Publikationer från Uppsala Universitet
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Shining the LIGHT on Glioblastoma : Understanding and exploiting vascular and immune co-targeting
No full textPatients diagnosed with glioblastoma (GBM) have an extremely poor prognosis despite extensive research in the recent years, with a five-year overall survival of only 7%. There is a multitude of barriers to effective treatment in GBM, including low levels of T cell infiltration. Chronic inflammation in cancer can lead to the formation of ectopic clusters of lymphoid tissue known as tertiary lymphoid structures (TLS), as well as specialised blood vessels called tumour-associated high endothelial venules (TA-HEVs), which are involved in the extravasation of different immune cell subsets. Both TLS and TA-HEVs have been associated with increased immune cell infiltration and prolonged survival in numerous peripheral cancers. In this work, we aimed to improve the anti-glioma immune response by increasing the infiltration of T cells through induction of TLS and TA-HEVs. Further, we aimed to deeply explore the characteristics and roles of these two components in the GBM setting. In Paper I, we pre-screened a panel of lymphoneogenic cytokines and selected LIGHT as the most promising therapeutic candidate. We then targeted LIGHT to the brain endothelial cells of glioma-bearing mice utilising an adeno-associated viral (AAV) vector (AAV-LIGHT). We found that this approach resulted in prolonged survival in association with the formation of TLS and functional MAdCAM-1+ TA-HEVs, as well as the promotion of effector/memory T cell responses and the TCF1+CD8+ stem-like T cell population. In Paper II, we correlated the presence of TLS with improved survival in GBM patients. We then combined advanced spatial transcriptomics techniques with functional studies in murine glioma to establish the developmental timeline of TLS in GBM, including the critical role of CCR7+CD4+ T cells with LTi-like features. In Paper III, we employed a murine knockout model of MAdCAM-1 to demonstrate its necessity in the anti-glioma immune response through the promotion of TCF1+CD8+ stem-like T cells. Furthermore, we identified the presence of TA-HEVs in human GBM in association with infiltrating T cells. Altogether, this work uncovers previously unknown mechanisms and highlights the potential of targeting the immune/vascular interface as a therapeutic option for GBM.
Association between autism diagnosis rates and adolescent depression : A population-based study in Sweden
No full textIntroduction: The association between increasing diagnosis rates of autism-related disorders (ASD-R) in Swedish regions and diagnosis rates of major depressive disorders (MDD) in adolescents remains unexplored. Methods: Following STROBE guidelines, this pre-registered (https://osf.io/duvq7) observational study, utilizing registry data from 2008 to 2022 across the 21 Swedish regions, employed a generalized linear mixed model (GLMM) to analyze the association between ASD-R (ICD-10: F84) and MDD diagnosis rates (ICD-10: F32) in 15-19 year olds, with registered primary diagnoses considered. The GLMM included psychiatric care affiliation rates (PCAR) as fixed effects and variations across years and regions as random intercepts. The model incorporated bipolar disorder (BD) rates and the male-to-female ratio of ASD-R diagnoses when justified. Separate models were created for combined sexes, males, and females. Results: A significant inverse relationship was observed between ASD-R and MDD diagnosis rates across all sex groups. In the combined-sex model, the mean ratio was 0.40 (P = 0.003), while the sex-specific models showed ratios of 0.28 for males (P < 0.001) and 0.37 for females (P = 0.017). All ratios were significantly below 1, indicating a negative association between ASD-R and MDD diagnosis rates. Conclusions: The study's observational nature limits causal inferences, but findings reveal that higher primary diagnosis rates of ASD-R correlate with lower primary diagnosis rates of MDD in adolescents of both sexes, although more pronounced in males. These results highlight the importance of further research on the relationship between ASD-R and MDD diagnosis rates, emphasizing the need for prospective, longitudinal, and individualized register data that include both primary and co-diagnoses
Redefining 'sustainability' : A systematic approach for defining and assessing 'sustainability' and 'social sustainability'
No full textIn recent years, the pursuit of social sustainability has intensified, especially in urban development. This has resulted in numerous definitions of 'social sustainability' from stakeholders including researchers, non-governmental organizations (NGOs) and both private and public sector entities. These definitions vary widely, encompassing values such as well-being, good governance, equality, trust, diversity, and accessibility. Despite extensive contributions, a universally accepted definition remains elusive, indicating the need for further conceptual work. The primary issue is the lack of explicit criteria for adequacy, leading to a stalemate in the literature. To address this issue, de Fine Licht and Folland, in 2019, proposed a framework with nine conditions of adequacy for evaluating definitions. Building on this framework, our paper systematically analyses and critiques existing definitions and proposes new, formal definitions for both 'sustainability' and 'social sustainability'. Our approach identifies central challenges in existing definitions, demonstrates their inadequacy and presents an enhanced formal definition that avoids these pitfalls. Although our definitions do not specify particular values, they offer substantial results relevant to the sustainability discourse. The novelty of our work lies in our formal definition, engagement with the conditions of adequacy and systematic critique of existing definitions
