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Tobacco exposure and health : from fetal life to adulthood
No full textTobacco causes adverse effects on health from both active and passive exposure and in all stages of life. While health effects of tobacco have been extensively studied, the current state of knowledge in certain research areas is poor. As trends of tobacco products change, new questions arise. Additionally, some well researched topics still contain important knowledge gaps.In Study I, the aim was to assess the validity of self-reported use of cigarettes, snus and e-cigarettes among Swedish young adults. Questionnaire data on tobacco use was compared to levels of cotinine, a biomarker of nicotine use, in urine samples. Overall, we found high validity of self-reported tobacco use compared to cotinine levels in the study population, with low levels of underreported tobacco use. The agreement between self-reported tobacco use and cotinine was particularly high among daily users, while somewhat lower for occasional users.In Study II, the aim was to investigate cross-sectional associations between current snus use at 24 years and cardiometabolic health markers at 24 and 26 years in a Swedish birth cohort. Exclusive daily snus use was associated with higher body mass index (BMI) and waist circumference (WC) among women at 24 years, as well as with higher BMI at 26 years, as compared to non-tobacco users. Among men, using 24 cans of snus/week was associated with higher BMI at 26 years. No significant associations were observed between snus use and body fat %, glycemic status or blood pressure.In Study III, the aim was to assess the association between early-life secondhand smoke (SHS) exposure (from maternal smoking during pregnancy and/or parental smoking during infancy) and development of atopic dermatitis (AD). Parental smoking during infancy was associated with a higher risk of AD up to 24 years, and particularly a phenotype defined by persistent AD with childhood onset of symptoms. Additionally, the association was stronger for AD with concurrent Immunoglobin E sensitization. Maternal smoking during pregnancy was associated with an increased AD risk up to 24 years, although only among participants not exposed to parental smoking in infancy. Furthermore, we found no gene- environment interaction between early-life SHS exposure and loss-of-function mutations in the FLG gene.In Study IV, the aim was to investigate the long-term effects of early-life SHS on asthma and lung function, and to disentangle the effect from those of tobacco use in adolescence and/or young adulthood. Early-life SHS was associated with asthma up to 24 years, and the risk was particularly high during pre-school age. Early-life SHS was not associated with prevalent asthma at 24 years, while smoking in adolescence and/or young adulthood was associated with prevalent symptoms of wheeze. Early-life SHS exposure was associated with lower ratio between forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC), irrespective of adolescent and/or young adulthood smoking. Smoking at a young age was additionally associated with a lower FEV1/FVC, regardless of early-life SHS exposure. Furthermore, dual exposure to early-life SHS and snus use in adolescent and/or young adulthood was associated with a lower FEV1/FVC.The results of this thesis indicate that I) validity of self-reported tobacco use is high among Swedish young adults, II) snus use is associated with higher BMI and WC in young adults, particularly among women, but not with body fat %, glycemic status or blood pressure, III) early-life SHS exposure is associated with AD up to adulthood, and the association differs by disease phenotype but not by FLG mutations, and IV) early-life SHS exposure is associated with asthma and lower lung function up to adulthood, regardless of smoking in adolescence and/or young adulthood, and smoking at a young age is associated with prevalent wheeze and lower lung function regardless of early-life SHS exposure.List of scientific papersI. Zettergren A, Sompa S, Palmberg L, Ljungman P, Pershagen G, Andersson N, Lindh CH, Georgelis A, Kull I, Melén E, Ekström S, Bergström A. Assessing tobacco use in Swedish young adults from self-report and urinary cotinine: a validation study using the BAMSE birth cohort. BMJ Open. 2023 Jul 12;13(7):e072582 https://doi.org/10.1136/bmjopen-2023-072582II. Zettergren A, Andersson N, Pershagen G, Lindh CH, Georgelis A, Kull I, Melen E, Ekstrom S, Ljungman P, Bergström A. Snus and cardiometabolic health markers among Swedish young adults. Nicotine & Tobacco Research. 2024 Nov 15:ntae267. https://doi.org/10.1093/ntr/ntae267III. Zettergren A, Andersson N, Merritt, AS, Kull I, Ljungman P, Melén E, Pershagen G, Lundin S, Johansson EK, Ballardini N, Ekström S, Bergstrom A. Early-life secondhand smoke exposure and development of atopic dermatitis up to adulthood. [Manuscript]IV. Zettergren A, Yu Z, Andersson N, Lindh CH, Merritt AS, Kull I, Pershagen G, Ljungman P, Melén E, Ekström S, Bergström A. Tobacco exposure from fetal life to adulthood and development of asthma and lung function. [Manuscript]</p
Chemical hazard characterisation of PFAS : current approaches in dose-response assessments and the lipidomic disruption in human cell models
No full textPer- and polyfluoroalkyl substances (PFAS) are a group of synthetic chemicals, abundantly produced and with a wide range of applications. The partial or full fluorination of alkyl substances with varying functional groups, leads to physicochemical properties that are mainly characterised by persistence and amphiphilicity. While these properties are highly valuable for industrial- and consumer products, they pose major challenges in environmental pollution and health implications. Especially influences on the lipid metabolism have been frequently connected to PFAS exposures, yet lack deeper mechanistic understanding, and were, hence, the main investigated experimental subject of this thesis.Regulatory efforts for PFAS have been made in the past and are currently underway. A harmonised approach for the assessment of human health effects, following PFAS exposure is, however, still needed. Dose-response assessment, through benchmark dose (BMD) modelling is the state of the science for hazard characterisation for risk assessment purposes. Specifically, the selection of a critical effect size (CES) - a threshold for adversity - of the assessed effect (response), is important in this context.This