Coming dissertations at Uppsala university
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Gaze Following in Infancy : Mechanisms and Developmental Context
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-524912
Few things are as fundamental to humans as the ability to share attention. It allows us to coordinate our actions with, and assimilate knowledge from, the actions of others with remarkable efficiency and accuracy. This ability emerges in infancy and sets the stage for all subsequent social development. In this thesis, I explore how infants align visual attention with others toward external objects, a skill known as gaze following. The included studies investigate this phenomenon at different levels, ranging from processes within the infant (Study I) to the impact of infants’ immediate emotional context at a micro-scale (Study II) and cultural variation at a macro scale (Study III).
Previous work has suggested different mechanistic explanations for emerging gaze following, ranging from perceptual cueing to reinforcement learning, to social motivation. Study I aimed to conduct a critical test comparing the perceptual cueing perspective with the social-first perspective. The results indicate that infants initially use both cues, but rely more on social information towards the end of the first year.
The theories of gaze following emergence can be framed in a broader discussion regarding the developmental base (experience-dependent or experience-expectant). It has been suggested that infants’ environment influences the early development of gaze following. However, some theoretical perspectives hold an experience-expectant perspective that infants are predisposed to align visual attention with others, suggesting that gaze following should be relatively robust early in life. In Study II, we found that infants’ gaze following was impacted by attachment quality and maternal Postpartum depression (PPD) at 6 and 10 months, respectively, aligning with an experience-dependent view of development.
Study III extends this work to test the universality of Study II and gaze following as a valid measure of attention sharing. We found that across different cultural contexts (Bhutanese and Swedish), infants follow gaze to a similar degree. However, the impact of infants’ social and emotional environment observed in Study II was not found in Bhutan. We discuss the possibility that cultures relying more on interdependent values possess inherent protective factors that mitigate the negative effects of PPD on the infant.
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The role of imaging in follow-up and prognosis of patients radically operated for melanoma
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-525153
Cutaneous malignant melanoma (CMM) is the cancer type in Sweden with the most rapidly increasing incidence. This thesis investigated if whole-body imaging improves the follow-up scheme post-surgery in high-risk CMM patients and explored the long-term outcomes for early-stage melanoma patients compared to the general population.
We launched the nationwide randomized phase III study: “Trial to assess the Role of Imaging after radical surgery of CMM stage IIB-C and III (TRIM study, NCT 03116412)” with allocation to physical examinations for three years according to Swedish national guidelines +/- five scheduled whole-body imaging procedures. Primary endpoint is overall survival (OS) at five years. Secondary endpoints include Health-Related Quality of Life (HRQoL) outcomes.
In paper I, the TRIM study protocol and the recruitment status were described and evaluated. Based on enrollment of more than 550 patients at 19 centra, we found the study protocol feasible and identified some obstacles for optimal inclusion rate.
In paper II, we evaluated HRQoL and anxiety/depression in > 200 patients in the TRIM study who responded to the Hospital Anxiety and Depression (HAD) scale and the EORTC Quality of Life Questionnaire (QLQ)-C30 at baseline and after one year. No statistically significant differences were found between the study arms. Levels of anxiety and depression symptoms were generally low.
The Malignant Melanoma Database Sweden (MMBaSe) was created by record linkages between the Swedish Melanoma Register and several population-based registers. The MMBaSe includes 67 000 individuals diagnosed with CMM or melanoma in situ (MIS) between 1996 and 2018 and matched, randomly selected, melanoma-free comparators representing the general population.
Overall survival and mortality risks were assessed in two cohort studies in patients with MIS (paper III) and thin CMM (≤ 1 mm) (paper IV) in comparison to their matched comparators. Mortality risks were adjusted for socioeconomic status (SES) and comorbidities. We found several statistically significant differences. Individuals diagnosed with melanoma had higher SES and a lower comorbidity burden. While melanoma patients were at higher risk of dying from CMM, they had lower risks of dying from several other diseases.
In paper III we found a better OS and a lower risk of death in MIS patients, findings that remained after adjustments.
In paper IV, patients with thin CMM had a similar OS as the general population. In individuals with stage T1a disease (< 0.8 mm), the OS at 5 years was slightly better than in comparators.
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Novel Endpoints To Unravel Developmental Neurotoxicity : From DNA methylation responses to methylmercury to the in vitro identification of endocrine disruptors
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-523935
The developing brain is especially sensitive to environmental stressors due to its dependence on the precise spatiotemporal regulation of multiple signals, and the long time period required for its formation. Some chemicals can interfere with molecular and cellular processes driving brain development, including epigenetic processes such as DNA methylation. Hence, identification of DNA methylation changes induced by chemical exposure may serve as early molecular markers for developmental neurotoxicity (DNT). Chemicals known as endocrine disruptors (EDCs) can produce adverse effects due to their capability to alter the endocrine system. Since brain development is highly dependent on endocrine signals, the potential adverse effects of EDCs on brain development needs to be addressed. Detection of DNT in the regulatory context has been based on in vivo testing, however, the financial costs and time intensive characteristics of these methods have resulted in a limited assessment of the DNT hazard of chemicals. In addition, in order to regulate EDCs, it is paramount to demonstrate that their adverse effects are a product of disruption of endocrine signals. Yet, at the moment, there are no approved methods which address both an endocrine mode of action and adverse neurodevelopmental outcomes. This doctoral thesis had two main aims: Firstly, to identify epigenetic changes, at the level of DNA methylation, underlying DNT induced by exposure to methylmercury (MeHg); and secondly, to develop new approach methods (NAMs) for the detection of DNT induced by endocrine disruption. Epigenetic effects were studied both in epidemiological data and experimentally in vitro. Associations between prenatal MeHg exposure and DNA methylation of GRIN2B and NR3C1 were found in children. In vitro validation of DNA methylation changes found in epigenome-wide association studies of populations exposed to MeHg, uncovered the potential involvement of the Mediator Complex Subunit 31 (MED31) in MeHg DNT. To contribute to the endocrine disruption (ED)-induced DNT field, the applicability of an in vitro model composed of murine neural progenitor cells (the C17.2 cell-line) was evaluated. We found that C17.2 neural differentiation and morphology were sensitive to retinoic acid (RAR), retinoic X (RXR), peroxisome proliferator-activated β/δ (PPARβ/δ), and glucocorticoid (GR) agonism. Furthermore, two out of 25 tested EDCs decreased neurite outgrowth and branching in the C17.2 system. These effects were recovered by co-exposure of the chemicals with antagonists of RAR, RXR, or PPARβ/δ, indicating that their DNT effect is mediated by hormonal disruption. Altogether, this thesis contributed to the development of new methodologies and endpoints for the assessment of DNT induced by MeHg and EDCs.