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The neurobiology of anorexia nervosa : focus on short-chain fatty acids, GDF15, and hypothalamic regulation of food intake
No full textAnorexia nervosa (AN) is an eating disorder characterized by persistent food restriction accompanied by markedly low body weight in relation to age, sex, and developmental trajectory. We currently lack evidence-based pharmacological treatment for AN, likely because we do not have sufficient knowledge about the etiology of the disorder. One perplexing phenomenon in AN is the aberrant response to starvation and emaciation. While most individuals quickly regain lost weight, individuals with AN remain in an underweight state, not rarely for years.The main purpose of this thesis is to explore why AN patients stay in a negative energy balance. To this end, we used a multidimensional approach to study changes in the gut, blood, and brain of AN patients during and after the onset of the disorder. This includes clinical biomarker studies using plasma collected from patients, cellular modeling based on patient-derived induced pluripotent stem cells (iPSC), as well as high-resolution spatial omics applied to a rodent model of anorexia.In Study I, we measured the plasma concentration of short-chain fatty acids (SCFAs) in females with AN, recovered from AN (AN-REC), and healthy individuals. We showed reduced butyric, isobutyric, and isovaleric acids in AN and AN-REC compared to the controls.In Study II, we analyzed the level of growth and differentiation factor 15 (GDF15) in the plasma of AN, AN-REC, and healthy female controls. There was no significant difference in GDF15 levels among the three groups, but a subgroup of study participants, mostly AN, had increased plasma GDF15 levels, combined with increased fibroblast growth factor 21, indicative of mitochondrial dysfunction. Using a large AN case-control cohort, we found that mitochondrial polygenic risk scores were significantly associated with the risk of AN.In Study III, we differentiated fibroblast-derived induced pluripotent stem cells from AN patients and healthy controls into microglia, hypothalamic neurons, and cortical neurons. We demonstrated that microglia from AN patients had an altered ability to engulf synaptosomes extracted from hypothalamic neurons compared with healthy controls, both before and after treatment with glucagon- like peptide-1, whereas no such difference was observed when the same microglia were used to phagocytose cortical synaptosomes.In Study IV, we profiled selected hypothalamic regions and, selectively, the agouti-related peptide (AgRP) expressing neurons of the anorectic anx/anx mouse using spatial transcriptomics. We reported changed expressions of genes related to immune response, synapses, and myelin in several of the anx/anx hypothalamic regions, and the AgRP neurons of the anx/anx mouse exhibited changed expression of genes regulating energy homeostasis and mitochondrial metabolism.The work presented here highlights our efforts to understand the biological changes that occur from the gut to the blood to the brain in patients with AN. I believe our research will contribute to the discovery of therapeutic targets and, in the long term, to the development of effective medications for AN, the most lethal psychiatric disorder.List of scientific papersI. Jingjing Xu, Rikard Landberg, Catharina Lavebratt, Cynthia M Bulik, Mikael Landen & Ida AK NilssonPlasma Concentrations of Short-Chain Fatty Acids in Active and Recovered Anorexia Nervosa Nutrients, 2022, 14(24), 5247https://doi.org/10.3390/nu14245247II. Jingjing Xu, Ruyue Zhang, Vincent Millischer, Miranda Stiernborg, Claire E Tume, Sara Mehdinia, Peter Barker, Zeynep Yilmaz, Vanessa F Gonçalves, Catharina Lavebratt, Mikael Landen, Stephen O'Rahilly, Cynthia M Bulik & Ida AK NilssonElevated plasma GDF15 combined with FGF21 suggests mitochondrial dysfunction in a subgroup of anorexia nervosa patientsTranslational psychiatry, 2025, 15(1), 215https://doi.org/10.1038/s41398-025-03425-0III. Jingjing Xu, Emmy Erskine, Barbara Eramo, Tianxu Feng, Karin Zimmer, Chiara Camoglio, Funda Orhan, Lars Selander, Tomas Hokfelt, Martin Schalling, Samudyta, Carl Sellgren & Ida AK NilssonMicroglia pruning of hypothalamic synapses is reduced in anorexia nervosa, 2025 [Manuscript]IV. Jingjing Xu, Emmy Erskine, Barbara Eramo, Chiara Camoglio, Lars Selander, Tomas Hökfelt & Ida AK NilssonSpatial transcriptomic profiling of the hypothalamus of the anorectic anx/anx mice, 2025 [Manuscript]</p
Hypoparathyroidism : epidemiological studies from prevalence to mortality
No full textBackgroundChronic hypoparathyroidism (hypoPT) is a rare endocrine disorder caused by insufficient parathyroid hormone (PTH) secretion, leading to hypocalcemia and hyperphosphatemia. Postsurgical damage to the parathyroid glands is the most common cause, while nonsurgical hypoPT may arise from autoimmune or genetic disorders. Standard treatment with active vitamin D and calcium supplements normalizes serum calcium but does not restore the physiological actions of PTH. Emerging evidence indicates that patients with chronic hypoPT are at risk of multiple long-term complications. The underlying mechanisms remain incompletely understood, and it is uncertain to what extent these outcomes relate to the disease itself, treatment-related factors, or in the case of nonsurgical hypoPT, diagnostic delay. In Sweden, neither population-based prevalence data nor validation of diagnostic coding for chronic hypoPT had previously been performed.ObjectiveThis thesis aimed to advance knowledge on chronic hypoPT by (study I) validating diagnostic coding in the Swedish registers; (study II) assessing fracture risks, osteoporosis diagnoses, and osteoporosis medication use; (study III) estimating prevalence and mortality; and (study IV) evaluating neuropsychiatric outcomes, including diagnoses, hospitalization, and medication use.MethodsStudy I validated register diagnoses through medical record review of 120 patients with ICD-10 codes for hypoPT, receiving conventional treatment (2004- 2016).Studies II-IV were nationwide cohort studies using the Swedish National Patient Register, Prescribed Drug Register, Cause of Death Register, and Total Population Register. Patients with chronic hypoPT were identified through ICD-10 codes combined with dispensations of active vitamin D. Ten population-based controls matched by age, sex, and county of residence were selected for each case. Subgroup analyses were performed by sex and etiology.In study II, the outcomes included fractures, osteoporosis diagnoses, and osteoporosis medication use.Study III estimated