Portal (Norway)

The tunable reactivity of the isocyanides by transition metals has evolved into numerous useful applications of this C1 building block, such as the Pd-catalyzed imidoylative cross-coupling reactions. In addition to Pd, the 1st row transition metals are increasingly used in imidoylation reactions as more benign and chemically divers alternative catalysts. Although mechanistic studies are still scarce, distinct proposed catalytic cycles in the literature are discussed and categorized according to (I) the (hetero)atom bound to, and (II) the type of bonding, with the transition metal (σ- or π- bond), in which the (formal) insertion occurs. Within the imidoylative transformations (formal) insertion into a TM-C/N σ -bond is rather established, however, insertion into a TM-C/N π-bond, or imidoylative group transfer reaction, remains less explored. In particular, transition metal-catalyzed carbene transfer to isocyanides, which provide chemically versatile and reactive heteroallenes (i.e. ketenimines). In chapter 1, the vibrancy and richness of isocyanide chemistry within transition metal catalysis are demonstrated. While Type I-A and I-B isocyanide insertion processes (Section 1.2) have seen significant development over the past decade, Type II isocyanide insertion (Scheme 6A, Section 1.3), particularly involving carbene transfer, is still in its early stages. The difference is evident not only mechanistically, but also in the number of reported base metal-catalyzed transformations. Despite this, both fields are stille largely dominated by noble metal-catalyzed processes. The remainder of this thesis will specifically focus on Type- II isocyanide insertion, emphasizing carbene transfer. In chapter 2, the discussion centers on the first iron-catalyzed carbene transfer to isocyanides, followed by the in situ transformation of the ketenimine intermediate. The catalyst, the ferrate complex [Fe(CO)3NO]Bu4N (Hieber anion), efficiently catalyzes carbene transfer using α-diazo ester as the carbene precursor. The resulting ketenimine can be trapped in situ by various bis-nucleophiles, yielding a diverse array of heterocycles. Notably, the transformation exhibits high tolerance for different types of isocyanides, including more functionalized ones like tryptamine-derived isocyanides. The use of the Hieber anion in the dearomative spirocyclization of tryptamine-derived isocyanides will be discussed in Chapter 3. The use of the iron-based catalyst in the carbene transfer/dearomative spirocyclization cascade results in the formation of spiroindolenines in good yields. Although the scope of α-diazo esters as carbene precursors is somewhat limited, careful modification of the indole moiety of the isocyanide enables the application of this methodology as a key step in the formal total synthesis of several monoterpenoid indole alkaloids. In chapter 4, the exploration of alternative carbene precursors for carbene transfer to isocyanides is presented, aiming to avoid the use of hazardous diazo compounds. Given the instability and potential explosiveness of diazo derivatives lacking an electron-withdrawing group, Zn-carbenoids are introduced as a novel carbene precursor. These Zn-carbenoids, derived from α-acyloxy halides, are, in turn, derived from the corresponding aldehyde. Rhodium is identified as the optimal catalyst for carbene transfer using Zn-carbenoids derived from α-acyloxy halides, following extensive screening of various (base) metal sources. Chapter 5 outlines future directions in the field of transition metal-catalyzed group transfer reactions to isocyanides, building on the research presented. Additionally, this chapter explores curiosity-driven projects related to the design and use of highly functionalized isocyanides. Overall, the concepts presented encompass projects that are either unfinished or based on conceptual ideas.

Background: While open datasets are adopting FAIR principles to improve their discovery and use, restricted data—those only accessible via request or application—have fallen behind. Metadata is not an inherent characteristic of restricted data, which limits its ability to be found and used. To better understand discoverability and accessibility of restricted data, this study reviewed restricted health data sources to determine how they describe their datasets and access procedures, what descriptive commonalities exist across data sources, and to what extent the commonalities we found can be accommodated within existing metadata schemas. Methods: This study extracted dataset and access information provided by a sample of 48 restricted data sources, identified commonalities across these data sources to develop possible metadata elements for restricted data, and mapped these metadata elements to existing metadata schemas (e.g., DataCite) to evaluate how well they accommodate information supplied by restricted data sources. Results: Restricted data sources describe their datasets (35 commonalities) and access procedures (27 commonalities) in similar ways. Dataset descriptions aligned with existing metadata schemas, with the DDI-Lifecycle and -Codebook schemas receiving 91.4% and 85.7% exact matches respectively with the dataset elements we identified. Access procedures did not align with metadata available in existing schemas. Discussion: While descriptive dataset metadata for restricted data sources will make their data more findable, the accessibility of these datasets could be significantly improved by structured metadata capturing data access information. Presently, metadata schemas do not accommodate the level of detail restricted data sources provide about access procedures and requirements.

