KI Open Archive Karolinska Institutet
Not a member yet
10598 research outputs found
Sort by
Deciphering mechanisms that regulate aging in Caenorhabditis elegans
No full textAging is a multifaceted and poorly understood process characterized by physiological changes that culminate in the decline of an organism's functions. The research field of Biology of Aging aims to provide insight into this process, thereby contributing to the development of therapies that alleviate age-related symptoms in humans. This thesis provides a concise overview of research in this field, primarily focusing on the model organism Caenorhabditis elegans. The thesis also encompasses the studies conducted during my PhD, uncovering novel regulators and mechanisms of aging in C. elegans. Additionally, it examines the role of primary cilia in neuron differentiation. We anticipate that these studies will deepen our understanding of aging and certain age-associated diseases, thus facilitating the development of anti-aging therapies.List of scientific papersI. Exploring the interplay between DAF-16/FOXO and BAF-1/BANF1 in the regulation of aging.II. Mapping of transcriptionally relevant chromatin accessibility changes reveals LIN-39 as a driver of longevity in Caenorhabditis elegans with reduced insulin/IGF-like signaling.III. Transcriptomics-Based Screening Identifies Pharmacological Inhibition of Hsp90 as a Means to Defer Aging. Cell Rep. 2019 Apr 9;27(2):467-480.e6. https://doi.org/10.1016/j.celrep.2019.03.044 IV. Primary cilia promote the differentiation of human neurons through the WNT signaling pathway. BMC Biol. 2024 Feb 27;22(1):48. https://doi.org/10.1186/s12915-024-01845-w </p
Bridging time and space in the brain : 14C dating and spatial transcriptomic analysis give new insight into neurological disease
No full textConditions affecting the nervous system are collectively the largest contributor to ill health and disability worldwide, and the therapeutic options for many neurological diseases remain limited. For a long time, it was believed that the central nervous system was fixed, with very limited potential for repair after injury. However, studies over the recent decades have demonstrated that the brain exhibits more plasticity than previously understood, which has led to significant efforts to harness these mechanisms for regenerative therapies. In addition, our increased understanding of how the central nervous system interacts with the immune system, opens further possibilities for novel therapeutic strategies. While animal models have provided important insights to brain plasticity and neuroimmune interactions, the involvement of these processes in neurological disease remain largely unexplored in the human brain. This is primarily due to a lack of methods to study cellular dynamics, such as cell generation and immune cell infiltration in brain tissues, without harming the individual. Using two innovative techniques, we have in this thesis explored cellular processes in time and space, in the healthy as well as the pathological human brain.In paper I, we utilized a 14C-based retrospective birth dating method to study how adult neurogenesis, the generation of new neurons in the adult brain, in the hippocampus may be affected in individuals that suffered from alcohol or cocaine addiction. We did not observe any difference in adult hippocampal neurogenesis between healthy controls and the addiction groups, indicating that reduced neurogenesis throughout life does not contribute to addiction vulnerability. Although it was not possible to exclude smaller, yet clinically relevant, changes in cell turnover during the time of abuse, we found that individuals with long-term abuse of alcohol must have similar levels of neuronal generation as many healthy controls during the time of abuse. Furthermore, we found large interindividual variability in neuronal turnover in the healthy control group, suggesting that lifestyle and genetic factors greatly influence adult neurogenesis in the healthy brain.The retrospective birth dating method was also applied in paper II to investigate the dynamics of oligodendrocyte generation in patients with multiple sclerosis (MS). We specifically examined shadow plaque lesions, which are believed to be remyelinated through the generation of new myelinating oligodendrocytes. Contrary to this belief, we found that oligodendrocytes in shadow plaques are old, indicating that potential remyelination in humans is performed by older oligodendrocytes. However, increased oligodendrocyte generation was found in non-lesion tissue of a few patients, possibly suggesting a heterogeneous reactive cell generation