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Tartrate-resistant acid phosphatase/ACP5 in bone development and maintenance : age- and sex-specific skeletal phenotypes in mice
No full textThe skeletal system is a dynamic organ network, integrating mechanical, hormonal, and molecular cues to continuously balance bone formation and resorption. Central to this homeostatic process is the interplay between osteoblasts, osteoclasts, and osteocytes, which orchestrate modelling and remodelling in response to developmental, metabolic, and mechanical stimuli. Among the osteoclast-derived factors contributing to skeletal regulation, tartrate-resistant acid phosphatase (TRAP/ACP5) has long been used as a histochemical marker of bone resorption. However, its broader physiological roles remain underexplored. Previous studies have identified TRAP as a marker of osteoclast activity and implicated it in bone resorption and immune-skeletal interactions. Building on this foundation, this doctoral thesis characterizes the multifaceted role of TRAP in bone biology using a murine knockout model, contributing significantly to the growing knowledge of its critical involvement in skeletal growth, structural maintenance, and mechanoadaptation across age, sex, and anatomical site.Through cross-sectional analyses combining high-resolution micro-computed tomography (uCT), histomorphometry, in vivo mechanical loading, and in vitro functional assays, we show that TRAP deficiency (TRAP-/-) leads to a spectrum of skeletal abnormalities. In young adult mice, TRAP deletion resulted in significantly shorter tibiae and altered cortical and trabecular architecture. These defects were sex- and site-specific: male TRAP-/- mice exhibited increased trabecular bone mass, thicker cortices, and wider metaphyseal zones, whereas female TRAP-/- mice showed pronounced disruption in growth plate organization but relatively modest changes in bone mass. Importantly, the growth plate of TRAP-/- mice demonstrated increased hypertrophic zone height and reduced chondrocyte column alignment, indicating impaired endochondral ossification.The role of TRAP in facilitating load-induced bone formation was assessed using strain-matched in vivo axial tibial loading in 16-week-old male mice. Wild-type animals displayed robust anabolic responses including periosteal expansion, cortical thickening, increased trabecular volume, and enhanced growth plate bridging. These load-responsive adaptations were absent in TRAP-/- mice, suggesting a critical requirement for TRAP in converting mechanical signals into bone-forming stimuli. Mechanical pre-loading confirmed that TRAP-/- tibiae were stiffer and required greater compressive force to reach target strain, yet the downstream skeletal response remained blunted. Serum bone turnover markers such as alkaline phosphatase (ALP) and procollagen type 1 N-terminal propeptide (PINP) were unchanged, suggesting that TRAP's mechanoadaptive role is not due to global osteoblast dysfunction but may involve osteocyte signalling, matrix interactions, or osteoclast-osteoblast coupling.Extending these findings to aged mice, 18-month-old male and female TRAP-/- mice displayed persistent reductions in bone length, a legacy of developmental impairment. Nonetheless, sex-specific cortical and trabecular phenotypes were evident: aged males exhibited higher cortical and trabecular bone, while females showed higher cortical density and narrowed marrow cavities compared to wildtype mice. The adaptive skeletal response to mechanical loading was abolished in both sexes. uCT analyses revealed no significant loading-induced gain in any bone compartment in aged TRAP-/- mice of both sexes, establishing TRAP's indispensable role in skeletal mechanosensitivity throughout life.Complementary in vitro assays further demonstrated that TRAP-deficient osteoclast progenitors exhibited reduced osteoclastogenesis in response to mechanical stimulation and aberrant ATP signalling particularly in males. These results suggest that TRAP may mediate key mechanosensitive processes through purinergic signalling pathways or redox modulation of the extracellular matrix. Notably, reduced growth plate bridging in loaded young TRAP-/- mice implicates TRAP in cartilage-to-bone transition and epiphyseal integration under mechanical challenge. In contrast, no loading-induced changes in bony bridging were observed in aged mice, suggesting an age-dependent mechanoadaptive role of TRAP.Taken together, these data expand our understanding of TRAP as a multifaceted regulator of bone biology, highlighting previously underappreciated roles in skeletal growth, remodelling, and mechanoadaptation. Beyond its canonical role in mineralized matrix degradation, TRAP is required for orchestrating structural adaptation to mechanical load, maintaining growth plate integrity, and coordinating site- and sex-specific skeletal responses during growth and aging. This work suggests TRAPs role as a mechanotransductive enzyme that links osteoclast function with broader skeletal plasticity, revealing new dimensions in the regulation of bone remodelling. The findings presented in this thesis argue for the reconsideration of TRAP's role in bone beyond resorption, with implications for therapeutic targeting in disorders such as osteoporosis, osteopetrosis, and age-related bone fragility, where mechanical responsiveness and bone turnover are impaired.List of scientific papers1) Bhavik Rathod , Suchita Desai , Hasmik Jasmine Samvelyan , Laura Bock , Jianyao Wu , Claes Ohlsson, Anders Palmquist , Jessica J. Alm , Phillip T. Newton , Goran Andersson, Sara H. Windahl. Tartrate-resistant acid phosphatase (TRAP/ACP5) promotes bone length, regulates cortical and trabecular bone mass, and maintains growth plate architecture and width in a sex- and site-specific manner in mice. Bone. 2024;188:117223. https://doi.org/10.1016/j.bone.2024.1172232) Bhavik Rathod, Hasmik Jasmine Samvelyan, Suchita Desai, Laura Bock, Nicole Gustafsson, Jianyao Wu, Claes Ohlsson, Per Magnusson, Göran Andersson, Sara H Windahl. Tartrate-resistant acid phosphatase (TRAP/ACP5) augments the bone anabolic response to mechanical loading in male mice. JBMR Plus. 2025;9(7):ziaf073. Published 2025 Apr 23. https://doi.org/10.1093/jbmrpl/ziaf0733) Bhavik Rathod, Jasmine Samvelyan, Nicole Gustafsson, Aneta Liszka, Narelle McGregor, Jianyao Wu, Claes Ohlsson, Anna Fahlgren, Natalie Sims, Jonas Fuxe, Goran Andersson, Jessica J Alm*, Sara H Windahl *. Tartrate acid phosphatase (TRAP/ACP5) sex-specifically regulates trabecular bone maintenance, and the bone anabolic effects of mechanical loading in old mice. [Manuscript]</p
