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Adult-onset type 1 diabetes: predictors of major cardiovascular events and mortality
No full textAbstract
Background and Aims
The prognosis of adult-onset type 1 diabetes (T1D) and prognostic factors are sparsely investigated. This study assessed mortality, major adverse cardiovascular events (MACE), and prognostic factors in adult-onset T1D, particularly focusing on those diagnosed at age ≥40.
Methods
Participants were people diagnosed with adult-onset T1D (n = 10 184) or type 2 diabetes (T2D, n = 375 523) in 2001–20 from the Swedish National Diabetes Register and 509 172 population controls from the Total Population Register, followed until 2022. Hazard ratios (HR) and population attributable risk fraction (PAR%) were estimated.
Results
People with T1D had higher incidence of MACE (HR 1.30 [95% confidence interval 1.17, 1.45]), all-cause mortality (1.71 [1.60, 1.84]), and mortality from cardiovascular or non-cardiovascular diseases, cancer, or infection than population controls. They had lower MACE incidence (0.67 [0.60, 0.75]) and higher mortality from diabetic coma or ketoacidosis (7.04 [4.54, 10.9]) than people with T2D. Smoking (PAR% 10.7%) and glycated haemoglobin (HbA1c) ≥ 53 mmol/mol (10.4%) accounted for most deaths while overweight/obesity (19.8%), smoking (8.4%), and high HbA1c (8.8%) accounted for most MACE events in T1D. Results were similar for T1D diagnosed at age ≥40, although they had lower insulin pump use and higher HbA1c than people diagnosed earlier.
Conclusions
Adult-onset T1D carries excess risk of death and MACE compared with population controls but less MACE risk than T2D. Individuals diagnosed after age 40 had similar excess risk and poorer glycaemic control than those diagnosed earlier, underscoring the need for improved management. Key prognostic factors were smoking, poor glycaemic control, and overweight/obesity.</p
Establishing thermal proteomics to study cellular dynamics in alphavirus infection
No full textViral pathogens, such as alphaviruses, are obligatory intracellular parasites that reprogram the host cell machinery for their replication. Alphaviruses, including the human pathogen chikungunya virus (CHIKV), can take over the host cell within a few hours. This thesis aims to establish the thermal proteomics technique, Mass- Spectrometry Coupled Cellular Thermal Shift Assay (MS-CETSA), to further investigate the cellular dynamics and identify and characterize viral host factors during the early infection. MS-CETSA enables the quantification of the thermal stability (TS) of the cellular proteome by extracting and measuring the soluble proteome after heat treatment, which leads to protein precipitation, followed by detergent-free lysis. Additionally, whole-cell protein abundance (WCA) after urea lysis and soluble abundance (SA) with detergent-free lysis are quantified and characterized.In the key project (Project 2), this setup allowed us to detect protein-level differences upon Semliki Forest virus (SFV) infection in two different cell lines and datasets. This led to novel insights into the mechanism of transcriptional arrest through modulation of the RNA polymerase II complex and the interaction of SFV nsP3 with host factors such as G3BP. We discovered that in the very early stage of infection, already at 2 hours post-infection, POLR2A (Rpb1) and the nsP3- interactor BIN1 were the only strongly destabilized proteins observed, validating the sensitivity and specificity of our approach. At a later infection stage, the infection significantly modulated the thermal stability or abundance of proteins involved in nonsense-mediated decay (NMD), glucose and nucleotide metabolism, and autophagosomes.In preparation for this project, we optimized our MS-CETSA approach to remove any experimental design bias that had previously affected our data. As described in Project 1, a Mock infection control experiment of this original experimental design was reanalyzed to evaluate the impact of confounding factors on the thermal proteome. This led to the identification of a list of volatile proteins and the development of an updated experimental design applied in Projects 2 and 3. In the final Project 3, an MS-CETSA experiment was conducted in a BSL3 environment, comparing chikungunya virus (CHIKV) with the live-attenuated vaccine CHIKV-Δ5nsp3 (VLA1553) to potentially identify host factors involved in the virus's pathogenicity. Data analysis for this project is still pending at the time of writing.</p
Translational studies on biological signatures, risk profiles, and prevention of dementia
No full textNeurodegenerative disorders that cause dementia, including Alzheimer's disease (AD), are multifaceted in their risk factor profiles and pathological changes. Today, we can use both fluid and imaging biomarkers to identify individuals with certain pathological changes, such as amyloid-beta (AB) aggregation, tau phosphorylation, and neurodegeneration, which can guide targeted interventions. However, these biomarkers account for a very limited biological signature. The mixed pathologies and risk factor profiles complicate the development of treatments and diagnostic tools for neurodegenerative disorders. There is an urgent need to expand on the biological signatures in neurodegenerative disorders and their relation to risk profiles to advance the understanding of both similarities and differences between patients, beyond and among different diagnostic and biomarker- classified groups. Knowledge about risk profiles and associated biological signatures could provide