thesis set out to tackle the outlined challenges in toxicological assessments of PFAS in three main approaches.1) Testing contrasting ways to select the CESs in different BMD modelling approaches and assess the outcome metrics for select PFAS case-studies (Study I).2) Utilise human cell models to gain insights into PFAS-effects on the human lipid metabolism. This was done by investigating PFAS (single and mixture) exposures and PPARa receptor activation, lipid metabolism-related gene expression and lipid accumulation in Study III. Further, PFAS (single) exposure was investigated with regards to affecting hepatocyte lipidomic profiles in Study II.3) Assessing the meaningfulness of comparative relative potency factors (RPFs) for PFAS, through characterisation of RPFs, based on the endpoints in Study III.The findings of Study I reveal that the CES choice alters the results of a dose- response assessment significantly for both, frequentist and Bayesian BMD modelling. Further, it became apparent that for the selected case-studies, the Bayesian BMD modelling - paired with flexible, effect-specific CES selection - led to more stable and biologically relevant results, supporting their use in regulatory decision-making.Study II unveiled wide-range influences of PFAS exposures on the intracellular (hepatocyte) lipid profile. Legacy PFAS (e.g., PFOS and PFOA), as well as substitute PFAS (e.g., HFPO-DA and ADONA), were shown to have lipid profile-altering properties, with PFOS and PFOA having displayed the largest effects.The cell-based assays in Study III confirmed PFAS influences in multiple mechanistic steps of the lipid metabolism. This further underscores the body of evidence for the investigated PFAS and PFAS mixtures to be involved in alterations of important lipid metabolic pathways with likely relevance to cardiovascular diseases and other metabolic conditions. With regards to their relative potencies, PFAS appeared to be endpoint-specific, with no unambiguous pattern of potency.This thesis offers an assessment of the BMD methodology in chemical hazard characterisation within the context of assessing the risks from PFAS. Further, multi-endpoint assessment and exposures to single PFAS and PFAS mixtures of human relevance, highlighted the importance of the lipid metabolism as a major target system for PFAS toxicity. The use of RPFs to compare PFAS effects in an endpoint-specific manner, however, needs to be further investigated and a universal approach across endpoints appears to be very challenging.List of scientific papersI. BRUNKEN, L., Vieira Silva, A., & Öberg, M. (2025). Selection of the critical effect size alters hazard characterization - a retrospective analysis of key studies used for risk assessments of PFAS. Frontiers in Toxicology. 7. https://doi.org/10.3389/ftox.2025.1525089II. Kashobwe, L.#, Sadrabadi, F.#, BRUNKEN, L.#, Coelho, A. C. M. F., Sandanger, T. M., Braeuning, A., Buhrke, T., Öberg, M., Hamers, T., & Leonards, P. E. G. (2024). Legacy and alternative per- and polyfluoroalkyl substances (PFAS) alter the lipid profile of HepaRG cells. Toxicology. 506, 153862. # Equally contributed. https://doi.org/10.1016/j.tox.2024.153862III. BRUNKEN, L., Vieira Silva, A., & Öberg, M. Relative Potency of PFAS in Human Cell Models: Linking PPARa Activation, Gene Regulation, and Lipid Accumulation. [Manuscript]</p
Exercise limitation in chronic kidney disease: An experimental pilot study with leg and arm exercise.
No full textMaximal oxygen uptake (VO2max) in healthy subjects is primarily limited by systemic oxygen delivery. In chronic kidney disease (CKD), VO2max is potentially reduced by both central and peripheral factors. We aimed to investigate the effect on VO2peak of adding arm exercise to leg exercise. Ten individuals with CKD stages 3-5 and 10 healthy controls, matched for age, sex, body size, and physical activity level, were included. Subjects performed two maximal exercise tests, one with legs only (L exercise) and one test where arm exercise was added to leg exercise (LA exercise). The increase in VO2peak, when comparing LA exercise with L exercise, was significantly higher in CKD (0.20 ± 0.18 L/min or 2.31 ± 1.78 mL/(kg·min)) than in controls (0.019 ± 0.12 L/min or 0.26 ± 1.62 mL/(kg·min); p = 0.02 and 0.01, respectively). The decrease in peak leg workload, when comparing L exercise with LA exercise, was larger in controls than in CKD, in absolute terms (p = 0.002) and relative to body weight (p = 0.01). VO2max in individuals with CKD is dependent on the active muscle mass, supporting a peripheral limitation to VO2max in CKD. By contrast, the control group appeared to have a more central limitation to VO2max.</p
Application of statistical and bioinformatics methods to study inflammation driven health challenges
No full textInflammation plays a crucial yet paradoxical influence on both acute and chronic disease, fostering tumor progression while also directing mechanisms for immune defense. This thesis comprises three studies that explore the molecular determinants of inflammation, symptomatology, and intercellular communication, with a particular focus on developing translational biomarkers for future therapeutic interventions.Paper I focuses on plasma proteins as robust non-invasive biomarkers for lung cancer (LC). By leveraging multiplex proximity extension assay (PEA), we have identified a signature of five- proteins panel (CD83, GZMA, GZMB, CD8A, and MMP12) that reliably distinguishes LC, including early-stage cancer compared with other cancer types and non-cancer patients. Expanding this panel with four other additional proteins (GAL9, PDCD1, CD4, and HO1), further enhanced sensitivity for advanced LC and improved discrimination of other cancers, which emphasize the value of integrating multiple inflammatory and immune-regulatory proteins for precise diagnosis.Paper II investigates the molecular basis of symptom burden (SB) in patients referred by primary health care provider for suspected LC. By integrating symptoms in patient-reported outcome measures (EORTC QLQ-C30) with plasma proteomic profiles, we have discovered distinct clusters of inflammation associated proteins that track with increasing SB severity. Despite clear shifts in protein expression at different SB levels, no single "inflammatory signature" fully captures symptom heterogeneity. This emphasizes the need for a noble integrative approach/domain proposed as "Symptomomics". This new domain will serve as a "big data" paradigm for clinical