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Distant suffering : on mediated suffering and health care
No full textThis thesis examines distant suffering, or when suffering of others who are far away is mediated or conveyed. Distant suffering often refers to when popular media or humanitarian campaigns display images of people suffering amidst catastrophes in faraway lands. Such displays of distant suffering can have negative implications for those who are suffering and those observing the images. In this digital age, an image of suffering can be easily transmitted widely and instantly. Also, use of telehealth technologies has now become common practice in settings globally. During telehealth care, providers may encounter the suffering of patients far away. The aim of this thesis is to explore the concept of distant suffering and its relevance for health care.Through four papers, distant suffering is explored empirically and theoretically. The first paper (Study I) explores telecare providers' experiences encountering patients who are suffering. The second paper (Study II) explores how suffering is perceived in humanitarian images. The third study (Study III) examines conceptualizations of distance in providers' encounters with suffering in telecare. The fourth paper (Study IV) is a concept analysis, advancing theoretical development of distant suffering and its relevance in health care.Providers' encounters with suffering in distant care were experienced as loose connections, both in compromised technology and compromised emotional connection. Insecurity in digital practice, inaccessibility of tools, and conviction in the value of telehealth care arose in providers' experiences (Study I). In humanitarian images, perceived suffering was described in themes of decoded emotions and their physical expressions, a nexus of uncertainty and vulnerability, and through relatability or resonance with what was observed (Study II). In tele- care, distance presented as physical and emotional distance, where, for some patients, telecare may not be suitable, while for others it is a bridge to accessing care (Study III). The concept of distant suffering includes attributes of mediated faraway suffering, a "recognizer" who observes it, and a potential moderator (Study IV). Through shared social and cultural understandings, consequences of distant suffering may include moral or emotional responses, inaction, or pity.Distant suffering is greatly relevant for both patients and health care providers. It is an important area of inquiry to further understanding, from its origins in humanitarian images to its presence via modern telecare, to ensure patients and providers have successful and rewarding distant health care encounters.List of scientific papersI. Åhs, J. W., Ranheim, A., Eriksson, H., & Mazaheri, M. (2023). Encountering suffering in digital care: a qualitative study of providers' experiences in telemental health care. BMC health services research, 23(1), 418. https://doi.org/10.1186/s12913-023-09367-xII. Åhs, J. W., Eriksson, H., & Mazaheri, M. Perceived suffering in humanitarian images: a photo-elicitation. [Submitted]III. Åhs, J. W., Ranheim, A., Mattelin, E., Eriksson, H., & Mazaheri, M. (2023). Distance in Distant Care: Qualitative Content Analysis of Providers' Experiences in Tele-Mental Care. Journal of medical internet research, 25, e38568. https://doi.org/10.2196/38568 IV. Åhs, J. W., Eriksson, H., & Mazaheri, M. (2024). Distant suffering: A concept analysis. International journal of nursing studies, 151, 104672. https://doi.org/10.1016/j.ijnurstu.2023.104672</p
Easy breathing : exploring aspects of interfaces and devices for neonatal respiratory support
No full textBackground: Newborn infants often need respiratory support at birth, particularly those born prematurely. Non-invasive approach is the commended method when supporting spontaneously breathing infants with respiratory distress. This is associated with improved outcome compared to mechanical ventilation. Continuous positive airway pressure (CPAP) is predominantly delivered with nasal interfaces while T-piece with face mask has been the common mode for neonatal stabilisation. The evidence is inconclusive on which interface is best suited to optimise clinical effect and outcome. Nasal interfaces for resuscitation have gained increased attention in recent years.Objectives: First, to quantify and compare leakage for nasal mask and nasal prongs, during CPAP treatment and to evaluate if simple care adjustments can reduce leakage. Second, to examine if infants exhale through the CPAP device by analysing flow curves from the first trial. Third, evaluate the feasibility of