Nurturing networks: A Social Movement lens on Community-Supported Agriculture

The political dimension of community-supported agriculture (CSA), beyond prefiguring alternatives to the conventional, capitalist agri-food system, has remained largely unexplored by the scientific community. The large majority of studies on CSA have explored questions on societal change by investigating the internal dynamics at the initiative level, and detailed explorations of CSA as a social movement as a whole are largely lacking. Therefore, this thesis studied the political dimension of CSA at the level of the network organisation by conceptualising and analysing CSA from a social movement lens. Such a perspective broadened the view beyond local initiatives and shed light on the role that CSA can play as a collective political actor to bring about change towards more environmentally sound and socially just agri-food systems. This study focussed on the German CSA network, the Netzwerk Solidarische Landwirtschaft, as the main case study and asked to what extent and in what ways CSA networks form and act as a collective, political actor of societal transformation. To answer this question, several chapters of this thesis drew on different strands of social movement studies: Chapter 3 used the concept of boundary work to shed light on the process through which CSA networks become a collective actor. Subsequently, drawing on literature on political advocacy, Chapter 4 analysed how CSA networks act via advocacy work to induce change within capitalist agri-food systems. Building on the literature on coalition building, Chapter 5 then investigated how political action can be broadened by systematically analysing the potential of entering a coalition between the CSA and degrowth movements. Finally, Chapter 6 examined the transformation of agri-food systems more broadly through the lens of degrowth literature and identified pertinent avenues for future research. Taken together, these chapters generate novel insights and positions on the German CSA network as a collective, yet heterogenous actor. Adopting a social movement lens was instrumental for exploring how CSA initiatives with differing values, ways of organising, and political goals are positioned towards each other, including how tensions and factionalism arise within the movement and how they are mitigated. Furthermore, this thesis showed that the German CSA network, apart from an outspoken distancing from the far-right, welcomes diversity; a pragmatic decision that has allowed the movement to grow and spread within different circles. The heterogeneity of the German CSA network is also reflected in its politics; while the network engages predominantly in a prefigurative politics, different understandings of what it means to be political co-exist within the movement. In addition, it is politicised to different extents and the extent to which the movement wants to be political remains internally contested and debated. While further politicisation is necessary to support societal transformation processes, for a social movement that consists of heterogenous initiatives, this process is complex and problem-ridden. In sum, this thesis gave a nuanced view of the ways in which CSA networks can be understood as political and offered important insights into how a common identity, political strategies, claims, and struggles are negotiated and enacted

Making up incapacity for work? How government officials, medical experts and disabled workers brought incapacity for work into being in the first Dutch social security law (1901-1967)

In 1901 the Ongevallenwet, the first act regulating the insurance of workers in cases of accidents, was introduced in the Netherlands. In the historiography of the welfare state, introductions of acts like the Ongevallenwet mark a moment in time in which the collective started to take care of individual misfortune. This new form of state funded compensation for the loss of income due to disabilities came with a pressing individual responsibility to not misuse this social security arrangement. The regulations have constantly been tightened to make sure ‘the right people’ receive benefits. But when was a person truly incapable to work? Social security legislation necessitated classification. As philosophers of science have shown, classifications are moving targets that interact with our investigations. Interaction with the classification therefore ‘makes up’ the label that is being described. In line with these insights, this research examines the search for identifying properties of incapacity to work as a process of making up incapacity to work. This dissertation provides a fresh look at the ways in which incapacity for work has historically been produced. It analyses the actions and practices that have created and sustained the phenomenon of incapacity for work. It examines how it was enacted not only through the Ongevallenwet, but also through the interactions between the officials who implemented policies, the medical experts who testified about the nature, veracity and severity of the incapacity for work, and the individuals whose working capacity was under scrutiny. This research has shown how the three actors enacted incapacity for work in different ways, taking into account their position, knowledge, interests, (professional) rationalisations and values. Each actor undertook its own situated search for the properties of incapacity, resulting in a variety of realities of incapacity. Each assessment, however, required mediation, navigation and negotiation between legal frameworks, values and interests. Each actor had to deal with doubt and used their own rationales and techniques, and did so in interaction with the other actors involved. In that process, the characteristics of incapacity were constantly changing. This thesis has shown that there is no such thing as a fixed category of disabled workers, instead this category is created in the process of claim assessment. This conclusion has far-reaching implications for the way we look at social security legislation. It is much more than the allocation of money: the process establishes categories associated with all sorts of socio-material realities. By recognising that the targeted group of people who earn benefits are shaped in the process, we can further explore what hierarchical dynamics are at work, how the narratives and perspectives of the actors involved are valued and taken seriously, and what rationalisations and prejudices about people claiming benefits shape examination practices

