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The role of HNRNPU-locus and circular RNAs in neuronal development and neurodevelopmental disorders
No full textNeuronal development is a complex process regulated by precise gene expression programs involving chromatin organization, epigenetic modifications and RNA processing. Understanding these regulatory mechanisms is essential for elucidating how neural cells acquire and maintain their identity. In this thesis, the roles of RNA-binding protein HNRNPU and circular RNAs in regulating neuronal development were investigated using in vitro cell cultures and cortical organoids as model systems.In Study I, the focus was on examining the effects of HNRNPU deficiency on neural differentiation, RNA splicing, and 3D genome organization using a 2D in vitro model. HNRNPU deficiency was shown to cause significant disruptions in these processes. Genes that are localized in chromatin regions with differential 3D conformation and genes encoding mRNAs with differential splicing in HNRNPU- deficient cells were associated with neurodevelopmental disorders. Additionally, HNRNPU deficiency was shown to result in increased proportion of neural progenitors within differentiating neural populations. These disrupted trajectories highlight the importance of HNRNPU in maintaining genomic integrity and neural stem cell commitment to differentiation.The molecular interactome of HNRNPU during neural differentiation was investigated in Study II. Key regulatory networks associated with HNRNPU were identified using ribonucleoprotein immunoprecipitation, mass spectrometry and RNA sequencing. HNRNPU was found to, for example, interact with mammalian SWI/SNF chromatin remodeling complex, bringing new insights into the regulatory mechanisms behind chromatin organization defects seen in relation to HNRNPU deficiency. Identifying HNRNPU binding to mRNAs encoding DNA methylation regulators led to measuring global DNA methylation levels after HNRNPU silencing, revealing significant hypomethylation. This finding linked HNRNPU deficiency to the distinct methylation episignatures reported in individuals with HNRNPU- related neurodevelopmental disorders.The expression of circular RNAs during neural differentiation was explored in Study III. Key circular RNAs with increasing expression patterns were identified and validated. Interestingly, several circular RNAs were formed from linear mRNAs encoding proteins with synaptic functions, elucidating their possible regulatory roles and contributions to neurodevelopmental processes. Additionally, the exons within these circular RNAs had an increased frequency of genetic variation, and RNA-binding protein SFPQ was identified as a key regulator of these circular RNAs. The findings from this study provide an important resource for further research focusing on the roles of circular RNAs in neuronal development.In Unpublished results, the effects of different types of mutations affecting the HNRNPU-locus were investigated using a 3D cortical organoid in vitro model. New insights into the early gene expression regulation and epigenetic control exerted by HNRNPU were uncovered during neuronal development through single-cell RNA sequencing and DNA methylation arrays. Preliminary results revealed differences from different types of genetic variants in the HNRNPU-locus.Collectively, these studies enhance our understanding of the genetic and molecular basis of neurodevelopmental disorders. By elucidating the roles of HNRNPU and circular RNAs in neuronal development, we provide valuable knowledge of the roles of RNA-binding proteins and non-coding RNAs in orchestrating gene expression control during neuronal development.List of scientific papersI. Mastropasqua F.#, Oksanen M.#, Soldini C., Alatar S., Arora A., Ballarino R., Molinari M., Agostini F., Poulet A., Watts M.E., Rabkina I., Becker M., Li D., Anderlid B.M., Isaksson J., Lundin Remnelius K., Molsem M., Jacob Y., Falk A., Crosetto N., Bienko M., Santini E., Borgkvist A., Bölte S., Tammimies K. Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis. Biol Open. 2023 Oct 15;12(10):bio060113. https://doi.org/10.1242/bio.060113II. Oksanen M., Mastropasqua F., Mazan-Mamczarz K., Martindale J.L., Ye X., Arora A., Banskota N., Gorospe M., Tammimies K. Molecular interactome of HNRNPU reveals regulatory networks in neuronal differentiation and DNA methylation. BioRxiv. [Submitted; Preprint]https://doi.org/10.1101/2025.02.19.638869III. Watts M.E., Oksanen M., Lejerkrans S., Mastropasqua F., Gorospe M., Tammimies K. Circular RNAs arising from synaptic host genes during human neuronal differentiation are modulated by SFPQ RNA-binding protein. BMC Biol. 2023 May 26;21(1):127. https://doi.org/10.1186/s12915-023-01627-w# Denotes equal contribution</p
Lipid-lowering therapy in a real-world setting : eligibility, utilization, and goal attainment
