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Multiple environmental factors and cardiovascular disease
No full textAir pollution, transportation noise and low greenness have been associated with incidence of myocardial infarction (MI) and stroke in single exposure models. However, few studies have explored them simultaneously. Furthermore, socioeconomic deprived groups have been suggested to face a higher environmental burden, and may also be more vulnerable to environmental pollution, which could lead to increased health disparities. Therefore, the overall aim of this thesis was to assess the associations between long-term exposure to air pollution, traffic noise and greenness, and incidence of MI and stroke, in single- and multiple-exposure models, accounting for sociodemographic and lifestyle determinants.A total of 20,407 women included in the Swedish Mammography Cohort (SMC), living in Uppsala County, Sweden, born between 1914 and 1948, were followed between 1997 and 2017 by linking spatiotemporally assessed long-term exposure to air pollution, road traffic noise and greenness, sociodemographic data from registers and lifestyle variables from questionnaire surveys. In study I, we prospectively assessed the associations between a set of individual and area- level sociodemographic variables and individual exposure to particles (PM2.5 and PM10), nitrogen dioxide (NO2), road traffic noise and greenness (NDVI in 500 m) using a fully time-varying model. Our results provide evidence of a diverse pattern of environmental-health disparities among different sociodemographic subgroups in urban settings.Study II, is based on pooled cross-sectional data from the NordSOUND project including eleven Nordic cohorts and up to 177,566 participants with overweight and obesity data. We assessed exposure-response relationships of long-term exposure to road traffic, railway and aircraft noise, and overweight, obesity and central obesity. Our findings provide evidence of an association between road traffic and railway noise, and obesity; a potential causal pathway connecting noise exposure to cardiovascular disease (CVD).Studies III and IV were based on the same time-varying data from the SMC, which were assessed in study I in conjunction with register data on MI and stroke. The aim was to assess associations of multiple environmental exposures and incidence of MI and stroke, respectively, in both single- and multi-exposure models, taking both individual- and area-level socioeconomic factors into account. We observed an inverse association between residential greenness and risk of MI in multi-exposure models. Air pollution, primarily fine particles (PM2.5), was associated with an increased stroke risk, accounting for co-exposures. We also found some evidence of a higher vulnerability in certain groups of the population, for instance in low educated women.In conclusion, the four constituent papers of this thesis provide novel insights into sociodemographic inequalities in relation to residential environmental exposures in a sample of Swedish women. Moreover, the combination of air pollution, road traffic noise and greenness, and the time-varying data on both exposures and covariates, allowed us to assess associations with CVD in a unique setting. It can be concluded from the results that already at relatively low levels of air pollution, detrimental cardiovascular effects may occur. This was indicated by consistently elevated risks of stoke in relation to long-term PM2.5 exposure, as well as by increased risk of MI in low-educated women. Interestingly, greenness appeared to be associated with a lower risk of MI, adjusted for air pollution and noise. Finally, we were able to provide evidence of a potential pathway via obesity from transportation noise to CVD. Although, we did not observe an increased risk of MI and stroke in the SMC, possibly a consequence of overall low exposure levels and exposure misclassification.It is our hope that the findings of this thesis may help to guide future recommendations and regulations on these environmental factors to protect human health.List of scientific papersI. Stucki L, Betnér S, Selander J, Lõhmus M, Åkesson A, Eriksson C. Sociodemographic inequalities in long-term exposure to air pollution, road traffic noise, and greenness: A population-based cohort study of women. Environ Epidemiol. 2023 Dec 1;7(6):e279. https://doi.org/10.1097/ee9.0000000000000279II. Persson Å, Pyko A, Stucki L, Ögren M, Åkesson A, Oudin A, Tjønneland A, Rosengren A, Segersson D, Rizzuto D, Helte E, Andersson EM, Aasvang GM, Gudjonsdottir H, Selander J, Christensen JH, Leander K, Mattisson K, Eneroth K, Barregard L, Stockfelt L, Albin M, Simonsen MK, Spanne M, Roswall N, Tiittanen P, Molnár P, Ljungman PLS, Männistö S, Yli-Tuomi T, Cole-Hunter T, Lanki T, Lim YH, Andersen ZJ, Sørensen M, Pershagen G, Eriksson C. Long-term exposure to transportation noise and obesity: A pooled analysis of eleven Nordic cohorts. Environ Epidemiol. 2024 Jul 8;8(4):e319. https://doi.org/10.1097/ee9.0000000000000319III. Stucki L, Helte E, Axelsson Ö, Selander J, Lõhmus M, Åkesson A, Eriksson C. Long-term exposure to air pollution, road traffic noise and greenness, and incidence of myocardial infarction in women. Environ Int. 2024 Aug 190:108878. https://doi.org/10.1016/j.envint.2024.108878IV. Stucki L, Helte E, Axelsson Ö, Selander J, Lõhmus M, Åkesson A, Eriksson C. Long-term exposure to air pollution, road traffic noise and greenness, and incidence of stroke in women. [Manuscript]</p
Evaluation of the proficiency test for dentists educated outside the European Union and EEA
No full textThe Proficiency test is the most common pathway for dentists, educated outside the European Union and the European Economic Area (EEA) who want to be licensed to practice dentistry in Sweden. The test involves passing a series of examinations designed to assess whether a dentist meet Swedish standards for licensure. Since exams directly affect the individuals who take the exams and patient safety, the assessments must be robust and provide credible evidence of candidate competency. The test consists of three main parts: the first is a theoretical examination, which evaluates candidates' knowledge and ability to apply that knowledge to dental scenarios, which is assessed through a computer-based examination. The second is a clinical skills examination, which focuses on clinical and communication skills in two parts: a 4-station Objective Structured Clinical Examination (OSCE) and manual skills on a dental manikin. Lastly, candidates must complete a six-month clinical practice under supervision, which assesses their professional practice in a real-world clinical setting. Given the high stakes of these exams the assessments must be robust and provide credible evidence of competency. There is limited research on proficiency tests for dentists educated outside the European Union and their outcomes, in Europe and in Sweden. The recognition and licensure testing processes are vital not only for ensuring high-quality patient care and safety within individual countries but also from a wider European perspective as the