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Predictors and treatment of fatigue in multiple sclerosis
No full textFatigue is a self-reported symptom, often described as an extreme lack of energy, which is common across many medical conditions. In multiple sclerosis (MS), it is frequently reported as the most prevalent and debilitating symptom, with significant impact on quality of life and daily functioning. Underlying causes of fatigue in MS are still elusive, which impedes development of effective therapeutic strategies. The objectives of my thesis were to investigate associations between fatigue among people with MS and a range of demographic and disease-related measures, as well as to explore potential effects of symptomatic pharmaceutical and non-pharmaceutical interventions. To this end, we conducted three nationwide cohort studies using data from the Swedish MS Register and other national registers, as well as a smaller randomized controlled trial (RCT) evaluating the effect of resistance training.Study I was a register-based, cross-sectional study to assess the association between fatigue and a range of demographic and disease-related measures. We included 3,179 Fatigue Scale for Motor and Cognitive Functions (FSMC) scores obtained from 2,165 individuals with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) between 2012 and 2018, all of which were or had been undergoing disease-modifying therapy (DMT) for MS. Of these, 40.7% reported no or low fatigue, 12.7% mild, 14.0% moderate, and 32% severe fatigue. Expanded Disability Status Scale (EDSS) score and information processing speed, measured with Symbol Digit Modalities Test (SDMT), were the only objective MS- related measures displaying a clinically meaningful differences across fatigue severity levels; FSMC scores were 17.6 points higher with severe (EDSS ≥6) vs mild disability (EDSS 0-2.5; 95% CI: 13.1-22.2), and 10.7 points higher in the lowest vs highest SDMT quartiles (95% CI: 8.0-13.4), respectively. However, self- reported impact of MS and quality of life showed even greater differences across fatigue severity levels. Additionally, fatigue severity was associated with work loss, psychiatric comorbidities, and treatments for depression, anxiety, and fatigue-related symptoms.Study II was a register-based cohort study in which we identified and compared fatigue and disability trajectories, measured with FSMS and EDSS, respectively, in individuals with RRMS. Additionally, we investigated associations between potential predictors of fatigue and the identified fatigue trajectories. We included 1,587 individuals followed for a mean (SD) of 7.1 (2.2) years from initiation of a first DMT (first DMT cohort), and 1,818 people with MS followed for a mean (SD) of 7.3 (1.9) years from initiation of a second DMT (DMT switch cohort). Using group-based trajectory modeling, we identified five fatigue trajectories in the first DMT cohort, and six in the DMT switch cohort. All fatigue trajectories displayed stable trends over time, except for one trajectory (20.1% of participants, moderate fatigue at treatment initiation) of the first DMT cohort, who reported an 11.5-point increase in FSMC during follow-up. A strong association was observed between fatigue and disability trajectories in both cohorts. Apart from fatigue severity at DMT initiation, few other covariates independently predicted membership in the higher stable or increasing fatigue trajectories.Study III was a two-armed RCT exploring the effect of group-based high- intensity resistance training (HIRT) for 12 weeks, supervised by a physiotherapist, in people with MS reporting at least moderate fatigue. Seventy-one participants were randomized 1:1 to HIRT once or twice a week, with an additional 69 individuals with similar characteristics serving as an uncontrolled, non- intervention control group. Based on intention-to-treat, mean changes in FSMC scores were -9.8 (95% CI: - 13.2 to -6.3) and -10.9 (95% CI: - 14.8 to -6.9) in the once and twice weekly HIRT groups, respectively, indicating clinically relevant improvements, but with no significant difference between the two groups. Corresponding values for the combined HIRT group and the non-intervention control group were -10.3 (95% CI: - 12.9 to -7.7) and 1.5 (95% CI: - 0.6 to 3.6), respectively.Study IV was a register-based cohort study to explore the use of central stimulants and amantadine as symptomatic off-label treatments for fatigue in MS, and to evaluate their impact on work loss. We identified 29,257 people with MS through the Swedish MS and National Patient Registers. To assess annual prescription rates, we created yearly cohorts of individuals alive and residing in Sweden from January to December of each year between 2006 and 2023. For additional analyses, we included 2,162 new modafinil users, 462 new amantadine users, and 424 new users of attention deficit hyperactivity disorder (ADHD) drugs, who were followed for 12 months before and 24 months after their first filled prescription (index date). We also identified a cohort of 9,762 individuals with no prior fatigue treatment, using risk-set sampling, matched on first modafinil start. Modafinil was the most prescribed treatment, with an annual prevalence of 8.5% in 2006 and 7% in 2023. All cohorts showed increasing work loss in the year preceding the index date, followed by no change in work loss rates during the subsequent 24 months. Modafinil users demonstrated a significantly greater reduction in the trajectory of average monthly work loss compared to the untreated cohort (-0.17 days; 95% CI: - 0.22 to -0.12). No significant differences were observed between the modafinil group and the other treated cohorts.In conclusion, fatigue in MS is associated with greater disability and slower cognitive processing speed, while other MS-related characteristics show weak or no associations. Fatigue severity remains relatively stable in the years following both the first and second initiation of DMT, except for a clinically meaningful increase among a minority with moderate fatigue at first DMT start. Moreover, HIRT is associated with clinically meaningful reductions in fatigue among fatigued individuals with MS, although a definitive causal relationship could not be established due to the lack of a randomized non-intervention control group. Over the past two decades in Sweden, modafinil has been the most commonly prescribed off-label pharmacological treatment for fatigue in MS. Modafinil and other stimulants may help mitigate the progression of work loss in people with MS, although no single treatment appears to be superior in effectiveness.List of scientific papersI. Predictors of patient-reported fatigue symptom severity in a nationwide multiple sclerosis cohort. Simon Englund, Marie Kierkegaard, Joachim Burman, Katharina Fink, Anna Fogdell-Hahn, Martin Gunnarsson, Jan Hillert, Annette Langer- Gould, Jan Lycke, Petra Nilsson, Jonatan Salzer, Anders Svenningsson, Johan Mellergård, Tomas Olsson, Elisa Longinetti, Thomas Frisell, Fredrik Piehl. Mult Scler Relat Disord. 