Extrapolating survival with applications to health technology assessment
No full textSurvival extrapolation is fundamental to health economic modelling, addressing the task of projecting long-term outcomes from short-term survival data. Clinical studies often have limited follow-up periods, yet accurate projections of survival curves are essential in order to estimate restricted mean survival time, life expectancy, and quality-adjusted life years for health technology assessment (HTA). These projections allow decision-makers to compare the costs and effectiveness of new and existing interventions, helping them decide whether to adopt new healthcare technologies.To evaluate the accuracy of survival extrapolation methods, we systematically compared standard parametric models (SPMs) and flexible parametric models (FPMs) in Study I. Using data from the Swedish Cancer Register, this study compared the all-cause survival framework (ASF) with the relative survival framework (RSF) to predict survival at 10-year and lifetime horizons. Results showed that FPMs generally outperformed SPMs in predicting 10-year survival. When extrapolating to a lifetime horizon, RSF models provided more accurate predictions than ASF models, especially when using FPMs. Notably, ASF models tended to overestimate survival from limited follow-up data, whereas RSF models showed a trend toward underestimation.In Study II, we developed a novel multistate framework integrating relative survival ex- trapolation with mixed time scales for cost-effectiveness analysis. We demonstrated this approach using an irreversible illness-death model applied to clinical trial data, extending and comparing it with previous cost-effectiveness analyses. This framework enables the in- corporation of external long-term mortality data into survival extrapolation from short-term follow-up data within a multistate model.The multistate framework was applied to model the natural history of chronic myeloid leukaemia (CML) treatment in Study III. We estimated life expectancy and quality-adjusted life expectancy for patients with chronic-phase CML (CP-CML) diagnosed in Sweden between 2007 and 2017, comparing these with the general population. Results showed proportional losses in life expectancy of 9-15% and in quality-adjusted life expectancy of 29-33% across age-sex strata, indicating modestly low losses in life expectancy but greater losses in quality- adjusted life expectancy among patients with CP-CML.The natural history model from Study III was extended to a cost-of-illness study through estimation and projection of the economic burden for CML in Sweden from 2015 to 2030 in Study IV. Results showed that prevalent cases are estimated to nearly double from 1205 (95% CI: 1014-1397) in 2015 to 2120 (95% CI: 1916-2325) by 2030, total direct healthcare expenditures declined from USD 40.04 million (95% CI: 33.70-46.40) to USD 30.67 million (95% CI: 27.70-33.64). This trend indicates that decreasing treatment costs may mitigate the economic burden on the Swedish healthcare system.In conclusion, in this thesis I have worked collaboratively to systematically evaluate and advance survival extrapolation methods for HTA. A key methodological innovation is the integration of relative survival extrapolation with multistate modelling, combining short-term survival data with long-term external information. Together with collaborators, I applied these methods in two CML studies to demonstrate how such advanced statistical modelling can provide practical insights to support clinical understanding and inform health policy.List of scientific papersThis thesis is based on the following scientific articles, which are referred to by Roman numerals throughout and presented in full at the end.I. Enoch Yi-Tung Chen, Yuliya Leontyeva, Chia-Ni Lin, Jung-Der Wang, Mark S. Clements, and Paul W. Dickman. Comparing Survival Extrapolation within All-Cause and Relative Survival Frameworks by Standard Parametric Models and Flexible Parametric Spline Models Using the Swedish Cancer Registry. Medical Decision Making. 2024;44(3):269-282.https://doi.org/10.1177/0272989x241227230II. Enoch Yi-Tung Chen, Paul W. Dickman, and Mark S. Clements. A Multistate Model Incorporating Relative Survival Extrapolation and Mixed Time Scales for Health Technology Assessment. PharmacoEconomics. 2025;43:297-310.https://doi.org/10.1007/s40273-024-01457-wIII. Enoch Yi-Tung Chen, Torsten Dahlén, Leif Stenke, Magnus Björkholm, Shuang Hao, Paul W. Dickman, and Mark S. Clements. Loss in Overall and Quality-Adjusted Life Expectancy for Patients with Chronic-Phase Chronic Myeloid Leukemia. European Journal of Haematology. 2025;114(2):334-342.https://doi.org/10.1111/ejh.14328IV. Enoch Yi-Tung Chen, Paul W. Dickman, Fabrizio Di Mari, Torsten Dahlén, Leif Stenke, Magnus Björkholm, Mark S. Clements, and Shuang Hao. Empirical and Projected Economic Burden of Chronic Myeloid Leukaemia in Sweden from 2015 to 2030: a Population-Based Study. [Submitted]</p
Antiviral T cell immunity in relation to age and infection history
No full textChildren and elders have an increased risk of severe disease to many infections that pose little risk in healthy young adults. In children this is attributed to their lack of immunological memory, and in elders it is believed to be a combination of increased frailty and declining immune function. Besides age, the memory (m) T cell repertoire is further shaped by the pathogens encountered throughout life. Yet, the quality of antigen-specific T cell responses against the most common viral infections are rarely studied in relation to age and previous infections. Thus, the overarching aim of this thesis was to explore the interaction of age and infection history on the phenotype and function of antigen-specific mT cells against common acute and chronic viruses using high-parameter flow cytometry and single-cell RNA sequencing.During the 2019 pandemic, the low incidence of severe COVID-19 in children was hypothesized to be due to cross-reactivity between endemic human coronaviruses (HCoV) and SARS-CoV-2. Our findings in Paper I supported this hypothesis, showing that cross-reactivity exist between HCoV-OC43 and SARS- CoV-2, and that both the prevalence and function of cross-reactive mCD4+ T cells against SARS-CoV-2 peak in childhood and decline with age.Infection by human immunodeficiency virus (HIV) requires life-long treatment, and still promotes immune-altering mechanisms on the immune system. In Paper II, we investigated the function of antiviral T cell immunity to common viruses in children living with HIV (CLWH). Compared to HIV-negative children, CLWH displayed a more adult-like mT cell