Cochlear implant positioning and fixation

Hearing loss is one of the most common conditions worldwide. Almost half a billion people globally suffer from disabling hearing loss, and this number is expected to increase in the coming years. Hearing aids are often helpful, but in cases of severe hearing loss, a cochlear implant (CI) may be considered. The CI takes over the function of damaged nerve cells by converting sound into electrical signals. The surgery required to place the CI, known as cochlear implantation, is a safe procedure with few complications. The surgical techniques used to secure the implant under the skin and in the cochlea vary between centers and CI surgeons. Increasingly, operators are using minimally invasive surgery, although there is no consensus among CI surgeons regarding the safety of these newer techniques. Despite the many advantages of minimally invasive techniques, there seems to be insufficient scientific evidence to safely use these methods. Incorrect positioning and inadequate fixation of the CI can lead to implant displacement, also known as migration. In this thesis, we have investigated the surgical techniques used during cochlear implantation to secure the CI, with a specific focus on complications related to drilling a bony recess and implant migration under the skin. We have developed new methods to position the implant, utilizing 3-D software and 3-D printing. Finally, we have attempted to develop objective means to determine CI migration and to map the impact of wearing a CI on patients

Individual differences in fear extinction learning and the endocannabinoid system

Anxiety, trauma and stressor-related disorders are the most common mental disorders in the world. The likelihood of developing these disorders is higher in occupations where there is an increased likelihood of exposure to stressful and traumatic situations, such as in the military. More insight into the development and treatment of these disorders is of great importance because current psychological and pharmacological treatments are insufficient for 40% of patients. This thesis investigates two important systems that can provide more insight into the development and treatment of anxiety, trauma and stressor-related disorders. First, individual differences in fear learning and the use of these differences in association with treatment outcome. Second, the role of the endocannabinoid system in these disorders. The studies in this thesis show that different fear learning classes can be distinguished using a fear conditioning task. The classes of ‘generalizing’ and ‘poor fear extinction’ were found but were not associated with treatment outcome. In the second part, it was found that compounds that enhances the endocannabinoid system may alleviate anxiety symptoms. There was also evidence of associations between endogenous cannabinoid and anxiety symptoms. This research contributes to translating more fundamental research into applicability in clinical practice in the development and treatment of anxiety, trauma and stressor-related disorders. This may contribute to the prevention and better treatment of these disorders

