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Physical activity and mental health among trauma-affected refugees : associations, experiences, and intervention efficacy
No full textAims: The overall aim of this thesis was to increase the understanding of physical activity (PA) and its impact on mental health and wellbeing among trauma-affected refugees and asylum-seekers, and with a particular focus on posttraumatic stress disorder (PTSD) as a prevalent disorder in this context. More specifically, we sought to investigate experiences and preferences of participation in PA and exercise-based treatments from a holistic and patientcentered perspective (study I), to examine the prevalence of different levels of PA and associations with PTSD symptom severity (study II), and to evaluate the efficacy of a multi-component and trauma-informed PA intervention on symptoms of PTSD, depression, anxiety, and subjective wellbeing (study III). In study III, we also examined adherence to the intervention, changes in levels of PA and sedentary time, and a follow-up of all outcomes after six months.Methods: The thesis comprises three studies, I) an explorative qualitative study with focus group discussions (n=33), II) a cross-sectional survey study (n=455), and III) a randomized controlled trial (n=183). Study I and III were conducted at the Swedish Red Cross Treatment Center for persons affected by war and torture (RCC Malmš) and study II at three housing facilities for asylum-seekers across Sweden. The methods for analyzing the collected data were conventional qualitative content analysis in study I, prevalence estimates, analysis of variance, and multivariable logistic regression analysis in study II, and mixed-effects linear regression models in study III. Basic descriptive statistics were also employed in all studies to describe the participants. The development of the study III intervention model and design were a part of the overall project, conducted in parallel with study I and II, and partially informed by the results of these preceding studies before the onset of study III.Results: The results of study I outline a detailed description of trauma-affected refugeesŐ subjective experiences and preferences of participation in PA and exercise treatments, pointing to a multitude of pathways towards improvements in both mental and physical health domains, increased self-empowerment, and improved social adjustment. Treatment characteristics were experienced as highly supportive and the treatment group settings as a vehicle for overcoming social fear and isolation. The analysis resulted in one overarching theme reflecting the participantsŐ overall experiences as a process and building resilience through relief and recovery.In study II, we found that almost half of the participants did not meet the general recommendations for a sufficient level of PA and there were significant differences in PTSD symptom severity between the groups with different levels of PA. Sufficient PA was associated with less PTSD compared to both insufficient PA and inactive, while insufficient PA was also associated with less PTSD compared to inactive. The associations between PA and PTSD persisted when controlling for sex, age, and exposure to torture, and level of PA was found to provide a high explanatory function for the variance in PTSD symptom severity.The results of study III revealed that the multi-component and trauma-informed PA intervention had a significant impact on all primary and secondary outcomes. The between group difference in PTSD symptom severity corresponded to a large effect size. The average decrease in PTSD was clinically significant, as was the decrease in depression and anxiety, and the increase in wellbeing. The change in level PA was also significant and corresponded to a move from below to above the cutoff for a sufficient level of PA. All positive effects at postintervention persisted, or even further improved, at the 6-month follow-up. The overall intervention model appeared to be well received and tolerated, as reflected by a high adherence and a low dropout rate, and where a higher adherence was also associated with a greater reduction in PTSD.Conclusions: The overall results of this thesis add to the empirical evidence of PA as an important factor in PTSD and support an increased focus on PA and exercise in the context of forced migration and trauma-affected refugeesŐ health and wellbeing. Increased PA promotion is justified at multiple levels, in line with the general guidelines and health benefits as associated with regular PA and exercise, and as a viable treatment modality to alleviate PTSD symptom severity and associated distress, and to increase wellbeing.List of scientific papersI. Nilsson, H, Saboonchi, F, Gustavsson, C, Malm, A, Gottvall, M. (2019). Trauma-afflicted refugeesŐ experiences of participating in physical activity and exercise treatment: a qualitative study based on focus group discussions. European Journal of Psychotraumatology. 2019; 10(1): 1699327. https://doi.org/10.1080/20008198.2019.1699327 II. Nilsson, H., Gustavsson, C., Gottvall, M., Saboonchi, F. (2021). Physical activity, post-traumatic stress disorder, and exposure to torture among asylum seekers in Sweden: a cross-sectional study. BMC Psychiatry. 2021; 21(1): 452. https://doi.org/10.1186/s12888-021-03461-2 III. Nilsson, H., Gottvall, M., Gustavsson, C., Nissen, A., Saboonchi, F. Evaluation of a trauma-informed physical activity intervention for posttraumatic stress disorder, depression, anxiety, and wellbeing in trauma-affected refugees: a randomized controlled trial. [Submitted]</p
Autoimmune pancreatitis : from bench to bedside
No full textBackground: Decreased microbial diversity had been associated with the establishment of an environment in which pathogens could incite and sustain chronic inflammation. Metabolomic analysis of fecal samples provides insights into the gut microbiome's interaction with the host's metabolism. Autoimmune pancreatitis (AIP) is a complex immune-mediated form of chronic pancreatitis, comprising two distinct entitiesŃType 1 and Type 2Ńwith differing histological features, clinical presentations, and prognoses. AIP type 1 is a systemic disease, while type 2 is strongly associated with inflammatory bowel disease. Diagnosing AIP is challenging, relying on a set of criteria rather than a definitive diagnostic marker, and requires the exclusion of pancreatic cancer before proceeding. Management backbone are glucocorticoids, with excellent response. Relapses and often in type 1 AIP and different strategies for relapse treatment are possible including advanced therapies. Pancreatic exocrine and endocrine insufficiencies are consequences of inflammatory damage but are considered transient.Aims: This thesis aims to enhance the scientific evidence surrounding the