current lack of standardisation can lead to unequal recognition processes, hindering harmonisation across the European Union and the EEA.The theoretical and clinical examination's ability to adequately discriminate between candidates who meet the qualifications of the dental degree, from those who do not, and factors effecting results was a tested in Study I and Study Il. In Study I, test results from seven theoretical examinations between 2018- 2019 (n = 316) were collected, along with demographic data. In Study II, test results from theoretical and clinical skills examinations between 2018-2022 was combined with self-reported language proficiency. Based on the tests we found that the assessments positively differentiate candidates who do not meet the requirements of the professional qualifications of the dental degree in the theoretical examination and in the Objective Structured Clinical Examination (OSCE) assessment tested in the clinical skills examination.Licensure examinations are limited to a sample of a full curriculum, and although participants are proficient enough to pass - the examinations cannot ensure that passing participants are equally proficient within all dental disciplines. The tests showed that age had a significant influence on results in both theoretical and clinical examinations. Language difficulties were also identified as a potential barrier to performance in the theoretical and practical examinations.The reliability and consistency of setting pass-mark in theoretical examinations using the three-level Angoff methodology was tested In Study I and Study III. In Study I the Angoff item ratings by panels between 2018-2019 were collected. In Study III, Angoff ratings across three theoretical examinations were collected from a reference panel at The Department of Dental Medicine, Karolinska Institutet and compared to item ratings from an invited Angoff panel for a dental program from another Swedish university. The tests of inter-rater reliability and credibility indicated that a three-level Angoff method is a defensible method for setting the pass mark for the theoretical examinations. The results from the comparison of the two independent panels showed that the three-level Angoff ratings produced similar standards for minimal qualification.In Study IV, we explored the experiences of dentists who participated in the theoretical and clinical assessments. Survey responses from six theoretical examinations (n=486) and four clinical skills examinations (n=190) were collected between 2022-2024. Systematic text condensation was used for analysis of written responses from post-examination surveys to describe participants' experiences of participation in the proficiency test. The descriptions from dentists revealed a need for guidance in preparation, language barriers, stress, and a perceived misalignment between exam content and clinical practice.The studies highlight the necessity of using multiple assessment formats to provide enough evidence that can be used to decide whether a participant has adequate competent for licensure. The assessments must be seen as part of a system of assessments where the three components of the Proficiency test are all important as they complement each other. The findings of this study are relevant for Sweden and other nations seeking to improve re-certification.List of scientific papersI. Dalum J, Christidis N, Myrberg IH, Karlgren K, Leanderson C, Sandborgh Englund G. Are we passing the acceptable? Standard setting of theoretical proficiency tests for foreign-trained dentists. Eur J Dent Educ. 2023 Aug;27(3):640-649.https://doi.org/10.1111/eje.12851II. Dalum J, Christidis N, Häbel H, Karlgren K, Leanderson C, Englund GS. Clinical skills examination as part of the Swedish proficiency test of dentists educated outside of the EU/EEA. Eur J Dent Educ. 2024; 28: 880-888. https://doi.org/10.1111/eje.13022III. Dalum J, Paulsson L, Christidis N, Andersson Franko M, Karlgren K, Leanderson C, Sandborgh Englund G. Consistency between inter- institutional panels using a three-level Angoff-standard setting in licensure tests of foreign-trained dentists in Sweden: A cohort study. [Submitted]IV. Dalum J, Brodén J, Johannsen A, Sandborgh Englund G. Barriers to showing competence: foreign-trained dentists' experiences of re- certification examinations in Sweden. [Manuscript]</p
Groin hernia repair : evaluation of clinical impacts and interactions of mesh and mesh fixation
No full textAIMSThe project underlying this thesis aimed to identify and quantify relative risk differences in reoperation rate (Papers I and II) and chronic postoperative inguinal pain (CPIP) following surgical repair of groin hernias, depending on diverse types of mesh implants and modes of mesh fixation.Paper III was a preparatory study to identify relevant preoperative effect modifiers, to streamline an upcoming CPIP study on mesh/fixation combinations in laparoscopic groin hernia repair.METHODSThe 3 individual studies were each based on large, nationwide cohorts from the Swedish Hernia Registry (SHR). For statistical analysis, Papers I and II used multivariable Cox regression. Paper III used multivariable logistic regression. P- values are 2-tailed with 95% confidence intervals (CI).The predictors of interest were:Paper I: Fixation suture material in the Lichtenstein repair: permanent vs long- term absorbable vs short-term absorbable sutures.Paper II: Mesh/fixation combinations in laparoscopic repairs. Standard polypropylene mesh (StdPPM) vs lightweight mesh (LWM); and metal tacks vs absorbable tacks vs fibrin glue vs no fixation.Paper III: Preoperative risk factors in laparoscopic repairs.RESULTSPaper I: 82,015 Lichtenstein repairs were included. With permanent sutures as reference (HR = 1) long-term absorbable sutures (HR 1.1; CI 0.8-1.6; P = 0.49) were not associated with an increased risk for reoperation . short-term absorbable sutures associated with a more than doubled reoperation risk (HR, 2.2; CI 1.7-3.0; P Paper II: Of 25,190 repairs, 924 (3.7%) were later reoperated for recurrence. The lowest, mutually equivalent, reoperation risks were associated with:StdPPM without fixation (reference = HR, 1) StdPPM + metal tacks (HR, 0.8; CI 0.4 - 1.4; P = 0.39), StdPPM + fibrin glue (HR, 1.1; CI 0.7 - 1.6; P = 0.63) LWM + fibrin glue (HR, 1.2; CI 0.95 - 1.6; P = 0.11) All other LWM options correlated with increased risk:LWM + metal tacks (HR, 1.6; CI 1.02 - 2.6; P = 0.040) LWM + absorbable tacks (HR, 2.4; CI 1.5 - 3.8; P LWM without fixation (HR, 2.0; CI 1.5 - 2.5; P Paper III: From 82 surgical centers, 15,363 patients (33% female) were eligible, with mean age 57 years. Of 10,524 (69%) questionnaire respondents, 3,026 (29%) had CPIP according to our primary definition used for the main analysis, and 1,614 (15%) according to our secondary definition. The response rate varied significantly across some variables, particularly age.Preoperative predictors significantly associated with CPIP were:female sex (OR, 1.2; CI, 1.1-2.3) younger age (eg, overweight (OR 1.3; CI 1.2-1.5) and obesity (OR, 1.6; CI, 1.3-1.9) ASA 2 (OR, 1.1; CI, 1.01-1.2), and ASA ≥3 (OR, 1.4; CI, 