response.MS is generally considered a T cell mediated autoimmune disease. However, the clinical success of B cell-depleting therapies suggest an important role of B cells in MS pathology. The specific T and B cells involved, and their target antigens, are not yet fully characterized. However, the diverse clones can be identified by their highly specific T and B cell receptors, and studying the lymphocyte clonality in a spatial context could shed light on specific clonesŐ involvement in MS pathology. However, high throughput methods for simultaneous analysis of the spatial distribution B and T cell clones in human tissues were not available. Therefore, in paper III, we developed a spatial transcriptomics method for variable, diversity and joining (VDJ) sequences, called Spatial VDJ, that maps the spatial distribution of T and B cell receptors in tissue sections, while simultaneously capturing the spatial gene expression. This method allows us to study lymphocyte clonal dynamics in a spatial context, link specific lymphocyte clones to local gene expression profiles as well as to lineage trace B cell clones, which can inform us of the development of B cell immune responses.In paper IV, we utilized the Spatial VDJ technique to characterize the spatial distribution of lymphocyte clones in MS lesions, with the goal of identifying candidate clones that may be involved in driving the lesion pathology. We found significant infiltrates of clones of the B cell lineage, possibly terminally differentiated and antibody producing plasma cells, in different lesion types. We identified locally expanded clones that had infiltrated the lesion parenchyma close to vessels and along active lesion borders This potentially suggest a local antigen-driven activity and involvement in driving lesion pathology.Together, these studies provide novel insights into how the generation of two types of brain cells might be involved in the pathological human brain. These studies also identify candidate B cell clones that potentially could be drivers of MS lesions. These are key insights into fundamental cellular dynamics of the human brain and how they may differ from the processes described in more commonly used animal models. Such new insights may help guide the development of future therapies for devastating diseases of the human brain.List of scientific papersI. Alkass K*, Steiner E*, Bernard S, Le Ma”tre TW, Dhanabalan G, LandŽn M, Spalding K, FrisŽn J, Mash DC, Druid H. Effect of alcohol and cocaine abuse on neuronal and non-neuronal cell turnover in the adult human hippocampus. *Shared first authorship. [Manuscript]II. Yeung MSY, Djelloul M, Steiner E, Bernard S, Salehpour M, Possnert G, Brundin L, FrisŽn J. Dynamics of oligodendrocyte generation in multiple sclerosis. Nature. 566, 538-542 (2019). https://doi.org/10.1038/s41586-018-0842-3 III. Engblom C, Thrane K, Lin Q, Andersson A, Toosi H, Chen X, Steiner E, Lu C, Mantovani G, Hagemann-Jensen M, SaarenpŠŠ S, Jangard M, Saez-Rodriguez J, Micha‘lsson J, Hartman J, Lagergren J, Mold JE, Lundeberg J, FrisŽn J. Spatial transcriptomics of B cell and T cell receptors reveals lymphocyte clonal dynamics. Science. 382, eadf8486 (2023). https://doi.org/10.1126/science.adf8486 IV. Steiner E, Lin Q ,Kolbeinsdottir H, Dumitru I, Brundin L, Engblom C, Mold JE*, FrisŽn J*. Dissecting the clonal architecture of lymphocytes in multiple sclerosis lesions. *Shared last authorship. [Manuscript]</p
Multiomic analysis of T cells in response to cancers and microbes
No full textThe human immune system consists of various cell subsets, cytokines and their interactions. Traditionally researchers focus on one compartment at a time, however, with the advance in high-throughput, multi-omics techniques, it is possible to monitor multiple compartments of the immune system simultaneously. Systems immunology is then proposed and provide a broader perspective of the immune landscape. This thesis will investigate the human immune responses against cancers and microbes with a focus on T cells using systems-level immunomonitoring.In paper I, we recruited a pan-cancer cohort of patients with pediatric solid tumors and performed systems-level immunomonitoring. We found that tumor type and age of patient have balanced contributions to the immune responses against tumor. The T cell clonal expansion is rare prior to treatment but can be elicited by treatments. Those clonally expanded T cells, although less abundant in children, are transcriptionally comparable to those in adults with more immunogenic cancers. This study demonstrated the possibility for precision immunotherapies for children with cancer.In paper II, we