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Inter-organ communication and metabolic regulators of adipose tissue and skeletal muscle
No full textInter-organ communication is essential for maintaining homeostasis, enabling different organ systems to coordinate and adapt to physiological demands. Disruptions in these communication networks can lead to metabolic dysfunction and disease. This thesis investigates the role of inter-organ communication in regulating metabolic processes, with a focus on adipose tissue and skeletal muscle. Additionally, we examine how specific signaling molecules-particularly those of the kynurenine pathway of tryptophan degradation-interact with these tissues to influence metabolic health and disease. We explore how these organs communicate in response to stressors and how this communication becomes disrupted in disease.In Paper I, we investigate how changes in circulating kynurenine metabolites affect metabolism. We show that despite marked changes in circulating kynurenine metabolites, whole-body energy metabolism remains largely unaffected. Importantly, we highlight how the metabolic benefits of kynurenic acid depend on its intermittent increase in circulation, similar to transient exercise-induced signals that mediate improved metabolic health.In Paper II, we identify the gene Zfp697/ZNF697 as a novel regulator of muscle regeneration, uncovering its crucial role in skeletal muscle recovery following injury.In Paper III, we demonstrate that sensory neuron-derived alpha-calcitonin gene- related peptide (CGRPa) regulates key factors of adipose tissue, including adipogenesis, extracellular matrix remodeling, and adipocyte size distribution.Together, these studies enhance our understanding of how inter-organ communication influences health and disease, offering exciting therapeutic opportunities for improving metabolic health.List of scientific papersI. Constitutive loss of kynurenine-3-monooxygenase changes circulating kynurenine metabolites without affecting systemic energy metabolismKyle D. Dumont, Paulo R. Jannig, Margareta Porsmyr-Palmertz, Jorge L. Ruas. Am J Physiol Endocrinol Metab. 2025 Feb 1;328(2):E274-E285. doi: 10.1152/ajpendo.00386.2024. Epub 2025 Jan 13. PMID: 39805032.https://doi.org/10.1152/ajpendo.00386.2024II. Zfp697 is an RNA-binding protein that regulates skeletal muscle inflammation and remodelingJorge C. Correia, Paulo R. Jannig, Maya L. Gosztyla, Igor Cervenka, Serge Ducommun, Stine M. Præstholm, José M. Dias, Kyle D. Dumont, Zhengye Liu, Qishan Liang, Daniel Edsgärd, Olof Emanuelsson, Paul Gregorevic, Håkan Westerblad, Tomas Venckunas, Marius Brazaitis, Sigitas Kamandulis, Johanna T. Lanner, Ana I. Teixeira, Gene W. Yeo, Jorge L. Ruas. Proc. Natl. Acad. Sci. U.S.A. 2024 Aug 20;121(34):e2319724121.https://doi.org/10.1073/pnas.2319724121III. Sensory neuron-derived a-calcitonin gene-related peptide controls adipogenesis Kyle D. Dumont, Saba Heydari Seradj, Yu Wang, Igor Cervenka, Paulo R. Jannig, Margareta Porsmyr-Palmertz, Carina Nihlen, José M. Dias, Simona S. Skiotyte, Shanshan Liu, Jon O Lundberg, Ana I. Teixeira, Jun Wu, Li Ye, Jorge L. Ruas. [Submitted]</p
Extracellular vesicles for immunotherapy and tumor profiling
No full textExtracellular vesicles are particles secreted by cells and mediators of intercellular communication, carrying a diverse cargo of lipids, nucleic acids, proteins and metabolites. The specific cargo and function of EVs depends on the cell of origin. EVs from dendritic cells (DC) loaded with tumor antigens induced anti-tumor CD8+ T cell responses and reduced tumor growth in mice. Studies have reported that EVs from human and cow's milk have anti-inflammatory effects and promote barrier functions. EVs from cancer cells can be detected in biofluids and may be useful tools