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Effects, experiences and perceptions of harm reduction interventions among people who inject drugs
No full textDrug-induced mortality remains a persistent public health issue globally, with Sweden historically reporting some of the highest overdose death rates in Europe. While harm reduction interventions such as Take-Home Naloxone (THN) programs and Supervised Consumption Sites (SCSs) have gained traction internationally, their implementation in Sweden has been slow, with THN only introduced in 2018 and SCSs yet to be adopted.This thesis brings together four studies that collectively examine the effectiveness, lived experience, and perceptions of harm reduction interventions among people who inject drugs (PWID) in Stockholm, using both quantitative and qualitative methodologies. The overarching aim was to inform and improve public health responses to morbidity and mortality in this patient group by assessing current strategies and identifying future possibilities.Study I explored the implementation and outcomes of Sweden's first THN program, launched at the Stockholm Needle and Syringe Program (NSP). This prospective cohort study followed 1,295 participants between January 2018 and March 2022, collecting data on naloxone refills and overdose reversals. Participants were provided with naloxone following a brief training and could return for refills at which point they reported whether the kit had been used and under what circumstances. Nearly half (44%) of participants reported reversing at least one overdose, amounting to a total of 1,625 reversals. In 95.6% of cases, the individual reporting the event stated that the person who overdosed survived.Zero-inflated Poisson regression identified stimulant use, benzodiazepine use, homelessness, and country of birth outside Europe as significant predictors of higher numbers of reported reversals in the multivariate model. The study demonstrated that an NSP infrastructure can effectively support large-scale THN distribution and reach high-risk individuals, many of whom were reversing overdoses within their social networks.Study II took a qualitative approach to understanding the lived experiences of people who survived an opioid overdose with the help of peer-administered naloxone. Drawing on Zinberg's 'Drug, set and setting' theory, semi-structured interviews were conducted with 22 PWID recruited through the Stockholm NSP between November 2021 and May 2022. The analysis revealed that THN influenced each dimension of the 'Drug, set and setting' framework.In terms of 'drug', participants described distressing withdrawal symptoms and emotional reactions from peers during overdose reversals. 'Set' involved complex feelings of shame, gratitude, and in some cases, denial of having overdosed. The 'setting' dimension highlighted how THN enabled overdose management within peer groups, often without the involvement of emergency services or police, a benefit in a context of pervasive drug-related stigma.Participants widely valued THN, integrating it into personal and communal risk management strategies. Yet the study also underscored the limitations of THN as a standalone solution, pointing to broader structural issues such as the lack of safer environments for drug use.Study III shifted focus to explore the potential role of SCSs in Sweden, a harm reduction measure not yet implemented here. This mixed-methods study used both survey and interview data to assess willingness among PWID to use an SCS, if one was available in Stockholm. The survey, administered to 219 PWID, captured a range of demographic and behavioural data, as well as opinions on SCSs. The results showed that 72.1% of respondents expressed willingness to use an SCS.Factors independently associated with willingness to use an SCS in a multivariate logistic regression model included injecting opioids, having experienced an opioid overdose within the past year, and public injecting in the past month. The most frequently cited reason for wanting to use an SCS was "to avoid stress". Conversely, the main reason for reluctance was already having a private, perceived safe space to use drugs.Interview data supported these findings and additionally highlighted concerns about privacy and restrictive rules, such as bans on assisted injecting or injecting into veins in the neck or groin. The findings underscore the high potential acceptability of SCSs among PWID in Sweden, while also pointing to the importance of tailoring services to user needs and preferences Study IV provided a broader epidemiological perspective by examining mortality among Stockholm NSP clients over a ten-year period (2013-2023), including a specific focus on the change in opioid overdose deaths after the introduction of the THN program in 2018. This register-based cohort study included 4,192 individuals enrolled in the Stockholm NSP. Data from the Swedish Cause of death register were linked with clinical and demographic data from the NSP's own database. All-cause and cause-specific mortality rates were calculated annually, and Fine and Gray regression was used to assess predictors of all-cause and opioid overdose deaths.Of the cohort, 685 individuals (16%) died during the study period. Although crude mortality rates remained high compared to international levels, a significant downward trend was observed over time. Opioid overdose was the leading cause of death, but rates decreased during the study period. THN access and participation in opioid agonist therapy (OAT) were associated with a reduced hazard of opioid overdose death. The study suggests that THN, when integrated into harm reduction services, may be effective in reducing fatal opioid overdoses.Taken together, these four studies demonstrate the multifaceted value of harm reduction interventions and their potential to reduce morbidity and mortality among PWID in Sweden. THN distribution through an NSP can be effectively scaled and reach high-risk individuals, enabling them to act as first responders within their communities. Qualitative findings highlight the emotional and social dimensions of overdose survival and the limitations of THN in isolation. SCSs are widely accepted among Swedish PWID and could address some of the gaps left by THN programs, particularly for those injecting in public. Finally, both cohort- and individual-level data support the protective effect of both THN and OAT in reducing opioid overdose deaths over time.This thesis contributes important evidence to the evolving field of harm reduction in Sweden. By combining quantitative and qualitative methods, it offers an expanded understanding of how structural and interpersonal factors shape overdose risks and responses. The findings provide a strong argument for the continued and expanded implementation of harm reduction services in Sweden, including comprehensive THN access and the introduction of SCSs tailored to the needs of PWID.List of scientific papersI. Holmen E, Warnqvist A, Kåberg M. Sweden's first Take-Home Naloxone program: participant characteristics, dose endpoints and predictors for overdose reversals. (2023) Substance Abuse Treatment Prevention and Policy. 2023;18(1):24. https://doi.org/10.1186/s13011-023-00533-2II. Holmén E, Hammarberg A, Kåberg M, Storbjörk J. (2023) Take- Home Naloxone and risk management from the perspective of people who survived an opioid overdose in Stockholm - An analysis informed by drug, set and setting. International Journal of Drug Policy. 2023;115:104021. https://doi.org/10.1016/j.drugpo.2023.104021III. Holmén E, Kåberg M, Lundeberg E, Storbjörk J, Hammarberg A. (2025) Willingness and contextual considerations for supervised consumption sites: a mixed-methods study among people who inject drugs in Stockholm. International Journal of Drug Policy. 143:104866. https://doi.org/10.1016/j.drugpo.2025.104866IV. Holmen E, Kåberg M, Hammarberg A. All-cause mortality and overdose deaths among 4,192 people who inject drugs in Stockholm [Submitted]</p