the simplified rPAP system for delivery room stabilisation and continued support. Fourth, to evaluate the effect of dead space on the time delay in oxygen delivery during positive pressure ventilation in simulated settings.Methods: A randomised cross-over study on 50 infants treated with nasal CPAP (nCPAP) was conducted. Leakage measurements were done with two different nasal interfaces. Then, respiratory flow-curves from the first study were retrospectively analysed (study II). In the third study we conducted a clinical feasibility trial of 32 preterm infants needing respiratory support directly after birth. Lastly, the time course for changes in FiO2 to reach the airway level, was measured and compared between different T-pieces and interfaces in a bench study (study IV).Results: We found higher leakage for nasal mask vs prongs. Leakage was common for both interfaces and could be reduced with simple maneuvers. In 43/100 recordings, infants treated with nCPAP, exhaled through the CPAP system. We found it feasible to use the new rPAP system for both stabilisation and extended respiratory support in the first hours. Mean time to reach desired FiO2 level was significantly shorter for rPAP with prongs compared to T-pieces with face mask.Conclusions: Leakage during nasal CPAP treatment is common and can be minimised. Infants can exhale through the CPAP device with nasal mask and prongs. Using the same system for stabilisation and continued support is achievable and can promote stabilisation near parents. There is considerable delay in achieving changes in oxygen concentration during simulated positive pressure ventilation attributable to the dead space of the interface.List of scientific papersThis thesis is based on the following papers which are referred to in the text by their roman numerals.I. Falk M, Gunnarsdottir K, Baldursdottir S, Donaldsson S, Jonsson B, Drevhammar T. Interface leakage during neonatal CPAP treatment: a randomised, cross-over trial. Archives of Disease in Childhood - Fetal and Neonatal Edition. 2021;106(6):663-7. https://doi.org/10.1136/archdischild-2021-321579II. Gunnarsdottir K, Falk M, Baldursdottir S, Donaldsson S, Jonsson B, Drevhammar T. Do newborn infants exhale through the CPAP system? Secondary analysis of a randomised cross-over trial. Archives of Disease in Childhood - Fetal and Neonatal Edition 2023;108:232-236. https://doi.org/10.1136/archdischild-2022-324462III. *Baldursdottir S, *Gunnarsdottir K, Donaldsson S, Jonsson B, Drevhammar T. Skin-to-skin stabilisation and uninterrupted respiratory support for preterm infants after birth: feasibility of a new and simplified rPAP system. Arch Dis Child Fetal Neonatal Ed 2024;0:F1-F5. *Shared first author. https://doi.org/10.1136/archdischild-2023-326409IV. Gunnarsdottir K, Stenson B, Foglia E.E, Kapadia V, Drevhammar T, Donaldsson S. Effect of interface dead-space on the time taken to achieve changes in set FiO2 during T-piece ventilation. Is face mask the optimal interface for neonatal stabilisation? Arch Dis Child Fetal Neonatal Ed 2024;0:F1-F6. https://doi.org/10.1136/archdischild-2024-327236</p
Developing culturally sensitive psychiatric diagnostic assessments : clinical evaluation of the DSM-5 Cultural Formulation Interview
No full textBackground: Culture and social context influence how symptoms of distress are expressed and interpreted, posing challenges in transcultural psychiatric assessments. This increases the risk that mental disorders among migrants and ethnic minorities are diagnosed late, misdiagnosed, or undetected.The Cultural Formulation Interview (CFI) in the DSM-5 is a person-centered tool developed to facilitate the exploration of cultural and contextual factors of mental distress in a non-stereotypic and individualized way.Aims: The overall aim of this research project was to evaluate the culture-sensitive and person-centered tool, the Cultural Formulation Interview (CFI), included in the psychiatric diagnostic manual DSM-5. Study I aimed to investigate whether adding the DSM-5 core CFI to routine diagnostic procedures impacts the diagnostic outcome. Study II aimed to assess the Clinical Utility (CU), Feasibility (F) and Acceptability (A) of the CFI for clinicians and patients, and to explore clinicians' experiences of using the CFI in a multicultural clinical setting. Study III aimed to find out the gain of information deriving from the use of the CFI questions with non-native Swedish speaking patients, and to understand how they may facilitate identification of psychiatric diagnoses among these patients. Study IV aimed to find out the gain of information deriving from the use of the CFI questions with native Swedish-speaking