No full textIntroductionLow-density lipoprotein cholesterol (LDL-C), and other lipid fractions containing apolipoprotein B, have been identified as key components in the process of atherogenesis and consequently the progression to cardiovascular disease (CVD). Lowering LDL-C with lipid-lowering therapy has been identified as an important aspect in the reduction of the incidence of atherosclerotic CVD (ASCVD) events. The European Society of Cardiology (ESC) have published guidelines on LDL-C and provided recommendations on the use of lipid-lowering therapy. This thesis aimed to evaluate the implementation and potential implications of these recommendations in a real-world setting.Methods and resultsIn study I, the attainment of the LDL-C goals of the 2011 (50% lowering from baseline levels) ESC guidelines were evaluated. Using nationwide registers, including the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART), we identified all adult patients In study II, the potential implications of implementing the 2019 ESC dyslipidemia guidelines and the eligibility of combination lipid-lowering therapy were evaluated. Using data from SWEDEHEART and other national registries, the application of the 2019 ESC guideline goals (50% baseline level reduction) and recommendations were assessed in a cohort of patients at 6-10 weeks after the index MI (n=25,466). Using a Monte Carlo simulation model, the effects of maximizing and escalating treatment with lipid-lowering therapies on the attainment of the 2019 LDL-C goals were estimated. Despite most patients (87%) receiving high-intensity statin therapy, 83% of the cohort were still eligible for escalation of their lipid-lowering therapy since they had not attained the 2019 LDL-C goals. Simulating the use of maximized high-intensity statin therapy, 20% of the cohort reached the goals, and adding therapy with ezetimibe an additional 29% percent reached the goals. Thus, 51% of the cohort were still eligible for additional therapy with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. After therapy with PCSK9 inhibitors were simulated, approximately 90% of all patients reached the LDL-C goals.In study III, in accordance with the 2021 ESC guidelines, the prevalence of CVD risk categories and the proportion potentially eligible for lipid-lowering therapy were assessed in apparently healthy individuals. Using the Swedish Cardiopulmonary Bioimage Study (SCAPIS), which randomly invited individuals in Sweden aged 50- 64 years, apparently healthy individuals were identified. Applying the Systemic Coronary Risk Estimation 2 (SCORE2) equation to these individuals (n=26,570), 32% and 4% were estimated as having high and very high 10-year risk of fatal and nonfatal CVD, respectively. Among these individuals, 99% had LDL-C levels above the guidelines' targets, resulting in 35% of the total cohort being eligible for lipid- lowering therapy as per the 2021 guidelines. In individuals eligible for lipid-lowering therapy, 38% had no evidence of atherosclerosis in their coronary arteries according to computed tomography. When the SCORE2 multicell chart was used, the proportion eligible for lipid-lowering therapy was 52%, in which 44% had no evidence of coronary atherosclerosis. The use of lipid-lowering therapy was reported in 7% of those with high and very high risk, and an additional 11% received lipid-lowering therapy within 6 months after participating in SCAPIS.In study IV, utilization and discontinuation rates of secondary preventive medications (statins, renin-angiotensin-aldosterone system (RAAS) inhibitors, beta-blockers, and low-dose aspirin) after an MI were evaluated. We identified all adult patients with a first-time MI that survived >30 days and were registered in SWEDEHEART during 2006-2021. Information on filled prescriptions were collected from national registries, and each drug class was analyzed separately for initiation, discontinuation, reinitiation, and the proportion of patients with ongoing therapy within 1-12 years after the index MI. We identified 122,288 patients discharged with a first statin prescription, 79,968 with a RAAS inhibitor, 105,095 with a beta-blocker, and 127,463 with low-dose aspirin. After discharge from the index MI, the proportion of patients filling a first prescription ranged from 95%-97% across the drugs. Using a grace period of 90 days, 12%-14% of those who initiated therapy discontinued it at 1 year, 79%-82% at 5 years, and 74%-79% at 12 years after the index MI. Among the patients who discontinued therapy, the rates of reinitiation ranged from 28% to 46% at 1 year, 42% to 62% at 5 years, and 47% to 67% at 12 years. The proportions of patients who were alive and had ongoing treatment (regardless of previous discontinuation) were 91%-92% at 1 year, 79%-82% at 5 years, and 74%-79% at 12 years after the index MI.ConclusionsIn a nationwide real-world setting in Sweden, the LDL-C goals of the 2011 and 2016 ESC dyslipidemia guidelines were not attained in many patients with a recent MI. When applying the 2019 ESC dyslipidemia guidelines on patients with an MI, despite maximizing the use of high-intensity statins and ezetimibe, eligibility for PCSK9 inhibitors was estimated to be present in approximately half of the patients. In apparently healthy middle-aged individuals, application of the 2021 ESC guidelines resulted in 35% being eligible for lipid-lowering therapy, with many having no signs of coronary atherosclerosis. After a first-time MI, many patients discontinue therapy with CVD preventive medications during a period of 1-12 years. However, many patients later reinitiate previously discontinued therapy, and among alive patients many have ongoing treatment at 1-12 years after the MI.List of scientific papersThis thesis is based on the following papers, which