for cancer diagnosis, prognosis and disease monitoring.Adequate T cell priming and infiltration into the tumor improve the efficacy of PD- 1- and PD-L1-targeted immune checkpoint blockade ICB). Therefore, T cell responses generated by antigen-loaded (Ag-loaded) DC EVs have the potential to enhance the response to PD-1 and PD-L1 blockade. In addition, T cell responses to Ag-loaded EVs are dependent on B cells. In study I, we investigated a combination of Ag-loaded DC EVs with ICB of PD-1 or PD-L1. Therapeutically administered EVs did not improve the response to ICB in mice, but prophylactic administration of EVs strongly increased the survival of mice receiving therapeutic PD-L1 blockade. In study II, we used a fusion protein to target EVs specifically to B cells through human CD21. This targeting increased the Ag-specific CD8+ T cell expansion, which can indicate an increased anti-tumor potential.In study II, we explored the use of bovine milk-derived EVs for antigen delivery and Ag-specific immunomodulation. EVs from bovine serum were studied in comparison. We achieved loading of the model antigen ovalbumin (OVA) into EVs, and these EVs increased OVA-specific CD4+ T cell proliferation compared to free OVA in vitro and in vivo. In vitro, OVA-loaded serum EVs induced a different phenotype of activated CD4+ T cells compared to OVA-loaded milk EVs or free OVA.In study IV, we analyzed the protein content of urinary EVs from urinary bladder cancer (UBC) patients and non-UBC controls using proximity extension assay. We identified a UBC-specific signature and were able to distinguish muscle invasive UBC compared to non-muscle-invasive UBC, supporting EVs as biomarkers.In conclusion, this thesis increases our understanding of the therapeutic and diagnostic potential of EVs.List of scientific papersI. Rosanne E. Veerman, Gozde Gucluler Akpinar, Annemarijn Offens, Loïc Steiner, Pia Larssen, Andreas Lundqvist, Mikael C.I. Karlsson, Susanne Gabrielsson. Antigen-loaded extracellular vesicles induce responsiveness to anti-PD-1 and anti-PD-L1 treatment in a checkpoint refractory melanoma model. Cancer Immunology Research. 11 217-227 (2023). https://doi.org/10.1158/2326-6066.cir-22-0540II. Annemarijn Offens, Loes Teeuwen, Gozde Gucluler Akpinar, Loïc Steiner, Sander Kooijmans, Doste Mamand, Hannah Weissinger, Alexander Käll, Maria Eldh, Oscar P.B Wiklander, Samir EL Andaloussi, Mikael C.I. Karlsson, Pieter Vader, Susanne Gabrielsson. A fusion protein that targets antigen-loaded extracellular vesicles to B cells enhances antigen-specific T cell expansion. [Manuscript]III. Extracellular vesicles from bovine milk and serum can be loaded with protein antigen by lyophilization and induce CD4+ T cell responses in mice. Annemarijn Offens, Maria Eldh, Loes Teeuwen, Gozde Gucluler Akpinar, Loïc Steiner, Rebeca Cardoso, Monisha Samuel, Eduardo Villablanca, Susanne Gabrielsson. [Manuscript]IV. Loïc Steiner, Maria Eldh, Annemarijn Offens, Rosanne E. Veerman, Markus Johansson, Tammer Hemdan, Hans Netterling, Ylva Huge, Abdul-Sattar Aljabery Firas, Farhood Alamdari, Oskar Liden, Amir Sherif and Susanne Gabrielsson. Protein profile in urinary extracellular vesicles is a marker of malignancy and correlates with muscle invasiveness in urinary bladder cancer. Cancer Letters. 609, 217352 (2025). https://doi.org/10.1016/j.canlet.2024.217352</p
Aspects of in-hospital triage in a Swedish trauma population : experiences and outcomes