the prevalence of chronic hypoPT and assessed all-cause and cause-specific mortality, stratified by sex, and etiology.Study IV included patients with chronic hypoPT diagnosed in 2005-2018. Dispensed medications were extracted from the Prescribed Drug Register, and neuropsychiatric morbidity was assessed using diagnoses, hospitalizations, and drug dispensations.ResultsIn study I, the positive predictive value of the hypoPT diagnosis was 91%, based on review of 120 medical records, confirming high diagnostic accuracy in the National Patient Register. In study II, 1,915 patients and 15,838 controls were included. The overall fracture risk was not increased (HR 0.93, 95% CI 0.69-1.26). However, the risk of vertebral fractures was higher (HR 1.55, 95% CI 1.12-2.14), and the risk of hip fractures was lower in patients compared with controls (HR 0.70, 95% CI 0.50-0.98). In study III, the prevalence was estimated at 19.4 per 100,000 inhabitants. Postsurgical cases accounted for 72% of all patients. All-cause mortality was significantly higher in patients compared to controls (HR 1.55, 95% Cl 1.40-1.72), with an observed excess risk particularly in nonsurgical hypoPT (HR 2.16, 95% CI 1.76-2.65) compared with postsurgical hypoPT (HR 1.39, 95% CI 1.23- 1.58). In study IV, patients with chronic hypoPT had higher use of antiepileptics (OR 1.68, 95% CI 1.35-2.08), hypnotics/sedatives (OR 1.28, 95% CI 1.11-1.47), and opioids (OR 1.21, 95% CI 1.05-1.40). No significant differences were observed for neuropsychiatric diagnoses or hospitalizations.ConclusionsChronic hypoPT is associated with multiple long-term health risks, including increased mortality, a higher risk of vertebral fractures and a lower risk of hip fractures compared to population controls. Furthermore, patients with chronic hypoPT had greater use of antiepileptics, hypnotics/sedatives, and opioids compared to controls. These findings highlight the importance of improved clinical awareness and structured long-term follow-up. Further research is needed to clarify the mechanisms behind the observed complications and to explore whether modifications in long-term management could mitigate comorbidity burden and improve quality of life.List of scientific papersI. Kamal W, Björnsdottir S, Kämpe O, Trolle Lagerros Y. Concordance Between ICD-10 Codes and Clinical Diagnosis of Hypoparathyroidism in Sweden. Clin Epidemiol. 2020 Mar 24;12:327-331. PMID: 32273771; PMCID: PMC7102876. https://doi.org/10.2147/CLEP.S242528II. Björnsdottir S, Kamal W, Mannstadt M, Mäkitie O, Spelman T, Kämpe O, Langdahl BL. Increased risk of vertebral fractures and reduced risk of femur fractures in patients with chronic hypoparathyroidism: a Nationwide cohort study in Sweden. J Bone Miner Res. 2025 Jun 25;40(7):860-867. PMID: 40324207; PMCID: PMC12188750. https://doi.org/10.1093/jbmr/zjaf061III. Kamal W, Trolle Lagerros Y, Mannstadt M, Spelman T, Kämpe O, Björnsdottir S. Increased Mortality in Chronic Hypoparathyroidism: A Nationwide Cohort Study in Sweden. [Submitted] IV. Kamal W, Mannstadt M, Trolle Lagerros Y, Spelman T, Husebye ES, Mäkitie O, Kämpe O, Björnsdottir S. Psychiatric drug use in patients with chronic hypoparathyroidism: A nationwide cohort study in Sweden. [Manuscript]</p
Gadolinium-based contrast agents and perivascular spaces in multiple sclerosis
No full textBackground and Purpose: MRI plays a key role in the diagnosis and monitoring of MS. While GBCAs reveal active inflammation, concerns about long-term retention drive the search for safer alternatives. This thesis investigates the effects of Gd on brain MRI by: (a) comparing conventional T1-weighted (T1W) with advanced MT imaging to assess Gd-related signal changes; (b) assessing GBCAs influence on brain volumetrics; and (c) developing a new automated method for quantifying enhancing MS lesion. Additionally, it examines the relevance of VRS as imaging biomarker and their histopathological correlates (d). Study Population: All these studies used cohorts of participants with confirmed MS diagnosis per current criteria. Additionally, in Studies I and IV, age- and sex-matched healthy control cohorts were also recruited. Study IV further included a validation cohort for the in vivo assessment, as well as an ex vivo cohort comprising both MS patients and healthy controls. Materials & Methods: Study I: A cohort of 23 MS patients with long-term GBCA exposure, followed prospectively for over 18 years, was compared with 23 age- and sex-matched controls. All underwent 1.5 T brain MRI including 2-dimensional T1W spin echo (2D T1W SE), 3-dimensional T1W gradient echo (3D T1W GRE) and 2D MT sequences. Signal intensity indices (SII) were calculated in the dentate nucleus (DN) and globus pallidus (GP) to evaluate gadolinium retention. Study II: Brain MRI from 200 MS patients, each with two contrast-enhanced 3D T1-weighted scans over a mean interval of 2.0 ± 0.9 years, were retrospectively analyzed. Whole brain and regional brain volumes, including cortex, thalamus, gray matter (GM), and white matter (WM), were quantified before and after GBCA administration, using an automated multi-atlas segmentation software (cNeuro) and a correction method to reduce GBCA-related bias was evaluated. Study III: To develop and validate an automated method for contrast-enhancing lesions (CELs) detection in MS, contrast-enhanced 3D T1W MRI from 1,768 exams (1,034 patients) were retrospectively analyzed. The algorithm, trained on 97 CELs from 10 scans and validated on 107 CELs from 16 scans, was than applied to the full dataset. All scans underwent standardized manually segmentation and neuroradiologist review as reference. Study IV: This cohort study assessed associations between non-dilated and dilated VRS and clinical as well as MRI outcomes in 142 MS patients and 30 healthy controls, with validation in an independent cohort of 63 MS patients. Furthermore, post-mortem samples from 6 MS patients and 3 controls were examined using ex vivo MRI and histopathology to assess the tissue substrates underlying VRS. Results: Study I confirmed a dose-dependent association between Gd-administrations and SII-changes in the DN and globus pallidus GP on conventional T1W imaging. SII alterations related to GBCAs were most effectively detected using 3D T1W GRE sequences, with the most pronounced changes observed in the GP. In contrast, no evidence of Gd retention was detectable using the applied 2D MT technique. Study II demonstrated that GBCAs significantly affects brain MRI volumetry, particularly in the thalamus and cortex, thereby complicating longitudinal assessments in MS. Applying the correction method to contrast-enhanced imaging