Clinical outcomes after valve surgery for infective endocarditis
No full textBackground: Infective endocarditis (IE) is a serious and often fatal disease with an increasing incidence rate. Mortality is 20-30% at one year and up to 50% of patients require cardiac surgery. Previous research on surgically treated IE patients has been limited by small cohorts, lack of granularity, and short or incomplete follow-up. The thesis aims to investigate mortality and morbidity after valve surgery for IE in important patient subgroups.Methods and results: The thesis comprises five population-based, observational cohort studies. Studies I-II were single center studies with the study population identified using the local Cardiac Surgery Register, part of SWEDEHEART, while most baseline data was sourced from medical records. Studies III-V were nationwide register-based studies; for which a comprehensive database was created by crosslinking SWEDEHEART with several other Swedish national health registers.Study I investigated all-cause mortality and reoperation rates in patients who underwent valve surgery for IE. It compared intravenous drug users (IVDU; n = 55; 11%) with non-IVDUs (n = 455; 89%). Among IVDUs only, reinfection and relapse to drug use were also investigated. There was no difference in 30-day mortality, whereas long-term mortality was more than four times higher among IVDUs as compared with non-IVDUs (adjusted hazard ratio (HR) 4.1, 95% confidence interval (CI): 2.5 to 6.7; P Study II investigated all-cause mortality in patients who underwent surgery for aortic valve IE, comparing those patients with a bicuspid aortic valve (BAV; n = 122; 36%) with those with a tricuspid aortic valve (TAV; n = 216; 64%). BAV patients were younger and healthier but had more abscesses than TAV patients. Overall, the mortality rate was similar for BAV and TAV patients (adjusted HR 0.6, 95% CI: 0.4 to 1.1). Among patients with native valve endocarditis patients, the mortality rate was lower for BAV patients (adjusted HR 0.4, 95% CI: 0.2 to 0.9). Among patients with prosthetic valve endocarditis patients, mortality rate was similar for BAV and TAV patients.Study III investigated all-cause mortality, heart failure, and reinfection among patients who underwent surgery for aortic valve IE. It compared patients who had a new permanent pacemaker implanted (n = 168; 8%) with those who did not (n = 2007; 92%). There was no difference in all-cause mortality between patients who received a pacemaker and those who did not (HR 1.2, 95% CI: 0.9 to 1.6). Heart failure (HR 1.4, 95% CI: 0.9 to 2.3) and reinfection (HR 0.9, 95% CI: 0.5 to 1.5) were also similar.Study IV investigated survival, loss of life expectancy, heart failure, and recurrent IE in patients undergoing surgery for aortic valve IE. It compared female patients (n = 502; 19%) with male patients (n = 2083; 81%). Thirty-day mortality was similar (age-adjusted OR 1.1, 95% CI 0.8 to 1.6). After adjustments, females had 4% (95% CI: 0.2% to 7.9%) higher survival than male patients at 15 years. Matched loss of life expectancy ranged from 16 years (95% CI: 9 to 22) for 50-year-old females undergoing surgery in year 2000 to 2 years (95% CI: 0.95 to 3) for 80- year-old male patients undergoing surgery in year 2020. There was no difference in heart failure or recurrent IE between female and male patients.Study V investigated 30-day mortality, survival conditional on 30-day survival, heart failure, stroke, and recurrent prosthetic valve endocarditis (PVE) in patients who underwent surgery for aortic valve IE. It compared patients with PVE (n = 685; 26%) with patients with native valve endocarditis (NVE; n = 1900; 74%). Thirty-day mortality was higher among PVE than NVE patients (12% vs. 6%; adjusted OR 1.8, 95% CI: 1.2 to 2.6). At 10 years, survival was similar for PVE and NVE (conditional survival difference: - 3.8%, 95% CI: - 8.3% to 0.7%). There was no difference in heart failure, stroke, or recurrent PVE.Conclusions: I) While intravenous drug users managed surgery well, they had poor long-term outcomes. Strategies to handle addiction and reinfection should be prioritized when managing these patients. II) A high proportion of NVE patients have BAV. Reassuringly, the prognosis for these patients was better than for those with TAV despite higher rates of abscess formation. Prior BAV did not impact long-term outcomes in PVE patients. III) New implantation of pacemaker at the time of IE surgery was not associated with adverse long-term outcomes in patients. Although pacemaker need suggests more advanced disease, our study suggests that it does not importantly jeopardize lifesaving surgery for IE. IV) IE was shown to have substantial long-term impact. Loss of life expectancy was up to 16 years and particularly accentuated in younger patients. Female patients were older, had higher surgical risk, and lower income than male patients, but after adjustments, survival was better. Clinicians should be aware of sex differences IE patients to achieve early diagnosis and better optimize preoperative patient care. V) Severity of disease and higher operative risk among PVE patients as compared with NVE patients was reflected in lower 30- day survival. Importantly, PVE patients who survived the postoperative period had a similar prognosis to NVE patients. Given the poor prognosis of these patients otherwise, our results suggest that clinicians should not be afraid to refer and perform surgery in patients with very complex PVE disease.List of scientific papersI. Bearpark L, Sartipy U, Franco-Cereceda A, Glaser N. Surgery for Endocarditis in Intravenous Drug Users. The Annals of Thoracic Surgery. Volume 112, Issue 2, 573-581. https://doi.org/10.1016/j.athoracsur.2020.09.013II. Bearpark LOF, Sartipy U, Franco-Cereceda A, Glaser N. Surgery for Endocarditis in Patients with Bicuspid Aortic Valves. Annals of Cardiothoracic Surgery. 2022, Volume 11, Issue 4:448-458. https://doi.org/10.21037/acs-2022-bav-fs-0062III. Bearpark LOF, Dismorr M, Franco-Cereceda A, Sartipy U, Glaser N. Implications of Pacemaker Implantation After Aortic Valve Surgery for Endocarditis: A Nationwide Study. European Journal of Cardio-Thoracic Surgery. Volume 67, Issue 4, April 2025, ezaf125. https://doi.org/10.1093/ejcts/ezaf125IV. Bearpark LOF, Dismorr M, Franco-Cereceda A, Sartipy S, Glaser N. Sex-based Differences After Aortic Valve Surgery for Infective Endocarditis: A SWEDEHEART Study of Outcomes and Loss of Life Expectancy. [Submitted]V. Bearpark L, Dismorr M, Franco-Cereceda A, Sartipy S, Glaser N. Survival Following Aortic Valve Surgery for Prosthetic Valve Endocarditis: A SWEDEHEART Study. [Submitted]</p
Cultural competence in Swedish paediatric hospital care