No full textEarly and accurate prioritization of trauma patients, known as triage, is crucial to identify those in need of emergency life-saving interventions. Excellent trauma care relies strongly on correct triage, which impacts patients' experiences and outcomes. Undertriage has been shown to be associated with an elevated risk of undetected injuries and missed interventions. However, the definition of severe trauma is still debatable. This thesis aimed to study aspects and consequences of in-hospital triage, examine over-and undertriage, trauma care processes, experiences and outcomes, providing insights to improve care for this patient group. Qualitative and quantitative approaches were used. Paper I was a 'before and after' study where the effect of a criteria-directed protocol for in-hospital triage of trauma patients in a Swedish trauma center was evaluated. The results showed that by using the protocol, overtriage was reduced from 74% to 58% while undertriage increased from 7% to 10%. No preventable deaths were detected after peer-review of those undertriaged. In Paper II, trauma patients' experiences after initial trauma management were explored, using individual face-to-face semi-structured interviews. The interviews were recorded, transcribed and analyzed using qualitative content analysis. Patients reported emotional responses to the trauma, physical discomfort and feeling prioritized or being ignored by the trauma team. The main category that emerged was: "Feeling safe in a frightening situation". In Paper III, the two scoring systems, the anatomic New Injury Severity score (NISS) and the physiology-based GAP score, for prediction on ICU-admission and 30-day mortality after trauma, were evaluated: in the Swedish trauma population. The findings showed that the GAP- score was better at predicting 30-day mortality compared to NISS, with AUROC (95% CI) values of 0.92 (0.91-0.93) and 0.84 (0.83-0.85) respectively, while NISS performed better than GAP at predicting ICU-admission. Both scoring systems were less accurate in predicting mortality in the older patient group. In Paper IV, undertriaged trauma patients were characterized and compared to non- undertriaged trauma patients, in age groups, to investigate potential differences in trauma care processes and 30-day mortality. The study results showed that undertriaged patients had fewer intubations, longer time to CT-scan and fewer admissions to ICU, were less severely injured, and had lower mortality compared to non- undertriaged patients. This demonstrates that undertriage was not associated with poorer outcomes compared to non-undertriage, in the current study.List of scientific papersI. A criteria-directed protocol for in-hospital triage of trauma patients. Granström A, Strömmer L, Schandl A, Östlund A. European Journal of Emergency Medicine 2018;25(1):25-31 (Included in Licentiate thesis). https://doi.org/10.1097/mej.0000000000000397II. Patient experiences of initial trauma care. Granström A, Strömmer L, Falk AC, Schandl A. International Emergency Nursing 2019;42:25-29 (Included in Licentiate thesis). https://doi.org/10.1016/j.ienj.2018.08.003III. Using the GAP score as a compliment to the NISS score in identifying severely injured patients- A registry-based cohort study of adult trauma patients in Sweden. Granström A, Schandl A, Mårtensson J, Strömmer L. Injury 2024;55(9):111709. https://doi.org/10.1016/j.injury.2024.111709IV. Impact of Undertriage on Trauma Care Processes and Mortality Across Age Groups. Granström A, Schandl A, Mårtensson J, Strömmer L. [Manuscript]</p
Mental health/illness and its social determinants in Uganda
