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Anaemia and iron deficiency anaemia during pregnancy in Nigeria : risk factors, treatment options and impact on maternal and perinatal outcomes
No full textAnaemia in pregnancy is a public health burden especially in low-middle-income countries with prevalence above 40% in many parts of sub-Saharan Africa and South-East Asia. It is a major contributor to the high maternal mortality in the regions. Anaemia is associated with an increased risk of preterm births, intrauterine growth restriction, intrauterine foetal death, and a higher risk of having postpartum haemorrhage. In addition, it has recently been associated with a higher risk of antenatal and postpartum depression.Nigeria has one of the highest maternal and perinatal mortality rates in the world. Among the leading causes of maternal mortality are haemorrhage which consequence is anaemia, and anaemia from other causes including nutritional deficiencies. To reduce the mortality burden, anaemia prevention and care of the condition needs to be clearly understood. It is important to identify risk factors for the condition in Nigeria, know the current screening and treatment methods in Nigeria, identify an effective and safe alternative to oral iron which is commonly used during pregnancy for prophylaxis and treatment, and understand the effect of improving anaemia severity or iron levels during pregnancy on the risk of postpartum depression. This doctoral thesis provides answers to these gaps in knowledge and its findings will impact maternal healthcare worldwide.The doctoral research comprised four studies. The Study I, as well as Studies III and IV were conducted within a clinical trial on intravenous versus oral iron in Nigeria (IVON) TRIAL. Study I included 872 pregnant women with moderate or severe anaemia (haemoglobin concentration We found a prevalence of 41% for iron deficiency among pregnant women with moderate or severe anaemia. Diet rather than sociodemographic factors played dominant role in the occurrence of iron deficiency anaemia. The study indicated that consumption of green leafy vegetables has a protective effect on the occurrence of iron deficiency anaemia while consumption of edible kaolin clay daily and soybeans three to four times a week increased the odds of having iron deficiency anaemia during pregnancy. Screening of anaemic pregnant women for iron deficiency in Nigeria is suboptimal, and oral iron is mostly used for iron deficiency anaemia treatment during pregnancy. The commonly available parenteral iron preparations were identified as iron dextran and iron sucrose with only 30% of the skilled healthcare providers having ever prescribed intravenous iron for iron deficiency anaemia treatment. We found intravenous ferric carboxymaltose which is a new medicine entering Nigeria for the first time for the IVON TRIAL, given as a single loading dose, to be a suitable alternative to oral iron for iron deficiency anaemia treatment during pregnancy. In the clinical trial, intravenous ferric carboxymaltose demonstrated better effectiveness for iron deficiency anaemia treatment and caused a faster rise in haemoglobin concentration by four weeks post-treatment compared to the standard of care, oral ferrous sulphate given thrice daily all through pregnancy. Furthermore, intravenous ferric carboxymaltose is as safe as oral ferrous sulphate when administered during pregnancy. Regarding long term sequelae of delayed correction of anaemia severity and iron levels on mental health disorders like depression, there was no evidence to suggest that an improvement in anaemia severity or iron levels during pregnancy significantly alters the risk for postpartum depression. However, an increased risk of postpartum depression in women who had postpartum haemorhage was observed.The findings of the doctoral research underscore the need to modify practice regarding anaemia treatment in Nigeria and other regions of the world where the disease burden is high to promote the health and well-being of pregnant and postpartum women.List of scientific papersI. Babah OA, Akinajo OR, Beňová L, Hanson C, Abioye AI, Adaramoye VO, Adeyemo TA, Balogun MR, Banke-Thomas A, Galadanci HS, Sam-Agudu NA, Afolabi BB, Larsson EC. Prevalence of and risk factors for iron deficiency among pregnant women with moderate or severe anaemia in Nigeria: a cross-sectional study. BMC Pregnancy Childbirth. 2024 Jan 5;24(1):39. https://doi.org/10.1186/s12884-023-06169-1II. Babah OA, Beňová L, Hanson C, Abioye AI, Larsson EC, Afolabi BB. Screening and treatment practices for iron deficiency in anaemic pregnant women: A cross-sectional survey of healthcare workers in Nigeria. PLoS One. 2024;19(11):e0310912. https://doi.org/10.1371/journal.pone.0310912III. Afolabi BB, Babah OA, Adeyemo TA, Balogun M, Banke-Thomas A, Abioye AI, et al. Intravenous versus oral iron for anaemia among pregnant women in Nigeria (IVON): an open-label, randomised controlled trial. The Lancet Global Health. 2024;12(10):e1649-e59. https://doi.org/10.1016/s2214-109x(24)00239-0IV. Babah OA, Beňová L, Larsson EC, Hanson C, Afolabi BB. Is an improvement in anaemia and iron levels associated with the risk of early postpartum depression? A cohort study from Lagos, Nigeria. BMC Public Health. 2025;25(1):808. https://doi.org/10.1186/s12889-025-21942-x</p
Shedding light on human gonadal development : perspectives from in vitro models for fertility preservation
No full textImpaired fertility is a common, often under-discussed lifelong side effect associated with treatments for malignant and non-malignant diseases. With effective interventions, cancer survivorship has steadily increased over the past decades, bringing to light the consequences that impact reproductive health. Adult males can conserve their fertility by cryopreservation of mature gametes before undergoing gonadotoxic treatments. To safeguard the future fertility for pre- and early pubertal patients, the only option is to cryopreserve immature testicular tissue. This experimental procedure aims to preserve the constituent spermatogonial stem cells (SSCs) in the hope that an experimental method can differentiate these cells later in life. The long-term objective is to restore fertility through either in vitro or in vivo clinical procedures. However, up until today, protocols to restore fertility using human immature testicular tissue remain under development, and ways to study the effects of gonadotoxic treatment before the onset of puberty remain flawed.This thesis aimed to improve in vitro systems that mimic the human testicular microenvironment, allowing us to better understand human gonadal development from early embryonic development until prepubertal maturation. Moreover, knowledge was gained about the adverse effects of gonadotoxic medical treatment on the prepubertal testis, concerning both the stem cells and their supportive somatic environment. The studies within this thesis include prepubertal testicular samples collected as part of a fertility preservation program and first-trimester gonadal tissue.The aim of study I was to model the human first-trimester gonadal environment (testes and ovaries) that recapitulates in vivo tissue organization. An established Matrigel-based gradient system, the three-layer gradient system (3-LGS), was utilized. When cell suspensions from human embryonic testicular tissue (5-9.5 weeks post conception) were used, the cells self-organized into structures resembling testis-like organoids within seven days. The organoids displayed