No full textBackground: Ensuring equitable access to care and enabling individuals to achieve optimal health is a fundamental goal of healthcare. Increasing global population diversity has led to corresponding cultural and linguistic diversity within healthcare systems. Culture and cultural backgrounds influence perceptions of health and illness, and hence it is important that cultural factors are acknowledged and integrated into clinical practice. The existing research in this area recognises the challenges in cross-cultural care encounters, primarily due to communication barriers. These challenges might impact the quality of care provided to children, raising concerns among parents and healthcare professionals about care outcomes. Cultural competence is essential for effective cross-cultural communication and for achieving equity and addressing disparities in healthcare. Cultural competence is important in paediatric care, as the cultural beliefs, values, and practices of healthcare professionals and family units shape their expectations of care relationships and the care provided to the child, ultimately influencing both the delivery and outcomes of care. The notion of cultural competence in nursing originated from Leininger's theoretical framework for transcultural nursing, emphasising the importance of understanding cultural factors in providing care.Aim: The overall objective of this thesis was to examine the experiences of culturally competent care and cross-cultural care encounters from both the parents and the healthcare professionals within Swedish paediatric hospital care. By highlighting these experiences, the intention is to contribute to a more inclusive healthcare environment and, ultimately, to promote safe, just, and equitable care for all children, regardless of cultural background.Method: This thesis is based on four studies: three qualitative (I-III) and one quantitative, cross-sectional study (IV). Semi-structured interviews have been used to collect data in the three qualitative studies. Study I employed an inductive exploratory qualitative design. Studies II and III were descriptive qualitative studies. The participants in Study I were 14 parents of Swedish ethnic background; in Study II, 12 parents from minority ethnic backgrounds; and in Study III, 21 nurses, nine of whom identified their cultural and linguistic background as being other than Swedish. Study IV was a cross-sectional study using the Cultural Competence Assessment Instrument-Swedish (CCAI-S)-to measure the perceived self-reported level of cultural competence among healthcare professionals. A total of 441 healthcare professionals participated in this study. All studies were conducted within Swedish paediatric hospital care. Qualitative content analysis was used to analyse data in Studies I and II, while Study III was analysed using the Framework approach. The data in Study IV were analysed using statistical methods. Bivariate associations were assessed through correlation analyses, independent Student's t-tests, or one-way ANOVA tests. Additionally, linear regression analyses were used to identify the factors associated with the three domains of cultural competence: openness and awareness, interaction skills, and workplace support.Results: The results indicated that Swedish parents did not feel that the ethnic background of the nurses influenced their experiences of the care provided to their child. The parents emphasised the importance of the nurses' professional knowledge, their language proficiency in Swedish, and their ability to adapt to Swedish norms and values (Study I). For parents from minority ethnic backgrounds, the cultural sensitivity of nurses and access to nurses who shared or understood their culture was important (Study II). Studies III and IV reported a high level of self-reported cultural openness, awareness, and sensitivity among participating healthcare professionals. Cultural encounters played a central role in increasing both cultural awareness and developing skills among healthcare professionals. Nurses described these encounters as fostering the recognition of personal biases and deepening the understanding of cultural differences (Study III). Healthcare professionals felt that cultural competence is primarily developed through practical experience in professional practice (Studies III & IV), reflective interactions with parents from diverse cultural backgrounds (Study III), and experimental and collaborative learning (Studies III & IV). Experiences of cultural diversity were also found to be significantly associated with perceived cultural competence (Study IV). The participants also reported the importance of organisational support in implementing effective strategies to enhance cultural competence among their staff and thereby facilitate cross-cultural care encounters (Studies I-III). Both parents and nurses reported some barriers in cross-cultural care encounters. This included a lack of knowledge and understanding of cultural similarities and differences, as well as challenges concerning language barriers. Additionally, a lack of familiarity with the culture of healthcare among parents from minority ethnic could also cause challenges in cross-cultural care encounters for both nurses and parents. The importance of effective communication in overcoming these challenges was also emphasised by both participating parents and nurses (Studies I-III).Conclusions: Experiences of cross-cultural encounters in paediatric settings have proven important for the development of cultural competence among healthcare professionals and for addressing the challenges that arise. Cultural competence was developed through reflective interactions with children, families, and colleagues of culturally and linguistically diverse backgrounds; practical experiences in professional contexts; and collaborative and experimental learning. Both participating healthcare professionals and parents of hospitalised children expressed satisfaction with cross-cultural care in Swedish paediatric settings, despite persistent challenges, primarily those related to language barriers. Experiences of cultural encounters, cultural competence, effective communication, and adequate organisational support were all found to be essential for providing culturally competent care and for facilitating effective cross-cultural encounters. Together, these factors might contribute to ensuring that all hospitalised children receive safe and equitable care and treatment.List of scientific papersThis thesis is based on the following studies, which are referred to in the text by Roman numerals.I. Tavallali, A G., Kabir, ZN., & Jirwe, M. (2014). Ethnic Swedish parents' experiences of minority ethnic nurses' cultural competence in Swedish paediatric care. Scandinavian Journal of Caring Sciences. 28 (2):255-63.https://doi.org/10.1111/scs.12051II. Tavallali, A G., Jirwe, M., & Kabir, ZN. (2017). Cross-cultural care encounters in paediatric care: minority ethnic parents' experiences. Scandinavian Journal of Caring Sciences. 31(1):54-62.https://doi.org/10.1111/scs.12314III. Tavallali, A G., Jirwe, M., Johansson Stark, Å., & Eckerblad, J. (2025). Nurses' experiences of cross-cultural care encounters in Swedish paediatric hospital care: A qualitative study. Journal of Pediatric Nursing. 81 (2025):74-82.https://doi.org/10.1016/j.pedn.2025.01.014IV. Tavallali, A G., Klompstra, L., Holstein, J., Johansson Stark, Å., Jirwe, M., & Eckerblad, J. Cultural competence in healthcare professionals in paediatric hospital care: A cross-sectional study. [Submitted]</p