manifestation by coupling patient-reported outcomes with multi-omics data to uncover underlying molecular hallmarks across complex symptom clusters.Paper III is focused on protozoan parasites, by demonstrating how Plasmodium falciparum in malaria responds to nutritional stress via increased extracellular vesicle (EV) release. Alterations in EV cargo composition, particularly small RNAs that reflect a conserved stress response mechanism and highlight EVs as potential biomarkers or therapeutic targets in malaria pathogenesis.Collectively, these studies represent how integrating high-throughput data, statistical and bioinformatics analyses, and patient-reported measures can begin to untangle the multifaceted roles of inflammation driven health challenges. Such knowledge might flag the way for developing more sensitive diagnostic tools, that target anti-inflammatory therapies, and personalized symptom management strategies across oncology and infectious diseases.List of scientific papersI. Multiplex plasma protein assays as a diagnostic tool for lung cancer. Mohammad Tanvir Ahamed, Jenny Forshed, Adrian Levitsky, Janne Lehtio, Amanj Bajalan, Maria Pernemalm, Lars E. Eriksson & Björn Andersson. Cancer Science, 2024, 115(10), 3439-3454. https://doi.org/10.1111/cas.16300 https://doi.org/10.1111/cas.16300II. Integrative analysis of differential protein expression and symptom burden using co- expression and gene ontology. Mohammad Tanvir Ahamed, Amanj Bajalan, Janne Lehtio, Maria Pernemalm, Lars E. Eriksson, Björn Andersson. [Manuscript] III. Starvation induces changes in abundance and small RNA cargo of extracellular vesicles released from Plasmodium falciparum infected red blood cells. Leonie Vetter, Amanj Bajalan, Mohammad Tanvir Ahamed, Caterina Scasso, Sulman Shafeeq, Björn Andersson & Ulf Ribacke. Scientific Reports, 2023, 13(1), 18423, https://doi.org/10.1038/s41598-023-45590-6</p
Features of innate lymphoid cells in human fetal tissues and adult respiratory infection
No full textNK cells and ILC3s are the first lymphoid cells to develop in the human fetus, and together with other immune cells, likely play crucial roles in fetal development and maternal-fetal tolerance. In adults these cells have varied distribution across human tissues with distinct protein expression and transcriptional profiles depending on the tissue. There are also indications that ILCs have distinct developmental trajectories in different adult tissues. However, it remains unexplored how closely related ILCs are across human tissues.To gain an understanding of how early fetal ILCs obtain these unique tissue profiles we investigated ILC composition and characteristics across paired fetal tissues. In study I we showed that NK cells and ILC3s have distinct distribution and gene expression profiles across fetal tissues. We also identified putative ILC and NK progenitors in the fetal intestine, suggesting that already first trimester tissues have unique ILC development which could contribute to the observed tissue differences.We further explored NK cell developmental relationship across fetal tissues and with other immune cells in study II. Here we employed single cell sequencing to simultaneously study fetal immune cell gene expression and somatic mitochondrial mutations. We showed that somatic mitochondrial mutations are present already in the first trimester fetus and can be used to infer clonal relationships. The resulting clonal populations likely expanded from multipotent progenitor cells, as the majority of clones were present in multiple cell types and tissues. However, some clones showed biased towards NK cells, and specific tissues. Similarly, in vitro clonal expansion of most CD34+ progenitors generated two or more distinct cell types, though clones with a strong bias towards a single subset were also detected.In study III, we investigated mechanisms of NK cells and T cell tissue homing during viral respiratory infections. We obtained peripheral blood from COVID-19 and influenza patients as well as publicly available single cell RNA sequencing data from bronchoalveolar lavage fluid from COVID-19 patients. Protein and gene expression analysis revealed that CXCR3+, CXCR6+ and/or CCR5+ NK cells and T cells are likely recruited to the lung during moderate infection. These cells also showed stronger activation profiles compared to those lacking chemokine receptors, indicating their universal role in airway infections.List of scientific papersI. Rødahl, I. E., M. A. Ivarsson, L. Loh, J. E. Mold, M. Westgren, D. Friberg, J. Mjösberg, N. K. Björkström, N. Marquardt, D. F. Nixon, and J. Michaëlsson. 2024. Distinct Tissue-Dependent Composition and Gene Expression of Human Fetal Innate Lymphoid Cells. Eur J Immunol. e202451150. https://doi.org/10.1002/eji.202451150II. Rødahl, I. E., Q. Lin, J. Hård, C. J. Eriksson, M. Ivarsson, N. Marquardt, M. Westgren, E. Sundström, E. Åkesson, J. Mold, & J. Michaëlsson. 2025. Clonal diversity of fetal NK cells explored by somatic mitochondrial mutations. [Manuscript]III. Brownlie, D., I. Rødahl, R. Varnaite, H. Asgeirsson, H. Glans, S. Falck- Jones, S. Vangeti, M. Buggert, H. G. Ljunggren, J. Michaëlsson, S. Gredmark-Russ, A. Smed-Sörensen, and N. Marquardt. 2022. Comparison of Lung-Homing Receptor Expression and Activation Profiles on NK Cell and T Cell Subsets in COVID-19 and Influenza. Front Immunol. 13: 834862. https://doi.org/10.3389/fimmu.2022.834862</p
Using benchmarking to assess aspects of specialisation in healthcare
No full textBackground Nordic health systems face challenges like an aging population, rising care demands, and high technology costs, making resource prioritization crucial. Efficiency, cost-effectiveness, and value for money are key for sustained performance, but market imperfections, such as information asymmetry and lack of price transparency, hinder affordable quality services. Benchmarking helps identify strengths, share best practices, and highlight areas for improvement, especially when market signals are lacking. Economies of scope can offer cost advantages from combining related services, but their benefits in healthcare are complex and context dependent.Aim This thesis makes a twofold contribution: methodological and empirical. It identifies and suggest solutions for data comparability and methodological challenges in international benchmarking of efficiency and productivity, helping future researchers to avoid potential pitfalls. Empirically, it tests these solutions in studies that