1.2-1.7) recurrent hernia (OR, 1.3; CI, 1.2-1.5) femoral hernia (OR, 1.3, ;CI, 1.1-1.6) vs lateral and/or medial hernias small (3cm) hernia defect Ø (OR, 1.2; C,I 1.03-1.4)CONCLUSIONSPaper I:Regarding recurrence risk, long-term absorbable sutures are an excellent alternative to permanent sutures for mesh fixation in Lichtenstein inguinal hernioplasty.Short-term absorbable sutures entail an independent risk factor for recurrence and should therefore be avoided.Whether there is a difference in impact on CPIP between these 2 suture alternatives needs to be explored.Paper II:With StdPPM, neither mechanical nor glue fixation associated with improved outcomes. Thus, for this mesh category, we recommend no fixation. This is also, by far, the least expensive option.With LWM, we recommend fibrin glue fixation, which was the only LWM alternative on par with non-affixed StdPPM.Paper III:This study identified relevant preoperative CPIP risk factors and quantified their relative impact. The results can be useful in designing and interpreting other studies.It also highlights selection bias, which appears to be a major general issue in CPIP studies but has not been satisfactorily addressed in prior reports. Future CPIP research should incorporate strategies to mitigate selection bias further.List of scientific papersI. Novik B, Nordin P, Skullman S, Dalenbäck J, Enochsson L. More recurrences after hernia mesh fixation with short-term absorbable sutures: A registry study of 82 015 Lichtenstein repairs. Arch Surg. 2011;146:12-17. https://doi.org/10.1001/archsurg.2010.302II. Novik B, Sandblom G, Ansorge C, Thorell A. Association of mesh and fixation options with reoperation risk after laparoscopic groin hernia surgery: A Swedish Hernia Registry study of 25,190 totally extraperitoneal and transabdominal preperitoneal repairs. J Am Coll Surg 2022;234:311-325. https://doi.org/10.1097/XCS.0000000000000060III. Novik B, Sandblom G, Thorell A. Preoperative risk factors for chronic pain after laparoscopic groin hernia repair: A Swedish Hernia Registry study. 2024. [Submitted]</p
The roles of music in the well-being of autistic adults
No full textWhile music-based support services have been widely implemented for autistic people, their subjective experiences with music remain underexplored. This thesis investigates the roles of music in the lives of autistic adults, emphasising its impact on well-being. Drawing on Self-Determination Theory (SDT), particularly the basic psychological needs for autonomy, relatedness, and competence, it aims to provide a framework for understanding both the positive and negative effects of music, thereby advancing research and informing future interventions.The thesis consists of three empirical studies. The first two studies aimed to explore autistic people's musical experiences and establish a framework that could provide a theoretical common ground for the existing exploratory studies. Studies I and II involved in-depth interviews with 13 autistic adults (aged 24-69). In the first study, a bottom-up thematic analysis identified emergent themes, while the second study applied a top-down approach using predefined categories derived from SDT. The aim of the third study was to develop and test a questionnaire assessing how people engage with music to support their well- being. Using a mixed-methods design, we analysed the answers of 63 autistic adults who filled out our questionnaire, as well as gave qualitative feedback on how clear the items were and how well the items reflected their experiences of music and well-being.Findings show that autistic adults experience musicking as both beneficial and detrimental, depending on the context. SDT seems to be a promising theory for investigating the mentioned context, given how important a sense of self- determination is in music engagement. Furthermore, the thesis provides an example of how we can extend and adapt models and theories developed on the general population to its sub-populations and use them to create assessment tools. By integrating autistic perspectives into existing theories and models, such as SDT, this work calls for a more pluralistic approach to understanding music engagement, one that respects the heterogeneity of people and agency of individuals and actively considers the potential for harms and negative experiences.List of scientific papersI. Korošec, K., Osika, W., & Bojner Horwitz, E. (2022). "It is more important than food sometimes"; Meanings and functions of music in the lives of autistic adults through a hermeneutic- phenomenological lens. Journal of Autism and Developmental Disorders, 54(1), 366-378. https://doi.org/10.1007/s10803-022-05799-2Il. Korošec, K., Backman Bister, A. & Bojner Horwitz, E. "A space to be myself": Music and self-determination in the lives of autistic adults. Psychology of Music. [Accepted]III. Korošec, K., Lundqvist, L .- O., Perkins, R., Détári, A., Osika, W., Bojner Horwitz, E. Development of the Participatory Music Engagement for Mental Well-being questionnaire (PaMEW): A pilot study with autistic adults. [Submitted]</p
Exploring human uterine immune cell dynamics with a focus on natural killer cells and mait cells
No full textThe uterine immune system is crucial for the establishment of a healthy pregnancy and further development of the embryo. Although a lot is known about endometrial immune cell frequencies, phenotype, and function there are several aspects of the endometrial immune system that remain unknown. In this thesis, I explored several different aspects of the uterine immune system.In paper I, we investigated the dynamics of endometrial mucosal associated invariant T cells (MAIT) cells in various reproductive states and assessed their ability to react to the sexually transmitted bacteria Neisseria gonorrhoeae. In addition, we examined the tissue-residency properties of endometrial MAIT cells using unique human samples obtained after uterus transplantation.In paper II, we conducted a twin study to investigate what drives baseline differences in the endometrial immune system between healthy individuals. The results provide understanding of how the uterine immune cells respond to environmental factors and change through the course of a woman’s life. We found that there is more immune variation in immune cells of the endometrium compared to blood immune cells and that the differences are driven by distinct factors.In paper III, we explored uterine NK (uNK) cell differentiation in relation to the endometrial regeneration occurring during the menstrual cycle and pregnancy. Our findings reveal that uNK cells differentiate continuously throughout the menstrual cycle, with a notable shift towards enhanced angiogenic function and immunomodulatory properties. This functional shift could potentially aid in spiral artery formation during early pregnancy.In summary, this thesis provides valuable new insights into reproductive immunology and explains various aspects of the function of the uterine immune system.LIST OF SCIENTIFIC PAPERSI. Jonna Bister, Ylva Crona-Guterstam, Benedikt Strunz, Bogdan Dumitrescu, Karin Haij Bhattarai, Volkan Özenci, Mats Brännström, Martin