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Coming theses from other universities

  • Acute Pulmonary Embolism : not just an acute condition after all Author: Therese Andersson Link: Publication date: 2022-04-29 07:00

    Background: Acute pulmonary embolism (PE) is the third most common cardiovascular disease following myocardial infarction and stroke. Despite diagnostic improvements, the diagnosis of PE is still associated with many difficulties, as the symptoms of an acute PE are nonspecific. Even though an acute PE is associated with a high short-term mortality, less attention has been given to long-term mortality. In addition, the clinical course following an acute PE may be accompanied by substantial morbidity, and one feared complication is chronic thromboembolic pulmonary hypertension (CTEPH), a progressive pulmonary vasculopathy. In addition to CTEPH, increasing evidence suggests that a large proportion of patients report persistent functional impairment several years after an acute PE. Recently, the term chronic thromboembolic pulmonary disease (CTEPD) has been proposed for those with remaining symptoms and signs of residual thrombotic material in the pulmonary arteries. 

    Methods and Results: A nation-wide Swedish cohort of all patients (n= 5793) diagnosed with an acute PE in 2005 was identified. The incidence of PE was 0.6/1000 person-years, and during a 4-year follow-up, the mortality was more than doubled compared with an age- and sex-matched control group. We found that the acute PE associated with multiple comorbidities, and with cardiovascular diseases in particular. All surviving patients in 2007 (n=3510) were invited to answer a questionnaire regarding dyspnea and related comorbidities. We demonstrated a substantially higher prevalence of both exertional dyspnea (53.0% vs. 17.3%) and wake-up dyspnea (12% vs. 1.7%) in patients compared to controls from the Northern Sweden MONICA study. Furthermore, PE associated independently with dyspnea in a multivariable analysis. Through a manual review of approximately 10 % of the patient’s medical records, a positive predictive value of 79% was found for the PE diagnosis. Post-PE patients with remaining dyspnea and/or previously known risk factors for CTEPH development were referred for blood sampling and levels of N-terminal (NT)-prohormone (pro) brain-type natriuretic peptide (BNP) were determined. Thereafter, they were referred to their local hospital for a pulmonary ventilation/perfusion (V/Q) scintigraphy and echocardiography. Approximately 45% of the V/Q-scans showed perfusion defects and 27 % of echocardiographies showed signs of pulmonary hypertension. In total, 24 cases of CTEPH were identified, resulting in a prevalence of 0.4 % (95 % confidence interval 0.2 %–0.6 %). 

    Conclusion: An acute PE is a serious event, associated with decreased survival, multiple comorbidities, frequent dyspnea, and pathological investigational findings. The term CTEPD seems reasonable as it captures that this is a disease of the pulmonary vasculature, and that pharmacological and surgical interventions used for CTEPH may be useful. Regardless, proper follow-up after acute PE is essential for timely identification of patients in need of appropriate investigations and care.

  • Lymphatic Vascular Morphogenesis : From Progenitors to Functional Vessels Author: Nina Daubel Link: Publication date: 2022-04-28 14:35

    The lymphatic vasculature is an important part of the circulatory system and crucial for normal functioning and maintenance of tissues. Yet, our understanding of the processes underlying lymphatic development and homeostasis are surprisingly limited. 

    Recent studies have uncovered a heterogeneous origin of lymphatic endothelium within different organs as well as different mechanisms of vessel formation. The mesentery is a fold of peritoneum that attaches the intestines to the abdominal wall and harbours nerves, blood and lymphatic vessels which supply the intestines. Here, the lymphatic vasculature forms through a process termed lymphvasculogenesis, during which non-venous derived lymphatic endothelial cell (LEC) progenitors assemble into vessels. Parallel to this process, the mesenteric blood vasculature undergoes extensive remodelling. In paper II we show that this is accompanied by a transient extravasation of red blood cells (RBCs). Engulfment of RBCs by developing lymphatic vessels indicate a novel role of lymphatics in clearance of extravasated RBCs. In paper III we further analyse early LEC progenitors in the mesentery and show that they exhibit unique characteristics including membrane blebbing that may facilitate LEC migration during lymphvasculogenic vessel formation. 