Metabolic aspects in heart failure phenotypes : impact of biomarkers, body measurements and coronary microvascular dysfunction
No full textBackground: In heart failure (HF) with preserved ejection fraction (HFpEF) phenotyping of patients, due to the heterogeneity of the syndrome, may be useful to explore underlying pathophysiology and find treatment targets. Obese-HFpEF is proposed as a phenotype and clinical characteristics may vary by region. In HFpEF coronary microvascular dysfunction (CMD) has been suggested as a unifying pathophysiological mechanism.Patients with worsening HF are hospitalised and given intravenous (IV) loop diuretics to treat congestion to relieve symptoms. The evidence showing improvements in outcomes outweighing side effects is scarce. Inotropes may be administered in the acute setting but are associated with increased risk of ischemia and arrhythmia. There is no approved drug improving contractility, with long-term outcome benefits. Acyl ghrelin is a hormone with the potential to be developed to a new inotrope in HF with reduced ejection fraction (HFrEF) by improving contractility in a load-independent manner. However, this could impair the right ventricular-pulmonary arterial coupling (RVPAC).Aim: The overall aim was to explore factors influencing metabolic health in HF patients, focusing on regional differences, body measurements, metabolic biomarkers, and HF therapies, in order to explore associations with outcomes and refine clinical management strategies. Specific aims were the following:1. To determine the regional differences in clinical characteristics and prevalence of CMD in patients with HFpEF (study I) 2. To explore associations between body mass index (BMI)-obesity (in Whites/Blacks >30 kg/m2; in Asians >27.5 kg/m2) and waist-to-height ratio (WtHR)-obesity (>0.6) with clinical characteristics, metabolic and fibrotic biomarkers, CMD and outcomes in patients with HFpEF (study II) 3. To investigate if acyl ghrelin increases cardiac output (CO) without worsening the right-sided hemodynamics assessed by RVPAC in patients with HFrEF (study III) 4. To explore the association between IV loop diuretic-induced weight loss, patient characteristics, changes in biomarkers and outcomes in HF (study IV)Method: In both study I and II patients with stable HFpEF were included from the multinational observational study Prevalence and Correlates of Coronary Microvascular Dysfunction (PROMIS)-HFpEF, whereof 202 patients in study I and 216 in study II. In study III 22 patients with RVPAC and HFrEF were included from the randomized double-blind placebo-controlled Karolinska Acyl Ghrelin Trial, which assessed acyl ghrelin versus placebo (120-min IV infusion). In study IV patients hospitalised for HF (HHF) enrolled in the Swede-HF registry between 2017-2021 with administered IV loop diuretics with weight recorded at admission and discharge, surviving to discharge, were selected. Decongestion was defined as absolute weight loss of ≥2 kg between admission and discharge.Results: In study I HFpEF patients from Singapore were leaner with more metabolic derangements; in Finland and Sweden the eldest, with more atrial fibrillation; and in the United States youngest and most obese. The prevalence of CMD was in Finland 88%, Singapore 80%, Sweden 77%, and United States 59%, with no association between country and CMD after adjustment. Associations between CMD and clinical characteristics did not differ by country.Among the 216 patients in study II patients with obesity (for both BMI and WtHR) vs non-obese were younger, had more diabetes and hyperlipidemia. Higher aldosterone and insulin and lower adiponectin were independently associated with both BMI-obesity and WtHR-obesity. CFR was not associated with either BMI-obesity (odds ratio (OR) 1.75 [95% Confidence interval (CI) 0.86 - 3.61]) nor WtHR-obesity (OR 1.27 [95% CI 0.65 - 2.51]) after adjustment. First HHF or CV death was 5/100 in BMI-obesity and 8/100 patient-years in WtHR-obesity. WtHR- obesity, but not BMI-obesity, was associated with all-cause hospitalisations [hazard ratio (HR) 2.21 (95% CI 1.12-4.33)] but not after adjustments.In study III 22 patients with HFrEF had available RVPAC (acyl ghrelin n = 12, placebo n = 10). RVPAC remained unchanged from 5.9 (5.3-7.6) to 6.3 (4.8-7.5) mm·(m/s)-1, p = 0.372, despite a 15% increase in CO in the acyl ghrelin group from 4.0 (3.5-4.6) to 4.6 (3.9-6.1) L/min, p = 0.003, while decreasing in placebo group, 5.2 (4.3-6.4) to 4.8 (4.2-5.8) mm.(m/s)-1, p = 0.035. CO change increased in the acyl ghrelin group vs placebo (p = 0.036) but RVPAC and the pressure gradient remained the same.Study IV comprised 4979 HF patients with median age of 80 years and 57% men. During the HHF weight change was -2.5 kg. Predictors of decongestion included male sex, atrial fibrillation, and obesity. Decreasing estimated glomerular filtration rate (eGFR) did not correlate with more weight loss (r= - 0.02, p=0.095). Patients decongested (>2 kg weight loss) had a lower risk of re-HHF [HR 0.61, (95% CI 0.54-0.69)] at 30 days, but not thereafter up until one year. Decongestion did not interact with the changes in biomarkers in relation to outcomes.Conclusion: CMD in HFpEF was equally prevalent in both regional phenotypes as well as differently assessed obese-HFpEF (study I-II). This suggests CMD as a therapeutic target across regions and different obese subtypes in HFpEF.WtHR-obesity and BMI-obesity had similar characteristics but there were trends toward a higher risk of all-cause hospitalisation when defined by WtHR-obesity (study II).Acyl ghrelin improves CO while preserving RVPAC which suggests it may be safe as a potential treatment in HFrEF with right ventricular failure (study III).Finally, decongestion following diuretic therapy was associated with a lower risk of re-HHF in the short-term and this effect was regardless of changes in biomarkers (study IV).List of scientific papersI. Mikael Erhardsson, Ulrika Ljung Faxén, Ashwin Venkateshvaran, Sara Svedlund, Antti Saraste, Maria Lagerstrom Fermer, Li-Ming Gan, Sanjiv J Shah, Jasper Tromp, Carolyn SP Lam, Lars H. Lund, Camilla Hage. Regional differences and coronary microvascular dysfunction in heart failure with preserved ejection fraction. ESC Heart Fail. 2023 Dec;10(6):3729-3734. https://doi.org/10.1002/ehf2.14569II. *Mikael Erhardsson, *Chanchal Chandramouli, Ulrika Ljung Faxén, Erik Michaelsson, Jasper Tromp, Ashwin Venkateshvaran, Antti Saraste, Sara Svedlund, Maria Lagerstrom Fermer, Li-Ming Gan, Sanjiv J Shah, Carolyn SP Lam, Lars H. Lund, Camilla Hage. Central and overall obesity in heart failure with preserved ejection fraction: Biomarkers, coronary microvascular dysfunction and outcomes. [Manuscript] *Shared first author. III. Mikael Erhardsson, Ulrika Ljung Faxén, Ashwin Venkateshvaran, Camilla Hage, Gianluigi Pironti, Tonje Thorvaldsen, Dominic-Luc Webb, Per M. Hellstrom, Daniel C. Andersson, Marcus Ståhlberg, Lars H. Lund. Acyl ghrelin increases cardiac output while preserving right ventricular-pulmonary arterial coupling in patients with heart failure. ESC Heart Fail. 2024 Feb;11(1):601-605. https://doi.org/10.1002/ehf2.14580IV. Mikael Erhardsson, Lina Benson, Gianluigi Savarese, Giulia Ferrannini, Ulrika Ljung Faxén, Ulf Dahlström, Lars H. Lund, Camilla Hage. Intravenous loop diuretic-induced decongestion in acute heart failure - associations with biomarker changes and 30-day and one-year outcomes. [Manuscript]</p
Unveiling frustration : underlying mechanisms and individual differences
