208,265 research outputs found
Big Data, Small Vessels
In recent years, the transformative potential of data science in reshaping various sectors, including healthcare, has become evident. This thesis explores the application of data science in cardiovascular research, which is heavily impacted by the prevalence and complexity of cardiovascular diseases (CVD), the leading global cause of death. The research addresses both large vessel disease (LVD) and small vessel disease (SVD), which are influenced by a combination of genetic, environmental, and lifestyle factors. Personalized treatment approaches are crucial due to the multifaceted nature of these diseases.
The core focus of the thesis is the utilization of "big data", specifically electronic health records, raw data from routine hematology analyzers, and large protein panels, which hold potential value for cardiovascular research. Advanced data science techniques, such as machine learning, natural language processing (NLP), and network analysis, are employed to analyze high-dimensional data, handle missing information, extract insights from unstructured textual data, and unravel biological networks.
Chapter Two describes the reuse of routine care data, especially laboratory data, for research purposes. It delves into the challenges and solutions related to data quality and availability, emphasizing the crucial role of multidisciplinary human expertise in data interpretation.
Chapter Three investigates the risks of acute cardiovascular diseases in patients post-carotid endarterectomy. It highlights the potential role of specific blood cell characteristics, such as neutrophil size, in inflammation and disease risk.
Chapter Four examines the sex-specific biological processes related to the success of endovascular thrombectomy in treating acute ischemic strokes. It uncovers significant differences in blood cell characteristics between males and females.
Chapter Five reveals a potential underreporting of cognitive problems in heart failure patients, identified through text mining of clinical anamneses from routine care.
Chapter Six details the development of a sex-specific decision-support algorithm trained on routine care data, to enhance the diagnostic process and cost-effectiveness by ruling out coronary artery disease before cardiac imaging in patients with chest discomfort.
Chapter Seven validates these algorithms across various settings and populations, confirming their effectiveness in accurately ruling out artery disease before cardiac imaging.
Chapter Eight utilizes cluster analysis to decipher the biological mechanisms of cerebral small vessel disease, identifying a protein network associated with blood clotting and inflammation.
Chapter Nine investigates protein networks linked to reduced cerebral blood flow and future cardiovascular events in patients with cardiovascular disease, identifying proteins related to extracellular matrix organization and inflammation.
Chapter Ten highlights the potential of data science in cardiovascular research. It discusses challenges in data cleaning, the necessity of robust IT infrastructure and skilled personnel, and the importance of interdisciplinary collaboration. The chapter advocates the Dataïsm paradigm, which considers data as central to understanding human health and well-being, and promotes a patient-centric approach where algorithms support, but do not replace, clinical judgment. Additionally, the chapter explores the future potential of data science in cardiovascular medicine, including the use of speech recognition systems and real-time data collection from wearable devices
Nurses’ support of hospitalized patients’ self-management
Self-management is the individual’s ability to prevent or, when necessary, handle the consequences of health problems. Supporting the patients’ self-management is essential to future healthcare and aligns with the new thinking about health as ‘the ability to adapt and to self-manage in the face of social, physical, and emotional challenges’ rather than the absence of disease. To investigate how nurses can support patients’ self-management during hospitalization, we performed several studies.
We conducted semi-structured interviews with patients to explore their motives for or not to perform self-management during hospital admission. The findings show that nurses can support inpatients’ self-management by discussing hospital stay expectations and inviting patients to participate. Patients’ motives to self-manage during hospitalization can also be strengthened by providing information about what the patient can do to stimulate recovery or prevent complications.
In addition, we conducted focus group interviews with nurses to assess their perceptions of patients’ self-management during hospitalization and their support in this regard. Nurses have a positive attitude towards self-management, but they often take over care tasks and decisions from patients, more often than is necessary given the patient’s condition. It seems unclear to nurses what is expected of them in the field of self-management support and they experience few opportunities to carry out this activity.
We explored how nurses support the self-management of hospitalized patients through verbal communication during routine nursing care through overt, non-participant observations of nurses working morning, afternoon, and evening shifts on three nursing wards. The findings show that while nurses have methods to support hospitalized patients’ self-management, this does not appear to be an integral part of daily practice. Nurses ask patients about their self-management at home and encourage patients to express their opinions and to be involved in the care process. However, this usually happens ad hoc, in short conversations during the performance of other care tasks, and often as a one-way flow of information from nurse to patient.