studied the immune development of the extremely preterm infants. We described a delayed immune normalization in the most immature infants with gestational age 22-24 weeks, but they follow the similar trajectory as indicated by term controls. We also demonstrated a strong influence of motherŐs own milk, but not pasteurized donor milk, in promoting healthy immune development comparable to healthy term infants. The different immune developments in infants fed with motherŐs own milk and donor milk are manifested by NK cell development. Neither of the differences can be explained by microbiome composition, indicating direct effects of bioactive components in motherŐs own milk.In paper III, we demonstrated that a deficiency of bifidobacteria, particularly the depletion of genes essential for human milk oligosaccharide (HMO) utilization in the metagenome, is linked to systemic inflammation and immune dysregulation in early life. In breastfed infants supplemented with Bifidobacterium infantis (B.infantis), which possesses all HMO-utilization genes, intestinal Th2 and Th17 cytokines were suppressed while IFN-_ was induced. Fecal water from B.infantis-supplemented infants contained abundant indolelactate (ILA) and indole-3-lactic acid, which upregulated immunoregulatory galectin-1 in Th2 and Th17 cells and induced a skewed Th1 polarization. This provides a functional connection between beneficial microbes and immunoregulation during the first months of life.In paper IV, we studied acute COVID-19 patients with longitudinal immunomonitoring and found an immune trajectory from admission to recovery that is shared in those patients. We also described an IFN_-eosinophil axis activated right before lung hyperinflammation.In paper V, we investigated severe long COVID patients with organ damage or dysfunction. By performing systems-level immunomonitoring, we identified elevated serological responses to SARS-CoV-2 in severe Long COVID, indicative of chronic antigen stimulation. Elevated serologic responses to SARS-CoV-2 were inversely correlated with clonally expanded memory CD8+ T cells with specificity to SARS-CoV-2. This suggests that restrained SARS-CoV-2-specific clonal expansion enables viral persistence, chronic antigen exposure, and elevated IgG responses.List of scientific papersI. Systems-level immunomonitoring in children with solid tumors. Chen, Q.*, Zhao, B.*, Tan, Z.*, Hedberg, G., Wang, J., Gonzalez, L., Mugabo, C. H., Johnsson, A., Pi–ero P‡ez, L., Rodriguez, L., James, A., Chen, Y., Mikes, J., Barcenilla, H., Wang, C., Davis, M. M., Carlson, L.-M., Pal, N., Herold, N., Blomgren, K., Repsilber, D., Lakshmikanth, T., Kogner, P., Ljungblad, L.*, Brodin, P. [Manuscript]II. MothersŐ own milk normalize immune system development in extremely preterm infants. Tan, Z.*, Zhong, W.*, Danielsson, H., Arzoomand, A., Lakshmikanth, T., Chen, Q., Mikes, J., Wang, J., Chen, Y., James, A., Nilsson, A. K., Elfvin, A., Brusselaers, N., Portlock, T., Lundgren, P., SŠvman, K., Wackernagel, D., Hansen-Pupp, I., Ley, D., UhlŽn, M., Hellstršm, A., Brodin, P. [Manuscript]III. Bifidobacteria-mediated immune system imprinting early in life. Henrick, B. M.*, Rodriguez, L., Lakshmikanth, T., Pou, C., Henckel, E., Arzoomand, A., Olin, A., Wang, J., Mikes, J., Tan, Z., Chen, Y., Ehrlich, A. M., Bernhardsson, A. K., Mugabo, C. H., Ambrosiani, Y., Gustafsson, A., Chew, S., Brown, H. K., Prambs, J., Bohlin, K., Mitchell, R. D., Underwood, M. A., Smilowitz, J. T., German, J. B., Frese, S. A., Brodin, P. Cell. 184, 3884Đ3898.e11, (2021). https://doi.org/10.1016/j.cell.2021.05.030 IV. Systems-Level Immunomonitoring from Acute to Recovery Phase of Severe COVID-19. Rodriguez, L.*, Pekkarinen, P. T.*, Lakshmikanth, T.*, Tan, Z.*, Consiglio, C. R.*, Pou, C., Chen, Y., Mugabo, C. H., Nguyen, N. A., Nowlan, K., Strandin, T., Levanov, L., Mikes, J., Wang, J., Kantele, A., Hepojoki, J., Vapalahti, O., Heinonen, S., KekŠlŠinen, E., Brodin, P. Cell Reports Medicine. 1, 100078, (2020). https://doi.org/10.1016/j.xcrm.2020.100078 V. Restrained memory CD8+ T cell responses favors viral persistence and elevated IgG responses in patients with severe Long COVID. Rodriguez, L.*, Tan, Z.*, Lakshmikanth, T., Wang, J., Barcenilla, H., Swank, Z., Zuo, F., Abolhassani, H., Pavlovitch-Bedzyk, A. J., Wang, C., Gonzalez, L., Mugabo, C. H., Johnsson, A., Chen, Y., James, A., Mikes, J., Kleberg, L., Sundling, C., Bjšrnson, M., Nygren Bonnier, M., StŚhlberg, M., Runold, M., Bjšrkander, S., MelŽn, E., Meyts, I., Van Weyenbergh, J., Hammarstršm, Q.-P., Davis, M. M., Walt, D. R., Landegren, N., COVID Human Genetic Effort, Aiuti, A., Casari, G., Casanova, J.-L., Jamoulle, M., Bruchfeld, J., Brodin, P. [Manuscript]</p