Clinical pharmacology of CFTR modulators

With the development of cystic fibrosis transmembrane receptor (CFTR) modulating drugs, the landscape in cystic fibrosis (CF) care has changed dramatically. These drugs enable the treatment of the underlying cause of the disease. Although CFTR modulators show an impressive clincal effect at group level in people with CF (pwCF) with specific mutations, the individual effect is variable. In daily practice, more side effects of these drugs are observed than expected. The variability of clinical outcome between patients stresses the need to better understand the pharmacology of these drugs. In this thesis we studied several aspects of the clincal pharmacology of CFTR modulators, with a focus on pharmacokinetic aspects, variability between pwCF with different clinical phenotypes and drug-drug interactions. More than 1700 CFTR mutations lead to cystis fibrosis. CFTR modulators have been developed to revert the effects of the disease-causing mutations. Predicting the clinical response of a certain CFTR modulator (combination) in pwCF with a certain CFTR mutation is dfficult, especially for rare mutations. Rectal organoids, in vitro primary cell cultures, are developed and help in predicting drug response. The value of the use of organoid models in predicting treatment response is highlighted in one of our studies. The hypothesis of this study was based on in vitro data showing swelling of F508del/A455E organoids after incubation with lumacaftor/ivacaftor. Although the sample size was small and the study duration relatively short, the results suggest a clinical benefit from lumacaftor/ivacaftor in pwCF and a A455E mutation. Different features of CF disease may influence pharmacokinetic properties of drugs which may contribute to variation in drug exposure. In this thesis we included our review article in which features of CF disease are described that may change pharmacokinetic properties by changing the absorption, distribution, metabolism or elimination of CFTR modulating drugs. An important feature of many pwCF is pancreatic insufficiency and thereby fatmalabsorption. We hypothesized that the presence of fatmalabsorption may change the absorption and thereby exposure to CFTR modulators. We compared pharmacokinetic parameters of ivacaftor (one of the four currently available CFTR modulators) in a group of pancreas sufficient pwCF with a group of pancreas insufficient pwCF. Fatmalabsorption due to pancreatic insufficiency did not change the absorption or exposure to ivacaftor. As CFTR modulators are substrates of cytrochrome P450 3A4 (CYP3A4) and cytochrome P450 3A5 (CYP3A5), drug-drug interactions (DDI’s) with inhibitors or inducers of these enzymes may occur and thereby change drug exposure. In two of our studies drug-drug interactions between CFTR modulators and other drugs that are important in CF treatment were investigated. With these studies we obtained insight in how to manage these interactions in clinical practice. This opens doors for treatment with CFTR modulators for more pwCF. An important finding observed in our studies is the high variability of CFTR modulator exposure in pwCF using the same dosage. Future studies are needed to evaluate the usefulness of therapeutic drug monitorin of CFTR modulators to determine the optimal dosing regimen for each patient

Fc glycosylation of alloantibodies in platelet refractoriness

Platelet transfusions are essential for the prevention and treatment of hemorrhagic complications in patients with platelet dysfunction or thrombocytopenia. However, patients requiring frequent platelet transfusions are at risk for alloimmunization, which can lead to immune platelet refractoriness. These alloantibodies are formed after alloantigen exposure during pregnancy, incompatible transfusions or transplantations, and most frequently against Class I Human Leukocyte Antigens (HLA), but occasionally also towards Human Platelet Antigens (HPA) and ABO blood groups. These alloantibodies will bind to the corresponding antigens expressed on donor platelets, leading to rapid clearance via multiple immunological processes, such as FcγR-mediated phagocytosis and complement-mediated cytotoxicity. However, even if alloantibodies are formed, not all patients become necessarily refractory to platelet transfusions. Hence, more research is required into antibody characteristics, which can explain these inter-donor variation in antibody responses. In this thesis we evaluated the role of Fc glycosylation of anti-platelet antibodies in platelet refractoriness. IgG contains a highly conserved N-linked glycan in its Fc region, which is essential for the antibody's function, structure, and stability. The glycan consists of highly variable extensions of a bi-antennary core structure and the configuration of these sugar residues can strongly affect the antibody's effector functions and therefore the clinical course of the immune response. In Chapter 4, we characterized the glycosylation profile of anti-HLA antibodies in haemato-oncological patients receiving platelet transfusions. We found IgG-Fc glycosylation of anti-HLA antibodies to be highly variable between patients, especially with respect to galactosylation and sialylation, which were significantly increased for the majority of the patients. Furthermore the level of galactosylation and sialylation of anti-HLA antibodies negatively correlated with the transfusion outcome. Aside galactosylation and sialylation, afucosylation of HLA-specific antibodies was also observed for two individuals. Previously, it was shown that both elevated antibody galactosylation and sialylation increases the potency of IgG antibodies to activate the complement system. At the time, it was known that monomeric IgG requires hexamerization, via noncovalent Fc:Fc interactions, to form an high avidity interaction platform for the first classical complement component, C1q, to bind. In Chapter 2 we showed that Fc galactosylation promotes IgG1 hexamerization and thereby complement activation. We observed that increased Fc galactosylation elevates C1q-binding, and downstream complement activity for wildtype IgG1, but not for antibodies with increased hexamerization potential. In addition to Fc glycosylation IgG hexamerization and thereby complement activation, is also dependent on numerous other factors, including the antigen’s size, expression level, spatial distribution and mobility but also the antibody’s titer, epitope position, binding angle, hinge length and flexibility. In Chapter 3 we showed that individual anti-HLA or anti-HPA-1a monoclonal antibodies are incapable of activating the classical complement pathway on the surface of platelets. In contrast, when specific combinations of anti-HLA mAbs with different specificities are used simultaneously, complement activation was strongly enhanced even in low antibody concentrations. The combination of mAbs increases the amount of opsonization, facilitating the formation of hetero-hexamers, which is further enhanced by Fc galactosylation and sialylation, leading to efficient complement activation. Although the majority of human IgG responses are dominated by fucosylated IgG, for some antigen-specific antibody responses much lower fucosylation levels are detected. Afucosylation has been shown to increase the affinity for FcγRIIIa/b up to 40-fold, which can turn into even larger functional effects for associated effector functions, including antibody dependent cellular cytotoxicity and – phagocytosis, and ultimately disease severity. In Chapter 5, we investigated the effect of Fc fucosylation, galactosylation and sialylation of anti-HLA antibodies on phagocytosis of opsonized platelets by monocyte-derived macrophages. Interestingly, we did not observe any differences in phagocytosis between differently glycosylated anti-HLA monoclonal antibodies, as our in vitro model appeared to be primarily FcγRI-mediated