2023;70:104481. https://doi.org/10.1016/j.msard.2022.104481II. Trajectories of self-reported fatigue following initiation of multiple sclerosis disease-modifying therapy. Simon Englund, Thomas Frisell, Ying Qu, Kavita Gandhi, Annika Hultén, Marie Kierkegaard, Fredrik Piehl, Elisa Longinetti. J Neurol Neurosurg Psychiatry. 2024;95:1012-1020. https://doi.org/10.1136/jnnp-2024-333595III. High-intensity resistance training in people with multiple sclerosis experiencing fatigue: A randomised controlled trial. Simon Englund, Fredrik Piehl, Marie Kierkegaard. Mult Scler Relat Disord. 2022;68:104106. https://doi.org/10.1016/j.msard.2022.104106IV. Use of symptomatic drug treatment for fatigue in multiple sclerosis and its impact on work loss: a register-based Swedish cohort study. Simon Englund, Johan Reutfors, Thomas Frisell, Fredrik Piehl. [Manuscript]</p
Adherence to dietary recommendations and chronic kidney disease : insights into disease onset and progression
No full textBackground: CKD is becoming a major global health concern, marked by a gradual, permanent decline in kidney function, constrained treatment possibilities, and rising healthcare expenses. Dietary modifications play an important role in managing risk factors for CKD incidence and in slowing its progression, and these adjustments should be based on dietary guidelines. However, current guidelines predominantly rely on Western-based evidence, leaving critical gaps in protein types, dietary patterns, and cultural adaptability. Given the significant differences in food structure and dietary habits between China and many Western countries, it is essential to explore these aspects within the Chinese population.Aim: The thesis aims to evaluate diet quality and adherence to the Chinese 2017 Dietary Guide for Chronic Kidney Disease Patients (WS/T 557-2017) in Chinese patients and to provide evidence on how adherence to recommendations from dietary guidelines influences the onset and progression of CKD.Study I is a cross-sectional study to investigates the dietary quality and adherence to Chinese CKD-specific nutritional guidelines among 261 non- dialysis-dependent CKD (NDD-CKD) stages G3-G5 patients. Findings revealed that a significant number of patients exhibited poor adherence to dietary recommendations, particularly regarding protein, energy, fiber, and sodium intake. The overall dietary quality in these patients was moderate, though characterized by notably reduced consumption of whole grains, dairy products, and soybeans.Study II evaluates the association between plant protein ratio and CKD progression in 259 CKD G3-5 patients. After a median follow-up period of 2.3 years, our analysis identified a U-shaped relationship between plant protein ratio and CKD progression, with a turning point observed at 47%. Among patients with a plant protein ratio below 47%, each 5% increase in the ratio was associated with a 33% reduction in the risk of disease progression.Study III included 197 participants with CKD stages 3-4 to evaluate the association between adherence to three healthy dietary indices and CKD progression and kidney function decline. Our key findings demonstrate that higher adherence to the Chinese Healthy Eating Index (CHEI) was associated with reduced CKD progression. Greater adherence to the CHEI and the healthy Plant-based Dietary Index (hPDI) was linked to a slower annual decline in eGFR in a dose-response manner. The Diet Quality Index-International (DQI-I) was not significantly associated with CKD progression or decline in eGFR.Study IV was a systematic review and meta-analysis. Evidence from four cohorts comprising 219,132 participants was synthesized to examine the association between ultra-processed food (UPF) consumption and the risk of developing CKD. The results indicated that higher UPF intake was associated with an increased risk of incident CKD.Conclusion: Patients with CKD stages 3-5 in our clinic exhibit that some nutrients that deviates from national recommendations and moderate diet quality. A U-shape association between plant protein ratio and CKD progression was observed in patients with CKD stages 3-5, with an inflection point at 47%. Among patients with CKD stages 3-4, greater adherence to the Chinese Healthy Eating Index (CHEI) was associated with a lower risk of CKD progression and a slower decline in kidney function. In the general population, higher consumption of UPFs was linked to an increased risk of developing CKD.List of scientific papersI. Ouyang W, Xiao B, Chen H, Fu L, Tang F, Marrone G, Liu X, Wu Y and Carrero JJ. Dietary quality and adherence to dietary recommendations in Chinese patients with chronic kidney disease. Front Nutr. 2025;12:1547181. https://doi.org/10.3389/fnut.2025.1547181II. Ouyang W, Chen H, Fu L, Tang F, Carrero JJ, Marrone G, Stålsby Lundborg C, Eriksen J, Liu X and Wu Y. U-shape Association Between Dietary Plant Protein Ratio and Chronic Kidney Disease Progression. [Manuscript]III. Ouyang W, Fu L, Tang F, Marrone G, Chen H, Wen Z, Wu Y and Liu X. Adherence to Four Dietary Indices and Chronic Kidney Disease Progression and Kidney Function Decline: Findings from the SMP-CKD Study. [Manuscript]IV. Xiao B, Huang J, Chen L, Lin Y, Luo J, Chen H, FU L, Tang F, Ouyang W, Wu Y. Ultra-processed food consumption and the risk of incident chronic kidney disease: a systematic review and meta-analysis of cohort studies. Ren Fail. 2024;46(1):2306224. https://doi.org/10.1080/0886022X.2024.2306224</p
Oral microbial signatures : from severe infections to immune responses