improved atrophy detection, but sensitivity remained lower than with non-contrast imaging. Study III showed that the fully automated CEL detection method matched manual performance, ensuring transparency, reproducibility, and easy integration. Lesion counts correlated strongly with manual segmentation, with even higher agreement for lesion volumes, demonstrating its promise for routine clinical detection of contrast-enhancing MS lesions. Study IV found that higher counts of dilated VRS in the centrum semiovale strongly correlated with increased T1 and T2 lesion volumes. Histopathology showed that VRS mainly correspond to arteries affected by vascular pathology but no MS-specific tissue damage, challenging the idea that VRS dilation reflects pre-inflammatory immune cell influx. Conclusion: Developing and integrating advanced MRI techniques, automated lesion detection, and emerging biomarkers may enhance MS diagnosis, support monitoring of disease progression and Gd-related changes and ultimately improve clinical management and patient outcomes.Conclusion: Developing and integrating advanced MRI techniques, automated lesion detection, and emerging biomarkers may enhance MS diagnosis, support monitoring of disease progression and Gd-related changes and ultimately improve clinical management and patient outcomes.List of scientific papersThis thesis is primarily composed of the following four papers, which will be referred to in the text by their corresponding roman numerals:I. MRI detection of brain gadolinium retention in multiple sclerosis: Magnetization transfer vs. T1-weighted imaging. Cananau C, Forslin Y, Bergendal Å, Sjöström H, Fink K, Ouellette R, Kristoffersen Wiberg M, Fredrikson S, and Granberg T Journal of Neuroimaging 2023; 33: 247-255. https://doi.org/10.1111/jon.13079II. Impact and correction of gadolinium-based contrast agent effects on clinical T1-weighted brain MRI volumetrics in multiple sclerosis. Cananau C, Ouellette R, Fredrikson S, Fink K and Granberg T [Submitted]III. Automated Detection and Segmentation of Contrast-Enhancing Lesions in Multiple Sclerosis on Brain MRI: Development of a new Deep Learning Method with Validation in a Clinical Cohort. Cananau C, Ouellette R, Fredrikson S, Fink K and Granberg T [Manuscript]IV. Dilated Virchow-Robin spaces are a marker for arterial disease in multiple sclerosis. Ineichen BV, Cananau C, Platten M, Ouellette R, Moridi T, Katrin B. M. Frauenknecht KBM, Okar SV, Kulcsar Z, Kockum I, Piehl F, Reich DS and Granberg T eBioMedicine - The Lancet. 2023;92: 104631 https://doi.org/10.1016/j.ebiom.2023.104631</p
Intergenerational transmission of mental health problems : observational and quasi-experimental studies
No full textMental health problems run in families, likely due to complex transmission mechanisms. Using nationwide Swedish registers following millions of parents and their children over decades, we investigated how and why mental health problems are transmitted across generations and whether modifiable factors can mitigate these intergenerational risks.Study I examined associations between six parental psychiatric diagnoses and 32 offspring outcomes using a matched cohort design. Most children exposed to parental psychiatric diagnoses were not diagnosed with specialist-assigned disorders by age 44. Nevertheless, these children demonstrated increased risks of all psychiatric, behavioral, and psychosocial outcomes, indicating largely transdiagnostic transmission.Study II explored whether intergenerational transmission was driven by parental psychiatric comorbidity (i.e., captured by a general factor of psychopathology) or by specific dimension- related effects not accounted for by this general factor (i.e., specific internalizing, externalizing, and psychotic factors), using multivariate modeling. We observed that parental general factor of psychopathology significantly predicted all offspring outcomes, while specific factors were primarily associated with corresponding dimensional outcomes. These findings indicate that the transdiagnostic intergenerational transmission of psychiatric risk appeared largely attributable to parental general psychopathology rather than to disorder-specific pathways.Study III explored the intergenerational transmission after controlling for unmeasured familial factors using the largest children-of-identical-twins design to date. Parent-offspring associations attenuated substantially and most (20 of 27) became non-significant when comparing differentially exposed cousins whose parents were identical twins, suggesting that the associations largely reflected unmeasured familial confounding. However, associations between broad psychiatric spectra persisted, suggesting either non-shared confounders or causal environmental effects.Study IV investigated the quasi-experimental effect of parental education on offspring psychiatric, behavioral, and suicidal outcomes using a fuzzy regression discontinuity design. Children of parents exposed to the Swedish education reform (extended compulsory schooling from 7 to 9 years) showed no significant improvement in these offspring outcomes. This indicates that among those parents who would have left school after completing the compulsory schooling (i.e., compliers), additional schooling did not improve their offspring mental health.Study V investigated the quasi-experimental effect of an enriched childhood environment (i.e., proxied by adoption) on broad psychiatric comorbidity using a home-reared versus adopted- away sibling comparison design. Adopted-away siblings scored lower on both the general factor of psychopathology and the externalizing factor, compared to their siblings who remained home-reared by biological parents with psychiatric and behavioral problems. These findings indicate that enriching rearing environments might reduce the transdiagnostic liability toward psychiatric comorbidity among at-risk individuals.In conclusion, the intergenerational transmission of mental health problems appeared largely transdiagnostic (but not deterministic) and driven by parental psychiatric comorbidity. The transmission was largely explained by shared familial factors but also plausibly shaped by environmental effects. While extending parental compulsory schooling showed no causal mental health benefits, enriched childhood rearing environments reduced broad psychopathology vulnerability. These findings support comprehensive and transdiagnostic prevention strategies that improve parental mental health, caregiving quality, and early-life environments, particularly for high-risk families.List of scientific papersI. Mengping Zhou, Christine Takami Lageborn, Arvid Sjölander, Henrik Larsson, Brian D'Onofrio, Mikael Landén, Paul Lichtenstein, Erik Pettersson. Psychiatric Diagnoses in Parents and Psychiatric, Behavioral, and Psychosocial Outcomes in Their Offspring: A Swedish Population-Based Register Study. American Journal of Psychiatry. 