compartment, such as elevated cell senescence. Particularly mT cells targeting the chronic viruses Epstein Barr virus (EBV) and Cytomegalovirus (CMV) were affected, with CMV-specific mCD8+ T cells displaying extensive clonal expansion in CLWH.Because young adults rarely develop severe disease from endemic respiratory viruses, including SARS-CoV-2, Paper III aimed to deepen our understanding of the qualities associated with an effective antiviral T cell response in this group. We found that antigen-specific mCD4+ T cells against the included viruses were prevalent and highly specialized by antigen-specificity, and that SARS-CoV-2- specific mCD4+ T cells mature alongside IgG seroconversion.That the function of the immune system declines with advancing age is well known, but in paper IV, we asked whether this decline would be further exacerbated at the end of life. By comparing mT cell and antigen-specific mT cell responses in elderly end-of-life patients in palliative care to healthy elders, we found that cell-mediated immunity remained functional until the end, contrasting our initial hypothesis. Notably, the frequency of cytotoxic mCD4+ T cells increased the last 30 days of life.In conclusion, the constituent work in this thesis underscores the adaptability and resilience within cell-mediated immunity that carries us through life. These findings may aid in the evaluation of new vaccines, antivirals and other clinical interventions with implications for cell-mediated immunity.List of scientific papersI. Humbert M*, Olofsson A*, Wullimann D, Niessl J, Hodcroft EB, Cai C, Gao Y, Sohlberg E, Dyrdak R, Mikaeloff F, Neogi U, Albert J, Malmberg KJ, Lund-Johansen F, Aleman S, Björkhem-Bergman L, Jenmalm MC, Ljunggren HG, Buggert M, Karlsson AC. Functional SARS-CoV-2 cross-reactive CD4+ T cells established in early childhood decline with age. Proc Natl Acad Sci U S A, March 2023;120(12), e2220320120 https://doi.org/10.1073/pnas.2220320120II. Olofsson A, Humbert M, Cai C, Scharf L, Tauriainen J, Soeria Atmadja S, Hagey D, Thalme A, Buggert, M, Navér L, Karlsson AC. Altered antiviral T cell immunity against common viruses in pediatric HIV [Manuscript]III. Olofsson A*, Lee JQ*, Björkander S, Buggert M, Melen E, Karlsson AC Distinct antiviral T cell immunity patterns against common viruses and its correlation with SARS-CoV-2 seroconversion [Manuscript]IV. Olofsson A, Humbert M, Rekha RS, Frankling MH, Lund-Johansen F, Bergman P, Björkhem-Bergman L, Karlsson AC Adaptive immune responses against common viruses are sustained and functional in end-of-life patients iScience, March 2025;28(3):112082 https://doi.org/10.1016/j.isci.2025.112082*These authors contributed equally to this work</p
Investigation of epigenome changes in quiescent fission yeast cells
No full textCellular quiescence is a reversible, non-proliferative state in which cells temporarily exit the cell cycle while maintaining the capacity to re-enter it upon receiving appropriate stimuli. This state enables cells to survive under unfavorable environmental conditions and protects them from stress-induced damage.In unicellular organisms such as bacteria and yeast, quiescence serves as a vital survival strategy in response to nutrient depletion, extreme temperatures, or pH fluctuations. Similarly, in multicellular organisms, quiescence is a hallmark of adult stem cells and other stress-responsive cell types, contributing to long-term tissue homeostasis and regeneration. Given its critical role in cellular stress resistance and regenerative capacity, elucidating the molecular mechanisms that govern quiescence has significant implications for regenerative medicine, particularly in enhancing stem cell activation and tissue repair strategies.In this study, the fission yeast Schizosaccharomyces pombe was employed as a model system to dissect the molecular basis of cellular quiescence. We integrated multiple high-throughput and functional genomics approaches- including fluorescence-activated cell sorting (FACS), fluorescence microscopy, RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP- seq), and chromosome conformation capture (Hi-C)-to investigate quiescence entry potential, chromosome condensation, genome-wide transcriptional changes, histone modification dynamics, and three-dimensional genome architecture.Our overarching goal was to gain mechanistic insight into how transcriptional programs and epigenomic landscapes are dynamically restructured during the transition into, and maintenance of, both early and long-term quiescence.In Study I, we identified 149 genes that were significantly upregulated during early quiescence, in contrast to a global downregulation of transcriptional activity across the genome. Among these, 16 genes sustained high expression levels from early to late quiescence and were predominantly located in subtelomeric regions. Genetic analyses using mutants of INO80 complex subunits and the H2A.Z-encoding gene revealed that INO80 plays a critical role in evicting H2A.Z prior to transcriptional elongation, thereby facilitating proper activation of quiescence-specific genes.In Study II, ChIP-seq profiling demonstrated that the active histone mark H3K4me3 is strongly associated with quiescence gene activation. H3K4me3 was found to regulate RNAPII pausing at promoter-proximal regions, and its deposition was dependent on set1, the catalytic component of the COMPASS complex. These results underscore the importance of H3K4me3 as a central epigenetic mark in the regulation of quiescence transcriptional programs.In Study III, live-cell fluorescence microscopy and flow cytometry (FACS) revealed that after 16 hours of nitrogen starvation, cells entering quiescence exhibited a halt in further chromosomal condensation. Complementary Hi-C analysis uncovered the emergence of highly interactive topologically associating domains (TADs) in subtelomeric regions, along with telomere hyper-clustering-a structural feature reminiscent of quiescent genome organization observed in other eukaryotic systems.Collectively, these three studies establish a core set of quiescence-specific genes and define an integrated epigenetic and 3D structural framework that orchestrates the establishment and maintenance of cellular quiescence in Schizosaccharomyces pombe.List of scientific papersI. Yasaman Zahedi, Shengyuan Zeng, Karl Ekwall. An essential role for the Ino80 chromatin remodeling complex in regulation of gene expression during cellular quiescence. Chromosome Res. 2023 Apr 12;31(2):14. https://doi.org/10.1007/s10577-023-09723-xII. Shengyuan Zeng, Karl Ekwall. Epigenome Mapping in Quiescent Cells Reveals a Key Role for H3K4me3 in Regulation of RNA Polymerase II Activity. Epigenomes. 2024 Oct 22;8(4):39. https://doi.org/10.3390/epigenomes8040039III. Shengyuan Zeng, Mickael Durand-Dubief, Job Dekker, Jean-Paul Javerzat, Karl Ekwall. Extensive chromosome reorganization in quiescent fission yeast cells. [Manuscript]</p
