Coming dissertations at MedFak
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Deciphering Adult Autism : Exploring Polygenic Risk, Brain Structure, Well-being, Migraine, and Mental Health Disorders
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-537917
This research work comprises four studies investigating mental health disorders, with a particular focus on Autism Spectrum Disorder (ASD, hereafter referred to as autism). The research integrates epidemiological perspectives and genetic frameworks to explore connections with well-being, conditions such as migraine, and neuroanatomical brain structure changes in adulthood, utilizing data from the large European population cohort, UK Biobank, with over half a million participants.
Paper I examined the relationship between job satisfaction, job tenure, and 16 self-reported physician posed diagnosed mental health conditions. The findings show that Neurotic & Stress Disorders, Eating Disorders, and Other Mental Health Disorders are strongly associated with lower job satisfaction and shorter job tenure, highlighting the impact of mental health on workplace participation. Personality trait neuroticism significantly influences job satisfaction but not job tenure.
Paper II explored the relationship between genetic predispositions for autism and five well-being traits (neuroticism, depression, loneliness, life satisfaction, and positive affect). Polygenic risk scores (PRS) for autism were significantly associated with decreased well-being, particularly an increased risk of negative traits such as neuroticism and depression, and reduced positive traits such as life satisfaction, highlighting the genetic basis of well-being in individuals with autism.
Paper III examined the genetic link between autism and migraine, revealing that individuals with a genetic predisposition for autism have an increased risk of migraine, including both major types, migraine with and without aura. While no moderating effect of sex was found, personality trait neuroticism significantly mediated the relationship between autism and migraine, emphasizing the complex genetic and pathophysiological connections between autism and migraine, with neuroticism playing a key role in mediating this association.
Paper IV investigated the association between autism polygenic risk scores and brain volume alterations in the cerebellum, brainstem, and global brain structures in adults. The results demonstrated significant correlations, with higher autism PRS linked to reduced brain volumes, particularly in the cerebellum and brainstem, highlighting the genetic influence on neuroanatomical changes in autism adulthood.
These studies highlight the intricate connections between mental health, genetics, and brain structure, offering valuable insights for improving workplace participation and well-being in individuals with mental health issues including autism.
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Growing up with pediatric hip disease– a companion for life : Exploring the multifaceted experiences throughout life, with special attention to Legg-Calvé Perthes disease
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-536903
Pediatric hip diseases such as developmental dysplasia of the hip, Legg-Calvé-Perthes disease, and slipped capital femoral epiphysis can lead to lasting hip deformities and early-onset osteoarthritis. This thesis explores the long-term impacts of these conditions, combining patient experiences with large-scale data.
Study I used data from the Swedish Pediatric Orthopedic Quality Register to examine the incidence, demographics, and risk factors for containment surgery in patients with unilateral Legg-Calvé-Perthes disease. 309 patients registered between 2015 and 2024. The study found a national yearly incidence of 4.2 per 100,000 children aged 2–12 years, somewhat lower than previously reported in Sweden. The disease was more common in boys (77%), with an average diagnosis age of 6 years. Notably, 30% of patients were overweight or obese at diagnosis, increasing to around 40% at the 2-year follow-up. The study also found that older age, a positive Trendelenburg sign, and limited hip abduction at diagnosis increased the likelihood of surgical intervention.
Study II focused on the long-term impact of Legg-Calvé-Perthes disease as experienced by patients through qualitative interviews. Themes that emerged included self-reinvention, concerns about future health, surgical interventions, and challenges with physical activities leading to sedentary lifestyles. The study also highlighted patients' sense of disconnection during the transition from pediatric to adult care and emphasized the need for continuous, age-appropriate information and structured healthcare transitions.
Study III explored whether individuals with a history of Legg-Calvé-Perthes disease or slipped capital femoral epiphysis are at increased risk of receiving prescriptions for pain or antidepressant medications in adulthood. The study, which included 1,292 Legg-Calvé-Perthes disease patients and 1,613 slipped capital femoral epiphysis patients, found a higher risk of analgesic prescriptions in both groups compared to matched controls. Additionally, slipped capital femoral epiphysis patients had a slightly higher risk of antidepressant prescriptions. The findings underscore the need for long-term pain management and health support.
Study IV investigated mortality risks after total hip arthroplasty in patients with a history of pediatric hip disease. Among 4,043 patients identified from the Swedish Hip Arthroplasty Register, the study found no increased 90-day mortality risk compared to the general population. These patients’ overall mortality risk was lower, suggesting that total hip arthroplasty does not increase mortality risks despite their pre-existing conditions.
In conclusion, this thesis provides a comprehensive view of the long-term impacts of pediatric hip diseases, highlighting the need for improved, continuous, and age-appropriate care strategies to enhance patient outcomes.
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Innate Immunity in Type 1 Diabetes
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-537440
Type 1 diabetes is characterized by impaired glycemic control due to an absence of insulin production. It is traditionally attributed to an autoimmune-mediated destruction of pancreatic β-cells. Research has shifted focus towards elucidating the role of genetic predispositions, viral exposures, and other possible triggers in type 1 diabetes pathogenesis.
This doctoral thesis aimed to investigate the influence of innate immune responses on the development of type 1 diabetes. The study utilized a novel animal model for type 1 diabetes and human pancreatic tissue obtained from the Nordic network for islet transplantation and the DiViD study.
Paper I sought to investigate a potential link between insulitis and the innate immune system using a novel animal model and compare the outcome with type 1 diabetes in humans. Macrophages and neutrophils were seen in the acute phase. A few islets were observed with peri insulitis three weeks later. Similar inflammation patterns in both human and rat subjects were observed. Upregulation of genes associated with bacterial response in both human and rat tissues was observed. Observed findings indicate a bridge between innate immunity and adaptive immunity in the development upon onset of type 1 diabetes.
Paper II aimed to characterize the differential expression profiles of the defensin system within human pancreas from individuals diagnosed with type 1 diabetes of different ages compared to normoglycemic-matched controls. Individuals with type 1 diabetes have reduced expression of several defensins in both the pancreatic islets and the exocrine parenchyma. This suggests a compromised innate immune system, tentatively predisposing them to heightened susceptibility to microbial threats and increased pro-inflammatory stress on the pancreas.
Paper III focused on quantifying the prevalence and spatial distribution of δ-cells in human pancreas from individuals diagnosed with type 1 diabetes compared to normoglycemic controls. The δ-to-α-cell connections and single δ-cell density in the exocrine area of the pancreas were increased. Additionally, isolated islets from an individual with type 1 diabetes showed impaired glucagon secretion at low glucose levels, but elevated secretion with a somatostatin receptor inhibitor. These findings suggest a disruption in paracrine control which affects glucagon secretion in individuals with type 1 diabetes.
In conclusion, several aspects of innate immunity and islet architecture were studied regarding human type 1 diabetes. Obtained findings suggest a dysregulation of innate immunity, however, further research is warranted to fully clarify the bridge between innate and adaptive immunity in the etiology of type 1 diabetes.