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Multimorbidity and kidney health in old age : methodological considerations and longitudinal associations
No full textIntroduction: Multimorbidity (the presence of ≥2 chronic conditions in one individual) and chronic kidney disease (CKD) are increasingly common in older adults, often occurring together and contributing to poor health outcomes. Both kidney function assessment and the operationalisation of multimorbidity pose important methodological challenges that influence how findings are interpreted and compared. Chronic conditions in older adults tend to cluster into multimorbidity patterns that may share common causes or mechanisms, yet the ways these patterns are measured and described vary widely, limiting comparability across studies. At the same time, assessing kidney function in this population is complicated by age-related physiological changes that affect the production and clearance of creatinine, a key biomarker for its estimation. Beyond these methodological issues, little is known about how specific combinations of chronic conditions relate to kidney outcomes, or how such insights might help identify individuals at higher risk of poor kidney health and shed light on underlying pathophysiological mechanisms.The aim of this thesis was to explore the intersection of multimorbidity, kidney health and ageing, focusing on how kidney function is measured, how multimorbidity patterns are identified, and how these patterns relate to changes in kidney structure and function over time. This was addressed through one systematic review and three observational studies from two well-characterised cohorts.Study I: Systematic review of 16 studies deriving multimorbidity patterns from primary care electronic health record data. Reported multimorbidity prevalence ranged from 14.0% to 93.9%. Mental health and cardiovascular patterns were identified in all studies, frequently alongside conditions from other organ systems, indicating that some patterns are highly replicable across populations. However, marked heterogeneity in analytical decisions related to disease ascertainment and coding, clustering methods, pattern labelling, and stratification limits comparability across studies and hampers evidence synthesis.Study II: Cohort study of 3,094 adults aged 60 years and older from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), comparing the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Revised Lund-Malmö (R-LM), Berlin Initiative Study (BIS), and European Kidney Function Consortium (EKFC) creatinine-based eGFR equations. CKD classification agreement ranged from moderate to very high (Cohen's K 0.42-0.91), with MDRD and CKD-EPI generally providing higher GFR estimates than the other three equations. Agreement was poorest between MDRD and BIS, and highest between R-LM and EKFC. BIS showed the best discrimination for 15-year all-cause mortality (Harrell's C = 0.73), although prognostic accuracy declined in those aged over 78 years and with low calf circumference. Discrepancies between equations were not consistent across the spectrum of age, calf circumference, and BMI.Study III: Cohort study of 3,094 adults from SNAC-K followed for 15 years, examining the number and patterns of chronic conditions in relation to kidney function decline. Multimorbidity was present in 87% of participants. The number of chronic conditions was independently associated with both absolute decline, measured as excess annual eGFR slope (ß -0.05, 95% CI: - 0.07; - 0.03), and relative decline, defined as ≥25% reduction from baseline (HR 1.23, 95% CI: 1.17; 1.29). Five multimorbidity patterns were identified, with the Unspecific, high burden and Cardiometabolic patterns showing the steepest absolute declines (ß -0.15, 95% CI: - 0.26; - 0.05 and ß -0.77, 95% CI: - 0.98; - 0.55, respectively) and relative declines (HR 1.45, 95% CI: 1.09; 1.92 and HR 3.45, 95% CI: 2.27; 5.23, respectively) compared with the least burdened pattern. The Cognitive and Sensory pattern was also associated with greater relative decline (HR 1.53, 95% CI: 1.02; 2.31), while the Psychiatric and Respiratory pattern showed no association.Study IV: Cohort study of 205,449 adults aged 65 years and older undergoing outpatient albuminuria testing, examining eGFR-independent associations between multimorbidity patterns and incident albuminuria (>30 mg/g) and macroalbuminuria (>300 mg/g). Six patterns were identified in ages 65-74 and seven in ≥75 years. Patterns included both organ-specific (e.g. Cardiovascular, Eye) and more general patterns (Unspecific, Multisystem). For albuminuria, compared to those without multimorbidity, the highest risk in ages 65-74 was observed for the Cardiovascular pattern (HR 3.09, 95% CI: 2.85; 3.34), while in those ≥75 years, the Vascular pattern had the highest risk (HR 2.41, 95% CI: 2.08; 2.80). The Dementia pattern was not associated with albuminuria risk. High- burden patterns in older adults had elevated albuminuria risk, although this was attenuated after accounting for competing mortality. The 5-year cumulative incidence of albuminuria exceeded 10-14% in the highest-risk patterns, 5-9% higher than in those without multimorbidity.Conclusions: This thesis synthesises evidence on multimorbidity patterns across primary care populations, showing that certain patterns are replicable and that methodological harmonisation is needed to improve comparability, strengthen evidence synthesis, and facilitate translation into clinical practice. It also shows that creatinine-based eGFR equations are not interchangeable when assessing kidney function in older adults, particularly in those with low muscle mass. They also differ in their predictive capacity for mortality risk, underscoring the importance of equation choice, clinical context, and confirmatory testing. Finally, the quantitative burden and qualitative composition of multimorbidity are important determinants of kidney health, with specific patterns differentially associated with the risk of functional decline and structural damage. Such patterns may serve as practical risk-stratification tools to identify older adults who could benefit from targeted monitoring, timely specialist referral, and earlier initiation of preventive interventions.List of scientific papersThis doctoral thesis is based on the following four papers, which are referred to in the text as Study I, II, III and IV.I. Beridze G*, Abbadi A*, Ars J, Remelli F, Vetrano DL, Trevisan C, Pérez LM, López-Rodríguez JA, Calderón-Larrañaga A. Patterns of multimorbidity in primary care electronic health records: A systematic review. J Multimorb Comorb. 2024;14. https://doi.org/10.1177/26335565231223350 *Shared first authorshipII. Beridze G, Vetrano DL, Marengoni A, Dai L, Carrero JJ, Calderón- Larrañaga A. Concordance and Discrepancies Among 5 Creatinine- Based Equations for Assessing Estimated Glomerular Filtration Rate in Older Adults. JAMA Netw Open. 2023;6(3):e234211. https://doi.org/10.1001/jamanetworkopen.2023.4211III. Beridze G, Dai L, Carrero JJ, Marengoni A, Vetrano DL, Calderón- Larrañaga A. Associations between multimorbidity and kidney function decline in old age: A population-based cohort study. J Am Geriatr Soc. 2025;73(3):837-848. https://doi.org/10.1111/jgs.19298IV. Beridze G, Mark PB, Sullivan MK, Walker H, Tanaka S, Faucon AL, Vetrano DL, Calderón-Larrañaga A, Carrero JJ. Multimorbidity patterns and the subsequent risk of albuminuria: Findings from the Stockholm Creatinine Measurements (SCREAM) project. [Submitted]</p
