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Everyday life in early adolescence after hypothermia-treated neonatal hypoxic-ischaemic encephalopathy
No full textTitle: Everyday life in early adolescence after therapeutic hypothermia following neonatal hypoxic-ischaemic encephalopathy: Motor development, executive functions, health-related quality of life, self-esteem, and physical activity. Background: Therapeutic hypothermia (TH) is the standard treatment for moderate to severe neonatal hypoxic-ischaemic encephalopathy (HIE). While early developmental outcomes are well documented, knowledge about long- term outcomes into early adolescence, especially in adolescents without severe cerebral palsy is limited.Aims: To investigate long-term outcomes in early adolescents treated with TH for neonatal HIE, focusing on motor development, executive functions (EF), health-related quality of life (HRQOL), self-esteem, and physical activity (PA).Methods: A regional cohort of 45 early adolescents, (mean age of 11 years) treated with TH following neonatal HIE between 2007 and 2009 in the Stockholm region, was followed prospectively from infancy to early adolescence. Motor development was assessed at four time points, at a mean age of 4 months, 2 years, 7 and 11 years, using age-appropriate standardised tools: Alberta Infant Motor Scale, Bayley Scales of Infants and Toddler Development, Third Edition, and Movement Assessment Battery of Children, Second Edition (MABC-2). Executive functions (EFs) were evaluated using a combination of standardised tools, including Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V), the Behavior Rating Inventory of Executive Function, Second Edition, and the Five to Fifteen Revised Questionnaire. Health-related quality of life (HRQOL) assessed with the Pediatric Quality of Life Inventory 4.0, Self-esteem with, I Think I Am-2 (ITIA-2). Physical activity (PA) was device-based measured using accelerometers and through self-reported questionnaire.Result: At 11 years, 69% of the participants scored above the 15th percentile on the MABC-2 test, indicating no motor difficulties. Thirty-one percent of the participants scored below the 15th percentile on MABC-2 indicating motor difficulties. Motor capacity was associated with weaker EFs, especially in processing speed, working memory, flexibility, and impulse control. Everyday motor challenges were reported by parents in 52%. No significant differences were found between the participants' self-reported and the parental proxy- reported HRQOL. Self-esteem was generally high, even among the participants with motor difficulties. Forty-one percent met the WHO recommendation of 60 minutes of moderate-to-vigorous physical activity per day. However, the participants with motor difficulties engaged in significantly less MVPA than peers without motor difficulties. The total participation in organised PA was high (73%). However, screen time was frequently above recommended levels, with 46% of the participants spending 2-3 hours per day.Conclusions: Most children treated with TH following neonatal HIE show favourable outcomes when reaching early adolescence, including high self- esteem, strong participation in organised PA, and generally positive HRQOL. However, a notable proportion still experience motor and executive function challenges, along with lower PA levels. These findings underscore the need for a multidimensional and multiprofessional approach that integrates clinical assessments with parental insights, to enable early identification of those at risk and ensure timely interventions.List of scientific papersI. Eriksson Westblad M, Löwing K, Grossmann KR, Blennow M, Lindström K. Long-term motor development after hypothermia- treated hypoxic-ischaemic encephalopathy. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2023;47:110-7. https://doi.org/10.1016/j.ejpn.2023.10.003II. Eriksson Westblad M, Löwing K, Robertsson Grossmann K, Andersson C, Blennow M, Lindström K. Motor activities and executive functions in early adolescence after hypothermia- treated neonatal hypoxic-ischemic encephalopathy. Applied neuropsychology Child. 2025:1-9. https://doi.org/10.1080/21622965.2025.2463498III. Eriksson Westblad M*, Kokkonen Nassef S*, Blennow M, Jirwe M, Lindstrom K. Motor performance, health-related quality of life and self-esteem in early adolescence after neonatal therapeutic hypothermia. Acta Paediatr. 2025. Epub ahead of print. *Shared first authorship. https://doi.org/10.1111/apa.70170IV. Mimmi Eriksson Westblad, David Moulaee Conradsson, Ulrika Einarsson, Katarina Lindström. Physical Activity in Early Adolescence after Hypothermia-Treated Neonatal Hypoxic-Ischaemic Encephalopathy. [Manuscript]</p
Improving treatment engagement for substance use disorders by leveraging digital interventions post-emergency care
No full textBackgroundSubstance use disorders (SUD) are common, preventable disorders characterized by persistent substance use despite adverse consequences. Although few affected individuals engage in treatment, many present for acute and hospital care for issues related directly or indirectly to their substance use. As such, acute and hospital care constitutes a critical healthcare access point, which ideally could link individuals with sustained treatment. Nonetheless, the treatment gap persists, with few individuals pursuing post-acute SUD treatment, resulting in missed opportunities to prevent disease progression, increase remission and, by extension reduce mortality. In the current thesis, the overall aim was to contribute actionable insights on how to increase post-acute treatment engagement for SUD in routine healthcare, with a special emphasis on digital interventions as a potential bridge to treatment.MethodsTo address our aim, we conducted four studies within a multi-method framework, all in preparation for developing and evaluating a novel digital aftercare guide titled the BRIDGE. The four studies utilized cohort (Study I), qualitative (Study II), secondary analyses, and psychometric (Study IV) study designs to address knowledge gaps in prior literature. Our practical objectives were to inform intervention development (Study II and III) and outcome selection (Study I and IV) for the intervention study. For studies I (n = 9,771) and II (n = 23), as well as the subsequent intervention study, participants were sampled from an emergency department (ED) specifically dedicated to the care of SUD, the Stockholm SUD-ED. Study III and IV included participants seeking a digital intervention for their alcohol use (n = 1,169) and study III additionally included online help-seekers for regular cannabis use (n = 303). In study IV, data was collected from