diagnosis, treatment, and follow-up of AIP patients by examining the relationship between pharmacological treatment and loss of pancreatic function in type 1 AIP, evaluating the outcomes of patients treated surgically and with advanced therapies, and investigating the association between type 2 AIP and IBD. Additionally, the thesis explores gut metabolic changes in AIP and identifies key metabolites associated with the disease.Methods: The thesis comprises four epidemiological studies (Studies I-IV) and one metabolomic study (Study V) on AIP patients followed at Karolinska University Hospital in Stockholm, Sweden, from 2001-2022. The epidemiological studies are retrospective cohort studies based on medical records, with systematic reviews conducted in Studies II and IV. In Study V, fecal samples were collected from patients, and after obtaining informed consent, the samples underwent UHPLCĐ MS/MS analysis for metabolite identification.Results: In Study I, prevalence of pancreatic exocrine insufficiency at diagnosis was 72.7% and 63.5% at follow-up. The cumulative incidence of diabetes mellitus was 17.9%, with a prevalence of diabetes mellitus at diagnosis of 32.8%. No strong association was found between pharmacological treatment and occurrence of pancreatic exocrine insufficiency and diabetes mellitus. In a multivariate analysis, only obstructive jaundice was identified as a risk factor for diabetes mellitus both at diagnosis and during follow-up. Study II showed that twelve (11.7%) of 103 patients with AIP type 1 were treated with rituximab during the study period: eight (66.7%) achieved complete and four (33.3%) partial remission. Rituximab was discontinued in one patient who developed fever and reactivation of latent tuberculosis. Altogether, eight studies with 110 AIP type-1 patients treated with rituximab were analyzed. Adverse effects ranged from 11Đ43% and the relapsefree period during follow-up ranged from 38Đ94%. Study III reported that 35 (22.0%) patients with AIP had surgery. Malignant and premalignant lesions were diagnosed in 8 (22.9%) patients for whom AIP was not the primary differential diagnosis, but in all cases, it was described as a simultaneous finding. One third of AIP type 1 patients experienced relapse in the follow up after surgery. Study IV revealed that diagnosis of inflammatory bowel disease was reported in 330 (47.8%) patients of our systematic review, whereas in 29/35 (83%) of AIP type 2 patients in our cohort. The relapse rate was 20.0% in both original and systematic analysis. Study V led to the discovery of newly identified metabolic signatures between both patient groups with enterolactone being prominent in AIP.Conclusion: Prevalence of endocrine and exocrine insufficiency in AIP is high at diagnosis with an additional risk during follow-up despite pharmacological treatment. Obstructive jaundice is a risk factor for diabetes mellitus both at diagnosis and at follow up. Rituximab is effective in inducing and maintaining remission in relapsing AIP type 1. Surgical treatment is justified where cancer cannot be excluded, although relapse risk is not annihilated. Clinical and radiological remission of AIP type 2 is high, while the cumulative incidence of relapse is around 20%. Concomitance of inflammatory bowel disease imposes no obvious risk of a different disease course for AIP type 2.List of scientific papersI. Nikolic S, Maisonneuve P, Dahlman I, Lšhr JM, Vujasinovic M. Exocrine and Endocrine Insufficiency in Autoimmune Pancreatitis: A Matter of Treatment or Time?. J Clin Med. 2022;11(13):3724. Published 2022 Jun 28. https://doi.org/10.3390/jcm11133724 II. Nikolic S, Panic N, Hintikka ES, et al. Efficacy and safety of rituximab in autoimmune pancreatitis type 1: our experiences and systematic review of the literature. Scand J Gastroenterol. 2021;56(11):1355-1362. https://doi.org/10.1080/00365521.2021.1963837 III. Nikolic S, Ghorbani P, Pozzi Mucelli R, et al. Surgery in Autoimmune Pancreatitis. Dig Surg. 2022;39(1):32-41. https://doi.org/10.1159/000521490 IV. Nikolic S, Lanzillotta M, Panic N, et al. Unraveling the relationship between autoimmune pancreatitis type 2 and inflammatory bowel disease: Results from two centers and systematic review of the literature. United European Gastroenterol J. 2022;10(5):496-506. https://doi.org/10.1002/ueg2.12237 V. Dovhalyuk V, Yang F, Nikolic S et al. Differences in the Fecal Metabolome of Autoimmune Pancreatitis Patients. [Manuscript]</p
Risk factors and prognosis of diabetes with and without an autoimmune component
No full textDiabetes is heterogenous and encompasses different types such as type 1 diabetes (T1D), type 2 diabetes (T2D), and latent autoimmune diabetes in adults (LADA), which shares clinical characteristics with T2D and genetic similarities with T1D. Smoking is associated with an increased risk of T2D while the underlying mechanism remains unclear. Evidence on modifiable risk factors for T1D and LADA is scarce and the prognosis in LADA is also understudied.Study I assessed the association between maternal smoking during pregnancy and childhood-onset T1D. We followed 2,995,321 children born in Sweden in 1983-2014 from birth until age 18 years or 2020. Apart from a traditional cohort analysis, we used a sibling and cousin comparison design which compares T1D risks between siblings (or cousins) with and without exposure to maternal smoking during pregnancy, to account for confounding from genetic and environmental factors shared within families. We identified 18,617 children with T1D during follow-up of 18.2 years. Maternal smoking during pregnancy was associated with a decreased T1D incidence in the offspring in the traditional cohort analysis (hazard ratio: 0.78, 95% CI: 0.75. 0.82]), sibling comparison (odds ratio [OR]: 0.78, 95% CI: 0.69, 0.88), and cousin comparison (OR: 0.72, 95% CI: 0.66, 0.79) analyses.Study II assessed the potential causal relationship between birth weight, adult body mass index (BMI) and LADA using a two-sample Mendelian randomization (MR) design. We used 49 independent SNPs associated with birth weight through fetal genome and not maternal genome as the instrumental variables for the exposure of birth weight and used 820 independent SNPs associated with adult BMI as instrumental variables for the exposure of adult BMI. Summary statistics from the only genome-wide association study (GWAS) study of LADA were used to provide outcome information. We found that one standard deviation (SD) decrease in birth weight was associated with a 68% increased LADA risk (OR: 1.68, 95% CI: 1.01, 2.82) while every SD increase in genetically determined BMI in adulthood was associated with a 40% increased risk of LADA (OR: 1.40, 95% CI: 1.14, 1.71).Study III assessed the risk of mortality and vascular complications, and clinical trajectories in individuals with LADA. We included 550 people with