Unveiling human white adipose tissue diversity at single-cell resolution
No full textObesity is a growing global health concern, currently affecting over one billion individuals worldwide and significantly increasing the risk of cardiovascular, metabolic, and many other diseases. White adipose tissue (WAT), a highly heterogeneous and metabolically active organ, plays a central role in maintaining energy homeostasis and regulating the endocrine system. The distribution and cellular composition of WAT, which vary markedly among individuals and anatomical depots, are critical determinants of metabolic health. While recent single-cell technologies have advanced our understanding of WAT cytoarchitecture, current studies predominantly focus on subcutaneous and omental visceral fat, often overlooking the diversity within visceral depots. Furthermore, adipocytes present technical challenges for single-cell RNA sequencing due to their physical properties, prompting the use of single-nucleus RNA sequencing (snSeq), which introduces specific biases. Spatial transcriptomics (STx) offers an alternative approach, capturing transcriptomic information while preserving spatial context, albeit at a limited resolution. In this thesis, we integrated snSeq and STx data to investigate WAT heterogeneity in obesity. In study I, we identified novel adipocyte substates and associated one with insulin responsiveness. In study II, we systematically mapped WAT cell types across multiple datasets, linking cell-type composition to clinical traits. In study III, we examined spatial and cellular differences between intraperitoneal and subcutaneous depots, revealing depot-specific inflammatory signatures. Our findings underscore the significance of spatial and cellular context in adipose tissue, providing new insights into the molecular underpinnings of metabolic disease in obesity.List of scientific papersI. Backdahl J*, Franzen L*, Massier L, Li Q, Jalkanen J, Gao H, Andersson A, Bhalla N, Thorell A, Rydén M, Ståhl PL*, Mejhert N *. Spatial mapping reveals human adipocyte subpopulations with distinct sensitivities to insulin. Cell Metab. 2021 Sep 7;33(9):1869-1882.e6. https://doi.org/10.1016/j.cmet.2021.07.018II. Massier L, Jalkanen J, Elmastas M, Zhong J, Wang T, Nono Nankam PA, Frendo-Cumbo S, Bäckdahl J, Subramanian N, Sekine T, Kerr AG, Tseng BTP, Laurencikiene J, Buggert M, Lourda M, Kublickiene K, Bhalla N, Andersson A, Valsesia A, Astrup A, Blaak EE, Ståhl PL, Viguerie N, Langin D, Wolfrum C, Blüher M, Rydén M*, Mejhert N *. An integrated single cell and spatial transcriptomic map of human white adipose tissue. Nat Commun. 2023 Mar 15;14(1):1438. https://doi.org/10.1038/s41467-023-36983-2III. Jalkanen J*, Zhong J*, Nono Nankam PA, Bhalla N, Elmastas M, Luo J, Weinbrenner S, Frendo-Cumbo S, Pesti B, Gourash W, Courcoulas A, Yang Loureiro Z, Dietrich A, Bäckdahl J, Buggert M, Kalucka J, Emont MP, Rosen ED, Blüher M, Kovacs P, Ståhl PL, Massier L, Rydén M*, Mejhert N *. Cytoarchitectural Profiling of White Adipose Tissue Depots Links Serum Amyloid A Expressing Adipocytes to Immune Cell Activation. [Submitted] * These authors contributed equally</p
Bridging the treatment gap for adolescents with depression : evaluating internet-based guided and self-guided behavioural activation
No full textBackground: Depression is a common and leading cause of disability among adolescents worldwide. Depression affects not only individuals but also society and economic productivity. Effective treatments for depression exist, and psychological treatments are the primary option; however, only a minority have access to them. Delivering treatments remotely is one way to narrow the treatment gap. Internet-delivered cognitive behavioural therapy (ICBT) has proven to be an effective method for adults with depression. Yet, properly conducted clinical trials for adolescents with clinical depression are lacking. Digital interventions can be delivered with or without therapist support. If treatment can be delivered in a self-guided manner while ensuring efficacy and safety, it may be more cost-effective and could benefit an even larger number of adolescents.Aim: The overarching aim of this thesis was to develop and evaluate a scalable treatment for adolescents with mild to moderate depression and assess the importance of therapist support for treatment outcomes. The specific aims per study were: (1) To assess the feasibility and acceptability of both therapistguided and self-guided internet-delivered behavioural activation (I-BA) with parental involvement; (2) To explore adolescents’ and parents’ experiences of therapist-guided and self-guided I-BA treatment; (3) In a study protocol describe the rationale and methods for the RCT; (4) Investigate the clinical efficacy and cost-effectiveness of therapist-guided and self-guided I-BA compared to treatment as usual (TAU).Methods: This doctoral project included four papers (I-IV). Paper I was a randomised controlled feasibility trial (N=32) to assess the study design's feasibility and the acceptability of the new treatments (I-BA). Paper II was a qualitative study in which eight adolescents and nine parents participated, sharing their experiences of I-BA. Thematic analysis was employed to analyse the data. Paper III details a protocol for the RCT (Study IV) with a planned sample of 215 participants aged 13-17 with mild to moderate depression, comparing therapist-guided I-BA versus TAU and self-guided I-BA versus TAU. Paper IV was a single-blinded, randomised controlled trial involving 219 adolescents aged 13 to 17 years with mild to moderate depression who were randomised to receive either therapist-guided I-BA, self-guided I-BA, or TAU. Clinical efficacy and cost-effectiveness were analysed at 3-months follow-up (the primary endpoint).Results: In Study I, we had two dropouts (in TAU), no severe adverse events, and high treatment completion rates in therapist-guided I-BA, and acceptable rates in self-guided I-BA. The results indicated large and statistically