No full textThis thesis investigates the diversity of oral microbial signatures, and the profound clinical and immunological significance they have in human pathologies, from localized infections to systemic immunological interactions.Study 1 was an 11-year epidemiological analysis of severe oral infections in Stockholm County. Characterization of 1,014 samples using MALDI-TOF mass spectrometry revealed highly dynamic microbial populations associated with different oral infections. Streptococcus spp., Prevotella spp., and Staphylococcus spp. predominated, while the evolving populations of Streptococcus anginosus and Actinomyces spp. had potential systemic implications.Study 2 was a 6-year retrospective analysis exploring the mycobiota profiles of head and neck cancer (HNC) patients with oral fungal infections (OFIs) and undergoing radiotherapy. Candida albicans was the most prevalent pathogen, co-occurring with emerging populations of non-albicans Candida (NAC) species and novel isolates, including Fusarium solani and Candida jadinii. Network analyses revealed significant multispecies co-occurrence, particularly during radiotherapy, underscoring the need for tailored antifungal strategies in this vulnerable population.Study 3 evaluated the oral microbiome's influence on coronavirus disease 2019 (COVID-19) vaccine immunogenicity in 115 participants, including healthy controls and people living with HIV (PLHIV). Comparative analyses revealed distinct microbial profiles in high- and low-responders. Gram-negative anaerobes, such as Campylobacter and Prevotella, predominated in low- responders, and Gram-positive saccharolytic species in high-responders, implicating the distribution of oral microbial populations in modulating mucosal immunity and possibly in long-term vaccine outcomes.Study 4 focused on MAIT cell responses to bacterial secretomes derived from blood, oral, and pancreatic tumor isolates. Activation patterns were strongly influenced by bacterial origin, irrespective of species, with tumor-derived strains inducing unique polyfunctional cytokine profiles. This highlights the pivotal role of microbial metabolites in shaping immune responses, offering novel insights into host-microbe interactions in oral infections and cancer.Collectively, this work advances our understanding of oral microbial signatures in health and disease, revealing their critical role in shaping systemic immunity and providing a foundation for microbiome-targeted therapeutic interventions.List of scientific papersI. Al-Manei K, Ghorbani M, Naud S, Al-Manei KK, Sobkowiak MJ, Lund B, Hazirolan G, Sällberg Chen M,, Özenci V. Clinical microbial identification of severe oral infections by MALDI-TOF mass spectrometry in Stockholm County: an 11-Year (2010 to 2020) epidemiological investigation. Microbiology Spectrum. 2022 Dec 21;10(6):e02487-22.https://doi.org/10.1128/spectrum.02487-22II. Al-Manei K, Sobkowiak MJ, Nagadia RH, Heymann R, Sällberg Chen M, Özenci V. Mycobiota profile of oral fungal infections in head and neck cancer patients receiving radiotherapy: A 6- year retrospective MALDI-TOF mass spectrometry study. Oral Oncology. 2023 Nov 1;146:106556.https://doi.org/10.1016/j.oraloncology.2023.106556III. Ghorbani M*, Al-Manei K*, Naud S, Healy K, Gabarrini G, Sobkowiak MJ, Chen P, Ray S, Akber M, Muschiol S, Bogdanovic G, Bergman P, Ljungman P, Buggert M, Ljunggren HG, Pin E, Nowak P, Aleman S, Sällberg Chen M. Persistence of salivary antibody responses after COVID-19 vaccination is associated with oral microbiome variation in both healthy and people living with HIV. Frontiers in Immunology. 2023 Jan 10;13:1079995.https://doi.org/10.3389/fimmu.2022.1079995IV. Al-Manei K, Unalan-Altintop T, Johnsson A, Santini R, Khan ZA, Halimi A, Özenci V, Sällberg Chen M, Sobkowiak MJ. MAIT cell polyfunctional response to bacterial secretome is dependent on site of microbial origin. 2025. [Manuscript]*Contributed equally</p
Lung cancer metabolism : from molecular mechanisms to translational studies
No full textCancer cells rewire their metabolism to sustain rapid proliferation, enhance survival, and evade therapeutic intervention. Deubiquitinating enzymes (DUBs) play a crucial role in regulating growth-related pathways by modulating protein stability and activity, yet their specific contributions to non-small cell lung cancer (NSCLC) remain largely unexplored. This thesis identified USP9x and USP39 as novel metabolic regulators in NSCLC. USP9x was found to deubiquitinate PYCR3, linking it to the proline cycle, while USP39 regulates mitochondrial metabolism by controlling PDHA, a component of the pyruvate dehydrogenase (PDH) complex. These findings expand our understanding of DUB-mediated metabolic control and suggest new potential therapeutic targets. In parallel, this thesis explored novel biomarker candidates for lung adenocarcinoma (LUAD) diagnosis through transcriptomics and metabolomics. Using machine learning, a 30-gene signature was identified that differentiates LUAD from a non-LUAD control group, including other lung cancers, benign and metastatic lesions, with high diagnostic performance. Additionally, metabolic profiling of tissue and plasma samples revealed pyrraline and phenol sulfate as potential biomarkers, raising the possibility of a minimally invasive diagnostic approach. While these findings provide exciting insights into lung cancer metabolism and diagnosis, limitations such as small sample size necessitate further validation in larger, independent cohorts. Future research should focus on confirming the clinical utility of these biomarkers and exploring the therapeutic relevance of DUB inhibition in lung cancer. By integrating functional studies and multi-omics approaches, this thesis contributes to deeper understanding of LUAD pathogenesis and paves the way for improved diagnostic and therapeutic approaches.List of scientific papersI. Becirovic T, Zhang B, Lindskog C, Norberg E, Vakifahmetoglu-Norberg H, Kaminskyy VO, and Kochetkova E. Deubiquitinase USP9x regulates the proline biosynthesis pathway in non-small cell lung cancer. Cell Death Discov. 2024;10(1):342.https://doi.org/10.1038/s41420-024-02111-2II. Becirovic T, Zhang B, Vakifahmetoglu-Norberg H, Kaminskyy VO, Kochetkova E, and Norberg E. USP39 regulates pyruvate handling in non-small cell lung cancer. Cell Death Discov. 2024;10(1):502.https://doi.org/10.1038/s41420-024-02264-0III. Becirovic T, Zhang B, Kochetkova E, Kas Elyas K, Talanti A, Grozman V, Nyrén S, Kamali C, Kaminskyy VO, Vakifahmetoglu-Norberg H, Hydbring P, Ekman S, and Norberg E. Integrative Transcriptomics and Meta- bolomics Analysis of Tumors and Plasma Identifies a Unique Gene Signature and Metabolites for the diagnosis of Lung Adenocarcinoma. [Submitted]</p