2024;181(8):761-773. https://doi.org/10.1176/appi.ajp.20230353II. Mengping Zhou, Henrik Larsson, Brian D'Onofrio, Mikael Landen, Paul Lichtenstein, Erik Pettersson. Intergenerational Transmission of Psychiatric Conditions and Psychiatric, Behavioral, and Psychosocial Outcomes in Offspring. JAMA Network Open. 2023;6(12):e2348439. https://doi.org/10.1001/jamanetworkopen.2023.48439III. Mengping Zhou, Henrik Larsson, Brian D'Onofrio, Mikael Landen, Ralf Kuja- Halkola, Zheng Chang, Isabell Brikell, Paul Lichtenstein, Erik Pettersson. Intergenerational Transmission between Parental Psychiatric Conditions and Offspring Psychiatric, Behavioral, and Psychosocial Outcomes: A Swedish Population-Based Children-of-Monozygotic Twins Study. [Submitted]IV. Mengping Zhou, Henrik Larsson, Brian D'Onofrio, Mikael Landen, Paul Lichtenstein, Erik Pettersson. Association between parental education and offspring psychiatric diagnoses, violent crimes, and suicidal behavior: A nationwide Swedish quasi- experimental study. [Submitted]V. Mengping Zhou, Henrik Larsson, Brian D'Onofrio, Mikael Landen, Paul Lichtenstein, Erik Pettersson. Association between the Childhood Rearing Environment and General and Specific Psychopathology Factors in Middle Adulthood: A Swedish National High- Risk Home-Reared versus Adopted-Away Sibling Comparison Study. Molecular Psychiatry. 2025;30(9):4023-4028. https://doi.org/10.1038/s41380-025-02979-1</p
Periodontitis in young individuals - follow up of treatment and disease progression
No full textBackground and aims: Periodontitis in young individuals, though rare, is often characterized by early onset, rapid progression, and aggressive clinical presentation. Despite the substantial disease burden, long-term data on treatment outcomes, risk factors for disease progression, and tooth loss in this population are limited. This thesis aims to evaluate treatment compliance, long- term disease progression, predictors of tooth loss, and the diagnostic potential of salivary and crevicular cytokines in young patients with periodontitis, followed over at least 10 years. The findings are based on a series of four studies that provide complementary perspectives on both clinical and molecular determinants of periodontal outcomes.Material and methods: Study I is a retrospective case-control study of 234 patients with aggressive periodontitis (AgP) compared to controls with chronic periodontitis (ChP), investigating treatment interruption rates and associated factors. Study II is a retrospective cohort study involving 215 individuals diagnosed with periodontitis before age 36 and re-examined after at least 10 years. Clinical, radiographic, and questionnaire-based data were collected to assess longitudinal marginal bone loss (MBL) and its relationship to behavioural and clinical parameters. In Study III we used national dental and demographic registers to evaluate tooth loss in a cohort of 471 young periodontitis patients and applied analysis to identify risk factors including socioeconomic status and treatment adherence. Study IV explored cytokine profiles in gingival crevicular fluid (GCF) and stimulated saliva in the same cohort as in study II, analysing 18 inflammatory cytokines and their correlation with periodontal grade according to the 2018 periodontal classification.Results: In Study I we found that patients with AgP were significantly more likely to discontinue periodontal treatment than controls (46% vs. 34%, p10 teeth.Generalized periodontitis, stage IV periodontitis, low education, smoking, and interruption of active periodontal treatment (APT) were significantly correlated with tooth loss. Furthermore, periodontal stage IV, low income and education were associated with treatment dropout. In Study IV, salivary levels of IL-1B, IL-6, and IL-18 were significantly elevated in patients with grade C periodontitis, while GCF samples from the same group showed significantly elevated IL-1ß but decreased levels of IL-4, IL-10, IL-15, IP-10, and MIG. Among the cytokines analysed, IL-18 in saliva and IL-4, IL-15, and MIG in GCF demonstrated the highest diagnostic potential in differentiating grade C from grade A, with area under the curve (AUC) values ranging from 0.84 to 0.86.Conclusions: This thesis provides evidence that while long-term periodontal stability is achievable in many young patients, specific risk factors, including poor treatment adherence, smoking, and lower socioeconomic status, are strongly associated with progression and tooth loss. A severe periodontal disease (stage (IV) may also be a predictive variable in this age group for tooth loss and interruption of periodontal treatment. In addition, cytokine profiling shows promising potential for early identification of individuals at risk of high disease progression. These findings support the need for individualized, prevention- oriented care strategies that integrate clinical, behavioural, and molecular assessments to optimize periodontal outcomes in young populations.List of scientific papersI. Treatment compliance in patients with aggressive periodontitis - a retrospective case-control study. Modin C, Abadji D, Adler L, Jansson L. Acta Odontologica Scandinavia 2017, 75:2, 94-99. https://doi.org/10.1080/00016357.2016.1259497II. Periodontitis in young individuals: Important factors for disease progression. Modin C, Dolk-Rinon C, Faham A, Gustafsson A, Yucel- Lindberg T, Jansson L. Journal of clinical Periodontology 2024 Jan;51(1):74-85. https://doi.org/10.1111/jcpe.13884III. Factors influencing tooth loss over 9 - 11 years in young individuals with periodontitis. Modin C, Cederlund A, Gustafsson A, Yucel- Lindberg T, Jansson L. Journal of Periodontology 2025, Aug 2. https://doi.org/10.1002/JPER.24-0687 IV. Cytokine profile in saliva and gingival crevicular fluid in relation to periodontal grade. Modin C, Dolk-Rinon C, Faham A, Eskander F, Jansson L, Gustafsson A, Yucel-Lindberg T. [Manuscript]</p
Acceptance and commitment therapy in supporting parents of children with disabilities