significant reductions in depressive symptoms assessed by clinicians in both I-BA groups, whereas changes in TAU were not significant. In Study II, although some participants found it difficult to engage with and benefit from online BA, the overall results indicated that internet-based BA for adolescents with depression is beneficial and generally well-received, particularly when supported by a therapist and parents. Study IV demonstrated that therapistguided I-BA was both more effective and more cost-effective compared to TAU at three months after ending treatment. Self-guided I-BA was not superior to TAU in clinical efficacy; however, treatment costs were statistically lower. Two serious adverse events for the same participants were reported in this trial, none assessed related to the trial participation.Conclusions: A therapist-guided, internet-based BA intervention is an acceptable, safe, effective, and cost-effective treatment for adolescents with depression when compared to TAU. Although self-guided I-BA was not statistically superior to TAU regarding efficacy, it could still serve as a feasible option for treatment and healthcare system costs if therapist support is unavailable. Pragmatic trials to evaluate this intervention in routine care and replication by independent researchers are encouraged to verify these findings. Continued development of I-BA treatments to enhance both engagement and the proportion of treatment responders is necessary.List of scientific papersI. Andersson, R., Ahlen, J., Mataix-Cols, D., Lenhard, F., Henje, E., Månsson, C., Sahlin, H., Beckman, M., Serlachius, E., & Vigerland, S. (2022). Therapistguided and self-guided internet-delivered behavioural activation for adolescents with depression: a randomised feasibility trial. BMJ Open, 12(12), e066357–e066357.https://doi.org/10.1136/bmjopen-2022-066357II. Andersson, R., Vigerland, S., Ahlen, J., Widström, H., Unger, I., Serlachius, E.,& Engberg, H. (2024). “Therapy without a therapist?” The experiences of adolescents and their parents of online behavioural activation for depression with and without therapist support. European Child & Adolescent Psychiatry, 33(1), 105–114.https://doi.org/10.1007/s00787-023-02142-7III. Andersson, R., Vigerland, S., Lenhard, F., Ahlen, J., Bottai, M., Mataix-Cols, D., & Serlachius, E. (2024). Single-blinded, randomised, parallel-group, controlled trial comparing the efficacy and cost-effectiveness oftherapist- and self-guided internet-delivered behavioural activation versus treatment as usual for adolescents with mild to moderate depression: study protocol. BMJ Open, 14(10), e083507-.https://doi.org/10.1136/bmjopen-2023-083507IV. Andersson R., Ahlen., J., Lenhard, F., Ohlis, A., Wachtmeister, V., Karemyr,M., Hogström, J., Bottai, M., Mataix-Cols, D., Vigerland, S., & Serlachius, E. (2025). Therapist- and self-guided internet-based behavioural activation versus treatment as usual for adolescents with mild to moderate depression: a single-blinded, randomised controlled trial with embedded economic evaluation. [Submitted]</p
Central manipulation of human thermoeffectors during prolonged cold exposure : interaction of thermal and non-thermal stressors
No full textHumans maintain an internal body temperature at ~37℃ through the seamless recruitment of autonomic and behavioural thermoeffectors. In the cold, autonomic thermal responses include cutaneous vasoconstriction, shivering and non-shivering thermogenesis. These responses are orchestrated by feedback- dependent neural networks that detect the cold stimulus, integrate this thermal cue in central regulatory centres, and then initiate the efferent pathways to the thermoeffectors. Behavioural actions, such as a voluntary increase in work rate, are also generally affected by input from thermal receptors. The function of the thermoeffectors can be influenced by the specific characteristics of the thermal stress (i.e., its severity and duration), but also, in an interactive manner, by various non-thermal factors. For instance, nitrous oxide (N2O) and cognitive loading typically act on the central neural circuits of the thermoregulatory system. Thereby, they can impinge on the integrative control function and, thus, alter the onset thresholds for and/or sensitivity of thermoeffector activity. Therefore, this thesis aimed to examine the interaction of thermal and specific non-thermal stressors on human thermoregulatory effector responses during prolonged exposure to cold.After approval by the Swedish Ethics Review Authority, four studies were conducted, all involving non-cold acclimatised healthy men and employing a within-subject design. To evoke sufficient degrees of deep-body cooling (i.e., mild hypothermia), studies I, II, and III employed an experimental model wherein subjects participated in three 120-minute cold water immersions within 10-12- hour experimental sessions. In study IV, to induce adequate degrees of peripheral vasoconstriction, subjects participated in a hand cold-water (8℃) immersion trial for 30 minutes.Study I investigated whether prolonged repeated exposure to cold within a day would provoke centrally mediated thermoregulatory fatigue. Twelve men participated in three experimental sessions. In each session, they were repeatedly submersed in either severely (15℃), moderately (20℃), or slightly (28℃) cold water. These water temperatures were selected to induce discrete amounts of heat-producing thermoeffector output, presumptively leading to distinct fatigue levels during each session. The results demonstrated that the function of autonomic thermoeffector responses was preserved over prolonged, repeated whole-body cold exposure, regardless of the severity of the cold stressor. Notably, repeated whole-body exposure to slight cold stress, evoked by 28℃ water, seemed to sensitise the heat-producing thermoeffector responses.Studies II and III, which were performed within the same experimental project, examined thermoregulatory plasticity and cognitive performance in response to prolonged repeated exposure to 30% N2O and cold. Fourteen men participated in two experimental sessions, during which they performed cold-water immersions in 20°C water, while breathing either normal air or a normoxic gas mixture containing 30% N2O. In study II, it was found that narcosis induced by N2O persistently blunted shivering thermogenesis and thermoperceptual responsiveness. In addition, it was observed in study III that N2O invariably compromised finger dexterity, attention, concentration, working memory, and spatial processing. Thus, a subanesthetic dose of N2O jeopardises human thermoregulatory functions, and, therefore, precipitates hypothermia.Study IV examined whether finger vasoreactivity and thermosensitivity to localised cooling would be modulated by