will be referred to by their corresponding Roman numerals:I. Ali Allahyari*, Tomas Jernberg, Dominik Lautsch, Pia Lundman, Emil Hagström, Jessica Schubert, Robert Boggs, Stina Salomonsson, Peter Ueda. Low-density lipoprotein-cholesterol target attainment according to the 2011 and 2016 ESC/EAS dyslipidaemia guidelines in patients with a recent myocardial infarction: nationwide cohort study, 2013-17. European Heart Journal - Quality of Care and Clinical Outcomes. Volume 7, Issue 1, January 2021, Pages 59-67. https://doi.org/10.1093/ehjqcco/qcaa016II. Ali Allahyari*, Tomas Jernberg, Emil Hagström, Margret Leosdottir, Pia Lundman, Peter Ueda. Application of the 2019 ESC/EAS dyslipidaemia guidelines to nationwide data of patients with a recent myocardial infarction: a simulation study, European Heart Journal. Volume 41, Issue 40, 21 October 2020, Pages 3900-3909. https://doi.org/10.1093/eurheartj/ehaa034III. Ali Yari, Peter Ueda, Pia Lundman, Joakim Alfredsson, Annica Ravn- Fischer, Stefan Söderberg, Troels Yndigegn, Emil Hagström, Tomas Jernberg. Eligibility for lipid-lowering therapy when applying systemic coronary risk estimation 2 according to guidelines on apparently healthy middle-aged individuals. European Journal of Preventive Cardiology. Volume 31, Issue 15, October 2024, Pages 1890-1897. https://doi.org/10.1093/eurjpc/zwae190IV. Ali Yari, Carl-Emil Lim, Emil Hagstrom, Pia Lundman, Jessica Schubert, Tomas Jernberg, Peter Ueda. Utilization and discontinuation of secondary preventive medications after myocardial infarction: a nationwide cohort study. [Manuscript]*Former last name</p
Improving detection and treatment of health anxiety : diagnostic tools, digital interventions, and substance-related risks
No full textBackground: Severe health anxiety is a disabling condition characterized by excessive fear of illness, leading to distress, functional impairment, and reduced quality of life. Despite available evidence-based treatments, many affected individuals remain undiagnosed and untreated. This thesis aimed to improve the identification, treatment, and understanding of severe health anxiety by examining diagnostic tools, treatment effectiveness, and potential negative consequences.Study 1: The first study evaluated the Swedish version of the Short Health Anxiety Inventory (SHAI-14), when used as a screening tool for severe health anxiety. Using data from 1,729 psychiatric patients and 85 healthy controls, the study established optimal cut-off scores for different clinical settings and explored severity classifications. Results confirmed SHAI-14's diagnostic accuracy and its potential use in routine screening and treatment outcome monitoring.Study 2: The second study assessed the effectiveness of guided internet-based cognitive behavioural therapy (ICBT) for severe health anxiety in routine psychiatric care. A total of 447 patients completed a 12-week ICBT program, and the primary outcome was the 14-item Short Health Anxiety Inventory (SHAI-14). A within-group design with repeated measures was utilized for the primary analysis. The treatment was associated with significant symptom reductions and high patient satisfaction. Participants who completed more treatment modules experienced greater reductions in SHAI-14 scores, emphasizing the importance of patient engagement in digital interventions.Study 3: The third study explored the feasibility of a brief, unguided digital self- care intervention for severe health anxiety. Adapted from the ICBT program in Study 2, this intervention aimed to improve accessibility by reducing treatment length and complexity. In this uncontrolled study, 25 participants completed the intervention, with the SHAI-14 as the primary outcome measure. Despite the lack of therapist support, participants reported significant symptom improvement at post-treatment, suggesting that brief self-guided interventions may serve as a viable option for individuals preferring unguided treatment. Future studies should evaluate its efficacy in controlled trials.Study 4: The fourth study investigated the association between severe health anxiety and substance-related problems using Swedish register data. A cohort of 4,129 individuals diagnosed with ICD-10 hypochondriasis was compared with 41,290 matched controls from the general population. The results revealed a 2.55-fold increased risk of substance-related problems, after controlling for sociodemographic factors and family history of substance-related problems. Although psychiatric comorbidities attenuated the association, the risk remained significant. The results highlight the need for routine substance use screening in individuals with severe health anxiety.Conclusions: This thesis advances the understanding of severe health anxiety by validating a practical screening tool, demonstrating the effectiveness of ICBT in routine psychiatric care, assessing the feasibility of a self-guided digital intervention, and identifying an elevated risk of substance-related problems in affected individuals. These findings highlight the importance of improved screening strategies, expanded access to evidence-based treatments, and the development of preventive measures to address long-term risks.List of scientific papersThe following manuscripts and publications were included in the