well- defined features similar to those in vivo. More specifically, a two-compartment architecture separated by a basement membrane was formed with seminiferous- like cords containing germ cells and an interstitial space with supporting somatic cells. However, when mesonephric cells were added to the tissue digest, this organization did not persist. The somatic cells within the testis-like organoids also displayed indications of differentiation. The SRY-Box transcription factor 9 (SOX9)-positive Sertoli cells within the seminiferous-like cords expressed anti- Müllerian hormone (AMH), whereas the Leydig cells in the interstitial space presented indications of steroidogenic enzyme activity. While compartmentalized testis-like organoids that supported somatic functions could be generated, germ cells did not survive. In contrast, ovarian-like organoids exhibited less organization but could maintain germ cells in the 3-LGS. This underlines the challenge of preserving germ cells in male organoid cultures. We conclude that the 3-LGS is a promising method for studying gonadal development, which could be a stepping stone for more complex in vitro models in development and regenerative medicine.Subsequently, our focus shifted from early gonadal development to male prepubertal maturation. A greater understanding of how testicular somatic cells develop and nurture SSCs could help advance tissue culture methodologies. Study II explored the ability of testicular cells originating from pre- and peripubertal patients (N=49, age: 0.8-13.4 years), with malignant diseases who have undergone chemotherapy, to culture testicular organoids. Eleven freshly obtained biopsy samples (age: 7.7 + 4.1 years [mean + SD]) were dissociated to acquire cell suspensions, which were then applied to the 3-LGS. Here, four out of eleven testicular cell suspensions self-organized into testicular organoids within one week. The patient-derived organoids presented distinct cord-like structures housing Sertoli cell marker-positive cells. Furthermore, levels of AMH and testosterone in the culture medium displayed an increasing trend within seven days. Additionally, SOX9 expression was positively correlated with testicular organoid formation, emphasizing its potential function as an indicator for successful organoid formation. In turn, prior exposure to alkylating agents before the biopsy was negatively associated with SOX9 expression, which draws attention to the adverse effects of chemotherapy. This study highlights the importance of supporting somatic cell populations, especially Sertoli cells, for the promotion of testicular organoid formation.As a functional somatic compartment is essential for potential fertility restoration and supporting future spermatogenesis, insights into the impact of chemotherapy on the testicular somatic compartment in samples collected for fertility preservation are needed. Study III examined how patient-specific factors (age, spermatogonial density, prior chemotherapy exposure) and tissue handling process affect the capacity of the somatic compartment to sustain hormone secretions ex vivo using fresh prepubertal testicular tissues from 59 patients (0.7-14.3 years). Testicular fragments were maintained in organotypic cultures at air-liquid interface conditions, and three hormones were quantified after a seven- day short-term culture. Levels of secreted AMH and inhibin B served as a measure of Sertoli cell function, whereas testosterone production was considered an indicator of Leydig cell activity. At large, the prepubertal testicular tissues sustained the secretion of hormones ex vivo, despite prior exposure to alkylating chemotherapy and transportation. The findings identified age at the time of biopsy and exposure to alkylating agent chemotherapy as significant predictors of in vitro hormone secretion. Interestingly, somatic cell functionality was maintained despite germ cell depletion. These observations underscore the importance of accounting for patient age as a significant variable in interpreting in vitro hormone secretion assays of prepubertal testicular tissue.Altogether, the findings presented in this thesis provide evidence of the feasibility of a Matrigel-based gradient system to promote the self-organization of human testicular cells into organoid structures. The human first-trimester embryonic organoid-like structures, as well as the patient-derived prepubertal testicular organoids, displayed testis-like features in terms of in vivo spatial architecture, including a compartmentalized organization and indicators of function. This improves on multi-layered in vitro approaches to investigate gonadal development. It is noteworthy that the success of these novel approaches was linked to the functional capacity of the supporting somatic compartment of the SSC, which was, in turn, impacted by prior exposure to chemotherapy. This body of evidence, combined with the findings that the somatic compartment is capable of sustaining hormone secretion in organotypic cultures, highlights the need to understand how somatic cells mediate the impact of chemotherapy on supporting germ cells in the prepubertal testis.List of scientific papersI. Elizabeth Oliver*, João Pedro Alves-Lopes*, Femke Harteveld, Rod T Mitchell, Elisabet Åkesson, Olle Söder, Jan-Bernd Stukenborg. Self-organising human gonads generated by a Matrigel-based gradient system. BMC Biology. 2021 Dec;19:1-1. * denotes that these authors contributed equally to this work. https://doi.org/10.1186/s12915-021-01149-3II. Yanhua Cui, Femke Harteveld, Hajar Ali Mohammed Ba Omar, Yifan Yang, Ragnar Bjarnason, Patrik Romerius, Mikael Sundin, Ulrika Norén Nyström, Cecilia Langenskiöld, Hartmut Vogt, Lars Henningsohn, Per Frisk, Kaisa Vepsäläinen, Cecilia Petersen, Rod T Mitchell, Jingtao Guo, João Pedro Alves-Lopes, Kirsi Jahnukainen, Jan-Bernd Stukenborg. Prior exposure to alkylating agents negatively impacts testicular organoid formation in childhood cancer patients. Human Reproduction Open. 2024 Aug 13;2024(3):hoae049. https://doi.org/10.1093/hropen/hoae049III. Femke Harteveld, João Pedro Alves-Lopes, Anu Haavisto, Yanhua Cui, Magdalena Kurek, Halima Albalushi, Olle Söder, Ragnar Bjarnason, Patrik Romerius, Mikael Sundin, Ulrika Noren Nyström, Cecilia Langenskiöld, Hartmut Vogt, Lars Henningsohn, Per Frisk, Kaisa Vepsäläinen, Rod T. Mitchell, Cecilia Petersen, Konstantin Svechnikov, Kirsi Jahnukainen, Jan-Bernd Stukenborg Short-term organotypic culture and in vitro hormone secretion analysis of prepubertal testicular tissue collected for fertility preservation. [Manuscript]</p
Does white matter matter? Neuroimaging in dementia with Lewy bodies and related conditions