A. Ivarsson, Sebastian Gidlöf, and Niklas K. Björkström. Human endometrial MAIT cells are transiently tissue resident and respond to Neisseria gonorrhoeae. Mucosal Immunology, 2021, vol.14 (2), pp. 357-365 https://doi.org/10.1038/s41385-020-0331-5II. Jonna Bister, Iva Filipovic*, Dan Sun*, Ylva Crona-Guterstam, Martin Cornillet, Andrea Ponzetta, Jakob Michaëlsson, Sebastian Gidlöf, Martin A. Ivarsson, Benedikt Strunz, and Niklas K. Björkström. Tissue-specific nonheritable influences drive endometrial immune system variation. Science Immunology, 2024, vol. 9 (94), eadj7168 https://doi.org/10.1126/sciimmunol.adj7168III. Benedikt Strunz, Jonna Bister, Russell S. Hamilton, Hanna Jönsson, Ylva Crona-Guterstam, Egle Kvedaraite, Iva Filipovic, Natalie Sleiers, Bogdan Dumitrescu, Danielle Friberg, Mats Brännström, Antonio Lentini, Björn Reinius, Martin Cornillet, Tim Willinger, Sebastian Gidlöf, Martin A. Ivarsson, and Niklas K. Björkström. Continuous human uterine NK cell differentiation in response to endometrial regeneration and pregnancy. Science Immunology, 2021, vol. 6 (56), eabb7800 https://doi.org/10.1126/sciimmunol.abb7800*These authors contributed equally to the manuscript</p
Enhanced mobilisation and physical rehabilitation after abdominal cancer surgery : feasibility, effects, and experiences
No full textCancer incidence is growing worldwide and, as advances in diagnostics, treatment, and rehabilitation are made, the numbers of cancer survivors are also increasing. Therefore, there is a need to find and evaluate methods to improve the lives of cancer survivors after treatment. Following abdominal cancer surgery, postoperative mobilisation and physical rehabilitation are recommended to improve outcomes, reduce the risk of complications, and improve health-related quality of life. However, there is a lack of evidence regarding its effects or how it should be structured to improve outcomes and promote adherence. The overall aim of this thesis was to contribute to the field of rehabilitation following abdominal cancer surgery by exploring methods to enhance postoperative mobilisation and evaluate the effects of physical rehabilitation following surgery. The goal was to facilitate patient adherence and engagement in rehabilitation and improve physical functioning and healthrelated quality of life following surgery.Study I explored healthcare professionals’ experiences of using the Activity Board as a tool to support postoperative mobilisation after abdominal cancer surgery. Seventeen healthcare professionals were interviewed, divided into four focus groups, and qualitative content analysis was used to analyse the interviews. The results indicate that the Activity Board is a tool that facilitates daily work and promotes patient participation. It was described as easy to use, providing valuable information and enabling healthcare professionals to support patients better, as well as having a positive impact on patient motivation.Study II evaluated the feasibility of using a digital version of the Activity Board, called Pedatim, to enhance mobilisation following abdominal cancer surgery. In this non-randomised feasibility trial, 20 patients were recruited and each received a Pedatim tablet to use during their stay in hospital following surgery. Based on predetermined criteria, the overall study design was deemed feasible apart from the eligibility criteria. The Pedatim tablet was also deemed scientifically feasible as a tool to enhance postoperative mobilisation.Study III evaluated the effects of an exercise intervention in primary care after radical cystectomy for urinary bladder cancer. In this randomised controlled trial, 90 patients were included and randomised to either control or intervention, with the intervention group receiving a referral to a physiotherapist following hospital discharge to perform a twice-a-week, 12-week exercise programme in primary care. The control group received encouragement to perform a simple home exercise programme. At the follow-up, four months after surgery, a positive effect could be seen in the intervention group compared to the control group in terms of physical activity in daily life, fatigue, and health-related quality of life.Study IV evaluated patients’ experiences of the exercise intervention in Study III. In this qualitative study, 20 patients were interviewed individually, and the interviews were analysed using thematic analysis. Four main themes were identified: 1) Having to adapt to new circumstances, describing the challenges regarding physical activity patients face after discharge; 2) Optimising conditions for rehabilitation, describing how practical conditions affect patients’ ability to exercise; 3) Motivated to get back to normal, describing patients’ desire to get back to normal life and the factors influencing that motivation; and 4) The importance of a supportive environment, describing the impact of social support, support from physiotherapists, and how the environment where exercise takes place influences patients’ ability to exercise.In conclusion, enhancing postoperative mobilisation following abdominal cancer surgery by using tools such as the Activity Board and the Pedatim tablet is feasible and useful for both patients and healthcare professionals. These tools increase patient motivation, participation, and adherence, as well as facilitating healthcare professionals’ work in supporting patients’ postoperative mobilisation. Furthermore, exercise in primary care following radical cystectomy for urinary bladder cancer improves physical activity in daily life, reduces fatigue, and has a positive impact on health-related quality of life compared to a simple home exercise programme. Patients who exercised in primary care following radical cystectomy were also positive towards exercise because they were motivated to get back to normal life. However, they did face challenges when arriving home from surgery, which affected their ability to exercise, and therefore conditions need to be optimised to facilitate patients’ rehabilitation.List of scientific papersI. Karlsson P, Porserud A, Hagströmer M, Nygren-Bonnier M. Healthcare professionals´ experiences of using the Activity Board as a tool for postoperative mobilization in patients after abdominal cancer surgery. Journal of Cancer Rehabilitation. 2022;5(1):90-97.II. Karlsson P, Nygren-Bonnier M, Henningsohn L, Rydwik E, Hagströmer M. The feasibility of using a digital tool to enhance mobilisation following abdominal cancer surgery—a non-randomised controlled trial. Journal of Pilot and Feasibility Studies 2023;9(1):147. https://doi.org/10.1186/s40814-023-01377-0 III. Porserud A/Karlsson P, Aly M, Rydwik E, Torikka S, Henningsohn L, Nygren-Bonnier M, Hagströmer M. Effects of an exercise intervention in primary care after robotassisted radical cystectomy for urinary bladder cancer. [Manuscript]IV. Karlsson P, Nygren-Bonnier M, Torikka S, Porserud A, Henningsohn L, B Olsson C, Rydwik E, Hagströmer M. Patients´ experiences of an exercise intervention in primary care following robot-assisted radical cystectomy due to bladder cancer: A qualitative study. [Manuscript]</p