No full textBackground: The overarching aim of this PhD thesis was to evaluate the feasibility and outcomes of the Navigator ACT intervention for stressed and distressed parents of children with disabilities within the context of outpatient habilitation (disability health care) services. Providing parents a treatment that is feasible, safe, acceptable, and effective is essential for supporting their well-being and caregiving capacity. A further objective was to contribute to research on the assessment and treatment of psychological inflexibility among caregivers.Methods: Data were collected mainly in habilitation services in Stockholm region but also in 15 other regions in Sweden and through web-based surveys. The participants were parents of children receiving services in habilitation clinics. In Study 1, over 2000 parents, both with and without children with disabilities aged 0-18 years, completed the Parental Acceptance and Action Questionnaire which measures parental psychological flexibility, to evaluate the psychometric properties of the main outcome measure used in this project. In Study 2, n = 94 parents of children with neurodevelopmental disabilities participated. We used attendance statistics, and treatment evaluations to examine the feasibility of the Navigator ACT. Five self-rate scales were used to measure, e.g., psychological flexibility, before and after the treatment and at a 4-month follow-up. In Study 3, which was an RCT, the same self-rating scales were used in a sample of n = 137 parents randomized to Navigator ACT (n = 70) or treatment-as-usual (TAU, n = 67). The Navigator ACT group received the treatment immediately, while the TAU group received it in the following term. In Study 4, predictors of attrition and treatment outcomes were examined in n = 529 parents who started the treatment.Results: In Study I, we found support for the construct validity and reliability of PAAQ. In Study 2, we concluded that Navigator ACT is a feasible and well-received treatment within open habilitation services. Parents and group leaders considered the treatment as highly credible. Additionally, we found positive preliminary outcomes in psychological flexibility, anxiety, depression, mindfulness, and child difficulties, mainly with large effect sizes. Changes in parenting stress were significant first at follow-up. In study 3, Navigator ACT outperformed TAU in reducing parental psychological inflexibility and parenting stress and in increasing parent-reported prosocial behaviors of the child with disability. Parents in both the ACT and TAU groups experienced reduced symptoms of depression and anxiety, but the Navigator ACT was not more effective than TAU. In Study 4, we found that the attrition rate of the Navigator ACT was 18.5%, which is comparable to other ACT-based treatments. Most sociodemographic or clinical variables did not predict attrition or treatment outcomes. However, parents with disabilities (mainly ADHD and autism), and parents with three or more children were at higher risk of attrition. Older age and higher educational levels were associated with a lower risk of attrition. High pre-treatment scores on credibility and outcome expectancy, and higher distress (anxiety/depression), predicted better outcomes in psychological flexibility. Although the findings were significant, these variables explained only a small portion of the outcome variance.Conclusions: Navigator ACT is a safe, feasible and promisingly effective option for addressing psychological inflexibility and parenting stress within Swedish habilitation services context. The long-term effects of Navigator ACT warrant further investigation.List of scientific papersI. Holmberg Bergman, T., Sandred, A., Lindström, T., Lappalainen, P., Ghaderi, A., & Hirvikoski, T. (2024). A psychometric Evaluation of the Parental Acceptance and Action Questionnaire (PAAQ) in Parents of Children with and without Disabilities. Journal of Contextual Behavioral Science, 32, 100757. https://doi.org/10.1016/j.jcbs.2024.100757II. Holmberg Bergman, T., Renhorn, E., Berg, B., Lappalainen, P., Ghaderi, A., & Hirvikoski, T. (2022). Acceptance and Commitment Therapy Group Intervention for Parents of Children with Disabilities (Navigator ACT): An Open Feasibility Trial. Journal of Autism and Developmental Disorders, 1-1. https://doi.org/10.1007/s10803-022-05490-6III. Holmberg Bergman, T., Lappalainen, P., Ghaderi, A., Hirvikoski, T. The Effectiveness of Acceptance and Commitment Therapy in Group (Navigator ACT) for Stressed Parents of Children with Disabilities-A Randomized Controlled Trial. [Submitted]IV. Holmberg Bergman, T. Lappalainen, P., Renhorn, E., Mahdi, S., Ghaderi, A., Hirvikoski, T. Predictors of Attrition and Treatment Outcome in ACT Group Treatment for Parents of Children with Disabilities. [Submitted]</p
Optimizing the therapeutic potential of extracellular vesicles in cancer
No full textExtracellular vesicles (EVs) are membrane-enclosed nanoparticles secreted by all cell types. They carry a variety of bioactive molecules, including lipids, proteins, and nucleic acids, which can act as signaling messengers to other cells. The two main types of EVs under investigation are microvesicles and exosomes. Microvesicles are formed by outward budding of the plasma membrane, while exosomes originate from inward budding within multivesicular bodies and are released upon fusion with the plasma membrane. EVs are found in various biological fluids such as blood, saliva, and urine, as well as in cell culture media. Their roles in intercellular communication have made them a focus of research in fundamental biology, biomarker discovery, and therapeutic development, including engineering EVs for clinical applications.Studying EVs often requires their isolation, which presents several challenges. The physical and molecular similarities between EV subtypes make them difficult to separate, and common isolation protocols often co-isolate contaminants such as protein aggregates and lipoproteins. In Study I, we compared five fundamentally different EV isolation techniques, each based on distinct EV properties such as density, size, affinity, and hydrophobicity. These methods were applied to two biofluids, cell culture supernatant and plasma, at varying volumes to assess whether the optimal isolation method depends on the biofluid type. Plasma, for instance, contains high levels of lipoproteins that overlap with EVs in size and density, complicating isolation. EV isolates were characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), Bioanalyzer, flow cytometry, and proteomic profiling. All methods successfully enriched for EVs, but the composition and quality of the isolates varied depending on the biofluid, sample volume, and isolation technique. This study emphasized the importance of method selection, as each technique isolates different EV subpopulations with different contaminants, which can affect study outcomes and comparability. It also highlighted that some components initially considered as contaminants