No full textIn this thesis, the role of white matter and white matter changes in dementia with Lewy bodies (DLB) is explored through neuroimaging. The overarching aim of this thesis project was to further increase the understanding of the role of cerebrovascular disease (CVD) in DLB. We wanted to elucidate the relationship between WMSA and markers of neurodegeneration as well as with clinical markers, such as cognition. Through the four projects included in the thesis, the role of white matter changes is evaluated using a range of research cohorts, imaging modalities, and statistical methods.As we age, there is an increasing risk of developing a cognitive or dementia disorder. In clinical practice, cognitive disorders are mainly diagnosed through the clinical presentation whilst in research biomarkers of pathology are more often used. There is a challenge to accurately diagnose these conditions, particularly as the symptoms can overlap and it is common with multiple pathologies in patients. In DLB, which is a relatively common dementia, patients often present with concomitant Alzheimer's Disease (AD) and with signs of white matter changes on neuroimaging. These concomitant pathologies can also alter the presentation of DLB. These findings among patients with DLB may lead to a delayed diagnosis or delay in treatment.Changes in the white matter can be evaluated through magnetic resonance imaging (MRI) and computer tomography (CT) through white matter signal abnormalities (WMSA). Furthermore, the white matter can be evaluated with a specific MRI sequence, diffusion-weighted imaging (DWI), which allows for the exploration of the microstructure of tissues. The images can then be evaluated through either clinically oriented visual rating scales or through more research oriented automatic methods. The WMSA are usually considered to be of a vascular origin.In the first project, the aim was to evaluate the frequency of high WMSA in DLB compared to other diagnoses. To evaluate this, neuroimaging of over 4,000 participants across seven different diagnostic groups and four cohorts was used. Using a clinically available rating scale for WMSA, the Fazekas scale, which was binarised into a low (0-1) or high (2-3) rating, it was observed that patients with DLB had a higher likelihood of a high rating compared to patients with AD and with controls, but a lower likelihood of a high rating compared to patients with vascular dementia (VaD). Furthermore, in patients with DLB, a high rating of Fazekas was associated with a high rating of medial temporal lobe atrophy. However, among patients with DLB, a high WMSA rating was not associated with lower performance on the cognitive test the Mini-Mental State Examination (MMSE), however; in patients with AD, a high WMSA was associated with lower MMSE performance.In the second project, the aim was to evaluate the regional placement of WMSA. In DLB, AD and other dementias, the cholinergic system is affected. The cholinergic system is important for attention and memory. Patients with DLB may also have more severe impairments of the cholinergic system compared to patients with AD. Therefore, the cholinergic system is an important target for investigation. Leveraging the finding that patients with DLB have more WMSA compared to controls, the aim was to evaluate if these WMSA were more likely to be placed in the cholinergic system in patients than in controls. Using an advanced imaging technique based on DWI, masks of the cingulate and external capsule pathways of the cholinergic system were created. The WMSA in the whole brain was assessed with an automated method and WMSA overlapping the mask of the pathways of the cholinergic system was considered cholinergic WMSA. We found that patients with DLB or prodromal-DLB had more WMSA in their cholinergic system pathways, both as a raw volume and as a proportion of all WMSA.In the third project, the aim was to evaluate the microstructure of both WMSA and normal-appearing white matter (NAWM). The aetiology of WMSA is multifactorial and its correlates can vary in postmortem analysis. Using DWI, the differences in microstructural tissue composition of patients with DLB or prodromal DLB compared to controls from two cohorts were evaluated. The method used for evaluating the microstructure is called Single-Shell 3-Tissue Constrained Spherical Deconvolution (SS3T-CSD) and allows for a probabilistic assumption of tissue fractions in each voxel of WMSA or NAWM. The patients with DLB or prodromal DLB in both cohorts differed in terms of microstructural tissue composition in the NAWM, and the results were suggestive of a neurodegenerative process. The results in WMSA suggested group differences only in the WMSA closest to the ventricles, which could be suggestive of less an inflammatory process among patients.In the fourth project, the aim was focused on clinically recruited patients with either mild cognitive impairment (MCI) or subjective cognitive impairment (SCI) from memory clinics in the Stockholm area. Using their results on neuropsychological test results, patients were subgrouped based on three different strategies. Two of the strategies were based on an a-priori-determined division based on the patient's performance on the tests whilst the third strategy was based on a data-driven clustering method. These subgroups were evaluated in terms of associations with abnormal ratings of WMSA. The only subgroup with a higher likelihood of WMSA was the data-driven subgroup with patients who had the most pronounced neuropsychological difficulties.To summarise, in this thesis, WMSA in DLB has been evaluated. The conclusions are that a high degree of WMSA is common in DLB, the WMSA is associated with more atrophy, and is likely to be placed in the cholinergic system of patients with DLB or prodromal DLB. Further, we found that the microstructural tissue composition of WMSA and NAWM is different in patients with DLB or prodromal DLB than in controls.List of scientific papersI. Rennie, A., Ekman, U., Shams, S., Rydén, L., Samuelsson, J., Zettergren, A., Kern, S., Oppedal, K., Blanc, F., Hort, J., Garcia-Ptacek, S., Antonini, A., Lemstra, A. W., Padovani, A., Kramberger, M. G., Rektorová, I., Walker, Z., Snædal, J. G., Pardini, M., ... , & Ferreira, D. (2024). Cerebrovascular and Alzheimer's disease biomarkers in dementia with Lewy bodies and other dementias. Brain communications. https://doi.org/10.1093/braincomms/fcae290II. Rennie, A., Nemy, M., Jerele, C., Rodríguez-Baz, Í., Montal V4., Bejanin, A., Kramberger, M., Aarsland, D., Fortea, J., Lleó, A., Westman E., Alcolea, D., Ferreira, D. Regional associations between cerebrovascular disease and cholinergic white matter pathways in the Lewy body continuum. [Manuscript]III. Rennie, A., Nemy, M., Badji, A., Habich, A., Castellanos-Perilla, N., Firbank, M., Donaghy, P., Rodriguez-Baz, I., Bejanin, A., Lleó, A., Fortea, J., O'Brien, J., Thomas, A., Aarsland, D., Alcolea, D., Taylor, J-P., Westman, E., Ferreira, D. Tissue compositional analysis reveals microstructural alterations in the white matter of patients with prodromal and manifest dementia with Lewy bodies. [Manuscript]IV. Rennie, A., Ekman, U., Wallert, J., Muehlboeck, J. S., Eriksdotter, M., Wahlund, L .- O., Ferreira, D., & Westman, E. (2023). Comparing three neuropsychological subgrouping approaches in subjective and mild cognitive impairment from a naturalistic multicenter study. Neurobiology of aging, 129, 41-49. https://doi.org/10.1016/j.neurobiolaging.2023.04.008</p
Stress-related mental disorders : an exploration astrocytic biomarkers, comorbidities, and cognition