thesis:I. Österman, S., Axelsson, E., Lindefors, N., Hedman-Lagerlöf, E., Hedman-Lagerlöf, M., Kern, D., Svanborg, C., & Ivanov, VZ. (2022). The 14-item short health anxiety inventory (SHAI-14) used as a screening tool: appropriate interpretation and diagnostic accuracy of the Swedish version. BMC Psychiatry, 22 (701).https://doi.org/10.1186/s12888-022-04367-3II. Österman, S., Axelsson, E., Forsell, E., Svanborg, C., Lindefors, N., Hedman-Lagerlöf, E., & Ivanov, VZ. (2024). Effectiveness and prediction of treatment adherence to guided internet-based cognitive behavioral therapy for health anxiety: A cohort study in routine psychiatric care. Internet Interventions, 38, Article 100780. https://doi.org/10.1016/j.invent.2024.100780III. Österman, S., Hentati, A., Forsell, E., Axelsson, E., Hedman-Lagerlöf, E., Lindefors, N., Ivanov, VZ., & Kraepelien, M. (2023). A Brief Digital Self-Care Intervention for Health Anxiety in a Swedish Medical University Clinic: A Prospective Single-Group Feasibility Study. BMJ Open, 13(12), Article e077376. https://doi.org/10.1136/bmjopen-2023-077376IV. Isomura, K *. , Österman, S *. , Hedman-Lagerlöf, E., Kuja-Halkola, R., Brikell, I., Chang, Z., D'Onofrio, B., Larsson, H., Lichtenstein, P., Mataix- Cols, D., Fernández de la Cruz, L., Ivanov, VZ., & Sidorchuk, A. Risk of substance-related problems in hypochondriasis. [Manuscript]* Shared first authorship</p
Acute Achilles tendon rupture : predictors for outcome and plan for intervention
No full textAcute Achilles tendon rupture (ATR) is a common tendon injury. Regardless of the initial treatment, many patients experience persistent symptoms and muscle weakness following ATR. This thesis aims to improve patient outcomes by identifying novel, modifiable, or preventable factors and subsequently plan an intervention study. The research questions addressed are: 1) What are the current incidence and treatment rates of ATR in Sweden? 2) Does the time between injury and surgical treatment affect patient outcomes after ATR? 3) Does the development of a deep venous thrombosis (DVT) during ATR immobilization impair patient outcomes? 4) To what extent does muscle deconditioning occur six weeks post-ATR, and how does it impact patient outcomes at one year?To investigate trends in ATR incidence and treatment in Sweden, a nationwide register-based study was conducted, including all adult in- and out-patients between 2002 and 2021. Over this period, the long-term incidence of ATR increased by 45%, from 28.8 in 2002 to 41.7 in 2021 per 100 000 person-years (pNext we examined the impact of TTS on patient outcomes and complications. A total of 228 ATR patients treated with a uniform surgical technique were retrospectively assessed. Patients were categorized into three TTS groups: 72 hours. Among those operated within 48 hours, 71% achieved a "good outcome", defined as an Achilles Tendon Total Rupture Score (ATRS) greater than 80. In contrast, only 44% of patients operated on after 72 hours reached this outcome. Additionally, the incidence of adverse events was significantly lower in patients treated within 48 hours compared those treated between 48 and 72 hours, and beyond 72 hours (1.4%, 11%, and 14.8% respectively).The effect of DVT on patient outcomes was then investigated in 251 surgically treated ATR patients who underwent duplex ultrasound screening for DVT at discontinuation of immobilization. The overall incidence of DVT was 49% (122 out of 251). Patients who developed a DVT reported significantly lower ATRS one- year post-injury compared to those without DVT (ATRS 76 vs. 83, pTo assess muscle deconditioning post-ATR and its impact in one-year outcomes, 15 patients underwent computed tomography scans six weeks after lower leg immobilization. Cross-sectional area (CSA) and radiological attenuation (RA) were measured, with lower values indicating muscle loss and muscle fat infiltration (MFI), respectively. CSA and RA values were significantly lower in 2 out of 7 and 6 out of 7 muscles respectively, in the injured compared to the uninjured lower leg. RA was most notably reduced in the triceps surae and its individual muscles, while CSA was only significantly reduced in the lateral and medial gastrocnemius, with decreases of 23% and 20% respectively. Notably, lower RA values, i.e. increased MFI, in the injured triceps surae were associated with impaired functional outcomes one-year post-injury, while CSA reductions did not demonstrated any significant relationship with outcomes.Given these findings, efforts should be made to mitigate the development of DVT and MFI during ATR immobilization. Intermittent pneumatic compression (IPC) is an intervention that aims to enhance blood circulation, decrease inflammation and provide muscle stimulation during immobilization. The Swedish multicenter Trial of Outpatient Prevention of Leg Clots (STOP Leg Clots) is a prospective multicenter superiority trial, investing IPC during lower leg immobilization after ATR and ankle fracture. The primary aim to reduce venous thromboembolic events (VTE), while secondary aims include reducing MFI, enhancing healing and improving patient outcomes. VTE is defined as either symptomatic pulmonary embolism or symptomatic DVT, or ultrasound detected DVT detected at immobilization discontinuation. Patients will be randomized to the intervention or treatment-as-usual. With 90% power and an