Treatment outcomes of regenerative endodontics and apexification of traumatized immature necrotic permanent incisors
No full textIntroduction: Presently, calcium hydroxide (CH) apexification and mineral trioxide aggregate (MTA) apexification are the available treatments for traumatized immature necrotic teeth. Although these treatments have been available for many years, few studies have assessed these techniques for long- term survival of teeth. Recently, a new treatment modality has emerged - regenerative endodontic treatment (RET). However, RET's clinical, radiographic, and disinfection protocols need to be evaluated.Aims: This thesis investigates the clinical, radiographical, and microbiological outcomes of regenerative endodontic treatment. In addition, this thesis investigates the long-term survival of traumatized immature necrotic teeth after the use of apexification and identifies the risk factors for premature tooth loss.Materials and methods: This thesis includes a systematic literature review (Study I), an observational prospective cohort design (Study II), a randomized clinical trial (Study III), and a retrospective longitudinal observational cohort design (Study IV).In Study I, five scientific databases were screened (PubMed, Web of Science, Cochrane Library, Ovid/Medline, and Embase) for intervention studies on RET and/or apexification of traumatized immature necrotic teeth. Only peer- reviewed studies with a study size of at least 20 cases with a follow-up of 24 months were included. Eligibility assessment was blinded and performed independently. Subgroup analyses were performed on three outcomes: survival, success, and continued root development.In Study II, RET was performed on 75 traumatized necrotic immature incisors. The radiographic outcome measures were continued root formation (width and length), root resorption, apex closure, periapical index, and root development stage. The clinical outcome measures were percussion pain, palpation pain, pathological tooth mobility, swelling, sinus tract, ankylosis, crown discolouration, and subjective pain. Treatment outcomes were categorized as a success or failure based on the clinical and radiographic outcome measures.In Study III, microbiological assessment was based on root canal samples from 41 traumatized immature necrotic teeth treated with RET where two different root canal dressing were used in a randomized order (CH and CHD). Analysis of the average bacterial load (CFU/sample) and bacterial diversity (taxa/sample) was performed at three timepoints - before root canal dressing (S2); after debridement (S); and after root canal dressing (S5).In Study IV, records of 2400 children and adolescents were screened for presence of TDI to immature incisors where endodontic treatment with the two apexification techniques was performed between January 2003 and December 2022. These incisors were compared to a control group of mature teeth treated with conventional endodontic techniques. The following variables were studied: age, sex, apexification technique, presence of luxation and hard tissue injuries, preoperative root development stage (RDS), preoperative and postoperative periapical index (PAI), when tooth loss occurred, and overall survival time in years.Results: Seven studies with heterogenous designs were included in the final synthesis. The included articles in Study I revealed that both regenerative and apexification techniques had equal rates of success and survival and proved to be effective in the treatment of immature necrotic permanent teeth. Regenerative endodontic techniques appeared to be superior to apexification techniques in terms of stimulation of root maturation - i.e., root wall thickening and root lengthening.Study II revealed that RET was successful in 60% of the cases. When successful, RET presented meaningful outcomes, with a resolution of periapical infection, increased root length and width, and apex closure. Two predictive variables for continued root maturation were identified - preoperative root development stage and preoperative dentine wall thickness. The failed cases were related to lack of bleeding and persistent infections.Study III revealed that the primary microflora were more diverse in successful cases than in failed cases. Decreases in bacterial loads and diversity/sample occurred between S2 and S3, although new increases were seen at S5 in the CHD subgroup (successful and failed) and load/sample in the CH subgroup (failed). At S5, the successful cases showed more bacterial decreases. No specific species were associated with the outcomes with no statistical differences between the disinfection efficacies.Study IV showed that the median survival time was up to 10 years for CH apexification, 16.1 years for MTA apexification, 15.5 years for luxation injuries other than intrusions and avulsions, 12.5 years for intrusions, and 6.8 years for avulsions. The variables with significant negative impact on tooth survival were CH apexification, avulsion, and postoperative PAI of 3-5. No significant relationships were found for the variables MTA apexification, concussion, subluxation, lateral luxation, extrusion, intrusion, hard tissue injuries, preoperative RDS, preoperative PAI scores and postoperative PAI scores of 1-2. After adjustment, the risk for premature tooth loss was 13.5 times higher in CH apexification, approximately 2 to 4 times higher in PAI 3-5, and 5.6 times higher in avulsions.Conclusion: According to the published literature, both RET and apexification techniques have equal rates of success, survival, and effectiveness in the treatment of immature necrotic permanent teeth, although only RET stimulates root maturation. Knowledge gaps were identified regarding the treatment and follow-up protocols for both techniques. When successful, RET provides satisfactory clinical and radiographical outcomes. The failed cases were related to lack of bleeding and persistent infections, indicating that new techniques are needed to improve the predictability of RET. For microbiological outcomes, there were no statistical differences in CH and CHD efficacy. After root canal dressing (S5), microflora persisted in both successful and failed outcomes, but the abundance and diversity increased significantly only in the failed cases. Compared to the failed outcomes, the successful outcomes presented higher diversity and higher