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Polytrauma patients : epidemiology and outcome
No full textBackgroundTrauma is a leading cause of death and disability worldwide, particularly among younger populations, but increasingly also among the elderly. Reliable data are crucial both for epidemiological understanding and for guiding improvements in trauma care. Trauma registers such as the Swedish Trauma Register (SweTrau) have therefore become vital resources as they can provide standardized information on injury mechanisms, severity, management, and outcomes. This thesis utilizes SweTrau data to address epidemiological questions and to evaluate the potential of machine learning methods for outcome prediction.MethodsAll four studies used data collected by SweTrau. Study 1 was a retrospective cohort study of patients with and without pelvic fractures. Baseline characteristics, injury severity, physiological status, and mortality at 30 days and one year after injury were compared between the two groups. Univariate logistic regression was used to identify crude mortality associations. Potential confounders of these associations were assessed using the change-in-estimate method, and variables identified as confounders were subsequently included together with pelvic fracture in a multivariable logistic regression model. Study 2 was a descriptive epidemiological study examining the distribution of musculoskeletal injuries among trauma patients. Studies 3 and 4 were both based on a machine learning (ML) approach. In Study 3, three different ML models were applied to predict mortality, while in Study 4, they were used to predict admission to intensive care unit (ICU) and hospital length of stay (LOS). Results were evaluated with C-statistics, calibration curves, and decision curve analysis.ResultsAcross the four studies, more than 37,000 trauma patients from the Swedish national trauma register were analyzed. In study 1, pelvic fracture was found to be associated with a higher crude mortality compared to patients without pelvic fracture (30-day mortality 9% vs. 4%). However, after adjustment for confounders including age, circulatory shock, severe head injury, and overall injury severity, a pelvic fracture was not a risk factor for mortality, suggesting they reflect injury burden rather than uniquely drive mortality. Study 2 demonstrated that musculoskeletal injuries in trauma were highly prevalent, affecting 41% of all trauma patients, with fractures representing the vast majority of the musculoskeletal injuries. The spine was the most frequently injured region, followed by upper and lower extremities, respectively. Patients with musculoskeletal injuries showed higher Injury Severity Score (ISS), longer hospital stay and slightly increased mortality. Distinct patterns were observed across injury mechanisms: traffic accidents dominated, while penetrating trauma showed clear associations with extremity injuries. In study 3, three ML methods were compared with the Trauma and Injury Severity Score (TRISS) for mortality prediction in 9,208 severely injured trauma patients. All tested ML models, particularly the extreme Gradient Boosting (XGB) model, outperformed TRISS, achieving an Area Under Curve (AUC) of 0.91 (95% CI: 0.88-0.93) versus 0.85 (95% CI: 0.82-0.88) for TRISS. The most important predictors identified for mortality were age, Glasgow Coma Scale (GCS), base excess, New Injury Severity Score (NISS), severity of head and thoracic injuries, systolic blood pressure, and American Society of Anaesthesiologists (ASA) class. The ML models also demonstrated better calibration and higher clinical utility than TRISS. In study 4, the ML approach was extended to the prediction of ICU admission and LOS in 9,056 severely injured trauma patients. The XGB model achieved excellent performance for ICU admission with AUC 0.85 (95% CI: 0.84-0.87), but only moderate accuracy for LOS prediction with AUCs between 0.64 and 0.71 depending on the category. The models were implemented in an online tool for individualized estimation of ICU needs and LOS.ConclusionTogether, the four papers demonstrated that trauma outcomes are influenced by injury patterns, physiological status, and comorbidities. They further showed how insights into these factors can be leveraged into predictive models that outperform traditional statistical methods for trauma prediction.List of scientific papersI. The pelvic Fracture - an indicator of injury severity or a lethal fracture? Jonas Holtenius, Peyman Bakhshayesh, and Anders Enocson. Injury, Volume 49, Issue 8, August 2018, Pages 1568-1571. https://doi.org/10.1016/j.injury.2018.06.016II. Musculoskeletal injuries in trauma patients: a Swedish nationwide register study including 37,266 patients. Jonas Holtenius, Hans E Berg, and Anders Enocson. Acta Orthopaedica, 2023; 94: 171-177. https://doi.org/10.2340/17453674.2023.11960III. Prediction of mortality among severely injured trauma patients: A comparison between TRISS and machine learning-based predictive models. Jonas Holtenius, Mathias Mosfeldt, Anders Enocson, and Hans E Berg. Injury, Volume 55, Issue 8, 111702 August 2024. https://doi.org/10.1016/j.injury.2024.111702IV. Development of a new tool for prediction of hospital length of stay and intensive care needs in trauma patients using Machine Learning. Mathias Mosfeldt, Jonas Holtenius, Hans E Berg, Anders Enocson. [Submitted]</p
Should we ban quick returns in shift work? Investigating acute effects on recovery
No full textBackground: Shift work is associated with negative effects on both health and safety, with insufficient sleep and recovery as a proposed pathway. The adverse effects from working shifts likely depend on the design of the shift schedule. A better understanding of individual shift components can help disentangle the complex relationship between shift work and its outcomes. The focus of this doctoral thesis is on quick returns, defined as having less than 11 hours of rest between consecutive shifts. Quick returns have been linked to reduced sleep duration, increased fatigue and higher risks of short-term sick leave and accidents. However, less is known about their effects on sleep quality, cognitive functioning, and work performance, as well as potential benefits of working quick returns. Moreover, few well-controlled field studies combining subjective reports with objective measures have examined the acute effects of quick returns.Aims: This doctoral project aimed to clarify the mechanisms through which quick returns influence recovery and fatigue related risks. Study I explored the perceived benefits, drawbacks, and self-rated tolerance for quick returns. Study II examined the acute effects on sleep, sleepiness and stress. Study III investigated the impact of quick returns