valuable information for targeted treatment and intervention options.A great proportion of dementia cases are attributed to modifiable risk factors, providing a window of opportunity for lifestyle-related interventions to prevent dementia. A way to circumvent the need to identify what lifestyle factor(s) to change in which individual to gain optimal cognitive benefits is to apply a multimodal lifestyle intervention simultaneously targeting several risk factors. Optimally, a holistic lifestyle intervention could elicit synergistic effects between the lifestyle domains, further enhancing the effect of a multimodal lifestyle change compared to only single-domain interventions. While a multimodal lifestyle intervention is likely beneficial for many, irrespective of the risk profile, there is currently limited knowledge about risk profile-stratified effects. Furthermore, although multimodal lifestyle interventions have demonstrated clinical efficacy, it is currently not known which mechanistic changes such interventions evoke and whether the brain changes are dependent on risk and pathological profile. This doctoral thesis aims to unravel biological signatures, risk profiles, and prevention of dementia.The first three constituent papers, Papers I, II, and III, investigate biological signatures and dementia-associated risk profiles. In Paper I, we measured 49 cerebrospinal fluid (CSF) proteins from a diverse memory clinic population, consisting of the full dementia continuum and different AD biomarker profiles, to assess biological variation within the population by applying principal component analysis. To our surprise, we found that most of the biological variance (up to 52%) between patients in our cohort was not attributed to pathology, but rather to physiological differences between patients. Nevertheless, we found a biological signature (accounting for 5% of biological variance), driven by gliosis and synaptic proteins, that was strongly associated with AD pathology, neurodegeneration, and cognitive impairment.Paper II studied memory clinic patients as well, comprising patients at different stages in the dementia continuum without the common comorbidities of hypertension, hypercholesterolemia, and diabetes. We measured 11 CSF markers relevant to vascular function, cholesterol dysmetabolism, inflammation, oxidative stress, and glucose homeostasis. Despite not having diagnoses of comorbidities, we identified a cluster of patients with higher CSF levels of markers indicating higher oxidative stress and cholesterol dysmetabolism. The two identified patient clusters were independent of clinical diagnoses and detectable brain AD pathology.Paper III studied a population of cognitively unimpaired older adults who had been dichotomized into those at greater and those at lower risk of developing AD, based on CSF measures of Aß42. We analyzed 67 CSF proteins to assess the biological signature related to the amyloid-associated dementia risk profile. We identified several proteins to be associated with a greater risk of developing AD, but these proteins did not predict cognitive decline during 3.5 years in the studied cohort.In the last paper, Paper IV, we applied a multimodal lifestyle intervention to three different mouse models: healthy (WT), cholesterol dysmetabolism (CYP27Tg), and brain amyloidosis (AppNL-G-F). The lifestyle intervention elicited cognitive gains in WT and AppNL- G-F mice, but not in the CYP27Tg mice. WT mice who underwent the lifestyle intervention had enhanced synaptic functioning and plasticity in the hippocampus, as determined by proteomics analysis, while in AppNL-G-F mice we did not detect differences in the hippocampal proteome. In CYP27Tg mice, despite non-detectable cognitive improvement, the lifestyle intervention revived homeostasis in the hippocampus. The lifestyle intervention ameliorated model-specific pathology in both CYP27Tg and AppNL- G-F mice.Collectively, the results from the constituent papers indicate that among patients in the dementia continuum, there are biological signatures that extend beyond the clinical diagnosis and AD-related biological stratification, and signatures that are associated with dementia-related risk profiles. We further established in animal models that the effects of lifestyle interventions, even if beneficial, are not universal but depend on dementia risk profiles. These findings endorse future efforts to deepen the knowledge regarding biological signatures for different dementia risk profiles. This information could be used to recognize how different people would benefit from lifestyle interventions.List of scientific papersI. Vilma Alanko, Sára Mravinacová, Anette Hall, Göran Hagman, Rosaleena Mohanty, Eric Westman, Peter Nilsson, Miia Kivipelto, Anna Månberg, Anna Matton. Biological signatures in the Alzheimer's continuum discriminate between diagnosis-related and -unrelated associations to ATN categories. Brain Communications. 2025 Feb 21;7(2):fcaf078. https://doi.org/10.1093/braincomms/fcaf078II. Makrina Daniilidou, Francesca Eroli, Vilma Alanko, Julen Goikolea, Maria Latorre-Leal, Patricia Rodriguez-Rodriguez, William J Griffiths, Yuqin Wang, Manuela Pacciarini, Ann Brinkmalm, Henrik Zetterberg, Kaj Blennow, Anna Rosenberg, Nenad Bogdanovic, Bengt Winblad, Miia Kivipelto, Delphine Ibghi, Angel Cedazo-Minguez, Silvia Maioli, Anna Matton. Alzheimer's disease biomarker profiling in a memory clinic cohort without common comorbidities. Brain Communications. 2023 Aug 25;5(5):fcad228. https://doi.org/10.1093/braincomms/fcad228III. Vilma Alanko, Oliver Robinson, Chinedu Udeh-Momoh, Sára Mravinacová, Jennie Olofsson, Janice Wong, Peter Nilsson, Anna Månberg, Miia Kivipelto, Lefkos Middleton, Anna Matton. Discrepancy between CSF protein profiles associated with amyloid positivity versus cognition in cognitively unimpaired older adults - Findings from the CHARIOT:PRO CSF substudy. [Manuscript]IV. Vilma Alanko, Francesca Eroli, Ákos Végvári, Alina Solomon, Tobias Hartmann, Per Nilsson, Miia Kivipelto, Silvia Maioli, Anna Matton. Mouse PAW: Reverse-Translation of the FINGER Multimodal Lifestyle Trial Improves Memory and Dementia-Related Mechanisms in Female Mice. [Manuscript]</p