estimated 8% absolute risk reduction, a sample size of 700 patients per arm was calculated.ConclusionThe incidence of ATR in Sweden has significantly increase and continues to rise. Delayed surgical intervention negatively impacts patient-reported outcomes and should be accounted for when comparing treatment strategies. ATR immobilization increases the risk of both DVT and MFI, significantly impacting patient outcomes. Preventive measures should be prioritized to optimize patient outcomes. The STOP Leg clots study, a ongoing prospective multicenter trial, aims to mitigate these negative effects and improve long-term recovery in ATR patients.List of scientific papersI. Svedman S, Marcano A, Ackermann PW, Felländer-Tsai L, Berg HE. Acute Achilles Tendon Ruptures Between 2002-2021: Sustained Increased Incidence, Surgical Decline and Prolonged Delay to Surgery - A Nationwide Study of 53,688 Patients in Sweden. https://doi.org/10.1136/bmjsem-2024-001960II. Svedman S, Juthberg R, Edman G, Ackermann PW. Reduced Time to Surgery Improves Patient-Reported Outcome and decreases the Risk of Adverse Events after Achilles Tendon Rupture. Am. J Sports Med. 2018, 46(12), 2929-2934.https://doi.org/10.1177/0363546518793655III. Svedman S, Edman G, Ackermann PW. Deep venous thrombosis after Achilles tendon rupture is associated with poor patient- reported outcome. Knee Surg Sports Traumatol Arthrosc. 2020;28(10):3309-3317.https://doi.org/10.1007/s00167-020-05945-2IV. Svedman S, Heijkenskjold M, Berg HE, Ackermann PW. Early lower leg muscle deconditioning after Achilles tendon rupture. [Manuscript]V. Svedman S, Alkner B, Berg HE, et al. STOP leg clots-Swedish multicentre trial of outpatient prevention of leg clots: study protocol for a randomised controlled trial on the efficacy of intermittent pneumatic compression on venous thromboembolism in lower leg immobilised patients. BMJ Open. 2021;11(5):e044103.https://doi.org/10.1136/bmjopen-2020-044103</p
From cognitive and behavioral impairment to clinical trial inclusion, for an inclusive approach of amyotrophic lateral sclerosis
No full textALS is a fatal and rapidly progressing neurodegenerative disease where the death of motor neurons results in the paresis of skeletal muscles and ultimately death from respiratory failure within 2 to 5 years. As no cures are currently available, people living with ALS (pALS) rely on clinical trials. However, the design of ALS trials does not always reflect the vast heterogeneity of the disease. Most pALS with behavioral or cognitive impairment are excluded from ALS trials, and many patients with bulbar ALS are struggling to perform some tests including in trial screening visits. In this thesis, we aimed to characterize cognitive and/or behavioral impairment of pALS in Sweden and use our findings as a stepping- stone to investigate clinical trial inclusiveness in a broader sense, with a focus on pre-screening and screening.In Study I, we conducted a systematic review on the use of population and disease registries for clinical trial pre-screening. Our goal with this study was to set the stage for what is currently done and learn from previous research. Therefore, we did not limit our search to the ALS field but included all publications from 2014 to 2022 reporting registry use of trial pre-screening. We found that during that timeframe, only 24 studies clearly reported such use despite obvious benefits being stated such as time efficiency of the pre-screening time and economic benefits. Pre-screening strategies being under-reported in the scientific literature, more population or disease registries may be used in a trial recruitment setting, however it seems like the clinical trial world is heavily relying on recruitment registries specifically designed for trial recruitment purposes.In Study II, we aimed to validate the Swedish version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), a screening tool for cognitive impairment. We found that the Swedish version of the ECAS was a valid and reliable tool to use, which led us to investigate cognition of pALS longitudinally, using the ECAS in Study III. We found that cognition was stable in pALS during the first 2 years following the ALS diagnosis, and we identified 3 main clusters of cognitive impairment profiles.In Study IV, we aimed to translate and implement the dimensional apathy scale (DAS) in Swedish within our cohort, characterize the apathy levels of pALS and investigate their longitudinal apathy levels. We found that the DAS was reliable to use in Swedish, that emotional and executive apathy levels were stable during the first year following the ALS diagnosis, but we did not observe a statistically significant relationship between apathy levels and clinical trial interest.Finally in Study V, we investigated venous bicarbonate as a potential proxy to vital capacity as a trial eligibility criterion. We found that venous bicarbonate was able to predict survival. Moreover, venous bicarbonate concentrations over 26 mmol/L were associated with higher risks of death for pALS.In summary, cognitive impairment and apathy levels in Swedish pALS were characterized in this thesis. Additional studies are required to investigate potential apathy clusters or profiles in pALS, as well as discriminative predictors for trial participation and considerations.List of scientific papersI. Foucher, J., Azizi, L., Öijerstedt, L., Kläppe, U., & Ingre, C. (2024). The usage of population and disease registries as pre-screening tools for clinical trials, a systematic review. Systematic Reviews, 13(1), 111. https://doi.org/10.1186/s13643-024-02533-0II. Foucher, J., Winroth, I., Lovik, A., Sennfält, S., Pereira, J. B., Fang, F., Lule, D., Andersen, P. M., & Ingre, C. (2023). Validity and reliability measures of the Swedish Karolinska version of the Edinburgh Cognitive and Behavioral ALS Screen (SK-ECAS). Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration, 1-6. Advance online publication. https://doi.org/10.1080/21678421.2023.2239857III. Öijerstedt, L., Foucher, J., Lovik, A., Yazdani, S., Juto, A., Kläppe, U., Fang, F., & Ingre, C. (2024). Repeated cognitive assessments show stable function over time in patients with ALS. Journal of Neurology, 271(8), 5267-5274. https://doi.org/10.1007/s00415-024-12479-xIV. Foucher, J., Lovik, A., Öijerstedt, L., Radakovic, R., Fang, F. & Ingre, C. Longitudinal apathy measures show stability of executive and emotional apathy levels but no association between apathy levels and clinical trial interest. [Manuscript]V. Foucher, J .* , Wellander, T .* , Lovik, A., Öijerstedt, L., Juto, A., Fang, F., & Ingre, C. Venous bicarbonate, a proposed proxy for vital capacity to be used as an eligibility criterion in amyotrophic lateral sclerosis clinical trials. [Submitted]* Equal contribution</p
Elucidating the genetic and functional basis of atopic dermatitis and psoriatic arthritis mutilans
No full textPsoriatic arthritis mutilans (PAM) and atopic dermatitis (AD) are two skin disorders. PAM is the most severe and rarest form of psoriatic arthritis, and it is characterized by osteolysis and joint erosion, leading to permanent disability. There are no clear susceptibility genes identified for PAM. AD, a chronic inflammatory skin condition, is influenced by genetic and environmental factors, resulting in skin barrier dysfunction, inflammation, and immune dysregulation. In AD, while genetic risk factors have been explained, these explain only a modest proportion of the heritability. The pathogenesis varies in different populations, such as those of African descent.In this thesis, I explore the genetic and molecular underpinnings of both PAM and AD through next-generation sequencing and functional studies. We aim to uncover novel susceptibility genes involved in disease development. The research goals were achieved by the following four studies included in this thesis.In study I, we performed Next-generation sequencing in the PAM Nordic cohort (n = 61) to study the genetic basis of PAM. We uncovered rare variants in the NADPH oxidase 4 (NOX4) gene and suggested NOX4 as the novel PAM candidate gene. NOX4 is an enzyme responsible for generating reactive oxygen species (ROS) production and is involved in osteoclast differentiation. Functional studies showed that these NOX4 variants upregulate ROS levels in patient- derived osteoclasts, zebrafish models and in HEK293 cells. All the data collected linked NOX4 dysfunction to PAM development. NOX4 is proposed as a candidate susceptibility gene, offering a potential therapeutic target by modulating ROS levels for addressing PAM.In study II, we shifted focus to AD, exploring its genetic origins in an Ethiopian family with multiple affected members. Notably, no mutations in the FLG gene in Ethiopians, highlighting the need to investigate alternative genetic contributors in this population. Whole-genome sequencing revealed two variants co-segregating with the disease in the family, in FLG2 - p.D13Y and NOD2 - p.A918S genes. Further genotyping in the Ethiopian case-control cohort showed significant association with AD for the FLG2 - p.D13Y variant. Additionally, two previously identified NOD2 variants - p.A849V and p.G908R were also linked to AD in Ethiopian AD patients. These findings highlight the importance of FLG2 and NOD2 in the etiology of AD, particularly in African populations.In study III, we further explored the role of the 2-amino ethanethiol dioxygenase (ADO) gene in AD. The idea arises from a previous study in which an AD GWAS variant was linked to the promoter of ADO by published Chromosome conformation capture (Capture Hi-C). The expression of ADO was significantly higher in lesional skin compared to non-lesional skin in AD patients. Zebrafish and in vitro models demonstrated that ADO dysregulation impairs skin barrier function and enhances ROS production and inflammation. This study suggests that ADO plays a critical role in maintaining skin homeostasis, with its dysregulation contributing to AD pathogenesis.In study IV, we investigated the FLG2 gene's role in AD susceptibility in a Swedish population, focusing on the p.S2377X variant. Genotypic analysis in two independent Swedish cohorts revealed a significant association between the FLG2 variant and AD, with reduced FLG2 expression observed in skin tissue from variant carriers. This study underscores the contribution of FLG2 to AD risk, particularly within the Swedish population.Collectively, this thesis broadens the genetic and molecular understanding of PAM and AD. Novel insights were provided by identifying the NOX4 gene as a potential susceptibility factor for PAM, presenting the first significant lead in pinpointing genetic