Development of iPSC-derived models and cell-penetrating peptides towards therapeutic targeting of vascular anomalies
No full textThe cardiovascular system maintains our body homeostasis and keeps body systems in balance to function correctly. This is achieved by the heart pumping blood with oxygen and nutrients through vessels which transport blood to all tissues and removes waste products from tissues. Vascular anomalies (VAs) are malformations of either blood, or lymphatic vessels. VAs usually arise during embryonic development, as a consequence of inherited or somatic mutations, and often manifest in early childhood. Hereditary Hemorrhagic Telangiectasia (HHT) is a VA characterized by arteriovenous malformations (AVMs) and dilated capillaries that are visible as red markings on the skin (telangiectasia). Patients suffer from recurrent bleeding (Hemorrhages) with increased incidence of anemia, heart failure and stroke. 80-90% of HHT cases are caused by loss-of-function (LOF) mutations in ACVRL1 (ALK1) or ENG (endoglin). Also, gain-of-function (GOF) mutations are known to cause VAs, like in the case of TIE21914F causing venous malformations (VMs). In spite of many known causative mutations, our understanding of disease mechanisms is incomplete, and therapies are limited. Therapeutic modalities, such as cell-penetrating and tissue-homing peptides, specific towards the cardiovascular system are highly promising as they open the potential to targeted therapies.In this thesis we generated induced pluripotent stem cell (iPSC)-derived endothelial cell (EC) models for HHT1 (causative gene ENG), HHT2 (causative gene ALK1) and VMs by knocking out ENG or ALK1 or creating a point mutation in TIE2, respectively. In paper I, HHT models were utilized for drug screening to find further medicines which can be repurposed for HHT therapies. Unlike previous cell models where the Tie2-mutant protein was overexpressed, in paper II we applied a mutation knock in strategy that generated endogenous expression levels, thereby resembling the patient situation and examined TIE2 pathway signaling in this model.In paper III, we identified cell-penetrating peptides (CPPs) in in vivo phage display and explored their targeted delivery capabilities. Using the CPPs we could demonstrate uptake of small interfering RNA (siRNA)-CPP-conjugates specifically into ECs.In paper IV, we utilized the phage display platform and identified heart-targeting peptides in a myocardial ischemia reperfusion injury (IRI) mouse model that specifically bind cardiomyocytes in the myocardial infarction region. We demonstrated binding of peptides to healthy cardiomyocytes, and furthermore two peptides binding to hypoxic and ischemic cardiomyocytes.List of scientific papersI. Kohl F, Roscales M, Keith B, Krimpenfort LT, Firth M, Hong X, Elgendy R, Lazovic B, Queiro Palou A, Hicks R, Jakobsson L, Wiseman J. iPSC- derived ENG and ALK1 KO endothelial cells facilitate modeling of Hereditary Hemorrhagic Telangiectasia and build up a platform for drug screening. [Manuscript]II. Lazovic B, Nguyen H-T, Ansarizadeh M, Wigge L, Kohl E, Li S, Carracedo M, Kettunen J, Krimpenfort LT, Elgendy R, Richter K,-De Silva L, Bilican B, Singh P, Saxena P, Jakobsson L, Hong X, Eklund L, Hicks R. Human iPSC and CRISPR targeted gene knock-in strategy for studying the somatic TIE2L914F mutation in endothelial cells. Angiogenesis. 2024, 27, 523-542. https://doi.org/10.1007/s10456-024-09925-9III. Kohl F, Laufkötter O, Firth M, Krimpenfort LT, Mangla P, Ansarizadeh M, Geylan G, Eklund L, De Maria L, Jakobsson L, Wiseman J. Identification of cell type-specific cell-penetrating peptides through in vivo phage display leveraged by next generation sequencing. Biomed. Pharmacother. 2025, 182, 117740. https://doi.org/10.1016/j.biopha.2024.117740IV. Ivanova A, Kohl F, González-King Garibotti H, Chalupska R, Cvjetkovic A, Firth M, Jennbacken K, Martinsson S, Silva AM, Viken I, Wang Q-D, Wiseman J, Dekker N. In vivo phage display identifies novel peptides for cardiac targeting. Sci. Rep. 2024, 14, 12177. https://doi.org/10.1038/s41598-024-62953-9</p
Spinal cord injury : diagnostics, treatment, complications and outcome
No full textThe global prevalence of spinal cord injury (SCI) is approximately 230-1300 cases per million populations per year and the estimated rate worldwide is 250,000 - 500,000 individuals per year. Preventable causes (traffic accidents and falls) are reported as the major cause of SCI. Fall is the most common cause of SCI in the elderly and compared to previous studies the mean age of individuals with SCI is now higher. No definite curative treatment is at the time available and depending on the extend and the level of the injury in the spinal cord the long-term neurological outcomes may differ considerably. Spinal cord infarction is an uncommon condition, with no available established diagnostic criteria at the time, no clearly clarified aetiology and despite the similarities to cerebral stroke, the implication of vascular risk factors in the pathophysiology of the condition is still not yet entirely understood. In traumatic SCI, the identification of predictors of long-term neurological outcome is crucial in the context of enabling the physician in decision-making regarding treatment strategies and rehabilitation approaches. Factors affecting quality of life in the aftermath of SCI are poorly understood. This thesis aims to study population-based cohorts with traumatic and nontraumatic SCI and to shine a new perspective by offering a fresh viewpoint to some of these questions.Study I analyzed the baseline findings and evaluated the long-term outcome for individuals with spinal cord infarction (SCInf), both spontaneous and periprocedural. T2-weighted and diffusion-weighted (DWI) MRI were instrumental imaging techniques for the definite setting of diagnosis. The retrospective application of the recently presented diagnostic algorithm favors the general adoption of the proposed diagnostic criteria. The overrepresentation of vascular risk factors compared with the general population, points out their role in the pathophysiology of the condition. In cases of spontaneous SCInf, a more favorable outcome was observed compared to the periprocedural cases which furthermore were more extensive compared to