decreases of the primary microflora at S5. Only the failed cases had significant increases in abundance and diversity at S5. The analysis of the long-term outcomes identified CH apexification, avulsion, and postoperative PAI of 3-5 as prognostic variables with significant negative impact on the risk for premature tooth loss.List of scientific papersI. What is the best long-term treatment modality for immature permanent teeth with pulp necrosis and apical periodontitis? Wikström A, Brundin M, Lopes MF, El Sayed M, Tsilingaridis G. Eur Arch Paediatr Dent. 2021;22(3):311-340 https://doi.org/10.1007/s40368-020-00575-1II. Endodontic pulp revitalization in traumatized necrotic immature permanent incisors: Early failures and long-term outcomes - A longitudinal cohort study. Wikström A, Brundin M, Romani Vestman N, Rakhimova O, Tsilingaridis G. Int Endod J. 2022;55(6):630-645 https://doi.org/10.1111/iej.13735III. Microbiological assessment of success and failure in pulp revitalization: A randomized clinical trial using calcium hydroxide and chlorhexidine gluconate in traumatized immature teeth. Wikström A, Romani Vestman N, Rakhimova O, Gimeno DL, Tsilingaridis G, Brundin M. J Oral Microbiol. 2024 Apr 24;16(1):2343518 https://doi.org/10.1080/20002297.2024.2343518IV. Outcomes of apexification in immature traumatized necrotic teeth and risk factors for premature tooth loss: A 20-year longitudinal study. Wikström A, Brundin M, Mohmud A, Andersson M, Tsilingaridis G. Dent Traumatol. 2024 Dec;40(6):658-671 https://doi.org/10.1111/edt.12973</p
Teamwork makes the dream work : systemic and mucosal immunity in shaping protection against SARS-CoV-2
No full textCOVID-19 triggered an unprecedented scientific response, and although knowledge gaps persist, large parts of the world had access to efficacious vaccines only a year after the virus first appeared. A detailed understanding of mechanisms of protection against infection, and not only against severe disease, is essential for comprehending the transition from the uncontrolled viral transmission to a low-grade, endemic circulation of this and future emerging viruses. The studies in this thesis focus on the role of serum and mucosal antibody responses in shaping protection against SARS-CoV-2 infection.Study I is a four-week screening study of 368 triple vaccinated health care workers, with a cumulative SARS-CoV-2 infection incidence of 22%. In this study, we assessed protection against Omicron infection in relation to ancestral spike- specific IgG levels in serum and explored their potential role in reducing viral load. We found that high levels of vaccine-induced spike-specific serum antibodies were associated with both protection against infection and lower viral load in those who became infected. Additionally, we suggested that the added protection against Omicron infection observed in individuals with hybrid immunity is largely mediated by mucosal spike-specific IgA.In Study II, we assessed protection against SARS-CoV-2 Omicron infection in relation to ancestral spike-specific IgA levels in nasal secretions, as well as the impact of prior infection on mucosal immune responses, in 337 healthcare workers who also participated in Study I. We observed a 65% reduction in the risk of infection among individuals with nasal spike IgA levels above the 75th percentile at study inclusion compared to the rest. Additionally, we identified a temporal relationship between rising nasal IgA levels and declining viral load during infection. A trend toward more rapid nasal spike IgA responses in reinfected individuals was also noted.In Study III, we investigated the duration of mucosal immune responses elicited during infections in Studies I and II, and the protection associated with those responses. We found that the significantly reduced risk of infection among participants with nasal spike IgA levels above the 75th percentile at baseline (Study I and II inclusion) persisted for eight months, with a Hazard Ratio of 0.55 (pIn Study IV, we assessed protection against the newly emerged Omicron BQ strains in relation to nasal spike IgA and found robust protection, incidence rate ratio of 0.42 [95% CI 0.26-0.70] for individuals with detectable nasal spike IgA, with a linear association between nasal spike IgA levels and protection against infection. We also found that nasal spike IgA demonstrated a stronger ability to bind viral variants compared to serum spike IgG. Interestingly, the protection against infection associated with serum spike IgG in this study was no longer significant when adjusted for nasal spike IgA levels.Study V was a retrospective cohort study investigating factors influencing nasal spike IgA levels. Prior mucosal viral encounter, i.e. infection, was paramount to nasal spike IgA development. We observed an increased likelihood of nasal spike IgA detection for as long as >22 months following the most recent infection and identified a boosting effect by repeated infections. We also found that parenteral vaccination was associated with lower nasal spike IgA levels, with an adjusted OR for detectable nasal spike IgA of 0.24 [95% CI 0.08-0.68] among individuals with 1-3 vaccine doses compared to those who were unvaccinated. Additionally, the temporal infection-vaccination sequence influenced nasal spike IgA levels, with higher levels in participants infected prior to vaccination as compared to those with break-through infection as first viral encounter. This finding is of importance to mucosal vaccine development, particularly to replicating vaccine platforms where systemic immunity may reduce viral replication and the resulting inflammation that shapes the subsequent mucosal immune response.The observations in this thesis illustrate the transition from early pandemic control-where serum-derived protection from vaccination was paramount-to the current phase of endemic transmission, where mucosal immune responses play a central role in population immunity. We argue that with evolution of immune evasive strains and concurrent development of mucosal defences, mucosal spike IgA replaces serum spike IgG as the most relevant correlate to protection against infection. Although parenteral vaccination and systemic responses are crucial in protection against severe COVID-19, a vaccine platform that evokes a robust mucosal response may be more potent in inducing population immunity, with a reduction of viral transmission and variant evolution.List of scientific papersI. Marking U, Havervall S, Greilert-Norin N, Bladh O, Christ W, Gordon M, Ng H, Blom K, Phillipson M, Mangsbo S, Alm JJ, Smed-Sörensen A, Nilsson P, Hober S, Åberg M, Klingström J, Thålin C. Correlates of protection and viral load trajectories in Omicron breakthrough infections in triple vaccinated healthcare workers. Nat Commun. 