Manuel Morrens professor

Research Manuel Morrens

Research team

Predictive enrichment strategies for immune-targeted interventions in depression. 01/11/2024 - 31/10/2026

Abstract

BACKGROUND: 30% of Major Depression Disorder patients display an immune-mediated subtype, associated with poor response to first-line antidepressant treatments. Immune-targeted augmentation with anti-inflammatory compounds shows promise and may be more effective for the immune-mediated subgroup. For optimal clinical trial designs, we require guidance on the selection of patients who may benefit, the outcome measures that capture the clinical benefits, and the subtype-specific effect sizes per compound. AIM: Identify baseline predictive blood-based and clinical biomarkers, define the optimal outcome measures for immune-targeted interventions, and rank these based on subtype-specific effect sizes. Facilitate science-to-policy translation by integrating research findings into clinical recommendations and predictive enrichment strategies for future clinical trials. APPROACH: I will address these questions through a dual approach, integrating insights (WP3) gained with stratification meta-analyses and individual participant data (of at least n=10 RCTs) (WP1) with the results of our pre-stratified clinical trial (WP2). IMPACT: My project will innovate MDD treatment guidelines and optimise future RCT protocols. This will result in a decreased number of failed RCTs, which will lead to cost-effective benefits and more interest among pharmaceutical industry players. The predictive enrichment strategies can then be used to innovate intervention trials also in other mental disorders.

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  • Research Project

Research line management for Neuromodulation and Immunopsychiatry 01/08/2023 - 31/12/2028

Abstract

This project aims to fund a postodoctoral fellow responsible for the Management of personnel and projects within CAPRI's research lines of neuromodulation and immunopsychiatry. Projects include the investigation of novel biomarkers for response to several neuromodulation interventions (ECT, rTMS); optimizing response to clinical ECT; investigating inflammatory biomarkers and anti-inflammatory treatment modalities in the context of mood and psychotic disorders.

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  • Research Project

Customization of prevention and treatment strategies for immune-mediated depression through immunomodulatory pharmacological and lifestyle interventions. 01/12/2022 - 30/11/2024

Abstract

Objective: Evaluate the effect of immunomodulatory pharmacological and lifestyle (exercise, nutrition) interventions in preventing and reducing depression through restoring immuneinflammatory dysregulations and related mediating neurobiological mechanisms.

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  • Research Project

The role of inflammatory pathways in depressive disorders. 17/10/2022 - 16/10/2026

Abstract

The etio-pathophysiology of psychiatric disorders such as Major Depressive Disorder (MDD), Schizophrenia (SZ), and Bipolar Disorder (BD) is complex and not fully understood. However, the involvement of various psychological and (neuro)biological systems is becoming increasingly clear. An important puzzle piece in this is the immune system, with research focusing on communication between the immune system, the central nervous system, and the psyche within the field of psychoneuroimmunology. Recently, there has been a shift towards understanding the 'bottom-up' influence of the immune system on the brain, resulting in the emergence of the field of immunopsychiatry. This project utilizes data collected during the Covid pandemic within a psychiatric population. Over a period of 2 years, blood samples were taken from new psychiatric patients admitted to the clinic, with blood samples also taken after anti-Covid vaccination. The concentration of Covid antibodies will be quantified to determine seroconversion. Additionally, important metabolites of the Kynurenine Pathway (KP) will be analyzed, given the role of the KP in the immune response and neurotransmission. Immune stimulation by Covid or anti-Covid vaccinations can lead to overactivation of the KP, potentially contributing to psychiatric symptoms following infection or vaccination. Analysis of KP metabolites can provide more insight into these processes. The KP may also influence comorbid conditions, such as sleep disorders in depression, by disrupting melatonin production. The current project analyzes KP metabolites over a period of 24 hours to examine rhythmic patterns and to identify potential differences between depressed patients and healthy controls. Further research on enzymes in the KP will be conducted to gain a better understanding of the mechanisms behind TRP metabolism and to lay the groundwork for future interventions.