Heart failure with preserved and reduced ejection fraction : comorbidities, therapies and cause-specific outcomes
No full textBackground: Heart failure (HF) is associated with worse prognosis and poor quality of life, and its rising global prevalence puts a growing strain on healthcare systems. While most previous studies have focused on cardiovascular (CV) comorbidities and CV death, especially in HF with reduced ejection fraction (HFrEF), less is known about the prognostic role of CV vs. non-cardiovascular (non-CV) comorbidities in HF with preserved ejection fraction (HFpEF). Although effective therapies exist for patients with HFrEF to improve survival, they remain underutilized in real-world healthcare settings.Aims: The overall aim of this thesis was to evaluate the relative impacts of CV and non-CV comorbidities on specific causes of death and hospitalizations in HFpEF, and to investigate the adherence to guideline-recommended therapies in HFrEF considering the time of HFrEF diagnosis in a real-world setting. There were four specific aims: (1) Assess rates and predictors of CV and non-CV death and hospitalizations in a short-term follow-up study in patients with HFpEF (Study I). (2) Identify predictors for long-term all-cause death or HF hospitalization and all-cause death in patients with HFpEF (Study II). (3) Assess rates and predictors of CV and non-CV death in a long-term follow-up study in patients with HFpEF (Study III). (4) Describe the use of guideline-recommended therapies in relation to duration of HFrEF diagnosis in a large nationwide HF registry (Study IV).Methods and Results: Study I-III included the Karolinska Rennes (KaRen) HFpEF cohort. Study I consisted of 539 patients with acute HF with data on short-term follow-up. Study II-III, consisted of 397 patients with data on long-term followup. Study IV was based on data from the Swedish Heart Failure (SwedeHF) Registry of 55 581 patients with HFrEF. Study I. Rates and predictors of CV and non-CV death and hospitalizations at short-term follow-up in HFpEF Over a median follow-up time of 2.0 (interquartile range 1.4, 3.2) years, the rates of CV vs. non-CV death (5.1 vs. 5.8 deaths per 100 patient-years) and CV vs. non-CV hospitalizations (33 vs. 27 per 100 patient-years) were similar. CV deaths were predominantly due to HF, while non-CV deaths were primarily linked to cancer. CV-related hospitalizations were mostly driven by HF and non-CV hospitalizations by lung disease. The severity of HF was the most important predictor of CV death, whereas history of anemia and prior stroke were predictors of non-CV death. Higher serum sodium levels were inversely associated with both outcomes. A range of CV and non-CV comorbidities were associated with hospitalizations, but they were difficult to assess as predictors. Study II. Predictors of all-cause death or HF hospitalization and all-cause death at long-term follow-up in HFpEF In the long-term follow-up (median [interquartile range]) 5.4 [2.1, 7.9] years) study, the rate of the primary endpoint (all-cause death or first HF hospitalization) was 227 events per 1000 patient-years and secondary outcome (all-cause death) 130 events per 1000 patients-years. Females had higher event-free survival. Several characteristics were associated with these outcomes with the strongest ones being tricuspid regurgitation peak velocity, diabetes mellitus, cancer, anemia, hyponatremia and male sex. Study III. Predictors of CV and non-CV death at long-term follow-up in HFpEF Nearly two-thirds of the 397 patients included died, half from CV and the other half from non-CV causes (62 vs. 58 deaths per 1000 patient-years, respectively). Significant predictors of CV death included coronary artery disease and tricuspid regurgitation peak velocity. Significant predictors of non-CV death included a history of stroke and kidney disease. Anemia and higher age were associated with both outcomes. Higher sodium concentrations and body mass index were inversely associated with non-CV death. Study IV. Guideline-recommended therapies in HFrEF in relation to the duration of HFrEF diagnosis Within 3 months, 3 to 12 months from diagnosis of HFrEF, 93%, 92%, 90% and 89% were on treatment with renin-angiotensin system inhibitors (RASI) or angiotensin receptor neprilysin inhibitors (ARNI), 9.8%, 17%, 19% and 22% on ARNI, 35%, 43%, 44% and 46% on mineralocorticoid receptor antagonist (MRA), 92%, 92%, 92% and 91% on beta-blockers, and 26%, 30%, 19% and 28% on sodium–glucose cotransporter 2 inhibitors, respectively. Additionally, 18% received cardiac resynchronization therapy or implantable