Dynamic Voltage and Frequency Scaling for Intermittent Computing
No full textWe present hardware/software techniques to intelligently regulate supply voltage and clock frequency of intermittently computing devices. These devices rely on ambient energy harvesting to power their operation and small capacitors as energy buffers. Statically setting their clock frequency fails to capture the unique relations these devices expose between capacitor voltage, energy efficiency at a given operating frequency, and the corresponding operating range. Existing dynamic voltage and frequency scaling techniques are also largely inapplicable due to extreme energy scarcity and peculiar hardware features. We introduce two hardware/software co-designs that accommodate the distinct hardware features and function within a constrained energy envelope, offering varied tradeoffs and functionalities. Our experimental evaluation combines tests on custom-manufactured hardware and detailed emulation experiments. The data gathered indicate that our approaches result in up to 3.75x reduced energy consumption and 12x swifter execution times compared to the considered baselines, all while utilizing smaller capacitors to accomplish identical workloads
”Can I trust you?” : A qualitative literature study on adult patients' and relatives' experiences of trustin ambulance personnel
No full textBakgrund: Prehospital vård är en central del av akutsjukvården och bidrar till trygghet isamhället. Ambulanssjuksköterskan möter patienter i akuta och ofta stressfyllda situationerdär tillit spelar en avgörande roll för vårdrelationen. För att skapa tillit krävs både medicinskkompetens och en förmåga att kommunicera lugnt och empatiskt. Tidigare forskning om tillitär begränsad och utrycker ett behov av att närmare studera patientens upplevelse av tillit. Syfte: Syftet med studien är att beskriva vuxna patienters och deras anhörigas upplevelser avtillit till ambulanspersonalen i det prehospitala vårdmötet. Metod: Kvalitativ litteraturstudiemed systematisk ansats med 19 inkluderade artiklar som analyserats med en latentinnehållsanalys. Resultat: Patienters tillit till ambulanspersonalen kan börja redan vidlarmcentralens besked om att hjälp är på väg och stärks av snabb ankomst och professionelltbemötande. Ambulanspersonalens medicinska kompetens är avgörande för tryggheten,medan bristande kunskap kan leda till misstro. Ett empatiskt och tydligt bemötande stärkerrelationen och ökar tilliten, medan dålig kommunikation och ifrågasättande kan minskaförtroendet. Slutsats: Tilliten till ambulanspersonalen är avgörande för patientens upplevelseav trygghet och vårdkvalitet i det prehospitala mötet. Studien visar att faktorer somprofessionellt bemötande, medicinsk kompetens, tydlig kommunikation och en respektfullvårdrelation bidrar till att stärka denna tillit. När patienter och anhöriga känner sig lyssnadepå, informerade och bekräftade skapas en vårdmiljö där tilliten kan utvecklas, vilket i sin turunderlättar samverkan mellan patient och ambulanspersonal. Vidare forskning bör undersökahur olika utbildningsnivåer hos ambulanspersonalen påverkar patientens upplevelse av tillitsamt om specifika utbildningsinsatser kan stärka patientens upplevelse av tillit
Long-term treatment with gamma-aminobutyric acid (GABA) fails to regain beta-cell function in longstanding type 1 diabetes : results from a randomized trial
No full textGamma-amino butyric acid (GABA) has in experimental studies been found to promote beta-cell proliferation, enhance insulin secretion and reduce inflammation, positioning it as a candidate drug for type 1 diabetes (T1D) therapy. This phase I/II randomized controlled trial assessed the safety and efficacy of long-term treatment with Remygen® (Diamyd Medical), a controlled-release oral GABA formulation, as a potential beta-cell regenerative therapy in adults with long-standing T1D. Thirty-five male subjects with T1D (≥ 5 years) were randomized into three arms receiving the study drug(s) once daily for 6 months: GABA 200 mg (Arm 1), GABA 600 mg (Arm 2) and GABA 600 mg + alprazolam 0.5 mg for 3 months followed by GABA 600 mg alone for 3 months (Arm 3). Safety measures, hormonal counter-regulation during hypoglycemic clamps, fasting- and stimulated C-peptide levels, were assessed at multiple timepoints. Safety concerns included elevated aspartate aminotransferase (AST) in nine subjects, leading to the withdrawal of two subjects. Most elevations were, however, transient with no dose-differences. No effects were observed on fasting- or stimulated C-peptide levels, CGM metrics or HbA1c. Hypoglycemic hormonal counter-regulation was unaltered. To conclude, we found no clinical evidence of a beta-cell regenerative effect of GABA, but side effects were commonly observed
CCL25 in the cerebrospinal fluid is negatively correlated with fatigue in chronic pain patients