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  • Research Project

Inflammation-based stratification for immune-targeted Augmentation in major depressive disorder (INSTA-MD). 01/10/2022 - 30/09/2026

Abstract

In 2018, 6% of people over the age of 15 had a depressive disorder in the Flemish Region (Statistiek Vlaanderen). In 2019, this was 36 million people per year for Europe, good for 92 billion euros in annual costs (WHO Global Burden of Disease 2019). The WHO estimates that depression will be one of the leading causes of disease burden by 2030. Depression, however, is very heterogeneous, with an estimate of 33-40% responding poorly or not at all to gold standard treatment. Innovation in the field of treatment could therefore have a major impact for this subgroup. This project aims to repurpose two established anti-inflammatory compounds as adjuvant therapy for immune-mediated depression, in line with state-of-the-art research of the last 10 years. Immune-mediated depression represents a subtype which accounts for approximately 30% of depressive disorders (Osimo et al., 2019). Patients with this immunosubtype are more likely to have a higher severity of depression, a lower quality of life and more somatic symptoms (Foley et al., 2021). Furthermore, it is accompanied by a high incidence of treatment resistance (Carvalho et al., 2013). While their mechanisms of action completely differ from those of existing antidepressant treatment options, immunomodulatory drugs celecoxib and minocycline have proven their merit as add-on treatment in depressive episodes. They have been on the Belgian market for years and come with a known pharmacological and safety profile. Patient stratification at baseline based on inflammatory status will reveal which inflammatory subpopulation benefits most from each of the two investigated anti-inflammatory compounds. Additionally, our distinctive study design allows head-to-head comparison of both add-on therapies and will as such provide the last stepping stones towards clinical implementation of individualised treatment strategies in depression. The novelty and clinical relevance of this project reside in (1) the direct comparison of each compound separately as well as (2) the selection of patients who may benefit from anti-inflammatory treatment via stratification based on baseline inflammatory levels. Hence, this project will tackle a knowledge gap vital for the development of clinical practice guidelines. The addition of this treatment option to the psychiatric arsenal and the inflammation-based stratification prior, opens the way to a pragmatic strategy in the form of personalised medicine in biological psychiatry. This could support and optimise the choice of psychiatric treatment, thus limiting exposure to ineffective treatments and shortening the length of hospital stay. As a result, this repurposing strategy will significantly reduce the associated health care costs, without the additional costs associated with bringing new compounds to market. Objectives Validate the efficacy of immune-targeted augmentation with minocycline or celecoxib in a Flemish cohort of patients with MDD who failed to remit with one or two trials of antidepressant treatment; Compare the respective acceptability, treatment response and remission rates of minocycline and celecoxib as adjunctive therapy; Compare the efficacy of both compounds as adjunctive therapy in an immune-mediated subtype of MDD versus an unstratified patient sample; Evaluate the use of hsCRP as a predictor for treatment response to minocycline and celecoxib.

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  • Research Project

Lab manager for biomarker analysis until 31/01/29 01/02/2022 - 31/01/2029

Abstract

The lab manager will be responsible for general lab organisation, equipment maintenance etc. In addition, she will execute experimental laboratory analyses upon request, including but not limited to ELISA analyses, LCMS analyses, IHC,...

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  • Research Project

IMARK. Network for image-based biomarker discovery and evaluation 01/01/2021 - 31/12/2026

Abstract

IMARK capitalizes on the deeply rooted expertise in biomedical imaging at the University of Antwerp to push the boundaries of precision medicine. By resolving molecular and structural patterns in space and time, IMARK aims at expediting biomarker discovery and development. To this end, it unites research groups with complementary knowledge and tools that cover all aspects of imaging-centred fundamental research, preclinical validation and clinical evaluation. IMARK harbours high-end infrastructure for electron and light microscopy, mass spectrometry imaging, magnetic resonance imaging, computed tomography, positron emission tomography and single-photon emission computed tomography. Moreover, IMARK members actively develop correlative approaches that involve multiple imaging modalities to enrich information content, and conceive dedicated image analysis pipelines to obtain robust, quantitative readouts. This unique blend of technologies places IMARK in an excellent position as preferential partner for public-private collaborations and offers strategic advantage for expanding the flourishing IP portfolio. The major application fields of the consortium are neuroscience and oncology. With partners from the Antwerp University Hospital and University Psychiatric Centre Duffel, there is direct access to patient data/samples and potential for translational studies.