Outcomes and their determinants in patients with sudden cardiac arrest: Population health approaches to improve clinical outcomes

This thesis describes a series of academic pursuits aimed at improving SCA outcomes. It comprises an introduction, a textbook chapter, as well as ten original investigations that address current issues in improving SCA outcomes. These investigations employ a number of study designs to interrogate interrelated topics surrounding risk factors, prognostication and treatment of SCA. Specific issues explored include the use of interventional study designs other than randomized controlled trials, the use of clinical outcomes with different time horizons, recurrence of SCA, social determinants of bystander cardiopulmonary resuscitation, global prevalence and access to basic life support training, ambient air quality as a risk factor, and the evaluation of community-wide interventions aimed to improve care processes in SCA. By advancing our understanding of the risk factors, prognostication, and treatment of OHCA, we hope to improve equitable access, precision of interventions and improved clinical outcomes for our patients

Sticking together: How adherens junctions orchestrate epithelial integrity

Epithelial tissues form regulated barriers that separate the outside world from the internal environment, and come in various forms to enable their organ-specific functions. All these intricate epithelial topologies need to be properly arranged during embryonic development and maintained throughout life. Epithelia hereto rely on adherens junctions that connect cells and act as key guardians of epithelial organization and integrity. In this thesis we investigate, across different scales, how regulatory mechanisms and functions of cadherin-based adhesions orchestrate epithelial architecture. Firstly, we describe a novel role for β-catenin in the supramolecular organization of adherens junctions. We find that condensation of β-catenin through its intrinsically disordered regions drives clustering of the cadherin complex, and that this clustering promotes the formation of de novo adherens junctions between epithelial cells. Secondly, we delineate the molecular response of adherens junctions to forces during mitosis. We uncover that to withstand elevated forces that arise from the rounding of mitotic cells, cadherin adhesions between the mitotic cell and its neighbors are reinforced through recruitment of the actin-binding protein vinculin. This mechanoresponse selectively occurs in neighbors of mitotic cells, and the resulting asymmetry in composition of the mitotic cadherin complex allows for the morphological rearrangements of cell rounding while maintaining epithelial integrity. Thirdly, we describe how the role of adherens junctions in epithelial architecture extends beyond its adhesive function. We review the potential mechanisms that drive the dissemination of E-cadherin-deficient cells from the gastric epithelium, which represents the initiating step of diffuse-type gastric cancer. We subsequently experimentally determine that this stems from the mispositioning of dividing cells due to the loss of E-cadherin-dependent planar cell divisions. Taken together, this thesis advances our understanding of adherens junctions in epithelial architecture, offering insights into their regulatory mechanisms at several levels