No full textBackground and aim Chronic pain is often accompanied by other symptoms such as fatigue and sleep disturbance, and these symptoms all correlate with neuroimmune activation. However, their relation to one another on a neuroimmune axis remains elusive. Based on a recent review, cytokines in the cerebrospinal fluid (CSF) seem to be generally upregulated in patients with chronic pain compared to controls, disregarding pain type. Some of these have the possilibity of altering blood–brain barrier (BBB) permeability. Therefore, cytokine levels in serum and CSF, as well as BBB permeability, were measured in a cohort of patients suffering from either degenerative disc disease (DDD), lumbar disc herniation (LDH) or osteoarthritis (OA). In this exploratory study, we were interested in whether cytokines in the serum or CSF are associated with sleep disturbance or fatigue, with special consideration of the effect of BBB permeability, and whether functional clusters can be found among these cytokines. Method One-hundred-twenty patients with DDD/LDH/OA, all awaiting surgery, were included. Blood and CSF were collected on the day of surgery. Pain was measured with a visual analog scale 0–100 mm, sleep disturbance was assessed using Pittsburgh Sleep Quality Index (PSQI), and fatigue was measured using the Multidimensional Fatigue Inventory (MFI). A 92-protein multiplex panel (OLINK, Sweden) was used to analyze cytokine expression in serum and CSF, respectively. CSF-serum albumin quotient was measured using ELISA. Non-parametric statistics were used for univariate analyses, and a false discovery rate (FDR) < 0.10 was considered statistically significant. Bonferroni correction was applied to all multivariable protein analyses to obtain conservative effect estimates. Main results There was an association between BBB permeability and serum-CSF dynamics: thirty-one cytokines showed significant CSF-serum correlation, and BBB permeability was significantly correlated to the quotients of 35 cytokines and to the CSF levels of 11 cytokines. Several cytokines were negatively correlated to both pain at rest and general fatigue. No correlations were found between sleep disturbance and cytokines. Network analyses of serum and CSF cytokines that were correlated with fatigue revealed functional clusters in both compartments. Anxiety, depression, and pain during rest were important regressors for sleep disturbance with an R2 = 0.41. In addition to depression and pain during rest, CSF levels of CCL25 was a significant regressor regarding general fatigue, with an R2 = 0.47. Discussion and conclusion In this exploratory study of immune profiles in chronic pain cohorts awaiting surgery, the importance of BBB dynamics on serum-CSF cytokine dynamics, and to a lesser extent on central levels of cytokines, is highlighted. Surprisingly, there were no associations between any cytokines in serum or CSF and sleep disturbance, despite a high prevalence of clinically significantly disturbed sleep. In contrast, several associations between general fatigue and cytokine levels in both serum and CSF were found. Cytokines of note are CXCL11 and CCL25 in the CSF, especially because of their direct functional association. CXCL11 has been found to exert neuroprotective effects in animal models, while CCL25 is known as a proinflammatory cytokine and is the only cytokine to fall out as a significant negative contributor to degree of fatigue. While causality cannot be addressed, the negative correlation between CCL25 and fatigue in both univariate and multivariate analyses implies that neuroimmune activity might have an ameliorating effect on the degree of fatigue. This study further adds to existing evidence that centrally acting cytokines are associated with severity of symptomatology, and highlights that pain and fatigue seem to have slightly different cytokine profiles. Sleep disturbance needs to be further addressed, ideally using both subjective and objective assessment methods. CCL25 and CXCL11 are interesting biomarkers for future research on pain and associated symptoms.De två sista författarna delar sistaförfattarskapet</p
Trollkonan och Oraklet : En jämförande studie av magiska kvinnor i fornnordisk religion och antika Grekland
No full textThis thesis aims to compare the religious perceptions of women practicing magic in ancient Greece and Norse mythology. The focus is on how these women are portrayed in mythological sources, with attention to how the authors and their cultural contexts may have influenced these depictions. Additionally, the study reflects on the actual living conditions of these women by examining historical and archaeological sources. The research is based on previous studies, a close reading of the mythological narratives, and an exploration of archaeological findings. The results show that women in both mythologies are often depicted in an overly sexualized, and in Greek traditions a dramatic manner, while in Norse mythology they are portrayed as outcasts. However, historical and archaeological evidence suggests that these portrayals may not accurately reflect their real lives. The conclusion is that further research is needed in this area, with a focus on moving beyond written sources and developing new understandings through a greater emphasis on archaeological discoveries and historical documents