two further sources: k = 15 brief intervention trials and k = 20,000 simulated samples based on general-population statistics. To examine post- acute treatment engagement and subgroup heterogeneity, we conducted systematic care-flow mapping and multinomial logistic regression modelling in Study I. Study Il analyzed patients' perceived treatment barriers and views on digital aftercare within a reflexive thematic analysis framework. Study III used arithmetic means and parametric confidence intervals to analyze between- group (cross-substance) differences in attitudes, and k-means clustering to explore within-group heterogeneity. In Study IV, we applied several psychometric techniques (including Pearson correlation and non-parametric item response theory) to examine the internal structure of AUDIT-C in clinical trials and simulated samples. We additionally utilized quantile regression to examine right censoring at baseline and simple slopes analysis to investigate responsiveness to change.ResultsFindings from Study I and II suggested that a purpose-built ED for SUD (the Stockholm SUD-ED) can achieve relatively high rates of post-acute treatment (50.1%) compared to prior literature, yet several preventable barriers persist even within this model. As shown in Study I, SUD-ED patients arriving by law- enforcement, and with probable milder levels of SUD, are subgroups with lower odds of engaging in post-acute treatment, signaling the need for both targeted efforts and broadening existing aftercare approaches.Importantly, patient interviews in Study II revealed overall sentiments of having benefited from digital aftercare guides, should such options have been available for them alongside regular aftercare. Particularly, the opportunity for self- directed support was highlighted as a desirable feature of digital interventions. Study III revealed key attitudinal differences toward digital interventions, between and within groups of participants with alcohol and cannabis use. Together, these findings signal the need for flexible digital interventions.Study IV revealed that most brief intervention trials sampled (68%) exhibited non-positive associations between AUDIT-C's frequency and quantity items, a sign shift in the frequency-quantity association that simulations indicated were due to selection on problematic alcohol use. Non-parametric item response theory analyses further demonstrated that these non-positive correlations disrupt ordinal measurement. Furthermore, responsiveness analyses demonstrated that a one-unit AUDIT-Ct2-ti change represented greater average SUt2-ti at higher versus lower baseline-consumption levels. Based on these findings, we recommend caution in repurposing the AUDIT-C screening measure for outcome monitoring in populations with problematic alcohol use. Within the context of this specific thesis, this led us to exclude AUDIT-C from the list of potential outcome measures for the main intervention study.Building on these studies, we developed a three-module digital aftercare guide, which was provided to SUD-ED patients during approximately fourteen months, ending patient recruitment on January 31, 2025. By that date, n = 195 users had created accounts for the guide, and the landing page of the aftercare guide had received 2,989 page views. A retrospective research evaluation is scheduled to commence in autumn 2025.ConclusionsSeveral barriers to post-acute treatment persist, even within a fully integrated SUD-ED model. Patients with indicators of lower SUD severity had lower odds of engaging in post-acute treatment. Aftercare options may need to be broadened to better engage this group and improve outcomes. Digital interventions may serve this purpose. Preliminary numbers from the clinic suggest that a proportion of patients are interested in using the guide. A natural next step is to evaluate the effectiveness of digital aftercare guides in increasing engagement in post-acute treatment. To improve the quality of evidence, both these intervention studies and the broader SUD field should exclude AUDIT-C from the set of outcome measures.List of scientific papersI. Romero, D., Kåberg, M., Carlbring, P., Berman, A., Franck, J., & Lindner, P. Care pathways and predictors of post-acute outpatient treatment engagement among individuals visiting an emergency department dedicated to substance use disorders: A cohort study. [Manuscript]II. Romero, D., Rozental, A., Carlbring, P., Johansson, M., Franck, J., Berman, A. H., & Lindner, P. (2024). From alcohol detoxification to treatment: A qualitative interview study on perceived barriers and assessed potential of mHealth among individuals postdetoxification. Psychology of Addictive Behaviors, 38(8), 879- 890. https://doi.org/10.1037/adb0001008III. Romero, D., Johansson, M., Hermansson, U., & Lindner, P. (2021). Impact of users' attitudes toward anonymous internet interventions for cannabis vs. alcohol use: A secondary analysis of data from two clinical trials. Frontiers in Psychiatry, 12, 730153- 730153. https://doi.org/10.3389/fpsyt.2021.730153IV. Romero, D., Johansson, M., Berman, A. H., & Lindner, P. (2025). Questionable generalizability of AUDIT-C scoring warrants caution when used for outcome monitoring: Evidence from simulated and real-world trial data. Addiction. Advance online publication. https://doi.org/10.1111/add.70074</p
Antibiotic prescribing in surgery and orthopedics : evolving practices, perceptions, and resistance in Central India
No full textBackgroundIndia has one of the world's highest burdens of antimicrobial resistance (AMR), largely driven by inappropriate antibiotic use. In surgical and orthopedic departments, broad-spectrum antibiotics are routinely used for perioperative antibiotic prophylaxis (PAP) and infection treatment, further contributing to AMR. Although surgical site infections (SSIs) pose a significant risk in surgical and orthopedic departments, there is a lack of surveillance systems and long-term studies on antibiotic prescribing practices and the factors influencing antibiotic use in Central India.Aim To increase knowledge about antibiotic prescribing practices, SSIs, and perceptions of AMR in surgical and orthopedic departments in Central India.MethodsResearch was conducted in the orthopedic and surgical departments of three private-sector hospitals in the Ujjain district, Madhya Pradesh. Studies I-III are cross-sectional, involving prospective data collection, while Study IV is a qualitative study based on the integrated Capability, Opportunity, Motivation- Behavior model and the Theoretical Domains Framework. In Studies I and III, data were collected from the orthopedic (Study I) and surgical departments (Study III) of the