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Heterogeneity in platelet differentiation pathways
No full textHematopoietic stem cells replenish billions of mature blood cells every day through a series of increasingly lineage-restricted progenitor cells and are therefore vital for immune response, oxygen transport and hemostasis. Upon acute depletion of the hematopoietic system, such as after cytotoxic treatment for blood cancer, one of the most troublesome complications is bleeding due to thrombocytopenia.Through mouse models, our lab has characterized a novel and direct pathway of platelet generation, initiated by a hitherto unrecognized subset of HSCs, that are activated in response to cytotoxic stress. Study I investigates the emergence of lineage restriction and bias in perinatal HSCs. Study II describes the non- hierarchical relationship of two distinct types of HSCs, von Willebrand factor positive platelet-restricted and -biased HSCs (P-HSCs) and von Willebrand factor negative multilineage HSCs (M-HSCs). The transcriptional expression of FMS-like tyrosine kinase (Flt-3) was found to be a marker that distinguishes the differentiation pathways of P-HSCs and M-HSCs. This finding was validated by fate mapping using a Flt3-Cre/Rosa26-tdTomato mouse model. Furthermore, we performed molecular characterization of the megakaryocyte progenitors, the unilineage progenitors responsible for platelet generation, finding distinct molecular profiles depending on the type of HSC that generated them. We therefore speculate that the different pathways can in part explain platelet heterogeneity, an issue that has gained interest due to expansion of prothrombotic subsets upon aging. To this end, Study III describes a protocol for RNA-seq of sorted platelet populations allowing for molecular studies of platelet heterogeneity within the same individual.Taken together, these studies show that a mature cell can be generated through more than one differentiation pathway, suggesting a revision of the established hematopoietic hierarchy that currently posits only one unique sequence of differentiation steps for each mature cell type.List of scientific papersI. Platelet and myeloid lineage biases of transplanted single perinatal mouse hematopoietic stem cells. (Cell Research. 2023, 33, 883-886). Karin Belander Strålin*, Joana Carrelha*, Axel Winroth, Christoph Ziegenhain, Michael Hagemann-Jensen, Laura M. Kettyle, Amy Hillen, Kari Högstrand, Ellen Markljung, Francesca Grasso, Masafumi Seki, Stefania Mazzi, Yiran Meng, Bishan Wu, Edwin Chari, Madeleine Lehander, Rickard Sandberg, Petter S. Woll, Sten Eirik W. Jacobsen. https://doi.org/10.1038/s41422-023-00866-4II. Alternative platelet differentiation pathways initiated by non-hierarchically related hematopoietic stem cells. (Nature Immunology. 2024, 25, 1007-1019). Joana Carrelha*, Stefania Mazzi*, Axel Winroth*, Michael Hagemann-Jensen, Christoph Ziegenhain, Kari Högstrand, Masafumi Seki, Margs S. Brennan, Madeleine Lehander, Bishan Wu, Yiran Meng, Ellen Markljung, Ruggiero Norfo, Hisahi Ishida, Karin Belander Strålin, Francesca Grasso, Christina Simoglu Karali, Affaf Aliouat, Amy Hillen, Edwin Chari, Kimberly SiIletti, Supat Thongjuea, Adam J. Mead, Sten Linnarsson, Claus Nerlov, Rickard Sandberg, Tetsuichi Yoshizato, Petter S. Woll, Sten Eirik W. Jacobsen. https://doi.org/10.1038/s41590-024-01845-6III. The platelet transcriptome is stable across age and is minimally responsive to spontaneous CD62 externalization. Masafumi Seki*, Axel Winroth*, Margs Brennan, Kari Högstrand, Tetsuichi Yoshizato, Michael Hagemann-Jensen, Christoph Ziegenhain, Amie Waller, Holly Foster, John W. Semple, Cedric Ghevaert, Sten Eirik W. Jacobsen^, Petter S. Woll^. [Manuscript](*Equal contribution, ^Shared senior authorship)</p
Prognostic Implications Of High-Sensitivity Cardiac Troponins In Patients With Acute Kidney Injury Without Myocardial Infarction
No full textNo description supplied</p
A task-invariant prior explains trial-by-trial active avoidance behaviour across gain and loss tasks
No full textFailing to make decisions that would actively avoid negative outcomes is central to helplessness. In a Bayesian framework, deciding whether to act is informed by beliefs about the world that can be characterised as priors. However, these priors have not been previously quantified. Here we administered two tasks in which 279 participants decided whether to attempt active avoidance actions. In both tasks, participants decided between a passive option that would for sure result in a negative outcome of varying size, and a costly active option that allowed them a probability of avoiding the negative outcome. The tasks differed in framing and valence, allowing us to test whether the prior generating biases in behaviour is problem-specific or task-independent and general. We performed extensive comparisons of models offering different structural explanations of the data, finding that a Bayesian model with a task-invariant prior for active avoidance provided the best fit to participants’ trial-by-trial behaviour. The parameters of this prior were reliable, and participants’ self-rated positive affect was weakly correlated with this prior such that participants with an optimistic prior reported higher levels of positive affect. These results show that individual differences in prior beliefs can explain decisions to engage in active avoidance of negative outcomes, providing evidence for a Bayesian conceptualization of helplessness.</p
Developments of stereotactic body radiotherapy in the metastatic setting and for central lung tumors
