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Innovations in neonatal monitoring:From physiology to technology, from concept to implementation
No full textExploring the borders:Diagnosis and surgical treatment of lentigo maligna
No full textEXPLORING THE BORDERS – Diagnosis and surgical treatment of lentigo malignaThis thesis demonstrates the increasing incidence of cutaneous melanomas in the Netherlands. The largest proportion of the cutaneous melanomas are in situ or thin melanomas. Possible explanations of this increase include a true increase, in conjunction with ‘overdiagnosis’ caused by increased awareness, early detection and diagnostic drift. Lentigo maligna (LM) is the most common in situ melanoma subtype and accounts for three quarters of all in situ melanomas. Retrospective, prospective, and national data show that upstaging to LMM occurs in approximately one of ten patients after surgery. This should be taken into account when making therapeutic decisions, especially when non-surgical treatments are being considered. Evaluating LM on frozen sections with additional staining is possible and should be further explored in the future to incorporate in daily practice and improve the tolerability of the surgical treatment of LM. Treating LM remains a therapeutic challenge due to its predominance in the face and in elderly patients. Surgical treatment is generally recommended, though striving for clear margins may not always be necessary, and a ‘wait and see’ approach should be considered in some cases. Future research should consider integrating frailty screening and focus on developing tools to support shared decision-making prior to treatment. In conclusion, the treatment of LM is challenging and there is no one-size-fits-all solution.<br/
Microcirculatory alterations in critically ill patients and the effect of venous congestion on kidney function
Get PDFHemodynamic management of critically ill patients aims to provide optimal hemodynamic support to maintain oxygenation. In routine clinical practice, macrohaemodynamic parameters such as systemic blood pressure, heart rate, and cardiac output are used as indices for assessing hemodynamic status. However, in states of cardiovascular compromise, improvement in systemic hemodynamic parameters following resuscitation does not necessarily correspond to a similar improvement in the microcirculation. This discrepancy between macro- and microcirculation is referred to as "loss of hemodynamic coherence," which underscores the necessity for microcirculatory monitoring of critically ill patients.The kidneys are among the primary organs that are particularly susceptible to the effects of hemodynamic changes and hypoxia, which can ultimately result in the development of acute kidney injury. The kidneys and heart exhibit a close bidirectional interaction, whereby injury of one organ can affect the other. This concept is known as cardiorenal syndrome and has a significant impact on the morbidity and mortality of critically ill patients.In the current thesis, we investigate the nature of microcirculatory alterations in critically ill patients using bedside microcirculatory hand-held vital microscopy techniques to visualize their anatomy, hemodynamics, and (patho)physiology. We have also characterized acute kidney injury in hemodynamically compromised patients, particularly in the setting of venous congestion.<br/
Cardiometabolic risk:Novel molecular and pharmacological insights
No full textVacuolar H+-ATPase (V-ATPase) is a multi-subunit protein, which predominantly acts as proton pump to maintain the acid environment in intracellular vesicles that are required for protein secretion, transport and degradation. Recent data support that it also determines receptor-mediated signaling. As such it may contribute to both physiological and pathophysiological processes, including diabetes. For instance, it influences insulin secretion, sensitivity and resistance. In relationship to hypertension/renal disease, it affects the cellular trafficking of various key members of the renin-angiotensin system (RAS) and is a determinant of sodium reabsorption [8-10]. Finally, the prorenin receptor [(P)RR], an accessory protein of V-ATPase, is a regulator of the low density lipoprotein (LDL) receptor and LDL cholesterol (LDL-c) metabolism. It is also required for the formation of high density lipoprotein, which facilitates cholesterol efflux. Thus, V-ATPase may also contribute to atherosclerosis.The RAS is a major player in the regulation of blood pressure. The membrane receptor megalin is capable of endocytosing multiple RAS members, including angiotensinogen, renin, and prorenin. It also contributes to protein reabsorption in the kidney. Previous studies in BN16 cells have suggested that the (P)RR is involved in megalin-mediated prorenin uptake, most likely because the (P)RR is an essential component of V-ATPase. Hence, we screened which other elements of V-ATPase affect prorenin uptake in BN16 cells, making use of siRNA. It turned out that the subunits Atp6v0a1 and Atp6ap1 played prominent roles, with silencing Atp6v0a1 downregulating prorenin uptake, and silencing Atp6ap1 upregulating this uptake. Mechanistically, inhibiting Atp6v0a1 reduced the cell surface megalin content, without altering the megalin mRNA and protein levels or endoplasmic reticulum stress (ERS). In contrast, inhibiting Atp6ap1 upregulated ERS and the mRNA and