • PhD defence
  • Supervisors: prof. F. Van Den Eede and em.prof. A. Maas

Abstract

The topic of posttraumatic stress disorder (PTSD) following a traumatic brain injury (TBI) has been extensively investigated in military conflict situations. A particular need exists for research in civilian settings. The main aim of this thesis was to investigate the occurrence of PTSD following civilian TBI and explore its relation with cognitive functioning. We performed a systematic review and meta-analysis and found that 15.6% of patients with TBI develop PTSD, regardless of injury severity. Neither did we find a clear effect of measure of PTSD used, and timing of assessment as the rates of PTSD remain high up to years after the event causing TBI. Further, a Dutch translation of the PTSD Checklist for DSM-5 (PCL-5) was validated in a civilian population of Dutch-speaking patients with TBI. The validation of the Dutch version of the PCL-5 was proven to be psychometrically sound and can now be used for clinical and academic purposes. The prospective part of this thesis was part of a larger study: the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI, www.center-tbi.eu) project. The project included a multicenter, longitudinal, observational study aiming to better characterize TBI as a disease and to identify the most effective clinical interventions for managing TBI. To explore the neurocognitive correlates of PTSD following TBI, a sample of 1,134 patients with TBI was evaluated in a cross-sectional design. Those with probable PTSD (13.5%), performed significantly worse on cognitive tests assessing cognitive flexibility and verbal, long-term memory, compared to patients with TBI only. Cognitive flexibility and reaction speed was associated to PTSD symptom severity. The impact of neurocognitive functioning on the course of PTSD symptoms following TBI, was investigated in a sample of 671 patients with assessment of PTSD symptoms at 6 and 12 months post injury, and neurocognitive assessment at 6 months. Results showed that better sustained attention was associated with improving PTSD symptoms. To conclude, health care professionals should be aware of the high risk of PTSD in patients with TBI, even in civilian populations. All patients with a TBI should be screened for PTSD, regardless of the injury severity. The use of a simple screening tool should be considered as a first approach to identify those at risk for PTSD and facilitate prompt intervention. Additionally, cognitive functioning can help to differentiate for PTSD in patients with TBI and to target risk patients for increasing PTSD symptoms.

Implementation practices of tuberculosis preventive therapy for children and HIV-positive adults: a prospective cohort study at primary care - Eva Van Ginderdeuren (14/03/2022)

Eva Van Ginderdeuren

  • 14 March 2022
  • Time: 2 PM - 4 PM.
  • PhD defence
  • Supervisor: prof. A. Van Rie

Molecular, histopathological and radiological profiling of the growth patterns of liver metastases - Pieter-Jan van Dam (11/03/2022)

Pieter-Jan Van Dam

  • 11 March 2022
  • Time: 5 PM - 7 PM.
  • PhD defence
  • Supervisors: Prof. S. Van Laere and prof. P. Vermeulen

Surgical innovations in the treatment of pudendal and/or cluneal nerve impingement syndrome - Katleen Jottard (10/02/2022)

Katleen Jottard

  • 10 February 2022
  • Time: 4 PM - 6 PM.
  • PhD defence
  • Supervisor: Prof. S. De Wachter

Endoscopic procurement of tympano-ossicular allografts - Jeroen Caremans (07/02/2022)

Jeroen Caremans

  • 7 February 2022
  • Time: 5 PM - 7 PM.
  • PhD defence
  • Supervisors: Prof. V. Van Rompaey and dr. M. Huizing

Abstract

Since the technique of tympano-ossicular allograft tympanoplasty was founded in the 1960s by Marquet, en bloc allografts have been procured using the Schuknecht bone plug technique. The technique was used in many centers around the world but the rise of infectious diseases that can potentially be transmitted from donor to recipient, like HIV and Creutzfeldt-Jakob disease, led to the downfall of the use of tympano-ossicular allografts in many countries. In many centers in the Antwerp region, the technique withstood these challenges. Technological progression and the shift towards the use of a tympanomeatal allograft with separate incus, enabled the introduction of an endoscopic procurement technique. We have shown that it is feasible to procure tympano-ossicular allografts of good quality via transmeatal approach using a 30° nasal endoscope. When comparing this new procurement technique to the traditional transcranial technique, the endoscopic technique is much more time efficient (the end product is retrieved immediately rather than being dissected in a separate step), it is safer (contact with the dura mater during procurement is avoided, eliminating the already low risk of transmission of Creutzfeldt-Jakob disease) and it is less invasive, which has significantly increased the donor volume and has made the procurement more acceptable for donor relatives and cooperating hospitals. On the other side it is more difficult to learn and the long term percentage of good quality allografts is lower. However, the increase in donor volume outweighs the decrease in percentage of good quality allografts. This aspect together with the other mentioned advantages have argumented our decision to fully replace the transcranial bone plug technique by the endoscopic procurement technique.