No full textBackgroundProlonged exposure to stressors without sufficient recovery can lead to physical and mental symptoms. In Sweden, individuals with symptoms related to chronic stress may receive diagnoses such as stress-induced exhaustion disorder (SED) or depression. As emerging research suggests that both SED and depression may be associated with subsequent cognitive impairments, a better understanding of the interplay between SED, depression and cognitive health is warranted.The overall aim of this thesis was to deepen the understanding of potential pathophysiological effects of chronic stress on the brain, to investigate whether SED and depression are associated with cognitive impairment and dementia, and to examine differences in the comorbidity patterns of SED and depression.MethodsStudy 1 and 2 recruited participants from two psychiatric clinics in Stockholm (2014-2018). Women and men (18-65 years) diagnosed with SED (as classified in ICD-10-SE) or depression (as classified in ICD-10) within the past three months were invited if diagnosed within the past three months. Exclusion criteria included any somatic or psychiatric condition that could better explain their symptoms. If patients fulfilled both SED and depression they were excluded if the physician did not judge that the depressive symptoms were secondary to the symptoms of SED. Healthy controls were recruited via Statistics Sweden (SCB) in 2009.Study 1 examined whether astrocyte-derived extracellular vesicles (EVs) could be detected in peripheral blood of individuals with SED, and if so, whether concentrations of these differed between individuals with SED, depression, and healthy controls. EVs were quantified using flow cytometry and labeled against glial fibrillary acidic protein (GFAP) and aquaporin 4 (AQP4) to verify astrocyte origin.Study 2 further explored the suggested impact of stress on neurons and astrocytes, using biofluid markers ("biomarkers") of brain injury. Levels of S100B and neurofilament light (NfL) in peripheral blood were analyzed by commercially available enzyme-linked immunosorbent assays (ELISAs).Studies 3 and 4 used ICD-10 codes from the Stockholm Regional Health Care Data Warehouse (VAL databases), covering primary care, outpatient specialist care, and hospital care in Region Stockholm. Included individuals (1.36 million) had no history of SED or depression in 2011, were aged 18-65 years in 2011, and remained in Region Stockholm during the follow up. In Study 3, individuals diagnosed with mild cognitive impairment (MCI) or dementia in 2012-2013 were excluded.Study 3 examined the association between SED, depression, or both (2012- 2013), and later diagnoses of MCI, other forms of dementia and Alzheimer's disease (AD) (2014-2022). Odds ratios (ORs) with 99% confidence intervals (CIs) were calculated, adjusting for age, sex, neighborhood socioeconomic status, diabetes, and cardiovascular disorders.Study 4 examined the association between SED, depression, or both (2012- 2013), and psychiatric disorders and post-viral fatigue during 2014-2022. ORs with 99% confidence intervals, were adjusted for age and neighborhood socioeconomic status.Results Study 1 and 2 included 31 individuals with SED, 31 with depression and 61 healthy controls.In Study 1 higher concentrations of astrocyte-derived EVs were observed in individuals with SED compared to both individuals with depression and healthy controls. Individuals with depression showed higher levels of GFAP-positive EVs and EVs co-expressing AQP4/GFAP compared to controls.Study 2: Levels of S100B were elevated in individuals with SED compared to those with depression and controls, though only in women. Levels of S100B positively correlated with symptoms of cognitive failure, depressive symptoms and levels of astrocyte-derived EVs. Plasma levels of NfL did not differ between groups or correlate with symptom severity.Study 3 included 4 346 individuals diagnosed with SED, 40 101 with depression, and 1 898 with both conditions (2012-2013). Individuals with SED had increased risk for AD (OR 2.45, CI 1.22-4.91) and MCI (OR 1.87, CI 1.20-2.91). Individuals with depression had similar risk for AD (OR 2.32, CI 1.85-2.90) but higher risk for MCI (OR, 2.85 CI 2.53-3.22). The risk was highest in individuals with both SED and depression, with an OR 4.00 (CI 1.67-9.58) for AD and OR 3.87 (CI 2.39-6.27) for MCI.Study 4 included 4 347 individuals diagnosed with SED, 40 134 with depression, and 1 902 with both conditions (2012-2013). Individuals with prior SED showed stronger associations with stress-related diagnoses than those with depression. Notable associations included acute stress reaction (OR 3.08, CI 2.79-3.41), unspecified reaction to severe stress (OR 4.08, CI 3.67-4.53), post-COVID-19 (OR 2.74, CI 2.06-3.66) and post-viral fatigue syndrome (OR 5.13, CI 4.19-6.28). In contrast, depression was more strongly associated with various psychiatric disorders. The highest associations between depression and other psychiatric diagnoses (OR > 5) were found for post-traumatic stress disorder (PTSD) (OR 6.44, CI 6.08-6.82), substance use disorders (OR 5.41, CI 5.11-5.73), manic episodes, bipolar affective disorder, persistent mood disorder, (OR 7.86, CI 7.44- 8.31, neurotic disorder (OR 5.86, CI 5.70-6.02), borderline personality disorder (OR 9.72, CI 8.88-10.64), autism spectrum disorders (OR 6.69 CI 6.20- 7.22), attention deficit hyperactivity disorder (ADHD) (OR 6.39, CI 6.09- 6.70), and suicide attempts (OR 6.77, CI 6.13-7.48), alcohol-related disorders (OR 4.02, CI 3.83-4.21) and schizophrenia, schizotypal disorders, delusional disorders (OR 2.87, CI 2.63-3.13). Notably, some conditions, including PTSD, autism spectrum disorders and ADHD, also showed strong associations with SED (OR >3.5). Conclusion This thesis adds to the knowledge about possible changes in the brain in individuals diagnosed with SED and indicates prognostic and comorbid differences between SED and depression. However, due to methodological limitations, causal relationships cannot be established.First, astrocyte-derived markers were elevated in peripheral blood in individuals with SED compared to healthy controls (Study 1 and 2). Second, SED and depression were both associated with an increased risk of MCI and AD, with the highest risk observed in individuals diagnosed with both conditions (Study 3). Third, SED and depression exhibit distinct and divergent patterns of psychiatric comorbidity (Study 4).Overall, this thesis supports the clinical relevance of distinguishing SED and depression as separate clinical phenotypes, and the possibility that SED and depression are both related to cognitive decline. Furthermore, our results suggests that glial cells are involved, though it does not seem to affect neurons or axonal integrity based on the biomarker results, in these conditions. Given the heterogeneity of these diagnoses, their suggested heightened risk for MCI and AD as well as differing comorbid patterns, their relation should be further explored.List of scientific papersI. Wallensten J, Nager A, Åsberg M, Borg K, Beser A, Wilczek A, Mobarrez F. Leakage of astrocyte-derived extracellular vesicles in stress-induced exhaustion disorder: a cross-sectional study. Sci Rep. 2021 Jan 21;11(1):2009. Erratum in: Sci Rep. 2023 Jun 23;13(1):10211. https://doi.org/10.1038/s41598-021-81453-8II. Wallensten J, Mobarrez F, Åsberg M, Borg K, Beser A, Wilczek A, Nager A. Plasma levels of S100B and neurofilament light chain protein in stress-related mental disorders. Sci Rep. 2022 May 18;12(1):8339. https://doi.org/10.1038/s41598-022-12287-1III. Wallensten J, Ljunggren G, Nager A, Wachtler C, Bogdanovic N, Petrovic P, Carlsson AC. Stress, depression, and risk of dementia - a cohort study in the total population between 18 and 65 years old in Region Stockholm. Alzheimers Res Ther. 2023 Oct 2;15(1):161. https://doi.org/10.1186/s13195-023-01308-4IV. Wallensten J, Ljunggren G, Nager A, Wachtler C, Petrovic P, Carlsson AC. Differences in psychiatric comorbidity patterns in patients diagnosed with chronic stress-induced exhaustion disorder and depression - A cohort study in the total population of Region Stockholm. J Affect Disord. 2024 Apr 15;351:765-773. https://doi.org/10.1016/j.jad.2024.01.273</p
Sleep Duration and Quality in Adolescents: Associations With Suicidal Ideation.