teaching hospital (TH) and the non-teaching hospital (NTH-1) between 2008 and 2017. Antibiotic prescribing patterns were analyzed at the group level based on diagnoses. Total antibiotic use was measured in Defined Daily Doses (DDDs) per 1000 patient-days. Additionally, in Study III, antibiotics were categorized by Access Watch Reserve classification. Time trends in antibiotic use were analyzed using linear regression (Studies I and III) and polynomial regression (Study III). In Study II, data were collected from 2013 to 2016 in the orthopedic department of the TH. SSIs were identified based on the Centers for Disease Control and Prevention National Healthcare Safety Network criteria. Pathogens causing SSIs were identified according to Clinical and Laboratory Standards Institute guidelines. The American Society for Anesthesiologists classification system was used to assess patients' operative risk. Risk factors for orthopedic SSI development were analyzed using univariable and multivariable backward stepwise logistic regression. In Study IV, semi-structured interviews were conducted in 2023 with 15 general and orthopedic surgeons at the TH, the NTH-1, and the NTH-2. The questions were designed to explore factors influencing antibiotic prescribing decisions, as well as surgeons' perceptions of antibiotic use, AMR, and potential solutions. Manifest and latent content analysis was applied.ResultsAntibiotic prescribing was rarely guided by culture and susceptibility testing, and no context-specific antibiotic prescribing guidelines were in place. In orthopedic departments, third-generation cephalosporins were the most used antibiotics, with fractures of the spine and limbs being the most prevalent indications. In surgical departments, fluoroquinolones and third-generation cephalosporins were the most commonly prescribed antibiotics, with inguinal hernia and calculus of kidney and ureter being the most common diagnoses. In orthopedic departments, total antibiotic use significantly increased over a 10-year period, whereas in surgical departments, it slightly decreased in the last three years (NTH-1) to five years (TH). Additionally, the proportion of prescribed Watch antibiotics significantly increased in surgical departments over the same period. Over a three-year period, the incidence of orthopedic SSIs was 7.6%. Risk factors for orthopedic SSI development included male sex (OR = 2.64, 95% CI 1.32-5.30), previous hospitalization (OR = 2.15, 95% CI 1.25-3.69), antibiotic use during hospitalization before PAP (OR = 4.19, 95% CI 2.51-7.00), postoperative length of stay longer than 15 days (OR = 3.30, 95% CI 1.83-5.95), and preoperative showering (OR = 4.73, 95% CI 2.72-8.22). The most used PAP in orthopedic surgery was a combination of a third-generation cephalosporin and a B-lactamase inhibitor with amikacin. The most common pathogen causing orthopedic SSIs was Staphylococcus aureus, which exhibited 100% resistance to penicillinase-labile penicillins. Various factors were found to influence the decision-making process for antibiotic prescribing among general and orthopedic surgeons, including environmental factors (e.g., dry and dusty rural setting); sociocultural factors (e.g., patients' socioeconomic status and beliefs); and the prescriber's experience, personal preferences, and seniority level. General and orthopedic surgeons largely perceived AMR as a social problem that requires a collective effort.ConclusionIn orthopedic departments, total antibiotic use significantly increased over 10 years, whereas in surgical departments, it slightly decreased over the last three to five years of the same period. Antibiotic prescribing was predominantly empirical and strongly influenced by environmental and sociocultural factors. A considerable proportion of patients in orthopedic and surgical departments received antibiotics without clear indications, and PAP selection deviated from internationally recommended standards. The incidence of orthopedic SSIs was 7.6% over three years, which is relatively high for orthopedic surgeries but low compared to reported SSI incidences in India. Preoperative showering was identified as a significant risk factor for orthopedic SSIs, a finding not previously reported in the literature. This research emphasized the need to develop hospital antimicrobial stewardship programs, strengthen infection prevention and control measures and diagnostic practices, develop and implement context-specific antibiotic prescribing guidelines, and foster regular interdisciplinary collaboration. AMR was recognized as a complex social issue that requires a collective, multisectoral effort.List of scientific papersI. Skender K, Singh V, Stålsby Lundborg C, Sharma M. Trends and patterns of antibiotic prescribing at orthopedic inpatient departments of two private-sector hospitals in Central India: A 10- year observational study. PLoS ONE. 2021 Jan 27;16(1):e0245902. https://doi.org/10.1371/journal.pone.0245902II. Skender K, Machowska A, Singh V, Goel V, Marothi Y, Stålsby Lundborg C, Sharma M. Antibiotic Use, Incidence and Risk Factors for Orthopedic Surgical Site Infections in a Teaching Hospital in Madhya Pradesh, India. Antibiotics. 2022 May 31;11(6):748. https://doi.org/10.3390/antibiotics11060748III. Skender K, Machowska A, Dhakaita SK, Stålsby Lundborg C, Sharma M. Ten-year trends of antibiotic prescribing in surgery departments of two private sector hospitals in Central India: a prospective observational study. BMC Public Health. 2024 Jan 27;24(1):310. https://doi.org/10.1186/s12889-024-17817-2IV. Skender K, Machowska A, Khare S, Singh V, Stålsby Lundborg C, Sharma M. "Our hands are tied": A qualitative exploration of antibiotic prescribing practices and perceptions of antimicrobial resistance among general and orthopedic surgeons in Central India. [Submitted]</p
Characterization of the immune cell landscape in neuroblastoma : for the discovery of novel therapeutics