contributors to this severe condition. Furthermore, the thesis highlighted the roles of FLG2, NOD2, and ADO in the etiology of AD, offering the potential genetic cause.Genome sequencing serves as the first tool to identify the genetic cause of the diseases; Subsequent functional studies further provided new insights into disease pathogenesis and potential treatment approaches for managing these diseases.List of scientific papersI. Rare coding variants in NOX4 link high ROS levels to psoriatic arthritis mutilansSailan Wang, Pernilla Nikamo, Leena Laasonen, Bjorn Gudbjornsson, Leif Ejstrup, Lars Iversen, Ulla Lindqvist, Jessica J Alm, Jesper Eisfeldt, Xiaowei Zheng, Sergiu-Bogdan Catrina, Fulya Taylan, Raquel Vaz, Mona Ståhle and Isabel Tapia-Paez EMBO Molecular Medicine.2024;16(3):596-615. https://doi.org/10.1038/s44321-024-00035-zII. Uncommon variants in FLG2 and NOD2 are associated with atopic dermatitis in the Ethiopian populationSailan Wang, Julia K. Elmgren, Jesper Eisfeldt, Samina Asad, Marlene Ek, Kassahun Bilcha, Annisa Befekadu, Carl-Fredrik Wahlgren, Magnus Nordenskjöld, Fulya Taylan, Isabel Tapia-Paez* and Maria Bradley *. JID Innovations. 2024 Apr 29;4(4):100284. https://doi.org/10.1016/j.xjidi.2024.100284III. The role of the cysteamine dioxygenase (ADO) gene in atopic dermatitisSailan Wang, Raquel Vaz, Josefin Lysell, Jesper Eisfeldt, Pelin Sahlén, Samina Asad, Carl-Fredrik Wahlgren, Magnus Nordenskjold, Maria Bradley* and Isabel Tapia-Paez *. [Manuscript]IV. The FLG2 gene is associated with atopic dermatitis in Swedish patientsSailan Wang, Mahsa Tayefi, Axel Svedbom, Samina Asad, Carl- Fredrik Wahlgren, Magnus Nordenskjold, Emma Johansson, Isabel Tapia-Paez* and Maria Bradley* [Manuscript]* Authors contributed equally</p
Patient safety in the intensive care unit during the COVID-19 pandemic
No full textThis thesis aims to investigate how patient safety was challenged and maintained in intensive care units (ICUs) during the COVID-19 pandemic using qualitative and quantitative methods. Data were collected through individual interviews with ICU professionals and first-line managers, as well as from a local COVID-19 patient registry. Analyses included qualitative content analysis, thematic analysis, and regression models.Study I described ICU staff experiences of patient safety risks, which increased due to the massive influx of patients, extreme workload, and extensive adaptations that pushed individuals beyond their usual roles and responsibilities. Safety performance relied more on individual adaptability than on system-based safeguards. Study II, a single-centre cohort study of 665 patients, found that 20% underwent interhospital transfer. Transfers were associated with lower 30-day (HR 0.47, 95% CI 0.30-0.76) and 90-day mortality (HR 0.52, 95% CI 0.34-0.79), but with fewer days alive and out of ICU at 30 days. Study III explored patient safety leadership among first-line managers, revealing conflicts between efficiency and safety, and the challenge of delivering care with limited resources. First-line managers emphasised that flexibility, continuous learning and mutual trust were essential for creating an adaptable environment that enabled early identification of safety risks. Study IV, a secondary analysis using an abductive approach and the Capacities for Resilience in Healthcare framework, showed that resilience relied on the system's ability to adapt, reorganise, and compensate under pressure. Patient safety was maintained through compensatory mechanisms, balancing reduced capacities in certain areas with strengths in others.In conclusion, the pandemic exposed systemic vulnerabilities. However, patient safety was largely upheld through the adaptability, clinical intuition, and individual responsibility of ICU professionals.List of scientific papersThis thesis is based on the following papers:I. Berggren K, Ekstedt M, Joelsson-Alm E, Swedberg L, Sackey P, Schandl AJ. Healthcare workers' experiences of patient safety in the intensive care unit during the COVID-19 pandemic: A multicentre qualitative study. Journal of Clinical Nursing. 2023 Oct;32(19-20):7372-7381. https://doi.org/10.1111/jocn.16793II. Toss Agegård L, Berggren K, Cronhjort M, Joelsson-Alm E, Sackey P, Jonmarker S, Schandl AR. Interhospital transports and mortality in patients with critical COVID-19: a single-centre cohort study. BMJ Open. 2025 Feb 18;15(2):e090952. https://doi.org/10.1136/bmjopen-2024-090952III. Berggren K, Ekstedt M, Lyngå P, Sackey P, Swedberg L, Joelsson-Alm E, Schandl A. Adaptive leadership to safeguard patient safety in intensive care units during the COVID-19 pandemic. [Submitted]IV. Berggren K, Ekstedt M, Joelsson-Alm E, Schandl A. Adaptive responses and compensatory mechanisms demonstrate resilience in ICU healthcare during the COVID-19 pandemic-an abductive analysis. [Manuscript]</p
Digital Media, Genetics and Risk for ADHD Symptoms in Children – A Longitudinal Study
No full textBACKGROUND
Children spend significant amount of time using digital media (DM), and longer exposure may increase attention-deficit/hyperactivity disorder (ADHD)-related symptoms, although findings are mixed. We investigated longitudinal association between different types of DM use and ADHD-related symptoms in school-aged children, accounting for genetic predisposition and socioeconomic status.
