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Malaria transmission and antibody responses to Plasmodium falciparum
No full textMalaria is a disease of public health concern. Globally, gains in malaria control seen over the last decades have recently stalled, with some areas experiencing a resurgence of malaria. Longitudinal studies in local areas provide valuable information about the changing epidemiology of malaria. This knowledge is crucial for surveillance and timely interventions.The aim of this thesis was to investigate trends in the prevalence of malaria and its influence on anaemia and antibody responses to P. falciparum in a previously highly endemic area in Tanzania. The population in Nyamisati, a coastal village in Tanzania, participated in a longitudinal epidemiology study with repeated cross- sectional surveys.In Study I, we assessed the prevalence of Plasmodium species from 1994 to 2016 using a species-specific real-time PCR assay targeting the Plasmodium 18S rRNA gene. We observed a reduction in the prevalence of P. falciparum, P. malariae, and P. ovale spp. until 2010. After 2010, P. falciparum prevalence decreased further, while P. ovale and P. malariae became relatively more common. In Study II, we further assessed the temporal trends of malaria using real-time PCR, microscopy, and rapid diagnostic tests, extending the analysis to include 11 surveys from 1986 to 2024. We also assessed the impact of malaria on anaemia. Over these four decades, malaria prevalence declined substantially, from 69.7% (95% CI 62.8-75.8) in 1986 to 3.5% (95% CI 2.1-5.7) in 2024 by real-time PCR. Anaemia prevalence decreased in parallel with malaria until 2016 but remained stable thereafter despite further reductions in malaria transmission.In Study III, we evaluated whether the antibody level to whole P. falciparum schizont extract is a marker of exposure as malaria transmission declines. We found that seropositivity and antibody levels against P. falciparum were higher in the high transmission period. Antibody levels and the odds of being seropositive were higher among individuals who were parasite positive at the survey, particularly during the low malaria transmission period. In Study IV, we assessed antibody function against P. falciparum merozoites as malaria transmission declined. Antibody-dependent respiratory burst (ADRB) activity was higher during the high malaria transmission period. Age was a significant predictor of ADRB activity in both malaria transmission periods. Ongoing infection significantly influenced ADRB activity during the low, but not the high, malaria transmission period.Collectively, these studies demonstrate a substantial decline in malaria transmission in Nyamisati, transitioning from very high to very low levels. Antibody responses, both in terms of levels and functional activity, were closely associated with parasite exposure, particularly as transmission waned. A deeper understanding of the factors contributing to reduced malaria transmission in this setting is essential. Overall, the findings highlight the importance of continuous monitoring of malaria epidemiology to guide control efforts and support future elimination strategies.List of scientific papersI. Persistent transmission of Plasmodium malariae and Plasmodium ovale species in an area of declining Plasmodium falciparum transmission in eastern Tanzania. Yman V, Wandell G, Mutemi D. D, Miglar A, Asghar M, Hammar U, Karlsson M, Lind I, Nordfjell C, Rooth I, Ngasala B, Homann M. V, Färnert A. PLOS Neglected Tropical Diseases, 13(5): e0007414 (2019). https://doi.org/10.1371/journal.pntd.0007414II. From high transmission to near elimination: Malaria trends in a rural village in coastal Tanzania from 1986 to 2024. Mutemi D. D, Yman V, Kinabo C, Makene T, Broumou I, Zerebinski J, Forsblom S, Miglar A, Ally J, Jesaja S, Mhoja L, Johansson M, Rooth I, Ngasala B, Färnert A. [Manuscript]III. Antibodies against Plasmodium falciparum schizont extract as a marker of malaria transmission intensity. Mutemi D. D, Yman V, Forsblom S, Foroogh F, Ribacke U, Vetter L, Tuju J, Nyamako L, Rooth I, Kinyanjui S, Ngasala B, Osier F, Färnert A. [Manuscript]IV. Antibody-dependent respiratory burst against Plasmodium falciparum merozoites in individuals living in an area with declining malaria transmission. Mutemi D. D, Tuju J, Ogwang R, Nyamako L, Wambui K. M, Cruz I. R, Villner P, Yman V, Kinyanjui S. M, Rooth I, Ngasala B, Färnert A, Osier F. H. A. Vaccines, 12(2):203 (2024). https://doi.org/10.3390/vaccines12020203</p
The role of creatine metabolism in human white adipose tissue
No full textWhite adipose tissue (WAT) is the main organ to store energy surplus in the form of fat. In obesity, chronic caloric overconsumption overwhelms the storage capacity of WAT leading to the enlargement of existing adipocytes and spillover of fatty acids into the bloodstream. This promotes ectopic fat accumulation in peripheral organs such as the liver and skeletal muscle, which in turn the development of drives insulin resistance and type 2 diabetes. At the tissue level, increased adipocyte size is associated with alterations in intracellular gene/protein expression and metabolite levels, leading to changes in reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, and chronic low-grade inflammation, accompanied by pro-inflammatory immune cell infiltration.Creatine is a very well-known supplement used by athletes and is present in many food sources, as well as being synthesized within our body. Recent studies have highlighted the importance of creatine metabolism in brown adipose tissue, emphasizing its role in managing energy expenditure, and insulin resistance. Creatine kinases are enzymes responsible for energy transport between mitochondria and cytoplasm through the cycling of creatine and phosphocreatine, generating ADP and ATP. One specific creatine kinase isoform, creatine kinase brain isoform (CKB), plays a central role in brown adipose tissue thermogenesis. Alterations in the expression of CKB impair thermogenesis, promote weight gain, and worsen metabolic parameters in rodents. However, less is known regarding the role of creatine and CKB in WAT biology. Therefore, the aim of this thesis is to deepen our understanding of creatine metabolism in human WAT and how this pathway is linked to obesity.In Study I, we examined creatine metabolism in subjects with and without obesity. Consistent with