protein levels of megalin, yet without modifying the cell surface megalin levels. There was no effect on either lysosomal function or autophagy. Results for albumin resembled those for prorenin.Elevated levels of LDL-c associate with atherosclerosis. LDL-c clearance depends on its endocytosis by the hepatic LDL receptor. The transcriptional factor sterol regulatory element-binding protein 2 (SREBP2) upregulates the LDL receptor, while proprotein convertase subtilisin/kexin type 9 (PCSK9) and inducible degrader of LDL receptor (IDOL) exert the opposite. MicroRNAs (miRs), non-coding small RNAs, are critical regulators of the expression and function of genes. In HepG2 and Huh 7 cells, miR-148a was found to reduce the amount of LDL receptor protein, thereby reducing LDL uptake. The underlying mechanism turned out to involve targeting the 3'-UTR region of the (P)RR, resulting in (P)RR downregulation. In support of this concept, overexpression of the (P)RR attenuated the reduction in LDL receptor protein and LDL uptake after miR-148 exposure. A link between the (P)RR and the LDL receptor has already been established, and likely involves sortilin-1. Since the (P)RR points to V-ATPase as the main player, we next evaluated the roles of other V-ATPase subunits as determinants of cell surface LDL receptor expression, again by using siRNA. This yielded the subunit ATP6V1B2 as the most prominent contributor. Silencing ATP6V1B2 upregulated cell surface LDL receptor expression and LDL uptake both by approximately 50%. The upregulation involved SREBP2, given that ATP6V1B2 silencing increased the mRNA levels of SREBP2-targeted genes (SQLE, HMGCR, HMGCS1 and NPC1). There was no role for PCSK9 or IDOL. Applying an adeno-associated virus expressing shAtp6v1b2 to mice, in order to generate liver-specific Atp6v1b2 knockdown, resulted in increased hepatic LDL receptor mRNA and protein levels, and decreased plasma total cholesterol levels, while plasma total triglyceride levels were unaltered. Thus, we were able to fully replicate our in vitro data in an in vivo model. Both statins and PCSK9 inhibitors lower LDL-c in patients with familial hypercholesteremia. Chemerin is a recently discovered SREBP2-induced adipokine that regulates adipogenesis and lipid metabolism. Unexpectedly, only statins, and not PCSK9 inhibitors lowered chemerin in the aforementioned patients. To address the underlying mechanism, we made use of HepG2 cells and activated macrophages. It turned out that statins inhibit chemerin secretion from HepG2 cells by upregulating the LDL receptor. The latter involved SREBP2, which then was no longer available to increase chemerin. Chemerin bound to the high-density lipoprotein component Apolipoprotein A-I, thus diminishing cholesterol efflux in macrophages. These data are among the first demonstrating that the protective effects of statins are not fully identical to those of PCSK9 inhibitors.<br/
Frugal innovation beyond its surface:The relevance of context for understanding the concept and its relation to sustainability
No full textTaking a deeper dive into the exploration of frugal innovation than what is found in current discourse, this article-based PhD thesis contributes to existing literature by emphasizing and operationalizing the relevance of contextual considerations for the study of frugal innovation, thereby advancing previous research that has noted the influence of context in the understanding of frugality in innovation. The work proposes two analytical frameworks that make this relevance operational by explicitly including the context as a criterion for the identification of frugal innovation and for the assessment of its relation to sustainability. This PhD thesis also makes a methodological contribution by exploring various techniques for qualitative inquiry and using them to gather and analyze primary and secondary data. In particular, the use of mind maps for qualitative data analysis in multiple-case study research makes a genuine contribution to knowledge by proposing a distinct way for accessing and analyzing qualitative data.While frugal products, services, processes, and business models do have the potential to contribute to sustainable development, as demonstrated by an increasing amount of empirical evidence, this PhD research is positioned within the growing set of literature that indicates that frugal innovations are not inherently sustainable. Frugal innovations may have both a positive and a negative influence on the social, environmental, and economic dimensions, and may inadequately address, or even (unintendedly) worsen, the root causes of socio-developmental challenges faced by communities in resource-scarce settings. Thus, this PhD thesis argues that an adequate consideration of local contextual conditions is essential in assessing frugal innovation to make it more responsive and appropriate for its intended users and their lived reality. The knowledge generated in this thesis is relevant because, while frugal innovation literature has experienced an upsurge in the past few years, the existing frugal innovation scholarship is predominantly focused on technological and innovation aspects of products, paying very little attention to contextual issues. Given its focus of analysis, this thesis makes an empirical contribution to both frugal innovation and social enterprise discourse by introducing new cases from Latin America, a region which is comparatively underrepresented in both of these sets of academic literature.<br/