Aspects of treatment of acute uncomplicated appendicitis in children and adults
No full textAcute appendicitis is a clinical term for inflammation of the vermiform appendix with a sudden onset. Symptoms depend both on the age of a patient and on the position of appendix intraabdominally. The aetiology remains unknown, although, there are multiple theories. The lifetime risk of acute appendicitis in Western countries has been established as 7-8%, with 8.6% for males and 6.7% for females. The standard treatment has been surgery for many decades, but non-operative treatment, in the form of antibiotics, has more recently come to light as a feasible alternative to appendectomies.Aims: The aim of this thesis was to assess intermediate and long-term outcomes of non- operative treatment in both children and adults. This included assessing safety and feasibility of non-operative treatment and its complications. An additional aim was to ascertain the failure rate of non-operative treatment and recurrence of acute uncomplicated appendicitis in children and try to establish the reasons for the treatment failure.Methods: Study I was a 5-year follow-up of all participants who underwent surgery or non- operative treatment with antibiotics in a previous randomised controlled pilot trial. Data was extracted from the hospital notes and telephone interviews.Study II was a long-term follow-up of adults with acute appendicitis who were involved in two randomised controlled trials, which compared non-operative treatment with appendectomy. The first trial consisted of 40 patients (13 female) and second trial was a multicentre study with 252 male patients. National registers were used to retrieve data at follow up, including the Swedish National Patient Register, the Cancer Register, the Cause of Death Register and Statistics Sweden.Study III was a systematic review that was registered in PROSPERO (CRD42024592607) and done according to PRISMA statement. We searched three databases (PubMed, Medline, Web of Science). Eligible studies were randomised controlled trials or prospective cohort studies with children aged Results: In Study I, we followed up all 50 children (26 children in the appendectomy group, 24 children in the nonoperative group) for at least 5 years. The surgical group was without failures and in the nonoperative group there were 11 failures and recurrences. In the first year there were nine failures, two of them had an appendicitis on the histopathology. Another two recurrences, that were histopathologically confirmed appendicitis occurred one to five years after the initial trial. At the 5-year follow-up, 54% of children had been successfully treated nonoperatively with antibiotics alone.In Study II, in total, we were able to trace down 259 patients in the Patient Register, 137 patients in the non-operative group and 122 in the surgical group. At the end of follow-up, 82 (60%) patients had had successful non-operative treatment without an appendectomy. In the non-operative group there were 21 (15%) failures during the first admission. Thirty-four recurrences happened after discharge, all with a diagnostic code of acute appendicitis. After successful initial treatment, 82/116 (71%) remained without appendectomy.In Study III, through a systematic search we were able to identify 2343 abstracts. Thirty studies were eligible, 8 randomised controlled trials and 22 prospective cohort studies reporting 27 different patient cohorts. An early failure rate occurred in 10% (95% CI 7-14%) and the recurrence rate was 29% (95% CI 24-34%) at the end of follow-up. When analysing studies with faecalith, a failure rate was higher (17% versus 6.4%) with P-value Conclusions: Studies I and II demonstrated intermediate- and long-term safety of non- operative treatment alone in children and adults. This treatment does not increase the risk of malignancy and other complications and patients avoid surgery. Study III demonstrated a low initial failure rate and the recurrence rate was 29%. Non-operative treatment was less successful in children with a faecalith, particularly during first admission. These results can be used for discussion about treatment options of uncomplicated appendicitis with child patients and their caregivers.List of scientific papersI. Patkova B, Svenningsson A, Almström M, Eaton S, Wester T, Svensson JF. Nonoperative Treatment Versus Appendectomy for Acute Nonperforated Appendicitis in Children: Five-year Follow Up of a Randomized Controlled Pilot Trial. Ann Surg. 2020 Jun;271(6):1030-1035. https://doi.org/10.1097/SLA.0000000000003646II. Pátková B, Svenningsson A, Almström M, Svensson JF, Eriksson S, Wester T, Eaton S. Long-Term Outcome of Nonoperative Treatment of Appendicitis. JAMA Surg. 2023 Oct 1;158(10):1105-1106. https://doi.org/10.1001/jamasurg.2023.2756III. Patková B, Svenningsson A, Jumah S, Wester T, Eaton S. Failure and recurrence of non-operative treatment of uncomplicated appendicitis in children; a systematic review and meta-analysis. [Manuscript]</p