No full textFrustration constitutes a complex, goal-oriented emotional response that occurs when individuals encounter obstacles or the omission of rewards that hinder the achievement of their intentions or expectations. Despite its widespread occurrence, frustration remains an underexplored construct within the field of affective science, particularly concerning its underlying psychological mechanisms and the impact of individual differences on experiencing frustration. This thesis investigates frustration not as a discrete emotion confined to specific contexts, but as a dynamic and multidimensional phenomenon manifested through various behavioral, emotional, and cognitive patterns. Based on three empirical studies, this doctoral thesis examines the triggers of frustration, its affective and behavioral expressions, and the modulation of these responses by stable dispositional traits and situational factors. Multiple driving scenarios were employed as an ecologically valid, semi-structured behavioral context, neither fully controlled nor entirely random, offering a perspective to observe frustration within a naturalistic, goal-driven setting.Study I examined the factors that trigger frustration within driving contexts and identified four latent categories: Achievement Obstacles, Unpredictable Experiences, External Distractions, and Distress Elicitors, which serve as predictors of frustration responses. Emotional expressions of frustration were similarly categorized into four affective dimensions: Irritation, Anxiety, Boredom, and Embarrassment. Regression analyses demonstrated that these affective dimensions are variably associated with behavioral tendencies, such as lapses, violations, and errors in self-regulatory functioning.Study II utilized a person-centered methodology to identify how prone to frustration individuals are through Latent Profile Analysis. Four distinct profiles were identified: Minimal, Low, Moderate, and Severe, distinguished by the probability and severity of frustration experiences. These profiles were influenced by emotional reactivity, age, gender, and behavioral styles, indicating that frustration is not experienced uniformly but rather reflects underlying psychological diversity.Study III introduced and assessed the Frustration Induction Task (FIT), an experimental paradigm designed to elicit frustration in controlled laboratory conditions. The FIT incorporates multiple components intended to induce frustration, such as ambiguous feedback, time pressure, and disrupted motor fluency, while enabling real-time assessment of frustration trajectories. The FIT task demonstrated psychological validity, capturing both the intensity and progression of frustration across trials.Together, the three studies presented in this thesis contribute to a more nuanced understanding of frustration as a psychological construct, advancing theoretical models of emotion regulation, stress reactivity, and personality- based susceptibility. By integrating naturalistic observation with experimental precision, the research offers both methodological innovations and theoretical insights into how individuals navigate blocked goals and emotional challenges. This work underscores the value of frustration not only as a research focus but also as a diagnostic lens through which broader patterns of human emotion and behavior may be understood.List of scientific papersI. Yazdi, H., Wickman, C., Ljung Aust, M., Selbing, I., Kowalski, L., & Axelsson, J. (2024). Understanding Frustration Triggers and Emotional Responses in Driving Situations. Scientific Reports, 14, 28613. https://doi.org/10.1038/s41598-024-76792-1II. Yazdi, H., Ljung Aust, M., Wickman, C., Bujacz, A., Kowalski, L., & Lundström, J. N. (2025). Who gets frustrated? Identifying Individuals Prone to Frustration Using a Latent Profile Analysis. Frontiers in Psychology, 16, 1483965. https://doi.org/10.3389/fpsyg.2025.1483965III. Yazdi, H., Dimoski, I., Gerikj, D., Celorio-Mancera, M. de la P., & Lundström, J. N. (2025). The Frustration Induction Task (FIT): A Method for Induction of Frustration in Experimental Studies. [Manuscript]</p
Tissue-specific responses to TFAM and mtDNA copy number manipulation in prematurely ageing mice
No full textSomatic mitochondrial DNA (mtDNA) mutations are implicated as important drivers of ageing and age-related diseases. Their pathological effect can be counteracted by increasing the absolute amount of wild-type mtDNA via moderately upregulating TFAM, a protein important for mtDNA packaging and expression. However, strong TFAM overexpression can also have detrimental effects as it results in mtDNA hypercompaction and subsequent impairment of mtDNA gene expression. Here, we have experimentally addressed the propensity of moderate TFAM modulation to improve the premature ageing phenotypes of mtDNA mutator mice, carrying random mtDNA mutations. Surprisingly, we detect tissue-specific endogenous compensatory mechanisms acting in mtDNA mutator mice, which largely affect the outcome of TFAM modulation. Accordingly, moderate overexpression of TFAM can have negative and beneficial effects in different tissues of mtDNA mutator mice. We see a similar behavior for TFAM reduction, which improves brown adipocyte tissue homeostasis, while other tissues are unaffected. Our findings highlight that the regulation of mtDNA copy number and gene expression is complex and causes tissue-specific effects that should be considered when modulating TFAM levels. Additionally, we suggest that TFAM is not the sole determinant of mtDNA copy number in situations where oxidative phosphorylation (OXPHOS) is compromised, but other important players must be involved.</p
Genetic characterization of patients with lymphoma and severe viral infections due to inborn errors of immunity
No full textIn this thesis, we discovered rare and novel inborn errors of immunity (IEIs) that impair antiviral defense and immune surveillance. These genetic defects, including mutations in TLR7 (Toll-like receptor 7), OAS1 (2'-5'-oligoadenylate synthetase 1), and TET2 (Ten-eleven translocation 2), contribute to unexpected disease severity, including vaccine failure, lymphoproliferation, and cancer. Our findings illustrate the power of genetic diagnosis in personalizing patient care and may contribute to the development of new treatment strategies for immune-related diseases.Study I describes a unique case of critical COVID-19 in a patient diagnosed with ataxia-telangiectasia (A-T) and a coexisting TLR7 deficiency. Although SARS- CoV-2 infection is typically mild in A-T patients, the TLR7 deficiency led to a severe phenotype. This underscores the necessity of broad genetic testing even when a primary IEI diagnosis is known, especially to guide prognosis and therapy. Study II explores SARS-CoV-2 breakthrough infections (BTIs) in vaccinated individuals without known immunodeficiencies. We found significant factors contributing to severe BTIs, including impaired CD8+ T cell responses and defective type 1 interferon or inflammasome signaling. A novel homozygous OAS1- p48 variant was also identified in one patient, impairing its apoptotic function and potentially explaining the severe disease despite vaccination. These findings reveal a critical role for apoptosis in antiviral immunity and support performing genetic screening in severe BTI cases. Study III presents an in-depth genomic analysis of lymphomas in IEI patients, revealing potential