on sleep, sleepiness and performance.Methods: In Study I, 96 nurses and assistant nurses completed a questionnaire on their views of quick returns. In Study II, 90 nurses and assistant nurses wore actigraphy wristbands and provided diary data during one quick return (evening-day transition) and one control condition (day-day transition). Study III used a quasi-experimental design following 36 newly graduated nurses across two prescheduled shift conditions: one with a quick return (off work-evening- day-day) and one control (off work-day-day-day). The participants wore actigraphy wristbands during sleep, kept work and sleep diaries, and performed short cognitive tests throughout the day.Results: In Study I, the self-rated tolerance varied, suggesting that some individuals may be more vulnerable to the adverse effects of quick returns than others. Most participants associated quick returns with insufficient sleep and increased daytime fatigue, which also interfered with leisure time. Some experienced an increased risk of performance errors and mistakes, while some reported that quick returns benefited work-home balance and reduced stress on day shifts, but even larger proportions did not share these views. Quick returns were also found to benefit continuity in work processes. In Study II, quick returns were found to reduce sleep duration by 1 hour compared to day-day transition, leading to increased sleepiness during and after work. Participants reported poorer subjective sleep quality and increased anxiety at bedtime, but worktime stress and objective measures of sleep fragmentation did not differ between conditions. In Study III, quick returns shortened sleep by 46 minutes (to about six hours) and increased fatigue, with possible lingering fatigue on the subsequent dayshift although this estimate was uncertain. Again, participants reported poorer subjective sleep quality, while objective sleep efficiency and sleep fragmentation were unaffected. Although participants reported poorer cognitive ability after quick returns, they did not perform worse on cognitive tests compared to day-day transitions.Conclusions: Quick returns do not allow for sufficient recovery, resulting in increased daytime fatigue, that could possibly interfere with work performance and safety. However, the cognitive test data suggest that nurses may be able to compensate for fatigue and maintain performance on short tasks. Furthermore, quick returns may benefit continuity in work processes in some organisations. Individuals may vary in their tolerance for quick returns, indicating that what constitutes a "safe" number of quick returns may differ depending on the individual and context. There was also tentative evidence that shift workers may not be able to recover properly when multiple day shifts follow quick returns, but these findings must be validated in future research. In sum, the findings of this thesis indicate that quick returns are associated with insufficient recovery and increased fatigue, which may help explain previously reported associations with higher risks of sick leave and accidents, and that they therefore should be avoided.List of scientific papersI. Öster, K., Tucker, P., Söderström, M., & Dahlgren, A. (2023). Pros and cons of quick returns-a cross-sectional survey among Swedish nurses and nurse assistants. Industrial Health, 61(5), 379-392. https://doi.org/10.2486/indhealth.2022-0033II. Öster, K., Tucker, P., Söderström, M., & Dahlgren, A. (2024). Quick returns, sleep, sleepiness and stress - An intra-individual field study on objective sleep and diary data. Scandinavian Journal of Work, Environment & Health, 50(6), 466-474. https://doi.org/10.5271/sjweh.4175III. Öster, K., Söderström, M., Tucker, P., Axelsson, J., Kecklund, G., & Dahlgren, A. Quick returns: a quasi-experimental field study on the effects of sleep, fatigue and cognitive performance. [Submitted]</p
Monocytes, dendritic cells and myeloid-derived suppressor cells in blood and airways across COVID-19 and influenza severity
No full textRespiratory viral infections including influenza and COVID-19 continue to cause substantial morbidity and mortality globally. Although several risk factors for severe disease are known, and include older age and underlying diseases, it is not fully known why certain individuals develop severe disease.Monocytes and dendritic cells (DC) are positioned in mucosal surfaces and also circulate in blood, and are important sensors and responders to these viruses. Importantly, DCs efficiently activate T cells that are typically needed to clear viral infection. Although epithelial cells in the upper respiratory tract are the primary site of infection for these viruses, and early events at this site are likely important for subsequent disease severity, most studies focus on blood samples. Moreover, monocytes and DCs differ in distribution and function depending on their anatomical location, and it is therefore important to sample the mucosa in addition to blood. While monocytes and DCs can initiate an inflammatory response upon viral infection, myeloid-derived suppressor cells (MDSC) are instead suppressors of T cell responses. Monocytic MDSCs (M-MDSC) are phenotypically similar to monocytes, and likely represent an altered monocyte state. These cells have mostly been studied in chronic inflammatory conditions such as cancer, but are also present in sepsis. The role of MDSC in influenza and COVID-19, however, is less clear.In this thesis, we focused on the role of monocytes, DCs and M-MDSC in influenza and COVID-19 patients, and investigate how these cells may influence disease severity. We collected longitudinal samples from the airways, including nasopharyngeal aspirates (NPA) and endotracheal aspirates (ETA), along with blood samples from two cohorts of patients with ongoing influenza or COVID-19 with varying degree of disease severity.We found an early recruitment of monocytes and DCs to the nasopharynx during influenza, while DCs instead decreased in blood. By separating patients based on severity, we found that lower DC levels in blood and decreased DC recruitment to the nasopharynx associated with more severe influenza. Similarly, we found that COVID-19 patients displayed substantial monocyte recruitment to the trachea, whereas DCs were not recruited. In blood, DCs were depleted and both monocytes and DCs displayed decreased maturation.In patients with COVID-19, we found a severity-dependent increase in levels of M-MDSC. These cells were capable of suppressing T cell proliferation in vitro. Moreover, levels of arginase 1, which is produced by M-MDSC, were increased in plasma of patients with more severe disease. Cells with the same phenotype were also increased in the blood of influenza patients.Comparing different