To map out the current state of research concerning self-management support during hospitalization we conducted a scoping review of the literature. Most activities identified by this review are part of regular nursing care. Nevertheless, the focus on patients’ self-management may influence their content. A relatively new self-management support activity highlighted in the review is the transfer of responsibility for care tasks to patients during hospitalization. Nurses sometimes transfer responsibility for ADL tasks to the patient, but do this much less for other self-management tasks that the patient must perform after discharge.
Based on the aforementioned studies, we developed a draft conceptualization of nurses’ support of hospitalized patients’ self-management and determine the appropriateness and completeness of this conceptualization in a Delphi study. The expert panel consisted of three groups of participants: patients, nurses and researchers. The final version of the conceptualization consists of 56 nursing activities categorized into 6 sets. The activities of the conceptualization should not be considered in isolation, but rather as a coherent whole from which to choose, depending on the needs, wishes, and possibilities of the patient
Southern Ocean, Antarctic ice and climate interactions during Neogene cooling
The partial pressure of atmospheric carbon dioxide (pCO2) has increased from 280 to 420 ppm (parts per million) since the industrial revolution due to anthropogenic emissions. As a result, the Earth's atmosphere, ocean, and cryosphere are undergoing changes due to increased radiative forcing, leading to a warming planet, loss of ice sheets and sea ice, sea level rise, ocean heat redistribution, and fluctuations in ocean circulation, as predicted in scenarios up to the year 2100. Nevertheless, future changes in these components remain highly uncertain—better understanding of these processes is crucial for human communities. To better comprehend the interactions between the Southern Ocean, the Antarctic ice sheet (AIS), pCO2, and climate in the future, I have studied sea surface temperatures, ocean front migrations and deep-sea temperatures during climate transitions in the geological past, specifically the Neogene (2.58–23.04 million years ago, Ma), which experienced pCO2 levels as high as, and sometimes higher than, the current levels.
A distribution model of modern dinocysts was developed based on newly collected surface sediment samples near Antarctica to reconstruct the positions of oceanic fronts in the Southern Ocean in the past (Chapter 2). Subsequently, I demonstrated a significant long-term cooling of ocean surface and northward migrations of ocean fronts during the Neogene near Tasmania. The substantial cooling at mid-latitudes is not caused by solar radiation combined with polar amplification but is attributed to ocean frontal migrations and the northward expansion of the polar sea. Additionally, I identified a substantial deep-ocean cooling, which nearly completely explains the increase in benthic δ18O, leaving little room for an ice volume effect. The relatively stable ice volume during climate cooling seems counterintuitive given the northward migrations of ocean fronts and other geological evidences suggesting the AIS advancing. Hence, I proposed a hypothesis that the AIS gradually decreased in height while expanding seaward, maintaining a relatively stable volume during the mid-Miocene climatic transition (~14.5 Ma) and verified using ice sheet modelling. The migrations of the subtropical front near Tasmania are closely linked to a high-resolution pCO2 dataset for the Pliocene (2.58–5.3 Ma), which shows a delay of ~10,000 years in pCO2 compared to δ18O during the M2 glaciation and, at least, an elevated pCO2 during glaciation. I proposed that carbon emissions from the deep sea, driven by frontal migrations, was the dominant process in regulating pCO2, rather than physical diffusion or the biological carbon pump. This leads to an higher pCO2 during cold phases because less CO2 is stored in the ocean than during deglaciation. In another crucial geographical area, the Agulhas Plateau, I discovered that migrations of the subtropical front, regulating the inflow of warm water into the Atlantic Ocean, play a significant role in the variability of the Atlantic Meridional Overturning Circulation in the Pliocene. I concluded that there was a connection between frontal migrations and the locality of North Atlantic Deep Water formation, significantly altering heat transport to high northern latitudes and providing insights into understanding future AMOC changes
Local immune responses in eosinophilic esophagitis: Implications for disease pathophysiology and dietary management
Once considered a rare condition, eosinophilic esophagitis (EoE) – a chronic, allergen-driven disorder of the esophagus – is now one of the most common conditions diagnosed during the evaluation of food impaction in adults. Since the first case description back in 1978, current prevalence has been estimated at 34.2 cases per 100,000 inhabitants in the USA and Europe. EoE substantially impacts patient’s quality of life because of symptoms, dietary restrictions, and the social and psychological implications of living with food-related illness. Current treatment options can be effective but may not provide long-term disease control for all patients due to differences in disease endotype. It is therefore crucial that we continue to unravel the complex etiology and pathophysiology of EoE to enable future therapies to be more effective.