No full textThe most common extracranial and deadliest tumor in infants, neuroblastoma (NB), is both clinically and genetically heterogenous in nature. NB patients with low-risk disease have good prognosis with over 90% of children surviving. In contrast, patients with high-risk disease presenting with bone/bone marrow metastasis at diagnosis have roughly a 40% chance of survival. Over the past decades, immune cells have been extensively studied in NB, however, conflicting results remain. In addition, studies have largely focused on a single cell type and metastatic tumors have hardly been included. Anti-GD2 immunotherapy is one element of the current standard of care but comes with severe toxicities leading to patients dropping out of treatment. Other immunotherapy approaches, such as T-cell-based approaches, are currently making their way into the standard of care treatment regimen. To further improve immunotherapy for these patients, it is necessary we understand the immune cell composition and their function in NB primary tumors and bone metastasis. To this end, we aimed to unravel the immune cell landscape in NB primary tumors (paper I) and bone/bone marrow metastasis (BMets) (paper II). Furthermore, we sought to elucidate alpha beta (aß) and gamma delta (yo) T-cell clonal expansion, and phenotypic and functional properties of T cells infiltrating NB primary tumors (paper III).We employed single-cell RNA sequencing (scRNAseq) and VDJ sequencing (scVDJseq) techniques, flow cytometry, immunohistochemistry (IHC) and bioinformatic tools. For scRNAseq, in paper I, 19 primary tumor samples derived from 17 patients were included, paper II included 7 non-metastatic and 8 metastatic bone/bone marrow samples, and for paper III, 11 primary tumor samples plus 4 matched blood samples were used for scRNA/VDJseq. To validate scRNAseq findings, IHC and flow cytometry were performed. Bioinformatic tools were used to extract T-cell clonotypes from scRNAseq data. Flow cytometry was also used for functional testing of yoTCR reactivity against a panel of NB cell lines.Paper I and II revealed a complex interactive immune cell network in NB primary tumors and BMets. Most immune cell subpopulations correlated with improved prognosis in NB primary tumors except for Macro-1. The main myeloid populations in primary tumors were macrophages and monocytes, whereas in BMets a higher number of neutrophils were detected. Furthermore, a significant reduction in B cells was found in BMets compared to non-metastatic samples (nonMets). There was an increase in the fraction of CD56bright NK cells in BMets whereas in NB primary tumors, CD56dim NK cells were increased in frequency in intermediate- and high-risk disease compared to low-risk. CTLs were significantly increased in numbers in BMets compared to nonMets and had high expression of cytotoxicity- related genes in both BMets and NB primary tumors. The gene signature score for Treg activity was unchanged comparing risk groups in primary tumors whereas this was significantly increased in BMets compared to nonMets. Paper III revealed a heterogeneous T-cell landscape in NB primary tumors and matched blood samples including an interesting 'repair' population. We detected a significant increase in percentage of V81+ and Vy9-V81-V82- in primary tumor compared to blood samples. Drastic clonal expansion was found for both aß and yo T cells suggesting antigen recognition in the tumors. And, expanded Vy9V83, Vy8V83 and Vy5V81 clonotypes cloned into Jurkat cells were reactive towards one or more NB cell lines measured by CD69 upregulation. This hints to their respective ligands existing on NB cells.Taken together, we mapped the immune cell landscape in NB primary tumors and BMets showing differences in cell numbers and phenotypic properties. Generally, immune cells were correlated to improved prognosis in NB primary tumors. Clonal expansion of aß and yo T cells, and yoTCR reactivity suggests tumor antigen recognition. This thesis outlines a deeper comprehension of the NB tumor microenvironment in both primary tumors and BMets. It provides novel insights into T-cell clonality and phenotypes, and functions as a basis for the discovery of novel immunotherapeutic targets.List of scientific papersI. Verhoeven BM, Mei S, Olsen TK, Gustafsson K, Valind A, Lindström A, Gisselsson D, Fard SS, Hagerling C, Kharchenko PV, Kogner P, Johnsen JI, Baryawno N. The immune cell atlas of human neuroblastoma. Cell Rep Med. 2022 Jun 21;3(6):100657. Epub 2022 Jun 9. https://doi.org/10.1016/j.xcrm.2022.100657II. Mei S, Alchahin AM, Embaie BT, Gavriliuc IM, Verhoeven BM, Zhao T, Li X, Jeffries NE, Pepich A, Sarkar H, Olsen TK, Wickström M, Stenman J, Reina- Bedoya O, Kharchenko PV, Saylor PJ, Johnsen JI, Sykes DB, Kogner P, Baryawno N. Single-cell analyses of metastatic bone marrow in human neuroblastoma reveals microenvironmental remodeling and metastatic signature. JCI Insight. 2024 Feb 15;9(6):e173337. https://doi.org/10.1172/jci.insight.173337III. Verhoeven BM, Ye K, Stenman J, Bedoya Reina O, Kreslavskiy T, Baryawno N. Single-cell clonal composition of T-cell repertoires in human neuroblastoma. [Manuscript]</p
The role of SAMHD1 and cGAS-STING associated anti-tumor response mechanisms in lymphomas
No full textLymphomas are a phenotypically and genetically heterogeneous group of malignant diseases of the lymphocytes, accounting for 4.4% of all cancers. They are broadly categorized into Hodgkin lymphoma (HL) and non-Hodgkin lymphomas (NHL), the latter comprising about 90% of all lymphoma types. The doctoral project aimed at investigating the emerging role of SAMHD1 and cGAS-STING anti-tumor immune response mechanisms in the biology and prognosis of lymphomas, focusing on HL and T-cell NHLs. In particular for T-cell NHL biology, the hypothesis was that the neoplastic T-cells, which derive from T lymphocytes, may retain the ability to produce critical mediators of anti- tumor immune responses, including interferons (IFNs), cytokines and chemokines. Therefore, stimulation of mechanisms triggering immune responses in the neoplastic T- cells may activate the normal natural killer (NK) and T-cells of the tumor microenvironment resulting in immunogenic cell death of the neoplastic T-cells. The overall goal of this research was to uncover potential new targets for immunotherapy and novel biomarkers that could better stratify the patients for optimal treatment options.Intensive research over the last decades has uncovered the dynamic interactions between the cancer cells and the host immune cells, leading to development of novel immunotherapy strategies. Although standard chemotherapy remains the first line treatment for most aggressive lymphomas, ongoing clinical trials are currently investigating new strategies with promising results, including combination of immune checkpoint immunotherapy with small-molecule-based precision therapeutics. In the present doctoral project, we hypothesized that the SAMHD1 and cGAS-STING pathway regulate anti-tumor immune responses in certain lymphoma types, and could represent novel therapeutic targets. In addition, expression of SAMHD1 and critical components of the cGAS-STING pathway assessed in clinical tumor samples may have prognostic and predictive value. The hypotheses are clinically relevant since pharmacologic modulators of SAMHD1 and cGAS-STING pathway activity are already available for clinical trials.First, in this doctoral research, SAMHD1 expression