No full textStereotactic body radiotherapy (SBRT) is a cornerstone of modern radiotherapy. As a non- invasive, high-dose radiotherapy treatment that provides high local tumor control and mild side effects, SBRT is a successfully used antitumoral local treatment with increasing application in primary and metastatic cancer.With the rapid development of SBRT, the treatment of central lung tumors has shown to be an area of its limitation, where lack of knowledge about dose tolerance to central organs at risk (OARs) when using high-dose radiotherapy has resulted in fatal toxic events. How to integrate SBRT as local treatment alone and in combination with systemic therapy in metastatic disease needs to be better characterized to deliver a personalized and beneficial antitumoral treatment.Project I is a retrospective pooled multicentre analysis of patients from the Nordic countries, including patients treated in the prospective phase II HILUS trial (1) and in a retrospective expansion cohort. In total, 230 patients were treated with SBRT in 8 fractions (56 Gy) for a lung tumor (primary lung cancer or metastasis) located within 2 cm from the tracheobronchial tree (i.e the trachea, the mainstem bronchi, the intermediate bronchus and the lobar bronchi). Fatal toxicity developed in 30 patients, of which 20 events presented as bronchopulmonary bleedings after a median time of 15 (11-22) months after SBRT. We identified tumor compression of the tracheobronchial tree and maximum dose to the mainstem and the intermediate bronchus as significant risk factors for fatal toxicity and bronchopulmonary bleedings.Project II is a retrospective subanalysis of project I, evaluating the clinical benefit of curative SBRT for 72 patients with inoperable central early-stage non-small cell lung cancer (ES NSCLC), T1-T3N0M0. Relapse was seen in 17 patients and distant recurrence was the most common form of relapse. We observed limited progression-free survival (31% at 3-year) and short survival (38% at 3 years), largely explained by comorbidities and a high incidence of fatal toxicity (17%). Despite excellent local tumor control (97% at 3- year) and favorable lung cancer-specific survival (76% at 3-year), the toxic profile of SBRT in the investigated approach outweighed the clinical benefit for the patients.Project III is a retrospective study of 70 patients treated with 1st line tyrosine kinase inhibitors (TKIs) (1st-2nd generation) for a metastatic EGFR-mutated NSCLC at Karolinska University Hospital between 2010-2017. The project was done in collaboration between the radiology and radiotherapy departments. By analyzing the radiological tumor response to TKIs, we could identify 25 patients with oligometastatic disease (OMD), defined as maximum 5 metastases +/- primary tumor, after a median of 4 (1-10) months with TKIs. Patients with primary disseminated metastatic disease who develop OMD in response to TKIs (induced persistent OMD (pOMD)) had the greatest benefits in terms of progression-free survival (median 16 months) and overall survival (median 30 months). Retrospectively, 90% of the patients with induced pOMD were considered eligible for consolidation radiotherapy. We found the "oligometastatic window" for induced pOMD limited to less than 1 year, which provide guidance on the optimal timing for consolidation SBRT in prospective studies.Project IV is a retrospective analysis including 85 patients treated with SBRT for a colorectal cancer metastasis at Karolinska University Hospital between 2008-2016. The benefit, time-to-relapse (TTR), after SBRT was identified by applying clinical variables prior SBRT significant for TTR (age, performance status, number of colorectal primaries, carcinoembryonic antigen (CEA) value, number of active metastases in the body prior SBRT) in the CLInical Categorical Algorithm (CLICALº). CLICALO categorized 4 subgroups (signature I-IV) of patients with different benefits (TTR) after SBRT. The greatest benefit of SBRT was seen for patients in signature III-IV who received high-dose SBRT to all metastases (curative intent) or to lung metastases only. Patients in signature I-II had a short TTR, why SBRT for these patients was judged non-beneficial. The study results are valuable for decision-making about who should be treated with SBRT for metastases from colorectal cancer.List of scientific papersI. Lindberg S et al. Expanded HILUS Trial: A Pooled Analysis of Risk Factors for Toxicity from Stereotactic Body Radiation Therapy of Central and Ultra central Lung Tumors. International Journal of Radiation Oncology Biology Physics. July 2023. https://doi.org/10.1016/j.ijrobp.2023.06.246II. Lindberg S et al. Stereotactic body radiation therapy (SBRT) of centrally located medically inoperable early-stage non-small cell lung cancer (T1- T3N0M0), - A subgroup analysis of the expanded HILUS study. Lung cancer. March 2025. https://doi.org/10.1016/j.lungcan.2025.108527III. Lindberg S et al. Analysis of tumor response to Tyrosine Kinase Inhibitors (TKIs) in advanced stage non-small cell lung cancer (NSCLC) with mutation in epidermal growth factor receptor (EGFR) - identifying candidates for consolidation with stereotactic body radiotherapy (SBRT). [Manuscript]IV. Lindberg S et al. Predicting the benefit of stereotactic body radiotherapy of colorectal metastases. Clinical Translational Radiation Oncology. Sep 2022. https://doi.org/10.1016/j.ctro.2022.07.006</p
Predictive modeling of psychiatric symptom outcomes in psychological treatment : a methodological evaluation