cognitive loading associated with prolonged performance of a mentally demanding task. Twelve men performed immersion of a hand either immediately after a 60-minute cognitive task battery, during the simultaneous performance of the cognitive task, or without any cognitive task. Based on the findings of this study, it appears that the mode of stressors' application determines the impact of cognitive loading. Notably, the repeated execution of a cognitive task appeared to provoke moderate mental fatigue and transiently attenuated cold-induced vasoconstriction and perceived discomfort. Concurrent sustained cognitive and cold stress did not affect finger vasoreactivity during cooling but facilitated digit reperfusion after cooling.List of scientific papersThis thesis is based on the following papers, which are referred to by their Roman numerals (I-IV).I. Moes, M. I., Elia, A., Eiken, O., & Keramidas, M. E. (2025a). Heat- producing thermoeffector plasticity in response to prolonged iterative exposure to a high-heat loss environment: no indication of thermoregulatory fatigue. American Journal of Physiology- Regulatory, Integrative and Comparative Physiology, 328(4), R433- R446. https://doi.org/10.1152/ajpregu.00310.2024II. Moes, M. I., Elia, A., Gennser, M., Eiken, O., & Keramidas, M. E. (2023). Nitrous oxide consistently attenuates thermogenic and thermoperceptual responses to repetitive cold stress in humans. Journal of Applied Physiology, 135(3), 631-641. https://doi.org/10.1152/japplphysiol.00309.2023III. Moes, M. I., Elia, A., Gennser, M., & Keramidas, M. E. (2024). Combined effects of mild hypothermia and nitrous-oxide-induced narcosis on manual and cognitive performance. American Journal of Physiology- Regulatory, Integrative and Comparative Physiology, 326(3), R197- 209. https://doi.org/10.1152/ajpregu.00246.2023IV. Moes, M. I., Elia, A., Eiken, O., & Keramidas, M. E. (2025b). Influence of sustained cognitive loading on finger circulatory and thermoperceptual responsiveness to localized cooling. BioRxiv, 2025-02. [Manuscript Preprint] https://doi.org/10.1101/2025.02.15.638420</p
Early childhood disability : Evaluating the burden and generating evidence for enhanced screening and support
No full textBackground: During the first years of life, neurodevelopment is susceptible for disruptions, in the form of poor nutrition, illness, and psychosocial depravation. It can also be strengthened, for example through universal actions including adequate nutrition, loving caregiving, and early childhood education.Disability, according to the biopsychosocial model, occurs when an individual has an underlying impairment or health condition, that in interaction with personal or environmental factors result in an activity limitation or participatory restriction. This definition emphasizes that consequences for individuals can and need to be mitigated on several societal arenas. In children, these disabilities are often closely linked to the ongoing development, underscoring the need for universal as well as targeted and indicated development- strengthening actions and interventions.Even so, children with disabilities have been excluded from mainstream developmental efforts for the better part of the 20th and 21th century. One reason for this have been the lack of information about how many children that have or are at risk of developmental disability. This lack of data is most outspoken in low- and middle-income countries, especially in the region of Sub-Saharan Africa.These studies utilized the introduction of a new survey method to address this data gap. The child functioning module was introduced in 2017 to measure functional difficulties, which identifies children at risk of disability.In the first study, data from the Sierra Leone Multiple Indicator Cluster Survey 2017 was used to understand how many children that were at risk of disability, and what risk- and resilience factors that could be established using the child functioning module. In the second study, the same dataset was used to explore whether children at risk of disability had increased odds of common childhood infections and looked at their healthcare seeking behaviour. The third study aimed to estimate the prevalence of being developmentally off- track or at risk of disabilities among children living in six different countries in Sub-Saharan Africa and understand how the two measures compare. The fourth study complements the three previous by exploring how stakeholders in child health living in Kampala, Uganda, envision the concept of expanded preventive child health activities.All studies contributed to the overall aim: To better understand the characteristics of childhood disability and how to increase early child development services, with focus on an underserved region.Methods: MICS are cross-sectional surveys that employ a multistage sampling procedure to ensure national and regionally representative samples. The data is collected through face-to-face interviews by local and trained field workers familiar to the cultural context, with data quality checks performed throughout data collection as per the MICS protocol. All MICS surveys included in these studies were part of MICS round six.Results from the child functioning module was used to estimate if a child was at risk of disability, by using several different thresholds. Information from another module, the ECDI2030, was utilised to identify children that did not reach their age-adjusted target for being developmentally track in in health, learning and psychosocial well-being. These children were considered at risk of developmental delay.Study one and two focus on Sierra Leone, as this was the first publicly released dataset that included the child functioning module. Study three includes datasets from Benin, Comoros, Eswatini, and Nigeria, as these were the only countries that included both the child functioning module and the ECDI2030.Multivariable logistic regression models were fitted to estimate the crude (OR) and adjusted odds rations (AOR) with 95% confidence intervals (CI) for childhood disability and not reaching age-appropriate developmental thresholds. Weighted, pairwise ORs were also used to estimate covariation of difficulties in different functional domains. Adjustments were made depending on the research question at hand. In study three prevalence ratios of children not reaching age-adjusted developmental thresholds were estimated through Poisson regressions.Study four utilized purposive sampling technique to recruit stakeholders in child health in Kampala, Uganda, according five pre-defined stakeholder groups. Four research assistants fluent in Luganda and English made the interviews. Thematic analysis, utilizing a top-down approach was employed following an inductive approach.Result: The prevalence of children at risk of disability was similar in in Sierra Leone (6.6% (95% CI 5.8 - 7.6%)), Comoros (6.8% (CI 5.6-8.1%)), Nigeria (7.6% (CI 6.9-8.3%)), and Benin 8.9% (CI 8.1-9.8%). Eswatini had a substantially higher prevalence at 14.1% (CI 12.2-16.3%). Children that were either male or young were at higher risk of disability in all countries except Comoros.The prevalence of children at risk of not reaching developmental thresholds was 52% (CI 49-55%) in Eswatini, 52% (CI 51-54%) in Nigeria, 59% (CI 58-61%) in Benin and 64% (CI 61-66%) in Comoros. Children who did not meet the criteria to be considered developmentally on track were more likely to be male, older, stunted, and from poorer households. In all countries except Eswatini, children not reaching developmental threshold more frequently had caregivers with lower levels of education.Children at risk of disability more often failed to meet age-appropriate developmental thresholds in three of four investigated countries (Benin, Nigeria, and Eswatini).In Sierra Leone, children at risk of disabilities had 30% higher odds (AOR 1.3, 95%CI 1.1 - 1.8) of fever compared to other children. Children at risk of severe disability had higher 60% higher odds (AOR=1.6, 95% CI 1.0 - 2.7), compared to children without functional difficulties. Children with severe functional difficulties also had a higher risk of diarrhoea (AOR=1.8, 95% CI=1.1 to 3.3).Conclusion: There is a high prevalence of children at risk of not reaching developmental milestones, along with links to stunting and poverty in several Sub-Saharan countries. This underscores the need for continued poverty reduction, improved access to a healthy and sufficient diet, and primary prevention. The increased health and development risks for children with functional difficulties which were reaffirmed in study two and three highlights the importance of early detection and intervention to mitigate risks. Study four indicated that integrating developmental monitoring with nutrition and poverty reducing efforts into well-child visits could be an acceptable way to address these challenges.List of scientific papersI. Ekman AT, Sengeh PA, Webber N, Jalloh MB, Hollander AC, Newby H, Cappa C, Orsini N, Alfvén T, Frielingsdorf H. Prevalence of children under five with disabilities in Sierra Leone: insights from a population-based Multiple Indicator Cluster Survey. Disabil Health J.2023 Oct;16(4):101481. https://doi.org/10.1016/j.dhjo.2023.101481II. Ekman AT, Cherry E, Sengeh PA, Webber N, Jalloh MB, Orsini N, Alfvén T, Frielingsdorf H. The occurrence of major infectious diseases and health care seeking among young children with disabilities in Sierra Leone using crosssectional population-based survey data. BMJ paediatrics open, 2024-06, Vol.8 (1), p.e002460. https://doi.org/10.1136/bmjpo-2023-002460III. Anna-Theresia Ekman, Diego Yacaman Mendez, Angelina Kakooza-Mwesige, Claudia Cappa, Tobias Alfvén, Helena Frielingsdorf. Development delay and disability among young children in Sub-Saharan Africa - a comparison of two methods for identifying children at risk at population level. [Manuscript]IV. Anna-Theresia Ekman, Lydia Kabiri, Helena Lindgren, Alma Nordenstam, Anna Wikström, Angelina Kakooza-Mwesige, Grace Ndeezi, Tobias Alfvén. Well-care visits in Kampala: A qualitative study of stakeholders' views on how to improve preventive health for young children. [Manuscript]</p
Targeting the kynurenine pathway in viral infections: neuropsychiatric implications, in vitro drug testing and target validation
No full textViral infections frequently induce persistent cognitive and neuropsychiatric sequelae, potentially mediated through immune-driven dysregulation of tryptophan metabolism along the kynurenine pathway. This pathway generates neuroactive metabolites like kynurenic acid (KYNA) and quinolinic acid (QUIN), which are implicated in psychosis and cognitive deficit. While kynurenine aminotransferase (KAT) II has been proposed as a therapeutic target, its applicability in inflammatory context remains unclear.This thesis investigates the role of the kynurenine pathway in viral-induced neuropsychiatric impairment and explores therapeutic strategies through four integrated studies. Using a combination of clinical, experimental and computational approaches, we:1. Characterized kynurenine pathway dysregulation in Coronavirus Disease 2019 (COVID-19) (Paper I) and tick-borne encephalitis (TBE) patients (Paper II), employing ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to quantify kynurenine pathway metabolites in cerebrospinal fluid (CSF) and serum/plasma.2. Identified correlations between elevated CSF levels of QUIN and kynurenine and neurodegenerative markers in acute COVID-19 (Paper I) and demonstrated persistent peripheral-central pathway dysregulation in TBE linked to long-term attention/vigilance deficits (Paper II).3. Developed human-derived in vitro models (primary fibroblasts, monocytes, A-431 carcinoma cells) to study cytokine-driven kynurenine metabolism (Paper III), revealing KAT III's critical role in inflammation-associated KYNA production.4. Validated KAT III as a novel therapeutic target using pharmacological inhibition in immune-activated systems and postmortem brain tissue from neuroinflammatory conditions (Paper IV).Key findings include:Peripheral inflammation drives central kynurenine metabolite accumulation via monocyte indoleamine 2,3-dioxygenase 1 (IDO1) upregulation in COVID-19.Serum kynurenine/tryptophan ratios (rKT) predict long-term cognitive impairment in TBE.KAT III (rather than KAT II) emerges as the dominant enzymatic contributor to neuroactive metabolite shifts during immune activation.In conclusion, these results establish the kynurenine pathway as both a biomarker source and mechanistic bridge between viral-induced inflammation and cognitive sequelae. Our data strongly suggest KAT III inhibition as a promising strategy for mitigating neuropsychiatric complications, and we further provide validated models for high-throughput therapeutic screening. By integrating clinical observations with mechanistic studies, this thesis lays a foundation for targeted interventions in infection-associated neurological disorders.List of scientific papersI. Xueqi Li, Arvid Eden, Susmita Malwade, Janet L. Cunningham, Jacob Ahlberg Weidenfors, Carl M. Sellgren, Göran Engberg, Fredrik Piehl, Magnus Gisslen, Eva Kumlien, Johan Virhammar, Funda Orhan, Elham Rostami, Lilly Schwieler, Sophie Erhardt. "Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses." Brain, Behavior, and Immunity 124 (2025): 163-176. https://doi.org/10.1016/j.bbi.2024.11.031II. Jacob Ahlberg Weidenfors, Vytautas Griška, Xueqi Li, Aistė Pranckevičienė, Jolita Pakalnienė, Ann Atlas, Elisabeth Franzén-Röhl, Fredrik Piehl, Lars