No full textINTRODUCTION: Inadequate sleep duration and sleep-related problems are highly prevalent among adolescents and pose a significant health risk during a critical development stage. This study seeks to explore associations between sleep and suicidal ideation among adolescents. METHODS: Cross-sectional questionnaire data from the baseline wave (2016-2018) of a cohort of 12- to 16-year-old Swedish adolescents (n = 4433, 50.39% girls) were analyzed. A split-sample approach was used for exploratory analyses and model selection. Logistic regression was used to estimate the associations between suicidal ideation and self-reported sleep parameters (weekday sleep duration, sleep quality), both adjusted and unadjusted for depression. RESULTS: Adolescents with suicidal ideation slept on average 60 min less on weekdays and reported worse sleep quality compared to those without suicidal ideation. Suicidal ideation was significantly associated with weekday sleep duration (p = 0.0267) and self-perceived sleep quality (p = 0.0003). Associations remained after controlling for depression. CONCLUSIONS: Sleep problems in adolescents are associated with suicidal ideation, beyond the effect of depression. Findings may have implications for screening and suicide prevention among clinical populations of adolescents, as well as for public health interventions aimed at promoting sleep and mental health in adolescents.</p
Towards understanding recurrent venous thromboembolism in clinical practice
No full textIntroduction: Diagnostic evidence for recurrent venous thromboembolism (VTE) is weaker than for first-time events. Standard pathways combine clinical decision rules (CDRs) and D-dimer testing before imaging, most commonly using ultrasound for deep vein thrombosis (DVT) and computed tomography pulmonary angiography (CTPA) for pulmonary embolism (PE). In suspected ipsilateral recurrent DVT of the leg, ultrasound may fail to rule out DVT in over 30% of cases. This is often due to chronic thrombotic changes after previous DVT and symptoms that frequently overlap with those of the post-thrombotic syndrome (PTS). Magnetic resonance direct thrombus imaging (MRDTI), a method that does not require intravenous contrast, has been shown to accurately differentiate acute thrombi from chronic thrombotic remains. The primary objective of this thesis was to examine how standard diagnostic tests perform in the diagnosis of acute recurrent ipsilateral DVT, and to explore the potential contribution of MRDTI in enhancing diagnostic accuracy.Methods: In the Theia study, a prospective international management study, we examined patients who presented with suspected acute ipsilateral recurrent DVT with MRDTI performed within 24 hours of clinical presentation. Treatment decisions were based on MRDTI results. Ultrasound examination, as a reference standard, was conducted in case of MRDTI negative for DVT but did not affect treatment decisions. Patient history and clinical parameters, including D-dimer and CDR (Wells score and modified Wells score for DVT), were obtained for all patients at baseline. All patients were followed for three months for recurrent DVT or PE, bleeding, and all-cause mortality. The primary outcome was the three-month incidence of VTE in patients with an MRDTI negative for DVT at baseline, defined by the failure rate. At one of the participating centers in the Theia study, ultrasound examinations were obtained for all patients with both positive and negative MRDTI results, without affecting treatment protocols. Additionally, prolonged follow-up of two years was conducted using standardized medical chart review. Furthermore, we reviewed the literature on diagnostic management of recurrent ipsilateral DVT and PTS, highlighting CDRs, D-dimer testing, imaging techniques, and surveillance strategies.Results: A total of 305 consecutive patients were included in the Theia study, both with and without anticoagulant therapy at inclusion. The prevalence of DVT in this cohort was 38%. The failure rate in MRDTI-negative patients without anticoagulant therapy at inclusion was 1.1% (95% CI, 0.13%-3.8%), below the predefined safety threshold. Interobserver agreement for MRDTI readings was excellent, with a Cohen's kappa of 0.91. The sensitivity for the combination of an unlikely ruling by the Wells score and a negative D-dimer to rule out DVT was 97% and the specificity was 36%, leading to a failure rate of 6.1% (95% CI 1.3%- 1.8%). Using the modified Wells rule, the sensitivity level was maintained, and the specificity was reduced to 20% (95% CI 14-27%). In patients with a MRDTI negative for DVT at Danderyd Hospital, 41% (27/66; 95% CI: 30-53%) had ultrasound results where DVT was confirmed or could not be ruled out, suggesting that MRDTI may help in reducing potential overdiagnosis. Of patients with positive MRDTI results, ultrasound was positive in 92%. During a two-year follow-up, 5.5% (5/91, 95% CI 2.4%-12.2%) of patients included at Danderyd Hospital suffered VTE recurrence. MRDTI has been applied into routine clinical practice at several centers.Conclusions: Our data do not support the use of the combination of an unlikely Wells rule or modified Wells rule score with a negative D-dimer to rule out recurrent ipsilateral DVT. MRDTI is a safe and reliable imaging modality for ruling out recurrent ipsilateral DVT and may be useful to prevent overdiagnosis, particularly when ultrasound findings are inconclusive.List of scientific papersThis thesis is based on the following papers, which will be referenced by their corresponding Roman numerals:I. van Dam LF*, Dronkers CEA*, Gautam G*, Eckerbom Å, Ghanima W, Gleditsch J, et al. Magnetic resonance imaging for diagnosis of recurrent ipsilateral deep vein thrombosis. Blood. 2020;135(16):1377-85. *Shared first authorship. https://doi.org/10.1182/blood.2019004114II. van Dam LF, Gautam G, Dronkers CEA, Ghanima W, Gleditsch J, von Heijne A, et al. Safety of using the combination of the Wells rule and D-dimer test for excluding acute recurrent ipsilateral deep vein thrombosis. J Thromb Haemost. 2020. https://doi.org/10.1111/jth.14986III. Gautam G*, Sebastian T, Klok FA. How to Differentiate Recurrent Deep Vein Thrombosis from Postthrombotic Syndrome. Hamostaseologie. 2020;40(3):280-91. *Shared first authorship. https://doi.org/10.1055/a-1171-0486IV. Gautam G, van Dam LF, Dronkers CEA, von Heijne A, Bröms G, Thålin C, Wallen H, Klok FA, Westerlund E. Role of magnetic resonance direct thrombus imaging in preventing overdiagnosis of ipsilateral recurrent deep vein thrombosis by ultrasonography. [Submitted]</p
DIORA1 in molecular signaling and cellular function
No full textAutoimmune diseases are a complex and diverse group of disorders arising from an interplay between genetic predisposition and environmental triggers. Genome-wide association studies have identified the link between polymorphisms in the FAM167A-BLK locus and several rheumatic autoimmune diseases, including Sjögren's disease, systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis. This locus encodes two genes: BLK, which encodes B-lymphocyte kinase, and FAM167A. Expression quantitative trait loci analyses show that disease-associated variants are strongly associated with an increased FAM167A expression, while effects on BLK are modest. Elevated levels of the FAM167A-encoded protein DIORA1 have also been observed in inflamed salivary glands of Sjögren's disease patients. Despite these findings, the molecular, cellular, and systemic functions of DIORA1 remain unknown. To address this, this thesis combines molecular, cellular, and in vivo approaches to elucidate the role of DIORA1 in immune regulation and its potential contribution to autoimmunity.Using proximity biotinylation and co-immunoprecipitation assays, we identified a direct interaction between DIORA1 and three conserved regions of the cytoskeleton-regulating MRCK kinase family - the KIM motif, C1-PH, and CNH domains. AlphaFold-based modeling guided further mapping experiments, confirming that the C-terminal half of DIORA1 mediates MRCK binding. Functionally, DIORA1 knockdown in human cells reduced phosphorylation of MRCK substrates, upregulated epithelial-mesenchymal transition signature, and increased cell invasion in our functional assays. This phenotype was reversed by pharmacological