No full textPredicting treatment outcome at an early stage of psychological treatment can benefit patients by informing clinicians and allowing them to make adaptations. Yet, the predictive performance of these models is unclear despite a renewed interest during the last decade. The methodological issues regarding the development of predictive models for clinical use remain pervasive, making it hard to draw conclusions about their useability or performance for treatment outcomes after psychological treatment.The aim of this thesis was to assess and increase performance of predictive models for symptom outcome after psychological treatment, using data from internet-delivered cognitive behavioral therapy in routine psychiatric care. This was done by exploring different: methodologies of validation, predictors, and predictive models.In Study I, we investigated a multitude of ways to develop predictive models. Predictive performance: increased linearly up to the final prediction timepoint of day 28, was maximised by pooling all treatment conditions, was increased by imputing data, was best with symptom variable predictors, and showed minimal differences across models. The linear regression with the benchmark set of predictors had a balanced accuracy of 77.8% and an R2 of 0.538. This study had a high risk of overfitting due to the imputation and validation procedure.In Study II, we investigated if predictive models which account for the time- dependency in symptom-ratings are superior to methods that do not. There was no differential effect depending on model type. The predictive performance for the last timepoint, which was treatment outcome, had a RMSE across models of 0.121, and a balanced accuracy of 73.46%, with a low risk of overfitting due to nested cross-validation and multiple imputation.In Study III, we investigated whether the use of natural language processing methods for the patient-therapist text interactions could improve predictions, compared to a simple symptom model. For each tested text-model, an additional was trained which modified the model to also incorporate the symptom variables. Linear regression using only symptom variables had the best predictive performance for both an RMSE of 0.14, and a balanced accuracy of 70%. Due to large variation across imputation datasets, for the RMSE metric, only the text model BERT, with an RMSE of 0.17, was significantly better than the dummy regression with 0.18. Adding symptom variables to the text models only significantly improved the BERT model from 60% to 68% balanced accuracy, and only for this metric.In Study IV, we investigated whether a psychometric improvement of symptom variables using Rasch measurement theory affected predictive performance, given the strong influence of the quality of a measurement for predictive models. A dataset for each datatype was created, 'Base' using the original scales, and 'Rasch' with the psychometrically improved version. For linear regression the Base dataset had an RMSE of 0.132, and Rasch had an RMSE of 0.139. It is inconclusive if Rasch improved precision and reduced overfitting, or if the Base dataset retained useful variability.There are several important methodological challenges for valid predictive models for treatment outcome after psychological treatment, including a lack of evidence for their clinical utility and generalizability. While models can predict with a potentially useful performance, the more important question is what they are predicting and if this performance results in a clinically favorable outcome. Once psychology is rooted in stronger foundations, the potential benefits of predictive modeling will be much easier to realise.List of scientific papersI. Hentati Isacsson, N., Ben Abdesslem, F., Forsell, E., Boman, M., & Kaldo, V. (2024). Methodological choices and clinical usefulness for machine learning predictions of outcome in Internet-based cognitive behavioural therapy. Communications Medicine. 4(1), 196. https://doi.org/10.1038/s43856-024-00626-4II. Hentati Isacsson, N., Zantvoort, K., Forsell, E., Boman, M., & Kaldo, V. (2024). Making the most out of timeseries symptom data: A machine learning study on symptom predictions of internet-based CBT. Internet Interventions. 38, 100773. https://doi.org/10.1016/j.invent.2024.100773III. Hentati Isacsson, N., Gómez-Zaragozá, L., Ben Abdesslem, F., Boman, M., & Kaldo, V. (2025). Natural Language Processing Models for Predicting Treatment Outcomes in Internet-Based Cognitive Behavioural Therapy. [Manuscript]IV. Hentati Isacsson, N., Johansson, M., & Kaldo, V. (2025). Latent Trait or Sum Score: Addressing Measurement Challenges in the Prediction of Self-Rated Symptom Outcomes in Psychological Treatment. [Manuscript]</p
Recurrent respiratory tract infections in young children : the use of pediatric Tuina in southern China
No full textBackground: Young children are particularly vulnerable to recurrent respiratory tract infections (RRTIs), which are associated with significant morbidity and mortality. When children experience RRTIs, caregivers face the dual challenge of preventing new episodes while maintaining a close relationship with their child. In China, medical pluralism is widely practiced, with caregivers often seeking treatment from both biomedicine and Chinese medicine. One commonly used Chinese medicine practice is pediatric Tuina (PT), a gentle massage technique performed by trained providers, which has long been used as a preventive approach against respiratory infections. When seeking healthcare for children with RRTIs, caregivers have their specific concerns and preferences. However, little is known about the use of PT in children's RRTIs from the clinical, caregiver, and practitioner perspectives.Aims: To enhance understanding of the use of PT in young children with RRTIs in Southern China.Methods: Both quantitative and qualitative approaches were employed. Study I involved a cohort of 2303 children with RRTIs. Data were extracted from electronic medical records. Children were divided into either the PT group or the non-PT group, based on whether they had