in vivo studies in mice, we identified CKB as one of the most downregulated genes in obesity. This alteration was associated with the accumulation of phosphocreatine within adipocytes. Mechanistically, this hypermetabolic state led to the inhibition of the catabolic sensor AMP-activated protein kinase (AMPK) and promoted the production of C-C Motif Chemokine Ligand 2 (CCL2), with consequent immune cell infiltration into WAT.After studying CKB in human WAT, we next focused on the mechanisms underlying its downregulation in obesity. In Study II, we identified that ER stress, specifically via inositol-requiring enzyme 1 (IRE1) - X-box binding protein 1s (XBP1s) - DNA (cytosine-5)-methyltransferase 3A (DNMT3A) axis, drove hypermethylation in the proximal promoter area of CKB. These findings were also corroborated in humans where, methylome and gene expression data, displayed an inverse correlation between proximal promoter area of CKB and its mRNA levels.In our previous studies, we noticed an upregulation of creatine kinases (CKB and CKMT2) during human white adipocyte formation de novo. In Study III, we therefore investigated the effects of creatine kinase depletion on adipocyte differentiation. Early depletion of CKB in differentiating human white adipocytes rewired intracellular metabolism driven by upregulated AKT signaling, promoting ChREBP expression via increased glycolytic rate. This led to increased expression of genes involved in de novo lipogenesis and promoted lipid accumulation both in vitro and in adipocyte-specific Ckb knockout mice.In summary, through studies in human adipocytes and mouse knockout models, this thesis provides new insights into the role of WAT creatine metabolism in regulating energy homeostasis, inflammation and insulin sensitivity.List of scientific papersI. Maqdasy S, Lecoutre S, Renzi G, Frendo-Cumbo S, Rizo-Roca D, Moritz T, Juvany M, Hodek O, Gao H, Couchet M, Witting M, Kerr A, Bergo MO, Choudhury RP, Aouadi M, Zierath JR, Krook A, Mejhert N, Ryden M. Impaired phosphocreatine metabolism in white adipocytes promotes inflammation. Nat Metab. 2022 Feb;4(2):190- 202. https://doi.org/10.1038/s42255-022-00525-9II. Renzi G, Vlassakev I, Hansen M, Higos R, Lecoutre S, Elmastas M, Hodek O, Moritz T, Alaeddine LM, Frendo-Cumbo S, Dahlman I, Kerr A, Maqdasy S, Mejhert N, Rydén M. Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammation. Mol Metab. 2024 Dec 13;92:102082. https://doi.org/10.1016/j.molmet.2024.102082III. Renzi G, Higos R, Vlassakev I, Abdoul Akim B, Hmeadi-Muhmmad O, Hansen M, Merabtene F, Rouault C, Hodek O, Massier L, Antonny B, Genevieve M, Rahbani JF, Lecoutre S and Maqdasy S. Creatine kinase B regulates glycolysis and de novo lipogenesis pathway to Control Lipid accumulation during adipogenesis. [Submitted]</p
The importance of trust - studies on live kidney donation and implementation of donation after circulatory death in Sweden
No full textBackground: Chronic kidney disease is estimated to have a global prevalence of 9.1 percent (2017) and is the 10:th deadliest disease in the world 2022. In Sweden, 5 percent of the population suffers from significantly reduced kidney function. Patients developing end stage renal disease have two options: dialysis or kidney transplantation. For eligible patients, transplantation results in a better quality of life, lower morbidity and increased life expectancy when compared to chronic dialysis. Kidneys for transplantation can be donated from both deceased and living donors. Transplantations with kidneys from living donors have better outcomes compared to transplantations with kidneys from deceased donors. As there is a shortage of donor organs for transplantation worldwide there has been a renewed interest to reintroduce Donation after Circulatory Death (DCD).Aim: The over-all aim of my thesis is to identify weaknesses and hurdles in the present processes of organ donation, thereby potentially finding ways to improve identification and handling of potential living donors and to identify elements that contribute to trust in Donation after Circulatory Death, and in the long run contribute to developing the field, both regarding donation during life and after death.Methods:In Study I, a questionnaire with preset responses and space allotted for comments, was sent to individuals who had previously donated a kidney in life, in order to identify areas of improvement and variables that predict less favorable outcomes after a living kidney donation.In Study II, we investigated the experiences of people close to a person with kidney disease regarding receiving a letter about living kidney donation from healthcare. In-depth interviews were conducted using a semi-structured interview guide. A short questionnaire was also answered by all participants that comprised questions regarding their characteristics and overall rating of the letter.In Study III, we investigated the attitudes and experiences of operating staff that had been involved in the implementation of Donation after Circulatory Death in Sweden. Focus group interviews were done both before and after the implementation of DCD using a semi-structured interview guide. Participants also answered a short questionnaire to obtain their individual characteristics and their motivation to take part in the implementation of DCD.Two different qualitative analysis methods were used: conventional content analysis (Study II) and thematic analysis (Study III). The first method results in categories and the second in themes. Conventional descriptive and inferential statistical methods were used for analysis of Study I.Results:Study I. Thirty-six percent of the living donors reported lacking information in some phase of the process, making this the most reported improvement area. Ten variables (red flags) were identified that negatively affected the experience of donating a kidney in life. The most prominent variables included having more fatigue than expected early postoperatively, experiencing more pain than expected post operatively, poor agreement between expectations and actual experience, and a desire to have had a mentor who has personal experience with donating a kidney in life.Study II. Participants found that the sentences in the letter that stated that living donation should always be based on free will and that the healthcare is neutral, were the most important as they gave them a sense of security and trustworthiness. They