applies benchmarking to understand the effects of specialisation on costs, outputs and efficiency within Nordic healthcare system. The specific objectives of the studies are:To target and provide recommendations for overcoming data-related and methodological challenges inherent in cross-country benchmarking of hospital efficiency and productivity (Study I).To assess the cost-efficiency of highly diversified Nordic university hospitals by including measures of patient care, teaching, and research (Study II).To analyse cost-efficiency of specialised versus diversified acute-care hospitals in the Nordics and the potential existence of economies of scope (Study III).To evaluate the cost-efficiency and productivity changes in Swedish cancer care during a period of government-mandated collaboration and specialisation (Study IV).Material and methods Study I presents solutions to data comparability and methodological challenges in international benchmarking, based on analyses of Nordic national patient administration databases from the Nordic Hospital Comparison Study Group. Study II uses the pooled Nordic patient database (2002-2004) from the Nordic Hospital Comparison Study Group, covering costs for patient care, teaching, research, outpatient visits, case-mix weighted admissions and discharges, full-time interns and residents, and bibliometric outcomes from Sweden, Finland, Norway, and Denmark. Study III uses an updated version of the database (2008-2009), including patient care costs, case-mix weighted outpatient visits, and inpatient admissions and discharges, all based on a common grouper with consistent DRG logic across the four countries. Study IV uses patient care costs and DRG points for malignant cancer (ICD-10 codes C00- C99) from the Swedish Association of Local Authorities and Regions' cost per patient database (2012-2022).In Study I, a descriptive method is used. In Study II, III, and IV the bootstrapped nonparametric Data Envelopment Analysis is applied to estimate bias-corrected cost-efficiency scores. In Studies II and IV, a second-stage regression analysis is performed on the efficiency scores using an ordinary least squares model. In Study III scope convexity is defined as the ratio of cost efficiency relative to specialised and diversified hospital frontiers, using a data-driven approach to differentiate between specialised and diversified hospitals based on surgical vs. medical care and outpatient vs. inpatient care. Sensitivity analysis includes variations in production technology assumptions. In Study IV productivity changes using the Malmquist Productivity Index are also calculated.Results In all Nordic analyses, Finnish hospitals consistently rank highest in average bias-corrected cost efficiency with the least variation around the mean, followed by Norwegian hospitals and Danish hospitals, while Swedish hospitals rank the lowest. Addressing data comparability and methodological challenges reduces variance and make results more robust, but the ranking across countries remains unchanged (Study I).The results of Study II shows that Finland achieves the highest average cost- efficiency score in the patient care production model, with scores ranging from 0.90 to 0.95, regardless of the production technology assumption. However, when including costs and outcomes related to medical teaching and clinical research are included, the statistically significant differences in average efficiency between countries disappear. The findings also reveal that the optimal hospital size for delivering patient care differs from the ideal size for delivering teaching and research outcomes and confirms that a high case-mix weight negatively co-varies with efficiency.The results of Study III confirm that the country specific efficiency rankings remain consistent with previous studies. A greater specialisation of surgical activity tends to generate higher average efficiency than a more diversified mix of surgical and medical activities. At the same time, bias-corrected scope convexity measures indicate economies of scope at the top- performing hospitals in Sweden (1.18), Finland (1.06) and Denmark (1.04). The impact of greater specialisation in outpatient care compared to inpatient care on hospital efficiency is more ambiguous.The productivity analysis in Study IV shows a significant decline in both cancer care delivery (24.1 percentage points), and total care delivery (27.6 percentage points) during the study period, despite the introduction of multiple National Cancer Strategies promoting collaboration and specialisation. The bias-corrected average efficiency for cancer care (0.68) is lower than for total care (0.72), with oncology departments at university hospitals presenting the lowest scores. In contrast, a higher degree of specialisation, reflected in a greater proportion of oncology activities compared to other services, is positively linked to efficiency. Results also indicate regional differences in efficiency. Additionally, a weak positive association is found between efficiency and regional cancer mortality.Conclusions This thesis addresses challenges in data comparability and methodology in international benchmarking using the Nordic countries' national patient administration databases, given their similar welfare models. It further explores these solutions through empirical studies that apply benchmarking to evaluate the effects of specialisation, contributing to the limited literature on the application of scope economics theory in healthcare. A better understanding of economies of scope, especially in hospital care, can inform healthcare configuration decisions. Policymakers should balance promoting specialisation for efficiency and innovation with supporting diversification when it improves patient outcomes. Future research should focus on defining outputs by clinical specialties, not care settings, and include episodes of care in efficiency analyses.List of scientific papersI. Medin E, Häkkinen U, Linna M, Anthun KS, Kittelsen SA, Rehnberg C; EuroHOPE Study Group. International hospital productivity comparison: experiences from the Nordic countries. Health Policy 2013 Sep; 112(1-2):80-7. https://doi.org/10.1016/j.healthpol.2013.02.004 II. Medin E, Anthun KS, Häkkinen U, Kittelsen SA, Linna M, Magnussen J, Olsen K, Rehnberg C. Cost efficiency of university hospitals in the Nordic countries: a cross-country analysis. Eur J Health Econ. 2011 Dec; 12(6):509-19. https://doi.org/10.1007/s10198-010-0263-1III. Medin E, Janlöv N, Anthun KS, Kittelsen SA, Häkkinen U, Rehnberg C. Economies of scope in Nordic acute hospitals. [Manuscript]IV. Medin E, Rehnberg C, Janlov N. Cancer care efficiency and productivity in Sweden. [Manuscript]</p