received PT in 2016. The primary outcome was the number of respiratory tract infection episodes in 2017 and 2018. Descriptive statistics and negative binomial regression analyses were used to examine the associations between PT and the outcomes. The data for Study II and III were collected simultaneously through semi-structured qualitative interviews. The participants were caregivers (n=16) whose children with RRTIs had participated in a one-month-long PT trial. Reflexive thematic analysis was used to analyze the data. The analysis of the data was informed by embodiment theory in Study I and the concept of child-centered care in Study II. Study IV explored PT practice in the treatment of children with RRTIs through semi-structured interviews with thirteen PT practitioners. Reflexive thematic analysis was used, informed by the concept of child-centered care.Results: Children who underwent PT at least six times in 2016 experienced fewer episodes of acute respiratory tract infections (ARTIs) in 2017 (IRR: 0.59, 95% CI: 0.42-0.84) and 2018 (IRR: 0.58, 95% CI: 0.36-0.94) compared to those who did not receive PT. They also had fewer outpatient visits for ARTIs in 2017 (IRR: 0.56, 95% CI: 0.38-0.83). However, there was no significant difference between the two groups in terms of the number of outpatient antibiotic prescriptions (Study I). Caregivers evaluated PT by listening to others' experiences and closely observing both the techniques applied to their children's body and their children's physical responses during sessions. They also attentively monitored bodily changes in the children after the treatment. Through PT, an embodied attachment between children and both caregivers and practitioners was fostered. Compared to other treatments or medical consultations, children appeared more relaxed and actively engaged in this form of embodied care, which involved direct skin contact and verbal interaction with the Tuina provider. Additionally, children integrated PT into family life by requesting caregivers to perform it on them and imitating the techniques on their caregivers' hands (Study II). Caregivers seek PT as part of a proactive, child-centered approach to selecting appropriate care for their sick children. When symptoms are mild, they prefer self-learning and home remedies to avoid hospital visits. Caregivers favor healthcare providers who offer personalized treatment plans and display a positive attitude. Given the recurrent and prolonged nature of RRTIs and access to various healthcare options, they often adopt a combined approach-using biomedicine for symptom relief and Chinese medicine to address underlying causes. Additionally, they are cautious about long-term medication use, particularly antibiotics, and may discontinue prescribed treatments based on their own assessment (Study III). PT Practitioners assessed each child's condition to determine whether PT was appropriate, ensuring it would not delay essential biomedical care. If PT was deemed suitable, they carefully chose acupoints and techniques that were tailored to the child's individual needs. During the treatment, practitioners engaged in discussions with caregivers to gain a deeper understanding of the root causes of the child's RRTIs. They also communicated directly with the children to encourage their cooperation both before and during the session. Additionally, practitioners built a relationship with the children by staying fully present and attentive throughout the treatment process (Study IV).Conclusions:Findings from this thesis indicate that PT is more than just a clinical intervention for children's RRTIs in Southern China. It also plays a vital role in supporting children's overall wellbeing and fostering their relationship with the adults who provide PT, whether they are caregivers or practitioners. Children who receive six or more sessions of PT within a year may have fewer infections in the following two years. Additionally, PT could provide support in the home for caregivers of children with RRTIs, as it may enhance embodied care. Caregivers' motivation in seeking PT highlights the broader interest in child-centered care for children with RRTIs. It is therefore crucial for healthcare providers to foster good communication, tailor the treatment, and respect cultural beliefs. In PT practitioners' practice, child-centered care is exemplified by focusing on children's medical needs while fostering a good relationship with them. Approaches observed within a context of medical pluralism offer valuable insights into the core principles of child-centered care, enhancing our understanding of its fundamental elements.List of scientific papersI. Yin L, Stålsby Lundborg C, Wu D, Yang J, Alvesson HM, Cai J, Lu T, Qian X, Marrone G. Effect of pediatric Tuina on children's recurrent acute respiratory tract infections: a retrospective cohort study in Southern China. Journal of Traditional Chinese Medicine, 2024, 44(3), 586. https://doi.org/http://doi.org/10.19852/j.cnki.jtcm.2024.03.003Il. Yin L, Chang B, Stålsby Lundborg C, Wu D, Alvesson HM. "She mimicked the manipulations on my hand": fostering embodied care among children with recurrent acute respiratory tract infections in Southern China. BMC Complementary Medicine and Therapies, 2024, 24(1): 359. https://doi.org/http://doi.org/10.1186/s12906-024-04660-6III. Yin L, Chang B, Wu D, Stålsby Lundborg C, Alvesson HM. A child-centered approach: Caregivers' motivations for seeking pediatric Tuina for children's recurrent respiratory tract infections in Southern China. [Manuscript]IV. Yin L, Liu Y, Liao X, Wu D, Stålsby Lundborg C, Alvesson HM. "Children's comfort matters": Pediatric Tuina practitioners' experiences of treating children with recurrent respiratory tract infections in Southern China. [Manuscript]</p