inhibition of MRCK activity, confirming the role of the DIORA1-MRCK interaction in regulating cytoskeletal reorganization and cell motility.Further investigation into MRCK regulation revealed a previously unrecognized family of DIORA1-related proteins containing a conserved MRCK-KIM-binding motif, which we named KIMURA. This motif was both necessary and sufficient for MRCK interaction, with three key amino acid residues critical for binding. While most KIMURA proteins depended on these residues, some retained MRCK binding despite their mutation, suggesting functional specialization within the family. Transcriptomic profiling after systematic knockdown of KIMURA family members revealed that KIMURA-containing proteins may regulate both shared and distinct gene programs and that this can depend on cellular context. Their co-expression with specific MRCK isoforms across tissues, along with genome-wide associations to anthropometric, autoimmune, and cancer traits, implies their physiological relevance in modulating MRCK signaling in tissue-specific and disease-relevant contexts.To explore the role of DIORA1 in immune regulation in vivo, we generated Fam167a knockout (Dioral-/-) mice and performed detailed characterization. Knockout animals exhibited cell-intrinsic alterations in B and T cell subsets, including expanded effector/memory and T follicular helper (Tfh) cells. Transcriptomic analysis of Dioral-/- Tfh cells revealed elevated activation signatures but also signs of reduced cellular fitness. These T cell alterations were accompanied by impaired antigen-specific IgA production, driven by B cell-intrinsic defects following T-dependent immunization. Furthermore, phosphoproteomic analysis of Diora1-deficient B cells revealed disrupted TGF-β signaling, a pathway essential for IgA class switching and regulation of T helper cell responses, suggesting a mechanistic link between Diora1 loss and altered immune homeostasis.To support future work dissecting DIORA1 and KIMURA functions with spatiotemporal precision, we developed an optogenetic CRISPR platform, BLU-VIPR, that uses blue light to induce expression of ribozyme-flanked guide RNAs. This genetically encoded system enabled multiple gene editing approaches, including CRISPR knockout, CRISPR activation, and base editing. Coupled with fiber-optic illumination, BLU-VIPR enabled precise spatiotemporal genome editing of T cells within a single lymph node in living mice, demonstrating targeted in vivo perturbation in otherwise inaccessible immune settings.In summary, this thesis identifies DIORA1 as a regulator of MRCK kinases, suggesting a role in cytoskeleton regulation. By integrating molecular interaction mapping, structural modeling, transcriptomic and proteomic profiling, and in vivo immunological studies, we uncover a mechanistic role for DIORA1 in shaping immune responses, possibly through MRCK modulation. The discovery of the KIMURA protein family expands the repertoire of MRCK regulators and offers new insight into how cytoskeletal signaling networks are tuned in health and disease. Together, these findings may help explain the genetic risk associated with the FAM167A-BLK locus and suggest a role for DIORA1 in maintaining cellular homeostasis and immune regulation.List of scientific papersI. Autoimmunity-associated DIORA1 binds the MRCK family of serine/threonine kinases and controls cell motility. Tršelič, T., Pelo, N., Martin de Fremont, G., lyer, V. S., Richardsdotter Andersson, E., Ottosson, V., Frei, D. A., Baas, E., Nyberg, W. A., Thorlacius, G. E., Mentlein, L., Boddul, S. V., Sandu, I., Velasquez Pulgarin, D., Végvári, Á., Gerlach, C., Wermeling, F., Sunnerhagen, M., Wallner, B., Espinosa, A., Wahren-Herlenius, M. Proc Natl Acad Sci U S A. 2025 Oct 7;122(40):e2426917122. https://doi.org/10.1073/pnas.2426917122II. The KIMURA motif defines a family of MRCK-binding proteins. Tršelič, T., lyer, V. S., Richardsdotter Möller, E., Ottosson, V., Ottosson, L., Thorlacius, G. E., Espinosa, A., Wahren-Herlenius, M. [Manuscript]III. DIORA1 regulates T follicular helper cell differentiation and immunoglobulin class switch. Richardsdotter Möller, E., Tršelič, T., Gerstner, C., Meneghel, L., Schurz, H., Martin de Fremont, G., Margenat Arqué, C., Iyer, V. S., Ottosson, V., Thorlacius, G. E., Boddul, S. V., Bharaj, T. K., Mentlein, L., Pelo, N., Velasquez Pulgarin, D., Liu, J., Adner, M., Skarstein, K., Gerlach, C., Noble, J., Reinius, B., Wermeling, F., Espinosa, A., Wahren-Herlenius, M. [Manuscript]IV. Light-induced expression of gRNA allows for optogenetic gene editing of T lymphocytes in vivo. Velasquez Pulgarin, D., Pelo, N., Ferrandiz, L., Tršelič, T., Nyberg, W. A., Bowlin, G., Espinosa, A. Nucleic Acids Res. 2025 Mar 20;53(6):gkaf213. https://doi.org/10.1093/nar/gkaf213</p
Functional precision medicine approaches to identify novel therapeutic strategies in ovarian cancer
No full textOvarian cancer (OC) is a rare yet highly aggressive disease, representing the most lethal gynecological malignancy. Despite covering multiple histological subtypes with different genetic alterations this disease is primarily treated through surgery followed by platinum-taxol based chemotherapy (Carboplatin and Paclitaxel in Sweden). Although this regimen initially leads to favorable responses, approximately 80% of patients relapse within 18 months and have limited further treatment options, leading to poor overall survival. Precision medicine (PM) has transformed oncology by leveraging genomic insights to stratify patients based on actionable mutations, enabling targeted, personalized therapies. In OC, this approach has led to the introduction of PARP inhibitors for patients with BRCA1/2 mutations or exhibiting homologous recombination deficiency. However, a high molecular heterogeneity of OC and lack of actionable alterations limit the efficacy of genomics-driven approaches. Increasing evidence also highlights the critical role of tumor microenvironment (TME) in driving therapeutic resistance and modulating drug response, emphasizing the need for diagnostic and treatment approaches that capture both tumor-intrinsic and extrinsic factors. Functional PM (fPM) and drug response profiling approaches, offers a powerful, phenotype- driven strategy to uncover clinically relevant vulnerabilities. Although its implementation in solid tumors remains technically challenging, fPM has already shown considerable success in hematological malignancies, highlighting its potential to guide individualized treatment strategies.In this thesis, we applied fPM and drug response profiling approaches to identify novel therapeutic strategies to overcome drug resistance in OC and integrating components of the TME.Study I aimed to establish a fPM platform compatible with OC tissue and ascites samples with a clinically relevant timeframe. We developed DET3CT (Drug Efficacy Testing in 3D Cultures), a scalable platform capable of generating patient-specific drug response profiles from 3D cultures of fresh patient material within 10 days. Compared to 2D cultures, 3D systems showed higher proliferation and were well suited for image-based profiling. Drug testing on 20 samples from 16 patients using a 58-drug library revealed strong correlation between Carboplatin sensitivity and clinical response, distinguishing patients with short (≤12 months) and long (>12 months) progression-free intervals. The Bcl-xL inhibitor A-1331852 and EGFR inhibitor Afatinib emerged as effective drugs in these patients, showing additive effects when combined with Carboplatin.Study II aimed to explore the suitability of DET3CT platform for cryopreserved high-grade serous OC (HGS-OC) samples. A total of 83 samples from 58 patients were screened across 16 drugs and two drug combinations, achieving an 84% assay success rate. Carboplatin combination with A-1331852 or Trametinib were among the most effective treatments. Targeted therapies generally showed greater cytotoxicity than standard chemotherapies, complicating correlation of clinical outcomes for standard-of-care. Notably, sensitivity to the SMAC mimetic Birinapant, as well as higher proportion of EpCam+CD24+ cancer-stem cells, were associated with shorter progression-free interval. In addition, spheroid morphology correlated with HRD and BRCA1/2 mutation status, suggesting its potential as predictive