may be biologically relevant.In Studies II and III, we explored the therapeutic potential of dendritic cell (DC)- derived EVs, particularly their use in cancer immunotherapy. Using EVs loaded with the model antigen ovalbumin (OVA), we investigated strategies to enhance their immunogenicity. In Study II, we focused on the immune checkpoint molecule PD-L1, which was present on our EVs. PD-L1 present on Tumor-derived EVs is known to suppress T cell activation, but its role on therapeutic DC-EVs was unclear. We generated PD-L1-deficient (PD-L1-/-) EVs and compared their immunogenicity to wild-type EVs in multiple mouse tumor models. While most models showed a trend toward stronger immune activation with PD-L1-/- EVs, a significant improvement was observed only in a prophylactic tumor model. These findings suggest that removing PD-L1 may enhance the efficacy of EV-based immunotherapies.In Study III, we tested whether targeting EVs to B cells could further improve their immunogenicity. A soluble fusion protein (C1C2-D123) was developed to bind phosphatidylserine on EVs and CD21 on B cells. This protein successfully directed EVs to B cells in vitro and in vivo without altering their biodistribution. In an in vivo immunization model, EVs decorated with the fusion protein induced a higher frequency of antigen-specific CD8+ T cells compared to non-targeted EVs, supporting B cell targeting as a strategy to enhance immune responses.In conclusion, this thesis highlights the importance of EV isolation strategy and cargo engineering in optimizing EV-based therapies. It demonstrates that both the method of isolation and the molecular composition of EVs significantly influence their biological and therapeutic potential.List of scientific papersI. Rosanne E. Veerman, Loes Teeuwen, Paulo Czarnewski, Gözde Güclüler Akpinar, AnnSofi Sandberg, Xiaofang Cao, Maria Pernemalm, Lukas M. Orre, Susanne Gabrielsson, Maria Eldh. Molecular evaluation of five different isolation methods for extracellular vesicles reveals different clinical applicability and subcellular origin. J Extracellular Vesicles. Volume 10, Epub e12128, (2021). https://doi.org/10.1002/jev2.12128II. Teeuwen*, L., Steiner*, L., Reinhardt, C., Offens, A., Kuipers, J.E., Martínez- Martínez, D., Mazouin, J., Chambers, B.J., Güçluler Akpinar, G., Gabrielsson, S. Removal of PD-L1 on extracellular vesicles for cancer vaccination modulates anti-tumor responses in a murine immunotherapy model. [Manuscript]III. Annemarijn Offens, Loes Teeuwen, Gozde Gucluler Akpinar, Loïc Steiner, Sander Kooijmans, Doste Mamand, Hannah Weissinger, Alexander Kall, Maria Eldh, Oscar P.B. Wiklander, Samir El-Andaloussi, Mikael C.I. Karlsson, Pieter Vader, Susanne Gabrielsson. A fusion protein that targets antigen-loaded extracellular vesicles to B cells enhances antigen-specific T cell expansion. J Controlled Release, Volume 382, 113665 (2025). https://doi.org/10.1016/j.jconrel.2025.113665* Shared first authorship.</p
Evaluating health-promoting parenting programs for migrant families
No full textBackground: For many immigrant families, the journey doesn't end at the border. While recently settled families often demonstrate considerable resilience, navigating life in a new culture can be highly stressful, placing immense strain on their well-being. These stressors, combined with the challenges experienced by all parents to adolescents due to the intensive development phase that young people go through, highlight the need of support for immigrant families. Parenting support programs are well- established tools for promoting positive parenting and youth well-being. However, programs tailored for underserved groups, such as migrants, remain limited. There is a particular scarcity of culturally sensitive programs aimed at strengthening parents' resilience early in the resettlement process and delivered in the parents' native language.Aim: The overall aim of the thesis was to provide an overview of existing health-promoting and preventive parenting interventions for forcibly displaced families. Informed by these previous interventions, and by parents expressed needs, the thesis also aimed to develop and evaluate a new brief, resilience- focused parenting program delivered in mother tongue for recently settled immigrant parents of adolescents in Sweden. Study I systematically evaluated available empirical knowledge regarding the efficacy of health-promoting and/or preventive parenting programs for forcibly displaced families. Study II explored the experiences and challenges of newly settled parents of adolescents to inform program development. Study III piloted the newly developed program, assessing its feasibility, acceptability and preliminary effects. Study IV evaluated the program's effectiveness for recently settled immigrant parents. Study V explored parents' perceptions of the program.Methods: A mixed-methods approach guided the thesis with both qualitative and quantitative components. Study I is a systematic review and meta- analysis of parenting interventions for forcibly displaced families. Study II is a qualitative study were 28 recently settled refugee parents were interviewed in native language regarding their experiences of coming to Sweden. Study III is a mixed-method pilot study combining quantitative self-reports with qualitative data from leader interviews and session reports. Study IV is a cluster randomized controlled trial involving 130 parents (90 intervention, 40 control), analyzed using Latent Change Models. Thereafter 17 parents who had participated were interviewed about their experiences (Study V).Results: Study I found growing research interest in parenting programs for forced migrant families. A total of 20 publications were included, showing that parenting interventions led to reduced externalizing behavior in children and improved parenting strategies, self-efficacy, and parental mental health. However, there was high heterogeneity, and more high-quality studies are needed to identify effective components and optimize interventions. Study II highlighted refugee parents' strengths and motivations, with language emerging as a central theme for integration and navigating parenthood in the new cultural context. This theme encompassed four categories: "parents' motivation and hope as driving forces," "navigating between past and present cultures and values," "loneliness as a risk factor," and "a new way of parenting and relating to the acculturation gap." A culturally sensitive parenting program should acknowledge and validate bicultural experiences, strengthen parental self- efficacy, and offer alternative strategies that align with both