Physiological and lifestyle-related cardiovascular risk factors for vessels, ventricle, and valve
No full textCardiovascular diseases are the most common cause of mortality globally, claiming twice as many lives as cancer and more than all nutritional disorders, infectious diseases, and maternal/neonatal conditions combined. The field of cardiovascular epidemiology has been highly influenced by the pioneering Framingham heart study, which has increased the focus on the prevention of CVD in susceptible populations. As a consequence, accurate risk stratification scores combining age, cholesterol, blood pressure, diabetes, and smoking have been developed. Nevertheless, CVD mortality remains high, and additional research is urgently needed to improve these prediction efforts. It also underscores the critical importance of managing other modifiable risk factors to mitigate the CVD burden.The thesis intended to elucidate the associations between physical activity, cardiovascular risk factors, and aortic valve stenosis in a variety of patient cohorts with a diverse set of methodologies. It focused on determining the significance of physical activity in relation to cardiovascular function in patients with rheumatoid arthritis (Article I), the potential protective role of physical activity regarding AVS risk (Article II), sex-specific transcriptomic driving factors for calcification of the aortic valve (Article III), and establishing the association between blood pressure and AVS incidence, as well as the impact of blood pressure-lowering therapies on AVS risk (Article IV).The first study in the thesis (Article I) aimed to determine the effects of guided physical activity on vascular and cardiac function in rheumatoid arthritis patients without known cardiovascular disease. The investigation involved a prospective substudy of the Physical Activity in RA trial 2010 and included 29 participants. The subjects were evaluated at three different points in time, namely, at baseline, after one year, and after two years, with pulse wave velocity, arterial augmentation index, and echocardiographic measures. The findings indicated that, in RA patients with normal blood pressure, there was an increase in vascular stiffness relative to normal reference values. Additionally, there was an association between decreased aerobic capacity and left ventricular diastolic dysfunction and a link between higher vascular stiffness and lower muscular strength. After completing a guided physical activity program, ventricular-arterial coupling significantly improved. The findings indicated that improved diastolic function and vascular stiffness are related, and ventricular-arterial coupling optimization may be a part of the positive benefits of exercise in RA patients.The project presented in Article II aimed to determine whether physical activity reduces the risk of aortic valve stenosis in a cohort of 69,288 Swedish adults aged 45– 83 years. Physical activity was assessed using a validated questionnaire, and AVS diagnosis was based on data from national registers. A total of 1,238 cases of AVS were identified during the 15.3-year follow-up. No significant associations were detected between AVS incidence and the levels of physical activity, reflected by walking or cycling or leisure-time exercise, after adjustment for possible confounders and mediators, including BMI and comorbidities. The results suggest that physical activity, both less strenuous (walking/bicycling) and more strenuous (exercise), does not decrease the risk of AVS overall or of AVS requiring aortic valve replacement. This evidence implies that PA may not serve as a preventative measure for AVS, illustrating the necessity for further research to identify modifiable lifestyle factors.The study presented in Article III aimed to establish sex-specific gene expression patterns in aortic stenosis patients through artificial intelligence-based analysis of transcriptome-wide array data from stenotic aortic valves. Thirty-six patients received surgical aortic valve replacement, and their valves were divided into three categories - non-diseased, thickened, and calcified based on macroscopic examination. Gene expression analysis showed that there are sex-specific differences differentiating calcified and non-diseased valve tissues. In particular, fibrotic pathways enriched in female patients were found, with collagen and elastic fibers pathways being highly represented. The obtained sex-specific gene expression data were used to predict aortic valve calcification using artificial intelligence models. Machine learning and deep learning algorithms showed high accuracy in this prediction task, outperforming logistic regression. Notably, several genes identified by the AI models have potential mechanistic roles in valvular calcification, such as tissue factor pathway inhibitor 2 and X-inactive-specific transcript. Thus, the results indicated that by using gene expression data, AI models can accurately predict the degree of valvular calcification and potentially pave the way for the discovery of novel medical interventions.The final study (Article IV) determined the association between blood pressure (BP) over time and the incidence of aortic valve stenosis. Subjects were enrolled from the Swedish Primary Care Cardiovascular Database (SPCCD), consisting of 72,756 hypertensive patients within the temporal interval of 2001-2008. The predictors of AVS included baseline, mean, and last measurements of systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. Cox proportional hazards regression models were used as the main multivariable model. The results showed that all measurements of systolic BP and pulse pressure were positively associated with AVS incidence, with mean pulse pressure having the strongest association. Mean diastolic BP was inversely associated with AVS. Age, ischemic heart disease, heart failure, and peripheral arterial disease were significant covariates associated with AVS risk. The association between BP and AVS was attenuated in patients with ischemic heart disease, and the use of antihypertensive medications did not significantly alter the risk of AVS. Ultimately, BP over time is an important risk factor for AVS incidence in hypertensive individuals, with pulse pressure being a particularly strong predictor.In conclusion, this thesis established the complex interplay between physical activity, cardiovascular risk factors, and aortic valve stenosis across diverse patient cohorts. While no significant association between physical activity and the risk of aortic valve stenosis was found in a large Swedish population, guided physical activity was shown to improve ventricular-arterial coupling in patients with rheumatoid arthritis. Furthermore, the sex-specific gene expression pattern and artificial intelligence classification proved to be effective in predicting valvular gene expression and may pave the way for the development of new therapeutic targets. The strong association between BP and AVS risk underscored the importance of effective hypertension management.List of scientific papersI. Sarajlic P, Fridén C, Lund LH, Manouras A, Venkateshvaran A, Larsson