sampling methods to study monocytes and DCs in the upper airways during respiratory viral infection, we found that NPA generated significantly higher cell yield as compared to nasal curettes and nostril swabs. In addition, NPA was not associated with more blood contamination or increased patient discomfort. NPA could also be used for longitudinal sampling, allowing temporal assessment of monocytes and DCs during acute infection and convalescence.Collectively, this thesis points out a recruitment of DCs to the airways in mild influenza, whereas DCs were less recruited in patients with more severe influenza and COVID-19. Instead, the most severe COVID-19 patients were characterized by airway recruitment of monocytes and high levels of circulating M-MDSC. We also establish NPA as a useful method to study monocytes and DCs longitudinally in the upper airways during ongoing infection.List of scientific papersI. Vangeti S, Falck-Jones S, Yu M, Österberg B, Liu S, Asghar M, Sonden K, Paterson C, Whitley P, Albert J, Johansson N, Färnert A, Smed-Sörensen A. Human influenza virus infection elicits distinct patterns of monocyte and dendritic cell mobilization in blood and the nasopharynx. Elife. 2023 Feb 8;12:e77345. https://doi.org/10.7554/elife.77345II. Falck-Jones S, Vangeti S, Yu M, Falck-Jones R, Cagigi A, Badolati I, Österberg B, Lautenbach MJ, Åhlberg E, Lin A, Lepzien R, Szurgot I, Lenart K, Hellgren F, Maecker H, Sälde J, Albert J, Johansson N, Bell M, Loré K, Färnert A, Smed-Sörensen A. Functional monocytic myeloid-derived suppressor cells increase in blood but not airways and predict COVID-19 severity. Journal of Clinical Investigation. 2021 Mar 15;131(6): e144734. https://doi.org/10.1172/jci144734III. Österberg B*, Falck-Jones S*, Vangeti S, Åhlberg E, Yu M, Granja D, Snik ME, Falck-Jones R, Barros G W F, Charles A, Lepzien R, Johansson N, Holmes TH, Maecker H, Czarnewski P, Bell M, Färnert A, Smed-Sörensen A. *Equal contribution. Decreased levels and function of dendritic cells in blood and airways predict COVID-19 severity. Clinical and Translational Immunology. 2025 Mar 3;14(3):e70026. https://doi.org/10.1002/cti2.70026IV. Falck-Jones S*, Österberg B*, Åhlberg E, Padhi A, Joshua V, Grundström J, Svensson J, Charles A, Yu M, Falck-Jones R, Bell M, Bergqvist L, Färnert A, Smed-Sörensen A. * Equal contribution. Temporal dynamics of dendritic cells in the upper airways distinguish influenza patients requiring hospitalization. [Manuscript]</p
Lifestyle factors and colorectal cancer : incidence, prognosis and genetics
No full textColorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death. This thesis examines how lifestyle factors affect CRC development and prognosis, the changing CRC incidence and survival trends in Sweden, and the recurrence risk prediction models used to guide adjuvant chemotherapy recommendations.Study I included 1,098 patients diagnosed with stage I-III CRC between 2003 and 2006. The exposure of interest was a healthy lifestyle, and the primary outcome was recurrence-free survival (RFS). Lifestyle data were self-reported using a semi-validated food frequency questionnaire. This data was used to calculate a healthy lifestyle and BMI (HL) score, categorizing participants into four groups, from the healthiest (4 points) to the least healthy (1 point). Follow- up data were collected from patient files, and survival analyses were conducted to assess recurrence-free survival across the four groups, each representing a different category of exposure, with the least healthy group serving as the reference. A healthy lifestyle was associated with a significant improvement in recurrence-free and overall survival.Study II involved 616 cases of sporadic CRC with self-reported lifestyle risk factors and 1,642 healthy controls. Both cases and controls were genotyped using the OncoArray 500 K BeadChip. Five separate sliding-window haplotype GWAS analyses were conducted, all using the same set of healthy controls. Logistic regression was used to estimate the associations between haplotype regions and CRC in cases compared to controls. We identified 17 candidate susceptibility loci that were significantly associated with CRC. Several of these loci contained protein-coding regions of genes involved in inflammation, cell cycle regulation, and cancer development.Study III was a nationwide registry-based study that included 135,610 incident CRC cases diagnosed in Sweden from 1993 to 2019. We used Poisson regression models to quantify incidence trends in early- versus late-onset CRC with annual percentage changes (APCs), and to assess differences in relative survival through excess mortality rate ratios (EMRRs). An increase in EOCRC incidence was observed across the right colon, left colon, and rectum during the study period. Right-sided colon cancer also increased among late-onset patients, while distal colon and rectal cancers decreased in this group starting in 2009. The EOCRC group had better stage-specific relative 5-year survival compared to late-onset patients. However, both groups experienced persistent excess mortality 5-10 years after diagnosis.Study IV included 1,083 cases of stage I-III CRC diagnosed between 2003 and 2006. An experienced pathologist performed a detailed micromorphological assessment for each case according to protocol. Follow-up data were collected from patient files. Two logistic regression models were developed to assess the recurrence risk of cases, one of which included the emerging micromorphological risk factor tumor budding. In univariate analysis, budding was significantly associated with disease recurrence; however, this association was not observed in multivariate regression analyses. The predictive performance of the two models was compared using receiver operating characteristic (ROC) curves. Adding tumor budding to the established risk factors did not improve the prediction of recurrence risk.List of scientific papersI. Barot S; Rantanen P; Nordenvall C; Lindforss U; Everhov AH; Larsson SC; Lindblom A; Liljegren A. Combined associations of a healthy lifestyle and body mass index with colorectal cancer recurrence and survival: a cohort study. Cancer Causes & Control, 2024;35(2): 367-376. https://doi.org/10.1007/s10552-023-01802-yII. Barot S; Vermani L; Blom J; Larsson S; Liljegren A; Lindblom A. Candidate Genetic Loci Modifying the Colorectal Cancer Risk Caused by Lifestyle Risk Factors. Clinical and Translational Gastroenterology, 2025;16(1):e00790. https://doi.org/10.14309/ctg.0000000000000790III. Barot S; Liljegren A; Nordenvall C; Blom J; Radkiewicz C. Incidence trends and long-term survival in early-onset colorectal cancer: a nationwide Swedish study. Annals of Oncology, 2025 ;: SO923- 7534(25)00920-2. https://doi.org/10.1016/j.annonc.2025.07.019IV. Barot S; Andersson-Franko M; Ghazi S; Lindforss U; Rantanen P; Blom J; Lindblom A; Liljegren A. Impact of Tumor Budding on Recurrence Risk Prediction in Stage I-III Colorectal Cancer: A Swedish Cohort study. [Submitted]</p