LADA (further classified LADAhigh and LADAlow by median autoimmune level), 2,001 people with T2D, and 1,573 people with adult-onset T1D diagnosed in 2007-2019, as well as 2,355 diabetes-free population controls. As compared to population controls, people with LADA (HR: 1.44, 95% CI: 1.03, 2.02), T2D and T1D all had increased all-cause mortality; Both LADAhigh (HR 1.67; 95% CI 1.04, 2.69) and T2D, but not LADAlow or T1D, were associated with elevated incidence of cardiovascular diseases. People with LADA had a higher incidence of retinopathy and worse glycemic control than people with T2D.Study IV investigated the metabolomic pathways linking smoking to T2D and assessed potential interaction between smoking-related metabolic changes and genetic susceptibility. Smoking was associated with changing levels of 131 metabolites in both the cross-sectional analysis of 93,772 UK Biobank participants and MR analysis. We created a smoking-related metabolic signature based on the smoking-related metabolites. In prospective analysis, 38.3% of the smoking-T2D association was mediated by the metabolic signature. The metabolic signature and its mediation role were externally validated in TwinGene. We observed additive interactions between the metabolic signature and genetic risk scores for T2D/insulin resistance.In conclusion, this doctoral project provides evidence in support of a causal link between maternal smoking during pregnancy and childhood-onset T1D, and between low birth weight and LADA. This indicates that early-life factors play a role in the development of autoimmune diabetes during childhood as well as adulthood. We also provide support on the causal link between adult BMI and both LADA and T2D, highlighting the importance of keeping a normal weight during adulthood to prevent or delay the development of adult-onset diabetes with and without an autoimmune component. In addition, smoking affects T2D risks through changes in a wide range of metabolites, and the adverse effects of such changes are more detrimental to people with high genetic susceptibility to T2D and insulin resistance, indicating the importance of avoiding or quitting smoking for the prevention of diabetes. In people with LADA, the equally high risks of mortality and CVD and higher risk of retinopathy coupled with worse glycemic control than people with T2D highlight the importance of differentiating people with LADA from those with T2D for more effective diabetes management.List of scientific papersI. Wei Y, Andersson T, Edstorp J, Lšfvenborg JE, TalbŠck M, Feychting M, Carlsson S. Maternal smoking during pregnancy and type 1 diabetes in the offspring: a nationwide register-based study with family-based designs. BMC medicine. 2022;20(1):240. https://doi.org/10.1186/s12916-022-02447-5 II. Wei Y, Zhan Y, Lšfvenborg JE, Tuomi T, Carlsson S. Birthweight, BMI in adulthood and latent autoimmune diabetes in adults: a Mendelian randomisation study. Diabetologia. 2022;65(9):1510-1518. https://doi.org/10.1007/s00125-022-05725-2 III. Wei Y, Herzog K, Ahlqvist E, Andersson T, Nystršm T, Zhan Y, Tuomi T, Carlsson S. All-Cause Mortality and Cardiovascular and Microvascular Diseases in Latent Autoimmune Diabetes in Adults. Diabetes Care. 2023 Oct 1;46(10):1857-1865. https://doi.org/10.2337/dc23-0739 IV. Wei Y, HŠgg S, Zhan Y, Tuomi T, Carlsson S. Metabolic profiling of smoking, associations with type 2 diabetes and interaction with genetic susceptibility. European journal of epidemiology. 2024 Jun;39(6):667-678. https://doi.org/10.1007/s10654-024-01117-5 </p
Genetic and epigenetic risk factors for asthma in infancy and childhood
No full textAsthma is among the most common non-communicable diseases, with an increasing prevalence worldwide. The pathophysiology behind the disease is heterogeneous, including risk factors like genes, sex, allergies, virus infections, and wheezing episodes. In recent years, epigenetic changes have been found to be associated with the development of asthma, but there is a lack of knowledge about the exact mechanisms of how these genes and epigenetic alterations contribute to disease onset and progression. Furthermore, loss-of-function mutations in the skin barrier gene filaggrin (FLG) are associated with atopic dermatitis (AD) that most often precedes the development of childhood asthma. Airway obstruction is also related to asthma development; nevertheless, less is known about lower lung function and skin barrier impairment in early infancy. Therefore, the overall aim of the thesis was to examine genetic and epigenetic factors for asthma in infancy and childhood.Study I focused on the genetics of asthma by investigating CST1 and CCL26 to better understand their function in the development of asthma, as these genes were previously identified to have the highest expression in the nasal epithelium of dog dander-sensitized children. CST1 and CCL26 were overexpressed separately in the human alveolar basal epithelial cell line A549. RNA sequencing and protein analyses were performed to investigate the downstream effects. On the RNA level a significant downregulation of type I and III interferons and interferon-stimulated genes was observed in A549 cells overexpressing CST1 or CCL26 compared to the controls. No significant downregulation of the analyzed inflammation proteins was observed due to the overexpression of CST1, however, CXCL11, CCL20, CCL3 and CXCL10 were significantly downregulated due to the overexpression of CCL26. Overall, the overexpression of CCL26 caused a downregulation of interferon related genes and inflammatory proteins.Study II evaluated the epigenetics of asthma by analyzing 14 hypomethylated CpG sites previously identified in whole blood of asthmatic children. Seven genes that are inferred to be regulated by these CpG sites were selected for deeper analysis. The overall aim of the study was to better understand the downstream effects of the methylation differences on the gene expression and gene function and their contribution to asthma. The seven genes (SLC25A25, MED27, NTNG2, BBLN, PTGES2, NAIF1, LCN2) or their respective control vectors were separately overexpressed via transfection in the airway epithelial cell lines A549 and BEAS-2B. Transcriptomic and proteomic analyses were performed to identify the downstream effects. The overexpression of MED27, NTNG2 and BBLN separately caused mainly an upregulation of type I and III interferon genes as well as interferon-stimulated genes. Due to the location of one asthma associated CpG site within an intronic region of MED27, the overexpression of MED27 was also analyzed at different timepoints and demonstrated to affect the expression of type I and III interferons in a time-dependent manner. On the protein level, the overexpression of MED27 caused an upregulation of CCL3, TGF-alpha and CCL20, whereas CCL3 and CCL20 were downregulated