Support in daily living for neurodivergent young adults : current practice and new methods
No full textBackground: Support in daily living is a municipal service for individuals with support needs primarily related to mental, behavioural, and neurodevelopmental conditions. The service offers practical, educational, and social support to help individuals living in ordinary housing manage their daily lives. While this service is increasingly being granted to emerging neurodivergent adults, there remains a lack of clarity regarding how the support is provided for this specific group and how it can be further developed.Aims: The overarching aim of this thesis was to enhance our understanding of the support provided to neurodivergent young adults as they transition into adulthood. Four studies were conducted to examine current practices and test new approaches. Study I provided a qualitative description of current practice. Study II was a feasibility study assessing the addition of the structured TRANSITION programme to regular support services. Study III explores perspectives on remote support elements. Study IV focused on the co- production and feasibility testing of a tool for enhanced service user engagement in designing their support.Methods: Study participants were young service users aged 18 to 29 and support workers from various municipalities across the country. Study I involved telephone interviews with 34 support workers, which were analysed through qualitative content analysis. Study II used a mixed-methods design, including pre- and post-measures from 26 service users and semi-structured telephone interviews with 11 service users and 9 support workers. In Study III, a convergent mixed-methods approach was used, which included a survey featuring both open- and closed-ended questions alongside online focus group discussions involving 10 service users and 3 support workers. The survey gathered responses from 34 service users and 65 support workers. In Study IV, a tool for enhanced user engagement was co-produced in online workshops with 10 service users and 3 support workers. Thereafter, its feasibility was tested with 15 service users and 11 support workers, using mixed-methods design with pre- and post- measures and semi-structured telephone interviews with 12 service users and 8 support workers. Integrative analyses were conducted through joint displays in Study II and III and narrative weaving in Study IV.Results: Study I highlights that support in daily living for neurodivergent young adults is a complex support service influenced by organisational aspects, practical aspects of support provision, and the key players' collaborative effort. Some aspects of the service were not adequately designed for the specific needs of the target group, and there was an expressed need for increased knowledge of neurodevelopmental conditions. The findings from Study II indicate that the TRANSITION programme was an acceptable addition to regular support, with service users rating it highly in terms of satisfaction and engagement. The clear structure, the focus on specific goals, and the long-term perspective were particularly valuable features, according to service users and support workers alike. While no serious adverse events were reported, some service users experienced stress related to the programme. Study III suggested that there was a lack of service routines for remote support. While remote contact was seen as a useful complement to on-site support to increase accessibility and user choice, service users were more hesitant than support workers to endorse remote support provision. Service users expressed concerns that this form of support could lead to miscommunication and insufficient interpersonal contact. The findings of Study IV showed that the co-produced structured guide 'Designing my daily living support' was deemed highly relevant and useful by both service users and support workers, in terms of building rapport and engaging service users in exploring and designing their support. Pre- and post- measures preliminary indicated that service users' quality of life improved during the study period.Conclusion: Supporting neurodivergent young adults transitioning into adulthood is a complex task that requires support services to balance young adults' needs for assistance with their desire for autonomy. To provide functional support that follows young adults' developmental process, the support service may need to be more flexible and responsive to the needs and preferences of young service users. To produce materials aligned with the target group's preferences and values, co-production is a promising research and development approach. The use of structured materials such as TRANSITION and 'Designing my daily living support' were found to be feasible complements to regular support. The enhanced clarity and direction from adding structured materials to current practice may help achieve person-centred support and improve some service users' quality of life. Organisations' readiness to provide resources, such as time, technology, and education/guidance for support workers, may be crucial for providing person-centred and equitable support to neurodivergent young service users.List of scientific papersI. Löthberg, M., Hirvikoski, T., Girdler, S., Bölte, S., & Jonsson, U. (2024). Support in Daily Living for Young Adults with Neurodevelopmental Conditions in Sweden: A Qualitative Description of Current Practice. Journal of Autism and Developmental Disorders, 54(8), 3043-3058. https://doi.org/10.1007/s10803-023-06014-6II. Löthberg, M., Meyer, J., Niman, A., Berggren, S., Hirvikoski, T., Bölte, S., & Jonsson, U. (2025). Feasibility of the TRANSITION program as an add-on to regular daily living support for young adults: an open mixed-methods study. Disability and Rehabilitation, 1-14. Advance online publication. https://doi.org/10.1080/09638288.2025.2459889III. Löthberg, M., Wirström, E., Meyer, J., Girdler, S., Bölte, S., & Jonsson, U. (2024). 'If I Don't Have My Support Worker in the Room ... ': A Multi- perspective Mixed Methods Study of Remote Daily Living Support for Neurodivergent Young Adults. Journal of Autism and Developmental Disorders.https://doi.org/10.1007/s10803-024-06425-zIV. Löthberg, M., Niman, A., Engström, S., Meyer, J., Wirström, E., Girdler, S., Bölte, S., Jonsson, U. 'Designing my daily living support' - Co- production and feasibility of a structured guide for enhancing service user involvement among neurodivergent young adults. [Submitted]</p