No full textBackgroundThe overall aim of this thesis was to investigate mental health and illness in Uganda. More specifically, to explore understandings of mental health and to measure anxiety and hazardous alcohol use. Mental illness exists worldwide, but conceptualisations vary across contexts and population-level prevalence data are scarce from many countries. Information on conceptualisations and prevalences is important for evidence-based mental health promotion.MethodsData were collected through an open population-based cohort study in Uganda, the Africa Medical and Behavioral Sciences Organization (AMBSO) Population Health Surveillance (APHS). APHS includes urban, semi-urban, and rural sites in two Ugandan districts, Wakiso and Hoima. The backbone of APHS is an annual household census of the study communities and subsequent individual surveys of individuals >13 years covering multiple health and behavioural outcomes. Paper I provided a detailed methods description as a basis for the subsequent papers.Paper II used data from a qualitative study nested in the first round of APHS. Three focus group discussions and 31 in-depth interviews were conducted with men and women aged 14 to 62 years recruited purposively from APHS sites to explore perceptions and knowledge of mental health. Coding followed a deductive approach. Thematic analysis was undertaken and results were organised according to the domains of the mental health literacy framework.For paper III and IV, cross-sectional data from the 2021-22 APHS survey were used. For paper III, the Generalized Anxiety Disorder-7 scale (GAD-7) was translated into Runyoro and Luganda and certain psychometric properties (construct validity, internal consistency and concurrent validity) of the translated scales were examined. Additionally, the prevalence of anxiety symptoms and likely anxiety disorders measured with GAD-7 was assessed. In paper IV, hazardous alcohol use was measured with the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) and covariates selected according to the World Health Organization's social determinants of health framework. Analysis was restricted to individuals aged ≥18 years, using Poisson regression with robust variance to estimate adjusted prevalence ratios.ResultsPaper I described baseline findings of APHS, including that HIV prevalence was highest in semi-urban areas. In paper II, participants recognised that mental illness exists in their communities and described more introvert (e.g. social withdrawal) or erratic (e.g. using vulgar language) behaviours as typical signs of it. Financial and other social stressors were identified as primary causes of mental illness, supernatural explanatory models were not mentioned. Poor social relationships were described as barriers for coping and care-seeking.In paper III, a total of 4107 individuals participated, of whom 2206 spoke Runyoro and 1901 spoke Luganda. Both the Runyoro and Luganda versions of GAD-7 fit the designed one-factor structure, had good (Runyoro) and excellent (Luganda) internal consistency and exhibited a moderate (Runyoro) and strong (Luganda) concurrent validity with the depression screening instrument Patient Health Questionnaire-9. Using GAD-7 >10 points as a binary cut-off, the total prevalence of likely anxiety disorders was 1.5%, 0.5% among males and 2.2% among females.In paper IV, among the 3459 participants aged >18 years, hazardous alcohol use in the past year was prevalent among 5% of women and 18% of men. Among the social determinants found to be associated with hazardous alcohol, for both women and men, Muslim and Pentecostal religion had the strongest negative associations, female aPR 0.4 (95%CI 0.2-0.6) and male aPR 0.3 (0.2-0.5) compared with Catholic or Protestant religion. Negative associations were also found for high educational attainment and for women living in a marriage or union. Smoking and living in semi-urban areas had the strongest positive associations for both women and men, female aPR 2.1 (95% CI 1.3-3.3) and male aPR 1.8 (95% CI 1.4-2.5) comparing semi-urban with urban residence. Positive associations were also found for past-year perpetration of intimate partner violence, men in middle age and women working in the hospitality sector. HIV status was not substantially associated with hazardous