SC, Nordgren B, Opava CH, Lundberg IE, Bäck M. Enhanced ventricular-arterial coupling during a 2-year physical activity programme in patients with rheumatoid arthritis: a prospective substudy of the physical activity in rheumatoid arthritis 2010 trial. J Intern Med. 2018 Dec;284(6):664-673. https://doi.org/10.1111/joim.12715 II. Sarajlic P, Wolk A, Bäck M, Larsson SC. Physical Activity Does Not Reduce Aortic Valve Stenosis Incidence. Circ J. 2018 Aug 24;82(9):2372-2374. https://doi.org/10.1253/circj.CJ-18-0598 III. Sarajlic P, Plunde O, Franco-Cereceda A, Bäck M. Artificial Intelligence Models Reveal Sex-Specific Gene Expression in Aortic Valve Calcification. JACC Basic Transl Sci. 2021 Apr 14;6(5):403-412. https://doi.org/10.1016/j.jacbts.2021.02.005 IV. Sarajlic P, Sundström A, Wettermark B, Bengtsson KB, Hasselström J, Hjerpe P, Ljungman C, Manhem K, Mourtzinis G, Qvarnström M, Kahan T, Bäck M. The impact of blood pressure control and pulse pressure on incident aortic valve stenosis in hypertensive patients, and associations with ischemic heart disease: A population-based longitudinal study from the Swedish Primary Care Cardiovascular Database. [Manuscript]</p
Temporal response to bioenergetic stress in adipose tissue and skeletal muscle
No full textDiabetes is a common disease—affecting more than 500 million people. Although type 2 diabetes maintains a genetic component—the implementation of lifestyle modification serves as a potent risk-reducing modality. Chronic exercise is among these lifestyle modifications, as it generates therapeutic effects at the tissue level. However, strategies to optimize exercise need further investigation. The aim of this doctoral work is to characterize the interplay between exercise, temporal variables, and tissue biology in the context of whole-body energy homeostasis.In study I we evaluated the timing-specific effects of acute exercise on adipose tissue biology in mice through measurement of circulating factors in blood and analysis of the adipose tissue transcriptome. Only early active phase induced an immediate increase in serum non-esterified fatty acids and expression of thermogenic and angiogenic markers in inguinal adipose tissue. Synchronized 3T3-L1 adipocytes also showed a timing dependent difference in β2 adrenergic receptor (Adrb2) expression and a greater lipolytic activity. Rest phase mice lacked the transcriptomic response to exercise, regardless of feeding state, suggesting that timing supersedes feeding status as a modulator of the post exercise adipose tissue transcriptome. These findings highlight that adipose tissue responds to exercise in a time-of-day-dependent manner, which may be partly driven by the circadian clock.In study II we followed up on the timing-specific effects of exercise with the additional context of obesity by feeding mice a 5-week high-fat diet. In both diet groups, acute exercise at the early active phase induced a shift towards oxidative metabolism for the duration of the phase and over 24 hours following. Effects were milder following rest phase exercise, with exercise leading to one hour of increased energy expenditure. Oxidation of glucose was reduced at the early active phase, regardless of diet; however, chow-fed mice showed a milder post-exercise shift in glucose oxidation, potentially indicating an exercise timing effect on substrate preference unique to lean mice. Upon measuring lipolysis in adipose tissue ex vivo, only adipose tissue from chow mice showed heightened lipolysis at the early active phase and in response to exercise. These data highlight the functional relevance of exercise timing for whole-body metabolism following exercise, and reveal an absence of diurnal lipolytic function in the adipose tissue of obese mice.In study III we evaluated if the circadian clock alters the lipolytic metabolism in concert with AMP-activated protein kinase (AMPK) in human skeletal muscle cells. We observed that core clock genes Neuronal PAS domain protein 2 (NPAS2) and D-box binding PAR bZIP transcription factor (DBP) were decreased in cells where AMPKα was silenced. These AMPKα-knockdown cells also showed increased expression of genes associated with fatty acid metabolism (Fatty acid translocase, CD36; Carnitine palmitoyltransferase 1B, CPT1B; and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PPARGC1A). Upon directly silencing expression of DBP and NPAS2, we observed a similar increase in expression of lipid metabolism markers (PPARGC1A, CD36, and Fatty acid binding protein 3, FABP3). Assessment of palmitate oxidation revealed that silencing of NPAS2 alone elicited an increase in lipid oxidation, revealing a role of the molecular clock on oxidative metabolism in human muscle cells. This work emphasizes the critical role of circadian function in the regulation of skeletal muscle lipid homeostasis, and may reveal NPAS2 as a therapeutic target to decrease ectopic lipid deposition in skeletal muscle.In study IV we evaluated the temporal dynamics of adipose tissue transcription following exercise in individuals with normal glucose tolerance or type 2 diabetes. This analysis revealed that adipose tissue from people with type 2 diabetes displays a robust upregulation of inflammatory transcriptional activity at 3 hours following exercise. Based on magnitude of fold change after exercise, we selected Oncostatin-M (OSM) as a candidate gene in adipose tissue. Upon treating human adipocytes with OSM, lipolysis was increased. Further, we identified that OSM expression is greatest in the immune fraction of adipose tissue, and observed that human THP-1 macrophages show increased expression and secretion of OSM following treatment with exercise-like stimuli. These results reveal the influence of time following exercise on transcriptional regulation, which can be unique depending on disease status. Additionally, this work highlights the necessity to consider time of sample collection in evaluating metabolic responses to bioenergetic stress.In conclusion, the works that comprise this thesis address the critical role of time in the response to exercise. In the preclinical rodent studies I and II, we discovered novel transcriptional and metabolic responses to exercise at the early active phase; these insights highlight potential for discoveries in human models, which may be used in the development of ideal individual exercise prescriptions. Identification of clock gene NPAS2 in study III as a regulator of basal metabolism in human muscle cells raises questions about the targeting of clock genes in therapeutic approaches to increase lipid clearance, which is particularly relevant in addressing ectopic lipid deposition. Lastly, characterizing the time course of post-exercise transcription in individuals with normal glucose tolerance or type 2 diabetes in study IV provided insights into the critical role of measurement timing in identifying gene candidates. The summative findings in these studies highlight critical metabolic factors, and emphasize the importance of future considerations of timing in exploratory research.List of scientific papersI. Pendergrast LA, Lundell LS, Ehrlich AM, Ashcroft SP, Schönke M, Basse AL, Krook A, Treebak JT, Dollet L, Zierath JR. Time of day determines postexercise metabolism in mouse adipose tissue. Proc Natl Acad Sci U S A. 2023 Feb 21;120(8):e2218510120. https://doi.org/10.1073/pnas.2218510120 II. Pendergrast LA, Ashcroft SP, Ehrlich AM, Treebak JT, Krook A, Dollet L, Zierath JR. Metabolic plasticity and obesity-associated changes in diurnal postexercise metabolism in mice. Metabolism. 2024 Mar 11:155834. https://doi.org/10.1016/j.metabol.2024.155834 III. Pendergrast LA*, Kamble P*, Björnholm M, Zierath JR. Skeletal muscle oxidative metabolism is mediated by clock gene NPAS2. *These authors contributed equally. [Manuscript]IV. Dollet L, Lundell LS, Chibalin AV, Pendergrast LA, Pillon NJ, Lansbury EL, Elmastas M, Frendo-Cumbo S, Jalkanen J, Barbosa TC, Cervone DT, Caidahl K, Dmytriyeva O, Deshmukh AS, Ryden M, Wallberg-Henriksson H, Zierath JR, Krook A. Exercise-induced crosstalk between immune cells and adipocytes in humans: Role of oncostatin-M. Cell Rep Med. 2024 Jan 16;5(1):101348. https://doi.org/10.1016/j.xcrm.2023.101348 </p