Lindquist, Auksė Mickienė, Göran Engberg, Lilly Schwieler, Sophie Erhardt. "Dysregulation of the kynurenine pathway is related to persistent cognitive impairment in tick-borne encephalitis." Brain, Behavior, and Immunity 125 (2025): 452-465. https://doi.org/10.1016/j.bbi.2025.02.005III. Xueqi Li, Anthi Faka, Marta Gómez-Galán, Neda Khanlarkhani, Göran Engberg, Sophie Imbeault, Carl Sellgren, Simon Cervenka, Nikolaos Venizelos, Lilly Schwieler, Funda Orhan, Sophie Erhardt. "Synergistic Effects of IFN-y and IL-1B on Kynurenine Pathway Activation and the Role of KAT Isoforms in KYNA Synthesis in Human Primary Fibroblasts." [Manuscript]IV. Varvara Louvrou, Lilly Schwieler, Xueqi Li, Xi-Cong Liu, Anthi Faka, Annika Lindqvist, Ylva Gravenfors, Funda Orhan, Susmita Malwade, Carl Sellgren, Marta Gomez Gallan, Federico Picciau, Sophie Imbeault, Robert Schwarcz, Sophie Erhardt. "KAT Ill as the Key Enzyme Driving Immune-Induced Kynurenic Acid Synthesis: A Novel Target for cognitive dysfuntions and psychotic disorders." [Manuscript]</p
Regulation of B cell differentiation : from actin dynamics to cancer evolution
No full textPrimary immunodeficiency (PID) disorders specify a heterogeneous group of diseases characterized by poor or absent function in one or more components of the immune system. Most often they arise because of congenital monogenetic mutations. Wiskott-Aldrich syndrome (WAS) and X-linked neutropenia (XLN) are two types of PIDs occurring as a consequence of loss-of-function and gain-of- function mutation in the Wiskott-Aldrich Syndrome protein (WASp), respectively. WASp is a regulator of the actin cytoskeleton, which is required for many hematopoietic and immune cell functions, including blood circulation, effective migration, and immune synapse formation. Besides compromised immune response giving autoimmunity, PID patients are predisposed to develop malignancies (e.g. lymphoma) of poor prognosis.In Paper I, we studied B cell affinity maturation in the germinal center (GC) of XLN patients and murine models. XLN patients had normal levels of naïve and plasma blasts B cells, but decreased B cell proliferation at the expense of IgA switched B cells as well as memory B cells. Immunized XLN mice presented smaller GCs but had increased plasma blasts and plasma cells output. In vitro XLN murine B cells resulted in reduced Ig class switching and faulty cell division. Overall, XLN patients and animal models showed decreased B cell proliferation, reduced IgA switching, and increased genomic instability.In Paper II, we investigated the nuclear function of WASp in WAS and XLN mouse models during differentiation from naïve to activated B cells. We performed nuclear-cytosol fractionation and WASp immunoprecipitation to reveal the presence of WASp in the nucleus of B cells besides its known localization in the cytoplasm. Chromatin immunoprecipitation (ChIP) of RNA polymerase II (RNA pol II) revealed an intrinsic role of WASp at transcription start sites (TSS), considering the decrease of RNA pol II coverage in WASp-KO activated B cells. Flow cytometry analysis of purified nuclei highlighted the different chromatin states of naïve (repressed, resting state) and activated (open, actively transcribing) B cells.Differences in the nucleus of WT, XLN and WASp-KO naïve and activated B cells were reflected by differentially expressed gene analysis identified by bulk RNA sequencing. In summary, our work suggests a coordinated activity of WASp and RNA pol II in murine naïve and activated B cells.In Paper III, we utilized a single cell-based approach coupled with VDJ sequencing to understand the mechanisms of lymphomagenesis during childhood. We collected aged-matched reactive lymph nodes, pediatric Burkitt Lymphoma (pBL), pediatric T cell lymphoblastic lymphoma (pTLBL) and pediatric Hodgkin lymphoma (pHL). We identified in pBL and pTLBL lymphoma cells by the hyperexpanded VDJ clone as well as infer copy number variation. pBL shared similarity with GC B cells, plasma cells and memory B cells, while pTLBL occupied a unique niche. pHL cells were characterized by expression of the CD30 marker both in single cell data and by special transcriptomics. HL cells were surrounded by exhaustion T cells supporting their growth. Our data revealed shared and unique transcriptomic profiles in BL, TLBL and HL patients and pediatric reactive lymph nodes.In Paper IV, we tested the small molecule CK666, an Arp2/3 inhibitor, in dendritic cells (DCs) to mimic WASp-KO DCs that have increased DC cross-presentation capacity. CK666-treated DCs maintained a neutral phagosome pH and increased T cell proliferation as a readout of an efficient cross-presentation when primed with ovalbumin (OVA). The combination of CK666-treated DCs with activated T cells increased the survival of mice with the aggressive B16-melanoma tumor. Mice survival was longer when we combined CK666-treated DCs and activated T cells with a-PD-1 checkpoint inhibitor therapy. Our results highlight the efficacy of a drug that impair the actin cytoskeleton to facilitate tumor killing.List of scientific papersI. He M, Saeed MB, Record J, Keszei M, Gonçalves Pinho L, Vasconcelos-Fontes L, D'Aulerio R, Vieira R, Oliveira MMS, Geyer C, Bohaumilitzky L, Thiemann M, Deordieva E, Buedts L, Matias Lopes JP, Pershin D, Hammarström L, Xia Y, Zhao X, Cunningham-Rundles C, Thrasher AJ, Burns SO, Cotta-de-Almeida V, Liu C, Shcherbina A, Vandenberghe P, Westerberg LS. Overactive WASp in X-linked neutropenia leads to aberrant B- cell division and accelerated plasma cell generation. Journal of Allergy and Clinical Immunology (2022) https://doi.org/10.1016/j.jaci.2021.07.033II. D'Aulerio R, Machado Matos G, Gonçalves Pinho L, Doukoumopoulos E, Calixto Vieira R, He M, Xue L, Gautier J, Westerberg LS. The actin regulator WASp associates with chromatin and regulates RNA polymerase II transcription in B cells. [Manuscript]III. D'Aulerio R*, Yong T*, Oertlin C, Record J, Elliot A, Kwiecinska A, Baecklund F*, Westerberg LS *. Clonal evolution analysis of pediatric lymphoma reveals a diversified transcriptome and targets for precision medicine. [Manuscript] *equal contributionIV. Oliveira MMS, D'Aulerio R, Yong T, He M, Baptista MAP, Nylén S, Westerberg LS. Increased cross-presentation by dendritic cells and enhanced anti-tumor therapy using the Arp2/3 inhibitor CK666. British Journal of Cancer (2023) https://doi.org/10.1038/s41416-022-02135-4</p
Improved survival in gastric adenocarcinoma