NORCAAD : the nordic consortium for acute type A aortic dissection
No full textBackgroundATAAD is a lethal condition, and emergency surgery is warranted for almost all patients. Despite advances in surgical techniques, as well as medical and anesthetic management, surgery for ATAAD continues to carry a high risk of major complications and early mortality. The optimal approaches to organizational, surgical, and medical management of ATAAD remain subjects of ongoing debate. The overall aim of this work was to investigate differences in management of ATAAD, as well as factors associated with short- and long-term adverse outcomes, with the goal of improving clinical decision-making and optimizing the management of ATAAD.Methods and resultsStudy I - Type A aortic dissection repair in patients with prior cardiac surgery. All patients who underwent surgery for ATAAD between 2005 and 2014 identified from the NORCAAD database were included in the study. Patients who had undergone PCS (n=40) were compared with those who had not undergone PCS (n=1119). The primary outcome measure was 30-day mortality, and the secondary outcome measure was a composite outcome of early major complications: 30-day mortality, perioperative stroke, postoperative cardiac arrest, or de novo dialysis. Patients with PCS had higher 30-day mortality (30% vs 17.8%, p=0.049) and a higher prevalence of major complications (52.5% vs 35.7%, p=0.030). However, PCS was not an independent predictor for 30-day mortality (OR 0.78; 95% CI 0.30-2.07, p=0.624) or major complications (OR 1.07, 95% CI 0.45-2.55, p=0.879).Study II - Improving outcomes of surgery for acute type A aortic dissection. All patients (n=204) who underwent surgery for ATAAD between 2015 and 2020 at Karolinska University Hospital were included. Patients were divided into two groups: recent (n=102) and earlier (n=102). Uni- and multivariable statistical analysis were performed to identify predictors of early mortality. A significantly lower 30-day mortality was observed in the recent group (recent: 3.9% vs earlier: 14.6%, p=0.014). There was no statistically significant difference in early mortality between high- and low-volume surgeons. Biological composite graft, concomitant coronary artery bypass grafting (CABG), intraoperative adverse event, preoperative lactate, non-normal left ventricular ejection fraction (LVEF) and dissection of any arch vessel were identified as independent predictors of 30-day mortality.Study III - Late aortic reinterventions after surgery for acute type A aortic dissection. All patients (n=225) who underwent surgery for ATAAD at least a decade earlier (2005-2013) at Karolinska University Hospital were included. Information regarding the indication for and type of reintervention(s) were obtained from local databases and medical records. Measurements of aortic diameters were obtained from serial computed tomography (CT) scans. A Fine- Gray multivariable model, treating death and contraindication to reintervention as competing risks, was used to investigate factors associated with reintervention. The median follow-up was 10.3 years (5.0-13.4). A total of 37 patients underwent at least one aortic reintervention. Aortic root diameter >45 mm and no root replacement at index repair, bicuspid aortic valve (BAV), and age were associated with proximal reintervention. Failure to completely resect the primary tear and connective tissue disease (CTD) were associated with distal aortic reintervention. Event-free survival at 1, 5, 10 and 15 years was 82% (77-87), 72% (65-77), 48% (41-54) and 33% (26-40), respectively.Study IV - Management of acute type A aortic dissection in the Nordic countries. A questionnaire with 32 questions regarding strategies for pre-, peri- and postoperative management of ATAAD was sent to participating centers in NORCAAD2. Of the 17 centers that received the questionnaire, 12 centers (71%) responded. Regarding the primary site of arterial cannulation, seven centers (58%) used femoral artery cannulation. Nine centers (75%) used cerebral perfusion in most cases requiring hypothermic circulatory arrest (HCA). Five centers (42%) reported that total arch replacements and valve-sparing root replacements were never performed. The number of annual ATAAD cases ranged from 5-50, and the number of surgeons performing ATAAD repairs ranged from 3 to 8. Regarding postoperative surveillance, 42% of centers had unlimited follow-up time, 25% followed patients for 10 years and 33% followed patients for 5 years. All centers reported that they used a CT scan interval of 6-12 months.ConclusionsPatients with PCS had a higher prevalence of major complications. However, PCS itself was not independently associated with adverse events. Previous cardiac surgery should not deter emergency surgery.Early outcomes after surgery for ATAAD improved in the most recent era. Possibly, having fewer surgeons performing more procedures, adopting a relatively conservative surgical approach, and ensuring adequate cerebral protection may have contributed to the improvement.With sufficient follow-up, event-free survival following ATAAD repair appears to be substantially compromised. Potentially, aortic root replacement in patients with moderate aortic root dilatation and ensuring complete resection of the primary tear may reduce the need for future aortic reinterventions.NORCAAD2 comprises low-, medium- and high-volume centers, each employing different strategies for cannulation, cerebral protection, extent of aortic resection, surgical techniques, and postoperative surveillance. These variations make NORCAAD2 an excellent opportunity to study these contested topics in a large patient population.List of scientific papersI. Bjurbom M, Olsson C, Geirsson A, Gudbjartsson T, Gunn J, Hansson E, Hjortdal V, Jeppsson A, Mennander A, Ede J, Zindovic I, Ahlsson A, Wickbom A, Dalén M. Type A aortic dissection repair in patients with prior cardiac surgery. Ann Thorac Surg 2023;115:591-9.https://doi.org/10.1016/j.athoracsur.2022.05.033II. Bjurbom M, Dalén M, Franco-Cereceda A, Olsson C. Improving outcomes of surgery for acute type A aortic dissection. Scand Cardiovasc J 2023 Dec;57(1):2210275https://doi.org/10.1080/14017431.2023.2210275III. Bjurbom M, Ma K, Dalen M, Franco-Cereceda A, Olsson C. Late aortic reinterventions after surgery for acute type A aortic dissection. Ann Thorac Surg [Submitted]IV. Bjurbom M, Franco-Cereceda A, Olsson C. Management of acute type A aortic dissection in the Nordic countries. Scand Cardiovasc J [Submitted]</p