METHODS
This study included children from the Adolescent Brain and Cognitive Development Study, followed annually for four years. Estimated time spent on social media, video games, and television/videos was self-reported using Youth Screen Time Survey. ADHD-related symptoms were assessed at each visit with the parent-reported Child Behaviour Checklist. Genetic predisposition was estimated using a polygenic risk score for ADHD (PGS-ADHD).
RESULTS
The study included 8324 children (53% boys; mean age: 9.9 years). On average, children spent 2.3 hours/day watching television/videos, 1.4 hours/day on social media, and 1.5 hours/day playing video games. Average social media use was associated with increased inattention symptoms over time (β [SE], 0.03 [0.01]; P<0.001), with a cumulative four-year effect of β=0.15 [SE]=0.03; P<0.001). No associations were found between playing video games or watching television/videos and ADHD-related symptoms. The association between social media use and inattention symptoms was not moderated by sex, ADHD diagnosis, PGS-ADHD, or ADHD medication status. Inattention symptoms were not associated with increased social media use over time.
CONCLUSIONS
Social media use was associated with an increase in inattention symptoms in children over time. Although the observed effect size was small, it could have significant consequences if behavior changes occur at the population level.</p
Adipose cellularity as a measurement of long-term changes in body weight: a Swedish cohort study spanning 1988-2016.
No full textNo description supplied</p
Preventive oral care strategies for care-dependent older adults
No full textBackground: With care dependency, irregular dental visits are common, leading to an increased risk of poor oral status and low oral health-related quality of life (OHRQoL). Therefore, the overall aim of this thesis was to evaluate the impact of domiciliary professional dental care on oral health and OHRQoL in care- dependent older adults, and to establish recommendations for home-based preventive care.Methods: The project was conducted between 2016 and 2024 and comprised four studies. Studies I, III and IV were randomized controlled trials. Study I followed care-dependent older adults at nursing homes for six months and investigated the effect of monthly professional dental cleaning on gingival bleeding compared with daily oral care as usual. Study II was a systematic review in which six researchers screened reports for inclusion (260 years of age and ≥1 natural tooth), intervention (professional dental cleaning at home) and outcome (root caries lesions [RCLs]), individually and in group sessions. Studies III and IV studied the additional effect of professional dental cleaning every third month on RCLs and OHRQoL among older adults with in-home care who received high- fluoride (Duraphat®) toothpaste for daily use.Results: Study I (n=124) showed less gingival bleeding and dental plaque at six months, and the intervention group (n=69) showed fewer active RCLs (p=0.05). Study II included four studies (out of 331) that showed fewer active and new RCLs at final registrations when adding fluoride products by dental personnel. Due to heterogeneity, no meta-analysis was performed. In Studies III and IV, 82 participants (intervention=50) remained at one-year registration. Progression of RCLs were seen in both groups (22%=intervention, 28%=control) without significant difference. Correlation investigation showed an association between progression of RCLs and dental plaque amount (p=0.0014). Study IV showed moderate OHRQoL at both baseline and follow-up.Conclusion: Additional sodium fluoride can prevent and arrest new RCLs. Professional dental cleaning may support oral hygiene at nursing homes but not among older adults with in-home care who use high-fluoride toothpaste daily. Therefore, preventive strategies should focus on availability and adherence to high-fluoride toothpaste for the dentate part of this population.List of scientific papersI. Girestam Croonquist C, Dalum J, Skott P, Sjögren P, Wårdh I, Morén E. Effects of Domiciliary Professional Oral Care for Care-Dependent Elderly in Nursing Homes - Oral Hygiene, Gingival Bleeding, Root Caries and Nursing Staff's Oral Health Knowledge and Attitudes. Clin Interv Aging. 2020;15:1305-1315.https://doi.org/10.2147/CIA.S236460II. Morén E, Skott P, Edman K, Gavriilidou N, Wårdh I, Domeij H. The Effect of Domiciliary Professional Oral Care on Root Caries Progression in Care-Dependent Older Adults: A Systematic Review. J Clin Med. 2023;12(7):2748. https://doi.org/10.3390/jcm12072748III. Moren E, Skott P, Gabre P, Sjögren P, Wårdh I. Impact of Home- Based Professional Dental Cleaning on Oral Health in Care- Dependent Older Adults - A Randomized Controlled Trial - Part 1: Clinical Variables. [Manuscript]IV. Moren E, Gabre P, Sjögren P, Wårdh I, Skott P. Impact of Home- Based Professional Dental Cleaning on Oral Health in Care- Dependent Older Adults - A Randomized Controlled Trial - Part 2: Self-Reported Data and Oral Health-Related Quality of Life. [Manuscript]</p