Leveraging implementation science to advance non-pharmacological dementia research
No full textDementia research has produced a wide range of non-pharmacological innovations and interventions that may be used to promote healthy ageing for people with dementia and their caregivers. However, there are complex real-world challenges that limit the adoption and use of this research in real, contributing to an “implementation gap”. Research often remains within the academic community, unable to reach the intended end-users in practice settings. The field of implementation science provides systematic approaches to study and address the broad and complex factors that may influence successful research adoption. This dissertation leveraged the field of implementation science to design and guide a systematic scoping review, qualitative interview studies, and multiple case studies to examine the dissemination and implementation of non-pharmacological dementia research. Results from the systematic scoping review determined that successful dementia research adoption is influenced by complex organizational, social, financial, and political factors present in the implementation environment. These results also signaled a gap in knowledge surrounding the roles, responsibilities, and activities of stakeholders in the implementation context. Interviews and multiple case studies were conducted to elucidate the various strategies used by dementia researchers and public and private research funders to address unique challenges in dementia research. Results highlighted the importance of approaching implementation challenges with a comprehensive “research ecosystem” approach. This dissertation contributed practical insights, revealing the resources, infrastructure, and competencies essential to dementia research implementation. Findings also determined key capacity-building areas to direct future research investment and accelerate the translation of non-pharmacological dementia interventions into practice.<br/
Discrete and portfolio choice experiments:Methodological considerations and health policy applications
No full textThe aim of this dissertation is to advance the literature on the elicitation of public preferences for health policies and, to this end, contains three more specific objectives. The first objective is to position a novel method, Participatory Value Evaluation (PVE), relative to other more commonly used multi-attribute preference-elicitation methods used in the health domain, like discrete choice experiments (DCEs). After a general introduction in Chapter 1, Chapter 2 introduces PVE in the health domain and, by comparing it conceptually to four established methods, aims to contribute to a well-informed selection of method for preference-elicitation by researchers and policymakers. The Chapter ends with recommendations for further development of PVE, in particular regarding the feasibility and validity of the method. The second objective is to examine the influence of design characteristics of a DCE or PVE on the preferences elicited with the choice experiment, which is addressed in Chapters 3 and 6. Chapter 3 discusses the findings of a review of the literature across different domains on the impact of the presentation order of alternatives, attributes and choice sets on respondents’ choices in a DCE. Chapter 6 examines whether expenditure preferences and consequentiality perceptions of respondents in a PVE are sensitive to the payment vehicle used in the experiment and to the priming of opportunity costs. The third objective is to explore public preferences for health policy alternatives from a citizen perspective using DCE and PVE, which is addressed in Chapters 4 and 5. Chapter 4 uses a DCE to elicit public preferences for collective skin cancer prevention policies in Austria, the Netherlands, and Spain. Chapter 5 uses PVE to elicit public preferences for policy action regarding long-term care (LTC) for older people in the Netherlands in 2040.Finally, Chapter 7 summarizes the main findings of Chapters 2 to 6 and discusses some strengths and limitations as well as several implications for future research and policy. In particular, the Chapter considers the validity of eliciting preferences for public policy from a citizen perspective and our current understanding of respondents’ choice processes and choice behaviours in PVE choice tasks.<br/
Gray Matter(s) in multicolor:Intraoperative delineation and treatment of glioblastoma and its infiltrative edge
No full textThe periconceptional diet and digital lifestyle coaching in reproductive health
No full textDiet is the most important lifestyle factor which connects to various aspects of human health.Besides its pivotal role in individual growth, metabolism, and influencing chronic diseaserisks, evidence is convincing that the maternal and paternal diet are essential in reproductionand early human health [1-4]. We refer to reproduction as the trajectory that begins withgametogenesis, continues through fertilization, implantation, embryo, fetal and placentaldevelopment, and ends after birth of the offspring [4]. With diet being an important daily andmodifiable factor, understanding associations between diet and human reproduction willprovide insights for interventions aiming at the prevention and management of adversereproductive health outcomes [5, 6]