After switching to the new technique, the clinical outcome of the tympano-ossicular allografts was reported. In a first step we compared in a prospective, randomized audit the results of transcranially versus endoscopically procured allografts. No statistically relevant difference was observed in a small group of patients with regards to the graft take rate three months after surgery. In a second step, the graft take rate was analyzed retrospectively on a bigger group of patients. The graft take rate at three months was shown to be similar to the graft take rate as reported in literature.

Finally, literature showed that the formaldehyde solution used for tympano-ossicular allograft preservation is efficient in inactivating viruses like HIV, HBV, HCV and coronaviruses. These results, combined with other safety measures, make tympano-ossicular allografts a very safe reconstruction material.

Fenfluramine in the treatment of Developmental and Epileptic Encephalopathies - An-Sofie Schoonjans ( 28/01/2022)

An-Sofie Schoonjans

  • 28 January 2022
  • Time: 5 PM - 7 PM.
  • PhD defence
  • Supervisors: Prof. B. Ceulemans and prof. P. Cras

Utilising Next-Generation Sequencing to investigate Staphylococcus aureus infections and associated alternative phenotypes - Jelle Vlaeminck (25/01/2022)

Jelle Vlaeminck

  • 25 January 2022
  • Time: 3 PM - 5 PM.
  • Online PhD defence
  • Supervisors: Prof. S. Malhotra and prof. H. Goossens

Abstract

Over the past thirty years, Next-Generation Sequencing (NGS) has enabled the fields of clinical microbiology and infectious diseases to investigate the genetic context of human pathogens. Its many applications such as whole genome sequencing (WGS), transcriptomics and metagenomics have deepened our understanding of human pathogens and their infection mechanisms, thereby improving patient care.

Staphylococcus aureus is a Gram-positive bacterium which is carried commensally by a significant proportion of the human population. However, it is also a notorious, opportunistic pathogen capable of inflicting several severe, and sometimes fatal, healthcare-associated infections (HAIs). Throughout history it has acquired high levels of antimicrobial resistance (AMR) against many clinically used antibiotic classes, impeding treatment and increasing medical costs and burdens on healthcare systems. Best known examples are methicillin-resistant S. aureus (MRSA) and, more recently, vancomycin-resistant S. aureus (VRSA). Moreover, S. aureus has developed several alternative phenotypes, such as shielding biofilm and antibiotic tolerant persisters, further complicating eradication of this pathogen in case of infection. All these factors make that the World Health Organization (WHO) classified S. aureus among the ESKAPE pathogens, a list of six highly virulent and antibiotic resistant bacterial pathogens which require urgent research and development of new targeted therapeutics.

Therefore, in this thesis, we utilise NGS to investigate S. aureus and aim to identify (genomic) determinants to characterise it as infectious pathogen. Firstly, we investigate the current molecular epidemiology of commensal S. aureus in the European surgical community by WGS. This is followed by results from a study where we elucidated the effect of colonisation on the development of S. aureus pneumonia (SAP) in critically ill, mechanically ventilated intensive care unit (ICU) patients. We also investigate the genomes of S. aureus isolated at ICU admission and SAP infection to identify genomic determinants causative of SAP. Both studies were imbedded in two pan-European, multicentre clinical trials conducted within COMBACTE-NET by the COMBACTE consortium. In the second part of this thesis, we investigate gene expression variation in S. aureus biofilm and persisters by transcriptomics to learn more about these alternative phenotypes and potential therapeutic targets.

In conclusion, this thesis utilises state-of-the-art sequencing technology to deepen our understanding of the S. aureus genome and its relation with the development of SAP and the formation of biofilm and persisters. This in order to identify current knowledge gaps and novel potential therapeutic targets to combat the many different mechanisms that make S. aureus a potent infectious pathogen.

Evaluation of cervical cancer screening uptake, HPV genotyping and self-sampling collection techniques in Ethiopia - Eshetu Lemma Haile (13/01/2022)

Eshetu Lemma Haile

  • 13 January 2022
  • Time: 5 PM - 7 PM.
  • Online PhD defence
  • Supervisors: Prof. JP. Bogers and prof. JP. Van geertruyden