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  • Research Project

The effect of REM sleep fragmentation on downregulation of emotional distress in patients with borderline personality disorder. 01/09/2020 - 30/11/2024

Abstract

Description: Several studies have shown that rapid-eye-movement (REM) sleep plays an essential role in the processing of emotions (Wassing et al., 2016). Research suggests that restless REM sleep reflects a process that impedes overnight resolution of emotional distress (Wassing et al. 2019). This finding is relevant when evaluating the effect that REM sleep fragmentation has in a population with severe emotional dysregulation problems, such as Borderline Personality Disorder (BPD). Particularly, as it has been shown that there is an association between subjective sleep disturbance and recovery status among BPD patients (Plante et al., 2013). This research project aims to investigate the effect that fragmented REM has on the down regulation of emotional distress in a clinical exploratory study of patients with severe emotion dysregulation, in particular borderline personality disorder. The methods of this research will include polysomnography, psychometric testing and additional (neuro)biological measures. This project will involve literature search, preparation of a doctoral thesis, contribution to research and teaching at CAPRI (Universiteit Antwerpen) en SINAPS (UPC Duffel. Coordination, management and quality assurance of the project, as well as the management of the contact with the participants and clinical health care staff of the involved hospitals (UPC Duffel and KARUS Gent). Active participation in the development of a plan for further implementation and distribution of the results of the project as well as the publication of scientific articles related to the research project of the assignment. The studies derived from this PhD appointment will be conducted in the Universiteit Antwerpen at the Department of Psychiatry, Faculty of Medicine. Research will be conducted at the Collaborative Antwerp Research Institute (CAPRI) (https://www.uantwerpen.be/en/research-groups/capri/) in combination with the Scientific Initiative for Neuropsychiatric and Psychopharmacological Studies (SINAPS) in Duffel (https://www.sinapsduffel.com/ ). Research participants recruitment will be conducted at the UPC Duffel Hospital (https://www.pz-duffel.be/ ) and the KARUS Gent Hospital (https://www.karus.be/t).

Researcher(s)

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  • Research Project

Predictive enrichment strategies for immune-targeted interventions in depression. 01/11/2023 - 31/10/2024

Abstract

BACKGROUND: 30% of Major Depression Disorder patients display an immune-mediated subtype that is associated with poor response to first-line antidepressant treatments. Immune-targeted augmentation with anti-inflammatory compounds shows promise and may be more effective for the immune-mediated subgroup. For optimal clinical trial designs, we require guidance on the selection of patients who may benefit, on the outcome measures that capture the clinical benefits, and the subtype-specific effect sizes per compound. AIM: Identify baseline predictive blood-based and clinical biomarkers to facilitate predictive enrichment strategies for future clinical trials on immune-mediated depression, define the optimal outcome measures for immune-targeted pharmacological interventions, and ranking these based on their subtype-specific effect sizes. APPROACH: I will address these questions through a dual approach, combining insights gained during the preparation of a new RCT with stratification meta-analyses, design harmonisation and machine learning strategies in existing datasets (n=9 RCTs) within an international consortium. IMPACT: My project will optimise future RCT protocols. This will result in a decreased number of failed RCTs, which leads to cost-effective benefits and more interest among pharmaceutical industry players. The predictive enrichment strategies can then be used to innovate intervention trials also in other mental disorders.

Researcher(s)

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Project type(s)

  • Research Project

Exploring experiential avoidance, rumination and the link with psychological and somatic complaints in bipolar disorder (EXPO study). 01/11/2023 - 31/10/2024

Abstract

The course of bipolar disorder (BD) is influenced by several factors. Experiential avoidance (EA) and positive rumination (PR) are two constructs whose presence and impact on BD have been studied to a limited extent. EA refers to not wanting to face one's own experiences, e.g. emotions, thoughts, bodily sensations. In this case, one will take action to reduce, change or avoid these experiences, despite negative consequences (Hayes, Wilson, Gifford, & Follette, 1996; Hayes et al., 2004). In PR, people will respond to positive affect with thoughts about their own positive experiences, traits or life circumstances (Feldman, Joormann, & Johnson, 2007). In the present longitudinal study, patients are compared to healthy controls in terms of presence of PR and EA. The antecedents of EA are examined, as well as the relationship between EA and PR. Possible negative consequences of EA and PR, such as duration of mood disturbance and current psychological and somatic symptoms are also investigated.