Harnessing proteomics for precision medicine in lung cancer
No full textLung cancer continues to impose a substantial burden on society. While progress has been made through prevention, new treatments, and, in some countries, screening, its impact remains profound. The emergence of targeted therapies for oncogene-mutated tumors and immune checkpoint inhibitors have contributed to significant improvements in patient survival in late-stage cases. However, not all patients have a suitable targetable mutation, not all respond to the prescribed treatment, and among those that do, many relapse. As a result, less than one-third of lung cancer patients in Sweden survive longer than 5 years after the diagnosis. There is a pressing need for continued development of precision medicine strategies to deliver the right treatment to the right patient.Genomics has been a driving force in cancer research and has become one of the key diagnostic tools in oncology, alongside immunohistochemistry. However, it has become evident that evaluation of individual marker expression and genome- level analyses may be insufficient to fully decipher cancer complexity and make lung cancer, if not curable, at least a manageable chronic disease. Proteomics has more recently emerged as a valuable tool for characterizing the phenotype and providing insights into cancer mechanisms and vulnerabilities. Thus, this thesis aimed to elucidate lung cancer biology at the proteome level and to demonstrate the clinical utility of proteomics methods.In Study I, we analyzed the proteomic landscape of non-small-cell lung cancer (NSCLC) using in-depth mass spectrometry (MS)-based proteomics on 141 resected tumors. We complemented the analysis with genomic, transcriptomic, epigenomic, and clinical data and described six proteomic subtypes of NSCLC. The subtypes reflected the expected histological groupings but exhibited distinct immune infiltration patterns and oncogene-driver mechanisms. We proposed mechanistic insights and therapeutic vulnerabilities underlying the observed phenotypes and developed classification methods to enable the study of new samples and cohorts in the context of these findings.In Study II, we investigated the post-translational modification farnesylation using lung cancer cell line models. Farnesylation and its inhibition using farnesyltransferase inhibitors (FTIs) play a role in cancer by determining the subcellular localization and activity of several cancer-related proteins. We used MS-based proteomics to identify farnesylated proteins, conduct a proteome- wide assessment of protein localization and relocalization in response to FTI treatment, and analyze global FTI effects on protein abundance. Our study revealed clinically relevant targets beyond Ras family proteins for which FTIs were initially developed and provided a comprehensive data resource for further exploration by the research community.In Study III, we demonstrated the performance of MS-based proteomics applied to the most common type of preserved tissue in the clinic - formalin-fixed, paraffin-embedded (FFPE). We analyzed 15 lung adenocarcinoma samples using label-free proteomics on three different modern MS instruments. We achieved deep proteome coverage, quantifying over 7,000 proteins in less than 45 min of analysis time on the two newest instruments. We also demonstrated the potential clinical utility of the generated data by exploring the identification and quantification of drug targets and potentially predictive biomarkers.In Study IV, we designed a protein-based predictive biomarker panel for immune checkpoint inhibitor (ICI) treatment selection in NSCLC and developed a complementary MS-based targeted proteomics assay. The panel covered tumor microenvironment features related to immune cell infiltration, interferon gamma signaling, antigen presentation, proteasome composition, and other immune- related processes and sample composition properties. We demonstrated the clinical relevance of the panel using a publicly available transcriptomics dataset from an ICI clinical trial. Our findings included distinct survival trends in the biomarker-stratified groups and complementarity to the PD-L1 expression status that is commonly used as a biomarker for ICI treatment selection. We then validated the targeted proteomics assay's analytical performance on an independent cohort of biopsy samples.Together, these studies have contributed to a deeper understanding of lung cancer biology at the proteome level and support ongoing efforts to integrate proteomics into clinical practice. By generating clinically relevant data and demonstrating the feasibility of proteomics in various settings, this work offers a foundation for future precision medicine applications.List of scientific papersI. Janne Lehtio, Taner Arslan, loannis Siavelis, Yanbo Pan, Fabio Socciarelli, Olena Berkovska, Husen M. Umer, Georgios Mermelekas, Mohammad Pirmoradian, Mats Jönsson, Hans Brunnström, Odd Terje Brustugun, Krishna Pinganksha Purohit, Richard Cunningham, Hassan Foroughi Asl, Sofi Isaksson, Elsa Arbajian, Mattias Aine, Anna Karlsson, Marija Kotevska, Carsten Gram Hansen, Vilde Drageset Haakensen, Åslaug Helland, David Tamborero, Henrik J. Johansson, Rui M. Branca, Maria Planck, Johan Staaf, and Lukas M. Orre. Proteogenomics of non-small cell lung cancer reveals molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms. Nature Cancer 2, 1224-1242 (2021). https://doi.org/10.1038/s43018-021-00259-9II. Yanbo Pan*, Olena Berkovska*, Soumitra Marathe, Georgios Mermelekas, Greta Gudoityte, Amare D. Wolide, Taner Arslan, Brinton Seashore-Ludlow, Janne Lehtio, and Lukas M. Orre. Functional-proteomics-based investigation of the cellular response to farnesyltransferase inhibition in lung cancer. iScience 28, 111864 (2025). https://doi.org/10.1016/j.isci.2025.111864III. Olena Berkovska*, Igor Schliemann*, Mahnaz Nikpour, Georgios Mermelekas, Janne Lehtio, and Lukas M. Orre. Label-free mass spectrometry-based proteomics delivers rapid, in-depth proteome-wide profiling of FFPE tissue. [Manuscript]IV. Olena Berkovska*, Georgios Mermelekas*, Soumitra Marathe, Marija Karadzovska-Kotevska, Mats Jönsson, Maria Planck, Janne Lehtiö, and Lukas M. Orre. Development of a targeted proteomics assay for immunotherapy response prediction in lung cancer. [Manuscript]*These authors contributed equally</p