due to the overexpression of NTNG2, BBLN, PTGES2, NAIF1 and LCN2. In general, MED27 might have an important role in the pathophysiology of asthma, due to the location of an asthma associated CpG site within the gene, its time-dependent effect on interferon genes and the increased protein expression which its overexpression causes. Study III placed the genetics in a clinical context and focused on AD, most often preceding asthma development. It is an epidemiological study of the Scandinavian mother-child cohort PreventADALL including 1836 infants with information on FLG genotyping. The objective was to investigate the role of the most common FLG loss-of-function mutations in the European population on skin barrier function, dry skin, eczema, and AD before one year of age. At 3 months, FLG mutations were associated with eczema and at 6 months, FLG mutation carriers had significantly higher transepidermal water loss (TEWL) than nonmutation carriers. Further, the risk for dry skin on the trunk and extensor limb surfaces was increased at 3 and 6 months for FLG mutation carriers. In conclusion, the study observed associations between FLG mutations and dry skin on the trunk and extensor limb surfaces, eczema, and AD before one year of age.Study IV was also an epidemiological study of the PreventADALL cohort and combined genetics, asthma, and asthma comorbidities. The study of 1337 children aimed to identify possible associations between early infant lung- and skin barrier function and asthma at age 3 years. Lower lung function and higher TEWL were associated with asthma at age 3 years, while eczema and FLG mutations were not. The strongest association was observed between lower lung function and asthma at age 3 years when the children had a diagnosis of either AD or allergic sensitization by 3 years. Taken together, lung- and skin barrier function at 3 months seemed to have already an effect on asthma at age 3 years.The four studies of the thesis contribute to the field of genetics and epigenetics in asthma with new findings. Potential functions were identified for genes previously identified in allergic children and for genes regulated by asthma associated CpG sites. The clinical studies of this doctoral thesis discovered that mutations in the skin barrier gene FLG influence the skin already before one year of age and assessed that skin barrier impairment as well as lower lung function in infancy were associated with asthma at age 3 years.List of scientific papersI. Hoyer A, Chakraborty S, Lilienthal I, Konradsen JR, Katayama S, Söderhäll C. The functional role of CST1 and CCL26 in asthma development. Immun Inflamm Dis. 2024 Jan;12(1):e1162. https://doi.org/10.1002/iid3.1162 II. Hoyer A, Chakraborty S, Lilienthal I, Katayama S, Söderhäll C. Overexpression of genes regulated by asthma associated CpG sites increases interferons levels. [Manuscript]III. Hoyer A, Rehbinder EM, Färdig M, Asad S, Lødrup Carlsen KC, Endre KMA, Granum B, Haugen G, Hedlin G, Monceyron Jonassen C, Katayama S, Konradsen JR, Landrø L, LeBlanc M, Olsson Mägi CA, Rudi K, Skjerven HO, Staff AC, Vettukattil R, Bradley M, Nordlund B, Söderhäll C. Filaggrin mutations in relation to skin barrier and atopic dermatitis in early infancy. Br J Dermatol. 2022 Jul;187(1):132. https://doi.org/10.1111/bjd.20831 IV. Färdig M, Hoyer A, Almqvist C, Bains KES, Carlsen KCL, Gudmundsdóttir HK, Granum B, Haugen GN, Hedlin G, Jonassen CM, Konradsen JR, Lie A, Rehbinder EM, Skjerven HO, Staff AC, Vettukattil R, Söderhäll C, Nordlund B. Infant lung function and early skin barrier impairment in the development of asthma at age 3 years. Allergy. 2024 Jan 18. https://doi.org/10.1111/all.16024 </p
Fatigue in brain injury and chronic pain : attention, emotional aspects, and neuronal correlates
No full textFatigue is common in patients with acquired brain injury (ABI), including traumatic brain injury as well as non-traumatic conditions, i.e., stroke, subarachnoid hemorrhage, anoxia, and brain tumors, and in patients with chronic pain (CP), and it has a negative impact on quality of life and working capacity. A major obstacle in fatigue research has been the absence of a clear definition of the concept. One model to sorting it out is to make a distinction between subjective self-assessed fatigue as opposed to objective performance-based cognitive fatigability (CF).This thesis aims to deepen the understanding of fatigue in patients with ABI or CP by investigating relationships with attention functions and emotional factors, and the communication in the brain's networks in patients with CP, and, furthermore, to explore whether targeted attention training might reduce CF in patients with ABI.Study I investigated the association between subjective fatigue and brain injury localization, diagnosis, and depression in a clinical group of ABI patients. A significantly higher proportion of patients with posterior and non-specific lesions reported fatigue compared to those with subcortical/frontal injuries. Stroke patients exhibited lower rates of fatigue compared to the other diagnostic groups. However, following logistic regression, only depression remained as an explanatory factor for self-reported fatigue. Nonetheless, while all depressed patients reported fatigue, not all fatigued patients were depressed.Study II evaluated the effect of targeted attention training in reducing CF in patients with ABI. The result showed a small baseline correlation between CF and automatic processing speed and attention span. Also, the group receiving targeted attention training reduced their CF significantly more than the group receiving activity-based attention training. After control for the baseline value of CF, revealing that the targeted attention training-group started at a lower level, there was no significant effect of type of intervention.Study III investigated the presence of CF in patients with CP and its relation to attention functions, self-rated fatigue, emotional factors, and pain characteristics. The patients with CP did not exhibit more CF than healthy controls. Self-rated fatigue measures and pain characteristics were not associated with CF, though there was an association between CF and processing speed on a test of sustained and selective attention in the CP group. Self-rated fatigue was strongly associated with self-rated pain intensity, spreading of pain, depression, anxiety, and sleep disturbance.Study IV examined the presence of CF in patients with CP during a vigilance task, and whether there was a difference in Blood oxygen level dependent (BOLD) signal during the performance of the task between patients and healthy subjects. While no effect of time was found when comparing regional blood flow across the vigilance task, there were group differences in the patterns of brain activation throughout the task. Patients with CP showed stronger