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  • Research Project

Unravelling the pathophysiology of psychotic depression: the search for peripheral and endophenotypical biomarkers. 01/12/2020 - 30/11/2022

Abstract

Introduction: Psychotic Major Depression (PMD) poses a significant challenge in psychiatric practice due to its complex symptomatology and limited treatment options. In this collaborative research endeavor between the Scientific Initiative of Neuropsychiatric and Psychopharmacological Studies (SINAPS) and Takeda Pharmaceutical Company Limited, we aim to elucidate the underlying pathophysiology of PMD through a multifaceted approach integrating blood-based biomarkers and neuroimaging data. Study Design: This collaborative research effort, conducted by the Scientific Initiative of Neuropsychiatric and Psychopharmacological Studies (SINAPS) in conjunction with Takeda Pharmaceutical Company Limited, adopts a comprehensive approach to elucidate the underlying pathophysiology of Psychotic Major Depression (PMD). Participants: The study aims to recruit a total of 40 patients diagnosed with PMD and an equal number of patients diagnosed with Non-Psychotic Major Depression (N-PMD). Additionally, for neuroimaging investigations, 16-18 patients per group will be included. Inclusion Criteria: Patients aged 18-65 years diagnosed with PMD or N-PMD, according to standardized diagnostic criteria such as the Diagnostic and Statistical Manual of Mental Disorders (DSM), will be eligible for inclusion. Exclusion Criteria: Patients with a history of other psychiatric or neurological disorders, substance abuse, or contraindications to MRI procedures will be excluded from the study. Procedures: Participants will undergo comprehensive clinical evaluations, including psychiatric assessments and medical histories. Blood samples will be collected for proteomic, transcriptomic, and genomic analyses to identify biomarkers distinguishing PMD from N-PMD and those associated with Electroconvulsive Therapy (ECT) response in PMD. Neuroimaging data will be acquired using structural and functional MRI techniques to characterize disrupted brain regions and networks in PMD. This pioneering research initiative holds promise for enhancing diagnostic accuracy, treatment efficacy, and patient outcomes in the realm of psychotic depression. By unraveling the intricate interplay between biological markers and brain imaging data, we aspire to transform the landscape of psychiatric care and foster a deeper appreciation of the underlying mechanisms driving PMD pathophysiology. Keywords: Psychotic Major Depression, Biomarkers, Neuroimaging, Proteomics, Transcriptomics, Genomics, Electroconvulsive Therapy, Structural MRI, Functional MRI, Precision Psychiatry.

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  • Research Project

Improving treatment strategies for bipolar disorder by discovery of novel drug target candidates and discriminatory diagnostic biomarkers. 01/05/2020 - 30/04/2024

Abstract

Psychiatric treatment of patients with bipolar disorder is characterized by very low remission and recovery rates due to a high non-responsiveness to all psychopharmacological medication (30-35%). With this project, we aim to optimize treatment strategies for bipolar disorder with or without psychotic symptoms by finding alternative entry points for the development of new mood stabilizing drugs. In order to establish databases of relevant biomarkers as well as putative targets for future development of psychopharmacological drugs, we will conduct a prospective clinical trial in which patients with bipolar disorder with or without psychotic symptoms, will receive electroconvulsive therapy (ECT), the treatment of last resort when other pharmacotherapeutic strategies have failed. In parallel, post-mortem patient brain tissues will be retrospectively investigated. Samples of both research arms will be analyzed by proteomic and metabolomic methodologies using state of the art liquid chromatography-mass spectrometry (LCMS). Final comparative analyses of differentially expressed proteins, protein networks and metabolic pathways will result in the establishment of drug target candidate (DTC) databases for both types of bipolar disorder. These databases will likely, in follow-up trajectories, lead to the development of novel drugs.

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  • Research Project

Research in the domain of Psychiatry for team CAPRI. 01/01/2020 - 31/12/2023

Abstract

Investigation into the impact of refugee status on mental health. This PhD trajectory investigates the impact of refugee status on mental health among participants recruited from the Psychiatric Acute Admission Unit (PAAZ) of the Vrije Universiteit Brussel. By examining the unique challenges faced by refugees in a psychiatric setting, the study aims to identify factors contributing to mental health outcomes and explore effective interventions. Utilizing a multidisciplinary approach, including psychological assessments, socio-demographic data collection, and cultural sensitivity training, the research seeks to provide valuable insights into the complex relationship between refugee status and mental well-being. Ultimately, findings from this study may inform targeted interventions and policy initiatives to support refugee mental health.