also reported that the living donor letter did not induce feelings of pressure to donate, guilt, or bad conscience if they chose not to donate a kidney. They also expressed a preference for a letter as the first step for communication about living donation and transplantation.Study III. The qualitative analysis of the focus group responses generated the theme: Trust for the DCD process. The participants pointed out the importance of receiving evidence-based documentation and comprehensive education on the DCD process. They also emphasized the importance of teamwork and a thorough handover from ICU to provide a picture of the donor's care. Having time to plan the surgery was important as it ensured all team members understood their role. In addition, it was vital for participants that the donors and their families were treated with dignity and respect throughout the process, similar to that given to other patients.Conclusion:Study I. Our data underlines the importance of early receipt of information and knowledge about living donation, helping potential donors gain insight and better understanding of the donation process. It is also important to assess living donors intake of information. Paying attention to the identified red flags can help to individualize treatment and act early in the course instead of having to handle an already established problem later.Study II. The use of a letter from healthcare is well accepted and considered a good way to bring up the subject of living donation.Study III. In order to install trust in the DCD process among the surgical personnel, they must be given knowledge about the entire DCD process and the right conditions for building a team spirit. A positive consequence of the teamwork and of the insights in the parts of the donation process that oneself is not involved in, was the trust that the donor and their relatives were treated with dignity and respect throughout the entire process - ending with a dignified donor operation.List of scientific papersI. Eva Lagging, Jonas Wadström, Linda Gyllström Krekula, Annika Tibell. Red Flags in the Living Kidney Donor Process. Transplantation Proceedings. 2023 Mar;55(2):279-287. https://doi.org/10.1016/j.transproceed.2023.01.008II. Eva Lagging, Kjerstin Larsson, Jonas Wadström, Linda Gyllström Krekula, Annika Tibell. Potential living kidney donors' positive experiences of an information letter from healthcare: a descriptive qualitative study. BMC Nephrology. 2022 Oct;14;23(1):332. https://doi.org/10.1186/s12882-022-02959-5III. Eva Lagging, Ulla Forinder, Annika Tibell, Kjerstin Larsson, Linda Gyllström Krekula. Factors that create trust in the DCD process among surgical personnel: a qualitative descriptive study. [Manuscript]</p
The relevance of cognitive reserve for the investigation of prognostic factors after acquired brain injury
No full textAcquired brain injury (ABI) is a leading cause of long-term disability worldwide. Traumatic brain injury (TBI) and stroke are the two most common causes of ABI. Both TBI and stroke vary in severity, with TBI often being classified as mild, moderate and severe TBI. Long-term outcomes after ABI are complex, often involving multiple areas of life and being influenced by various factors. Cognitive reserve, the brain's capacity to mitigate the impact of pathology or injury on clinical outcomes, has been identified as a factor explaining some of the variability in outcomes following ABI. Although cognitive reserve cannot be directly measured, it is typically estimated through indicators such as educational attainment or assessments of premorbid cognitive functioning. Despite its significance, many aspects of cognitive reserve remain unresolved. This thesis explores various outcomes post-ABI and examines the influence of cognitive reserve on these outcomes.The first paper investigated the relationship between cognitive functioning 3 months after injury and long-term outcome measured by the Mayo-Portland Adaptability Index (MPAI-4) in 41 patients with severe TBI (sTBI) 6-8 years after injury. The result from an early cognitive screening was related to long-term participation, ability and adaption according to the MPAI-4 after sTBI. However different neuropsychological tests appeared to measure complementary aspects of outcomes. Furthermore, as early as three months after sTBI, educational level affected scores on neuropsychological screening instruments, suggesting a ceiling effect for individuals with higher education levels, which may mask cognitive deficits.The second paper examined differences in symptoms after mild TBI (mTBI), symptom resolution, and functional connectivity between 15 patients with mTBI and 15 with minor orthopedic injuries at one week and three months post-injury. Assessments comprised of neuropsychological tests including a test of premorbid intelligence, resting state functional magnetic resonance imaging (rs- fMRI) scans, and symptom ratings. One-week post-injury, the mTBI group had significantly higher post-concussion symptoms, state fatigue, and fatigability compared to controls. After three months, the patients with mTBI still scored higher post-concussion symptoms but had returned to the same level as the controls regarding fatigability. Functional connectivity differences between groups in the frontoparietal network were noted. Improvement in post-concussion symptoms was related to cognitive reserve, measured with educational level but not with results on a test of premorbid intelligence, in the mTBI group.In the third and fourth papers 83 patients with TBI or stroke, who had undergone specialized brain injury rehabilitation, were interviewed 5-15 years after brain injury. The third paper explored how cognitive reserve (measured by education) and neuropsychological test results affect return-to-work and life satisfaction after ABI. Higher return-to-work rates were linked to higher cognitive reserve, lower age, less fatigue, and better working memory and processing speed. Less fatigue was associated with better satisfaction with mental health, but no other variables significantly impacted aspects of life satisfaction. Verbal and spatial abilities were related to education but not to return-to-work.The fourth paper investigated differences in healthcare usage based on cognitive reserve and its relationship to outcomes following stroke and TBI. It found that individuals with higher education levels utilized more