disease-causing germline mutations in ~60% of cases and recurring somatic mutations in genes in the DNA repair and apoptosis pathways. EBV-positive lymphomas were more frequent, and these IEI-related lymphomas showed distinct somatic mutational patterns. Our data support a two-hit model, germline IEI mutation followed by multiple somatic drivers, and advocate for integrating immunogenetic profiling in early- onset lymphomas to guide treatment. Study IV identifies a novel homozygous TET2 variant in an IEI patient with autoimmune lymphoproliferative syndrome-like features. The mutation caused DNA hypermethylation, defective class switch recombination, and B cell hyperproliferation. Functional studies confirmed the pathogenic role of this variant and suggested a mechanism for TET2 in lymphomagenesis. These insights pave the way for targeted therapies in cases where standard treatments like hematopoietic stem cell transplantation fail.These studies demonstrate the diverse and profound consequences of IEI-related genetic variants on human immunity. They thus reinforce the need for personalized genomic approaches in diagnosing and managing immune dysregulation, especially in severe infections, vaccine failure, and lymphoid malignancies.List of scientific papersI. X-linked TLR7 deficiency underlies critical COVID-19 pneumonia in a male patient with Ataxia-Telangiectasia Abolhassani H, Vosughimotlagh A, Asano T, Landegren N, Boisson B, Delavari S, Bastard P, Aranda-Guillen M, Wang Y, Zuo F, Sardh F, Marcotte H, Du L, Zhang SY, Zhang Q, Rezaei N, Kämpe O, Casanova JL, Hammarström L, Pan- Hammarström Q. J Clin Immunol. 2022 Jan;42(1):1-9.https://doi.org/10.1007/s10875-021-01151-yII. Genetic and immunological evaluation of a patient cohort with severe breakthrough SARS-CoV-2 infection identifies a case of inherited OAS1 deficiency Wang Y, Delavari S, Salami F, Zuo F, Du L, Dargahi Mal-Amir M, Nashibi R, Houshmandfar S, Marcotte H, Khoirunnisa N, Dabrowka Podolan J, Bastard P, Lee D, Zhang SY, Casanova JL, Rezaei N, Hammarström L, Abolhassani H, Pan- Hammarström Q. [Manuscript]III. Genomic characterization of lymphomas in patients with inborn errors of immunity Ye X*, Maglione PJ*, Wehr C*, Li X*, Wang Y, Abolhassani H, Deripapa E, Liu D, Borte S, Du L, Wan H, Plötner A, Giannoula Y, Ko HB, Hou Y, Zhu S, Grossman JK, Sander B, Grimbacher B, Hammarström L, Fedorova A, Rosenzweig SD, Shcherbina A, Wu K, Warnatz K, Cunningham-Rundles C, Pan-Hammarström Q. Blood Adv. 2022 Sep;6(18):5403-5414 *Shared authorshiphttps://doi.org/10.1182/bloodadvances.2021006654IV. B cell lymphoproliferation and genome-wide methylation defects associated with a novel biallelic germline TET2 mutation Wang Y, Abolhassani H, Ye C, Dai Q, Behniafard N, Zuo F, Yang M, Liu M, Delavari S, Salami F, Vlachiotis S, Sun R, Du L, Kalmar D, Palmeri A, Rezaei N, Hammarström L, Wilhem M, He C, Pan-Hammarström Q. [Manuscript]</p
lncRNAs and miRNAs : key regulators in the pathogenesis of cSCC, senescence, and psoriasis
No full textThe skin is the body's largest and outermost organ, serving as a dynamic interface between the internal environment and external stimuli. It plays a vital role in maintaining physiological balance by acting as a barrier against physical injury, pathogens, and environmental stressors. In addition to its protective functions, the skin contributes to pigmentation through melanin production and manages hydration via its barrier properties. Structurally, the skin consists of three layers: the epidermis, dermis, and hypodermis. Maintaining a delicate balance between keratinocyte growth and differentiation is essential for preserving epidermal integrity and function. This balance is regulated by a complex network of signalling pathways, transcription factors, epigenetic regulators, and non-coding RNAs. Disruption of these regulatory mechanisms can disturb skin homeostasis, leading to various pathological conditions. These include malignant diseases such as cutaneous squamous cell carcinoma (cSCC), benign inflammatory disorders like psoriasis, and contributions to aging and cellular senescence. Understanding the molecular frameworks that maintain skin homeostasis is crucial for developing targeted treatments for skin diseases.In this thesis, I have examined the role of non-coding RNAs as key regulators in the development of cSCC, psoriasis, and cellular senescence.Paper I: In this study, we investigated the role of miR-23b in cSCC and identified this microRNA as a tumour suppressor in the context of this disease. We demonstrated that miR-23b expression is downregulated in both cSCC and actinic keratosis (AK). Furthermore, we demonstrated that the MAPK signalling pathway regulates the expression of miR-23b, a key pathway in cSCC disease progression. In addition, we show that miR-23b suppresses the expression of a gene network associated with key oncogenic pathways, and its gene signature is enriched in human cSCCs. We observed that overexpression of miR-23b suppressed the ability of cSCC cells to form colonies and tumor spheroids. Additionally, we demonstrate that CRISPR/Cas9- mediated deletion of MIR23B leads to increased colony and tumor sphere formation in vitro. In vivo, we observed that miR-23b-overexpressing cSCC cells formed significantly smaller tumours upon injection into immunocompromised mice, with decreased cell proliferation and angiogenesis. Mechanistically, we verified Ras-related protein RRAS2 as a direct target of miR-23b in cSCC. We demonstrated that RRAS2 is overexpressed in cSCC and that interference with its expression impairs angiogenesis, as well as colony and tumor spheroid formation. These findings suggest that miR-23b acts as a tumor suppressor in cSCC, and its expression is decreased during the initiation and progression of cSCC.Paper II: In this study, we identified a long non-coding RNA, CYDAER (RP11-295G20.2), which is significantly upregulated in keratinocytes from psoriatic skin. We demonstrate that CYDAER is mainly expressed in the suprabasal layers of the epidermis and is induced by the psoriasis-associated cytokine IL-17A. Functional studies show that CYDAER suppresses keratinocyte terminal differentiation, suggesting that its overexpression contributes to the impaired differentiation characteristic of psoriasis. These findings highlight CYDAER as a potential regulator of epidermal dysfunction in psoriasis.Paper III: In this study, we show that the expression of a skin aging-associated microRNA (miR-383) increases during replicative senescence and stress-induced senescence of fibroblasts. Moreover, we demonstrate that overexpression of miR-383 induces a senescence-like phenotype in primary human fibroblasts, indicated by increased senescence-associated ß-galactosidase (SA-B-Gal) activity, altered expression of senescence markers, characteristic morphological changes, and reduced proliferative capacity. Conversely, we found that CRISPR-Cas9-mediated knockout of MIR383 delays the onset of the senescence-like phenotype and extends the replicative capacity of dermal fibroblasts. Transcriptome analysis of fibroblasts overexpressing miR-383 revealed that high levels of miR-383 decrease the expression of genes involved in repairing double-stranded DNA breaks. Furthermore, overexpression of miR-383 also leads to increased DNA damage, a hallmark of aging and senescence, in fibroblasts. Mechanistically, we demonstrate that miR-383 regulates the DNA damage response by directly