The brain can be understood as a complex network with interconnected brain regions linked by white matter pathways on the macroscale. In this thesis, we explored the connectivity between these regions and its disruption in brain disorders. By employing a relational approach that examines interactions and relationships across different scales, modalities, and domains, we aimed to gain a more comprehensive understanding of the brain. Our findings highlight a common pattern of disconnectivity across neurological and psychiatric disorders, showing that connections central in the network architecture are particularly vulnerable to disruptions. In an in-depth examination of insomnia, depression, and anxiety disorders, we identified multimodal brain correlates associated with symptoms of these conditions. We distinguished between common and unique associations of brain structure and function with the severity of symptoms characteristic of each disorder, providing insights into both shared and specific brain circuits. Additionally, this thesis contributes to the development and application of tools for reconstructing and analyzing brain networks. We introduced the CATO toolbox, an open-source software tool for structural and functional connectivity reconstruction. We also proposed the normalized Laplacian eigenvalue spectrum as a method for comparing neuronal networks across species and assessing differences in connectome organization. Overall, the research presented contributes to our methodologies for reconstructing and analyzing brain networks and provides insights into the organization of neuronal networks and the disruptions in network organization in brain disorders.

In Chapter 2, we present the findings of the ALPHA-study, exploring the link between vaginal hygiene practices and SPTB. Our study revealed a significant association between the use of vaginal gels, both before and during pregnancy, and an increased risk of SPTB, particularly between 28+0 and 31+6 weeks of gestation. Chapter 3 examines sexual intercourse during pregnancy in relation to SPTB, comparing incidences between SPTB and term birth groups. While there was a comparable frequency of sexual intercourse during pregnancy between the groups, we observed a trend suggesting higher frequency might be associated with SPTB among primiparous women. However, due to small study groups, this association couldn't be significantly demonstrated. Besides exploring SPTB risk factors, this thesis delves into the long-term maternal health effects of SPTB. Chapter 4 presents findings from the PreCaris-study, a retrospective case-control study comparing cardiovascular risk between women with histories of SPTB and uncomplicated term births. Hypertension was more prevalent among women with SPTB, as was abdominal obesity, especially in extreme preterm births. Left ventricular diastolic dysfunction was investigated in Chapter 5. Women with a history of SPTB diagnosed with hypertension at follow-up showed early yet significant signs of impaired left ventricular diastolic function. Although not exceeding normal range in the general healthy population, these significant changes could indicate a subgroup of women at elevated risk of left ventricular diastolic dysfunction later in life. Acknowledging the heterogeneous nature of SPTB, Chapter 6 identifies a subgroup of women at risk for CVD using placental maternal vascular malperfusion (MVM) as a discriminator. Women with SPTB and placental MVM exhibited significantly higher cardiovascular risk. SPTB also impacts maternal psychosocial wellbeing, detailed in Chapter 7. While maternal depression, anxiety, and psychosocial distress incidences were comparable after SPTB and term birth, a notable percentage of women experiencing SPTB reported unmet needs for professional psychosocial support, correlated with higher anxiety and distress scores. In Chapter 8, we investigated whether stress-reducing interventions could lower the incidence of preterm birth in general low-risk obstetric populations. We conducted a systematic review and meta-analysis to investigate the association between stress-reducing interventions and pregnancy outcomes, indicating significant reduction of preterm birth and low birth weight with interventions such as yoga, despite low-quality study evidence. In Chapter 9 we recommend discouraging the use of vaginal gels as part of comprehensive efforts to reduce the incidence of SPTB. Secondly, healthcare professionals should communicate with women that overall sexual intercourse during pregnancy does not increase SPTB risk. Future research should focus on understanding the link between vaginal hygiene and SPTB, and explore the impact of sexual intercourse on SPTB risk in specific groups. Additionally, we recommend future research to focus on evaluating the effects of early cardiovascular screening among women after SPTB, along with investigating the potential advantages of including placental MVM as a criterion. Lastly, we recommend integrating psychosocial support into standard care for women after SPTB, and conducting a high-quality RCT to assess the effectiveness of stressreducing interventions in preventing preterm birth across various gestational ages.