healthcare services in the year of injury, even after adjusting for confounding variables such as injury severity. This increased healthcare usage was significantly associated with better long-term life satisfaction, although it did not correlate with a higher likelihood of returning to work.In summary, the studies in this thesis confirm the complex link between cognitive reserve and brain injury outcomes. Higher education levels generally correlate with better outcomes, particularly for return-to-work rather than life satisfaction. Some of the positive effects of cognitive reserve may also result from other factors such as ceiling effects in cognitive tests or better rehabilitation access for more educated individuals.List of scientific papersI. Ekdahl N, Godbolt AK, Deboussard CN, Lannsjö M, Stålnacke BM, Stenberg M, et al. Cognitive Reserve, Early Cognitive Screening, and Relationship to Long-Term Outcome after Severe Traumatic Brain Injury. J Clin Med. 2022;11(7). https://doi.org/10.3390/jcm11072046II. Ekdahl N, Möller MC, Deboussard CN, Stålnacke BM, Lannsjö M, Nordin LE. Investigating cognitive reserve, symptom resolution and brain connectivity in mild traumatic brain injury. BMC Neurol. 2023;23(1):450. https://doi.org/10.1186/s12883-023-03509-8III. Ekdahl N, Lannsjö M, Stålnacke BM, Möller MC. The relationship between cognitive reserve, cognitive performance and outcomes of return to work and life satisfaction after brain injury: A retrospective cohort study. Disability and Rehabilitation. 2025;16:1-11. https://doi.org/10.1080/09638288.2025.2517240IV. Ekdahl N, Lannsjö M, Stålnacke BM, Möller MC. Cognitive Reserve and Disparities in Healthcare Usage after Traumatic Brain Injury and Stroke: An Observational Cohort study. Journal of Rehabilitation Medicine. 2025; 57. https://doi.org/10.2340/jrm.v57.42400</p
Internet-based psychological interventions for athletes : a contextual behavioral approach
No full textBackground: Psychological interventions are applied in sports worldwide, although it is still unclear whether and which methods have an effect on sports performance. Acceptance and commitment therapy (ACT) is a behavioral change model that targets psychological processes related to acceptance, mindful awareness, and values-consistent behavior, and has been adapted for athletes. Further, using the internet format to deliver psychological services has had a great impact in clinical psychology, although it is still an underexplored format for delivering psychological interventions in sports.Research aims: The overall aim of this thesis was to develop and evaluate the feasibility and preliminary effectiveness of an internet-based psychological intervention based on ACT (I-ACT) in an elite sports context (Studies II and III). It also aimed to develop and psychometrically evaluate a therapeutic tool and measure of values and values-based behavior in athletes (Study IV), and to review the current evidence regarding psychological interventions' effect on sports performance in athletes (Study I).Methods and results: Study I: A systematic review was conducted of studies investigating psychological interventions' effect on sports performance in athlete samples. Five meta-analyses using cluster robust variance estimation were quantitatively synthesized for studies with comparable research designs. Significant moderate effects were found for PST, MA approaches, and Imagery compared to no-intervention controls. The effects were no longer significant in the sensitivity analyses when inferior research designs (non-randomized trials) were removed from the syntheses.Study II: I-ACT was developed to focus on performance enhancement and to promote a psychologically sustainable sports participation. Four male elite ice hockey players took part in the intervention, and semi-structured interviews were conducted afterwards regarding their experiences. Data was analyzed using qualitative content analysis. Results suggest that I-ACT was feasible and acceptable in an elite sports context and relevant to their sport endeavor.Study III: A total of 55 elite ice hockey players in two separate I-ACT intervention cohorts participated. Each intervention cohort (outfield players in I-ACT1 N = 40; outfield players in I-ACT2 N = 10) was compared with a statistical comparison group based on players from the rest of the leagues (N = 1051) regarding objective performance outcomes (goals, assists, Total points, and PlusMinus). Goaltenders (N = 5) were investigated with save percentage as the objective performance outcome. A significant moderate effect in I-ACT2 compared to the statistical comparison group was found for PlusMinus, and the significant effect lasted at follow-up. No significant effects were found for the objective performance outcomes in the other intervention cohort (I-ACT1), nor in I-ACT participating goaltenders. Significant small within-group effects were found for ice hockey-related psychological flexibility and sleep quality in I-ACT players. No significant effects were found regarding subjective performance, life quality, or general anxiety. Linear mixed-effects models were used to analyze the results, except for goaltenders' objective performance, for which a within-group repeated measures ANOVA was conducted.Study IV: A therapeutic tool and measure of values and values-based behavior in athletes was developed called Bull's-Eye for Athletes (BEA). 155 athletes from junior elite to international senior level took part in the study. BEA was administered digitally and psychometrically evaluated using Rasch analysis. BEA demonstrated satisfactory psychometric properties in general regarding unidimensionality, local independence, invariance, and response category monotonicity. Although the results should be interpreted while considering the limited sample size.Conclusions: The effects of PST, MA approaches, and Imagery on athletic performance are unstable and should be interpreted with caution, and further randomized trials are required (Study I). The internet format was a feasible option for delivering an internet-based psychological intervention in elite athletes (Study II). I-ACT had an effect on objective sports performance in one out of two intervention cohorts. The results should be interpreted carefully in general, and I-ACT should be further evaluated in an RCT while also investigating mediators of change related to the ACT model (Study III). BEA offers a