targeting PCNA clamp-associated factor (PCLAF/KIAA0101), a key DNA repair regulator, resulting in increased DNA damage, enhanced nuclear localization of p21, and a senescence-like phenotype.These findings identify miR-383 as a key regulator of the DNA damage response and a promoter of dermal fibroblast senescence, thereby enhancing our understanding of the molecular mechanisms that influence skin aging process.Paper IV: In this study, we identified LINC01605 as an upregulated long non-coding RNA in cSCC compared to healthy skin. We demonstrate that LINC01605 expression is positively regulated by TGF-B, a key inducer of epithelial-to-mesenchymal transition (EMT) that is involved in cSCC progression. Functional studies showed that both siRNA-mediated knockdown and CRISPR-Cas9 knockout of LINC01605 in cSCC cell lines impair cell growth, colony formation, migration, and tumor spheroid formation. Loss of LINC01605 reduces metabolic activity, slows cell proliferation, increases epithelial cohesion, and suppresses EMT. RNA sequencing of LINC01605-knockout cells reveals downregulation of genes involved in cell-matrix adhesion, emphasizing its role in tumor cell adhesion dynamics. In vivo zebrafish xenograft models confirm increased cell aggregation after LINC01605 loss.Together, these results suggest that elevated LINC01605 expression promotes cSCC progression by enhancing the plasticity of cancer cell proliferation, migration, and adhesion.List of scientific papersI. MicroRNA-23b Plays a Tumor-Suppressive Role in Cutaneous Squamous Cell Carcinoma and Targets Ras-Related Protein RRAS2. Chengxi Sun, KunalDas Mahapatra, Jonathan Elton, Chen Li, Winnie Fernando, Warangkana Lohcharoenkal, Jan Lapins, Bernhard Homey, Enikö Sonkoly, Andor Pivarcsi. Journal of Investigative Dermatology, 2023 Dec 1;143(12):2386-2396. https://doi.org/10.1016/j.jid.2023.05.026II. RNA Sequencing Reveals the Long Non-Coding RNA Signature in Psoriasis Keratinocytes and Identifies CYDAER as a Long Non-Coding RNA Regulating Epidermal Differentiation. Jan Cedric Freisenhausen, Longlong Luo, Evelyn Kelemen, Jonathan Elton, Viktor Skoog, Andor Pivarcsi, Eniko Sonkoly. Experimental Dermatology, 2025 Feb;34(2):e70054. https://doi.org/10.1111/exd.70054III. miR-383, a skin ageing-associated microRNA, includes fibroblast senescence through targeting PCNA clamp-associated factor (PCLAF) and regulating DNA damage repair. Chen Li, Jonathan Elton, Ankit Srivastava, Claire Marionnet, Françoise Bernerd, Enikö Sonkoly, Andor Pivarcsi. [Manuscript]IV. Investigation of the role of LINC01605 in Cutaneous Squamous Cell Carcinoma. Jonathan Elton, Zi Xin Ong, Finn Glockner, Longlong Luo, Eniko Sonkoly, and Andor Pivarcsi. [Manuscript]</p
Designed for equity? Studies on parental leave and the mental health of parents
No full textThe transition to parenthood is regarded as an exciting time for prospective parents; however, it can also be a challenging period marked by uncertainty, stress, and anxiety. These challenges may arise from biological and hormonal changes, as well as a range of socio-emotional and psychosocial pressures, as well as financial pressures due to time off work and the prospect of reduced income, all of which can impact mental health. Mental disorders are common in the postpartum period, with postpartum depression affecting an estimated 17% of mothers and 9% of fathers globally. Generous parental leave may help alleviate mental health symptoms by reducing financial stress and providing job-protected time for parents to recover from childbirth and bond with their child. However, access to generous parental leave is generally linked to an individual's attachment to the labour market, meaning that those with weaker labour market ties are less likely to qualify for more generous benefits. As a result, the work requirement for eligibility for generous parental leave may contribute to widening health inequalities in society. Using the Social Determinants of Health framework, which recognises that health is shaped by the social, economic, and environment conditions in which people live, this thesis aims to deepen our understanding of the relationship between parental leave generosity and poor mental health of parents. The thesis draws data from a systematic review of peer-reviewed international literature as well as empirical studies using Swedish population registers.Study I systematically reviewed peer-reviewed international literature on the effects of different aspects of parental leave generosity, including remuneration and duration of leave, on both mothers' and fathers' mental health after childbirth. Overall, mothers generally experienced better mental health both in the postpartum period and in later life with more generous parental leave policies such as, paid leave and longer duration, compared to those with shorter or unpaid leave. Although findings for fathers were less conclusive due to fewer studies, available evidence suggests that fathers also benefit from policies that offer adequate wage replace or incentives, such as individual uptake quotas. The review identified several key knowledge gaps. First, no studies have explicitly considered the role of work requirements for eligibility for paid parental leave in relation to parental mental health. Second, many observational studies did not account for mental health conditions before parenthood, which limits the ability to distinguish whether postpartum symptoms reflect new onset of poor mental health or a continuation of pre-existing mental health conditions. Third, evaluations of paid parental leave often lack clear and consistent comparison groups. Lastly, there is limited research on fathers, which may contribute to the inconclusive findings regarding the effects of parental leave on fathers' mental health. These knowledge gaps have guided the subsequent empirical studies of the thesis.Study II examined whether first-time mothers with poor health before pregnancy were less likely to be eligible for more generous parental leave benefits in Sweden. The study found that mothers with preconception health conditions, particularly those with mental disorders or those with chronic health conditions (except musculoskeletal conditions), were less likely to qualify for more generous paid benefits. These findings suggest there is health selection into parental leave entitlements and that the strong work requirement for qualifying for generous parental leave may unintentionally reinforce socioeconomic inequalities between mothers with and without prior health conditions.Studies III and IV evaluated the association between levels of paid parental leave benefits and postpartum mental health (examined through differing levels of severity and healthcare utilisation) in first-time mothers (Study III) and fathers (Study IV) in Sweden. Overall, both mothers and fathers who received higher-level paid parental leave benefits generally experienced better postpartum mental health than those receiving basic paid benefits even after accounting for key variables that influence eligibility for higher-level paid benefits: mental health conditions before parenthood, income and employment status. Specifically, mothers receiving higher-level benefits were less likely to receive care for moderate-to-severe mental disorders, while fathers were less likely to receive any mental healthcare across all levels of severity, compared to those receiving only basic benefits. These findings suggest