patients, and to understand what kind of information the questions about background and identity yielded when used with these patients.Materials and methods: In Study I, we conducted a randomized controlled trial comparing the outcome of a diagnostic procedure that included the CFI (intervention) with routine diagnostic procedures (control) at Swedish psychiatric clinics. New patients (n=256) admitted to a psychiatric outpatient clinics were randomized to control (n=122) or CFI-enhanced diagnostic procedure (n=134). An intention-to-treat analysis was performed, calculating the prevalence ratios and corresponding 95% confidence intervals (CI) for diagnoses of depressive and anxiety disorders, multiple diagnoses, and delayed diagnoses.In Study II, a mixed method design was applied, using a Debriefing Instrument for Clinicians (DIC) (N=15) and a Debriefing Instrument for Patients (DIP) (N=114) (DIC and DIP, scored from -2 to 2). Focus group interviews were conducted with clinicians using the CFI.In Study III, qualitative thematic analysis was used to analyze the 47 documented CFI answers from non-native Swedish speaking patients and in Study IV the same method was used on the 62 documented CFI answers from native Swedish speaking patients.Results: Results from Study I showed a prevalence ratio (PR) of a diagnosis of depressive disorder of 1.21 (95% CI=0.83-1.75). The prevalence ratio was higher among patients whose native language was not Swedish (PR =1.61, 95% CI=0.91-2.86). In the CFI group, the prevalence ratio for receiving multiple diagnoses was higher among non-native speakers and lower among native Swedish speakers (PR =. 39, 95% CI=0.18-0.82).In Study II, both patients and clinicians found the CFI to be acceptable (A), feasible (F) and clinically useful (CU). The results from the DIP showed a CU mean 0.98 (SD 0.93), on a scale between -2 and +2, and a F mean 1.07 (SD 0.83). The overall rating of the interview was 8.30 (SD 1.75) on a scale between 0 and 10. For DIC (response rate 94%), the CU mean was 1.14 (SD 0.52), F mean 0.58 (SD 0.93) and A mean 1.42 (SD 0.44). The focus-group interviews indicated that using the CFI at the initial contact can facilitate the patient's illness narrative.The thematic analysis of CFI answers in Study III and IV yielded information about how the patients described, managed, and made sense of their distress. In Study III, the non-native Swedish speakers often described their distress in relation to functionality in everyday life and used a combination of somatic and emotional expressions. These patients often related their identity to a sense of belonging to their culture of origin. In Study IV, the native Swedish speaking patients often described and explained their symptoms in psychiatric terms. They often used emotional expressions and related their identity to the ability to perform in relation to a social role.Conclusions: The results suggest that• the CFI in the DSM-5 seems to be a feasible, acceptable, and clinically useful assessment tool• the contextualized information gained through the CFI can assist clinicians in identifying psychiatric symptoms when language, psychiatric terminology, and explanations are not shared between the patient and clinician• implementing the DSM-5 CFI in routine psychiatric diagnostic practice can facilitate identification of symptoms of certain psychiatric disorders• there is a need of re-framing the questions about cultural identity and its impact on healthList of scientific papersI. Wallin, M. I., Galanti, M. R., Nevonen, L., Lewis-Fernández, R., & Bäärnhielm, S. (2022). Impact on routine psychiatric diagnostic practice from implementing the DSM-5 cultural formulation interview: a pragmatic RCT in Sweden. BMC psychiatry. 22(1), 149. https://doi.org/10.1186/s12888-022-03791-9II. Wallin, M. I., Dahlin, M., Nevonen, L., & Baarnhielm, S. (2020). Patients' and clinicians' experiences of the DSM-5 Cultural Formulation Interview: A mixed method study in a Swedish outpatient setting. Transcultural psychiatry. 57(4), 542-555. https://doi.org/10.1177/1363461520938917III. Wallin, M. I., DeMarinis, V., Nevonen, L., & Bäärnhielm, S. (2024). A qualitative analysis of the documentation of DSM-5 Cultural Formulation Interviews with non-native speaking patients in a Swedish mental health care setting. Frontiers in psychiatry. 15, 1298920. https://doi.org/10.3389/fpsyt.2024.1298920IV. Wallin, M. I., DeMarinis, V., Nevonen, L., & Baarnhielm, S. (2024). What information did the DSM-5 Cultural Formulation Interviews provide when used with Swedish-speaking patients in a psychiatric setting in Stockholm? Frontiers in psychiatry. 15, 1377006. https://doi.org/10.3389/fpsyt.2024.1377006</p