by the neoplastic Hodgkin cells was found to be an independent adverse prognostic factor in patients with HL uniformly treated with standard chemotherapy protocols. These results may contribute to better stratification of the patients for optimal treatment options, and also might have additional therapeutic implications since modulation of SAMHD1 activity is currently available using SAMHD1 inhibitors.Second, the results of the doctoral research showed that STING gene and protein expression are restricted to T- and NK-cell NHLs, with anaplastic lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma (ALCL) showing the highest frequency of positive tumors. By contrast, STING seems to be downregulated in normal and neoplastic B-cells, likely due to decreased STING1 gene transcription; however, the mechanisms remain to be investigated. The data suggest that therapeutic targeting of the cGAS-STING pathway may be more efficient in T- and NK-cell NHLs.Since recent evidence suggests that the natural compound sulforaphane (SFN) may inhibit SAMHD1 phosphorylation, the biologic effects of SFN were investigated in vitro in classic HL. SFN significantly inhibited cell growth and viability of HL cells, and more importantly, SFN substantially enhanced anti-tumor immune responses and NK cell- mediated killing of the co-cultured neoplastic HL cells. NK cell-mediated killing of HL cells was associated with induction of IFN-ß gene expression, production of NK ligands MICA/B and release of numerous cytokines and chemokines in part through cGAS-STING- dependent mechanisms. These results indicate that pharmacologic modulation of the cGAS-STING pathway by SFN or STING agonists may contribute to novel investigational strategies for patients with refractory or relapsed cHL.Using an in vitro study model for ALK+ ALCL, the findings of the doctoral project also showed the suppressive effects of NPM-ALK oncogenic kinase on anti-tumor immune responses, partially through inhibition of the cGAS-STING pathway. STAT3, one of the most important downstream targets of NPM-ALK, likely mediates the suppressive effects of NPM-ALK on anti-tumor immune responses by controlling gene and protein expression of type I IFNs, cytokines and chemokines. Moreover, the cGAS-STING pathway is functional and responds to STING stimulation. These results suggest that modulation of the cGAS-STING activity may contribute to immunotherapy and targeted therapy in addition to ALK inhibitors and anti-CD30 antibodies currently used in clinical trials.In the last doctoral study, a novel patient-derived cell line, namely BIA-XR1, and xenograft model (PDX) derived from a patient with BIA-ALCL was established and characterized. This new cell line showed a unique KRAS mutation (in addition to a common STAT3 mutation). Novel in vitro systems, including PDX for uncommon types of T-cell lymphomas, such as BIA-ALCL, represent essential experimental tools to uncover the molecular pathogenesis and novel therapeutic targets.In summary, the results of the doctoral study enriched our knowledge on the clinical and biologic involvement of SAMHD1 and cGAS-STING anti-tumor immune response pathways in HL and T-NHLs with potential therapeutic implications, but also raised scientific questions that merit further investigation.List of scientific papersI. Xagoraris I*, Vassilakopoulos TP*, Drakos E, Angelopoulou MK, Panitsas F, Herold N, Medeiros LJ, Giakoumis X, Pangalis GA, Rassidakis GZ. Expression of the novel tumour suppressor sterile alpha motif and HD domain-containing protein 1 is an independent adverse prognostic factor in classical Hodgkin lymphoma. Br J Haematol. 2021 May;193(3):488-496. https://doi.org/10.1111/bjh.17352II. Xagoraris I, Farrajota Neves da Silva P, Kokaraki G, Stathopoulou K, Wahlin B, Österborg A, Herold N, Ng SB, Medeiros LJ, Drakos E, Sander B, Rassidakis GZ. STING is Commonly and Differentially Expressed in T- and NK-cell But Not B-cell Non-Hodgkin Lymphomas. Cancers (Basel). 2022 Feb 24;14(5):1186. https://doi.org/10.3390/cancers14051186III. Xagoraris I, Yang Y, Bougka E, Trogrlic D, Xyderou P, Stathopoulou K, Herold N, Lundqvist A, Rassidakis GZ. Sulforaphane Promotes NK Cell- Mediated Anti-Tumor Immune Responses Partially Via cGAS-STING Pathway in Classical Hodgkin Lymphoma. [Accepted]IV. Xagoraris I, Yang Y, Trogrlic D, Månsson A, Plastira C, Leventaki V, Qian H, Lundqvist A, Rassidakis GZ. NPM-ALK Oncoprotein Suppresses Anti- Tumor Immune Responses Partially Through STAT3 and cGAS-STING Pathway in ALK+ Anaplastic Large Cell Lymphoma. [Manuscript]V. Xagoraris I, Stathopoulou K, Aulerio R, He M, Ketscher A, Jatta K, de Flon FH, Barbany G, Rosenquist R, Westerberg LS, Rassidakis GZ. Establishment and characterization of a novel breast implant-associated anaplastic large cell lymphoma cell line and PDX model (BIA-XR1) with a unique KRAS mutation. Curr Res Transl Med. 2023 Jun 20;71(3):103401. https://doi.org/10.1016/j.retram.2023.103401* Denotes equal first author contribution</p
Understanding long-term outcomes in traumatic injury
No full textTraumatic brain injury (TBI) is a complex and impactful medical condition, capable of altering the life of a patient long after the initial trauma. This thesis strives to increase our understanding of long-term outcomes following TBI, from mild to severe cases. The studies aimed to explore predictive factors that influence patient recovery and to evaluate potential treatments targeting the chronic neuroinflammation that follows such injuries.The research project started with an experimental study (Study I) using a rodent model to assess the chronic inflammatory response after a penetrating brain injury. We employed a treatment known as Resolvin D1, a lipid mediator derived from omega-3 fatty acids, hypothesized to aid in resolving inflammation and promoting tissue repair. Although results did not show significant changes in inflammation levels or tissue loss between treated and control groups, the study provided important insights into the timeline and complexities of chronic inflammation in TBI.In the clinical studies (Studies II-IV), we examined data from trauma registries to evaluate patient outcomes following TBI. One key focus was the relationship between pre-injury health, as measured by the American Society of Anesthesiologists (ASA) score, and patient outcomes. The ASA-score is based on the burden of comorbidities and rates a patient's overall health status.The second study (first clinical study) explored health-related quality of life (HRQoL) two years post-TBI, an often overlooked aspect of recovery. Using tools like the RAND-36 and EQ-5D questionnaires, we assessed how 170 trauma patients perceived their physical, emotional, and