Impact of childhood leukemia and its treatment on Nordic children and families : the consent process, toxicity, and quality of life
No full textBackground: The survival rate in acute lymphoblastic leukemia (ALL) has improved remarkably over the last half-century and is now reaching above 90%. The treatment is lengthy, however, and with a high risk of short- and long-term side effects. The advances in treatment outcome have underscored the importance of addressing not only cure, but also the potential side effects of the treatment, as well as quality of life. The Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol was used in the Nordic and Baltic countries between 2008-2019. Treatment duration was 2.5 years, and there were 3 randomized clinical trials (RCTs) within the protocol. RCTs are essential in improving treatment outcomes, but the process of being informed and asked to decide on RCT participation may put further stress on the families.The aim of this thesis was to investigate the impact of the treatment period on the children and their families by assessing parents’ experiences of the informed consent process for the RCTs, by evaluating health-related quality of life (HRQOL) in the children and their parents, and by assessing how parents perceived the different treatmentrelated side effects observed in their children.Methods: Families of patients aged 1-17.99 years at diagnosis in Sweden, Finland, and Denmark who had been treated according to the NOPHO ALL2008 protocol and were alive and in first remission ≥6 months after end of therapy, without any secondary malignancy, were eligible. Patients with Down syndrome, mixed phenotype leukemia, or stem cell transplant in first remission were excluded for substudies I-III, but their parents were eligible for substudy IV. Three different questionnaires were sent: First, a studyspecific questionnaire that was developed by the authors in collaboration with 7 families of children previously treated for ALL in Stockholm through a face validation process. It contained questions on socioeconomic factors before and after treatment, sibling support, toxicity and impact of treatment, and how parents perceived the process regarding being asked to consent to RCT participation. The second questionnaire was the HRQOL-instrument PedsQL™ 4.0 Generic Core Scales (self and proxy-report) for the child’s HRQOL, and the third was the SF-36 for parents’ HRQOL. Eligibility was crosschecked with local nurses at each center before sending the questionnaires to patients and their families. Data were collected between 2013-2019.Results: Overall, families of 320 children participated in at least 1 of the substudies. In substudy I (n=483 parents of 279 children), on the informed consent process for the RCTs, we found that parents in general reported the consent process as satisfactory, with sufficient time and information to make a well-informed decision and that they did not feel pressured to participate. Those who declined study participation reported a more negative experience overall, with significantly less confidence in study design and less satisfying process that those who consented. More than a third of all parents, and over half of parents who had refused participation, felt that it was burdensome to have to make the decision. Two-thirds of parents in general, and one-third of those with children 8 years or older, reported that their child had not been involved in the decisionmaking process. In substudy II (n=299 children; 276 self-reports and 270 proxy-reports), children over 8 years reported HRQOL similar to that of a Finnish reference population, except lower scores in the school functioning domain for high-risk patients. Children 5-7 years old had notably lower scores in all domains, which may in part be due to the different construct of the PedsQL™ questionnaire for this age group specifically (with 3, instead of 5, levels on the response scale for their self-report). Parent-proxy reports were also lower than reference data. Parent-reported toxicity in the study-specific questionnaire was associated with lower total and physical HRQOL scores in adjusted models for all ages in both self- and proxy reports, and for parent-proxy reports also lower psychosocial HRQOL. Substudy III investigated how parents perceived treatment-related side effects during ALL treatment, with focus on specific side effects from vincristine, corticosteroids, pegasparaginase, and maintenance therapy. Parents of 307 children (296 mothers, 244 fathers) responded. For vincristine and corticosteroids, more than a third rated the overall negative impact as high. Walking difficulties, muscular weakness, and pain, and appetite and mood swings, were the most common and severe side effects for vincristine and corticosteroids, respectively. For peg-asparaginase and maintenance therapy, symptoms were less frequent and the overall impact reported by parents was less than for vincristine and corticosteroids. For toxicities also reported in the NOPHO ALL2008 database, e.g., thrombosis and pancreatitis, parent reports were similar with database reports. Although parents in general reported that their child had been negatively affected to a high extent overall during treatment, they reported that their child was affected to a lower, or similar, extent when asked to compare with other children with ALL. In substudy IV, parents’ HRQOL were assessed using the SF-36 questionnaire. Data from 526 parents of 310 children showed that the participating parents had significantly lower scores than the reference population on both physical and mental component summary measures that surpassed minimal clinically important difference for the mental component summary. Mothers had lower mental HRQOL than fathers as well as higher absence from work. Higher mental HRQOL scores were also associated with living in Denmark or Finland (compared to Sweden). When comparing HRQOL within couples living together, correlations were weak to moderate.Conclusion: ALL treatment impacted the children and their families to a large extent. Parents