biomarker.Study III sought to systematically profile the drug response of a living biobank of patient-derived models from OC patients to identify effective drugs and rational strategies to overcome resistance. We established a collection of patient-derived models (PDMs) from 22 OC patients, including 21 cancer and 14 fibroblast models across seven OC subtypes, predominantly representing HGS-OC, the most common OC subtype. Panel sequencing confirmed that PDMs retained key tumor-specific aberrations. High-throughput drug screening revealed individualized response profiles, with 85% of compounds showing low toxicity in healthy bone marrow cells. EGFR/ERBB2 inhibitors, rapalogs, and BH3 mimetics emerged as active drug subclasses. The Bcl-xL inhibitor A-1331852 showed variable efficacy among models derived from the same patient, prompting proteomics analysis to understand determinants of drug response. The analysis revealed NOTCH pathway upregulation in resistant cells. Combination of Y- secretase inhibitors, A-1331852, and Carboplatin produced a durable cytotoxic effect in long-term treatment and ex vivo cultures, suggesting its potential as promising candidate for future clinical studies.Study IV aimed to characterize how fibroblasts influence OC cell behavior and drug response. Using both direct and indirect co-culture systems, we observed that fibroblasts significantly altered OC cell proliferation, morphology and cytokine secretion profiles. An imaging based high-throughput drug screen of 528 oncology compounds revealed that fibroblast presence broadly reduced drug efficacy, highlighting their role in mediating therapy resistance. Notably, combinations of Carboplatin with either Birinapant or Vorinostat effectively restored cancer cell sensitivity, exploiting fibroblast-induced phenotypic changes. These findings were further validated in ex vivo patient samples, where both combinations exhibited enhanced cytotoxicity.Together, these studies demonstrate the power of fPM and drug response profiling to uncover patient-specific vulnerabilities and novel therapeutic strategies for OC. By integrating short-term ex vivo cultures, PDMs, and methods incorporating components of the TME, this work identified several drug candidates and synergistic combinations. In particular, inhibition of the Bcl-xL and NOTCH pathways, as well as Birinapant or Vorinostat in combination with Carboplatin, showed potential to overcome resistance. Overall, these finding open the door for fPM in guiding individualized treatment strategies and advancing our understanding of OC biology.List of scientific papersI. Åkerlund E, Gudoityte G, Moussaud-Lamodière E, Lind O, Bwanika HC, Lehti K, Salehi S, Carlson J, Wallin E, Fernebro J, Östling P, Kallioniemi O, Joneborg U, Seashore-Ludlow B The drug efficacy testing in 3D cultures platform identifies effective drugs for ovarian cancer patients NPJ Precis Oncol. 2023 Oct 31;7(1):111https://doi.org/10.1038/s41698-023-00463-zII. Gudoityte G, Hutyra-Gram Östvos R, Haffa M, Juhani K, Wikström S, Kallioniemi O, Fernebro J, Joneborg U, Seashore-Ludlow B Ex vivo drug screening of biobanked high-grade serous ovarian cancer samples as a scalable approach to precision medicine [Manuscript]III. Gudoityte G, Berkovska O, Orre L, Moussaud-Lamodière E, Bergström R, Lindberg J, Haraldsson M, Bou Nafeh S, Louhaur M, Kallioniemi O, Fernebro J, Joneborg U, Seashore-Ludlow B Functional drug screening of patient-derived models uncovers combination therapy to overcome platinum resistance in ovarian cancer [Manuscript]IV. Gudoityte G, Sharma O, Leuenberger L, Wallin, E Fernebro J, Östling P, Bergström R, Lindberg J, Joneborg U, Kallioniemi O, Seashore-Ludlow B Systematic profiling of cancer-fibroblast interactions reveals drug combinations in ovarian cancer Mol Oncol. 2025 May 24https://doi.org/10.1002/1878-0261.70051</p
Hepatitis C in people who inject drugs : prevalence, incidence, mortality, and treatment uptake
No full textHepatitis C virus (HCV) infection can progress to liver cirrhosis and hepatocellular carcinoma (HCC) and was in 2022 estimated to cause 240,000 deaths worldwide. The virus is bloodborne, and a main transmission route is injection drug use through sharing of unsterile needles and syringes. The prevalence of HCV infection is consequently high in people who inject drugs (PWID). The World Health Organization (WHO) has set a goal to eliminate HCV as a public health threat, by the year 2030, which includes a 90% reduction in new chronic infections, a 65% reduction in mortality, and a target of >80% treated. To achieve this goal a deeper understanding of the epidemiology of HCV in PWID, the main drivers of the epidemic, is essential. The aims of this thesis were to study the prevalence and incidence of HCV infection, liver-related mortality, and HCV treatment uptake in PWID.In Study I, we demonstrated a high prevalence of HCV infection (11%) in detainees in Stockholm County, which highlights that prisons could constitute a target facility for testing and treatment of HCV infection.In Study II, we reported a high liver-related mortality in PWID with HCV infection. Amphetamine users had an even higher liver-related mortality than opioid users, probably as they lived longer and were less likely to die from drug-related causes at younger ages, which enabled late consequences of HCV infection to emerge. In addition, amphetamine users had a higher alcohol-consumption, which was a risk factor for liver-related death.In Study III, we noted a great decline in HCV prevalence in PWID in Stockholm (from 62% to 30%) in recent years, following the introduction of direct-acting antiviral (DAA) treatment and the startup of a needle syringe program (NSP) in Stockholm. However, no significant reduction in incidence was observed, indicating that treatment efforts to date have primarily reached individuals with lower injection-related risk behaviors, while those at highest risk of onward transmission may remain untreated.In study IV, we reported that >80% of individuals notified with HCV infection in Sweden have initiated treatment, indicating that Sweden has reached the WHO HCV treatment target. Median time to treatment initiation was only a few months in recent years. The odds of receiving treatment were, however, lower among people with drug use diagnoses.In conclusion, this thesis demonstrates high HCV prevalence and incidence rates in PWID, as well as elevated liver-related mortality. Along with an increasing treatment uptake in recent years, the HCV prevalence has decreased, suggesting that a scale up of HCV treatment is effective. However, the lack of reduction in incidence among PWID highlights the importance of further expanded testing and treatment efforts. To achieve the WHO elimination goal, PWID need to remain a key focus, especially those with the highest risk behaviors for viral transmission, and high-prevalence settings such as prisons, NSPs, and addiction treatment centers should be targeted.List of scientific papersI. Gahrton C, Westman G, Lindahl K, Öhrn F, Dalgard O, Lidman C, Nilsson LH, Said K, Duberg AS, Aleman S. Prevalence of Viremic hepatitis C, hepatitis B, and HIV infection, and vaccination status among prisoners in Stockholm County. BMC Infect Dis. 2019;19(1):955. https://doi.org/10.1186/s12879-019-4581-3II. Gahrton C, Håkansson A, Kåberg M, Jerkeman A, Häbel H, Dalgard O, Duberg AS*, Aleman S*. Mortality among amphetamine users with hepatitis C virus infection: A nationwide study. PLoS One.2021;16(6):e0253710. https://doi.org/10.1371/journal.pone.0253710III. Gahrton C, Navér G, Warnqvist A, Dalgart O, Aleman S, Kåberg M. Changes in hepatitis C virus prevalence and incidence among people who inject drugs in the direct acting antiviral era. International Journal on Drug Policy, 2024;128:104433. https://doi.org/10.1016/j.drugpo.2024.104433IV. Gahrton C, Kåberg M, Lybeck C, Lindahl K, Patil S, Dalgard O, Aleman S*, Duberg AS*. Treatment uptake among individuals notified with HCV infection 1990- 2022 in Sweden. Infectious diseases. 2025:1-11. https://doi.org/10.1080/23744235.2025.2569504*shared last authorship</p
The inflammatory response of the lung in COVID-19 : correlations between imaging-based methods and clinical outcomes