protective factors for child development and the sociocultural realities of the host context. Study III showed that the program was feasible and acceptable, with cultural bridging and relationship-building being crucial. Preliminary effects were observed in parents' ability to provide a safe haven for their adolescents, as well as in their increased sense of societal belonging. The integration of quantitative and qualitative findings suggested that the parenting program was a space where parents could explore new parenting strategies, engage in discussions and openly talk about challenges. Study IV demonstrated the program's effectiveness in improving parental resilience and self-efficacy in supporting the child's schooling. Notably, parents who entered the program with greater difficulties experienced significantly greater advances compared to those starting from a more favorable position. The program was well received, and parents expressed a strong willingness to recommend it to other parents. Study V confirmed that the program was both well accepted and effective in strengthening parental self-efficacy. The categories included learning about the new society, balancing cultural contrasts, enhancing general parenting skills, and recognizing both barriers and facilitators - such as fear of social institutions and the value of social support. The program's cultural sensitivity, in both its design and delivery, appears to be essential to its perceived value and acceptability among participants.Conclusions. In summary, parenting programs for migrant families represent a growing research field yet remain an underutilized resource in contemporary societies. Recently settled parents often demonstrate remarkable resilience and motivation during the resettlement process, while also encountering challenges in adapting to new cultural contexts. This new, brief, and culturally sensitive parenting program shows promise as an empowering intervention for immigrant families with adolescents, in the face of an often stressful post- migration reality. With thoughtful implementation and continued research, such programs can serve as important tools in promoting family resilience and advancing equity in health promoting interventions globally.List of scientific papersI. Västhagen, M., Giles, CJ., Hollander, A-C., Ghaderi, A., Van Leuven, L., Edenius, A. & Enebrink, P. The efficacy of parenting interventions for forced migrant families on child internalizing and externalizing symptoms, parental self-efficacy, and parental competence: A systematic review and meta-analysis. Transcultural Psychiatry. [Accepted]II. Västhagen, M., Özdemir, M., Ghaderi, A., Kimber, B., Giles, CJ., Bayram Özdemir, S., Oppedal, B., & Enebrink, P. (2022). Refugee parents' experiences of coming to Sweden: A qualitative study. International Journal of Intercultural Relations, 91, 97-109.https://doi.org/10.1016/j.ijintrel.2022.08.010III. Västhagen, M., Özdemir, M., Kimber, B., Ghaderi, A., Place, V. & Enebrink, P. (2025). A brief universal parenting program for recently settled immigrants in Sweden: a feasibility study. [Submitted].IV. Västhagen, M., Enebrink, P., Kimber, B., Ghaderi, A., Bayram Özdemir, S., Oppedal, B. & Özdemir, M. (2025). The Effectiveness of a Universal Parenting Program for Immigrants in Sweden: A Cluster Randomized Controlled Trial. [Submitted].V. Västhagen, M., von Schreeb, A., Özdemir, M., Kimber, B. & Enebrink, P. (2025). A qualitative study of immigrant parents' experiences of participating in a universal parenting program in Sweden. [Submitted].</p
Mapping the prefrontal cortex : structure, activity, function
No full textThe mouse prefrontal cortex (PFC) is an umbrella term for rostrally located neocortical brain regions. The PFC serves a fundamental role in computing and integrating signals underlying the generation of purposeful, goal-directed actions. Despite increasing knowledge about the molecular, morphological, and physiological diversity of PFC networks, our current knowledge about the exact mechanisms of prefrontal action remains limited.In the present thesis, we aimed at filling this knowledge gap by creating detailed maps of the PFC based on different structural and functional criteria agnostic to preconceived borders of PFC subregions. As mapping the PFC requires adequate methods, we developed two research tools that enable researchers to map the brain. The DMC-Behavior Platform allows for rigid and standardized training of head-fixed mice on auditory detection and decision-making tasks, while DMC- BrainMap is a software for mapping of anatomical features to reference spaces in different model organisms.We subsequently created maps of the PFC based on structural and functional criteria including the anatomical organization of prefrontal top-down projections and spontaneous as well as task-related prefrontal activity patterns. We found that the mappings of the respective features do not adhere to preconceived delineations of PFC subregions, but are organized in spatially cohesive modules transcending PFC subregion borders, or in networks distributed across the entire PFC.These findings challenge the notion that brain regions constitute the fundamental organization unit of the PFC to which functional labels can be assigned, and warrant a careful re-examination of existing findings concerning the structural and functional organization of the PFC. Conversely, a data-driven research approach, as exemplified in this thesis, harbors the potential to elucidate previously uncharted organizational principles of the PFC, with the prospect of understanding PFC function in health and disease.List of scientific papersI. DMC-Behavior Platform: An Open-Source Framework for Auditory-Guided Perceptual Decision-Making in Head-Fixed Mice. Jung, F., Cao, X., Heymans, L., Carlén, M. eNeuro, 2025 Apr 10;12(4):ENEURO.0457-24.2025. https://doi.org/10.1523/ENEURO.0457-24.2025II. DMC-BrainMap - an open-source, end-to-end tool for multi- feature brain mapping across species. Jung, F., Cao, X., Heymans, L., Carlén, M. bioRxiv (preprint), 2025. https://doi.org/10.1101/2025.02.19.639009III. Mouse prefrontal cortex displays region- and cell-type-specific projections to sensory cortices. Jung, F., Heymans, L., Cao, X., Carlén, M. [Manuscript]IV. A Prefrontal Cortex Map based on Single Neuron Activity. Le Merre, P., Heining, K., Slashcheva, M., Jung, F., Moysiadou, E., Guyon, N., Yahya, R., Park, H., Wernstal, F., Carlén, M. bioRxiv (preprint), 2024. https://doi.org/10.1101/2024.11.06.622308V. Esr1+ hypothalamic-habenula neurons shape aversive states. Calvigioni, D., Fuzik, J.,Le Merre, P., Slashcheva, M., Jung, F., Ortiz, C., Lentini, A., Csillag, V., Graziano, M., Nikolakopoulou, I., Weglage, M., Lazaridis, I., Kim, H., Lenzi, I., Park, H., Reinius, B., Carlén, M., Meletis, K. Nature Neuroscience, 2023 Jul;26(7):1245-1255. https://doi.org/10.1038/s41593-023-01367-8</p