Major advances in the understanding of EoE disease course and pathophysiology have been made over the past 25-30 years. Nonetheless, many unmet needs associated with the prevention, phenotyping, diagnosis, and management of the disease remain. It is evident that there is a demand to better understand the (food-induced) local immune responses that lead to eosinophilic inflammation of the esophagus to enable future therapies to be more effective. Therefore, this thesis aims to investigate these local immune mechanisms that underly EoE. Furthermore, due to the need for novel (dietary) treatment protocols, we studied the potential of local esophageal food challenge to identify causative foods and make a personalized diet possible, and assessed the therapeutic potential of short-chain fatty acids on the esophageal epithelial barrier
Formation and function of binucleated human hepatocytes
Development of multicellular organisms, including humans, begins with one cell. Through many cell divisions and differentiations, this cell ultimately develops into an organism. All the information that is needed for the development of an organism is coded in its DNA and it is crucial that the DNA is passed on correctly to all cells. To protect the DNA during cell division, DNA is carefully packaged into X-shaped structures called chromosomes. Most human cells are diploid, which means they contain two sets of chromosomes. However, some cells accumulate more than two sets of chromosomes as part of their normal development. Cells that contain more than two sets of chromosomes are called polyploid cells. In humans, polyploid cells can be found in the liver, heart, mammary gland, and bone marrow.
Even though polyploid cells are found in many organs, we do not completely understand how and why they are formed. In this thesis, I present the results of our studies on the mechanism, regulation, and function of polyploid cells in diploid organisms, with a focus on human hepatocytes.
In Chapter 1, we present an overview of previous studies on the regulation and formation of polyploid cells during animal development. In addition to polyploid cells that are formed as part of normal development, polyploid cells can also arise due to errors in cell division or in response to organ damage. The parallels in the function of polyploidy in development and disease are reviewed in Chapter 2.
One of the ways in which polyploid cells are formed is through a process called endomitosis. In endomitosis, a cell replicates its DNA and package it into chromosomes as it would during a normal division; however, the cell does not physically divide in two, resulting in a polyploid cell that has twice the amount of DNA. How this process happens in human cells is not completely understood. In Chapter 3, we look into the mechanisms of endomitosis in human hepatocytes.
Apart from E2F proteins, not much is known about which other proteins regulate endomitosis. In Chapter 4, we use a CRISPR-based method to look for genes that promote endomitosis. This study identifies new candidate regulators of endomitosis, but a lot of work is still required to understand the role of these candidate regulators in the regulation of endomitosis.
Polyploid cells are often thought to have increased capacity for cellular processes, such as protein synthesis, but there are not many studies that have tested this hypothesis directly. In Chapter 5, we look at the effect of polyploidy towards cellular processes in human hepatocyte organoids and in the intestines of the nematode Caenorhabditis elegans, which represents an ideal model organism to study the effect of extreme polyploidy in a diploid organism.
Finally, in Chapter 6 we present how the results of our studies on polyploidy contribute to the field of developmental biology. The studies presented in this thesis represent one of the first steps on our journey to understand the mechanism and function of polyploidy
The old and the new: immune inhibitory receptors for the treatment of cancer
Despite great efficacy in various cancers, current immune checkpoint blockade therapies remain insufficient for most patients. These therapies are limited by a lack of response, the development of resistance and the presence of immune-related adverse events. Many inhibitory receptors are currently being explored to overcome these limitations. We and others have shown the potential of LAIR-1 as a target in cancer immunotherapy, and the studies described in this thesis further contribute to our understanding of how LAIR-1 and collagen are involved in modulating the immune response against cancer. Furthermore, we move beyond currently described inhibitory receptors and identify a novel set of putative inhibitory receptors that have potential as targets for cancer immunotherapy. All together, the work in this thesis contributes to our understanding of immune inhibitory receptors for the treatment of cancer and outlines key considerations for the development of therapies targeting LAIR-1 and novel inhibitory receptors as cancer immunotherapy
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