activation in frontal areas, and lower activation primarily in the left middle orbital gyrus and right insula, regions associated with expected reward-value, as compared to healthy controls.Part V is a study protocol describing a research project targeting chronic pain, fatigue and cognition, encompassing study III and IV.In conclusion, the results showed that subjective fatigue was strongly correlated with depression in both CP and ABI. In CP, subjective fatigue also correlated strongly with self-rated pain characteristics. No correlation between subjective fatigue and CF was found, in line with what has previously been shown in other neurological conditions. Concerning ABI, the result suggests that although depression contributes significantly to fatigue post ABI, fatigue should be recognized as partly distinct from depression in the context of brain injury. CF, in turn, was, although weakly, related to attention functions both in ABI and CP, and furthermore the results indicate that attention training might be a viable method for reducing CF in ABI. Patients with CP showed CF and reduced activation in reward-related brain areas during performance of a vigilance task, implicating deficits in reward processing in CP. This finding is interesting from both theoretical and clinical perspectives, and merits further investigation.List of scientific papersI. Holmqvist, A., Lindstedt, M. B., & Möller, M. C. (2018). Relationship between fatigue after acquired brain injury and depression, injury localization and aetiology: An explorative study in a rehabilitation setting. J Rehabil Med, 50(8), 725-731. https://doi.org/10.2340/16501977-2365II. Holmqvist, A., Bartfai, A., Markovic, G., & Möller, M. C. (2021). Does Intensive Training of Attention Influence Cognitive Fatigability in Patients With Acquired Brain Injury? Front Neurosci, 15, 656876. https://doi.org/10.3389/fnins.2021.656876III. Holmqvist, A., Berginström, N., Löfgren, M., Stålnacke, B. M., & Möller, M. C. (2024). Fatigue and cognitive fatigability in patients with chronic pain. Scand J Pain, 24(1). https://doi.org/10.1515/sjpain-2023-0085IV. Holmqvist, A., Engström Nordin, L., Berginström, N., Löfgren, M., Nyberg, L., Stålnacke, B-M., Möller, M. C. Cognitive fatigability and neuronal correlates in chronic pain - a cross-sectional fMRI study. [Manuscript] V. Moller, M. C., Berginstrom, N., Ghafouri, B., Holmqvist, A., Lofgren, M., Nordin, L., & Stalnacke, B. M. (2023). Cognitive and mental fatigue in chronic pain: cognitive functions, emotional aspects, biomarkers and neuronal correlates-protocol for a descriptive cross-sectional study. BMJ Open, 13(3), e068011. https://doi.org/10.1136/bmjopen-2022-068011</p
Physiological and psychological factors in symptomatic atrial fibrillation
No full textIntroduction and overall aimsAtrial fibrillation (AF) is the most common clinical cardiac arrhythmia, with an estimated prevalence of 2-4% in the adult population. AF is associated with an increased risk of mortality and stroke and substantial costs, which can also relate to AF symptoms such as palpitations, shortness of breath, fatigue, and anxiety that affect healthcare-seeking patterns.An intriguing observation is that some AF patients are asymptomatic, while others report debilitating symptoms despite a low AF burden. The factors that influence symptoms in AF can be divided into physiological and psychological factors, some of which are not fully understood. Psychological factors such as symptom preoccupation, manifesting as fear and hypervigilance toward cardiac-related symptoms, and avoidance behavior might play a pivotal role in AF symptomatology.This thesis aimed to improve our understanding of symptomatic AF by studying the association of physiological and psychological factors with symptoms and AF- specific quality of life (QoL). A significant part of this work pertains to a novel psychological intervention that targets symptom preoccupation in paroxysmal AF.Methods and ResultsStudy I evaluated changes in physiological parameters and symptoms after electrical cardioversion (ECV) and assessed their correlation. We studied 44 patients (age 66.2+7.9 years, 84% males) before and 5+2 days after ECV when 28 (64%) were still in sinus rhythm (SR). In these patients, cardiac output (CO), as measured by non-invasive inert gas rebreathing, increased (0.8+0.7 L/min) as compared to those with recurrent AF (pStudy II is a pilot study where we devised an AF-specific cognitive behavioral therapy (AF-CBT) in collaboration with a team of psychologists and tested its feasibility in an uncontrolled study. Nineteen patients with symptomatic paroxysmal AF and troubling symptoms (i.e. EHRA class > 2b) were referred from local cardiology clinics. All patients completed the 10-week therapist-led intervention. We observed a significant improvement in AFEQT from 56.9+19.6 at baseline to 82.0+10.7 and 75.7+17.2 at post and six-month follow-up, respectively (pStudy III&IVStudies III and IV are secondary studies to a randomized controlled trial that aimed to test the effect of a therapist-led, online AF-CBT on Qol in patients with paroxysmal symptomatic AF. We recruited patients from local cardiology clinics and nationwide by self-referral. The study included 127 patients (65.4+8.3 years, 58% women) who were randomized to a 10-week therapist-led online AF-CBT (n=65) or AF education (n=62). All participants underwent a thorough cardiological assessment to ensure they were on optimal medical therapy, excluding patients with an ejection fraction ≤35%. AFEQT increased from 62.4+14.3 to 83.7+ 13.8 points at the three-month follow-up (primary endpoint), with a relative difference of 15.0 points (pStudy IIIAF-CBT exposes patients to avoided activities, including physical exercise, and although sleep is not targeted, it is related to anxiety and well-being. Heart rate variability (HRV) is linked to many behavioral risk factors for AF and anxiety. Thus, this study assessed the effects of AF-CBT on HRV, physical activity, and sleep.A 5-day Patch-Holter with an integrated accelerometer was applied at baseline, post-treatment, and three-month follow-up. Physical activity and sleep duration did not change from baseline (8040+2600 steps/day and 8.0+1.1 hours of sleep), with no significant difference between the groups. Subjective insomnia, however, went from subclinical to near normal values, which was significant compared to controls (p=0.032). No significant changes were found in AF burden, HR, or HRV indices.Study IVIn this study, we assessed the short-term cost-effectiveness of AF-CBT from a societal perspective. Direct and indirect costs were assessed using a self-report questionnaire at baseline and three months after treatment and extrapolated to six months. A relative incremental cost-effectiveness ratio (ICER) was calculated for each point improvement on the