cardioverter-defibrillator >12 months after diagnosis.Conclusions: Patients with HFpEF have poor prognosis with similar rates of CV and non-CV death and hospitalizations. Several characteristics were associated with CV and non-CV outcomes at short- and long-term follow-up. In a comprehensive real-world registry of HFrEF patients, we found that the recent recommendation of immediate start of guideline-recommended HF therapies after a HFrEF diagnosis was adhered to regarding RASI and beta-blockers, but there was a substantial underuse of ARNI and MRA. These findings highlight the need to search for novel and tailored therapeutic approaches in HFpEF and close adherence to guideline-recommended therapies in HFrEF to improve outcomes.List of scientific papersI. Rates and predictors of cardiovascular and non-cardiovascular outcomes in heart failure with preserved ejection fraction. Angiza Shahim, Erwan Donal, Camilla Hage, Emmanuel Oger, Gianluigi Savarese, Hans Persson, Ida Haugen-Löfman, Pierre-Vladimir Ennezat, Catherine Sportouch-Dukhan, Elodie Drouet, Jean-Claude Daubert, Cecilia Linde, Lars H. Lund. [Submitted]II. Predictors of long-term outcome in heart failure with preserved ejection fraction: a follow-up from the KaRen study. Angiza Shahim, Marion Hourqueig, Erwan Donal, Emmanuel Oger, Ashwin Venkateshvaran, Jean-Claude Daubert, Gianluigi Savarese, Cecilia Linde, Lars H. Lund, Camilla Hage. ESC Heart Fail. 2021 Oct;8(5):4243-4254. https://doi.org/10.1002/ehf2.13533 III. Long-term outcomes in heart failure with preserved ejection fraction: Predictors of cardiac and non-cardiac mortality. Angiza Shahim, Marion Hourqueig, Lars H. Lund, Gianluigi Savarese, Emmanuel Oger, Ashwin Venkateshvaran, Lina Benson, Jean-Claude Daubert, Cecilia Linde, Erwan Donal, Camilla Hage. ESC Heart Fail. 2023 Jun;10(3):1835-1846. https://doi.org/10.1002/ehf2.14302 IV. Implementation of guideline-recommended therapies in heart failure with reduced ejection fraction according to heart failure duration: an analysis of 55,581 patients from the Swedish Heart Failure (SwedeHF) Registry. Angiza Shahim, Gianluigi Savarese, Ulf Dahlström, Cecilia Linde, Lars H. Lund, Camilla Hage. [Manuscript]</p
Sex differences in adipose insulin resistance are linked to obesity, lipolysis and insulin receptor substrate 1.
No full textNo description supplied</p
Long-term impact of digital media on brain development in children
No full textDigital media (DM) takes an increasingly large part of children's time, yet the long-term effect on brain development remains unclear. We investigated how individual effects of DM use (i.e., using social media, playing video games, or watching television/videos) on the development of the cortex (i.e., global cortical surface area), striatum, and cerebellum in children over 4 years, accounting for both socioeconomic status and genetic predisposition. We used a prospective, multicentre, longitudinal cohort of children from the Adolescent Brain and Cognitive Development Study, aged 9.9 years when entering the study, and who were followed for 4 years. Annually, children reported their DM usage through the Youth Screen Time Survey and underwent brain magnetic resonance imaging scans every 2 years. Quadratic-mixed effect modelling was used to investigate the relationship between individual DM usage and brain development. We found that individual DM usage did not alter the development of cortex or striatum volumes. However, high social media usage was associated with a statistically significant change in the developmental trajectory of cerebellum volumes, and the accumulated effect of high-vs-low social media users on cerebellum volumes over 4 years was only β = - 0.03, which was considered insignificant. Nevertheless, the developmental trend for heavy social media users was accelerated at later time points. This calls for further studies and longer follow-ups on the impact of social media on brain development.</p
Geometric deep learning for medical image processing problems