No full textBackground Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus SARS- CoV-2, was first identified in China in late 2019. Its rapid global spread led to a pandemic. Clinical presentation varies from asymptomatic to critical illness. Although multiple organs may be affected, severe cases are marked by a dysregulated immune response that primarily targets the lungs and can progress to acute respiratory failure and death.As pulmonary involvement is central to severe disease, chest computed tomography (CT) rapidly emerged as an essential tool for assessing lung injury in hospitalised patients. CT provided higher sensitivity than chest radiography and supported clinical decision-making when molecular testing was limited. Guidance from the European Society of Thoracic Imaging (ESTI) and the European Society of Radiology (ESR) emphasised that CT should be reserved for hospitalised patients with moderate to severe disease or when differential diagnoses needed to be excluded.However, the prognostic value of specific radiological patterns on CT and their relationships to pathology, clinical outcomes, and long-term sequelae remained unclear. Studies in this thesis included hospitalised COVID-19 cohorts, spanning the acute phase, intensive care unit (ICU) survivors, and post-discharge follow- up. The work integrates radiological, pathological, functional, and computational imaging perspectives to clarify how pulmonary inflammation presents on imaging and how image derived measures relate to clinical trajectories from acute illness through to convalescence.The overall aim was to characterise the extent of pulmonary inflammation as visualised by CT in hospitalised COVID-19 patients, and to investigate the underlying structural and physiological mechanisms reflected in imaging findings, in relation to pathology, lung function, and clinical outcomes across different disease phases. Specifically, the thesis sought to: (i) determine the prognostic significance of widespread parenchymal abnormalities (WPA) with or without pulmonary embolism (PE) on contrast-enhanced CT pulmonary angiography (CTPA) in the acute setting; (ii) evaluate whether artificial intelligence (AI) can reproducibly quantify opacity burden on contrast-enhanced CT compared with radiologists; (iii) assess the prevalence and functional impact of residual radiological abnormalities in ICU survivors during follow-up; (iv) identify structural vascular and airway correlates of reduced diffusion capacity using functional respiratory imaging (FRI) on non-contrast high-resolution CT (HRCT); and (v) validate in-vivo CT patterns against post-mortem histopathology in fatal cases.Material and MethodsThe thesis comprises five studies conducted primarily in hospitalised COVID-19 cohorts, ranging from acutely admitted patients to ICU survivors and selected follow-up groups. In paper 1, a retrospective analysis of contrast-enhanced CTPA for suspected PE during acute COVID-19 was performed. Extent of WPA, presence and distribution of PE, and associations with markers and 60-day mortality were assessed. In paper 2, AI-based opacity quantification was tested on contrast-enhanced CTPA in prospectively included acute-phase patients, by comparison with two radiologists. In paper 3, a cohort of ICU-treated survivors underwent non-contrast CT, lung function testing, and exercise assessment at ~10 months, with a subset re-imaged at two years to evaluate fibrotic-like changes and their correlates. In paper 4, FRI was applied to non-contrast inspiratory and expiratory HRCT 4-11 months post-discharge in a homogeneous male cohort, deriving vascular and airway metrics and related them to diffusion capacity (DLCO) and walking performance. In paper 5, systematic radiology- pathology correlation of in-vivo chest CT shortly before death and autopsy was undertaken, examining how CT patterns corresponded to histopathological features in fatal COVID-19.Main ResultsPaper 1: In the acute phase, WPA on CT, particularly when combined with PE, were strongly associated with severity and 60-day mortality. Emboli were frequently small and peripheral, consistent with recognition of pulmonary vascular involvement in COVID-19.Paper 2: On contrast-enhanced CTPA, an AI tool trained on non-contrast data showed strong agreement with radiologists in estimating opacity burden. Performance held despite intravenous contrast, supporting its applicability in real-world CTPA workflows where contrast is required to exclude PE.Paper 3: Beyond the acute phase, residual widespread opacities on follow-up CT were common. At two years, "fibrotic-like" changes were frequent (92%). These abnormalities correlated with reduced lung volumes, lower DLCO, and exercise-induced desaturation, though the relation between radiology and function was heterogeneous.Paper 4: FRI revealed vascular and airway remodelling 4-11 months post- discharge. Patients with reduced DLCO had lower BV5% and higher siVaw% aligned with reduced lobar volumes, supporting small-vessel loss and airway calibre changes as contributors to impaired gas transfer.Paper 5: Correlation of in-vivo CT with post-mortem histopathology showed that typical CT patterns (ground-glass opacities, consolidations, organising pneumonia, and crazy paving), corresponded to diffuse alveolar damage with oedema, hyaline membranes, and organising pneumonia. Thromboembolic events were identified in larger pulmonary arteries at autopsy, while microvascular thrombi were not consistently visible on CT, reflecting resolution limits and timing relative to autopsy.ConclusionsAcross hospitalised cohorts and disease stages, CT and advanced imaging capture COVID-19 lung injury from acute inflammation to chronic sequelae. In the acute setting, WPA, especially with PE on CTPA, are strongly associated with mortality, supporting CT for risk stratification in addition to diagnosis. AI offers reliable quantification of parenchymal involvement on contrast-enhanced scans, integrating with clinical workflows where contrast is required. During long-term follow-up of ICU survivors, persistent abnormalities align with physiological impairment, underlining the value of structured surveillance and the need to interpret imaging alongside function. FRI revealed structural changes, with loss of pulmonary vessels (reduced BV5%) and airway calibre changes (higher siVaw with reduced lobar volumes) as correlates of reduced diffusion capacity. Finally, radiology-pathology correlation validates CT features of diffuse alveolar damage and organising pneumonia, while clarifying CT's limits for microvascular thrombosis.Taken together, these complementary approaches delineate how acute inflammation can evolve into chronic structural and functional sequelae. Overall, this thesis advances our understanding of COVID-19-related pulmonary inflammation by linking imaging findings to clinical, functional, and pathological outcomes.List of scientific papersI. Jalde FC, Beckman MO, Svensson AM, Bell M, Sköld M, Strand F, Nyren S, Kistner A. Widespread Parenchymal Abnormalities and Pulmonary Embolism on Contrast-Enhanced CT Predict Disease Severity and Mortality in Hospitalized COVID-19 Patients. Front Med (Lausanne). 2021 Jun 29;8:666723. PMID: 34268322 https://doi.org/10.3389/fmed.2021.666723II. Svensson AM, Kistner A, Kairaitis K, Prisk GK, Farrow C, Amis T, Wagner PD, Malhotra A, Harbut P. Quantitative assessment of lung opacities from CT of pulmonary artery imaging data in COVID-19 patients: artificial intelligence versus radiologist. BJR Open. 2025 Apr 29;7(1):tzaf008. PMID: 40370862 https://doi.org/10.1093/bjro/tzaf008III. Björnson M, Svensson AM, He C, Sköld M, Nyrén S, Nygren- Bonnier M, Bruchfeld J, Runold M, Jalde FC, Kistner A. Residual radiological opacities correlate with disease outcomes in ICU- treated COVID-19. Front Med (Lausanne). 2024 Apr 3;11:1263511. PMID: 38633311 https://doi.org/10.3389/fmed.2024.1263511IV. Svensson AM, Björnson M, Sköld M, Kauczor HU, Nygren- Bonnier M, Bruchfeld J, Runold M, Kistner A, Nyrén S. Pulmonary vascular and airway changes in previously hospitalised COVID- 19 patients: long-term functional respiratory imaging findings correlate with reduced DLCO. [Accepted]V. Svensson AM, Sakely L, Brunnström H, Nyrén S, Kistner A, Ortiz- Villalón C. Pulmonary findings in COVID-19: radiology correlates with the histopathological post-mortem findings in patients with fatal acute disease. [Submitted]</p