2023 Mar 22;14(1):1577. PMID: 36949041. https://doi.org/10.1038/s41467-023-36984-1II. Havervall S*, Marking U*, Svensson J, Greilert-Norin N, Bacchus P, Nilsson P, Hober S, Gordon M, Blom K, Klingstrom J, Åberg M, Smed- Sörensen A, Thålin C. Anti-Spike Mucosal IgA Protection against SARS- CoV-2 Omicron Infection. N Engl J Med. 2022 Oct 6;387(14):1333-1336. Epub 2022 Sep 14. PMID: 36103621. https://doi.org/10.1056/NEJMc2209651III. Marking U, Bladh O, Havervall S, Svensson J, Greilert-Norin N, Aguilera K, Kihlgren M, Salomonsson AC, Månsson M, Gallini R, Kriegholm C, Bacchus P, Hober S, Gordon M, Blom K, Smed-Sörensen A, Åberg M, Klingström J, Thålin C. 7-month duration of SARS-CoV-2 mucosal immunoglobulin-A responses and protection. Lancet Infect Dis. 2023 Feb;23(2):150-152. Epub 2023 Jan 11. PMID: 36640796. https://doi.org/10.1016/S1473-3099(22)00834-9IV. Marking U, Bladh O, Havervall S, Greilert-Norin N, Gordon M, Alm JJ, Blom K, Åberg M, Klingström J, Thålin C. Mucosal IgA protects against BQ.1 and BQ.1.1 infection. Lancet Infect Dis. 2023 Aug;23(8):e272-e273. Epub 2023 Jul 12. PMID: 37453441. https://doi.org/10.1016/S1473-3099(23)00421-8V. Marking U, Bladh O, Aguilera K, Pongracz T, Havervall S, Greilert-Norin N, Blom K, Klingström J, Wang Y, Åberg M, Thålin C. Systemic SARS-CoV-2 vaccination shapes subsequent generation of mucosal IgA responses - a retrospective cohort study. [Manuscript]* Shared first authorship</p
Contemporary and future prostate cancer detection
No full textThe landscape of prostate cancer diagnostics and management continues to evolve, driven by efforts to balance early detection, minimize overdiagnosis, and enhance clinical outcomes. This thesis aims to examine critical aspects of this field, encompassing the relationship between lower urinary tract symptoms (LUTS) and prostate cancer, the validation of risk calculators, the integration of magnetic resonance imaging (MRI) in diagnostic pathways, and the implications of biopsy strategies.The association between LUTS and prostate cancer was assessed in Study I, which is a population-based study involving men aged 50-69 years. Using data from the STHLM3 screening cohort, we compared International Prostate Symptom Score (IPSS) and biopsy outcomes and thereby the risk of prostate cancer. Among 45,595 men, 75% reported no or mild LUTS, and only 3% experienced severe symptoms. Also, men with high-risk prostate cancer (ISUP grade group ≥3 or cT ≥3) did not have higher IPSS values than those with benign biopsies. In multivariate logistic regression analysis, adjusting for age, PSA, prostate volume and clinical T-stage, there was no significant association between LUTS and prostate cancer risk. These findings challenge the assumption that prostate cancer commonly presents with worsening urinary symptoms, suggesting that reliance on LUTS for cancer suspicion may lead to unnecessary testing and overdiagnosis. Clinicians should instead focus on validated biomarkers and imaging tools for early detection.The accurate prediction of prostate cancer risk is essential to optimize diagnostic and therapeutic decision-making. In Study II, we evaluated the Rotterdam Prostate Cancer Risk Calculator (RPCRC) and the Prostate Biopsy Collaborative Group Risk Calculator (PBCG-RC). We again used available data from the STHLM3 trial, identifying 5,841 men with PSA 23 ng/ml who underwent systematic biopsies. We assessed the performance of both RCs in predicting clinically significant prostate cancer (ISUP grade group ≥2) by calculating the risk for all men and comparing to biopsy outcome.Both risk calculators exhibited good discriminatory ability, with area under the curve (AUC) values of 0.74 for the RPCRC and 0.70 for the PBCG-RC. The PBCG- RC demonstrated adequate calibration and clinical utility in its current form, offering a net benefit in decision curve analyses. In contrast, the RPCRC underestimated the risk of csPCa and showed no clinical benefit before recalibration. Recalibration of the RPCRC improved its performance, narrowing the differences between the two calculators. This study underscores the necessity of external validation and recalibration of risk prediction tools to ensure their reliability and applicability in various clinical settings.The adoption of MRI before prostate biopsy has reshaped the field of prostate cancer diagnostics. MRI facilitates the detection of significant cancer by enabling targeted biopsies of suspicious lesions. In Study III we explored the implications of omitting systematic biopsies completely. Using data from the STHLM3-MRI screening trial, we included 395 men with either elevated PSA (>3 ng/ml) or Stockholm3 test (>11%) who had had a positive MRI (PI-RADS ≥3) followed by combined targeted and systematic biopsies. In total, 13% had ISUP grade group 1, and 58% had ISUP grade group ≥2 cancer. Omitting systematic biopsies decreased detection rates for both ISUP grade group 1 (risk ratio (RR) 0.83) and ISUP grade group ≥2 (RR 0.85) tumors. For every case of ISUP grade group 1 averted, there were 3.8 of missed ISUP grade group ≥2 and 1.1 ISUP grade group >3 cancer. Furthermore, omitting systematic biopsies increased the rate of misclassification at radical prostatectomy, with a higher proportion of men being upgraded following targeted-only biopsies compared to those receiving combined biopsies (31% vs. 19%, p 0.05 ng/ml2 as a threshold for biopsy yielded similar reductions in ISUP grade group 1 detection while improving the detection rates for clinically significant cancers. These findings highlight the need for future research to further improve biopsy strategies that would maximize cancer detection while minimizing overdiagnosis and misclassification.In Study IV, we conducted a longitudinal, population-based study examining trends in prostate cancer diagnostics in the Stockholm region from 2010 to 2023. Using data from the Stockholm PSA and Biopsy Register, we included all men aged 40 years and older without a prior prostate cancer diagnosis. We analyzed how the use of PSA testing, MRI, and prostate biopsies evolved over time, particularly in the context of MRI being incorporated into the diagnostic pathway. We also examined changes in the distribution of ISUP grade groups on biopsy.PSA testing remained common and stable throughout the study period, with 59% of all men - and over 75% of men aged 60 and above - being tested at least once. Following an elevated PSA, MRI usage increased markedly from 3% to 30%, while biopsy rates declined from 23% to 16% (RR 0.66; 