Molecular and cellular landscape of endometriosis
No full textEndometriosis is a prevalent benign gynecological disease in women of reproductive age. It is estimated to affect globally around 190 million people, or approximately every tenth woman. Symptomatically endometriosis usually manifests with chronic pelvic pain, impaired fertility and reduced quality of life. These nonspecific symptoms or asymptomatic course of disease make it difficult for women to suspect the presence of disease. Thereby, the diagnosis is often delayed on average for seven to nine years. In many cases, endometriosis is identified during medical examination and surgical intervention due to other pathology, or investigation of possible reasons for infertility. However, even after confirmation of endometriosis diagnosis women cannot be fully cured and their treatment is limited to the management of symptoms or surgical removal of endometriotic lesions (ectopic endometrium, EcE).Endometriotic lesions are presented as extrauterine ectopic growth of endometrial-like tissues. They are mostly found in the peritoneum but can also form ovarian endometrioid cysts or spread locally or distally to other organs and tissues, affecting their function. The origin of this multifaceted disease remains unclear, and the theory of retrograde menstruation is the most widely accepted. According to this theory, fragments of shed endometrial tissues spread outside the uterus and implant on surrounding tissues and organs, adapting to the unfavorable microenvironment. Endometriotic lesions exhibit a molecular signature distinct from eutopic endometrium (EuE), which allows their survival and growth in ectopic sites. Research on the pathogenesis of endometriosis unraveled a key role of hormone imbalance and hypoxia on the regulation of processes, like cell proliferation, migration, metabolism and angiogenesis.With the development of advanced powerful techniques, such as high-throughput transcriptomics, proteomics and metabolomics, we can perform a comprehensive analysis of tissues. Moreover, the identified molecular signatures can be linked to the single cell populations. By utilizing these techniques to study endometriosis pathogenesis, we can explore RNA, protein and metabolite profiles of single cell populations within endometriotic lesions. This knowledge will facilitate further understanding of disease pathobiology with potential applications in diagnostics and treatment of endometriosis.List of scientific papersI. Sarsenova, M.*, Lawarde, A.*, Pathare, A. D. S., Saare, M., Modhukur, V., Soplepmann, P., Terasmaa, A., Käämbre, T., Gemzell-Danielsson, K., Lalitkumar, P. G. L., Salumets, A., & Peters, M. (2024). Endometriotic lesions exhibit distinct metabolic signature compared to paired eutopic endometrium at the single-cell level. Communications Biology. 7(1), 1026. https://doi.org/10.1038/s42003-024-06713-5II. Sarsenova, M., Boggavarapu NR., Kask K., Modhukur V., Samuel K., Karro H., Gemzell-Danielsson K., Lalitkumar PGL., Salumets A., Peters M., Lavogina D. (2024). Hypoxic conditions affect transcriptome of endometrial stromal cells in endometriosis and promote TGFBI axis. Frontiers in Endocrinology. 15. https://doi.org/10.3389/fendo.2024.1465393III. Sarsenova, M., Stepanjuk, A., Saare, M., Kasvandik, S., Soplepmann, P., Mikeltadze, I., Götte, M., Salumets, A., & Peters, M. (2024). Carboxypeptidase Inhibitor LXN Expression in Endometrial Tissue Is Menstrual Cycle Phase-Dependent and Is Upregulated in Endometriotic Lesions. Genes. 15(8), 1086. https://doi.org/10.3390/genes15081086Journal articles are reprinted with permission from copyright holders. *Joint first authorship.</p
Multimodality imaging of chronic thromboembolic pulmonary hypertension : new insights into old challenges
No full textBACKGROUND:Most forms of pulmonary hypertension carry unsatisfactory prognosis with the notable exception of chronic thromboembolic pulmonary hypertension (CTEPH), a complication of acute pulmonary embolism (APE) where complete cure is possible with pulmonary endarterectomy (PEA). CTEPH is often underdiagnosed leading to delayed referral or missed diagnosis. Computed Tomography Pulmonary Angiography (CTPA) is commonly performed in patients with suspected CTEPH or dyspnoea of unknown cause; however, the frequency of misdiagnosis of CTEPH findings on CTPA is currently unknown. There is abundant CT literature describing arterial abnormalities of CTEPH but none regarding venous flow disturbances. Hypodense filling defects within the pulmonary veins (pulmonary vein sign: PVS) has been noted in APE but its presence and relevance in CTEPH is unascertained. CTPA used for CTEPH diagnosis contains information on cardiac chamber size that has potential for adverse outcome prediction but this is unproven. As normative values for atrial volumes on non-ECG gated CTPA is lacking, it is necessary to establish normal ranges prior