Equity in mental healthcare use in Sweden : needs-adjusted utilisation rates, trends, and modifiable factors
No full textIndividuals with lower socioeconomic position face higher risk and burden of mental disorders, but it is unclear if their mental healthcare use matches their needs. Migrants use less mental healthcare than non-migrants, but whether this reflects differences in needs is unclear. The aim of this thesis was to enhance our understanding of unmet mental healthcare needs and the modifiable mechanisms underlying inequities in mental healthcare utilisation in Sweden.A registry-based follow up of mental healthcare use was performed in a selected group of adolescents and adults who answered questionnaires about their mental health status in surveys. Adolescents were from the KUPOL longitudinal study (Kunskap om ungas psykiska hälsa och lärande; 2013-2018) which was conducted in eight counties in Sweden. Adults were from the Hälsa Stockholm surveys in 2006, 2010, 2014, and 2021. Adolescents' mental healthcare use was based on records from secondary care and filled prescriptions of psychotropic medication during 12 months after each survey (Study I). Adults' mental healthcare use was identified using records from primary and secondary care and filled prescriptions of psychotropic medication during six months after the date of survey response (Study II-V).Study I assessed socioeconomic differences in adolescents' mental healthcare use, accounting for mental health status (measured by the Strengths and difficulties questionnaire). The sample included 3,517 adolescents aged 13-16 years, observed in grades 7-9. Logistic regression and negative binomial regression analyses were used to estimate differences in mental healthcare use (yes/no) and in the frequency of outpatient visits among users, with mental health status as a moderator. Adolescents with lower socioeconomic position (parental education and household income level) were more likely to use services, especially for attention-deficit/hyperactivity disorder or autism spectrum disorders (ADHD/ASD), but these differences diminished with increasing symptom severity. However, adolescents with lower socioeconomic position were less likely to use services for other mental disorders such as depression and anxiety.Study Il assessed socioeconomic differences in adults' mental healthcare use, accounting for psychological distress. Data from 31,433 adults (18-64 years) in the 2014 and 2021 Hälsa Stockholm surveys were analysed using logistic and negative binomial regressions, with psychological distress as a moderator. Adults with lower socioeconomic position (education and household income level) were more likely to use mental healthcare than those with higher socioeconomic position. Education-related differences diminished with increasing distress severity, but income-related differences did not. Among those with moderate- to-severe distress, adults with lower education were less likely than those with higher education to use primary mental healthcare services. Differences in the number of outpatient visits among patients were generally marginal.Study III assessed changes in income-related differences in adults' use of mental healthcare services. The sample included 81,650 adults aged 18-64 years from the Hälsa Stockholm surveys (2006-2021). Using indirect standardisation and concentration indices, need-standardised differences were estimated for each period (2006/07, 2010/11, 2014/15, 2021/22). In addition to psychological distress (the main need-indicator), additional need-indicators included general health status and long-term limiting illness. Lower-income individuals consistently used more mental healthcare services in all study periods, but differences became marginal after standardising for all need-indicators. Between 2006/07 and 2014/15, lower-income groups' use of services increased more than that of higher-income groups. By 2021/22, their use of services stagnated or declined relative to higher-income groups. Among patients, lower-income groups made more visits, but these differences decreased over time.Study IV assessed differences in mental healthcare use by migrant status among 81,650 adults (18-64 years) from Hälsa Stockholm surveys (2006-2022). Period-stratified logistic regressions estimated differences in service use (yes/no), and zero-truncated negative binomial regressions assessed visit frequency, conditional on at least one outpatient visit. Non-Nordic migrants were consistently less likely to use mental healthcare than Swedish-born individuals, with differences widening over time and after adjusting for need-indicators. By 2021/22, non-Nordic migrants used services at half the rate of Swedish-born individuals. However, among patients, migrant-related differences in outpatient visits were marginal.Study V explored modifiable factors behind the gap in mental healthcare use between migrants and Nordic-born individuals among 15,943 adults (18-64 years) from the 2021 Hälsa Stockholm survey. Separate causal mediation analyses were performed, with exposure-mediator interaction, for each of the eight measured mediators. A two-way decomposition was used to decompose the "observed inequalities" (Total Effect) into (1) "residual inequalities" (Controlled Direct Effect) and (2) proportion eliminated, while controlling for sociodemographic factors. The proportion eliminated is the portion of the "observed inequalities" that would be removed if the mediator were set to a single value for everyone i.e., under a hypothetical intervention that modifies exposure to a barrier in the entire sample (or target groups). The results suggested that hypothetically removing cost barrier or increasing length of residence in the neighbourhood (≥3 years, e.g., indicating familiarity with the healthcare system) would reduce observed inequalities by 8.9% and 17.6%, respectively. While setting individual trust in healthcare services at the highest level would reduce the observed migrant inequalities by 18%. Setting neighbourhood socioeconomic deprivation, migrant density, or neighbourhood average trust in public institutions at the most advantaged levels (e.g., the tenth percentiles) would reduce observed inequalities by about 