    The primitive lymphatic plexus further develops into mature vessels with blind ended, highly specialized segments termed lymphatic capillaries. Individual capillary LECs possess a characteristic oak leaf like shape and discontinuous button like junctions. In paper IV we propose a new model of cell shape regulation in lymphatic capillaries that is based on the interplay of the cytoskeleton and a unique organization of cell-cell junctions. We further report that acquisition of oak leaf shape precedes junctional specification, and is not a mere result of button junction formation in dermal lymphatics. 

    CreERT2 mouse lines are used across many fields of biological research, including the here presented studies, because they allow for targeted gene deletion upon inducible genetic recombination. In paper I we report that, unexpectedly, several commonly used CreERT2 mouse lines exhibit a weak baseline Cre activity leading to induction-independent recombination. This has important implications for the interpretation of results from Cre/loxP experiments, especially when performing lineage tracing.

    Focusing on different aspects of lymphatic vascular biology, this thesis work reveals yet undescribed mechanisms by which LECs form new vessels, contribute to tissue integrity during vascular remodelling and maintain mature lymphatic vessel integrity through a unique interplay of cell shape and junctional organization.

  • Antibiotic use among children in low- and middle-income countries : Studies on global trends, and contextual determinants of antibiotic prescribing in Eastern Uganda Author: Gbemisola Allwell-Brown Link: Publication date: 2022-04-27 08:42

    This thesis aimed to systematically map trends in reported antibiotic use (RAU) among sick under-five children across low- and middle-income countries (LMICs) in 2005-2017, and, to understand the contextual determinants of antibiotic prescribing in Eastern Uganda. 

    Based on 132 national surveys from 73 LMICs, and using Bayesian linear regression models, trends in RAU among sick under-five children (with symptoms of fever, diarrhoea or cough with fast/difficult breathing) across LMICs in 2005-2017 were mapped by WHO region, World Bank country income group, symptom complaint (Study-I), and by the following user characteristics: rural/urban residence, maternal education, household wealth and source of care (Study-II). To provide context, Study-III investigated patterns and contextual determinants of antibiotic prescribing for febrile under-five outpatients (FUO) attending 37 primary and secondary healthcare facilities across Bugisu, a sub-region in Eastern Uganda, based on a healthcare facility survey, and a two-year retrospective review of outpatient registers from January 2019-December 2020. To further strengthen the understanding of contextual determinants of antibiotic prescribing, in Study-IV, 10 focus group discussions and 10 in-depth interviews were conducted with 85 healthcare providers across primary and secondary healthcare facilities in Bugisu, and analysed using thematic analysis.

    A modest (17%) relative increase in RAU for sick under-five children across LMICs in 2005-2017 was found, with about 43% of the children reportedly receiving antibiotics for their illness in 2017. Low-income, African, and South-East Asian countries consistently recorded the lowest RAU for sick under-five children. Within LMICs, RAU for sick under-five children increased across all user groups in 2005-2017 but remained lowest among the poorest children, those living in rural areas, and having mothers with the lowest education levels. In Bugisu, 62.2% of FUO in surveyed healthcare facilities received antibiotic prescriptions. Amoxicillin and co-trimoxazole accounted for two-thirds of all antibiotic prescriptions. Cotrimoxazole and ampicillin/cloxacillin were prescribed, despite not being indicated in any of the reported conditions in Study-III. Among other interrelated factors across multiple levels of the health system, availability of antibiotics and diagnostics within healthcare facilities, caregiver demands, and governance at national and sub-national levels were important health worker considerations in antibiotic prescribing for febrile under-five patients.

    These studies suggest that inequitable access to antibiotics remains a challenge between and within LMICs. Yet, misuse and wastage of antibiotics persists in the same populations with the greatest lack of access to antibiotics and formal healthcare services. A health systems strengthening approach is required to improve antibiotic stewardship and overall quality of care in LMICs.