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  • Research Project

Improving treatment strategies for different depressive disorders by discovery of novel drug target candidates and discriminatory diagnostic biomarkers. 01/01/2020 - 31/12/2022

Abstract

Psychiatric treatment of patients with depressive illness is characterized by very low remission and recovery rates due to inefficient and inaccurate diagnoses along with a high final non-responsiveness to all psychopharmacological medication (30% to close to 64% in psychotic depression ). With this IOF-SBO project, we aim to optimize treatment strategies for uni- and bipolar depression with or without psychotic symptoms by finding alternative entry points for the development of new antidepressant drugs and through the discovery of peripheral biomarkers for accurate and objective discriminatory diagnostics. In order to establish databases of relevant biomarkers as well as putative targets for future development of psychopharmacological drugs, we will conduct a prospective clinical trial in which patients with uni- or bipolar disorder, with or without psychotic symptoms, will receive electroconvulsive therapy (ECT), the treatment of last resort when other antidepressants have failed. In parallel, post-mortem patient brain tissues will be retrospectively investigated. Samples of both research arms will be analysed by proteomic and metabolomic methodologies using state of the art liquid chromatography-mass spectrometry (LCMS). Final comparative analyses of differentially expressed proteins, protein networks and metabolic pathways will result in the establishment of drug target candidate (DTC) databases for each of the aforementioned disorders and one diagnostic database containing biomarkers objectively discriminating between the 4 depressive subtypes. These databases will likely, in follow-up trajectories, lead to the development of novel antidepressant drugs and diagnostic assays to be implemented in a diagnostic device. Preliminary interviews with potential industrial partners revealed a great interest for collaboration with both pharmaceutical and technology investors.

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  • Research Project

Unravelling the pathophysiology of psychotic depression: the search for peripheral and endophenotypical biomarkers. 01/12/2018 - 30/11/2022

Abstract

Major depressive disorder (MDD) is a severe psychiatric condition with a major impact on quality of life. Some MDD-patients experience psychotic symptoms (such as hallucinations or delusions) and are therefore classified under psychotic major depression (PMD). As this condition is associated with a high mortality risk, it should be identified as soon as possible. However, PMD remains underdiagnosed and thus undertreated, even though up to 20% of MDD-patients present with psychotic features. Moreover, little is known about the biological mechanisms underlying these two distinct types of depression. The recommended first line treatment for PMD consists of either combining an antidepressant with an antipsychotic, or electroconvulsive therapy (ECT). However, pharmacotherapy is linked with several disadvantages, such as delayed start of treatment effects and lower responsiveness in PMD-patients, whereas ECT provides faster effects and seems to be more effective in PMD than non-PMD. Although ECT appears to be a valuable therapeutic option, the biological mechanisms underlying its effects remain yet unclear. This project aims to establish biomarkers linked to ECTresponse in psychotic depressed patients. We will explore changes in several peripheral biomarkers related to ECT response in PMD. We will investigate effects on molecules of interest (immune markers, oxidative stress markers, growth factors), but will also explore new potential biomarkers by use of genomics, transcriptomics and proteomics. Moreover, structural and resting-state MRI will provide information on specific brain region and/or network alterations to differentiate psychotic from non-psychotic major depression. In total, 100 subjects will be allocated to age- and gender-matched groups: 1) PMDpatients(n = 40), 2) non-PMD patients (n = 40) and 3) healthy controls (n = 20). PMD- and non-PMD patients will undergo ECT and will therefore be evaluated before and after completion of the ECT treatment schedule.

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  • Research Project

Unravelling the pathophysiology of psychotic depression: the search for new biomarkers in the post mortem brain. 01/12/2018 - 30/11/2022