30%. However, large unexplained residual inequalities remained in each model.In conclusion, lower socioeconomic groups used mental healthcare services more than those with higher socioeconomic position, consistent with indicated mental healthcare needs (i.e., more equitable use). However, there were indications of unmet need for depression and anxiety care among adolescents with lower socioeconomic position, and inequities faced by adults with lower education in primary mental healthcare services.Non-Nordic migrants faced persistent inequities in mental healthcare use, which widened during the COVID-19 pandemic. To reduce these inequities and meet Sweden's equity goals, policies should target modifiable barriers to seeking and accessing mental healthcare services.List of scientific papersI. Muwonge JJ, Dalman C, Burström B, de Leon AP, Galanti MR, Jablonska B, Hollander AC. Are the estimated needs for mental health care among adolescents from different socioeconomic backgrounds met equally in Sweden? A longitudinal survey-registry linkage study. European Child & Adolescent Psychiatry. 2023. https://doi.org/10.1007/s00787-023-02341-2II. Muwonge JJ, Dalman C, Burström B, Jablonska B, Hollander AC. Exploring socio-economic inequalities in mental healthcare utilization in adults with self-reported psychological distress: a survey-registry linked cohort design. Epidemiology and Psychiatric Sciences. 2025;34:e6. https://doi.org/10.1017/s2045796024000842III. Muwonge JJ, Jablonska B, Dalman C, Burström B, Galanti MR, Hollander A-C. More or less equal? Trends in horizontal equity in mental health care utilization in Stockholm county, Sweden (2006- 2022). Repeated survey-registry linked studies. International Journal for Equity in Health. 2025;24(1):98. https://doi.org/10.1186/s12939-025-02453-yIV. Muwonge JJ, Jablonska B, Dalman C, Burström B, Galanti MR, Hollander A-C. Mental healthcare utilisation among migrants and Swedish born adults accounting for probable needs, 2006-2022. [Submitted]V. Muwonge JJ, Jablonska B, Dalman C, Burström B, Galanti MR, Hollander A-C, Dykxhoorn J. Modifiable factors to migrant-related inequalities in mental healthcare utilisation among adults in Stockholm County, Sweden. [Manuscript]</p
Flame-synthesized nanomaterials for drug delivery and immunostimulation
No full textCalcium phosphate (CaP) nanoparticles are highly attractive for biomedical applications due to their inherent biocompatibility, biodegradability, and close compositional similarity to mineral components of human bone. However, "CaP" is an umbrella term encompassing multiple polymorphs and crystalline phases, each exhibiting distinct biological behaviors. This structural variability has severely limited the establishment of clear structure-function relationships, impeding the rational design and clinical translation of CaP-based nanomedicines. To address this bottleneck, there is a need for a nanofabrication method capable of producing CaP nanoparticles with precise, tunable, and reproducible physicochemical properties. These criteria are well met by flame spray pyrolysis (FSP), a continuous and scalable synthesis platform.Across four integrated studies in this thesis, FSP is employed to engineer CaP-based nanomaterials for immunomodulation, protein antigen, and nucleic acid delivery. As well as synthesize morphology-matched luminescent nanoprobes for studying the biodistribution of FSP-made phosphate nanoparticles. Collectively, these studies establish mechanistic relationships between nanoparticle structure and biological function.In Paper I, through systematic variation of flame residence time and precursor concentration, three CaP nanoparticle formulations with distinct sizes and crystallinity were synthesized. All formulations demonstrated excellent biocompatibility in A549 cells with no cytotoxicity observed. Surface area-dependent OVA adsorption revealed smallest CaP nanocarrier achieved the highest loading capacity. Proteinase K degradation assays highlighted the potential of flame-made nanocarriers in protecting the surface adsorbed antigen. CaP crystallinity dictated their immunostimulatory behavior. Amorphous CaP nanoparticles function as potent antigen-dependent immunopotentiators, promoting dendritic cell activation and costimulatory marker expression (CD86, CD80) primarily when conjugated with antigen, whereas crystalline hydroxyapatite particles demonstrate inherent adjuvant activity independent of antigen presence. Paper II extends this mechanistic understanding through single step co-oxidation of CaP with SiO2, yielding colloidally stable, amorphous CaP-SiO2 composite nanoparticles. Comparative immunological analysis reveals that increasing amorphous CaP size progressively shifts immune activation toward crystalline-like, antigen-independent behavior. On the other hand, SiO2 incorporation enhances colloidal stability but reduces antigen loading capacity and immunogenicity. This positions CaP-SiO2 as a promising low-immunogenicity carrier platform for biomolecule delivery applications where minimized immune activation is desired.Paper III explored flame-made CaP for nucleic acid delivery through two complementary surface-engineering strategies. First, inorganic modification via single-step SiO2 co-oxidation during FSP, and second, post-synthesis polymeric functionalization using poly-L-lysine (PLL). SiO2 incorporation with CaP reduced the hydrodynamic size and demonstrated good DNA loading. However, the negative surface charge impeded with the transfection efficiency. The PLL functionalization of CaP nanoparticles reversed the surface charge to positive thus aided in the transfection efficiency.Paper IV develops near-infrared luminescent neodymium-doped lutetium phosphate (LuPO4:Nd3+) nanoprobes that structurally mimic the fractal-like aggregates characteristic of flame-synthesized CaP particles. Nd3+ doping enabled deep-tissue fluorescent imaging and precise in vivo biodistribution assessment. These imaging studies reveal predictable liver and spleen accumulation patterns driven by nanoparticle aggregate morphology.List of scientific papersI. Anshika Maheshwari, Rebecca Dookie, Meztlli O. Gaytán, Birgitta Henriques-Normark and Georgios A. Sotiriou. In Vitro Evaluation of Flame-Made Calcium Phosphate Nanoparticles for Antigen Delivery and Immunostimulation. ACS Applied Nano Materials, 2025, Vol 8, 11986-11996. https://doi.org/10.1021/acsanm.5c01535II. Anshika Maheshwari, Rebecca Dookie, Thomas Thersleff, Dmytro Danilian, Inge K. Herrmann, Birgitta Henriques-Normark and Georgios A. Sotiriou. Flame Synthesis of CaP-SiO2 Nanoparticles with Tunable Immunogenicity: In Vitro Evaluation with Dendritic Cells. Powder Technology, 2026, Vol 468, 121645. https://doi.org/10.1016/j.powtec.2025.121645III. Anshika Maheshwari, Eleni Chronopoulou, Natalia Teixeira, Andrea Del Valle, Francesco Righetti, Reshma Ramachandran, Birgitta Henriques-Normark and Georgios A. Sotiriou. Surface engineering of flame-made calcium phosphate nanoparticles for nucleic acid delivery. [Manuscript]IV. Olof Eskilson, Padryk Merkl, Eleni Bletsa, Anshika Maheshwari, Abhilash Kulkarni, Uliana Kostiv, Anandi Narayana Moorthy, Jerker Widengren, Birgitta Henriques-Normark & Georgios A. Sotiriou. Morphology-Preserving Flame Synthesis of Fractal Like Nanoaggregates for Deep-Tissue Bioimaging. [Manuscript]</p