alcohol use in the adjusted models.ConclusionsFor paper I, we concluded that a more nuanced distinction in epidemiological research of different types of urbanity beyond rural and urban, such as semi- urban, is important to capture specific health effects of such environments.For paper II, we concluded that symptoms of mental illness may stem from economic and social factors that can be changed by political action. Further research should explore how economic and supernatural explanatory models of mental health and illness are related in rapidly changing African societies.In paper III, likely anxiety disorders were less prevalent than previously reported in similar settings. Possible explanations for this discrepancy include individuals with more severe anxiety symptoms avoiding participation or GAD-7 not considering local idioms of anxiety. Given robust psychometrics but highly varying prevalence estimates, use of GAD-7 in healthcare settings should be preceded by clinical validation. Further research should also investigate whether people with more severe symptoms of mental illness are systematically missed in population cohort studies.In paper IV, hazardous alcohol use was prevalent and specific target groups for public health and clinical interventions were identified. Residents of semi-urban areas may be exposed to unique health risks, including for hazardous alcohol use, which warrant further longitudinal investigation and mitigation through public health policy.List of scientific papersI. Cohort Profile: The Africa Medical and Behavioral Sciences Organization (AMBSO) Population Health Surveillance (APHS) in rural, semi-urban and urban Uganda. Mugamba S, Ziegel L, Bulamba R, Kyasanku E, Johansson Århem K, Sjöland CF, Miller AP, Nakigozi G, Nalwoga GK, Watya S, Kiwanuka N, Kagaayi J, Kiwanuka D, Ddaaki W, Wagman JA, Kigozi Go, Ekström AM, Nalugoda F International Journal of Epidemiology. 2023 Apr 19;52(2):e116-e124. https://doi.org/10.1093/ije/dyac164II. Not Enough Money and Too Many Thoughts: Exploring Perceptions of Mental Health in Two Ugandan Districts Through the Mental Health Literacy Framework. Miller AP, Ziegel L, Mugamba S, Kyasanku E, Wagman JA, Nkwanzi-Lubega V, Nakigozi G, Kigozi Go, Nalugoda F, Kigozi Gr, Nkale J, Watya S, Ddaaki W Qualitative Health Research. 2021 Apr;31(5):967-982. https://doi.org/10.1177/1049732320986164III. Prevalence of anxiety symptoms in a Ugandan population sample and psychometric properties of the Generalized Anxiety Disorder-7 scale (GAD-7) in Luganda and Runyoro Ziegel L, Espinosa da Silva C, Bulamba R, Daama A, Kigozi Gr, Miller AP, Kigozi Go, Kyasanku E, Mugamba S, Hammarberg A, Ekström AM, Nalugoda F, Hollander AC [Manuscript]IV. Social determinants of hazardous alcohol use in a Ugandan population cohort. Ziegel L, Sjöland CF, Nabunya E, Bulamba R, Kyasanku E, Mugamba S, Kigozi Go, Daama A, Kigozi Gr, Miller AP, Hollander AC, Hammarberg A, Nalugoda F, Ekström AM [Manuscript]</p
Prostaglandins and other lipids as therapeutic targets and prognostic biomarkers in rheumatoid arthritis
No full textRheumatoid arthritis (RA) is an autoimmune disease characterised by systemic inflammation, joint destruction, and chronic pain. Current insights into RA pathogenesis have led to the development of various novel disease-modifying antirheumatic drugs (DMARDs) that suppress inflammation but do not cure the disease. Prostaglandins, along with other lipid mediators, play roles in multiple inflammatory diseases. However, their specific contributions to RA pathogenesis remain largely unknown, and their potential as biomarkers for predicting treatment outcomes has not been thoroughly explored. Therefore, the primary aim of this thesis is to elucidate the mechanisms by which prostaglandin signalling pathways are implicated