therapeutic tool and measure of values and values-based behavior in athletes. It demonstrated satisfactory psychometric properties in an initial psychometric evaluation. It should, however, be further evaluated with larger samples in various sports contexts and also in a longitudinal intervention study as a measure of values-based behavioral change in athletes (Study IV).List of scientific papersI. Reinebo, G., Alfonsson, S., Jansson-Fröjmark, M., Rozental, A., & Lundgren, T. (2024). Effects of psychological interventions to enhance athletic performance: A systematic review and meta-analysis. Sports Medicine, 54, 347-373. https://doi.org/10.1007/s40279-023-01931-zII. Reinebo, G., Björverud, L. G., Parling, T., Andersson, G., Jansson- Fröjmark, M., & Lundgren, T. (2024). Development and experiences of an internet-based acceptance and commitment training (I-ACT) intervention in ice hockey players: a qualitative feasibility study. Frontiers in Sports and Active Living, 6, 1297631. https://doi.org/10.3389/fspor.2024.1297631III. Reinebo, G., Jansson-Fröjmark, M., Parling, T., Andersson, G., Lindner, P., Lundgren, T. (in press). Internet-based acceptance and commitment therapy (I-ACT) for elite ice hockey players: A quasi-experimental multiple-cohort intervention study. International Journal of Sport and Exercise Psychology. https://doi.org/10.1080/1612197X.2025.2531840IV. Reinebo, G., Johansson, M., Jansson-Fröjmark, M., Wiklund, A., Ekman Öhrn, G., Parling, T., Rozental, A., Andersson, G., & Lundgren, T. Bull's-Eye for Athletes (BEA): A measure of values-based behavior in sport and a psychometric evaluation using Rasch analysis. [Manuscript]</p
Metformin for the Prevention of Hyperemesis Gravidarum: An Observational Cohort Study
No full textTo evaluate if metformin treatment prior to pregnancy reduces the likelihood of nausea and vomiting in pregnancy (NVP) and hyperemesis gravidarum (HG) compared to no exposure. Observational cohort study. The MotherToBaby Pregnancy Studies in the United States and Canada. Live-born singleton pregnancies enrolled between 2012 and 2023, with HG diagnosis data available. Data were collected via maternal telephone interviews during pregnancy and medical records. Outcomes were compared between women with preconceptional metformin exposure and those unexposed to metformin before or during pregnancy. Risk ratios (RR) and 95% confidence intervals (CI) for HG and NVP, and mean duration of NVP symptoms. Data from 80 women exposed to metformin before conception and 4411 non-exposed women were analysed. In this cohort, the frequency of women with HG was lower among the exposed than the unexposed women (n = 1/80; 1.25% vs. n = 97/4411; 2.20%), but the study was not powered to detect statistical significance (adjusted RR 0.50, 95% CI 0.07-3.39). Rates of NVP were similar between groups (n = 32/80; 88.90% in the exposed and n = 1664/4111; 82.60% in the unexposed), with adjusted RR 1.06; 95% CI, 0.94-1.19. The mean duration of NVP symptoms was also similar between the groups. This cohort study found a lower rate of HG in the preconceptional metformin-exposed group compared to unexposed, although the study was not powered to identify a significant association. Rated and durations NVP were similar between groups. These are relevant to guiding future clinical trials on the efficacy of metformin as a prophylactic agent for HG.</p
Modelling ovarian development using human pluripotent stem cells
No full textGonads originate from the intermediate mesoderm and start out as a paired structure that has the capacity to further differentiate into both testes and ovaries depending on the sex chromosomes of an individual. In the past, it was largely assumed that ovarian development was a passive process that occurred due to the lack of male determining factors. However, research in recent years has shown that ovarian development is an intricate process that requires the involvement and interplay of many different genes and pathways. Mutations in genes involved in ovarian development can lead to a variety of gonadal disorders, which can result in infertility. Unfortunately, despite increasing research efforts over the last few years, ovarian development is not well understood and the function of many genes involved in early ovarian development remain unknown for the most part.The NR5A1 gene is thought to be a crucial factor for normal gonadal development and function. Additionally, it is also an important regulator of steroidogenesis. Previous studies done by our group have elucidated the role of NR5A1 in male gonadal differentiation as being necessary for the generation of more mature male somatic gonadal cells. However, its role in the maturation of female bipotential gonadal-like cells has not been studied yet. Another important gene, FOXL2, encodes a transcription factor that is well known for its role in female sex determination and ovarian development, function and maintenance. It has also been identified as one of the earliest markers of ovarian development. However, its role in the formation of granulosa cell precursors is unknown.Human pluripotent stem cells provide a valuable method to model human gonadal development as they can be differentiated into derivatives of all three germ layers, namely endoderm, mesoderm and ectoderm. Although there are protocols available by which stem cells can be differentiated to gonadal cells, in most cases the resulting cells are immature and the protocols itself do not recapitulate gonadal development completely. Previously, our laboratory developed a protocol for gonadal differentiation that accurately replicates gonadal development up to the bipotential gonadal cell stage.In this thesis work, I aimed to elucidate the role of NR5A1 and FOXL2 in early human ovarian development. To do so, a female human embryonic stem cell line (H9) was genome-edited using the CRISPR/Cas9 technology to induce either NR5A1 or FOXL2. The dual-inducible activation lines were then subjected to the previously established gonadal differentiation protocol and either NR5A1 or FOXL2 was activated at day 4 of differentiation.Initial RT-qPCR findings combined with bulk RNA-sequencing results showed that NR5A1 induction did not upregulate many bipotential or female gonadal genes aside from INHA, but instead significantly increased the expression of several steroidogenic genes. Additionally, several pathways relating to adrenal or ovarian