social health over the long term. Interestingly, we found that TBI patients sometimes reported better HRQoL outcomes than those who experienced non-TBI (NTBI) trauma, particularly in physical functioning and daily role limitations. This could be attributed to factors such as cognitive biases, reduced expectations due to aging, or an impaired ability to fully recognize deficits after brain injury. A high ASA-score (indicating worse health before the injury) was strongly associated with a reduced HRQoL in both the TBI and NTBI cohort. Increased injury severity, measured with the head value of the abbreviated injury score (AIS), showed a trend to association with lower HRQoL, but this was not statistically significant. We found no difference in symptoms of depression, assessed with the self-assessed Montgomary-Åsberg depression score (MADRS-S), between any of the groups.In the third study, we included 823 trauma patients and examined 90-day mortality after mild TBI with intracranial findings (complicated mTBI) compared to NTBI. We found ASA-score to be strongly associated with higher mortality rates, independent from age and injury severity, an association we did not see in the NTBI cohort. This difference could be either due to a treatment bias and under-triage of mTBI patients, a selection bias excluding frail NTBI patients, or that the ASA-score captures an important vulnerability in mTBI patients. AIS (head) was not independently associated with mortality. We also tested the predictive value of the Trauma and Injury Severity Score (TRISS). The accuracy of TRISS was very low, which suggests that this score is not useful in milder trauma.In the fourth and final study we tested the added value of ASA-score to the well- established International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) model, on a cohort of 720 patients with moderate to severe TBI (msTBI). Here we confirmed a strong and independent association between ASA-score and both 90-day mortality and 1-year functional outcome (measured with Glasgow Outcome Score). The inclusion of ASA-scoring yielded a significantly increased estimated explained variance of the already comprehensive IMPACT model. Patients with an ASA-score of 3 or above had a pronounced increase in mortality compared to healthier individuals, which held true even in younger patients. In this cohort, TRISS proved to be strongly associated with GOS, and even more to mortality, highlighting the importance of the overall burden of injury.While these studies provided valuable insights, limitations such as the lack of baseline HRQoL data and the challenges in differentiating chronic inflammation types in experimental models point to avenues for future research. The findings stress the necessity of early and tailored interventions to improve long-term outcomes and reinforce the importance of considering a patient's overall health in management and outcome prediction.By investigating both the biological underpinnings and clinical outcomes of TBI, this work aims to contribute to more refined and effective approaches to treatment and rehabilitation. Understanding these long-term trajectories can enhance care protocols, allowing for a more personalised approach that accounts for individual health profiles, ultimately improving patient outcomes and quality of life following TBI.List of scientific papersI. Kiwanuka O, Cheung J, Hånell A, Lindblad C. Immunological response and tissue loss in a rodent model of chronic traumatic brain injury treated with resolvin. [Manuscript]II. Kiwanuka O, Lassarén P, Thelin EP, Hånell A, Sandblom G, Fagerdahl A, Boström L. Long-term health-related quality of life after trauma with and without traumatic brain injury: a prospective cohort study. Sci Rep. 2023. 13(1): p. 2986. https://doi.org/10.1038/s41598-023-30082-4III. Kiwanuka O, Lassarén P, Hånell A, Boström L, Thelin EP. ASA-score is associated with 90-day mortality after complicated mild traumatic brain injury - a retrospective cohort study. Acta Neurochir (Wien). 2024. 166(1): p. 363. https://doi.org/10.1007/s00701-024-06247-zIV. Kiwanuka O, Lassarén P, Fletcher-Sandersjöö A, Tatter C, Tjerkaski J, Nelson DW, Thelin EP. ASA-score is an independent predictor of 1-year outcome after moderate-to-severe Traumatic Brain Injury. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. (2025) 33:25. https://doi.org/10.1186/s13049-025-01338-x</p
Sexual health in young adult survivors of childhood cancer : prevalence, predictors and web-based support
No full textAim: The overall aim of this thesis was to investigate the prevalence of sexual activity and dysfunction in young adult survivors (19-40 years) of childhood cancer in comparison to the general population. A further aim was to test the efficacy and usage of a psychoeducational web-based intervention (Fex-Can Sex) to alleviate sexual problems among survivors.Methods: This thesis comprises four studies; one population-based observational survey study (n=2,546) to investigate sexual dysfunction (study I) and sexual activity (study II) in comparison to a group of young adults from the general population (n=819), one randomized controlled trial (n=278) testing the efficacy of a 12-week web-based psychoeducational intervention targeting sexual dysfunction (study III). Study IV was a mixed methods study that examined the participants’ (n=322) experiences of sexuality and fertility through the content of posts made in the discussion forum included within the intervention.Results: Approximately half of female and one-third of male childhood cancer survivors report sexual dysfunction. Intensive cancer treatment, negative body image, and emotional distress were associated with higher risk of sexual dysfunction (study I). Most survivors were sexually active, however, to a lesser extent with a partner than the comparison group. Only a small proportion of survivors had never experienced sex with a partner. Among both female and male survivors, younger age at the time of the study, cranial irradiation, and not currently working or studying were factors associated with never having had partner sex (study II). The Fex-Can Sex intervention showed limited effects and participants had demonstrated an overall low adherence. However, those with more sexual dysfunction at baseline (both the intervention group and the control group) improved in several domains of sexual dysfunction over time (study III). Half of the intervention group accessed the discussion forum, most without writing any posts. The content of discussion forum posts included experience of a changed body, concerns about fertility and family building, and a longing for support (study IV).Conclusion: Childhood cancer survivors, particularly those who have undergone intensive cancer treatment, are at a higher risk of reporting negative effects on their sex life. Therefore, sexuality is recommended to be addressed in follow-up care. Web-based interventions may have the potential to improve sexual dysfunction. However, further development of the web-based intervention is necessary to increase adherence by including more interactive components and the use of more stricter inclusion criteria.List of scientific papersI. Hovén, E., Fagerkvist, K., Jahnukainen, K., Ljungman, L., Lähteenmäki, P.M., Axelsson, O., Lampic, C., Wettergren, L. (2021). Sexual dysfunction in young adult survivors of childhood cancer – A population-based study. European Journal of Cancer. 