Epidemiologic studies on Kawasaki disease during 30 years in Sweden
No full textKawasaki disease (KD) is a paediatric vasculitis that presents with fever, affecting mostly medium-sized arteries. Inflammation is visible in the skin, eyes, mouth, and lymph nodes, while other organs such as the gastrointestinal tract and the nervous system can also be involved. KD develops dependent on genetic susceptibility in combination with certain, yet unknown triggers. Untreated, it leads to coronary artery aneurysms (CAA) in a quarter of affected children with a risk for myocardial infarction in the acute or chronic phase.Incidence rates are significantly higher in Asian populations than elsewhere in the world. For the Nordic population, the last comprehensive study of KD at a national level was performed in 2013. The overall aim of this thesis was therefore to characterize the epidemiologic features of KD in a Nordic population over a long period of time from different perspectives. With data from the Swedish national healthcare registers, we developed a dataset to study KD over 32 years in the Swedish population. We found that the incidence rate of KD rose steadily prior to the SARS-CoV-2 pandemic, with certain peak years and an increasing percentage of children that are born outside Sweden themselves, or with parents born outside Sweden. We concluded that migration patterns may be associated with generally increasing numbers of KD.As we used register data for KD with previously unvalidated diagnostic codes, we performed a validation study of the clinical diagnosis of KD based on the medical records. We found a 95% concordance between the registered KD diagnosis and the medical records in relation to international KD criteria. We thus concluded that the validity of a KD diagnosis in our national registers is high with high specificity. These data are therefore reliable both for studies of risk factors for KD and future epidemiological research. When examining clinical care data, we observed that treatment guidelines were followed, and that outcomes were usually favourable.In our population, we also wanted to identify risk factors for KD. First, we performed a case-control study to investigate if a history of infection associated with a higher risk of developing KD. We found that children who later developed KD already have a higher rate of diagnoses of infections from birth than controls, not just directly before KD.In a second case-control study, we investigated perinatal risk factors. We found that prematurity was a significant risk factor for developing KD. In addition, prenatal maternal smoking, advanced maternal age, and Asian or African descent were also found to be risk factors.For the clinician, it is important to know the extent of CAA so that diagnostics and treatment are precise. As Sweden only has low numbers of children with CAA that underwent detailed imaging by cardiac catheterization, we developed a comparative study of the prevalence and morphology of CAA in a mixed European population. We found that distal CAAs were almost exclusively detected alongside proximal CAAs. Thus, distal CAA are not likely to be missed with standard diagnostic technique, helping to avoid unnecessary interventions.In conclusion, this thesis adds to the current understanding of epidemiologic and clinical factors in Kawasaki disease.List of scientific papersI. Patterns of migration underlie changing epidemiology of Kawasaki disease outside of Covid-19: a cohort study. Rudolph A, Mofors J, Frisk A, Schiller B, Elinder G, Nordenstam F, Eliasson H, Bergman G, Granath F, Wahren-Herlenius M. [Submitted]II. Clinical features and treatment of Kawasaki disease in validated cases in the Swedish National Patient Register. Rudolph A, Mofors J, Eliasson H, Bergman G, Wahren-Herlenius M. [Manuscript]III. Associations of infection burden with Kawasaki disease in a population-based setting during 30 years. Mofors J, Rudolph A, Schiller B, Elinder G, Sonesson SE, Eliasson H, Bergman G, Wahren-Herlenius M. RMD Open 2025;11:e005160. https://doi.org/10.1136/rmdopen-2024-005160IV. Swedish nationwide study found that prematurity was associated with Kawasaki disease. Frisk A, Rudolph A, Eliasson H, Nordenstam F, Bergman G, Wahren-Herlenius M, Mofors J. Acta Paediatrica, 2025; 0:1-10. https://doi.org/10.1111/apa.70071V. Specific morphology of coronary artery aneurysms in mainly white patients with Kawasaki disease: Initial data from the cardiac catheterization in Kawasaki disease registry. Weisser J, Arnold L, Wällisch W, Quandt D, Opgen-Rhein B, Riede FT, Gräfe F, Michel J, Arnold R, Schneider H, Tanase D, Herberg U, Happel C, Tietje M, Tarusinov G, Grohmann J, Hummel J, Rudolph A, Haas N, Jakob A. J Am Heart Assoc. 2024;13:e034248. https://doi.org/10.1161/JAHA.124.034248</p
Smartphone-based photoplethysmographic measurements for diagnosis of cardiac arrhythmia
No full textBackgroundAtrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia and is associated with an increased risk of stroke, heart failure, dementia, and all-cause mortality. Early diagnosis and treatment are essential but often delayed due to the intermittent nature of the arrhythmia and limited access to electrocardiogram (ECG)-based diagnostics. Smartphone-based photoplethysmography (PPG) is a non-invasive optical technique using the phone's built-in camera as measurement sensor, with the potential to serve as a scalable and accessible tool for heart rhythm and heart rate assessment in ambulatory settings. This thesis investigated the diagnostic performance and clinical utility of a smartphone-PPG system when used by patients with AF and atrial flutter (AFL) in their home environment.Methods and ResultsThe studies were prospective, single-centre, and conducted with patients at Danderyd University Hospital in Stockholm. In the studies, the participants performed ambulatory, unsupervised smartphone-PPG recordings (CORAI) simultaneously with single-lead ECG (KardiaMobile) as reference.Study I - Prospective validation of arrhythmia diagnostics by manual reading of smartphone PPG. Adults undergoing elective or acute direct current cardioversion (DCCV) for AF/AFL performed simultaneous heart rhythm recordings with PPG and ECG daily for 30 days after DCCV. The reference heart rhythm from ECGs was read by experienced cardiologists (gold standard), and the heart rhythm from PPG reports was read by trained physicians blinded to the heart rhythm from ECGs. Among 280 participants providing 18 005 paired recordings, manual heart rhythm reading from PPG achieved a sensitivity of 