the spontaneous cases that in turn, to a great degree, affected a single segment of the spinal cord. The neurological improvement shown at long-term follow-up draws special attention to the meaningfulness of active rehabilitation.Study II, a systematic analytic review of the current literature on spontaneous SCInf, revealed that in 72% of the cases, although the exact pathophysiology is yet to be understood, at least one vascular risk factor was documented, thus underlying the importance of proper prophylactic management of factors such as hypertension, diabetes, hyperlipidemia and smoking in the context of stroke prevention. Potential to functional recovery was good and ability to walk with or without aids was reported in 71% of the cases, at approximately three years after spontaneous SCInf. Additionally, the introduction of DWI in the diagnostic work-up of SCInf is a valuable tool assisting in the definite diagnosis-setting.Study III evaluated the impact of SCI on health-related quality of life (HRQoL) in patients that underwent surgery for traumatic subaxial spine injury. The patient- reported outcome measures (PROMs), specifically EQ-5D-3L and Neck Disability Index (NDI), were studied for the period 2006-2016. Source of data was the Swedish Spine Registry (Swespine). Analysis of PROMs at long-term follow-up times at 1-, 2- and 5-years post-surgery, revealed that the presence and the extend of SCI had negative impact on both outcome measures and that the Frankel grade scale (a classification of the extent of the neurological - functional impairment) was a significant predictor of PROMs. Additionally, analysis of PROMs results at follow-ups beyond 1-year post-surgery showed altogether no significant changes, regardless the extend of the SCI.Study IV evaluated long-term follow-up for patients treated surgically for posttraumatic tethered cord syndrome and demonstrated that in the largest part of the patients, the surgical treatment either resulted in improvement of the neurological function or discontinued the neurological decline.Study V evaluated retrospectively the long-term outcome and the predictors for neurological recovery in patients with cervical spinal cord injury by analyzing a decade's volume of data from a single, specialized care unit in Stockholm, Sweden. The extend of the initial SCI was a significant predictor for neurologic recovery and regaining of ambulation ability. The median age of the cohort was 64 years, displaying a shift toward an aging population being affected by cervical SCI. Old age was a negative prognostic factor associated with decreased recovery potential. The observed neurological improvement at follow-up underlined the potential for favorable outcome and illustrated the key role of tailored rehabilitative interventions in boosting patient outcomes. In that context, specialized rehabilitation strategies for the more vulnerable and frail older individuals, often presenting with pre-existing comorbidities, might prove to be beneficial and lead to improved functional outcome.Study VI, a qualitative study based on semi-structured interviews, evaluated the subjective factors that have impact on quality of life (QoL) in individuals with SCI. Important parameters with impact on well-being were the management of SCI- related physical problems, desire to live an independent life and, the significance of community and a sense of belonging. Contrarily, long-term complications after SCI, especially pain, have a negative impact on QoL and underline the need for further research to enhance treatment options.In conclusion, the findings of this thesis, draw attention to the role of MRI imaging techniques for the setting of the diagnosis of SCInf and turn the spotlight on the role of vascular risk factures in the pathophysiology of the condition. The periprocedural cases of SCInf were more extensive and were associated with less favorable outcome compared to the spontaneous cases. In subaxial traumatic cervical injuries, the presence of associated SCI and its severity had a negative impact on the HRQoL based on patient-reported outcomes measures. The potential for neurological improvement in the aftermath of traumatic cervical spinal injury, emphasized the key role of tailored rehabilitative interventions, especially for the more vulnerable older individuals. Components such as autonomy, management of long-term complications and the sense of belonging in the community, carry instrumental positive weight on QoL of individuals with SCI.List of scientific papersI. Long-term outcomes after periprocedural and spontaneous spinal cord Infarctions: a population-based cohort study. Stenimahitis V, Fletcher-Sandersjöö A, El-Haj VG, Hultling C, Andersson M, Sveinsson O, Elmi-Terander A, Edström E. Neurology. 2023 Jul 11;101(2):e114-e124. https://doi.org/10.1212/wnl.0000000000207377II. Spontaneous spinal cord infarction: a systematic review. Gharios M, Stenimahitis V, El-Hajj VG, Mahdi OA, Fletcher-Sandersjöö A, Jabbour P, Andersson M, Hultling C, Elmi-Terander A, Edström E. BMJ Neurol Open. 2024 May 28;6(1):e000754. https://doi.org/10.1136/bmjno-2024-000754III. The effect of concomitant spinal cord injury on postoperative health-related quality of life after traumatic subaxial cervical spine injuries: a nationwide registry study. El-Haj VG, Stenimahitis V, Singh A, Blixt S, Edström E, Elmi-Terander A, Gerdhem P. Arch Phys Med Rehabil. 2024 Jun;105(6):1069-1075. https://doi.org/10.1016/j.apmr.2024.01.021IV. Long-term outcome following surgical treatment of posttraumatic tethered cord syndrome: a retrospective population-based cohort study. Stenimahitis V, Fletcher-Sandersjöö A, Tatter C, Elmi-Terander A, Edström E. Spinal Cord. 2022 Jun;60(6):516-521. https://doi.org/10.1038/s41393-022-00752-7V. Long-term outcome and predictors of neurological recovery in cervical spinal cord injury: a population-based cohort study. Stenimahitis V, Gharios M, Fletcher-Sandersjöö A, El-Hajj VG, Singh A, Buwaider A, Andersson M, Gerdhem P, Hultling C, Elmi-Terander A, Edström E. Sci Rep. 2024 Sep 9;14(1):20945. https://doi.org/10.1038/s41598-024-71983-2VI. Quality of life after spinal cord injury: a qualitative interview-based study. Stenimahitis V, Guenna Holmgren A, El-Hajj VG, Hultling C, Elmi-Terander A, Edström E. [Manuscript]</p
Compound heterozygosity for two variants in BMP5 in human skeletal dysostosis with atrioventricular septal defect.