No full textMedical image processing provides an expanding set of methods and applications to improve clinical diagnosis, decision-making, and treatment planning through specific computational methods. Recent advances in deep learning (DL) have led to enhanced processing techniques that, in effect, increased the quality of medical image analysis. The success of DL models in medical imaging is often accompanied by the dependence on the quality and quantity of training data. However, available data is often sparse in medical imaging because of the cost of acquisition, the rarity of certain diseases, and the requirements for advanced imaging hardware. Furthermore, since medical images are derived from intricate anatomical structures and often depend on specific physical phenomena (e.g., water diffusion in magnetic resonance imaging), they reside in geometric domains or obey structural relationships that standard DL models do not necessarily respect. Geometric deep learning (GDL) is a family of DL methods designed to address both the data sparsity and the geometric complexity of medical images.This thesis consists of four studies, each utilising appropriate GDL methods to develop a problem-specific medical image processing pipeline. The first study focuses on predicting stiffness tensors from micro-CT (μCT) trabecular bone scans. Trabecular bone involves complex structures, and the task requires learning relationships between input bone volumes and output stiffness tensors while operating under limited data availability. We project and learn the data in the spherical domain, extending established stiffness tensor prediction models. The second study investigates the prediction of the lung cancer survival rate based on tumour shape. We propose training a spherical convolutional neural network (SphCNN) model to infer survival rates from segmented CT images of non-small cell lung cancer. Our method is benchmarked against existing models, including radiomics feature-based approaches for image-based survival rate prediction. The third and fourth studies explore the structural tractography of diffusion MRI, addressing different parts of the connectivity pipeline. The third study deals with the challenge of rotational equivariance in reinforcement learning-based tractography algorithms. We propose integrating an SE3-equivariant transformer model into the tractography framework to improve performance under rotational transformations. The fourth study is centred around structural connectivity, combined with subsequent classification, where we apply graph neural networks (GNNs) in addition to other brain network-specific analyses to identify group differences in brain connectivity related to Parkinson’s disease.Together, these four studies demonstrate how GDL methods can be adapted to different medical imaging problems, from biomechanics to oncology and neurology.List of scientific papersI. Fabian Sinzinger, Jelle van Kerkvoorde, Dieter H. Pahr, Rodrigo Moreno. Predicting the trabecular bone apparent stiffness tensor with spherical convolutional neural networks. Bone Reports. Volume 16, - 2022. https://doi.org/10.1016/j.bonr.2022.101179II. Fabian Sinzinger, Mehdi Astaraki, Örjan Smedby, Rodrigo Moreno. Spherical Convolutional Neural Networks for Survival Rate Prediction in Cancer Patients. Frontiers in Oncology. Volume 12, - 2022. https://doi.org/10.3389/fonc.2022.870457III. Fabian Sinzinger, Antoine Théberge, Rodrigo Moreno. Leveraging Rotational Equivariance for Reinforcement Learning in Tractography. [Manuscript]IV. Fabian Sinzinger, Marvin Köpff, Joana Pereira, Rodrigo Moreno. Impact of Tractogram Filtering and Graph Creation for Structural Connectomics in Subjects with Parkinson’s Disease. [Manuscript]</p
Congenital optic disc malformations : prevalence, clinical and oct findings, long-term follow-up and quality of life
No full textCongenital optic disc malformations are structural anomalies of the optic nerve that can cause different grades of visual impairment and even blindness. Correct diagnosis and early intervention are crucial to optimising visual function and providing the patient and their family with appropriate care, as these conditions can sometimes be associated with systemic diseases. This thesis is about the most common ones: optic nerve hypoplasia (ONH) and optic disc coloboma (ODC).In Study I, the prevalence of ODC was reported as 8.9/100,000 children, and the ocular, neurological, and behavioural problems of a population-based ODC cohort were described. Thirty-one (18 with unilateral) ODC patients, aged 2.4-18 years (median 10 years), with median best corrected visual acuity (BCVA) of 0.3 (range 0-1.3), were included. Nystagmus presented more often in patients with bilateral ODC (p=0.04). Median BCVA was better (0.82) in eyes with isolated ODC compared to eyes with concurrent macular involvement (0.15). Twenty-one patients underwent behavioural/psychological screening, and a deeper analysis revealed severe deficits in six of them. Intellectual disability was present in seven patients, while eight patients had neurological deficiencies. All these patients had already received a systemic disease diagnosis before the ODC diagnosis. This indicates that the child health care screening system in Sweden excels in identifying extraocular comorbidities.In