99.0% and specificity of 99.7% for diagnosing AF. With AFL recordings included, sensitivity and specificity were 97.7% and 99.4%, respectively.Study II - External validation of automatic arrhythmia diagnostics from PPG using a machine learning (ML) algorithm. A support vector machine classifier, trained on 16 092 PPG recordings made by 180 patients in an independent training cohort was externally validated on the recordings from the 280 participants in the cohort in Study I. The ML model for rhythm classification had higher accuracy compared with manual reading in diagnosing AF, with both a sensitivity and specificity of 99.7%. With AFL recordings included, the diagnostic performance decreased slightly but remained high (sensitivity 99.3%, specificity 99.1%). The PPG recordings had a high proportion with sufficient quality for diagnosis, and only a small fraction of recordings was excluded due to either insufficient quality or low algorithmic certainty.Study III - Randomised clinical trial (RCT) investigating efficacy and feasibility of pre-cardioversion heart rhythm monitoring with smartphone PPG. In this RCT with patient-blinded allocation, participants scheduled for DCCV were randomised 1:1 to either intervention or control. The heart rhythm from PPG recordings pre-cardioversion was read daily by the investigators. In case of spontaneous conversion to sinus rhythm (SR) or if non-adherence to oral anticoagulation (OAC) treatment protocol were detected in the intervention group, their scheduled DCCV were cancelled or postponed, respectively. No such action was taken for participants in the control group. Among 104 (intervention) and 99 (control) participants, the monitoring strategy using smartphone PPG reduced same-day DCCV cancellations from 23.2% to 4.8%, a relative risk reduction (RRR) of 79.3% and an absolute risk reduction (ARR) of 18.4%. Same-day cancellations due to spontaneous conversion to sinus rhythm were reduced from 18.2% to 1.0%, with a RRR of 94.7% and an ARR of 17.2%. Adherence to twice-daily recordings was high (median 2.1 recordings/day), and 100% of pre-cardioversion PPGs had a sufficient quality to make a heart rhythm diagnosis, based on automatic signal-quality analysis. No same-day cancellations were attributed to OAC non-adherence.Study IV - Validation of heart-rate measurements using smartphone PPG. The recordings from the participants in Study III were used to assess the agreement of heart rate from simultaneous PPG and ECG recordings on a per- measurement basis using automatic heart rate algorithms. In 203 participants with 17 588 paired recordings peri-cardioversion, the overall agreement between heart rate from PPG and ECG was high. The mean absolute error was 2.4 beats per minute (bpm), the root mean square error was 4.6 bpm, and the mean heart rate difference was 0.3 bpm. The heart rate agreement was higher for regular heart rhythms, such as SR and AFL, with regular AV conduction, compared with irregular heart rhythms, such as AF and AFL, with variable AV conduction.ConclusionsThe studies in this thesis showed that the smartphone-PPG method can be used by patients in ambulatory, unsupervised settings to achieve highly accurate heart rhythm diagnostics of atrial fibrillation and atrial flutter. A machine learning algorithm demonstrated excellent diagnostic accuracy, reducing the need for manual interpretation. Pre-cardioversion monitoring with smartphone PPG significantly reduced same-day cancellations of DCCV by detecting spontaneous conversion to sinus rhythm. Heart rate assessment from PPG recordings showed excellent overall agreement with heart rate derived from ECG recordings. These results support the use of smartphone PPG as an independent diagnostic tool for heart rhythm and heart rate in ambulatory settings, minimising the need for manual review and ECG confirmation.List of scientific papersI. Fernstad J, Svennberg E, Åberg P, Kemp Gudmundsdottir K, Jansson A, Engdahl J.Validation of a novel smartphone-based photoplethysmographic method for ambulatory heart rhythm diagnostics: the SMARTBEATS study.EP Europace. 2024 Mar 30;26(4):euae079https://doi.org/10.1093/europace/euae079II. Fernstad J, Svennberg E, Åberg P, Kemp Gudmundsdottir K, Jansson A, Engdahl J.External validation of a machine learning-based classification algorithm for ambulatory heart rhythm diagnostics in pericardioversion atrial fibrillation patients using smartphone photoplethysmography: the SMARTBEATS-ALGO study.EP Europace. 2025 Mar 28;27(4): euaf031https://doi.org/10.1093/europace/euaf031III. Fernstad J, Svennberg E, Åberg P, Engdahl J.Pre-cardioversion heart rhythm monitoring using smartphone PPG - A Randomized Clinical Trial[Submitted]IV. Fernstad J, Svennberg E, Åberg P, Engdahl J.Validation of a method for ambulatory heart rate measurements using smartphone photoplethysmography: the SMARTBEATS-RATE study[Manuscript]</p
Paediatric-onset multiple sclerosis : epidemiology and treatment with a special focus on rituximab
No full textBackground: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system, affecting almost 3 million people worldwide. Approximately 5% experience disease onset during childhood or adolescence, yet data on its occurrence in this age remain limited. Paediatric-onset MS (PoMS) is typically associated with higher inflammatory activity than Adult-onset MS, which calls for early and effective treatment to prevent long-term disability. Despite this, comparative data on PoMS treatment are scarce. Of the more than 20 disease-modifying therapies (DMTs) approved for adult MS, only fingolimod, teriflunomide, and dimethyl fumarate are approved for paediatric use in Europe, and only fingolimod is approved in the United States. None of the highly effective DMTs are approved for children, highlighting the need for better evidence to guide treatment decisions.This thesis further characterises the epidemiology of PoMS and provides real- world evidence on treatment patterns and outcomes, with particular emphasis on rituximab-a highly effective B-cell depleting therapy (BCDT) widely used in Sweden over the past decade.Methods: The thesis comprises five studies. First, it validates the Swedish Multiple Sclerosis registry for use in PoMS by comparing registry data against medical records. Second, it characterises the occurrence of PoMS in Sweden using data from two complementary national population-based registers: the Swedish Multiple Sclerosis Registry and the Swedish Patient Register. Third, it examines international treatment patterns based on a cross-sectional survey. Finally, it investigates real-world outcomes of DMT use in PoMS through both an international multicentre case series of rituximab and a Swedish population- based cohort design, allowing for comparison across DMTs.Results: In the validation study, MS registry data from 122 individuals with PoMS demonstrated an overall concordance exceeding 90% when compared with medical records. However, more than 30% of the data were missing for rituximab infusions, magnetic resonance imaging (MRI) examinations, and relapses.The incidence rate of PoMS in Sweden was 1.12 per 100,000 person-years (95% Confidence Interval [CI]: 0.98-1.27), and the prevalence was 2.82 per 100,000 children and adolescents (95% CI: 2.60-3.06), with slightly lower age- and sex- standardised estimates. Estimates increased with age and showed a female predominance from age 12, remaining stable over time.In the survey conducted within the International Paediatric Multiple Sclerosis Study Group, 66 respondents from 25 countries reported that interferons and fingolimod, which are moderately effective DMTs, were the most commonly used DMTs. However, a trend toward earlier use of highly effective DMTs was observed.In the rituximab case series, which included 61 individuals with PoMS treated over a median of 20.9 months (range 1.1-151.1), rituximab was associated with an annualised relapse rate of 0.02 (95% CI: 0.01-0.05) and an annualised rate of new MRI lesions of 0.08 (95% CI: 0.03-0.25), representing a highly significant decrease compared to before therapy was initiated. Adverse events occurred in 67% of cases, mostly mild to moderate, and treatment persistence was 90%.In the treatment persistence study, which included 383 individuals with PoMS and 934 treatment episodes, all other DMTs were associated with significantly higher risks of discontinuation compared to rituximab, with adjusted hazard ratios of 4.33 (95% CI: 3.26-5.76) for natalizumab, 4.57 (95% CI: 3.23-6.46) for fingolimod, 5.51 (95% CI: 3.81-7.96) for dimethyl fumarate, and 11.23 (95% CI: 8.30-15.20) for injectables. Results remained robust throughout sensitivity analyses.Conclusion: In PoMS, moderately effective DMTs remain widely used internationally, although there is a growing trend toward initiating highly effective therapies earlier. In our real-world studies, rituximab appeared as a promising option, demonstrating strong effectiveness and a favourable safety profile. Treatment persistence was significantly higher, not only compared to the moderately effective DMTs approved for paediatric use but also compared to the highly effective DMT natalizumab. These findings support a more proactive, evidence-informed approach to managing PoMS, with rituximab and other BCDTs as promising candidates for early intervention.List of scientific papersI. Sandesjö F, Alping P, Fink K, Wickström R, Piehl F, Frisell T, Mckay KA. Validation of the Swedish Multiple Sclerosis registry for pediatric-onset multiple sclerosis. Multiple Sclerosis Journal - Experimental, Translational and Clinical. 2025;11(1):20552173251314118. https://doi.org/10.1177/20552173251314118Il. Sandesjö F, Tremlett H, Fink K, Marrie RA, Zhu F, Wickström R, Mckay KA. Incidence rate and prevalence of pediatric-onset multiple sclerosis in Sweden: A population-based register study. European Journal of Neurology. 2024;31(5):e16253. https://doi.org/10.1111/ene.16253III. Sandesjö F, Wassmer E, Deiva K, Amato MP, Chitnis T, Hemingway C, Krupp L, Pohl D, Rostasy K, Waubant E, Banwell B, Wickström R. Current international trends in the treatment of multiple sclerosis in children - Impact of the COVID-19 pandemic. Multiple Sclerosis and Related Disorders. 2021;56:103277. https://doi.org/10.1016/j.msard.2021.103277IV. Breu M*, Sandesjö F*, Milos RI, Svoboda J, Salzer J, Schneider L, Reichelt JB, Bertolini A, Blaschek A, Fink K, Höftberger R, Lycke J, Rostásy K, Seidl R, Siegert S, Wickström R ** , Kornek B **. Rituximab treatment in pediatric-onset multiple sclerosis. European Journal of Neurology. 2024;31(5):e16228. *Shared first authorship. ** Shared last authorship. https://doi.org/10.1111/ene.16228V. Sandesjö F, Mckay KA, Fink K, Piehl F, Wickstrom R. Treatment Persistence in Pediatric-onset Multiple Sclerosis - A Swedish nationwide registry study. [Submitted]</p
Narrowing the translational gap in metabolic dysfunction-associated steatotic liver disease (MASLD) drug development
No full textMetabolic dysfunction-associated steatotic liver disease (MASLD) currently poses a significant health burden, with a prevalence of 38% in the general population. With the parallel increase of obesity and type 2 diabetes prevalence, MASLD is currently one of the top indications for liver transplantation. Its progressive form, termed metabolic dyfunction-associated steatohepatitis (MASH), remains a major risk factor for liver-related morbidity and mortality. Despite its clinical relevance, the development of effective treatments has been hindered by the lack of physiologically relevant in vitro systems capable of capturing human-relevant disease mechanisms, pharmacological responses, and enabling compound screening for novel target discovery. This thesis aims to improve the fidelity and pathophysiological relevance of biological liver model systems for preclinical research in MASLD and MASH.In the first study, we showed that primary human hepatocyte (PHH) spheroids can recapitulate insulin resistance when challenged with nutrient-excess media and free fatty acids (FFA), mimicking a key hallmark of MASLD onset. Basal expression of genes involved in gluconeogenesis and de novo lipogenesis was elevated in insulin-resistant PHH spheroids, but their expression was not markedly affected by acute insulin challenge, corroborating the insulin resistance phenotype after chronic exposure to excess nutrients and FFA. Additionally, the development of a sensitive glucose sensor enabled longitudinal measurement of glucose utilization in PHH spheroids, allowing us to quantify both insulin-dependent and -independent glucose uptake, reproducing values observed in human clamp studies and previous simulations.The second study showed that incorporating non-parenchymal cells (NPC) from MASH patients with biopsy-proven fibrosis allows for the phenocopying of MASH hallmarks, including steatosis, inflammation, and fibrosis. Not only could we aggravate the fibrosing phenotype by adding FFA, but we also demonstrated that the model is amenable to pharmacological intervention. We benchmarked the model against several compounds in clinical development, including resmetirom and obeticholic acid, and observed delayed, dose-dependent reductions in pro-collagen I secretion as a proxy for fibrosing liver microtissues, consistent with clinical outcomes. Chemogenomic screening further revealed the CHRM1-TRPM8 axis as a novel regulatory pathway in hepatic fibrosis, demonstrating the platform's utility in target discovery.In the final study, we systematically examined how different polymers influence compound