Physical activity and fitness measures in healthy older adults and hip osteoarthritis patients
No full textBackgroundPhysical inactivity and functional decline represent significant challenges for aging populations, warranting effective intervention strategies and reliable assessment methodologies. This thesis investigated test-retest reliability of physical activity and fitness measurements in older adults, examined effects of structured exercise, and assessed longitudinal recovery trajectories in hip osteoarthritis patients following total hip arthroplasty (THA).MethodsFour studies were conducted. Study I (n=78, age 70.9+4.7 years) evaluated accelerometer measurement reliability and monitored physical activity changes following an 8-week exercise intervention (twice-weekly, 60-minute combined training). Study II (n=1,407, age 65-84 years) assessed test-retest reliability of a comprehensive field-based fitness test battery and post an 8-week exercise period across multiple age groups. Study III (n=265, age 71.4+4.7 years) examined sustained and cumulative effects of identical 8-week exercise programs performed in consecutive years. Study IV (n=78, age 74.0+4.5 years) investigated physical fitness and activity patterns in hip osteoarthritis patients undergoing THA, with two assessments pre-operative, 4 months, and 1-year post-surgery.ResultsPhysical activity parameters demonstrated good to excellent test-retest reliability. Similarly, field-based fitness tests generally showed good reliability across age and sex strata. The 8-week exercise intervention produced significant improvements in physical activity pattens and multiple physical fitness tests. Most fitness test parameters remained stable during the 9-month inter-intervention period, with declines observed in trunk strength endurance. Hip osteoarthritis patients exhibited pre-operative deficits compared to healthy controls in several fitness tests and in moderate- to vigorous physical activity, whereas post-operative improvements at 1-year follow-up were observed for a multitude of physical fitness parameters and exceeding the recommended physical activity levels.ConclusionsThis thesis established good test-retest reliability of accelerometer-measured physical activity and most included fitness assessments for monitoring older adults. Structured exercise generated physical activity and fitness benefits in healthy older adults. Moreover, substantial functional and activity improvements were seen following total hip arthroplasty without structured post-operative intervention. These findings underscore the importance of exercise engagement and appropriate surgical intervention to improve both functional capacity and physical activity in older adult populations.List of scientific papersThis thesis includes four papers, these will be referenced using their Roman numerals listed below:I. Manne Godhe, Marjan Pontén, Johnny Nilsson, Lena Kallings & Eva Andersson. Reliability of the accelerometer to control the effects of physical activity in older adults. Plos One, 17(9), e0274442. (2022). https://doi.org/10.1371/journal.pone.0274442II. Manne Godhe, Gustaf Rönquist, Johnny Nilsson, Örjan Ekblom, Lillemor Nyberg, Gustav Edman, & Eva Andersson Reliability in Novel Field-Based Fitness Measurements and Postexercise Scores from a Physical Fitness Test Battery in Older Adults. Gerontology, 70(6), 639-660. (2024). https://doi.org/10.1159/000538446https://doi.org/10.1159/000538446III. Manne Godhe, Johnny Nilsson, & Eva Andersson. Short-and Long-Term Effects on Physical Fitness in Older Adults: Results from an 8-Week Exercise Program Repeated in Two Consecutive Years. Geriatrics, 10(1), 15. (2025). https://doi.org/10.3390/geriatrics10010015https://doi.org/10.3390/geriatrics10010015IV. Manne Godhe, Anders Stålman, Johnny Nilsson & Eva Andersson. Physical fitness Improvements and Achievement of Recommended Physical Activity Levels One Year After Total Hip Arthroplasty: A Longitudinal Study of Physical Function and Activity Patterns [Manuscript]Papers I & III were published under Creative Commons CC BY license. Paper II is reproduced in this thesis with permission from Karger Publishers. Paper IV is in manuscript form.</p
Capnodynamic assessment of mixed venous oxygen saturation