Electronic cigarettes and pulmonary effects : a translational approach
No full textDespite the observed health hazards associated with using e-cigarettes, the popularity of e-cigarettes remains high, with millions of users worldwide. The lungs are the primary organs targeted by inhaled external stimuli, including the constituents in e-cigarette vapours. This thesis investigated the use of e- cigarettes and their pulmonary effects to contribute to a better understanding and knowledge in this area.In Paper I, we found that 3.9% of young adults in the BAMSE cohort were current e-cigarette users at the 24-year follow-up. We observed significant associations between e-cigarette use, male gender, and cigarette smoking. E-cigarette users reported higher chronic bronchitis-like symptoms, such as cough and mucous production, compared to non-users. Additionally, dual use of e-cigarettes and traditional cigarettes was linked to an increased risk of respiratory symptoms. We concluded that although the prevalence of e-cigarette use was low, the increased prevalence of respiratory symptoms in e-cigarette users poses a risk to respiratory health, even considering the short duration of e-cigarette use in our participants.In Paper II, the levels of biomarker for local airway inflammation FeNO were higher in e-cigarette users and lower in traditional cigarette smokers compared to healthy non-smokers. Bronchial responsiveness also increased in e-cigarette users, like conventional cigarette smokers. The percentages of IL13-positive and IFNy-positive cells increased in e-cigarette users and dual users. Additionally, the innate immune receptors TLR2 on blood granulocytes and TLR2 and TLR4 on sputum immune cells were higher in e-cigarette users and dual users. Moreover, total cellular ROS was higher in both e-cigarette and dual users in blood and sputum. The concentration of TIMP1 decreased in sputum, while MMP9 increased significantly in saliva in both e-cigarette users and dual users. Considering that markers of inflammation, oxidative stress, and innate immune receptors were induced both locally in sputum/saliva and systemically in blood/serum not only in e-cigarette users but also in dual users of e-cigarettes and traditional cigarettes, we conclude that e-cigarettes and dual users had developed altered inflammatory and innate immune response both locally and systemically.In Paper III, we observed that exposure of bronchial mucosa models to e- cigarette fruit flavour 1 increased inflammation and oxidative stress markers at the transcript level when nicotine was present. Similarly, exposure of bronchial mucosa models to e-cigarette fruit flavour 2 resulted in increased markers of inflammation and oxidative stress at the transcript level, regardless of the presence of nicotine. On the other hand, exposing alveolar mucosa models to e- cigarette fruit flavour 1 increased inflammation and oxidative stress markers at the transcript level in the absence of nicotine. However, exposure of alveolar mucosa models to e-cigarette fruit flavour 2 decreased inflammatory mediators at the transcript level, regardless of the presence of nicotine. In conclusion, our findings suggest that the toxic effects differed between models and flavours, indicating that different lung regions react differently and that different flavour compositions have different exposure effects.In Paper IV, exposure of bronchial mucosa models to e-cigarette vapours in vitro increased transcript expression of mucociliary markers FOXJ1, CFTR, and KCNMA1. Exposure of alveolar mucosa models to e-cigarette vapours decreased transcript expression of epithelial junction protein marker claudin. On the other hand, exposure to CSC and dual exposure to e-cigarettes and CSC increased junction protein markers in alveolar models. In bronchial models, exposure to e-cigarettes and dual exposures increased transcript expression of inflammatory (IL6 and IL8) and oxidative stress (HMOX1) markers. HMOX1 also increased after CSC exposures. In alveolar models, markers of inflammation and oxidative stress were decreased after e-cigarette exposures. Exposure to CSC and dual exposures increased total cellular ROS and surface TLR expression in both bronchial and alveolar models. In contrast, exposure to e-cigarettes showed no significant changes in either type of cell model. In conclusion, exposure to e-cigarettes had different effects in bronchial and alveolar lung mucosa models. Additionally, exposure to e-cigarettes or CSC had varying effects in the lung models.List of scientific papersI. Sompa SI, Zettergren A, Ekström S, Upadhyay S, Ganguly K, Georgelis A, Ljungman P, Pershagen G, Kull I, Melen E, Palmberg L, Bergström A. Predictors of electronic cigarette use and its association with respiratory health and obesity in young adulthood in Sweden; findings from the population-based birth cohort BAMSE. Environmental Research. 