Abstract

A depressive disorder is a psychiatric disorder characterized by a depressive state of mind, negative thoughts, anhedonia and suicidality. Patients often suffer from recurrent psychotic episodes, which has an enormous impact on all aspects of their lives. A subpopulation of these patients also suffers from psychotic symptoms such as delusions and auditory hallucinations (Schatzberg, 2006) on top of the characteristic depressive symptoms. Current imaging studies and molecular studies point to specific characteristics that differentiate between psychotic depression and non-psychotic depression, such as reduced functional activity in the insula in psychotic depression (Farret et al., 2011), and to shared factors between both forms such as disruption of the HPA axis (review Dean and Keshavan, 2017). Although there is already some knowledge about the underlying neurobiology of psychotic depression, the characterization is far from complete, which is illustrated by the low diagnosis and suboptimal treatment of this serious disorder. This is problematic as these patients account for a significant 14-20 percent of patients (Ohayon & Schatzberg, 2002) and this subpopulation shows a different course of disease and a different response to treatment (Buoli et al., 2013, Van Diermen et al. , 2018). New techniques such as proteomics and transcriptomics can offer a solution. These techniques provide the opportunity to map both syndromes on a large scale and from an atheoretical perspective. For example, interesting findings have been made in post-mortem brains of patients with various syndromes such as schizophrenia, bipolar disorder and depressive disorder (review Saia-Cerada, 2017). As far as psychotic depression is concerned, so far only a small-scale study has been undertaken by Martin-De Souza et al (2012) in which quantitative differences were found between protein concentrations related to energy metabolism and synaptic activity. Furthermore, differences were also found in the expression of proteins previously linked to schizophrenia, as one would expect given the aforementioned overlap in genetic risk factors. Although these interesting initial findings show that this form of research can make a valuable contribution to the knowledge of psychotic depression in the field of neurobiology, larger studies are needed that ideally use predictive statistical methods such as sensitivity, specificity and reclassification tables (Pencina, 2008) to distill potential biomarkers for psychotic depression. Furthermore, knowledge of the underlying interaction network can yield interesting drug targets (Hopkins, 2008).  These two goals are therefore central to this PhD. In order to achieve this, brains from the Corsella collection will be examined with different molecular techniques. In the first phase medical records will be read and inventoried in an electronic database together with information about the available tissue. In a second phase, four types of cases will be selected from this database, namely healthy controls, patients with a depressive disorder without psychotic characteristics, patients with a psychotic depressive disorder and patients with a psychotic disorder without affective characteristics. These samples will then be analyzed by means of proteomics and transcriptomics.

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  • Research Project

Optimizing self-management in bipolar disorder by correlating mood and behavioural patterns using mHealth technology. 16/10/2018 - 15/10/2022

Abstract

This research is directed towards the promotion and optimization of blended self-management training in bipolar disorder (BD) via mobile health (mHealth) prospective monitoring. A new prototype of such self-management mobile application has recently been designed in the research group and will be used in the project. A Database containing (inter-)episodic self-management parameters, such as triggers, prodromes and self-management strategies of the patients will be constructed.

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  • Research Project

Using molecular signaling profile in white blood cells measured by highly-sensitive mass spectrometry (MS)-based proteomics in the differential diagnosis between major depressive disorder and bipolar disorder. 01/04/2017 - 31/03/2018

Abstract

Major depressive disorder (MDD) and bipolar spectrum disorder (BD) are severely debilitating mental disorders both characterized by an elaborate depressive symptomatology. In clinical reality, patients with either unipolar or bipolar depression often present with identical symptoms, resulting in a profile of clinically observable symptomatology that in itself remains insufficient for reliable and objective distinction and consequent correct treatment of both forms of depression. Numerous attempts have been made to use single, specific biomarkers to objectively differentiate between MDD and BD, until now without success. Therefore, using large scale biomedical data, such as quantitative proteomics, to extract relevant biomarker sets associated with specific psychiatric illnesses has recently been put forward to fill the current objective diagnosis deficiency. In the current project, we will establish whether proteomic analysis of peripheral blood mononuclear cells (PBMC) can serve as a highly specific diagnostic tool to discriminate patients with unipolar versus bipolar depressive disorder. The project will be a collaboration between Collaborative Antwerp Psychiatric Research Institute (CAPRI, faculty of medicine, University of Antwerp) and the VIB Department of Molecular Genetics (VIB DMG, University of Antwerp). CAPRI will tend to the clinical study arm by recruiting suitable study subjects and procuring patient samples, while proteome analysis will be performed at VIB DMG. Currently the optimal MS platform for in-depth quantitative proteomics, in terms of accuracy and reliability of protein identification is the ThermoScientific Tribrid Fusion Orbitrap MS system. The laboratory of Prof. Maudsley (VIB DMG) possesses the only current Tribrid Fusion MS in Belgium to date.

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  • Research Project