No full textBackgroundMixed venous oxygen saturation (SvO2) is considered an important parameter for assessing the balance between oxygen supply and demand. Currently, obtaining SvO2 requires catheterization of the pulmonary artery which carries risks of adverse events and is technically demanding. For some patients, e.g. children, this approach may not be feasible or justified, necessitating less invasive monitoring alternatives. Capnodynamic monitoring has been proposed as a non-invasive alternative, but its accuracy and clinical applicability require further investigation. Furthermore, hemodynamic assessment in anesthetized and critically ill children remains challenging and, in this context, Capnodynamic cardiac output monitoring (COEPBF) and SvO2 (Capno-SvO2) could provide additional insight. The overall aim of this thesis was to investigate the accuracy and trending ability of Capno-SvO2 compared to pulmonary artery blood samples, in both experimental and clinical settings. In addition, COEPBF was compared to Esophageal Doppler in anesthetized children.MethodsIn study I, including anesthetized children, cardiac output measured by an Esophageal Doppler was compared to capnodynamic COEPBF during moderate hemodynamic interventions. Study II investigated the performance of Capno-SvO2 in comparison to blood gas CO-oximetry (Coox-SvO2) in anesthetized pigs undergoing major changes in oxygen delivery. Study III addressed the accuracy of Capno-SvO2 in a clinical context. Children undergoing anesthesia for cardiac catheterizations were included and Capno-SvO2 was compared to Coox-SvO2 during baseline conditions and moderate changes in oxygen delivery. Study IV, using a similar setup to study II, employed an experimental endotoxemia model to evaluate the performance of Capno-SvO2 under sepsis-like conditions. Across all studies, Bland-Altman analysis was used to determine the bias and agreement of absolute values between the modalities, while concordance analysis and four-quadrant plots were used to assess the ability of Capno-SvO2 to track physiological change.ResultsIn study I, the main finding was that the moderate reduction in cardiac output induced by increasing the positive end expiratory pressure (PEEP) was not detected by the esophageal doppler and did not noticeably alter the blood pressure. In contrast, the capnodynamic method recorded a 15 % reduction in cardiac output, consistent with previous, experimental findings. Study II-IV revealed an average bias of +1% to +3% between Capno-SvO2 and the reference method. In study II and III, limits of agreement were within the predefined acceptable range, while the spread of data points was slightly wider in study IV. The capnodynamic method demonstrated a high ability to track changes in SvO2, across all three studies.ConclusionsCapnodynamic assessment of SvO2 produced average values close to the reference method with limits of agreement within the predefined range of acceptance, even though the accuracy was negatively affected in the presence of sepsis. Capno-SvO2 reliably tracks changes in in both clinical and experimental settings. Furthermore, COEPBF tracked the moderate reduction in cardiac output caused by PEEP elevation in study I, not detectable by the established Esophageal Doppler. Capnodynamic monitoring of cardiac output and mixed venous oxygen saturation could offer valuable additional hemodynamic data in populations where pul- monary artery catheters are unavailable or not warranted. Being non-invasive, available also for small children, and easy to set up makes it particularly appealing for pediatric anesthesia practice, though certain limitations need to be considered. Further clinical trials are mandated to determine the role of capnodynamic monitoring in the intensive care setting.List of scientific papersI. Cardiac Output Assessments in Anesthetized Children: Dynamic Capnography Versus Esophageal Doppler. Jacob Karlsson, Anders Svedmyr, Marion Wiegele, Per-Arne Lönnqvist, Mats Wallin, Magnus Hallbäck Anesth Analg. 2022 Mar 1;134(3):644-652. https://doi.org/10.1213/ane.0000000000005679II. Non-invasive capnodynamic mixed venous oxygen saturation during major changes in oxygen delivery. Anders Svedmyr, Mark Konrad, Mats Wallin, Magnus Hallbäck, Per-Arne Lönnqvist, Jacob Karlsson. J Clin Monit Comput. 2022 Oct;36(5):1315-1324. https://doi.org/10.1007/s10877-021-00762-5III. Validation of a Novel Method for Noninvasive Mixed Venous Oxygen Saturation Monitoring in Anesthetized Children. Anders Svedmyr, Kristoffer Steiner, Andreas Andersson, Gunnar Sjöberg, Magnus Hallbäck, Mats Wallin, Per-Arne Lönnqvist, Jacob Karlsson. Anesth Analg. 2024 Oct 1;139(4):781-788. https://doi.org/10.1213/ane.0000000000007083IV. Capnodynamic assessment of mixed venous oxygen saturation in a porcine experimental endotoxemic model. Anders Svedmyr, Joakim Hedov, Miklos Lipcsey, Mats Wallin, Magnus Hallbäck, Per-Arne Lönnqvist, Jacob Karlsson. Scientific Reports. 2024 Nov 5;14(1):26807. https://doi.org/10.1038/s41598-024-77483-7</p
Comorbidities, quality of life and cause-specific outcomes in heart failure across the ejection fraction spectrum
No full textBackgroundHeart failure (HF) is frequently accompanied by multiple comorbidities that correlate with poor outcomes and reduced health-related quality of life (HRQoL). However, the burden and influence of comorbidities may vary in HF with preserved (HFpEF), mildly reduced (HFmrEF), and reduced (HFrEF) ejection fraction (EF). Increased knowledge about the links between specific comorbidities and the different HF phenotypes and outcomes, along with a better understanding of the causes of death in HF patients, may contribute to improved phenotyping, prognostication, clinical management, and improved design of clinical trials in HF. Furthermore, there is a need for a better understanding of the characteristics associated with HRQoL and its prognostic implications in HF, especially across the EF categories.Aims1) To perform a comprehensive comparison of concomitant Type 2 diabetes mellitus (T2DM), atrial fibrillation (AF), and/or chronic kidney disease (CKD) in