steroidogenesis seemed to be upregulated. Therefore, it seems that in contrast to its role in male gonadal development, NR5A1 steers the differentiating cells towards a potential steroidogenic cell fate instead of a more mature gonadal cell fate in a female background. Similar experiments showed that FOXL2 on the other hand was found to not merely be a marker of early ovarian development, but a driver in the formation of early supporting gonadal cells, which are the precursors of granulosa cells. Moreover, the combination of FOXL2 activation and the gonadal differentiation protocol allowed us to replicate the early weeks of ovarian development in vitro.Altogether, this thesis work provides valuable insight in the functional role of NR5A1 and FOXL2 in early human ovarian development. This information in turn contributes to our understanding of pathological gonadal development, which will hopefully allow for the establishment of better therapies and personalised patient care for individuals suffering from gonadal disorders and infertility.This thesis is based on the following publications:I. Danti L, Lundin K, Sepponen K, Yohannes DA, Kere J, Tuuri T, Tapanainen JS. CRISPR/Cas9-mediated activation of NR5A1 steers female human embryonic stem cell-derived bipotential gonadal-like cells towards a steroidogenic cell fate. J Ovarian Res. 2023 Sep 20;16(1):194. https://doi.org/10.1186/s13048-023-01264-5II. Danti L, Lundin K, Nedeczey-Ruzsák P, Tuuri T, Tapanainen JS. FOXL2 drives the differentiation of supporting gonadal cells in early ovarian development. Reprod Biol Endocrinol. 2025 Mar 18;23(1):44. https://doi.org/10.1186/s12958-025-01377-0</p
Screen time effects on adolescent mental health
No full textIntroduction: Depression and anxiety are the most common causes of illness in Europe, especially among young people, and suicide is the leading cause of death among adolescents in Sweden. The use of digital media is often discussed in relation to mental health. Time recommendations, bans, legislation, and media use guidelines are frequently published-often without clear evidence of their effects or mechanisms of action. This thesis aims to improve our understanding of this phenomenon.Aim: Through three studies (I, II, III), this thesis explores the main psychological health mechanisms involved in how leisure screen time may contribute to mental health issues-or simply co-occur with them. It aims to establish a theoretically grounded, empirically supported, and scientifically replicable framework and model for understanding how screen time affects mental health.Methods: Longitudinal three-wave psychometric health data were collected over six years in conjunction with two school-cluster randomized trials on psychoeducation and suicide prevention, always administered in classroom settings. Intervention effects were held constant or nullified. Three statistical analyses of screen-health associations were conducted using adolescent health data (N = 4810 from 55 Swedish schools; N = 1544 from 30 schools in seven European countries).Analyses: The primary health outcome was subclinical depression (BDI-II scores), which correlated with anxiety, and stress (DASS-42). All main statistical tests were longitudinal (3-12 months). Study I used hierarchical linear regression of change scores to examine screen activities and their consequences. Study II applied GEE gamma regression to examine moderating effects of coping styles and structural regression to assess their mediating pathways. Study III used preregistered, theory-driven multigroup structural equation modelling to analyze multiple mediation and simultaneous screen-sleep displacements.Results: Screen time consistently had a negative impact on various sleep patterns and reduced cognitive coping styles. It was associated with small but adverse health outcomes for the average adolescent. Girls had twice the depression levels of boys and appeared more sensitive to screen-related sleep loss. Long screen times negatively affected Problem-Focused Engagement (PFE) coping, including cognitive restructuring, but not Socio-Emotional coping (EFE) (data collected before the COVID-19 outbreak). Notably, moodiness when screens were inaccessible-i.e., difficulty coping without screens-was the strongest predictor of depression in the first European study.Discussion: The three studies showed that, regardless of gender, longer screen time was associated with sleep loss and/or reduced ability to cope with stress. Independent research confirms that sleep loss further reduces the tendency to use cognitive engagement coping. While causality could not be established, the correct temporal order was identified in the two latter studies, which replicated the initial exploratory findings. The final framework is termed the "Screen Time Displacement Theory of Mental Health" (though not so important). Sleep problems often underlie depression-especially among girls in this sample- where sleep facets (quality, duration, chronotype) mediated 38-57% of the depressive effect over 12 months. Problem-focused coping both mediated and moderated depression in both genders over 12 months (the screen-coping interaction effect equaled maximum +3.4 BDI-II points; p List of scientific papersI. Hökby S, Hadlaczky G ... Carli V. Are Mental Health Effects of Internet Use Attributable to the Web-Based Content or Perceived Consequences of Usage? A Longitudinal Study of European Adolescents? JMIR Ment Health. 2016. 13;3(3):e31. https://doi.org/10.2196/mental.5925II. Hökby S, Westerlund J, Alvarsson J, Carli V, Hadlaczky G. Longitudinal Effects of Screen Time on Depressive Symptoms among Swedish Adolescents: The Moderating and Mediating Role of Coping Engagement Behavior. IJERPH. 2023;20(4):37. https://doi.org/10.3390/ijerph20043771III. Hökby S., et al. Adolescents' screen time displaces multiple sleep pathways and elevates depressive symptoms over twelve months. PLOS Glob Public Health. 2025, 2;5(4):e0004262. https://doi.org/10.1371/journal.pgph.0004262</p
Towards an integrated understanding of bronchiectasis : pathogens, microbiome, host metabolomics, and clinical characterization