No full textDespite advances in surgical treatment and systemic therapy during recent decades, the prognosis of gastric adenocarcinoma remains poor. This thesis aims to identify factors that may contribute to improving long-term survival in patients with gastric adenocarcinoma. Four population-based cohort studies were conducted:Study I tested two hypotheses: (1) that gastric bypass for obesity is followed by an increased risk of adenocarcinoma in the excluded stomach (i.e., gastric non- cardia adenocarcinoma), and (2) that the diagnosis of such tumors is delayed if they occur. In a cohort of 98,881 patients who underwent bariatric surgery in Denmark (1996-2019), Finland (1997-2019), and Sweden (1980-2019), with follow-up through 31 December 2019, 31 cases of gastric non-cardia adenocarcinoma were identified. Gastric bypass was associated with an increased risk of gastric non-cardia adenocarcinoma 10-40 years after surgery compared to other bariatric surgeries, but not within the first 1-9 years. The rates of gastrectomy and survival seemed decreased following gastric bypass, indicating delayed tumor detection.Study II tested the hypothesis that a later weekday of surgery is associated with increased 5-year mortality after gastrectomy for gastric adenocarcinoma. Among 1,678 patients who underwent gastrectomy for gastric adenocarcinoma in Sweden between 2006-2015, surgery performed in later weekdays (Thursday- Friday) was not associated with increased 5-year mortality compared to early- mid weekdays (Monday-Wednesday). When analyzing each weekday separately, Friday showed an increased point estimate for 5-year mortality, but statistically non-significant. These findings suggest that weekday of gastrectomy may not influence long-term survival in gastric adenocarcinoma, at least on Monday through Thursday.Study III tested the hypothesis that surgeon age influences 5-year survival after gastrectomy for gastric adenocarcinoma. Among 1,647 patients who underwent gastrectomy for gastric adenocarcinoma in Sweden between 2006-2015, surgeon age 247 years was associated with increased 5-year mortality compared to Study IV evaluated whether survivors of gastric adenocarcinoma have a longer, shorter, or similar survival compared to the general Swedish population of the same age, sex, and calendar year. Among 767 patients who underwent gastrectomy for gastric adenocarcinoma in Sweden between 2006-2015 and survived at least 5 years (these were considered cured), observed survival was lower than expected survival. The decline was more pronounced among patients who underwent gastrectomy in earlier calendar years, had lower education level, more comorbidities, and had not undergone neoadjuvant therapy. These findings suggest that gastric adenocarcinoma survivors have a decreased survival compared to the general population, particularly if they belong to certain subgroups.List of scientific papersI. Leijonmarck W, Santoni G, Holmberg D, von Euler-Chelpin M, Ness- Jensen E, Kauppila JH, Lagergren J. Cancer in the excluded stomach after gastric bypass surgery for obesity. [Manuscript]II. Leijonmarck W, Asplund J, Markar SR, Mattsson F, Lagergren J. Weekday of gastrectomy and long-term survival in gastric adenocarcinoma. Eur J Surg Oncol. 2023;49(1):83-88.https://doi.org/10.1016/j.ejso.2022.07.011III. Leijonmarck W, Mattsson F, Asplund J, Markar S, Lagergren J. Surgeon age in relation to patients' long-term survival after gastrectomy for gastric adenocarcinoma: nationwide population-based cohort study. BJS Open. 2024;8(2):zrae015. https://doi.org/10.1093/bjsopen/zrae015IV. Leijonmarck W, Mattsson F, Lagergren J. Survival among patients cured from gastric adenocarcinoma compared to the background population. Gastric Cancer. 2024;27(6):1180-1188. https://doi.org/10.1007/s10120-024-01545-y</p
System-level approaches for biomarker discovery in complex and malignant diseases
No full textEarly diagnosis and effective treatment of complex and malignant diseases are critical challenges in modern medicine. These diseases exhibit significant heterogeneity, manifesting differently across patients and involving diverse genes and pathways. This variability complicates the identification of universal biomarkers, necessitating innovative, system-level approaches to uncover robust and predictive biomarkers across various biological contexts.This dissertation addresses these challenges by leveraging both knowledge- based and data-driven methods to analyze multi-omics data, including spatial and single-cell transcriptomics, as well as bulk data. The goal is to prioritize potential biomarkers that can provide system-level insights into disease mechanisms, ultimately facilitating personalized medicine. The findings of this thesis promise to transform biomarker discovery, leading to earlier diagnoses, improved treatment outcomes, and enhanced patient care.The thesis encompasses four comprehensive studies:1. Multi-organ single-cell analysis reveals an on/off switch system with potential for personalized treatment of immunological diseases: We analyzed scRNA-seq data from mice and humans with immune-mediated inflammatory diseases (IMIDs). We identified upstream regulators acting as on/off switches, which collectively serve as candidate biomarkers and potential drug targets. These findings were validated in a study involving sera from nearly 300 systemic lupus erythematosus patients.2. An interactive atlas of genomic, proteomic, and metabolomic biomarkers promotes the potential of proteins to predict complex diseases: Using multiomics data from UK Biobank (UKBB), we identified reliable biomarkers for nine complex diseases and constructed an interactive atlas to explore their performance. Proteomics outperformed other omics types in most of the diseases.3. Multiomics biomarkers were not superior to clinical variables for pan- cancer screening: We analyzed multiomics data to find early diagnostic biomarkers for cancers. While proteomics data from peripheral blood did not outperform routine clinical variables for most cancers, promising biomarkers were identified for cancers in highly vascularized organs.4. Combining spatial transcriptomics and pseudotime to find urine biomarkers for prostate cancer: We analyzed spatial transcriptomics data of prostate cancer to identify transcripts correlated with malignant transformation. Using pseudotime and machine learning, we validated the diagnostic accuracy of these transcripts in various samples from over 2,000 patients and controls.In conclusion, this thesis demonstrates the potential of systems-level approaches in biomarker discovery, providing insights into disease mechanisms and paving the way for personalized medicine. The studies highlight the importance of considering disease heterogeneity and the need for tailored biomarker strategies, ultimately contributing to earlier diagnoses and improved patient outcomes.List of scientific papersI. Sandra Lilja*, Xinxiu Li*, Martin Smelik*, Eun Jung Lee, Joseph Loscalzo, Pratheek Bellur Marthanda, Lang Hu, Mattias Magnusson, Oleg Sysoev, Huan Zhang, Yelin Zhao, Christopher Sjöwall, Danuta Gawel, Hui Wang, Mikael Benson. Multi-organ single-cell analysis reveals an on/off switch system with potential for personalized treatment of immunological diseases. Cell Rep Med. 2023 Mar 21;4(3):100956. https://doi.org/10.1016/j.xcrm.2023.100956II. Martin Smelik*, Yelin Zhao*, Xinxiu Li, Joseph Loscalzo, Oleg Sysoev, Firoj Mahmud, Dina Mansour Aly, Mikael Benson. An interactive atlas of genomic, proteomic, and metabolomic biomarkers promotes the potential of proteins to predict complex diseases. Sci Rep. 14, 12710 (2024). https://doi.org/10.1038/s41598-024-63399-9III. Martin Smelik, Yelin Zhao, Dina Mansour Aly, AKM Firoj Mahmud, Oleg Sysoev, Xinxiu Li, Mikael Benson. Multiomics biomarkers were not superior to clinical variables for pan-cancer screening. Communications Medicine. 