reported high levels and severe impact of treatment-related side effects, and children with higher parent-reported toxicity compared to other ALL patients had lower HRQOL. This determinant was more important for child’s HRQOL than i.e., risk group or socioeconomic factors, and was not seen for toxicity in the NOPHO ALL2008 database. Children 8 years and older otherwise reported their HRQOL at similar levels as the reference population, while parent-proxy reports, and younger children (5-7 years), reported lower HRQOL. The parents' own HRQOL was negatively affected, especially the mental domains and especially in mothers, which may indicate a need for extra support. For the informed consent process, parents were generally satisfied with the process overall, although a high number of parents thought it was burdensome to make the decision, especially among those who refused participation. Fewer than expected of the school-aged children were involved in the decision-making process, and efforts to improve children’s involvement in this process should be considered. The work done within this thesis highlights the importance of including patient/parentreported outcomes, not least in toxicity reporting, and of the task to keep striving to minimize complications from treatment in future ALL protocols. It also shows some of the burden that parents experience, and calls for awareness that RCT decisions put a stress on families, even when declining participation, and of parents' high levels of altruism, confidence, and trust.List of scientific papersI. Parental experiences of the informed consent process in randomized clinical trials-A Nordic study. Mogensen N, Kreicbergs U, Albertsen BK, Lähteenmäki P, Heyman M, Harila A. Pediatr Blood Cancer. 2023 Dec;70(12):e30684. https://doi.org/10.1002/pbc.30684 II. Quality of life in children and adolescents after treatment for acute lymphoblastic leukemia according to the NOPHO ALL 2008 protocol. Mogensen N, Kreicbergs U, Albertsen BK, Lähteenmäki P, Heyman M, Harila A. Pediatr Blood Cancer. 2024;e31018. https://doi.org/10.1002/pbc.31018 III. Parents’ perception of treatment-related toxicity in children treated according to the NOPHO ALL-2008 protocol for acute lymphoblastic leukemia. Mogensen N, Kreicbergs U, Albertsen BK, Lähteenmäki P, Heyman M, Harila A. [Submitted]IV. Quality of life in mothers and fathers of children treated for acute lymphoblastic leukaemia in Sweden, Finland and Denmark. Mogensen N, Saaranen E, Olsson E, Klug Albertsen B, Lähteenmäki PM, Kreicbergs U, Heyman M, Harila A. Br J Haematol. 2022;198(6):1032-40. https://doi.org/10.1111/bjh.18350 </p
Regulation of mtDNA gene expression and the role of respiratory chain supercomplexes in mammalian mitochondria
No full textMitochondria are cellular organelles found in nearly all eukaryotic cells, where they fulfill a plethora of functions, including energy conversion. They harness energy from carbon sources to synthesize adenosine triphosphate (ATP) through the process of oxidative phosphorylation (OXPHOS). Mammalian mitochondria contain ~1200 proteins and only 13 of these are encoded by mitochondrial DNA (mtDNA). Despite the small contribution to the mitochondrial proteome, expression of mtDNA is nevertheless critically important for biogenesis and normal function of the OXPHOS system. The expression of mtDNA is dependent on ~200 nucleus-encoded proteins that are imported into mitochondria to control maintenance, replication, and transcription of mtDNA, as well as translation of the mtDNA-encoded messenger RNAs (mRNAs). Mitochondrial gene expression is thus controlled at many different levels. In the first part of this thesis, molecular mechanisms are reported for initiation and completion of mtDNA replication. Furthermore, mechanisms controlling the switch from transcription initiation to elongation, as well as a putative link between transcription elongation and RNA processing are reported. These results were based on extensive analysis of conditional knockout mouse models for RNase H1, TEFM, and mtSSB. In the second part of the thesis, the organization of the OXPHOS system is studied. It consists of the respiratory chain enzyme complexes, two electron shuttles and the ATP synthase. A wide range of studies have shown that the different respiratory chain enzyme complexes can interact with each other to form higher order assemblies, so called supercomplexes. The respirasome is a particularly interesting supercomplex as it consists of a complete respiratory chain. Results from multiple studies have suggested that the respirasome plays a crucial role in cellular bioenergetics by facilitating translocation and routing of electrons. To address this question, we extensively characterized a knockin mouse model engineered to have normal levels of respiratory chain complexes that cannot interact to form respirasomes. Surprisingly, mice with drastically reduced levels of respirasomes are healthy without any clear impact on bioenergetics or whole animal physiology. Our results thus challenge the multiple proposed roles for respirasomes in physiology and disease.List of scientific papersI. Jelena Misic, Dusanka Milenkovic, Ali Al-Behadili, Xie Xie, Min Jiang, Shan Jiang, Roberta Filograna, Camilla Koolmeister, Stefan J. Siira, Louise Jenninger, Aleksandra Filipovska, Anders R. Clausen, Leonardo Caporali, Maria Lucia Valentino, Chiara La Morgia, Valerio Carelli, Thomas J. Nicholls, Anna Wredenberg, Maria Falkenberg, Nils-Göran Larsson†. (2022). Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for mtDNA replication completion. Nucleic Acids Res. 50, 8749–8766. †Corresponding author(s). https://doi.org/10.1093/nar/gkac661 II. Shan Jiang, Camilla Koolmeister, Jelena Misic, Stefan Siira, Inge Kühl, Eduardo Silva Ramos, Maria Miranda, Min Jiang, Viktor Posse, Oleksandr Lytovchenko, Ilian Atanassov, Florian A. Schober, Rolf Wibom, Kjell Hultenby, Dusanka Milenkovic, Claes M. Gustafsson, Aleksandra Filipovska, Nils-Göran Larsson†. (2019). TEFM regulates both transcription elongation and RNA processing in mitochondria. EMBO Rep. 20, 1–18. †Corresponding author(s). https://doi.org/10.15252/embr.201948101 III. Min Jiang*, Xie Xie*, Xuefeng Zhu*, Shan Jiang, Dusanka Milenkovic, Jelena Misic, Yonghong Shi, Nirwan Tandukar, Xinping Li, Ilian Atanassov, Louise Jenninger, Emily Hoberg, Sara Albarran-Gutierrez, Zsolt Szilagyi, Bertil Macao, Stefan J. Siira, Valerio Carelli, Jack D. Griffith, Claes M. Gustafsson, Thomas J. Nicholls, Aleksandra Filipovska, Nils-Göran Larsson†, Maria Falkenberg†. (2021). The mitochondrial single-stranded DNA binding protein is essential for initiation of mtDNA replication. Sci Adv. 7, eabf8631. *These authors contributed equally. †Corresponding author(s). https://doi.org/10.1126/sciadv.abf8631 IV. Dusanka Milenkovic, Jelena Misic, Johannes F. Hevler, Thibaut Molinié, Injae Chung, Ilian Atanassov, Xinping Li, Roberta Filograna, Andrea Mesaros, Arnaud Mourier, Albert J.R. Heck, Judy Hirst†, Nils-Göran Larsson†. (2023). Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes. Cell Metab. 35, 1799-1813.e7. †Corresponding author(s). https://doi.org/10.1016/j.cmet.2023.07.015 </p