AFEQT and per case of significant clinical improvement (defined as an increase of >5 AFEQT points). The intervention had a 97.3% probability of being cost-saving. The number needed to treat to achieve a significant improvement (>5 AFEQT points) compared to the control group was 2.5, and societal savings over six months for each case of clinically significant improvement was $6219.Conclusions. Symptom improvement after ECV correlated with physiological parameters, most notably CO. In a pilot study, the novel psychological intervention, AF-CBT, demonstrated potential efficacy and feasibility in reducing symptoms and increasing Qol in AF patients. This was later corroborated in an RCT, which showed substantial AF-specific Qol improvements by AF-CBT.However, this was achieved without affecting the AF burden, physical activity, sleep duration, or HRV, suggesting that the improvements are mediated by psychological and behavioral factors not targeted by current treatment modalities. Furthermore, AF-CBT appeared to be a cost-effective intervention from a societal perspective in the RCT setting.AF-CBT might thus complement established medical treatments, including rhythm-controlling therapies and lifestyle interventions, within an integrated AF management approach. However, it must be tested in different populations and healthcare settings over an extended follow-up.List of scientific papersI. Klavebäck S, Skúladóttir H, Olbers J, Östergren J, Braunschweig F. Changes in cardiac output, rhythm regularity, and symptom severity after electrical cardioversion of atrial fibrillation. Scand Cardiovasc J. 2023;57(1):2236341. https://doi.org/10.1080/14017431.2023.2236341II. Särnholm*J, Skúladóttir*H, Rück C, Pedersen S, Braunschweig F, Ljótsson B. *Equal contributors. Exposure-Based Therapy for Symptom Preoccupation in Atrial Fibrillation: An Uncontrolled Pilot Study. Behav Ther. 2017;48(6):808-819. https://doi.org/10.1016/j.beth.2017.06.001III. Skúladóttir H, Särnholm J, Ólafsdóttir E, Arnardóttir ES, Hoppe K, Bottai M, Ljótsson B, Braunchweig F. Cognitive Behavioral Therapy for Paroxysmal Atrial Fibrillation: Heart Rate Variability, Physical Activity and Sleep. JACC Adv. 2024;3(11):101289. https://doi.org/10.1016/j.jacadv.2024.101289IV. Skúladóttir H, Särnholm J, Wallén H, Ólafsdóttir E, Ólafsson G, Braunchweig F, Ljótsson B. Cost-effectiveness of internet-based cognitive behavioral therapy for symptomatic paroxysmal atrial fibrillation. [Manuscript]</p
A biophysical symphony : the interplay of factors determining microRNA-34a activity
No full textmicroRNAs (miRNAs) play a pivotal role as post-transcriptional regulators in gene expression, adding a layer of complexity to the intricate system of molecular interactions within cells. Despite their short length, miRNAs exhibit remarkable specificity in targeting messenger RNAs (mRNAs), forming specific interaction networks termed the miRNA targetome. Predicting mRNA targets and their repression efficacies remains a significant challenge due to the vast number of potential interaction partners, and the lack of methodologies capable of detecting and extracting biochemical and structural information from these small molecules.This thesis investigates the structural and functional aspects of miRNA-mediated gene regulation, aiming to elucidate the underlying mechanisms governing miRNA activity via the Argonaute (AGO) protein, which forms the core of the RNA induced silencing complex (RISC). Using the conserved miR-34a and 12 mRNA targets as a model system, we develop and employ various tools including electrophoretic mobility shift assays (EMSA), structural probing techniques, luciferase gene reporter assays, and molecular dynamics simulations, to delineate the biophysical features of miRNA and their interactions.Our findings demonstrate the importance of the underlying RNA:RNA interactions in determining regulatory outcomes by RISC. We show that the structural binding mode is encoded by the underlying miR-34a:mRNA interaction, independent of the AGO2 protein. Moreover, our analysis suggests that repression efficiency is influenced by the RNA duplex structural class. We observed that miRNA-bulge structures exhibit the strongest repression effect, correlating positively with affinity, whereas mRNA-bulge structures show moderate repression with no significant correlation to affinity. In contrast, symmetrical structures exhibit weak repression effects. Using molecular dynamics simulations, we further illustrate that the novel miRNA-bulge structure can be readily accommodated within the AGO2 protein. We find that AGO2 plays a bidirectional role in modulating the miR 34a:mRNA affinity: weakening strong RNA:RNA binders while enhancing weak binders. Additionally, we observe that miRNA duplex release is more pronounced in high affinity miR-34a:mRNA interactions.This thesis presents two related projects. Project I describes the methodological developments necessary for achieving the results presented in Project II and has extended applicability to the broader study of RNA structure beyond the scope of this thesis. Project I was published in the RNA Journal (2023). In Project II (manuscript under review), we describe the functional implications of RNA:RNA interactions within the RISC complex, highlighting the impact of the RNA binding mode in determining miRNA-mediated repression and contributing insights into the interplay of biophysical factors determining miRNA function.List of scientific papersI. Elnaz Banijamali, Lorenzo Baronti, Walter Becker, Joanna J. Sajkowska-Kozielewicz, Ting Huang, Christina Palka, David Kosek, Lara Sweetapple, Michael D. Stone, Emma R. Andersson, Katja Petzold. RNA:RNA Interaction in Ternary Complexes Resolved by Chemical Probing. RNA Journal. 2023 Mar;29(3):317-329. https://doi.org/10.1261/rna.079190.122 II. Lara Sweetapple, David Kosek, Elnaz Banijamali, Christina Karadiako, Lorenzo Baronti, Walter Becker, Juliane Müller, Dimitri Schritt, Alan Chen, Emma R. Andersson, Katja Petzold. Biophysics of microRNA-34a targeting and its influence on down-regulation. 2024. [Submitted]</p
Pediatric eosinophilic esophagitis