Regulated professions: Public-private partnership for drafting legislation This research is about the cooperation between the government and a professional association in the regulation of professions. Well-known regulated professions are the classic professions such as doctors, lawyers and notaries. For the regulation of these professions, both the government and the professional association have an important responsibility. When regulating other professions in cooperation between the government and a professional association, the responsibility of the professional association or of the government may also be more limited. This research focuses on how the government and the professional association can achieve a division of responsibilities in regulating a profession. The division of the responsibility between the government and a professional association for the regulation of a profession is the result of a process of negotiation in the creation of laws. During this negotiation process, the parties involved do not only negotiate the drafting of legislation, but also the joint responsibility for the implementation of the regulations by assigning tasks and powers to these parties. This provides an additional dimension compared to other, regular legislative processes or negotiated law-making processes, where only the government is responsible for the exercise of tasks and powers. In order to determine the outcome of the drafting process, the question arises as to what drafters of regulations should pay attention to in order to achieve the intended purpose of regulating a profession. The purpose of this research is to help politicians, lawyers and policy officers involved in the drafting of legislation to make decisions about the allocation of responsibilities between the parties involved in protecting the public and private interests involved in regulation. This research addresses the following topics, which are summarised below for each chapter. In Chapter 2 of this research, a literature review was conducted on topics that are relevant to the development of laws and regulations and on the conditions for cooperation between the parties involved in the regulating of a profession. In addition, the research in Chapter 3 consists of a case study based on document analysis. In the case study, four cases were used to further explore the division of responsibilities between the government and a private party, such as the professional association. Taken together, the description and the analysis of the theory and the case study provide the necessary knowledge about the division of responsibilities in the regulation of a profession by the government and a professional association for the protection of public and private interests. This knowledge is described in Chapter 4. Chapter 5 uses the results of this research to provide a practical framework for allocating responsibility in the regulation of the profession. With this framework, the government and a professional association can make decisions about the allocation of responsibilities between the parties when drafting legislation to protect the public and private interests involved. Finally, in Chapter 6, I reflect on this practical framework. In doing so, I discuss the interest of the autonomy of the professional association and the profession. I also discuss the restraint that the government should exercise in intervening in the regulation of a profession. Finally, as a reflection on the practical framework, I discuss the context of the social and political negotiation.

In recent decades, the scale and speed at which humans move around the world has increased dramatically. Countries and their respective points of entry (POE) increasingly need each other to cooperatively fight disease spread along with humans and goods. This thesis aimed to find out how to best train and prepare the POE workforce, including largely from non-health backgrounds, to meet internationally formulated conditions to deal with internationally spreading diseases. Chapter 2–4 were executed in this period. In Chapter 2, we performed a training needs assessment among representatives of European airports, ports and ground-crossings to assess the priorities and needs of public health professionals involved in the infectious disease control. These results clearly showed that core capacities for PHEP&R were considered important where they covered human health and infectious diseases. In Chapter 3, we translated the requirements on organizational level (capabilities and capacities) to the personal level. We used the RAND-modified Delphi method to design a competency profile for the PH tasks, and restricted our method to airports. Performing infectious disease control in the POE setting requires much more than (public) health knowledge alone, and it is a complex task requiring intense collaboration and communication with POE partners. In Chapter 4, we mapped the available evidence for effective education, training and exercise methods on infectious disease preparedness and response from a public health perspective. We had particular interest in methodologies used in cross-border settings and with a wide geographic reach. The wide-reach methodologies such as online training, combined with practice, showed effective results. We used the COVID-19 pandemic to learn from the response practice at POE during that crisis period. Chapter 5–7 were executed during the course of this pandemic. In Chapter 5, we presented the results of interviews held with POE professionals involved in the COVID-19 response in order to develop a guided transition from generic preparedness to specific response situations. Applying a model from crisis response in military practice to public health at POE, we learned how this run-up phase is an important distinct phase to tailor generic preparations to the specific response at hand. In March 2021, we performed two intra-action reviews (IARs) in the Dutch port and airport setting, and evaluated its outcomes, as shown in Chapter 6. The IARs were highly valued by participants, even amidst the challenging time of a turbulent crisis. An important lesson for the organizing team has been that the IAR method needs to be prepared in interpandemic times. One of the main lessons from the discussed studies is how multi-sectoral PH response at POE are. In Chapter 7, we took a public administrative perspective and studied effectiveness of response of the multi-sectoral network. Although airports stated pre-defined plans according to which response situations needed to be handled, the information burden following from the involvement of a wide variety of parties remained extremely complex. Synthesizing from this thesis’ different studies on different levels, we outlined the multiple dimensions of what capability entails. Furthermore, we have shown that within public health, capability is primarily used as a prescriptive concept, but is not sufficient to ensure good execution of response as well. In the future, it is important to better link preparedness with response. A first step could be to acknowledge operationalization as a separate phase, requiring its preparation and timing.