in RA and to investigate the potential of prostaglandins and lipids as prognostic biomarkers.In Paper I, we examined the metabolism of 15-deoxy-∆12,14-prostaglandin J2 (15dPGJ2), a metabolite of prostaglandin D2 (PGD2), via microsomal glutathione S- transferase 3 (MGST3). We identified novel cyclopentenones and incorporated them into a comprehensive oxylipin panel for biomarker discovery. In Paper II, we analysed the RNA and protein expression of prostaglandin E2 receptor 2 (EP2) and EP4 receptors in monocytes from RA patients. We observed increased mRNA levels of EP2 and EP4 in monocytes from RA patients; however, their protein expression was suppressed, particularly in CD16+ monocytes. We next focused on biomarker discovery using urine and plasma samples from the NORD-STAR trial. In Paper III, we found that urinary prostanoids increased following anti-TNF and anti-IL6R treatments in RA; however, urinary prostanoids were not predictive of treatment outcomes. In Paper IV, we observed that high baseline levels of very-low-density lipoprotein (VLDL) triglycerides (TG) predicted non-responsiveness to abatacept. RA patients with total TG levels above 150 mg/dl had a remission rate of 10% at week 12, whereas those with total TG levels below 100 mg/dl had remission rates exceeding 50%.In summary, the findings of this thesis advance our understanding of the roles of prostaglandins and lipids in RA development and progression. These results also encourage further research into the impact of MGST3 depletion and triglyceride metabolism in the pathogenesis of RA.List of scientific papersI. Biosynthesis of prostaglandin 15dPGJ2-glutathione and 15dPGJ2- cysteine conjugates in macrophages and mast cells via MGST3. Julia Steinmetz-Späh, Jianyang Liu, Rajkumar Singh, Maria Ekoff, Sanjaykumar Boddul, Xiao Tang, Filip Bergqvist, Helena Idborg, Pascal Heitel, Elin Rönnberg, Daniel Merk, Fredrik Wermeling, Jesper Z Haeggström, Gunnar Nilsson, Dieter Steinhilber, Karin Larsson, Marina Korotkova, Per-Johan Jakobsson. J Lipid Res. 2022; 63(12):100310. https://doi.org/10.1016/j.jlr.2022.100310II. Reduced expression of prostaglandin E receptors on circulating monocytes as a potential self-protective mechanism in RA. Jianyang Liu, Patricia Riedlova, Helena Idborg, Katerina Chatzidionysiou, Kieran Woolcock, Marina Korotkova, Carl Goodyear, Per-Johan Jakobsson. [Manuscript]III. Urinary prostanoids are elevated by anti-TNF and anti-IL6 receptor disease-modifying antirheumatic drugs but are not predictive of response to treatment in early rheumatoid arthritis. Jianyang Liu, Helena Idborg, Marina Korotkova, Kristina Lend, Ronald van Vollenhoven, Jon Lampa, Anna Rudin, Dan Nordström, Bjorn Gudbjornsson, Gerdur Gröndal, Till Uhlig, Kim Hørslev-Petersen, Merete Lund Hetland, Mikkel Østergaard, Michael Nurmohamed, Per-Johan Jakobsson. Arthritis Res Ther. 2024; 26(1):61. https://doi.org/10.1186/s13075-024-03295-9IV. High plasma very-low-density lipoprotein-triglyceride predicts non-responsiveness to abatacept in early untreated rheumatoid arthritis. Jianyang Liu, Mohan Ghorasaini, Kristina Lend, Aswin Verhoeven, Marina Korotkova, Jon Lampa, Michael Nurmohamed, Anna Rudin, Dan Nordström, Tuulikki Sokka-Isler, Bjorn Gudbjornsson, Gerdur Gröndal, Marte Schrumpf Heiberg, Till Uhlig, Kim Hørslev-Petersen, Merete Lund Hetland, Mikkel Østergaard, Ronald van Vollenhoven, Helena Idborg, Martin Giera, Per-Johan Jakobsson. [Manuscript]</p
Effectiveness of Ultra-Rapid (20 minute) High-Frequency In-Situ Cardiac Arrest Simulations in a High-Volume Operating Department – a Tool for Evaluating and Implementing Emergency Routines
No full textNo description supplied</p
Mixed vulnerabilities: the biological risk of high parity is aggravated by emergency referral in Benin, Malawi, Tanzania and Uganda.