bioavailability through absorption. Using a panel of eight polymers and hepatotoxic drugs with varying physicochemical properties, we found that hydrophobic compounds were substantially lost in highly absorptive materials such as poly(dimethyl siloxane) (PDMS), leading to false-negative toxicity results. In contrast, low-absorption materials like thiol-ene epoxy (TEE) and poly(tetrafluoroethylene) (PTFE) retained bioactive concentrations and enabled accurate toxicity profiling. This work establishes key design rules for polymer selection in drug-screening platforms and informs future assay standardization strategies.Altogether, this thesis provides a coherent framework for improving the physiological relevance and translational reliability of in vitro human liver models. By integrating biological fidelity with engineering considerations, these contributions support the development of more predictive platforms for MASLD research and compound evaluation.List of scientific papersI. Insulin-dependent glucose consumption dynamics in 3D primary human liver cultures measured by a sensitive and specific glucose sensor with nanoliter input volume. Kemas AM, Youhanna S, Zandi SR, Lauschke VM. FASEB Journal. 2021 35;3 e21305. https://doi.org/10.1096/fj.202001989rrII. Chemogenomic Screening in a Patient-Derived 3D Fatty Liver Disease Model Reveals the CHRM1-TRPM8 Axis as a Novel Module for Targeted Intervention. Youhanna S*, Kemas AM*, Wright S, Zhong Y, Klumpp B, Klein K, Motso A., Michel M, Ziegler N, Shang M, Sabatier P, Kannt A, Sheng H, Vilarnau N, Büttner FA, Seashore-Ludlow B, Windbergs M, Hülsmeier AJ, Hornemann T, Olsen JV, Wang Y, Gramignoli R, Sundström M, Lauschke VM. Advanced Science. 2025, 12;3 e2407572. *SY and AMK contributed equally. https://doi.org/10.1002/advs.202407572III. Compound Absorption in Polymer Devices Impairs the Translatability of Preclinical Safety Assessments. Kemas AM*, Zandi SR*, Taebnia N, Michel M, Preiss L, Hofmann U, Lauschke VM. Advanced Healthcare Materials. 2024, 13;11 e2303561. *AMK and SRZ shared first co-authorship. https://doi.org/10.1002/adhm.202303561</p
Studies on surgical site infections after orthopaedic surgery : focusing on air-born transmission
No full textPaper I presents a retrospective cohort study based on data from the Swedish Hip Arthroplasty Register (SHAR) and the Swedish Cause of Death Register. The aim was to investigate the risk of mortality following revision surgery for prosthetic joint infection (PJI) after total hip arthroplasty (THA), compared with revisions for non-infectious causes, and more specifically to assess whether the infection itself contributed to the increased risk of death. We included all patients who underwent revision THA between 1998 and 2017. Revision due to PJI was defined as the exposure, and mortality as the outcome. Patients undergoing revision for non-infectious reasons served as the control group. The outcome was analyzed using a Cox proportional hazards model. A total of 4,943 PJI revisions and 12,529 non-infected revisions were included in the final analysis. The incidence rate ratio (IRR) was 1.19 (95% CI 1.13-1.25), the crude hazard ratio (HR) was 1.19 (95% CI 1.13-1.25), and the adjusted HR was 1.05 (95% CI 0.99-1.12). Mediation analysis identified age and comorbidity status as the strongest predictors of mortality. We concluded that the increased mortality risk following revision for PJI is primarily attributable to patient age and comorbidities rather than the infection itself.Paper II presents a register-based retrospective cohort study aimed at investigating the association between air quality in the operating theatre (OT), measured as colony-forming units per cubic meter (CFU/m3), and the risk of surgical site infection (SSI) following orthopaedic surgery. The primary outcome was SSI within 12 weeks postoperatively, defined using a proxy variable termed the post-surgery infection marker (PSIM), a novel composite indicator based on antibiotic prescription data and diagnostic codes. The secondary outcomes were antibiotic use within 30 and 90 days respectively after surgery, and mortality within 2 years after surgery. Associations were analyzed using logistic regression models adjusted for sex, age, comorbidity score, surgery duration, and hospital regarding the primary outcome and first two secondary outcomes. Mortality was analysed using a Cox proportional hazards model. A total of 429 CFU measurements collected between 2013 and 2019 from 101 unique OTs across 30 hospitals were included. Patients who had undergone orthopaedic surgery in these OTs within three months prior to the CFU measurement were identified through the Swedish Perioperative Register (SPOR). After excluding patients with pre-existing infections or contamination at the index surgery, 4,603 procedures were included in the final analysis. No significant association was observed between CFU levels and SSI risk (adjusted OR per CFU unit: 1.00; 95% CI, 0.99-1.01; p = 0.81). The strongest predictors of SSI were male sex (OR: 1.34; 95% CI, 1.08-1.65) and comorbidity burden (OR per Elixhauser unit: 1.32; 95% CI, 1.22-1.43). CFU count showed no significant association with antibiotic use within 30 days (adjusted OR, 0.99; 95% CI, 0.97-1.01) or within 90 days (adjusted OR, 1.00; 95% CI, 0.98-1.01). For mortality, the adjusted hazard ratios (HR) was 1.00 (95% CI, 0.99-1.01; p = 0.90) per unit increase in CFU count. Surgery duration showed a modest but statistically significant association with SSI risk. We concluded that these findings challenge the assumption that lower CFU levels reduce the risk of SSI in modern OTs, suggesting that preventive efforts may be better focused on optimizing preoperative patient health and minimizing surgical duration.Paper III represents the largest study in this thesis. It describes a multicenter, cluster-randomized, crossover, placebo-controlled, double-blinded trial designed to assess whether a new type of air purifier using plasma technology could reduce the risk of SSIs following orthopaedic surgery. We installed three air purifiers in each of 34 OTs at seven major hospitals across Sweden. These purifiers were programmed to switch ON and OFF at random intervals. Each set of three purifiers operated in synchronization, making each OT a defined cluster with crossover between intervention and placebo periods. All patients undergoing orthopaedic surgery in these OTs between 2017 and 2021 were identified using data from SPOR and included in the study. Patients who underwent surgery while the purifiers were ON formed the intervention group, while those operated on when the purifiers were OFF formed the control group. The primary outcome was SSI within 12 weeks postoperatively, defined using the same proxy variable (PSIM) as