Myocardial injury in patients undergoing vascular surgery
No full textBackground: Cardiac complications are one of the most common complications after non-cardiac surgery. Perioperative myocardial injury (PMI), defined as a perioperative rise in troponin, is in turn, one of the most common cardiac complications after noncardiac surgery. PMI is associated with increased short- and long-term mortality after non-cardiac surgery. The overarching aim of this thesis was to find potentially preventable risk factors for PMI and study the effect of PMI on different organ systems.Aims: Study I aimed to study the association between supplementary oxygen, in non-hypoxemic patients, and major postoperative complications, PMI and postoperative elevation in N-terminal pro-B-type natriuretic peptide (NT proBNP). Study II aimed to study the association between PMI, preoperative high-sensitivity cardiac troponin T (hs-cTnT) and NT-proBNP, respectively, and non-cardiac complications. Study III aimed to explore the association between predefined thresholds for intraoperative hypotension (IOH) (systolic, mean, and diastolic arterial pressure) and tachycardia, and PMI. Study IV aimed to determine if the postoperative increase in troponin, in patients with PMI, is associated with newly found regional wall motion abnormality (RWMA) or perioperative change in other echocardiographic parameters commonly used to describe cardiac morphology and function.Materials and Methods: Study I was a single-blinded, multicenter, randomized controlled trial in patients undergoing vascular surgery. Patients were randomized to group H (Hyperoxia) F;O2250 % and a target SpO2 > 98 % or group N (Normoxia) F;O2 = 0.21 % and a target SpO2 ≥ 90 %. The primary endpoint was postoperative complications within 30 days after surgery. The secondary endpoints were PMI and postoperative elevation in NT-proBNP, determined by hs-cTnT and NT-proBNP preoperatively and at 4, 24 and 48h after surgery. The secondary outcomes were one-year mortality. Data was analyzed using Fisher's exact test or General estimating equations (GEE) as appropriate. Study II was a post-hoc analysis of Study I. The primary outcome was NCC, defined the same as in Study I, with the exclusion of cardiac complications. Data was analyzed using GEE or logistic regression as appropriate. Study III was a single-center, prospective observational trial in patients undergoing vascular surgery. Absolute and relative thresholds were used to define intraoperative systolic, mean, and diastolic arterial hypotension, measured every 15 seconds by invasive arterial pressure monitoring and heart rate using the Philips IntelliVue X3 monitor. Decision tree machine-learning (ML) models were used to explore which thresholds for IOH and tachycardia best predict PMI. A whitebox-model was used to prioritize clinical utility and transparency over the performance of the ML model. Study IV was a prospective observational sub-study nested within Study III. The primary outcome was newly detected RWMA (hypokinesia or akinesia) determined by a blinded assessor comparing pre- and postoperative transthoracic echocardiography (TTE). Data was analysed using an exact logistic regression model.Results: In Study I, 191 patients were randomized. Seven patients were excluded after randomization, mostly due to canceled operations and equipment problems. A per-protocol principle was used for analysis. In total, postoperative complications were incurred by 43 out of 94 patients (46%) in group H and 36 out of 90 patients (40%) in group N (p = 0.46). The incidence of PMI was 27 % in group H and 22 % in group N (p = 0.41). At one-year follow-up, one patient had died in group H. In Study II, NCC was incurred by 67 patients (36 %). There was a significant association between PMI and NCC, OR 2.71 (95 % CI 1.33-5.55, p = 0.01). No association was found between pre-operative hs-cTnT or NT-proBNP and NCC. In Study IV, 498 patients were included. In total, 99 patients (20 %) incurred PMI. Thresholds based on absolute diastolic arterial pressure (DAP) had the strongest correlation with PMI and the ML model with DAP Conclusion: No difference was found in the incidence of postoperative complications or perioperative myocardial injury in non-hypoxemic patients randomized to a fraction of inspired oxygen of 0.21 or 20.50. There is an association between perioperative myocardial injury and an increased risk of non-cardiac complications. However, no association was found between preoperative levels of high-sensitivity cardiac troponin T and N-terminal pro-B- type natriuretic peptide, and non-cardiac complications. An absolute, not relative, intraoperative hypotension threshold based on diastolic arterial pressure, and not systolic or mean arterial pressure, or tachycardia, was most predictive of perioperative myocardial injury. In patients with perioperative myocardial injury, there is an association between a postoperative increase in troponin and a newly detected decrease in regional and global cardiac function. Pre- and postoperative transthoracic echocardiography may be needed to distinguish between old and newly detected perioperative changes in cardiac functionList of scientific papersI. POSTOPERATIVE COMPLICATIONS AND MYOCARDIAL INJURY IN PATIENTS RECEIVING AIR OR OXYGEN. PROSPECTIVE, RANDOMISED AND PILOT STUDY. Valadkhani A, Henningsson R, Nordström JL. Granström A, Hallqvist L, Wahlgren CM, Peterzén B, Eriksson J, Bell M, Gupta A. Acta anaesthesiologica Scandinavica. 2022;66(10):1185-1192. https://doi.org/10.1111/aas.14136II. PERIOPERATIVE MYOCARDIAL INJURY IS ASSOCIATED WITH INCREASED POSTOPERATIVE NON-CARDIAC COMPLICATIONS IN PATIENTS UNDERGOING VASCULAR SURGERY: A POST HOC ANALYSIS OF A RANDOMISED CLINICAL PILOT TRIAL. Valadkhani A, Gupta A, Bell M. Perioperative medicine (London, England). 2023;12(1):58 https://doi.org/10.1186/s13741-023-00350-yIII. DIASTOLIC VERSUS SYSTOLIC OR MEAN INTRAOPERATIVE HYPOTENSION AS PREDICTIVE OF PERIOPERATIVE MYOCARDIAL INJURY IN A WHITE-BOX MACHINE-LEARNING MODEL. Valadkhani A, Gupta A, Cauli G, Nordström JL, Rohi A, Tufexis P, Hällsjö Sander C, Jacobsson M, Bell, M. Anesthesia and analgesia. Published online February 20, 2025. https://doi.org/10.1213/ANE.0000000000007379IV. CARDIAC FUNCTION IN PATIENTS WITH PERIOPERATIVE MYOCARDIAL INJURY. A PROSPECTIVE OBSERVATIONAL SUB-STUDY. Valadkhani A, Gupta A, Mellbin L, Bell M. [Submitted]</p