No full textBackground Bronchiectasis is a chronic respiratory disease characterized by irreversible bronchial dilation, persistent microbial infection, and chronic inflammation that drive progressive lung damage through a self-perpetuating pathological cycle. While airway infections are recognized as key drivers of disease progression, critical gaps remain in understanding the complete microbial ecosystem - including bacteria, fungi, and viruses - and its ecological dynamics within the airways. Furthermore, the metabolic consequences of host-microbe interactions and their role in sustaining inflammation remain poorly characterized. The pathophysiological mechanisms governing the transition from stable chronic infection to acute exacerbations are particularly unclear, largely due to the current inability to capture these transitional events in real time.Aim This study seeks to establish an integrated understanding of bronchiectasis by systematically characterizing airway microbial ecology, host-microbe interactions, and developing a tool to monitor transitional phases between disease states, thereby addressing the challenges associated with infection- driven disease progression.Study I conducted a global systematic review and meta-analysis of 98 studies (54,384 participants) to evaluate microbial patterns in bronchiectasis. Culture- based data revealed Pseudomonas aeruginosa as the most prevalent pathogen across all disease stages (stable: 26%; exacerbation: 23%), while Haemophilus influenzae and Streptococcus pneumoniae were more common in stable phases. Fungal isolations highlighted Aspergillus spp. (stable: 15%) and Candida spp. (exacerbation: 11%). Sequencing-based microbiota analysis revealed reduced bacterial diversity and increased fungal diversity during exacerbations, characterized by dominance of Pseudomonas and Candida, respectively. Intriguingly, viral detection rates were generally higher in sputum than nasopharyngeal samples, with most of the viruses showing disease stage- independent prevalence.Study II performed shotgun metagenomic sequencing on sputum, saliva, and throat swabs from 46 stable bronchiectasis patients and 43 healthy controls. Dirichlet Multinomial Mixtures (DMM) modeling stratified patients into two clusters: DMM1 (mild disease, microbiome resembling healthy controls) and DMM2 (severe disease, enriched with P. aeruginosa and depleted oral commensals like Streptococcus spp.). Notably, rare environmental fungi (Eremothecium gossypii, Trichoderma breve) correlated with disease severity. Inter-site microbial correlations revealed stronger saliva-sputum than throat-sputum associations, suggesting oral microbiota as a potential modulator of lung ecology.Study III analyzed serum metabolomes from the same participants as Study II, identifying significant perturbations in bronchiectasis patients versus controls. Key findings included dysregulation of membrane lipid metabolism pathways (e.g., ABC transporters, linoleic acid metabolism), particularly in severe patients (DMM2), which were closely linked to microbial biofilm formation. Altered levels of Steroid hormones (e.g., pregnanediol, corticosterone), suggested impaired anti- inflammatory responses and potential sex-related differences in disease pathogenesis. Diagnostic models using sorbitol (AUC = 0.965) and betaine (AUC = 0.945) showed high accuracy.Study IV transculturally adapted and validated the Wisconsin Upper Respiratory Symptom Survey (WURSS-24) for Chinese populations (n = 300). The 4-domain structure (activity/function, systemic, nasal, and throat symptoms) demonstrated excellent reliability (Cronbach's a = 0.940) and validity (strong correlation with SF- 8 health scores). Nasal congestion, fatigue, and poor sleep were the most common symptoms, with Minimally Important Differences (MIDs) ranging from 0.41-1.14. The tool's responsiveness to clinical change supports its utility in exacerbation monitoring.Conclusions This work establishes bronchiectasis as a disease of microbial dysbiosis, where P. aeruginosa dominance and loss of oral commensal taxa drive severity, pointing toward a potential dysregulated oral-lung microbial translocation. Metabolomic profiling revealed disrupted membrane lipid metabolism reflecting microbial biofilm-mediated host interactions, and dysregulated steroid hormone pathways potentially underlying sex-specific disease manifestations. The validated WURSS-24-C addresses unmet needs in patient-reported monitoring of exacerbations.List of scientific papersI. Yuanyuan Wang, Jingmin Xiao, Xiaolin Yang, Yanmin Liu, Juan Du, Apostolos Bossios, Xi Zhang, Guobin Su, Lei Wu, Zhongde Zhang and Cecilia Stålsby Lundborg. Pulmonary microbiology and microbiota in adults with non-cystic fibrosis bronchiectasis: a systematic review and meta-analysis. Respiratory Research. 2025;26(1):77. https://doi.org/10.1186/s12931-025-03140-wII. Yuanyuan Wang, Chengrui Wang, Yanmin Liu, Xiaolin Yang, Apostolos Bossios, Guobin Su, Zhongde Zhang, Cecilia Stålsby Lundborg and Juan Du. The airway microbiomes in patients with stable bronchiectasis: A cross-sectional observational study [Manuscript]III. Yanmin Liu, Yuanyuan Wang, Chengrui Wang, Xiaolin Yang, Apostolos Bossios, Guobin Su, Zhongde Zhang, Juan Du and Cecilia Stålsby Lundborg. Serum metabolomic profiling reveals disease heterogeneity in bronchiectasis patients stratified by airway microbiome [Manuscript]IV. Yuanyuan Wang, Zehui He, Simin Chen, Yuntao Liu, Fang Li, Bruce Barrett, Zhongde Zhang, Guobin Su & Cecilia Stålsby Lundborg. Validation of the Wisconsin upper respiratory symptom survey-24, Chinese version. Annals of Medicine. 2022;54(1):655-665. https://doi.org/10.1080/07853890.2022.2043559</p
Care and financial support in ageing families : the changing shape of inequality