4, 234 (2024). https://doi.org/10.1038/s43856-024-00671-zIV. Martin Smelik*, Daniel Diaz-Roncero Gonzalez*, Xiaojing An, Rakesh Heer, Lars Henningsohn, Xinxiu Li, Hui Wang, Yelin Zhao, Mikael Benson. Combining spatial transcriptomics, pseudotime and machine learning to find biomarkers for prostate cancer. [Manuscript]* Shared first-author</p
Type 1 diabetes in young women : aspects on person-centered care and BMI in risk assessment
No full textBackground and aimsYoung women with type 1 diabetes (T1D) have higher relative risks of vascular complications and premature mortality than their male counterparts. Girls with T1D report higher disease burden, diabetes-related distress and lower health- related quality of life (HRQoL) than boys with T1D, and for many years, girls with T1D have had higher mean glycosylated hemoglobin (HbA1c). Targeted interventions for this patient group are lacking. Diabetes treatment is challenging, in particular in adolescence and young adulthood. It is important to find out which treatment the person with T1D prefers since treatment satisfaction can impact treatment burden and adherence. International guidelines recommend a person-centered approach in the care of young people with T1D, with individualized treatment and education. Guided Self-Determination-Young (GSD-Y) is a person-centered reflection and problem-solving model intended to guide the patient to become self-determined and to develop skills to deal with challenges in diabetes self-management. There is little data on time-trends in Body Mass Index (BMI) in young women with T1D, and it is unclear if overweight and obesity are independent risk factors for diabetes-related vascular disease in this population.The overall aim of this thesis was to improve HbA1c, self-management of diabetes and HRQoL and to increase empowerment in young women with T1D. A further objective was to examine BMI time-trends in young women with T1D in comparison to a background population, and the potential impact of BMI on their risk of diabetes-related vascular complications.Methods and resultsStudy I was a cross-sectional study of perceived treatment satisfaction in young individuals with T1D, 15-20 years, preceded by a translation and validation of a questionnaire for assessing treatment satisfaction in adolescents with T1D. A total of 138 adolescents with T1D participated in the cross-sectional study. We showed that treatment satisfaction was associated with both HbA1c and perceived burden of diabetes in adolescents with T1D but found no correlations with type of treatment, sex or age.Study II was a randomized controlled trial to investigate the effects of an intervention with the GSD-Y in young women with T1D, 15-20 years. A total of 51 young women with T1D were included and randomized to intervention group (n=25) or control group (n=26). We demonstrated that the GSD-Y model may increase empowerment in young women with T1D but could not show a significant effect on HbA1c.Study III was a qualitative interview study of a subset of participants from study II. 12 young women were interviewed. Inductive content analysis showed that the GSD-Y model initiated both an individual and a relational process including deep reflection and a mutual exchange of information beyond HbA1c. GSD-Y facilitated exploration and clarification of the young women's individual needs, leading to improved diabetes self-management and increased empowerment. Study IV was a population-based cohort study with data from several Swedish registries. We identified 3,473 young women with T1D in the national diabetes registries and included 8,487 young women from the background population. We demonstrated a similar BMI increase over time in both populations but young women with T1D had a higher BMI at baseline. Furthermore, we showed that overweight and obesity independently increased the risk of diabetes-related vascular complications in young women with T1D.ConclusionsIn young persons with T1D, treatment satisfaction is important to assess since it is associated with both perceived disease burden and glycemic control. The Diabetes Treatment Satisfaction Questionnaire (DTSQ) Teen is well-suited for use in clinical trials and in diabetes care. The finding of increased empowerment after the GSD-Y intervention is important since it may lead to improved diabetes self-management and glycemic control. The GSD-Y intervention encouraged young women to take an active role in their diabetes care, facilitating person- centered care. As a result, the GSD-Y model can be a valuable tool in the healthcare of young women with T1D. BMI is increasing in young women with T1D and overweight and obesity should be addressed as important modifiable risk factors for diabetes-related vascular complications in this population.List of scientific papersI. Haas J, Persson M, Toft EH, Rathsman B, Brorsson AL, Lindholm Olinder A. Treatment satisfaction correlated with glycaemic control and burden of diabetes in Swedish adolescents with type 1 diabetes. Acta Paediatr. 2020; 109 3:573-80. Epub 2019 Sep 16. https://doi.org/10.1111/apa.14991II. Haas J, Persson M, Brorsson AL, Toft EH, Lindholm Olinder A. Person-centered care in in young women with type 1 diabetes - a Swedish multicenter randomized controlled trial with Guided Self Determination-Young (GSD-Y). [Manuscript]III. Haas J, Persson M, Toft EH, Back-Nirs J, Lindström M, Lindholm Olinder A, Brorsson AL. Improved self-management of type 1 diabetes in young women: Experiences of Guided Self-Determination-Young: A qualitative interview study. Diabet Med. 2025 Mar 28:e70029. doi: 10.1111/dme.70029. Epub ahead of print. https://doi.org/10.1111/dme.70029IV. Haas J, Andersson Franko M, Lindholm Olinder A, Nyström T, Persson M. Time-trends in body mass index, and overweight and obesity as independent risk factors for diabetes angiopathy in young females with type 1 diabetes - A nationwide study in Sweden. Diabetes Res Clin Pract. 2023 Sep 9;204:110899. https://doi.org/10.1016/j.diabres.2023.110899</p