154, 147-156. https://doi.org/10.1016/j.ejca.2021.06.014 II. Fagerkvist, K., Haavisto, A., Jahnukainen, K., Axelsson, O., Lampic, C., Wettergren, L. Sexual activity in young adult survivors of childhood cancer – A population-based study. [Manuscript]III. Fagerkvist, K., Jahnukainen, K., Ljungman, L., Lampic, C., Wettergren, L. (2024). Efficacy of a web-based intervention, Fex-Can Sex, in young adult survivors of childhood cancer: A randomized controlled trial. Internet Interventions. 36. https://doi.org/10.1016/j.invent.2024.100739 IV. Gottvall, M.*, Fagerkvist, K.*, Lampic, C., Wettergren, L. (2022). Including a discussion forum in a web-based intervention on fertility and sexuality – Usage and content. Internet Interventions. 29. *Shared first authorship. https://doi.org/10.1016/j.invent.2022.100559 </p
Network and behavioral correlates of prefrontal neurons
No full textThe prefrontal cortex is located in the front of the brain. This region is considered crucial for cognitive processes, such as decision-making, attention, and working memory. Neuronal activities in this region are found to correlate with cognitive features, as well as behavioral variables such as location and movement.Within the rodent brain, there are distinct neuron types. Research indicates that the function of neurons, whether in relation to local networks or to behavior, is to some extent cell-type-specific.In this thesis I explore methods to study neuronal cell-types in the rodent brain. Further, I use these methods to investigate the role of parvalbumin (PV) expressing interneurons in rats, in relation to network dynamics and behavioral features. This thesis contains 2 papers.Paper I: We developed and described a method for concurrent electrophysiological recordings and optogenetic manipulation in freely moving rodents. Specifically, we designed a low-cost microdrive system and demonstrated its utility in freely moving rats and mice.Paper II: We presented and characterized a novel PV-Cre rat line. We used this rat line to study the activity of prefrontal neuronal subpopulations in rats performing a goal-directed reward-seeking task. Consistent with previous findings, our data reveal neuronal tuning to both spatial and movement variables, with the strongest tuning observed for linear position. Additionally, in a subset of neurons, we observe activities that correlated with the conjunction of location and movement direction, referred to as the spatial context. While the activity of single neurons of all types were correlated with the spatial context, it was most prominently observed in the PV interneuron population.List of scientific papersI. Hoseok Kim*, Hans Brünner*, Marie Carlén. The DMCdrive: practical 3D-printable micro-drive system for reliable chronic multi-tetrode recording and optogenetic application in freely behaving rodents. Scientific Reports. 10 (2020), Article 11838. *Equal contribution https://doi.org/10.1038/s41598-020-68783-9 II. Hans Brünner, Hoseok Kim, Sofie Ährlund-Richter, Josina Ana van Lunteren, Ana Paula Crestani, Konstantinos Meletis, Marie Carlén. Cell-type-specific representation of spatial context in the rat prefrontal cortex. iScience. Volume 27, Issue 5, 15 April 2024, 109743. https://doi.org/10.1016/j.isci.2024.109743 </p
Volumetric and cortical brain development and outcome in children born extremely preterm
No full textChildren born extremely preterm (EPT) survive at an increasing rate. But they continue to have an increased risk for neurodevelopmental impairments. Magnetic resonance imaging (MRI) is used in a clinical setting, but can also be used as a research tool to detect differences in growth patterns between studied groups. The aim of this thesis was to explore differences in brain volumes and cortical thickness of children born EPT compared to term-born controls up into childhood, and to relate these to language and cognitive outcomes.We included 51 children born EPT and 38 term-born controls with high-quality MRI scans at 10 years of age. Out of these, more than half also had volumetric data from term age. Out of the included children with MRI assessments at 10 years of age there were 42 children born EPT and 29 term-born controls with cognitive follow-up data at 12 years of age.Imaging softwares, Statistical Parametric Mapping (SPM) and Freesurfer, were used to calculate global and regional brain volumes and cortical thickness.In Study I the children born EPT had similar global brain volumes at term age as compared to term-born controls, but at 10 years of age their total brain tissue volume was reduced. After correction for total intracranial volume, we found a relative decrease of grey matter volume at term age and a relative decrease of white matter volume at 10 years of age.In Study II, regions important for higher-order cognitive functions were found to be especially affected when children born EPT were compared to term-born controls at 10 years of age. A pattern with both volumetric increases and decreases was detected. Children born EPT with low-grade intraventricular hemorrhages and that were operated for patent ductus arteriosus had small, but persistent volumetric alterations.In Study III the aim was to explore pre-selected language-related brain regions, and we found that their volume and cortical thickness were generally reduced at 10 years of age for children born EPT compared to term-born controls. In the children born EPT the brain volume of language-related regions was related to language scores, prior to adjustments for general cognition. Volumetric asymmetry or cortical thickness of language-related regions at 10 years were not related to language outcomes when children born EPT reached 12 years of age.In Study IV we found that larger volumes of both grey and white matter corresponded to better cognitive performance. Conversely, increased thickness in the right cortex was linked to lower cognitive function in children born EPT. These relationships were consistent with those observed in term-born children. Growth in the brain volume from term age to 10 years of age did not appear to influence cognitive abilities at 12 years of age. However, for the children born EPT, the volume of the insula at age 10 years showed a connection to cognitive outcome.List of scientific papersI. Kvanta H, Bolk J, Strindberg M, Jiménez-Espinoza C, Broström L, Padilla N, Ådén U. Exploring the distribution of grey and white matter brain volumes in extremely preterm children, using magnetic resonance imaging at term age and at 10 years of age. PLoS One. 2021 Nov 5;16(11):e0259717. https://doi.org/10.1371/journal.pone.0259717 II. Kvanta H, Bolk J, Broström L, Fernández de Gamarra-Oca L, Padilla N, Ådén U. Extreme prematurity and perinatal risk factors related to extremely preterm birth are associated with complex patterns of regional brain volume alterations at 10 years of age: a voxel-based morphometry study. Front Neurol. 