No full textBackground: Sweden is often seen as a place where older adults and their families are well supported, thanks to comprehensive social policies such as generous pensions, universal healthcare, and publicly funded old age care. These pillars of the Nordic welfare model are designed to ensure equity and relieve families of extensive care and financial responsibilities. However, recent developments such as population ageing, growing socioeconomic inequality, welfare retrenchment, and care marketisation have begun to challenge this model, potentially reshaping how support is provided and received in families. Little is known about how families are adapting to these shifts, especially when it comes to important intergenerational support, such as care for older parents and financial help to adult children and grandchildren. Although prior research has contributed valuable insights, less attention has been paid to the oldest-old, the inclusion of grandchildren, and shifts in multiple care sources over time. Moreover, families may adapt in different ways depending on their gender, social circumstances and socioeconomic position, as access to resources and capacities to provide or seek support vary.Aim: The aim of the thesis was twofold: (1) to deepen understanding of how patterns of care and financial support within ageing families are evolving in the Swedish context, with a focus on intergenerational exchange, and (2) to explore gender and socioeconomic disparities that may both shape and result from these patterns, in light of broader societal change.Data: This thesis addresses the knowledge gaps using nationally representative data from the Swedish Panel Study of Living Conditions of the Oldest Old (SWEOLD), which includes those with the greatest care needs and allows for analysis at the parent-child dyad level, including financial support to grandchildren.Study I: Using data from the sixth wave of SWEOLD from year 2021 and parent- child dyads, findings showed that half of the pairs had some form of support exchange. One-third involved only care from adult child to parent, 14 percent involved only financial support from older parents to adult children and/or grandchildren, and 7 percent engaged in both exchanges. Mothers were more likely to be involved than fathers in any support exchange, even after adjusting for family characteristics and geographical proximity. A higher parental social class belonging increased the likelihood of giving financial support, regardless of the child's social class. Gender differences appeared only among working-class families: fathers were least involved in any support exchanges, mothers were most likely to receive care, and sons were particularly absent from support roles. Bidirectional support was not patterned by gender or social class.Study II: Using SWEOLD waves from the years 1992, 2002, 2011 and 2021, this study examined care trends among older adults needing support with instrumental activities of daily living (IADL). Results showed a significant decline in formal care over time, while informal care, particularly from partners, increased. Support from adult children showed no consistent trend over the period. While men were the only ones whose access to formal care remained stable, all other groups, including those most likely to need it, such as women, individuals living alone, those with greater functional limitations, and those with basic education, experienced a marked decline in informal care. By 2021, the use of privately paid care was as common as formal care, with women and those with higher education being most likely to rely on privately financed services.Study III: Drawing on SWEOLD data from 2011, this study used parent-child dyads to examine which groups of adult children were reported to provide care, and to what extent, using a typology of care tasks ranging from personal to practical care. About one-third of adult children provided any care, mostly in the form of transportation in combination with tasks such as shopping for clothes or repairs. One in ten adult children also provided tasks such as food shopping, cleaning, cooking and bathing or showering. Gender differences in care provision appeared mainly among working-class children, where daughters provided more care tasks than sons. Overall, working-class daughters were the most active caregivers among all children regardless of of gender and social class.Study IV: Using parental-level data from SWEOLD conducted in 2002, 2011 and 2021, this study examined the occurrence and amount of financial transfers provided by older parents to children and grandchildren. About one in four parents provided downward financial support overall, with an increasing proportion directed toward grandchildren over time. By 2021, the earlier differences between children and grandchildren as recipients of financial support were erased. No consistent gender differences were found in the likelihood of providing financial support. However, fathers' involvement declined somewhat over time, whereas mothers' contributions remained stable. Notably, mothers' contributions of larger amounts increased, unlike fathers'. Social class differences became more pronounced by 2021, with higher social classes being more likely to give any financial support and to give larger sums compared to manual workers.Conclusion: These findings lead to three key takeaway messages. First, they show how families are adapting to a changing welfare landscape by leaning more on each other, often at the risk of negative health and social consequences, while those with greater financial means increasingly turn to private solutions. Second, as populations age and socioeconomic inequalities grow, the foundation of universal support is at risk of erosion. Third, the results highlight how disparities in family-based support, both in terms of care and finances, contribute to inequalities that are increasingly passed down across generations. Acknowledging these shifts is essential for shaping policies that ensure more equitable and sustainable support for all.Keywords: intergenerational support, informal care, formal care, privately paid care, financial support, gender, socioeconomic inequalities, SwedenList of scientific papersThe thesis builds upon the following studies, which are referenced in the text using their respective Roman numerals.I. von Saenger, I., Silverstein, M., Dahlberg, L., Fritzell, J., & Lennartsson, C. Intergenerational care and financial support in families of older adults - a social inequality perspective in a Nordic Welfare State. [Manuscript]II. von Saenger, I., Dahlberg, L., & Lennartsson, C. The changing landscape of old age care. Subgroup variations in sources of care over three decades in Sweden. [Submitted]III. von Saenger, I., Dahlberg, L., Augustsson, E., Fritzell, J., & Lennartsson, C. (2023). Will your child take care of you in your old age? Unequal caregiving received by older parents from adult children in Sweden. European Journal of Ageing, 20(1), 8. https://doi.org/10.1007/s10433-023-00755-0IV. von Saenger, I., Dahlberg, L., Silverstein, M., Fritzell, J., & Lennartsson, C. (2025). Gender and social class dynamics in intergenerational financial transfers among older adults: national trends over two decades in Sweden. Ageing and Society, 1-25. https://doi.org/10.1017/S0144686X24000825</p