No full textThe growth and development of the skeleton is regulated by bone morphogenetic proteins of which several are linked to genetic skeletal disorders. So far, no human skeletal malformations have been associated with variants in BMP5. Here, we report a patient with biallelic loss of function variants in BMP5 and a syndromic phenotype including skeletal dysostosis, dysmorphic features, hypermobility, laryngo-tracheo-bronchomalacia and atrioventricular septal defect. We discuss the phenotype in relation to the known tissue-specific expression of Bmp5 and similar morphological abnormalities previously reported in experimental animal models. Our findings suggest a new association between BMP5 variants and a range of developmental anomalies, involving ears, heart and skeleton, thereby increasing understanding of BMP5's role in human development.</p
Precision medicine and patient perspectives in systemic lupus erythematosus
No full textSystemic lupus erythematosus (SLE) is an autoimmune disease (AID) with diverse clinical presentations and complex immunopathogenesis. Its chronic and variable course necessitates regular monitoring, yet optimal biomarkers for assessing disease activity are lacking. Neuropsychiatric SLE (NPSLE) is generally considered a severe manifestation but remains less well understood. Patients often experience fatigue, pain, and reduced health-related quality of life (HRQoL), which are not well captured by current clinical instruments. Since the early 21st century, most clinical trials in SLE have failed, leaving the treatment landscape behind other rheumatic diseases.The overall aim of this thesis is to contribute to optimised surveillance and treatment evaluation, and to identify drug targets in patients with SLE, with a particular focus on NPSLE.Paper I investigated psychometric properties of patient-reported experience of full health state (FHS) using the EQ-5D health questionnaire in two successful phase III randomised clinical trials (RCTs) of belimumab in SLE, i.e., BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384). FHS distinguished belimumab from placebo and responders from non-responders in this large SLE population (N=1665) from week 36 through week 52.Paper II further explored whether EQ-5D FHS after trial intervention was associated with prevention of subsequent organ damage progression during nearly eight years of open-label extension follow-up (NCT00724867; NCT00712933) in a subset of the same patients as in Paper I (N=973). FHS heralded a reduced hazard of accruing organ damage after adjustments (HR: 0.60; 95% CI: 0.38-0.96), suggesting its potential as a useful PROM in SLE studies. This also supports optimising its HRQoL dimensions as a relevant treatment target in patients with SLE, alongside clinical and laboratory parameters.Paper III investigated the transcriptome, expression quantitative trait loci (eQTLs), and levels of cytokines and autoantibodies in peripheral blood of 350 SLE patients from the European cross-sectional PRECISESADS cohort (NTC02890121). We replicated 18 gene modules of apparent relevance in the SLE patients by splitting the cohort into a discovery (60%) and a replication (40%) set, and we further validated 11 of those in 1760 SLE patients from two RCTs of tabalumab, ILLUMINATE-1 (NCT01196091) and ILLUMINATE-2 (NCT01205438). We assessed their dysregulation in comparison to 497 healthy controls (HC), corroborating the roles of interferon (IFN) and lymphocyte signalling, plasma cells, and inflammation in SLE. eQTL analysis revealed an association between rs7918733 T > C and reduced expression of CTSL, leading us to speculate that carriers of this polymorphism might exhibit a less favourable response to the proteasome inhibitor bortezomib, known for modulating CTSL expression.Paper IV explored potential serum biomarkers for diagnosis and disease activity in 422 patients with SLE compared with 546 HC or 1223 patients with AIDs from the PRECISESADS project. CCL8 and CXCL13 levels were elevated in patients with active SLE, but not in those with inactive SLE, compared to HC. These levels were also higher in SLE patients compared to those with AIDs. The chemokine levels correlated, albeit weakly, with SLE Disease Activity Index 2000 (SLEDAI-2K) scores, suggesting their potential as biomarkers in SLE upon further validation.Paper V examined the whole-blood transcriptome of 26 patients with active central nervous system (CNS) lupus, comparing them to 38 patients with active non-neuropsychiatric SLE and 497 HC from the PRECISESADS project. We identified gene dysregulation patterns related to innate and adaptive lymphoid immunity in active CNS lupus, stratifying the patients into two subgroups. One subgroup showed prominent upregulation of the IFN gene module and a greater anticipated response to type I IFN inhibition with anifrolumab (73% versus 20% of patients) based on in silico druggability analysis, advancing precision medicine in NPSLE.Paper VI explored novel autoantibodies in relation to global and organ-specific disease activity in SLE. Plasma samples from a discovery cohort of 196 SLE patients (NTC02890121) and an independent validation cohort of 30 SLE patients (NCT02890134) as well as 110 HC and 84 HC, respectively, matched for age and sex, all from the European PRECISESADS project, were screened for IgG and IgA seroreactivity against 1609 human proteins using the i-Ome Discovery protein microarray. We validated 89 IgG and 66 IgA differentially