Mastocytosis : Registry-based studies of a rare condition
No full textMastocytosis is a condition characterized by the accumulation of aberrant clonal mast cells in different organs and mediator related symptoms. It is divided into two major categories, cutaneous mastocytosis and systemic mastocytosis, with subtypes ranging from indolent to aggressive forms. Although mastocytosis is considered an uncommon condition, its epidemiology has for a long time been incompletely understood, as have several aspects of comorbidity in mastocytosis patients. Paper I aimed to investigate the epidemiology of mastocytosis by estimating the incidence, prevalence and overall survival, and the comorbidity burden between individuals with mastocytosis and comparators using data from Swedish national registers. This population-based study found an annual incidence of 1.56 per 100,000 and a prevalence of 23.9 per 100,000, exceeding previous estimates from other studies. The comorbidity burden was higher in the mastocytosis patients, compared to comparators. We confirmed that the prognosis generally is favorable, but with marked survival differences between subtypes. Paper II aimed to examine whether mastocytosis patients are at an increased risk of developing malignant melanoma (MM), melanoma in situ (MIS) or basal cell carcinoma (BCC) compared to the background population. By merging data from several Swedish population-based registries we found that patients with mastocytosis were at a more than two-fold higher risk for MM and MIS. The risk estimates for BCC were also elevated. We also found that a substantial portion of skin cancers were diagnosed near index date, suggesting a possible influence of detection bias. Paper III further evaluated the risk of skin cancer through a large-scale, retrospective, propensity-score-matched cohort study utilizing data in a large U.S. healthcare database. We found that mastocytosis patients had significantly elevated lifetime risks of all skin cancers compared to comparators. Sensitivity analyses designed to assess detection bias indicated that detection bias alone cannot fully explain the increased risk of skin cancers in mastocytosis patients. In conclusion, we found higher incidence and prevalence of mastocytosis than previously reported, along with evidence of a higher comorbidity burden. Additionally, our data suggest that patients with mastocytosis are at an increased risk of being diagnosed with skin cancer, warranting heightened dermatological surveillance
Accessibility of eHealth Before and During the COVID-19 Pandemic Among People With and People Without Impairment : Repeated Cross-Sectional Survey
No full textBackground: The adoption of eHealth accelerated during the COVID-19 pandemic. Inequalities in the adoption of eHealth during the COVID-19 pandemic have been reported, but there are few such studies among people with impairment. Objectives: This study aimed to investigate self-reported use and difficulty in the use of eHealth before the COVID-19 pandemic compared to during late social distancing restrictions in Sweden, among people with and without impairment, as well as between different types of impairment. Methods: A cross-sectional survey was distributed twice by snowball sampling to people with self-reported impairment and a general population matched by age, gender, and county. Use and difficulty in the use of six eHealth services were compared between groups using chi-square test and logistic regression with year interaction terms, reported as odds ratio adjusted (aOR) for gender and age with 95% CI. Results: The surveys included 1631 (in 2019) and 1410 (in 2021) participants with impairment, and 1084 (in 2019) and 1223 (in 2021) participants without. Participants with impairment, compared to those without impairment, reported less use and more difficulty in booking health care appointments online, digital identification, and the Swedish national web portal for health information and eHealth services (1177.se), both before and during the pandemic (P=.003 or lower). Video health care appointments were the exception to this disability digital divide in eHealth as video appointment adoption was the most likely among participants with attention, executive, and memory impairments (interaction term aOR 2.10, 95% CI 1.30‐3.39). Nonuse and difficulty in the use of eHealth were consistently associated with language impairments and intellectual impairments. For example, language impairments were inversely associated with use of the logged-in eHealth services in 1177.se in 2021 (aOR 0.49, 95% CI 0.36‐0.67) and were associated with difficulty in the use of 1177.se in 2019 (aOR 2.24, 95% CI 1.50‐3.36) and the logged-in eHealth services in 1177.se in 2021 (aOR 1.89, 95% CI 1.32‐2.70). Intellectual impairments were inversely associated with the use of the logged-in eHealth services in 1177.se in 2021 (aOR 0.19, 95% CI 0.13‐0.27). Conclusions: This repeated cross-sectional survey study, including participants with diverse types of impairment and a control group without impairment, reveals persisting disability digital divides, despite an accelerated adoption of eHealth across the pandemic. eHealth services were not accessible to some groups of people who were identified as being at risk of severe disease during the COVID-19 pandemic. This implies that all people could not use eHealth as a measure of infection protection