2023 May 19;14:1148781. https://doi.org/10.3389/fneur.2023.1148781 III. Kvanta H, Bolk J, Broström L, Nosko D, Fernández de Gamarra-Oca L, Padilla N, Ådén U. Language performance and brain volumes, asymmetry, and cortical thickness in children born extremely preterm. Pediatr Res. 2024 Mar;95(4)1070-1079. https://doi.org/10.1038/s41390-023-02871-0 IV. Kvanta H, Padilla N, Nosko N, Mårtensson G, Broström L, Fernández de Gamarra-Oca L, Bolk J, Ådén U. Brain volumes and cortical thickness and associations with cognition in children born extremely preterm. [Manuscript]</p
Life changing moments : transitions and critical points in young-onset dementia
No full textBackground: Persons who are diagnosed with dementia before the age of 65 are commonly referred to as persons with young-onset dementia (YOD). Younger persons and their families have different needs from those in older persons with dementia. However, previous research has identified a lack of support services addressing these specific needs. Persons with YOD and their family members will experience various critical points and transitions during the disease trajectory. As we are not yet able to cure underlying diseases causing dementia, support should focus on enhancing well-being and Quality of life (QoL) / Health Related Quality of Life (HRQoL). This could be achieved by paying extra attention when persons with YOD and their family members experience critical points, to facilitate healthy transitions.Aim: The overall aim of this thesis is to enhance the knowledge and understanding of how to facilitate healthy transitions in YOD, by describing changes in QoL and HRQoL over time, and by exploring the critical points and transition processes that persons living with YOD and their family members experience in different phases of dementia.Methods: Studies I – III were part of a longitudinal project, including participants with YOD after diagnosis. Study I included data on self-reported QoL and HRQoL from 33 participants, collected every six months over a period of 24 months. We assessed changes over time and differences between ‘completers’ and ‘noncompleters’. Trajectories in self-rated QoL and HRQoL were also explored by visual inspection of scatter plots. A sub-sample of 15 participants from study I took part in yearly interviews. These interviews were conducted shortly after diagnosis (study II) and one year after diagnosis (study III) and analyzed by means of qualitative content analysis. In study II we used an inductive approach, and in study III we took on a deductive approach using the categories identified in study II as a framework for data coding. Study IV focused on the perspectives of family members. For this study, 15 family members of persons with YOD were recruited from residential care homes and one support group. To be included in the study the person had to be over 18 years of age and have a family member with YOD living in a residential care home. The family members were interviewed twice and asked to retrospectively describe their experiences of critical points and transitions throughout the disease trajectory. The interviews were analyzed with thematic analysis.Findings: Study I showed great variation in individual scores and trajectories of QoL and HRQoL over time, without identifying specific time points in need of attention. In the qualitative studies with persons with YOD (studies II and III) and family members (study IV), being diagnosed with YOD was described as a lifechanging event. Four critical points clearly emerged from the analyses. These were related to receiving the diagnosis, the premature ending of working life, not receiving formal support, and relocation to a residential care home. The critical points, especially receiving the diagnosis, consequently led to changes in roles and redefinition of identity, and for many, a withdrawal from social activities.Conclusion: Facilitating transitions in YOD is a shared responsibility between the health care sector and social service sector. Therefore, all professionals who meet persons with YOD need to have knowledge about critical points and be aware of signs of unhealthy responses to the transitions. Support for persons with YOD and their family members should focus on regaining control over the changed life situation and facilitating engagement in meaningful activities as a means of reducing the risk of social isolation. The immediate period following disclosure of diagnosis emerged as an especially vulnerable period, in which persons with YOD are likely to need more frequent contact and follow-up from the memory clinics than what is offered today. The findings also emphasize the need to improve knowledge and understanding of the specific needs in YOD, including education of employers and social service officers.List of scientific papersI. Aspö, M., Visser, L.N.C., Cronfalk, B. S., Kivipelto, M., & Boström, A.M. Quality of life of persons with young-onset dementia – repeated self-reported assessment over two years from diagnosis. [Manuscript]II. Aspö, M., Visser, L., Kivipelto, M., Boström, A. M., & Cronfalk, B. S. (2023). Transitions: Experiences of younger persons recently diagnosed with Alzheimer-type dementia. Dementia. 22(3), 610–627. https://doi.org/10.1177/14713012231155516 III. Aspö, M., Visser, L. N. C., Kivipelto, M., Boström, A. M., & Cronfalk, B.S. Transitions: Living with young-onset Alzheimer’s disease – a qualitative interview study. [Submitted]IV. Aspö, M., Visser, L. N. C., Kivipelto, M., Boström, A. M., & Seiger Cronfalk, B. (2023). Family Members’ Experiences of Young-Onset Dementia: Becoming Responsible Yet Feeling Powerless. Journal of multidisciplinary healthcare. 16, 2379–2390. https://doi.org/10.2147/JMDH.S418285 </p