abundant autoantibodies. Of these, IgG anti-LIN28A and IgG anti-IRF5, as well as IgA anti- IRF5, were positively associated with high disease activity (SLEDAI-2K ≥10) and negatively associated with Lupus Low Disease Activity State (LLDAS). These autoantibodies were highly prevalent across patient subgroups with activity in various organ systems, including the nervous system. The multiple identified IgA autoantibodies highlight a potential role of mucosal immunity in SLE pathogenesis.List of scientific papersI. Julius Lindblom, Alvaro Gomez, Alexander Borg, Sharzad Emamikia, Dimitris Ladakis, Joaquin Matilla, Martin Pehr, Flordelyn Cobar, Yvonne Enman, Emelie Heintz, Malin Regardt, Ioannis Parodis. EQ-5D-3L full health state discriminates between drug and placebo in clinical trials of systemic lupus erythematosus. Rheumatology (Oxford). 2021 Oct 2;60(10):4703-4716. https://doi.org/10.1093/rheumatology/keab080II. Julius Lindblom, Sture Zetterberg, Sharzad Emamikia, Alexander Borg, Gunilla von Perner, Yvonne Enman, Emelie Heintz, Malin Regardt, David Grannas, Alvaro Gomez, Ioannis Parodis. EQ-5D full health state after therapy heralds reduced hazard to accrue subsequent organ damage in systemic lupus erythematosus. Front Med (Lausanne). 2022 Dec 20;9:1092325. https://doi.org/10.3389/fmed.2022.1092325III. Julius Lindblom, Daniel Toro-Domínguez, Elena Carnero-Montoro, Lorenzo Beretta, Maria Orietta Borghi, Jessica Castillo, Yvonne Enman, PRECISESADS Clinical Consortium, Chandra Mohan, Marta E Alarcón- Riquelme, Guillermo Barturen, Ioannis Parodis. Distinct gene dysregulation patterns herald precision medicine potentiality in systemic lupus erythematosus. J Autoimmun. 2023 Apr;136:103025. https://doi.org/10.1016/j.jaut.2023.103025IV. Julius Lindblom, Lorenzo Beretta, Maria Orietta Borghi, PRECISESADS Clinical Consortium, Marta E Alarcón-Riquelme, Ioannis Parodis. Serum profiling identifies CCL8, CXCL13, and IL-1RA as markers of active disease in patients with systemic lupus erythematosus. Front Immunol. 2023 Nov 30;14:1257085. https://doi.org/10.3389/fimmu.2023.1257085V. Julius Lindblom, Guillermo Barturen, Lorenzo Beretta, Daniel Toro- Domínguez, Elena Carnero-Montoro, Maria Orietta Borghi, Jessica Castillo, Ellen Iacobaeus, Yvonne Enman, PRECISESADS Clinical Consortium, Chandra Mohan, Marta E. Alarcón-Riquelme, Dionysis Nikolopoulos, Ioannis Parodis. Innate and adaptive lymphoid immunity dysregulation may guide symptom attribution and predict responses to targeted therapies in neuropsychiatric systemic lupus erythematosus. [Manuscript]VI. Julius Lindblom, Dionysis Nikolopoulos, Denis Lagutkin, Helena Idborg, Lorenzo Beretta, Maria Orietta Borghi, PRECISESADS Clinical Consortium, Janique M. Peyper, Guillermo Barturen, Per-Johan Jakobsson, Marta E. Alarcón-Riquelme, Natalia Sherina, Ioannis Parodis IgG and IgA seroreactivity to protein antigens associates with disease activity and determines organ manifestations in systemic lupus erythematosus: implications for autoantibodies targeting LIN28A, HMGN5, IRF5, and TGIF1 in two independent cohorts. [Manuscript]</p
Subclonality and genetically defined transcriptional constraints across solid tumors and leukemias
No full textCancer is a highly heterogeneous disease, both at the genomic and phenotypic level. Single-cell methods have allowed exploration of phenotypic cell states and genomic evolution, but the association between genotype and phenotype remains largely elusive. Activating or deleterious single nucleotide variants (SNVs) can have very clear effects on a phenotype, but copy number variations (CNVs), which are ubiquitous in cancers, are not well understood functionally. Recent advances within ultra-low coverage, single-cell whole genome sequencing (WGS) have enabled high throughput analysis of CNV. However, downstream analysis is still largely dependent on tools developed for high coverage bulk data.In paper I we developed a computational method, ASCENT, which enables accurate breakpoint detection, absolute copy number calling, and haplotyping of clonal segments. We showed that by using ASCENT we could find minor subclones not detected in bulk WGS data, and produce accurate high-resolution copy number profiles from ultra-low coverage single-cell WGS.By running ASCENT on joint mRNA/WGS data from 57 patients representing six cancer types, we were able to make generalizable inferences about how subclonal genetics affect cell phenotypes (paper III). We found that highly amplified CNVs constrain the phenotype to a much greater degree than lowly amplified whole chromosome aneuploidies. We found that gene dosage is largely tissue-dependent and that oncogenes, such as MYC, are often not sensitive to dosage. We identified a previously underappreciated group of tumors that lack a clear clonal structure, where each cell division leads to two distinct genotypes.In paper IV we analyzed the relationship between genotype and phenotype during induction treatment in pediatric acute lymphoblastic leukemia (ALL). We found that while some genotypes have specific phenotypes, during induction treatment cell states shifted toward a more mature B-cell-like state, independent of genomic background. We contrast this to the mechanism which leads to relapse, which always includes additional genomic aberrations, selection on the genetic level, and inter-patient heterogeneity in cell states.Single-cell sequencing methods are often used to determine which cell states are responsible