95% CI: 0.64- 0.69)). By 2023, 83% of men undergoing biopsy had had a pre-biopsy MRI. Additionally, we observed a reduction in the proportion of benign biopsies and ISUP grade group 1 cancers, alongside a substantial increase in detection of ISUP grade group >2 cancers. These findings offer real-world evidence of improved diagnostic precision following the integration of MRI into routine clinical practice.This thesis aims to give an overview in the rapidly evolving field of prostate cancer diagnostics. The four outlined studies discuss various aspects of patient selection, risk prediction and diagnostic strategies. In summary, they highlight the need for a more precise, evidence-based approach to improve clinical outcomes and reduce unnecessary interventions.List of scientific papersI. Chandra Engel J, Palsdottir T, Aly M, Egevad L, Grönberg H, Eklund M, Nordström T. Lower urinary tract symptoms (LUTS) are not associated with an increased risk of prostate cancer in men 50-69 years with PSA ≥3 ng/ml. Scand J Urol. 2020 Feb;54(1):1-6. https://doi.org/10.1080/21681805.2019.1703806II. Chandra Engel J, Palsdottir T, Ankerst D, Remmers S, Mortezavi A, Chellappa V, Egevad L, Grönberg H, Eklund M, Nordström T. External Validation of the Prostate Biopsy Collaborative Group Risk Calculator and the Rotterdam Prostate Cancer Risk Calculator in a Swedish Population-based Screening Cohort. Eur Urol Open Sci. 2022 May 19;41:1-7. https://doi.org/10.1016/j.euros.2022.04.010III. Chandra Engel J, Eklund M, Jäderling F, Palsdottir T, Falagario U, Discacciati A, Nordström T. Diagnostic Effects of Omitting Systematic Biopsies in Prostate Cancer Screening. Eur Urol Oncol. 2024 Oct 22:S2588-9311(24)00229-3. https://doi.org/10.1016/j.euo.2024.10.002IV. Chandra Engel J, Rai B, Eklund M, Jäderling F, Clements M, Nordström T. Trends and patterns in prostate cancer diagnostics during the era of MRI implementation - real world evidence from a population-based study in the Stockholm Region, Sweden 2010- 2023. [Manuscript]</p
Non-standard employment and health : exploring the pathways to health inequality
No full textIn today's increasingly fragmented labour market, there is a growing reliance on non-standard forms of employment (NSE), often characterized by instability, low income, and limited access to rights and protections. While the term NSE captures a contrast from the Standard Employment Relationship (typically associated with stable, full-time, permanent contracts), the concept of precarious employment (PE) more accurately reflects disadvantageous conditions experienced by workers. The expansion of PE has raised concerns about the implications for workers' health and well-being. While previous research has established links between PE and adverse health outcomes, less is known about the mechanisms and the contextual factors that shape and modify the effects. This thesis addresses these gaps through a mixed-methods approach, drawing on four studies that examine how PE impacts health and well-being across different settings and study populations. Given the overlapping but distinct use of terminology across the studies, a brief clarification is warranted. This thesis focuses on the health implications of disadvantageous employment conditions. While the term NSE is used when referring to specific study populations in studies Il and III-reflecting the terminology applied in those original publications-the thesis adopts PE as the primary analytical concept, as it more directly captures the conditions of insecurity and vulnerability at the core of the investigation.Study I used cross-sectional survey data to investigate the association between PE and psychosocial work environment hazards (experiences of violence, sexual harassment, bullying, discrimination, high demands, and low control). Respondents (n=401) were recruited through web-based respondent driven sampling in Stockholm County (2016-2017). A precarity score was calculated using the Swedish version of the Employment Precariousness Scale (EPRES-Se) and participants were categorized according to level of PE (low/high). Prevalence ratios were calculated to analyze the relationship with psychosocial hazards, adjusting for gender, age, education, and country of birth. Results showed that high PE (compared to low PE) was associated with bullying (PR 1.07, 95% CI: 1.01- 1.13), discrimination (PR 1.52, 95% CI: 1.00-2.32), low control (PR 1.59, 95% CI: 1.30- 1.96), and passive work (PR 1.60, 95% CI: 1.23-2.08). Psychosocial hazards were more prevalent among women.Study Il is a qualitative multi-case study exploring workers' experiences of NSE and implications for health and well-being across six countries with different welfare state regimes: Belgium, Canada, Chile, Spain, Sweden, and the United States. The study draws on 250 in-depth interviews (Jan-Sept 2021) from a purposive sample of NSE workers. Interviews were analyzed thematically in two phases, first within countries and then across. Findings revealed that workers across all contexts faced multiple insecurities (employment, income, schedule) and imbalanced power relations that negatively impacted health, particularly for those with intersecting social disadvantages. Welfare state support helped buffer the most severe insecurities, but similar patterns appeared in all study countries.Study III draws on the same interview material and explores how NSE workers experience labour regulations and social protection policies, their coping strategies, and ideas for supportive reforms. Despite differences in formal protections, participants across countries described similar challenges related to policy gaps and access barriers. Many relied on personal savings or family support and used risk-averse coping strategies (e.g., work intensification, avoiding conflict), which often reinforced vulnerability. Participants struggled to imagine improvements and expressed low expectations for change. Responses reflected a desire for basic security (e.g., stable income, housing), highlighting the limitations of employment-based protections and the need for more comprehensive and inclusive social protections that extend beyond standard employment models.Study IV is a longitudinal register-based cohort study investigating if the association between PE and mental health is moderated by household disposable income and family type. The study population (n=2,509,229) included all individuals between 27-65 years who were employed in 2016. PE was assessed based on the Swedish Register-based Operationalization of Precarious Employment (SWE-ROPE). Data on household variables (2016), and mental health (2017-2019) were extracted from