Study II, we included 37 eyes with ONH from 20 patients (17 bilateral cases), with a median age of 10.5 years (range 2.8-18.9). We recruited a control group of 140 eyes from 70 healthy individuals. The OCT exam showed that the disc diameter as measured by the Bruch's membrane opening (BMO) was shorter (mean 1030um vs mean 1737um, pIn Study III, we used different methodology to examine 52 ONH eyes and 17 fellow eyes from 36 patients, aged median 15.0 years (range 5-24), with Spectral Domain OCT. The images were analysed semi-manually using a MATLAB program. ONH eyes had shorter disc diameter (1061+375um vs. 1751+221 um, pStudy IV was a long-term retrospective follow-up study of patients with ONH. Median age at the first and last visit was 7.8 (0.4 to 19.2) and 16.3 years (range 9.0 to 28.3) respectively. Median follow-up was 8.5 years (range 5.1-12.6). BCVA was unchanged but a myopic refractive shift was observed during follow-up. Quality of life scores were low compared to other chronic extraocular diseases and correlated strongly to BCVA.In conclusion, infants and toddlers with colobomas should be referred to paediatricians for a work-up to exclude syndromic ODC, while healthy teenagers do not need to be referred if they are otherwise healthy. Visual acuity in ODC eyes depends more on the involvement of the fovea. OCT can aid in the diagnosis of ONH, while pRNFL, GCC, and BMO can forecast visual acuity. GCC and pRNFL thinning can reveal the location and severity of visual field defects. Optic disc parameters such as the BMO and Zeki's ratio had a stronger correlation to visual acuity than macular parameters. We recommend using OCT in all patients with suspected ONH. However, in equivocal cases, confirming the diagnosis may require a thorough ophthalmological examination, which may involve multimodal imaging, electrophysiologic testing, an endocrinological and neurological evaluation, including neuroimaging, a genetic analysis in selected cases, and critical medical skepsis.Keywords: optic disc coloboma; optic nerve hypoplasia; behaviour; cognition; neurology; visual outcome; prevalence; optical coherence tomography; foveal hypoplasia; ganglion cell complex; retinal nerve fibre layer; long-term follow-up; quality of life.List of scientific papersThis thesis is based on the following papers which will be referred to by their Roman numerals:I. Optic Disc Coloboma in children - prevalence, clinical characteristics and associated morbidity. Skriapa-Manta, A., Olsson, M., Ek, U., Wickström, R. and Teär Fahnehjelm, K. (2019), Acta Ophthalmol, 97: 478-485. https://doi.org/10.1111/aos.13999II. Optical Coherence Tomography Can Predict Visual Acuity in Children with Optic Nerve Hypoplasia. Skriapa-Manta A, Nilsson M, Svoboda J, Olsson M, Nilsson M, Teär Fahnehjelm K. Clin Ophthalmol. 2022 Nov 17; 16:3785-3794. PMID: 36419566; PMCID: PMC9677923. https://doi.org/10.2147/OPTH.S387084III. Characteristic deviations of the optic disc and macula in optic nerve hypoplasia based on OCT. Skriapa-Manta, A., Venkataraman AP, Olsson M, Nilsson M, Teär Fahnehjelm K. Acta Ophthalmol. 2024 May 23. Epub ahead of print. PMID: 38782817. https://doi.org/10.1111/aos.16722IV. Quality of life and long-term follow-up of patients with optic nerve hypoplasia. Skriapa-Manta, A., Olsson M, Nilsson M, Britt-Marie Anderlid, TeärFahnehjelm K. [Manuscript]</p
The liver in pediatric obesity : risks and consequences of increased transaminases and steatotic liver disease
No full textMore than 175 million children are living with obesity today. The rise in childhood obesity leads to the increased prevalence of metabolic dysfunction associated steatotic liver disease (MASLD), whose previous term was non-alcoholic fatty liver disease. Yet, the evidence of the risk and long-term consequences of MASLD in pediatric obesity remains limited. This thesis sought to (1) investigate children with obesity at the greatest risk of MASLD, (2) assess the effect of MASLD in pediatric obesity on the development of type 2 diabetes and severe liver disease, and (3) determine the effect of obesity treatment response on the risk of MASLD and type 2 diabetes.This thesis consists of five studies. In all the studies, the main population was children and adolescents undergoing obesity treatment across Sweden enrolled in the Swedish Childhood Obesity Treatment Register (BORIS, https://www.e- boris.se/in-english/). BORIS was linked with several national registers containing medical data. Matched comparators for individuals in BORIS were obtained from the Total Population Register. In addition, Study II also included children with obesity in Germany, Austria, and Switzerland