to appreciating morphological differences in CTEPH. OBJECTIVES: Comprehend extent of CTEPH misdiagnosis on CT by radiologists, evaluate venous flow abnormalities in CTEPH with proximal and distal distribution with hemodynamic correlation, derive normal ranges for biatrial volumes on non-ECG gated CT and assess if cardiac chamber size on CTPA is useful for CTEPH risk estimation and outcome prediction. MATERIALS & METHODS: Study 1: Original CT reports 35 patients awaiting PEA scored for pulmonary vascular, cardiovascular and lung parenchymal abnormalities and compared to reading by two investigators with cardiothoracic subspeciality experience. Control group for expert reads included 35 CTPAs negative for thromboembolism. Study 2: Blinded CTPA analysis of 50 proximal CTEPH cases and 50 controls each in 3 groups— APE, nonthromboembolic cohort, and pulmonary arterial hypertension (PAH). Pulmonary venous flow reduction was assessed by the presence of filling defect of at least 2 cm in a pulmonary vein draining into left atrium. Study 3: Retrospective multi-institutional study of 93 CTEPH cases with CTPA and right heart catheterisation performed with in 3- month period. After excluding 17 suboptimal CTPAs, there were 52 proximal and 24 distal cases. Blood flow in the major pulmonary veins was graded. Subgroup analysis of PVS was performed in 38 proximal cases before and after PEA. Study 4: Of 3334 cases who had CTPA over a 12-month period, 304 also had transthoracic echocardiography (TTE) within a 6-month period. Of these 74 had normal diastology on TTE. After applying CT exclusion criteria (thromboembolic disease, LA attenuation Study 5: Out of 53 patients who had PEA between 2014-2019, 44 had paired CTPA and right heart catheterisation before and after surgery. After excluding 11 cases with suboptimal CTPA, semiautomated and manual CT biatrial and biventricular size quantifications were performed in 33 patients and correlated with hemodynamic parameters. RESULTS: Study 1: Expert readers correctly identified all 35 CTEPH cases. Amongst original reporters, the terminology “CTEPH” was used in 2 patients. Another 7 descriptive reports picked up combination of PH and few vascular signs of CTEPH without stating a definitive diagnosis. Taking these 9 reports as being consistent with radiologists diagnosing CTEPH, overall sensitivity for original reporters was 26%. Pulmonary arterial abnormalities were described in isolation in 63% with no mention of PH or CTEPH. Signs of PH and mosaic attenuation were documented in 53% and 6% respectively. Study 2: PVS was most prevalent in CTEPH. Compared with all controls, sensitivity and specificity of PVS for CTEPH was 78.0% and 85.3% (95% CI, 64.0–88.5 & 78.6–90.6) versus 34.0% and 70.7% in APE, 8.0% and 62% in nonthromboembolic and 2.0% and 60% in PAH. Occlusive arterial disease was most commonly associated with corresponding absent venous flow. Study 3: There was no significant difference in hemodynamic parameters (mPAP 46±11 and 41±12 mm Hg and PVR 9.4±4.5 and 8.4 ±4.8 WU) between the 2 groups but PVS was more frequent in proximal (79%) than distal (29%) CTEPH. PVS was present in 29/38 patients (76%) before surgery. Postoperatively, 33/38 cases (87%, PStudy 4: Normal ranges for indexed LA and RA volumes were 27 + 5 and 20 + 6 mL/m2, and 30 + 8 and 29 + 9 mL/m2 for TTE and CT respectively. Bland–Altman analysis revealed underestimation of biatrial volumes by TTE. CT intraclass correlation coefficients (ICC 95% CI) for LA and RA volumes were 0.99 (0.96– 1.00) and 0.96 (0.76–0.99), respectively with excellent correlation between semiautomated and manual measurements for left (r 0.99, 95% CI 0.98–0.99) and right atrium (r 0.99, 95% CI 0.99–1.00). Study 5: Indexed right atrioventricular volumes were twice that of left atrioventricular volumes pre-PEA with significant (p CONCLUSION: Radiologists frequently miss CTEPH findings giving falsely low sensitivity for CT. PVS is easy to detect with higher sensitivity and specificity in CTEPH compared with APE and is not a PAH characteristic. Asymmetric pulmonary venous enhancement is an additional parameter in CT assessment of CTEPH and can differentiate CTEPH from PAH. PVS is a common feature in proximal but infrequent in distal CTEPH. PVS does not correlate with hemodynamic severity. PVS resolution following PEA can be a measure of successful clearance. Cardiac chamber assessment on CTPA is easy and reproducible. A RV:LV ratio of ≥1.01 is a simple metric that can be used for CTEPH outcome prediction.LIST OF SCIENTIFIC PAPERSI. Rogberg AN, Gopalan D, Westerlund E, Lindholm P. Do radiologists detect chronic thromboembolic disease on computed tomography? Acta Radiol. 2019 Nov;60(11):1576-1583. PMID: 30897932.https://doi.org/10.1177/0284185119836232II. Gopalan D, Nordgren-Rogberg A, Le EPV, Pavey H, Tarkin J, Nyrén S, Auger W, Lindholm P. Abnormal Pulmonary Venous Filling: An Adjunct Feature in the Computed Tomography Pulmonary Angiogram Assessment of Chronic Thromboembolic Pulmonary Hypertension. J Am Heart Assoc. 2020 Nov 3;9(21):e018075. PMID: 33115320; PMCID: PMC7763423.https://doi.org/10.1161/JAHA.120.018075III. Gopalan D, Riley JYJ, Leong K, Guo HH, Zamanian RT, Hsi A, Auger W, Lindholm P. Pulmonary Vein Sign on Computed Tomography Pulmonary Angiography in Proximal and Distal Chronic Thromboembolic Pulmonary Hypertension With Hemodynamic Correlation. J Thorac Imaging. 2023 May 1;38(3):159-164. PMID: 36919975; PMCID: PMC10128904.https://doi.org/10.1097/RTI.0000000000000706IV. Gopalan D, Riley J, Leong K, Alsanjari S, Ariff B, Auger W, Lindholm P. Biatrial Volumetric Assessment by Non-ECG-Gated CT Pulmonary Angiography Correlated with Transthoracic Echocardiography in Patients with Normal Diastology. Tomography. 2022 Nov 17;8(6):2761-2771. PMID: 36412689; PMCID: PMC9680340.https://doi.org/10.3390/tomography8060230V. Gopalan D, Riley JYJ, Leong K, Alsanjari S, Auger W, Lindholm P. Computed Tomography Pulmonary Angiography Prediction of Adverse Long-Term Outcomes in Chronic Thromboembolic Pulmonary Hypertension: Correlation with Hemodynamic Measurements Pre- and Post-Pulmonary Endarterectomy. Tomography. 2023 Sep 26;9(5):1787-1798. PMID: 37888734; PMCID: PMC10611069.https://doi.org/10.3390/tomography9050142</p