in Paper II. Secondary outcomes were also identical to those in Paper II: antibiotic use within 30 and 90 days postoperatively, and mortality within two years. Logistic regression was used to evaluate the primary and antibiotic-related outcomes, while mortality was analysed using a Cox proportional hazards model. After excluding patients with pre-existing infections or contamination at the index surgery, 40,547 procedures were included in the final analysis. Of these, 19,869 were in the intervention group and 20,678 in the control group. The PSIM rate was 9.2% in the intervention group and 9.4% in the control group, yielding an OR of 0.98 (95% CI, 0.91-1.05) for the intervention. This finding was consistent across various subgroups defined by diagnosis, hospital, and ventilation type. Likewise, no association was observed between air purification status and the secondary outcomes. We concluded that in modern OTs equipped with standard, midrange airflow ventilation systems, the addition of wall-mounted plasma air purifiers did not reduce the PSIM rate after orthopaedic surgery. Furthermore, no impact was observed on antibiotic use or mortality.List of scientific papersI. Persson A, Sköldenberg O, Mohaddes M, Eisler T, Gordon M. Increased mortality after total hip prosthetic joint infection is mainly caused by the comorbidities rather than the infection itself. Acta Orthopaedica 2023 Sep 26:94:484-489. https://doi.org/10.2340/17453674.2023.18619II. Persson A, Sköldenberg O, Gordon M. The correlation between bacterial load in the operating theatre and surgical site infections following orthopaedic surgery: a register-based cohort study [Manuscript]III. Persson A, Atroshi I, Tyszkiewicz T, Hailer NP, Lazarinis S, Eisler T, Brismar H, Mukka S, Kernell P-J, Mohaddes M, Sköldenberg O, Gordon M. Effect of Plasma Air Purifiers on Infection Rates in Orthopaedic Surgery. NEJM Evidence 2025 2025 Apr;4(4):EVIDoa2400289. Epub 2025 Mar 25. https://doi.org/10.1056/EVIDoa2400289</p
Tympanic membrane regeneration : clinical and experimental human studies
No full textThe keratinized squamous epithelium of the tympanic membrane (TM) possesses a great inborn capacity for cell migration and proliferation. This regenerative capacity is reflected in the fact that most tympanic membrane perforations (TMP) heal spontaneously within a few weeks. However, when early complete healing does not occur, the perforation may become chronic, leading to persistent discharge and hearing loss. The reasons why some TMPs fail to heal remain unclear. Therefore, a deeper understanding of the early stages of TM regeneration is essential for developing strategies to prevent chronic TMPs (cTMP).The overall aim of this thesis is to gain understanding of the healing process in the human TM and why some cTMPs do not heal.In Paper I we studied the presence and specific locations of epidermal progenitor cells in the keratinocyte layer in the healthy human TM. Ten healthy human TMs were stained with a panel of antibodies specific against epidermal stem cell (SC) and proliferation markers (Ki-67, CK19, p63, and the integrins a6 and B1). The results showed presence of progenitor cells along the whole keratinocyte layer in the TM and with a significantly higher presence close to the malleus and annulus region.In Paper II, by inducing a local trauma to the TM in vivo, we explored the early regenerative events in the human TM by mapping the presence and changes of epidermal progenitor cells. Twenty hours after traumatization there was significant upregulation of CK19 and a6 integrin in the unattached pars tensa (UPT) close to the trauma and with comparable levels of those in the previously shown regenerative regions in Paper I. The proliferation marker Ki-67 was stronger seen in the UPT far away from the location of the traumatization. CK19, Ki-67, and p63 were still strongly seen close to the malleus and annulus confirming the regenerative regions seen in Paper I. This first study of the acute healing response in the keratinocyte layer of human TMs following in vivo traumatization provide important insights through the use of an experimental model.In Paper III we evaluated the investigational medicinal product Plasminogen (human) 10 in patients with cTMP in a phase 1 clinical study, aiming to set a base for a new cost-effective and safe treatment method for cTMPs. By subcutaneous injections of plasminogen (PLG) close to the TM in patients with cTMP, the safety, feasibility and effect of the drug was measured. The results showed no serious adverse events (AE). The AEs reported were overall mild and of transient character. Patients could tolerate the treatment of three PLG injection days in one week. No differences were seen in the active treatment group compared to placebo regarding healing outcome. The results suggest future trials on PLG, including dose escalating studies.In Paper IV risk factors for an unhealed TMP after surgical intervention with myringoplasty was identified. Swedish quality register data was analyzed for the years 2014-2019, including all patients undergoing a myringoplasty with a registered follow-up visit. The results indicated that age of the patient, surgical aim, history of prior ear surgery, and postoperative infection constituted risk factors for unsuccessful healing following myringoplasty. Interestingly, cases that required simultaneous ossiculoplasty showed a higher rate of successful healing. The study presents one of the largest cohorts on myringoplasty outcome and adds new insights on why cTMPs do not heal despite facilitating healing support.In conclusion, this thesis contributes to an enhanced understanding of the natural regenerative processes of the TM and determines that there are putative SCs in the human TM. Further, the methodologies and findings presented herein provide a foundation for future research to improve treatment and management of cTMPs.List of scientific papersI. Sepehri E, Engmér Berglin C, Liu Y, Eriksson PO, von Unge M, Arebro J. Mapping the Regenerative Pattern in the Human Tympanic Membrane. Audiology and Neurotology. 2025 Aug 16:1-24. doi: 10.1159/000547944.https://doi.org/10.1159/000547944II. Sepehri E, Engmér Berglin C, Liu Y, Eriksson PO, von Unge M, Arebro J. The Early Regenerative Events in the Human Tympanic Membrane after In Vivo Traumatization. [Submitted]III. Sepehri E, Tideholm B, Hellström S, Engmér Berglin C. Plasminogen - Safe for Treatment of Chronic Tympanic Membrane Perforation: a Phase 1 Randomized, Placebo-Controlled Study. Acta Otolaryngol. 2024 Jul-Aug;144(7-8):439-445. https://doi.org/10.1080/00016489.2024.2396488IV. Sepehri E, Arebro J, Westman E, Eriksson PO. Unsuccessful Healing of Tympanic Membrane Perforations Following Myringoplasty - a Nationwide Study. [Submitted]</p