national registers. The effect of PE on mental health was estimated using Cox regression models, and by adding two- way interaction terms to the main effects model. All analyses were stratified on sex. Findings showed that workers in PE (compared to SE) had a higher risk of mental ill-health (HR 1.21 CI95% 1.18-1.23), consistently across household income levels and family types. High household income was protective in general, but less so for the PE group due to synergistic interaction effects for both men (HR 1.22 CI95% 1.04-1.43) and women (HR 1.25 CI95% 1.13-1.38). Compared with the reference category (couple without children), all other family types (couple with children, single, single parent) amplified the negative effects of PE on mental health among women in PE, especially single mothers (HR 1.27 CI95% 1.14-1.42). Findings highlight that higher household income does not fully buffer the risk of mental ill-health for workers in PE, and the negative impact of PE appears stronger for women, especially single mothers.Together, the studies shed light on how PE impacts health and well-being through intersecting material, psychosocial, and contextual mechanisms. Findings show how PE generates economic and social vulnerability, which in turn triggers coping strategies that may further deplete resources and reinforce disadvantage. Across diverse national contexts and populations, the findings reveal a consistent pattern of adverse health-related experiences, disproportionately affecting women and workers with limited individual resources or family support. While policy context made a difference in terms of severity, the convergence of experiences across countries suggests that broader labour market transformations-characterized by a shift of risk from employers to individuals-have created shared structural conditions that transcend welfare regime type.The thesis contributes new knowledge by providing insight into the pathways through which PE affects health, and by highlighting the role of contextual factors and social inequalities in shaping these outcomes. By deepening our understanding of how labour market fragmentation contributes to unequal health risks, the findings support future research and policy efforts aimed at reducing health inequalities in a rapidly evolving world of work.List of scientific papersI. Kvart, S., Jonsson, J., Bodin, T., Håkansta, C., Kreshpaj, B., Orellana, C., et al. (2021). Precarious employment and psychosocial hazards: A cross-sectional study in Stockholm County. International Journal of Environmental Research and Public Health. 18, 11218. https://doi.org/10.3390/ijerph182111218II. Bosmans, K., Vignola, E.F., Álvarez-López, V., Julià, M., Ahonen, E.Q., Bolíbar, M., et al. (2023). Experiences of insecurity among non-standard workers across different welfare states: A qualitative cross-country study. Social Science & Medicine. 327, 115970. https://doi.org/10.1016/j.socscimed.2023.115970III. Kvart, S., Cuervo, I., Gunn, V., Lewchuk, W., Bosmans, K., Davis, L., et al. (2025). Labour and social protection gaps impacting the health and well-being of workers in non-standard employment: An international comparative study. PLOS ONE. 20, e0320248. https://doi.org/10.1371/journal.pone.0320248IV. Kvart, S, Mangot-Sala, L, Aronsson, A, Badarin, K, Bosmans, K, Gunn, V, et al. Precarious Employment Increases Mental Health Risks Regardless of Family Type and Household Income: A Swedish Register Study. [Manuscript]</p
Urine complement-related proteins in IgA nephropathy and IgA vasculitis nephritis, possible biomarkers of disease activity.
No full textINTRODUCTION: The activation of the complement system plays an important role in the pathogenesis of IgA nephropathy (IgAN). Our primary aim was to evaluate a range of complement-related proteins, including pentraxin-3 (PTX-3), in blood and urine at diagnosis and their association with disease activity in the kidney biopsy, eGFR, albuminuria, and outcome. Our secondary aim was to compare the same biomarkers between patients with IgAN and IgA vasculitis with renal involvement (IgAVN). METHODS: In a longitudinal Swedish cohort of 96 patients with IgAN (n = 65) or IgAVN (n = 31), with a median follow-up time of 10.8 years, we analysed mainly lectin-pathway-related proteins and PTX-3 in plasma and urine (u) samples stored at the time of kidney biopsy. Outcome was defined by the GFR slope or by the combined outcome of 50% loss of eGFR or end-stage kidney disease (ESKD). RESULTS: Patients with detectable vs undetectable u-PTX-3 and u-mannose-binding lectin (MBL) more frequently had mesangial hypercellularity, endocapillary proliferation, and crescents in their kidney biopsy. u-C4c levels were higher in patients with advanced tubulointerstitial fibrosis, and u-C4c was also an independent predictor of a more severe eGFR slope. There were no differences in the levels of biomarkers between patients with IgAN and IgAVN. CONCLUSION: u-PTX-3 and u-MBL might be biomarkers of an active proliferative stage of the disease, while higher u-C4c levels indicate more chronic lesions in both IgAN and IgAVN. These results must, however, be confirmed in larger and multiethnic cohorts.</p
Adolescents’ screen time displaces multiple sleep pathways and elevates depressive symptoms over twelve months
No full textRecently the Swedish Public Health Agency published recommendations of a maximum of two-to-three hours of daily leisure screen time for adolescents aged 13–18, partly to promote better sleep (2024-Sep-02). Biologically and socially, adolescence is characterized by belated sleep times, and depressive effects of screen time can arise through sleep displacements. Theorized links between screen time, sleep, and depression, merited examination of four sleep mediators to determine their relative importance and determine which of them mediate future depression. Hypotheses were preregistered. Three-wave psychometric health data were collected from healthy Swedish students (N = 4810; 51% Boys; ages 12–16; N = 55 schools; n = 20 of 26 Stockholm municipalities). Multiple imputation bias-corrected missing data. Gender-wise Structural Equation Modelling tested four sleep facets as competing mediators (quality, duration, chronotype, social jetlag). The primary model result included the three first mediators to achieve acceptable fit indices (RMSEA = 0.02; SRMR = 0.03; CFI = 0.95; TLI = 0.94). Screen time deteriorated sleep within three months and effect sizes varied between mediators (Beta weights ranged: 0.14–0.30) but less between genders. Among boys, screen time at baseline had a direct adverse effect on depression after twelve months (Beta = 0.02; p </p