No full textBackground and aims: Eosinophilic Esophagitis (EoE) is an immune-mediated antigentriggered inflammatory disease, strictly located to the esophagus. The pathogenesis is still partly unknown, and there is a lack of biomarkers for the disease. A foreign body impacted in the esophagus could be a sign of EoE. Our aim was to investigate if children previously diagnosed with a foreign body in the esophagus had a missed diagnosis of EoE, to investigate inflammatory responses by an ex vivo biopsy provocation-based method, stimulating biopsies with milk, wheat, and egg extracts and finally, study a variety of biomarkers in both blood and saliva.Methods: Study I was a population-based longitudinal study, were all children diagnosed with a foreign body in the esophagus in Stockholm, Sweden 2006-2016, were identified. In addition to a review of medical files, each family was contacted (n=325) and asked standardized questions. Children with symptoms indicating EoE were offered esophagogastroduodenoscopy (EGD). Study II was an experimental study on esophageal biopsies from 26 children, half of whom had active EoE and the other half served as controls. The biopsies were placed in test tubes and were stimulated with food extracts from cow’s milk, egg, and wheat. Supernatants were collected before and after stimulation and analyzed for 45 different inflammatory markers. Special staining of biopsies was also performed. Study III was a cohort study with a longitudinal part. Blood, saliva, and anamnestic data were prospectively collected from 52 children with EoE and 53 healthy controls. The analyses were performed with enzyme linked immunosorbent assays (ELISA).Results: Study I. In the 325 pediatric cases involving foreign bodies, 207 (64%) underwent EGD during the event, while the remaining cases experienced spontaneous expulsion of the foreign body. Among children with a previous foreign body, either spontaneously released or endoscopically removed, 12 (3.7%) were diagnosed with EoE. Characteristic of EoE patients were dysphagia, food impactions, excessive drinking during meals, and food allergies. Study II. Markers showing significant differences between patients with active EoE and controls included Granzyme B (GzmB), IL-1ra, and CXCL8 (p Conclusions: Study I. Children with a foreign body in the esophagus are at risk of having EoE. Biopsies should be taken during foreign body removal and questions about swallowing problems and allergic diseases should be carefully explored in children who do not need EGD because of spontaneous release. Study II. The presence of GzmB in the esophageal mucosa of children with active EoE suggests its potential involvement in the pathogenesis of the disorder. Study III. Novel biomarkers associated with EoE were identified, and a panel was proposed that together with symptoms, could discriminate between active EoE, EoE in remission, and healthy individuals. Cutoff values to distinguish between active EoE and healthy was also presented. The findings may contribute to a less invasive diagnostic method and may be a potential surveillance tool for pediatric EoE patients.List of scientific papersI. Thulin H, Nilsson C, Svensson JF, Olén O, Altman M. Long-term Follow-up for Missed Cases of Eosinophilic Esophagitis in Children With Previous Foreign Body in the Esophagus. J Pediatr Gastroenterol Nutr. 2021 May 1;72(5):e119-e124. https://doi.org/10.1097/MPG.0000000000003045 II. Thulin H, Säfholm J, Lundahl J, Jovic V, Adner M, Nilsson C. Granzyme B is elevated in esophageal biopsies from children with eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2024 Feb;78(2):313-319. https://doi.org/10.1002/jpn3.12084 III. Thulin H, Mansouri L, Altman M, Kebede Merid S, Lundahl J, Nilsson C*, Säfholm J*. Biomarkers for a Less Invasive Strategy for Children with Eosinophilic Esophagitis. *Co-authors with equal contribution. [Submitted]</p
From autoimmunity to inflamed joints : study of risk factors, mediators and cellular targets in rheumatoid arthritis
No full textRheumatoid arthritis (RA) is a chronic autoimmune disease affecting mainly the joints and leading to disability. Circulating antibodies against citrullinated proteins (ACPA) are present in the majority of patients and are considered important to disease pathogenesis, however the mechanisms triggered by these antibodies remain unclear. Although significant progress has been made in refining disease modifying therapies during the last decades, to date there is still no curative treatment. In this context identification of individuals likely to develop the disease from those being at risk can help rethink the therapeutic strategy towards prevention and personalized medicine.The main objective here was to study the role of ACPA in disease pathogenesis in the very early stages of RA in order to a) set up a predictive model for arthritis development and b) have a better understanding of ACPA effects on cellular targets, especially of the immune system. This work followed a translational approach: the observations from the clinics were assessed in experimental models, in a laboratory setting.In Paper I we followed-up a cohort of individuals at risk for developing RA (Karolinska RiskRA cohort) i.e. individuals positive for CCP2-antibody test and musculoskeletal symptoms (joint stiffness and pain) in the absence of clinical or ultrasound signs of arthritis or any other rheumatic diagnosis. Baseline data was collected, including clinical and ultrasound assessments of the joints and blood samples were analyzed for 9 ACPA reactivities, a panel of 92 inflammation-related markers and HLA shared epitope. 101/267 individuals progressed to arthritis within a median of 14 months of follow-up. The multivariate analysis showed that the presence of at least one ACPA reactivity, tenosynovitis detected by ultrasound, high levels of IL-6 and low levels of IL-15Rα had independent and significant predictive value in a model for arthritis progression.Next, in Paper II we tested whether a symptom-based e-questionnaire called “Rheumatic?” could be used as a tool for prediction of arthritis development. This was an international collaboration with two other centers, in Leiden, The Netherlands and in Erlangen, Germany. The tool was primarily aimed to be used by patients and, based on their answers, to suggest visit to the general practitioner or directly to the rheumatologist. In the case of the Karolinska RiskRA cohort the tool had limited usability regarding discrimination for an inflammatory outcome, suggesting that symptomatology alone is not sufficient for prediction. This confirms our previous observations from our cohort where clinical parameters were not significant for risk prediction in univariate analysis.In Paper III we studied the effects of ACPA on pain-like symptoms, tenosynovitis and bone loss in the preclinical stages of RA. Briefly, ACPA obtained from RA patients were injected in healthy mice. MRI of the joints at 28 days post injection showed signs of tenosynovitis, which was further confirmed by histological analysis. Moreover ACPA-treated mice showed pain-like behavior and had signs of bone resorption in Xray microscopy.In Paper IV we aimed to further characterize the citrullinated targets of ACPA in neutrophils, cells potentially important in disease pathogenesis. For this purpose we tested ACPA obtained from RA patients and an at-risk individual. Some but not all ACPA could bind to citrullinated targets released by activated neutrophils, suggesting that neutrophils could be important sources for citrullinated antigens. However, ACPA