enrolled in the Adiposity Patients Registry (APV).In Study I - III, factors associated with pediatric MASLD were identified.Study I was a cross-sectional study of children with obesity who had alanine aminotransferase (ALT) data in BORIS. Of them, 38% had mildly increased ALT and additionally 11% had markedly increased ALT. Using ALT as a proxy for MASLD, a sex-age interaction in pediatric MASLD was observed; increasing age strengthened the odds of increased ALT among boys, whereas the odds tended to be static among girls. Moreover, increased ALT was more likely to be found in children with higher degree of obesity, dyslipidemia, and impaired fasting glycemia in a dose-response manner.Study II was a cohort study of children with overweight or obesity in BORIS and APV registers. Those children born small for gestational age had 20% higher odds for elevated ALT. In addition, they were more likely to have elevated glycated hemoglobin and elevated blood pressure than their peers born appropriate for gestational age.Study III was a nested case-control study on clinical determinants of MASLD diagnosis. We found that higher degree of obesity, impaired fasting glycemia, and hypertriglyceridemia were associated with a higher risk of MASLD. On the other hand, body mass index standard deviation score (BMI SDS) reduction of at least 0.25 units was associated with at least 44% relative risk reduction of MASLD.Study IV assessed the effect of MASLD in pediatric obesity on type 2 diabetes, whereas Study V assessed the effect of pediatric obesity on severe liver disease.Study IV was a cohort study, with the main exposure being ALT-based and diagnosis code-based MASLD, separately. MASLD in pediatric obesity was associated with at least doubled risk of developing young-onset type 2 diabetes. The risk was particularly prominent before age 20. Synergistic effect of MASLD and intermediate hyperglycemia on the risk of type 2 diabetes was observed (attributable proportion due to the synergistic effect: 67%). In addition, optimal response in obesity treatment was associated with 77% relative risk reduction of type 2 diabetes, irrespective of the MASLD status.Study V was a cohort study, with severe liver disease during adolescence and young adulthood as the main outcome. Pediatric obesity was associated with a two times higher risk for severe liver disease. Moreover, the risk seems to be even higher in individuals with obesity in childhood who develop alcohol use disorder during follow-up. Nevertheless, only a small proportion of children with obesity were affected by severe liver disease (1.1% of individuals in the obesity cohort had severe liver disease diagnosis by age 40).To conclude, factors associated with increased risk of MASLD in pediatric obesity include boys of older age, born small for gestational age, higher degree of obesity, impaired fasting glycemia, and hypertriglyceridemia. Further, MASLD increases the risk of young-onset type 2 diabetes. Moreover, pediatric obesity is also associated with increased risk of severe liver disease in adolescence and young adulthood. Obtaining optimal response in pediatric obesity treatment is important to prevent MASLD and reduce the risk of young-onset type 2 diabetes.List of scientific papersI. Putri, R. R., Casswall, T., & Hagman, E. (2021). Prevalence of increased transaminases and its association with sex, age, and metabolic parameters in children and adolescents with obesity - a nationwide cross-sectional cohort study. BMC pediatrics, 21(1), 271. https://doi.org/10.1186/s12887-021-02747-4II. Prinz, N .* , Putri, R. R .* , Reinehr, T., Danielsson, P., Weghuber, D., Norman, M., Rochow, N., Marcus, C., Holl, R. W., & Hagman, E. (2023). The association between perinatal factors and cardiometabolic risk factors in children and adolescents with overweight or obesity: A retrospective two-cohort study. PLoS medicine, 20(1), e1004165. https://doi.org/10.1371/journal.pmed.1004165 (*shared first authorship)III. Putri, R. R., Casswall, T., & Hagman, E. (2022). Risk and protective factors of non-alcoholic fatty liver disease in paediatric obesity: A nationwide nested case-control study. Clinical obesity, 12(2), e12502. https://doi.org/10.1111/cob.12502IV. Putri, R. R., Casswall, T., Danielsson, P., Marcus, C., & Hagman, E. (2024). Steatotic Liver Disease in Pediatric Obesity and Increased Risk for Youth-Onset Type 2 Diabetes. Diabetes care, dc241236. Advance online publication. https://doi.org/10.2337/dc24-1236V. Putri R. R., Caswall T., Danielsson P., Marcus C., Hagman E. Childhood obesity and increased risk for severe liver disease in adolescence and young adulthood. [Manuscript]</p