A study of the immune response to malaria using systems-level analysis strategies
No full textPathogens causing febrile infections can engage with our immune system on several levels, leading to a broad range of disease spectra. Malaria, caused by infections with Plasmodium falciparum continues to impose a global burden, despite being one of the oldest febrile diseases plaguing humans. In malaria, the parasite-blood stage is linked to symptomatic disease due to the parasite invading erythrocytes, sequestration, and triggering inflammation and a systemic immune response. This thesis investigated the peripheral immune response to P. falciparum malaria and other febrile infections using systems-level approaches to understand the activation and interaction of different immune compartments in the host response. These approaches are beneficial in infection immunology as they offer a comprehensive view of interactions and networks of the immune system, providing insights into mechanisms affecting disease outcomes and generating new hypotheses.In Study I, we characterized the immune response of patients treated for acute malaria in Sweden after returning from travel. Using a systems-level approach, we first described the immune landscape during and after acute malaria and explored the impact of previous exposure. We revealed that previous malaria exposure was associated with a reduced expansion of yo T cells. We also showed that this reduction was strongly associated with reduced inflammatory cytokines and further associated with an increased breadth and levels of cytophilic antibodies and expansion of FcyRIII+ monocytes.In Study II, we investigated how clinical malaria perturbs the blood plasma proteome, the origins of these perturbations, and the potential functions of the circulating proteins, as well as how proteomic profiles can stratify patients into subgroups associated with disease severity. Using an unbiased, data-driven approach we revealed molecular patterns linked to disease severity, immune cell regulation, and tissue-specific origins. The proteomic profile-based patient stratification linked to disease severity offered novel insights into the systemic host response to malaria.In Study III, we followed up on findings from Study I by focusing on the impact of previous malaria exposure on monocytes during acute malaria. We discovered transcriptional changes in monocytes linked to the acute inflammatory response and immune-modulatory mechanisms affecting the B cell response during malaria.In Study IV, we utilized computational approaches to assess how plasma protein profiles were associated with the magnitude and longevity of the antibody response after acute malaria. We identified elevated levels of pro-inflammatory mediators associated with low antibody responses, suggesting that excessive inflammation may hinder effective B cell activation and long-lasting immunity. Conversely, high levels of soluble FcRL5 and other FcRL-family proteins were linked to robust and sustained antibody responses, indicating their potential as markers for effective B cell activation.In Study V, we investigated how a selection of host response proteins in plasma can be used to distinguish different pathogens causing febrile diseases in patients who had traveled to tropical regions. Our findings revealed that malaria exhibited the most distinct protein profiles in this comparison, corroborating other malaria- specific studies that highlight the significant role of certain disease-specific markers.Collectively, the studies in this thesis provide an increased understanding of the immune response to malaria and elucidate how various components of our defense system are coordinated to combat the infection, leading to improved disease outcomes.List of scientific papersI. Systems analysis shows a role of cytophilic antibodies in shaping innate tolerance to malaria Lautenbach MJ, Yman V, Silva CS, Kadri N, Broumou I, Chan S, Angenendt S, Sonden K, Plaza DF, Färnert A, Sundling C Cell Reports, Volume 39, Issue 3, 110709 (2022)https://doi.org/10.1016/j.celrep.2022.110709II. Integrated proteomics and single-cell transcriptomics reveal immune dynamics and severity markers in acute Plasmodium falciparum malaria Lautenbach MJ, Wyss K, Yman V, Foroogh F, Satarvandi D, Mousavian Z, Sonden K, Wang J, Bueno-Álevez M, Bergström S, Nilsson P, Edfors F, Brodin P, Uhlen M, Sundling C, Färnert A [Submitted]III. The immunomodulatory effect of previous malaria exposure on monocytes and dendritic cells in acute P. falciparum infection Lautenbach MJ, Kleberg L, Courey-Ghaouzi AD, Serene Gower M, Sousa Silva C, Edfors F, Uhlen M, Färnert A, Sundling C [Manuscript]IV. Elevated levels of Fc-receptor-like proteins during acute malaria are indicative of extensive B cell activation and long- lived antibody responses Lautenbach MJ, Kleberg L, Yman V, Tuju J, Edfors F, Osier FHA, Uhlén M, Färnert A, Sundling C [Manuscript]V. Disease-specific plasma protein profiles in patients with fever after traveling to tropical areas Sundling C, Yman V, Mousavian Z, Angenendt S, Foroogh F, von Horn E, Lautenbach MJ, Grunewald J, Färnert A, Sonden K European Journal of Immunology 54:2350784 (2024)https://doi.org/10.1002/eji.202350784</p