could not induce neutrophil activation nor bind to intact cells, suggesting a limited role in perpetuating ACPA response via boosting autoantigen release from neutrophils. When testing polyclonal ACPA preparations from individual RA patients we observed a highly variable binding capacity to neutrophil-derived antigens and similarly, a variable effect on another target cell for ACPA, specifically the osteoclast. These results suggest high patient-to-patient variability in the ACPA effects in line with the clinical observations on the heterogeneity in RA clinical phenotypes.In conclusion, on the timeline from systemic autoimmunity to clinical diagnosis of RA, we propose a particularly high at-risk for disease phase, characterized by the presence of ACPA, subclinical tenosynovitis and inflammation-related factors. Digital tools such as Rheumatic? e-questionnaire show promising use and should be further developed to help arthritis prediction. ACPA could directly contribute to symptomatology of the risk phase, where a heterogeneity in targeting different cell types may contribute to the various clinical presentations.List of scientific papersI. Cîrciumaru A, Kisten Y, Hansson M, Mathsson-Alm L, Joshua V, Wähämaa H, Haarhaus ML, Lindqvist J, Padyukov L, Catrina SB, Fei G, Vivar N, Rezaei H, Af Klint E, Antovic A, Réthi B, Catrina AI, Hensvold A. Identification of early risk factors for anti-citrullinated-protein-antibody positive rheumatoid arthritis-a prospective cohort study. Rheumatology. (Oxford). 2024 Mar 8:keae146. Epub ahead of print. https://doi.org/10.1093/rheumatology/keae146 II. Knevel, R., Knitza, J., Hensvold, A., Cîrciumaru, A., Bruce, T., Evans, S., Maarseveen, T., Maurits, M., Beaart-van de Voorde, L., Simon, D., Kleyer, A., Johannesson, M., Schett, G., Huizinga, T., Svanteson, S., Lindfors, A., Klareskog, L., & Catrina, A. (2022). Rheumatic?-A Digital Diagnostic Decision Support Tool for Individuals Suspecting Rheumatic Diseases: A Multicenter Pilot Validation Study. Frontiers in medicine. 9, 774945. https://doi.org/10.3389/fmed.2022.774945 III. Krishnamurthy, A., Cîrciumaru, A., Sun, J., Kisten, Y., Damberg, P., Sakuraba, K., Sandor, K., Jarvoll, P., Zhou, T., Malmström, V., Svensson, C. I., Hensvold, A., Catrina, A. I., Klareskog, L., & Réthi, B. (2023). Combination of Two Monoclonal Anti-Citrullinated Protein Antibodies Induced Tenosynovitis, Pain, and Bone Loss in Mice in a Peptidyl Arginine Deiminase-4-Dependent Manner. Arthritis & rheumatology. (Hoboken, N.J.), 75(2), 164–170. https://doi.org/10.1002/art.42320 IV. Cîrciumaru A, Afonso MG, Wähämaa H, Krishnamurthy A, Hansson M, Mathsson- Alm L, Keszei M, Stålesen R, Ottosson L, de Vries C, et al. Anti-Citrullinated Protein Antibody Reactivity towards Neutrophil-Derived Antigens: Clonal Diversity and Inter-Individual Variation. Biomolecules. 2023; 13(4):630. https://doi.org/10.3390/biom13040630 </p
Infections, antibiotics, tobacco, genetic factors and risk of lada : latent autoimmune diabetes in adults, and type 2 diabetes
No full textDiabetes is a spectrum of chronic diseases characterized by hyperglycaemia. The aetiology and pathogenesis differ between types of diabetes, but all can lead to severe complications. Latent autoimmune diabetes in adults (LADA) is the most prevalent type of autoimmune diabetes with onset in adulthood, yet risk factors are largely unknown. Therefore, this thesis was devoted to the study of potential risk factors for LADA compared to type 2 diabetes.The Swedish Epidemiological Study of Risk Factors for LADA and type 2 diabetes (ESTRID) constituted the foundation of the four studies in this thesis. ESTRID is a case-control study with incident cases of LADA and type 2 diabetes along with control participants from the general population. Study I, II, and IV were complemented with incident cases of LADA and type 2 diabetes as well as diabetes-free individuals from the Norwegian cohort study HUNT. Study I and II investigated the role of tobacco use and genetic susceptibility for the risk of LADA, using data from ESTRID and HUNT. These analyses were supported by Mendelian randomization studies based on data from genome-wide association studies. In Study III and IV, data from national and regional health registers were linked to ESTRID and HUNT to investigate the association between LADA and prior infections and antibiotic exposure. Results for LADA were compared to those for type 2 diabetes in all four studies.We found that smoking increases the risk of LADA, particularly in those with genetic susceptibility conferred by risk genes associated with autoimmunity, type 2 diabetes, or insulin resistance. The increased risk of LADA and type 2 diabetes in smokers seen in the observational data was confirmed in the Mendelian randomization studies. In contrast, no increased risk of LADA was observed with infections or antibiotic exposure up to 10 years prior to diagnosis, neither in those with high genetic risk nor in those with low-moderate risk. Instead, a reduced risk associated with antibiotic exposure 6-10 years prior to diagnosis was observed.In conclusion, tobacco use, which is associated with type 2 diabetes and insulin resistance, seems to increase the risk of LADA. Genetic susceptibility plays a role by aggravating these associations. However, infections and antibiotic exposure, previously linked to type 1 diabetes, were not associated with LADA. Further studies are needed to confirm these results, particularly the finding of a reduced risk of LADA with prior exposure to antibiotics.List of scientific papersI. Edstorp, J., Wei, Y., Ahlqvist, E., Alfredsson, L., Grill, V., Groop, L., Carlsson, S. (2023). Smoking, use of smokeless tobacco, HLA genotypes and incidence of latent autoimmune diabetes in adults. Diabetologia. 66(1), 70-81. doi:10.1007/s00125-022-05763-w. https://doi.org/10.1007/s00125-022-05763-w II. Edstorp, J., Ahlqvist, E., Alfredsson, L., Mansour Aly, D., Grill, V., Rasouli, B., Carlsson, S. (2023). Incidence of LADA and Type 2 Diabetes in Relation to Tobacco Use and Genetic Susceptibility to Type 2 Diabetes and Related Traits: Findings From a Swedish Case-Control Study and the Norwegian HUNT Study. Diabetes Care. 46(5), 1028-1036. doi:10.2337/dc22-2284. https://doi.org/10.2337/dc22-2284 III. Edstorp, J., Rossides, M., Ahlqvist, E., Rasouli, B., Tuomi, T., & Carlsson, S. (2024). Does a prior diagnosis of infectious disease confer an increased risk of latent autoimmune diabetes in adults? Diabetes Metab Res Rev. 40(3), e3758. doi:10.1002/dmrr.3758. https://doi.org/10.1002/dmrr.3758 IV. Edstorp, J., Rossides, M., Ahlqvist, E., Alfredsson, L., Askling, J., Di Giuseppe, D., Carlsson, S. Exposure to antibiotics and the risk of latent autoimmune diabetes in adults and type 2 diabetes - results from a Swedish case-control study and the Norwegian HUNT study. [Manuscript]</p