No full textIdentification of interacting vulnerabilities is essential to reduce maternal and perinatal mortality in sub-Saharan Africa (SSA). High parity (≥ 5 previous births) is an underemphasized biological vulnerability linked to poverty and affecting a sizeable proportion of SSA births. Despite increased risk, high parity women rarely use hospitals for childbirth. We assessed whether emergency referral during childbirth was associated with adverse events in high parity women in hospitals in Benin, Malawi, Tanzania and Uganda. We used e-registry data collected in 16 hospitals included in the Action Leveraging Evidence to Reduce perinatal morbidity and morTality (ALERT) trial. Main outcomes were severe maternal outcomes and in-facility peripartum death (fresh stillbirth or very early neonatal death). Main exposure was parity; emergency (in-labour) referral was included as effect modifier with potential confounders. We used multivariable logistic regression including parity/referral interaction and post-regression margins analysis. Among 80,663 births, 4,742 (5.9%) were to high parity women. One third reached hospital following emergency referral. Severe maternal outcomes and peripartum mortality were over 2.5-fold higher in high parity women with emergency referral compared to the lowest risk group. To avert these adverse events, emergency referral must be avoided by ensuring high parity women give birth in hospitals.</p
Cardiac function in congenital diaphragmatic hernia : a longitudinal perspective
No full textBackgroundCongenital diaphragmatic hernia (CDH), occurring in approximately 1 in 3,000 live births, remains a life-threatening condition despite advances in neonatal care. In recent years, cardiac function has been increasingly recognized as an important marker of disease severity. Current knowledge emphasizes the complex interplay between pulmonary hypoplasia, pulmonary hypertension, and biventricular dysfunction, and their impact on outcomes. Speckle-tracking echocardiography has emerged as a reproducible and user-friendly method for assessing myocardial strain, but its applicability and clinical value in CDH are uncertain, and published studies are limited by small sample sizes. It is plausible that severe illness in the neonatal period, accompanied by cardiac dysfunction, have lasting effects on cardiac performance and cardiovascular morbidity. However, little is known about cardiac function in older children and adolescents with CDH, and evidence on long-term cardiovascular morbidity is scarce.AimsTo explore cardiac function in children, adolescents, and young adults with CDH. To evaluate myocardial strain as a potential marker of disease severity. Further, to assess long-term cardiovascular morbidity in children and young adults with CDH.MethodFour studies were conducted using different methodological designs. In a registry-based study, we investigated whether children and young adults born with CDH had a higher risk of developing cardiovascular diagnoses compared with matched controls. A retrospective cohort study described cardiac function measured using strain and examined whether cardiac dysfunction correlated with prolonged length of stay (LOS) in the pediatric intensive care unit (PICU). A prospective study included a similar cohort of neonates born with CDH, aiming to describe cardiac function using strain analysis and to examine its association with LOS and milrinone use. Lastly, the thesis included an exploratory randomized crossover study that explored cardiac function in adolescents born with CDH and assessed cardiopulmonary responses to beetroot juice intake.ResultsIndividuals with CDH had markedly increased mortality in infancy and a higher risk of cardiovascular morbidity, including pulmonary hypertension, arrhythmia, and systemic hypertension, during follow-up. Neonates demonstrated impaired cardiac function at birth, with reduced left ventricle (LV), right ventricle, and atrial strain. LV dysfunction and smaller LV size were associated with longer intensive care. Although cardiac function improved over the first weeks of life, values remained below those of controls, and low LV strain values correlated with prolonged ventilation and stay in intensive care. Pharmacological support with milrinone was linked to longer intensive care overall, though early administration appeared beneficial. In adolescence, lower LV strain values than in controls were observed. In contrast to controls, who exhibited reduced exercise blood pressure and improved peak oxygen delivery, the CDH group showed no cardiovascular response to beetroot juice.ConclusionThe findings show that newborns with CDH have impaired cardiac function, and that the degree of cardiac dysfunction, measured using strain, correlates with a longer stay in the PICU. Early assessment of cardiac function may help guide treatment and potentially shorten the duration of intensive care. We found that cardiac function, measured using strain, improved but remained lower compared with in controls at one month of age and in adolescence. In adolescents with CDH, no cardiovascular response to organic nitrate intake was observed, in contrast to in the control group. These findings may help explain the increased risk of cardiovascular morbidity observed in this population and highlight the importance of systematic cardiovascular assessment and follow-up in individuals with CDH.List of scientific papersI. Hidden cardiovascular morbidity in children and young adults born with congenital diaphragmatic hernia: A population-based study. Tyden KO, Nordenstam F, Frenckner B, Burgos CM. J Pediatr Surg. 2022;57(11):510-5. https://doi.org/10.1016/j.jpedsurg.2022.03.028II. Left atrial strain in neonates with congenital diaphragmatic hernia and length of stay in pediatric intensive care unit. Tyden KO, Mesas Burgos C, Jonsson B, Nordenstam F. Front Pediatr. 