HFrEF, HFmrEF, and HFpEF regarding prevalence, clinical correlates, predictors and prognosis.2) To assess the proportions and incidence rates (IRs) of cause-specific death within cardiovascular (CV) and non-CV death in HF in the three different EF categories.3) To examine patients' characteristics and outcomes associated with HRQOL measured by EuroQoL 5-Dimensional Visual Analogue Scale (EQ-5D-vas) in HFrEF, HFmrEF, and HFpEF in hospitalized and outpatient settings.4) To assess the characteristics of patients and their clinical outcomes related to self-reported anxiety/depression across different EF categories in hospitalized and outpatient settings.MethodsIn all four studies, data from the SwedeHF, linked to other national registries were used. The main statistical methods included logistic regression, cumulative incidence, Cox regression, and Fine-Gray regression models.Comorbidities and cause-specific outcomes in different EF categoriesOut of 42,583 patients included 2000-2012, 24% had T2DM, 51% CKD, 56% AF, and 8% all three comorbidities. Patients with HFpEF had a higher prevalence of CKD and AF, HFmrEF had an intermediate prevalence of AF, and the prevalence of T2DM was similar across the EF spectrum. Cardiovascular events were highest in HFrEF, and non-CV events were highest in HFpEF. Type 2 diabetes increased CV and non-CV events similarly but less so in HFpEF. Chronic kidney disease increased CV-events more than non-CV events, less so in HFpEF. Atrial fibrillation increased CV events substantially more than non-CV events, particularly in HFpEF and HFmrEF.Cause-specific death in HF across the EF spectrumAmong 100,584 patients included 2000-2021, most deaths across all EF categories were attributed to CV causes. Within five years, HFpEF showed a higher adjusted risk of non- CV death, and a lower adjusted risk of CV death compared to HFrEF. Regardless of the EF category, the leading causes of death were ischemic heart disease (IHD) and cancer. The IR of CV death due to IHD was highest in HFrEF, while IRs of CV death due to pulmonary vascular disease, stroke, valvular heart disease, and AF increased with increasing EF. As EF increases, the IRs of non-CV deaths caused by cancer, respiratory diseases, and infections also rise.HRQoL in HFrEF, HFmrEF and HFpEFWe studied 40,809 patients 2000-2021. Patients were categorized into four strata of HRQoL levels based on the EQ-5D-vas. Twenty-nine percent fell into the "best" category, 41% into the "good", 25% into the "bad", and 5% into the "worst", evenly distributed across all EF categories. Regardless of EF categories, a higher New York Heart Association (NYHA) class was strongly associated with lower EQ-5D-vas scores, as were liver disease, chronic obstructive pulmonary disease, smoking, higher body mass index, a history of stroke, the use of diuretics, and living alone. Conversely, higher income and being male were inversely related to lower EQ-5D-vas categories. Patients in the "worst" EQ-5D-vas category as compared with the "best" had the highest risk of all-cause death.Anxiety/depression in HF across the EF spectrumOut of 57,251 patients 2008-2023, 58% reported no anxiety/depression, 38% moderate, and 4% severe anxiety/depression, showing a comparable distribution across EF categories. Anxiety/depression was closely linked to HRQoL components, most strongly symptoms of fatigue, out of breath, and incapability to maintain main activities. When not accounting for HRQoL components, significant associations included higher NYHA class, liver disease, smoking, female sex, younger age, and inpatient status. Anxiety/depression levels correlated with increased risks of hospitalization and death within 12 months of follow-up. After adjusting for other HRQoL components, the association with mortality was no longer present.ConclusionsPatients with HFpEF is characterized by more comorbidities and non-CV events compared to HFmrEF and HFrEF, but the impact of T2DM and CKD on events is lower in this group. Cardiovascular events occur most frequently in HFrEF. Across all EF categories, CV deaths were more prevalent than non-CV deaths, although the five-year risk of non-CV death increased with higher EF. Ischemic heart disease and cancer were the leading causes of CV and non-CV deaths, respectively, regardless of EF category. Most patients fell into the top two EQ-5D-vas categories. In all EF categories, a higher NYHA class exhibited the strongest relationship with lower EQ- 5D-vas levels. Patients with the worst EQ-5D-vas category faced the highest risk of mortality. Self-reported anxiety/depression was prevalent in all EF categories, closely linked to HRQoL, and associated with higher risks of HF- and all-cause hospitalization and mortality. However, the effect on mortality decreased once adjustments for HRQoL were made.List of scientific papersI. Comorbidities and cause-specific outcomes in heart failure across the ejection fraction spectrum: A blueprint for clinical trial design. Savarese G, Settergren C, Schrage B, Thorvaldsen T, Löfman I, Sartipy U, Mellbin L, Meyers A, Farsani SF, Brueckmann M, Brodovicz KG, Vedin O, Asselbergs FW, Dahlström U, Cosentino F, Lund LH. Int J Cardiol. 2020 Aug 15;313:76-8. https://doi.org/10.1016/j.ijcard.2020.04.068II. Cause-specific death in heart failure across the ejection fraction spectrum: A comprehensive assessment of over 100 000 patients in the Swedish Heart Failure Registry. Settergren C, Benson L, Shahim A, Dahlström U, Thorvaldsen T, Savarese G, Lund LH, Shahim B. Eur J Heart Fail 2024 May;26(5): 1150-1159. https://doi.org/10.1002/ejhf.3230III. Health-related quality of life across heart failure categories: associations with clinical characteristics and outcomes. Settergren C, Benson L, Dahlström U, Thorvaldsen T, Savarese G, Lund LH, Shahim B. ESC Heart Failure. 2024. https://doi.org/10.1002/ehf2.15206IV. Anxiety/depression in Heart Failure Across the Ejection Fraction Spectrum: Analyses from the SwedeHF. Settergren C, Benson L, Thorvaldsen T, Dahlström U, Savarese G, Lund LH, Shahim B. [Submitted]</p