that more generous parental leave benefits could promote postpartum mental health for mothers and fathers.This thesis demonstrates that generous parental leave can positively support postpartum mental health for both mothers and fathers. However, it also highlights how strict work requirements to qualify for better paid benefits reinforces structural inequalities. The parental leave scheme may unintentionally exclude those most in need of support during the transition to parenthood since eligibility for more generous benefits are tied to labour market attachment. Policies that promote stable employment prior to childbirth and relax strict work requirements could help support postpartum mental health. These findings should be carefully considered by policymakers when designing or reforming parental leave schemes. Overall, this thesis underscores the importance of applying a Health in All Policies approach, which considers the health implications across all public policies, to address postpartum mental health.List of scientific papersI. Heshmati A, Honkaniemi H, Juárez SP. The effect of parental leave on parents' mental health: a systematic review. The Lancet Public Health. 2023; 8(1): e57-e75. https://doi.org/10.1016/s2468-2667(22)00311-5II. Heshmati A, Dunlavy A, Mussino E, Fritzell S, Juárez SP. Health before pregnancy and eligibility for parental leave benefits: a Swedish total population cohort study. BMC Public Health. 2025; 25: 1045. https://doi.org/10.1186/s12889-025-22248-8III. Heshmati A, Honkaniemi H, Fritzell S, Juárez SP. Parental leave benefits and maternal postpartum mental health in Sweden. JAMA Network Open. 2025; 8(4):e258062. https://doi.org/10.1001/jamanetworkopen.2025.8062IV. Heshmati A, Juárez SP. Parental leave benefits and paternal mental health: a Swedish register-based cohort study. [Manuscript]</p
Postpartum hemorrhage in Sweden : temporal trends and novel approaches for risk assessment
No full textBackgroundPostpartum hemorrhage (PPH)—in Sweden defined as blood loss >1000 mL after delivery—is the largest contributor to maternal morbidity in high-income countries. Severe cases can require interventions such as hysterectomy or, more commonly, blood transfusions. Additional complications include maternal infection, iron deficiency anemia, fatigue and impaired breast-feeding, all of which can contribute towards a negative childbirth experience. The incidence of PPH has increased in high-income countries over recent decades, with the underlying causes remaining unclear. Up to 40% of postpartum hemorrhages occur in women without known risk factors. Identifying new risk factors and improving the ability to predict women at risk is therefore central for improving the care and management of birthing women.Materials and methodsStudy I used the Swedish Pregnancy Register to examine the accuracy of diagnostic codes (according to the International Statistical Classification of Diseases and Related Health Problems, 10th edition) for PPH in Sweden. We also investigated whether this accuracy varied by obstetric characteristics. Study II used the Swedish Medical Birth Register to investigate temporal trends in PPH in Sweden, stratified by Robson groups, and whether these changes could be attributed to changes in risk factors. Study III used the Stockholm-Gotland Perinatal Cohort to investigate the relationship between first stage labor duration and PPH. Study IV used the Stockholm-Gotland Perinatal Cohort to examine the accuracy of the Californian Maternal Quality Care Collaborative’s (CMQCC) risk assessment tool for identifying women at risk of PPH in Sweden. Study V used the Swedish Medical Birth Register to examine whether crowding of deliveries was more pronounced in births complicated by PPH, compared to non- PPH births. We further investigated whether this association varied by hospital size, or whether the delivery occurred during summer or on a weekend.Main findingsI. The sensitivity for the diagnostic codes was 88.5% (95% confidence interval; CI: 88.2– 88.7) and the specificity was 99.4% (95% CI: 99.4–99.4). The sensitivity for PPH was higher in vaginal (92.9%; 95% CI: 92.6–93.2) than cesarean deliveries (79.0%; 95% CI: 78.4–79.7).II. The rate of PPH increased with 34% between 2000 and 2016 (5.4%–7.3%). Adjusting for changes in risk factors did not attenuate this increase in PPH in the overall population or when stratified by Robson group. In the cohort of singleton, term deliveries, with the fetus in vertex presentation, induction of labor: Robson groups 2a (nulliparous) and 4a (parous without prior CD) contributed largely to the overall increase in PPH.III. The risk of PPH increased with longer first stage labor duration (adjusted risk ratio for duration ≥12.1 h vs IV. The accuracy of the PPH risk stratification tool was poor, with a sensitivity of 53.6%, indicating that near half of all the PPH cases occurred in deliveries that were classified as low-risk.V. The risk of PPH was not increased if the delivery ward was crowded around the time of birth (odds ratio; OR: 0.97, 95% CI: 0.95‒0.99). These results were not modified by hospital size or having a weekend or summer delivery.ConclusionsGiven the demonstrated high accuracy of PPH diagnostic codes, these can be used for population-based studies when blood loss volume is unavailable. The increasing trend in PPH is of concern, particularly given that this trend could not be explained by changes in population characteristics or obstetric management. Whether this increase, in part, could be due to changes in quantification practices or labor management that are not captured in the registers, was not possible to evaluate. The validity of the CMQCC tool for classifying women in Sweden at risk for PPH was low and this tool should not be implemented in a Swedish setting. Our findings suggest that first stage of labor duration should be incorporated into in risk assessments for PPH during labor while there was no indication that delivery ward crowding increased the risk of PPH. These insights have the potential to advance future research on PPH, inform clinical decision-making and improve maternal health outcomes.List of scientific papersI. Ladfors LV, Muraca GM, Butwick A, Edgren G, Stephansson O. Accuracy of postpartum hemorrhage coding in the Swedish Pregnancy Register. Acta Obstet Gynecol Scand. 2021 Feb; 100(2):322-330. https://doi.org/10.1111/aogs.13994II. Ladfors LV, Muraca GM, Zetterqvist J, Butwick AJ, Stephansson O. Postpartum haemorrhage trends in Sweden using the Robson ten group classification system: a population-based cohort study. BJOG. 2022 Mar;129(4):562-571. https://doi.org/10.1111/1471-0528.16931III. Ladfors LV, Liu X, Sandström A, Lundborg L, Butwick AJ, Muraca GM, Snowden JM, Ahlberg M, Stephansson O. Risk of postpartum hemorrhage with increasing first stage labor duration. Scientific reports. 2024 Sep; vol. 14,1 22152. https://doi.org/10.1038/s41598-024-72963-2IV. Ladfors LV, Butwick A, Stephansson O. A validation of The California Maternal Quality Care Collaborative obstetric hemorrhage risk assessment tool in a Swedish population. Am J Obstet Gynecol MFM. 2024 Jan;6(1):101240. https://doi.org/10.1016/j.ajogmf.2023.101240V. Ladfors LV, Holowko N, Liu C, Lundborg L, Ahlberg M, Granath F, Stephansson O. The relationship between crowding in the delivery ward and the risk of postpartum hemorrhage. Acta Obstet Gynecol Scand. 2025 Jul;104(7):1295-1303. https://doi.org/10.1111/aogs.15137</p