for phenotypes found in bulk sequencing. In paper II we investigated the complicated relationship between shear stress and vascular disease in the aorta. We used single-cell sequencing to deconvolve which cell type caused an immune-pro phenotype in AmotL2-depleted mice and found a subset of endothelial cells to be responsible.In conclusion, we have charted the transcriptional effect of different genetic aberrations across human cancer. We conclude that specific genomic aberrations can affect the functional phenotype of a cell. We found that dosage effects are largely tissue-dependent and that the amplification of oncogenes is often compensated for on the mRNA-level. We additionally found that induction treatment confers a common cell state in ALL, while relapsed samples had evolved divergent phenotypes during low intensity treatment.List of scientific papersI. Solrun Kolbeinsdottir*, Vasilios Zachariadis*, Christian Sommerauer, Olli Lohi, Merja Heinäniemi, Martin Enge. Absolute copy number aware CNV calling of sub megabase segments in ultra-low coverage single-cell DNA sequencing data. Nucleic Acids Research, Volume 53, Issue 17, 23 September 2025. https://doi.org/10.1093/nar/gkaf919II. Yuanyuan Zhang, Yumeng Zhang, Evelyn Hutterer, Sara Hultin, Otto Bergman, Solrun Kolbeinsdottir, Hong Jin, Maria J Forteza, Daniel F J Ketelhuth, Joy Roy, Ulf Hedin, Martin Enge, Ljubica Matic, Per Eriksson, Lars Holmgren. The VE-cadherin/AmotL2 mechanosensory pathway suppresses aortic inflammation and the formation of abdominal aortic aneurysms. Nature Cardiovascular Research, 2023, 7, 629-644. https://doi.org/10.1038/s44161-023-00298-8III. Solrun Kolbeinsdottir, Vasilios Zachariadis, Muyi Yang, Luuk Broeils, Christian Sommerauer, Huaitao Cheng, Xinsong Chen, Yingbo Lin, Sampsa Hautaniemi, Johanna Hynninen, Suzanne Egyhazi Brage, Dhifaf Sarhan, Anna Vähärautio, Nikolas Herold, Johan Hartman, Hildur Helgadóttir, Felix Haglund de Flon, Martin Enge. Subclonal copy number alterations and their transcriptional impacts across human cancers using joint single-cell genome and transcriptome sequencing. [Manuscript]IV. Vasilios Zachariadis, Solrun Kolbeinsdottir, Jessica Hacheney, Huaitao Cheng, Laura Oksa, Aonghus Naughton, Arghavan Alizadeh, Sanni Moisio, Olli Lohi, Merja Heinäniemi, Martin Enge. Persister states and relapse in childhood leukemia. [Manuscript]*These authors contributed equally</p
Vascular trauma and haemorrhage after firearm injuries
No full textFirearm injuries are an increasing global health problem resulting in deaths and disabilities among its victims as well as an immense burden both for the society as well as the health care system. Vascular injuries and haemorrhage are particularly lethal after gun violence. The aim of this thesis was to investigate management strategies and patient outcomes of vascular injuries and haemorrhage after firearm injuries.Paper I was a systematic review characterising injuries and mortality after CPMSs focusing on in-hospital management of haemorrhage and vascular injuries. The paper showed an overall high mortality after CPMSs with injuries mainly located to the extremities (35%), abdomen (20%) and thorax (19%) with approximately one quarter of deaths being related to haemorrhage involving central large vessel injuries. 47% (97/206) of all hospitalised patients required a surgical procedure.Paper II was a retrospective nationwide epidemiological study including all patients with firearm injuries between 2011 and 2019 (n=1010). The most common injury location was lower extremity (30%) followed by upper extremity (14%), abdomen (14%), and thorax (13%). The head was the most severely injured body region. It showed an annual increase of firearm-related injuries and fatalities (P Paper III was also a retrospective nationwide epidemiological study from 2011 and 2019 (n=162), showing that firearm-related vascular injuries increased annually (PPaper IV was a retrospective nationwide observational study investigating pre-hospital and hospital mortality after firearm injuries between 2012 and 2023 (n=519). There was an annual increase in deaths (PIn conclusion, this thesis showed that firearm injuries increased in Sweden and that firearm-related vascular injuries and haemorrhage caused significant morbidity and mortality. It underscores the need for early haemorrhage control strategies and better preparedness in the health care system to improve outcomes following future incidents of gun violence.List of scientific papersThis thesis is based on the following papers, which are referred to in the text by their Roman numerals.I. Nyberger K, Strömmer L, Wahlgren CM. A systematic review of haemorrhage and vascular injuries in civilian public mass shootings. Scand J Trauma Resusc Emerg Med. 2023 Jun 19;31(1):30. https://doi.org/10.1186/s13049-023-01093-xII. Nyberger K, Caragounis EC, Djerf P, Wahlgren CM. Epidemiology of firearm injuries in Sweden. Eur J Trauma Emerg Surg. 2022 Jun;48(3):2349-2357. https://doi.org/10.1007/s00068-021-01735-8III. Nyberger K, Caragounis EC, Djerf P, Wahlgren CM. Management and outcomes of firearm-related vascular injuries. Scand J Trauma Resusc Emerg Med. 2023 Jul 7;31(1):35. https://doi.org/10.1186/s13049-023-01098-6IV. Nyberger K, Kahn L, Rezaie A, Strömmer L, Wahlgren CM. Injury patterns in fatal gun violence - time to death and cause of death. [Submitted]All previously published papers were reproduced under the terms of the Creative Commons CC BY license.</p