A multimodal brain imaging dataset on sleep deprivation in young and old humans
No full textThe Stockholm Sleepy Brain Study I is a functional brain imaging study of 48 younger (20-30 years) and 36 older (65-75 years) healthy participants, with magnetic resonance imaging after normal sleep and partial sleep deprivation in a crossover design. We performed experiments investigating emotional mimicry, empathy for pain, and cognitive reappraisal, as well as resting state functional magnetic resonance imaging (fMRI). We also acquired T1- and T2-weighted structural images and diffusion tensor images (DTI). On the night before imaging, participants were monitored with ambulatory polysomnography and were instructed to sleep either as usual or only three hours. Participants came to the scanner the following evening. Besides MRI scanning, participants underwent behavioral tests and contributed blood samples, which have been stored in a biobank and used for DNA analyses. Participants also completed a variety of self-report measures. The resulting multimodal dataset may be useful for hypothesis generation or independent validation of effects of sleep deprivation and aging, as well as investigation of cross-sectional associations between the different outcomes.V. 2 of this manuscript published 2017-10-12. Changes: new co-author (Claus Lamm), changed affiliations for Kristoffer Månsson, minor changes in the abstract, and revisions of the main text and figures.</p
Symtom vid behandling av urinblåsecancer med bcg-instillationer : omvårdnadsperspektiv
No full textBakgrund: Intravesikal instillation med BCG är rekommenderat vid icke muskelinvasiv urinblåsecancer med hög risk för progression. Behandlingens biverkningar är kända och kan både visa sig lokalt i urinvägarna och som systemisk påverkan såsom feber eller ledvärk. Syftet med den här avhandlingen är att öka kunskap om och förståelse för de besvär som patienten har vid BCGbehandling för att bättre kunna hantera eventuella besvär, öka följsamhet till behandling samt att utforma ett validerat skattningsinstrument för patienter som genomgår BCG-behandling.Metod: I den Nordiska T1 G2-G3 blåsbevarande studien, som genomfördes 1999–2006, randomiserades patienter till behandling med BCG alternativt Epirubicin + Interferon. I studien fick patienter besvara ett studiespecifikt frågeformulär med både fasta svarsalternativ och fritextsvar med frågor som bland annat berörde urinvägsbesvär och välbefinnande. Första formuläret besvarades inför start av behandling, därefter månad 3, 6, 12, 24, 36 samt månad 60 efter den första behandlingen. I delstudie 1 har frågeformulären analyserats från de 116 personer som randomiserats till BCG. I delstudie 2 konstruerades ett skattningsinstrument utifrån riktade intervjuer, litteratursökning, djupanalys av fritextsvaren från Nordic T1 studien ovan, och efter analys av tre identifierade befintliga biverkningsprotokoll för BCG. Skattningsinstrument har validerats och reliabilitetstestats under framtagandet med direkta intervjuer med patienter och med sjuksköterskor samt läkare som behandlar blåscancerpatienter.Resultat: Det första frågeformuläret vid delstudie 1. besvarades av 113 personer (97 procent). Vid de sex andra tillfällena var det mellan 74–112 (74–97 %) som besvarade frågeformulären. Resultaten visar att 30 % av patienterna som behandlades med BCG-instillationer hade sjukdomsspecifika besvär med trängningar och sveda innan start av instillationsbehandling och att symtombördan avtog över tid. BCG-installationerna påverkade patienternas välmående negativt. Patienter som var yngre än 65 år var mer besvärade av symtombördan än de som var äldre än 65 år och kvinnor var mer besvärade än män. Skattningsinstrumentet som är utvecklat i studie 2. benämns ”Bladder instillation Therapy Form (BITF) och har förutom svenska också översatts till engelska för att även kunna användas internationellt. Formuläret är tänkt att användas för att strukturerat fånga upp eventuella biverkningar och besvär innan första instillationsbehandlingen och därefter inför varje nästkommande instillation.Sammanfattning: Studien visar att patienter som ska få behandling med BCG-instillationer har lokala urinvägsbesvär innan behandlingen startas. Yngre personer än 65 år är mer besvärade än de som är äldre än 65 år. Kvinnor är mer besvärade av sina symtom än män. Ett validerat skattningsinstrument (BITF) är framtaget i syfte att strukturerat kunna följa patienten under behandlingen för att bättre kunna hantera eventuella besvär och öka följsamhet till behandling.Lista över vetenskapliga artiklarI. Bladder health in patients treated with BCG instillations for T1G2- G3 bladder cancer- a follow-up five years after start of treatment Gun Danielsson, Per Uno Malmström. Staffan Jahnson, Hans Wijkström, Tommy Nyberg, Helena Thulin Scand J Urol, 2018 Vol. 52, Issue 5-6, Pages 377-384. https://doi.org/10.1080/21681805.2018.1538162II. Bladder instillation Therapy Form (BITF) – Nursing instrument for recording and follow up during intravesical Bacillus CalmetteGuérin (BCG) instillations. Gun Danielsson, Tomas Thiel, Helena Thulin I. [Manuscript]</p