2024;12:1404350. https://doi.org/10.3389/fped.2024.1404350III. Cardiac function in children with congenital diaphragmatic hernia: cardiac strain at birth and at 2-5 weeks of age. Tyden KO, Magnusson K, Burgos CM, Jonsson B, Nordenstam F. Front Pediatr. 2025;13:1598695. https://doi.org/10.3389/fped.2025.1598695IV. Cardiac and Pulmonary Function in Teenagers with Congenital Diaphragmatic Hernia: A Matched-Control Study with a Double-Blinded Beetroot Juice Crossover. Tyden KO, Sorqvist E, Burgos CM, Carlstrom M, Nordenstam F. [Manuscript]</p
Evaluation of the topographic classification of placenta accreta spectrum: protocol for an ongoing prospective multicenter study
No full textAbstractBackground: Placenta accreta spectrum (PAS) is a life-threatening obstetric condition associated with increasingcesarean delivery rates worldwide. Existing classifications, such as the World Health Organization International Statistical Classification of Diseases and Health-Related Problems and the International Federation of Gynecology and Obstetrics system, describe depth of invasion and histopathological features but do not adequately predict surgical outcomes or guide individualized management. The PAS topographic classification describes the anatomical extent of uterine wall remodeling and the presence of uterovesical adhesions, allowing surgical teams to anticipate intraoperative complexity, organ involvement, and appropriate therapeutic strategies. Although successfully applied in selected centers, its broader evaluation across diverse healthcare settings is lacking.Methods: We designed a prospective, multicenter, international cohort study enrolling patients with a high prenatal suspicion of PAS. Eligible patients are aged ≥ 18 years, undergoing surgery after 20 weeks’ gestation, and managed by multidisciplinary PAS teams familiar with the topographic classification. Standardized prenatal ultrasound staging and intraoperative surgical staging are required, with photographic and video documentation. Surgical strategies include one-step conservative surgery, total hysterectomy, and modified subtotal hysterectomy, guided by intraoperative classification. The primary outcome is intraoperative blood loss, measured using a standardized protocol. Secondary outcomes include intraoperative complications, operative time, treatment type, and usability assessments of the classification through structured surveys. Data are collected in REDCap with external review of imaging records.</p
Prenatal exposure to maternal hypertension and higher body mass index and risks of neurodevelopmental and psychiatric disorders during childhood
No full textIntroduction: Hypertensive disorders of pregnancy (HDP) or prepregnancy overweight/obesity are independently associated with the risk for certain neurodevelopmental and psychiatric disorders in offspring. These two conditions often co-exist but the risk from combined exposure is unknown. We investigated whether specific subtypes of maternal HDP, along with prepregnancy overweight/obesity, were associated with the distinct risk of neurodevelopmental and psychiatric disorders in offspring during childhood.Material and methods: This prospective, population-based cohort study used data from 652 732 singleton children born alive in Finland between 2004 and 2014 and followed until 2018. The Cox proportional hazards model was used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI).Results: Children exposed to both chronic hypertension and obesity exhibited a 2.4-3.5-fold higher risk for mood disorders, specific developmental disorder, autism spectrum disorders, and attention-deficit/hyperactivity disorders. Similarly, exposure to both gestational hypertension and overweight increased the risk for anxiety disorders and attention-deficit hyperactivity disorders by 2.4-fold. Meanwhile, combined exposure to preeclampsia and overweight increased the risk of mood and anxiety disorders, specific developmental disorders, and other behavioral disorders, by 1.8-2.2-fold. The effect size of combined exposure to HDP and overweight/obesity was greater than that of the individual exposure to HDP subtypes or overweight/obesity. Furthermore, overweight/obesity synergistically modified these associations between the HDP subtype exposure and offspring mental disorders, except for specific developmental disorders.Conclusions: Our findings suggest that combined exposure to different subtypes of HDP and higher prepregnancy BMI have distinct impacts on the mental health of offspring. Notably, a more pronounced effect was observed in cases where chronic hypertension and obesity coexisted. Future research should focus on exploring dose-related relationships rather than amalgamating maternal HDP for investigating the offspring outcomes.</p