Summary The main aim of this thesis was to gain more insight in shoulder kinematics and muscle activation patterns after a latissimus dorsi transfer (LDT) in patients with a massive irreparable posterosuperior rotator cuff tear (MIRT). Part 1 includes treatment options for the repairable and irreparable rotator cuff tear and part 2 is specifically on the LDT for an MIRT. Chapter 1 presents the general introduction on the rotator cuff tear and its reparability. If considered repairable, primary repair can be achieved by different surgical techniques. Moreover, several concomitant procedures may be performed as adjunct to the rotator cuff repair. These techniques and concomitant procedures are described in the review article presented in chapter 2. A systematic review and meta-analysis reporting clinical outcome after primary cuff repair techniques, concomitant surgical procedures and aftercare is presented in chapter 3. Treatment options for irreparable posterosuperior rotator cuff tears are reported and compared in a systematic review and meta-analysis in chapter 4. The LDT is a well-known and viable treatment option for an MIRT. However, the mode of function is yet to be understood. 3-Dimensional shoulder kinematics and muscle activation patterns after an LDT for an MIRT are presented in chapter 5 and compared to the asymptomatic contralateral shoulder (ACS). The change in shoulder kinematics after an LDT is achieved by reprogramming activation in the muscles that are responsible for active shoulder elevation. Shoulder muscle activation patterns in active shoulder elevation were reported after an LDT and compared to the ACS in chapter 6. Although long-term good results after an LDT are reported, failure is not uncommon. To determine the type of failure after LDT, the intra and interobserver agreement after LDT with MRI was assessed in chapter 7. The thesis concludes with a general discussion in chapter 8.

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Intrauterine adhesions (IUAs), first described in the nineteenth century, represent an acquired condition. IUAs are characterized by intrauterine scarring leading to obliteration of the endometrial surface. As pregnancy-related IUAs account for more than 90% of all IUA cases, this thesis focuses on pregnancy-related IUAs. The pathophysiological process leading to pregnancy-related IUA formation remains undetermined. IUAs can be asymptomatic and remain undiscovered, but women may experience menstrual abnormalities, secondary infertility, and recurrent miscarriages. The exact prevalence of IUAs remains undetermined, and the reported prevalence in the literature varies considerably; mainly symptomatic women are included with different diagnostic modalities. In current practice, IUAs remain a difficult medical condition; the management of women with IUAs remains a clinical challenge. The work presented in the studies in this thesis evaluated different aspects of pregnancy related IUAs and prevention strategies. The first part focuses on the prevalence of pregnancy-related IUAs, etiological and risk factors, and (long-term) complications. The second part describes the effects of a strategy for preventing pregnancy-related IUAs in high-risk women and its impact on reproductive performance. The third part focuses on the relationship between pregnancy-related IUAs and reproductive performance and describes underlying mechanisms and processes that may lead to impaired reproductive performance in the case of IUAs. In this thesis, pregnancy-related IUAs were encountered in one in five women after miscarriage, TOP and RPOC. D&C was identified as the most important risk factor. It is of the utmost importance to limit the number of D&C procedures as much as possible. D&C should be performed only in cases of clinical necessity, and the application of an adhesion barrier such as APC should be considered, particurarly in women with a high risk for IUA formation, as IUAs are associated with impaired reproductive performance and an increase in obstetric complications.