Coming dissertations at Uppsala university
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Proximal hamstring avulsions : Epidemiology, MRI-imaging and treatment outcomes
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-539140
Proximal hamstring avulsion (PHA) is an injury mostly occurring with slip-and fall accidents. MRI is important for the diagnosis, and MRI-findings together with patient characteristics are used for the allocation of treatment, but little is known about their prognostic value. The treatment can be either operative or nonoperative, but the evidence for the treatment options is limited. There is also no data on incidence and on trends in treatment of hamstring injuries, including PHA.
In paper I we analyzed data from the Swedish National Patient Register between 2001 and 2020 for patients aged 18–90 diagnosed with hamstring injuries (ICD-10 code S76.3), with operative treatment identified using the NOMESCO classification NFL49. The incidence of hamstring injuries increased from 2.2 to 7.3 per 100,000 person-years between 2001 and 2020, with the rate of surgical treatment rising from 3.0% to 14.2%.
In paper II we conducted a survey of 125 orthopedic surgeons from Sweden, Norway, Finland, and Denmark to explore current practices and rationales for PHA treatment decisions. Surgical decision-making was largely influenced by patient-specific factors, including age, BMI and lifestyle, and MRI-findings such as, degree of tendon retraction and number of avulsed tendons.
In paper III we conducted a randomized noninferiority trial at 10 centers that compared operative tendon reinsertion versus non-operative management in patients aged 30–70 with PHA. The primary outcome was the Perth Hamstring Assessment Tool (PHAT) at 24 months. The RCT demonstrated that nonoperative treatment was noninferior to surgery in terms of PHAT, but also in secondary outcomes, such as Lower Extremity Functional Scores (LEFS) and functional test, and with more adverse events in the operative group.
In paper IV we investigated if MRI findings at time of diagnosis had an association with muscle degeneration at 24 months of follow up with tendon retraction emerging as a key factor in predicting muscle degeneration in nonoperatively treated patients.
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Immune response in a human endotoxin model and critical COVID-19
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-540368
Background: Sepsis arises, by definition, from a dysregulated immune response to infection, leading to organ dysfunction and high mortality. Despite advances in antimicrobial treatments and organ support, pharmacological breakthroughs remain limited. The human endotoxin model serves as a bridge between animal models and human trials, simulating systemic inflammatory response syndrome (SIRS) and sepsis for evaluating potential therapies.
The COVID-19 pandemic, driven by SARS-CoV-2, caused widespread morbidity and mortality. Patients with severe disease exhibited immune dysregulation, characterized by hyperinflammation and immune suppression. Given the similarity in immune dysregulation, insights from previous SARS outbreaks and sepsis research were applied to the SARS-CoV-2, emphasizing the need to balance immune suppression and infection-fighting capacity in both conditions.
Methods: Part one involved a human endotoxemia model, where endotoxin was administered to healthy volunteers, to simulate systemic inflammatory response syndrome (SIRS). Inhaled nitric oxide (iNO) and glucocorticoid (GC) co-administration was assessed for immune modulation based on previous results from a porcine model.
Part two focused on COVID-19 patients in the PRONMED cohort with severe disease admitted to the ICU, investigating longitudinal immune cells and biomarker levels. In addition potential sex-based differences in inflammatory profiles were evaluated.
Results: In the human endotoxemia model, iNO/GC failed to modify the immune response, despite promising results in a porcine study. Differences in species-specific responses and endotoxin dosing likely contributed to these outcomes.
Among COVID-19 patients, elevated pro-inflammatory cytokines (TNFα, IL-6, IL-8), neutrophil activation, marked lymphopenia with attenuated expressions of lymphokines receptors were observed. In addition a dynamic aberrant expression of CD-markers was observed on neutrophils.
Men had an overall heightened immune response compared to women, except for cytokines for Th1 response, where no difference was found.
Conclusions: The failure of iNO/GC to replicate animal results highlights challenges in translating findings across species.
In COVID-19 patients, significant immune dysregulation was observed. Tailored interventions—with precise patient selection, optimized timing and dosing, and potential influences from sex hormones—are likely key to improving outcomes and minimizing harm in sepsis patients. Additionally, further research is crucial to better understand the role of neutrophils in the adaptive immune response.
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Novel Synthetic Methodologies for Main Group Element Reagents and Substrates
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-539714
Carbon-carbon double bonds in alkenes are highly valuable due to their versatility in chemical transformations and their presence in pharmaceuticals and natural products. As such, discovering new methods for synthesizing compounds containing C=C double bonds has been at the heart of organic chemistry for a long time. In this context, chapter 2 introduces a novel [2+2] cycloaddition reaction between the Si=C double bond of a silene and the C=O bond of aldehydes and ketones as a key reaction for alkene synthesis. The initial product of this non-ionic version of the Peterson olefination is an unusual four-membered 1,2-silaoxetane, which subsequently undergoes retro-cycloaddition to form alkene products.
On the other hand, light-mediated chemistry presents a compelling alternative to traditional radical reactions from a green chemistry perspective, as it operates under mild conditions and exhibits high functional group tolerance. Herein, we applied principles of organic photoredox catalysis for the activation of halophosphines, and the preparation of phosphine derivative. Chapter 3 gives a brief introduction to photochemistry, including visible light-driven photoredox catalysis and photochemical reactions of electron donor acceptor (EDA) complexes.
In chapter 4 and 5, the development of a new photocatalytic method for the reduction of trivalent phosphorus compounds using an iridium-based photocatalyst is discussed. The developed methodology can be used to prepare complex organophosphorus species, as well as secondary arylphosphines. It is found that product speciation and reaction kinetics are sensitive to the nature of the P-substituent (aliphatic or aromatic), solvent, and nature of the halide and heteroatoms.
In chapter 6, the formation of an EDA complex between N-containing electron donors and halophosphonium salts, and the use of this adduct in a phosphine synthesis is described. This method offers a photochemical approach for transforming phosphine oxides into phosphines, addressing the drawbacks of traditional metal-mediated P=O bond reductions.