Biological impact and clinical relevance of long non-coding RNAs and post-transcriptional alterations in acute myeloid leukemia
No full textAcute myeloid leukemia (AML) represents the most common acute leukemia in adults, marked by the abnormal expansion of myeloid progenitor cells that fail to properly differentiate. These immature cells accumulate in the bone marrow thereby distrupting normal hematopoiesis. Although advances in AML research have led to improvements in patient outcomes, the overall prognosis remains poor, particularly for relapsed and refractory cases. A deeper understanding of the molecular biology of AML is therefore urgently needed.Therefore, in this thesis, we aim to clarify how long non-coding RNAs (lncRNAs) contribute to AML pathogenesis, considering their recognized involvement in various biological functions and their altered expression patterns across many cancers, including AML. Additionally, we examine post-transcriptional regulatory mechanisms, a layer of gene regulation that has received comparatively limited attention in AML research.In Study I, using transcriptomic analyses of 7 AML patients and 5 normal bone marrow CD34+ samples, we identified 136 de novo lncRNAs that were differentially expressed in AML blasts. Among these, we characterized a novel transcript, which we named myeloid and AML-associated intergenic lncRNA (MALNC). MALNC was overexpressed in AML, particularly in patients harboring PML-RARA fusion or NPM1/IDH2R140 co-mutations, and higher expression was associated with better prognosis, independent of other established risk factors. Furthermore, MALNC knockout reduced AML cell growth and colony formation. In parallel, MALNC- depleted cells showed increased all-trans retinoic acid (ATRA)-induced differentiation and increased sensitivity to arsenic trioxide (ATO). To further characterize MALNC, transcriptomic analyses were performed in MALNC knockout clones both at baseline and following ATRA treatment, revealing modulation of genes involved in retinoic acid signaling. In addition, chromatin- binding experiments showed that MALNC interacted with genes related to the retinoic acid and Rho GTPase pathways.In Study II we employed high-throughput CRISPR-interference (CRISPRi) screens to knock down 7,996 lncRNAs and investigate their roles in AML proliferation, differentiation, and response to venetoclax. The screens identified 58 lncRNAs involved in proliferation, 4 lncRNAs affecting differentiation, and 23 lncRNAs associated with venetoclax response. Among these, AC009299.3 emerged as a candidate linked to venetoclax resistance, with patient data further showing a correlation between its expression and poor prognosis under standard chemotherapy treatment. In the proliferation screen, MIR17HG, CATG00000106133.1, and CATG00000056792.1 were identified as candidate lncRNAs promoting leukemic cell growth. Notably, CATG00000106133.1 was enriched in de novo and cytogenetically normal AML, strongly associated with NPM1 and IDH2_R140 mutations, and exhibited high expression in specific hematopoietic lineages. Functional validation through complete knockout of CATG00000106133.1, followed by transcriptomic profiling, revealed differential expression of genes involved in cytokine signaling and immune response pathways, providing insights into its role in AML biology.In study III, we investigated genes involved in post-transcriptional mechanisms in AML. Using CRISPR knockout screens from the DepMap database, the exon junction complex helicase eIF4A3, a regulator of RNA polymerase I- and II- dependent processes previously linked to cancer progression, emerged as a top essential gene across 18 AML cell lines. Transcriptomic analyses revealed higher eIF4A3 expression in AML cell lines and patient samples compared to normal controls, with gene ontology analysis highlighting RNA metabolism and translation as key affected pathways. In addition, functional experiments showed that chemical inhibition or siRNA-mediated silencing of eIF4A3 induced AML cell death through impaired ribosome biogenesis and p53 activation, as well as through p53- independent mechanisms.In summary, across these three studies, we identified novel lncRNAs and post- transcriptional regulators that expand our understanding of AML biology and drug response, pointing to their possible use as biomarkers or therapeutic targets to improve patient care.List of scientific papersI. Elisabetta Cozzi*, Anne Neddermeyer*, Xiangfu Zhong, Angelica Gamboa Cedeno, Dimitris C. Kanellis, Albin Österroos, My Björklund, Nona Struyf, Kasper Karlsson, Ying Qu, Alma Månsson, Tatjana Pandzic, Sofia Bengtzen, Christer Nilsson, Roland Fiskesund, Panagiotis Baliakas, Tom Erkers, Jiri Bartek, Olli-Pekka Kallioniemi, Hong Qian, Andreas Lennartsson, Sören Lehmann. MALNC: a new muntant NPM1/IDH2R140 and PML-RARA-associated lncRNA with impact on AML cell proliferation, maturation and drug response. Cancer Gene Therapy. (2025). https://doi.org/10.1038/s41417-025-00954-0II. Elisabetta Cozzi, Anne Neddermeyer, Sophia Miliara, Xiangfu Zhong, Tyler Weirick, Chung Chao Hon, Andreas Lennartsson, Sören Lehmann. Identification of long non-coding RNAs involved in leukemogenesis and venetoclax response in acute myeloid leukemia through functional CRISPR-dCas9 interference screens. [Manuscript]III. Sophia Miliara, Elisabetta Cozzi, Xiangfu Zhong, Isaac Chan, Karl Ekwall, Sören Lehmann, Andreas Lennartsson, Jiri Bartek, Dimitris C. Kanellis. The exon-junction complex helicase eIF4A3 holds therapeutic potential in acute myeloid leukemia. Leukemia. 2024 Mar;38(3):663-666. https://doi.org/10.1038/s41375-023-02098-2*Equal contribution</p