2022 May 15;208:112760. https://doi.org/10.1016/j.envres.2022.112760II. Sompa SI, Ji J, Rahman M, Sjögren B, Upadhyay S, Ganguly K, Olin AC, Bergström A, Palmberg L. Local and systemic effects in e-cigarette users compared to cigarette smokers, dual users, and non-smokers. [Manuscript]III. Ganguly K, Nordström A, Thimraj TA, Rahman M, Ramström M, Sompa SI, Lin EZ, O'Brien F, Koelmel J, Ernstgård L, Johanson G, Pollitt KJG, Palmberg L, Upadhyay S. Addressing the challenges of E-cigarette safety profiling by assessment of pulmonary toxicological response in bronchial and alveolar mucosa models. Scientific reports. 2020 Nov 24;10(1):20460. https://doi.org/10.1038/s41598-020-77452-wIV. Sompa SI, Upadhyay S, Ganguly K, Bergström A, Ji J#, Palmberg L#. Epithelial effects of exposure to e-cigarettes alone or in combination with cigarette smoke using multicellular lung mucosa models. #Equally contributed [Manuscript]</p
Autism in young adulthood : etiology, health outcomes and sex differences
No full textAutism is a spectrum of neurodevelopmental conditions characterized by differences and difficulties in social communication, behavioral flexibility, and sensory processing. The progressive understanding of autism, recognizing it as a lifelong and heterogeneous condition, together with research priorities voiced by the autistic community, has underscored the need to better understand the continuity of autism and associated mental and physical health challenges beyond childhood and into adulthood. The reconceptualization and the growing recognition of the experiences of autistic females has also emphasized the importance of understanding sex-specific healthcare needs to adequately support autistic individuals of all sexes.This thesis uses nationwide Swedish registers to enhance the understanding of etiological factors underlying autism into young adulthood, as well as the mental and physical health of autistic females and males compared to nonautistic individuals and each other.In Study I we estimated the heritability of a clinical autism diagnosis and the etiological stability of autistic traits from childhood to adulthood. Heritability estimates of the clinical diagnosis were high in childhood and adulthood. Genetic influences shared across different ages contributed to the moderate stability of autistic traits into adulthood, although we also observed new genetic influences emerging over time. The findings highlight the importance of genetic factors on autism across development into adulthood.Study II investigated sex differences in psychiatric diagnoses preceding autism diagnosis and their stability, indicated through continued specialist care needs within five years after autism diagnosis. Compared to autistic males, autistic females were more likely to receive various psychiatric diagnoses prior to autism diagnosis with persistent difference over a ten-year period. Preceding diagnoses were associated with a later age at autism diagnosis in females compared to males. The stability varied between conditions but was higher in females for most conditions. This study demonstrates the persistently increased vulnerability of autistic females to be diagnosed with potentially persistent psychiatric conditions from an early age and underscores the need for better understanding the fluctuating nature of mental health problems in autistic individuals over time.In Study III we explored sex differences in psychiatric diagnoses and hospitalizations in autistic compared to nonautistic young adults. Both, autistic females and males were at increased risk for various psychiatric diagnoses and hospitalization due to different psychiatric conditions compared to nonautistic individuals of the same sex. Compared to autistic males, autistic females were more likely to experience mental health problems and be hospitalized for different conditions. The findings emphasize the profound mental health support required by autistic individuals, notably autistic females, in the transition to adulthood across care levels and consequently the need for clinical monitoring and tailored support.Study IV examined the association between childhood somatic conditions and psychiatric conditions in young adulthood and vice versa (childhood psychiatric conditions and adult somatic conditions). Childhood conditions, except for epilepsy, were generally associated with a risk increase across different adult mental and physical health problems in autistic individuals. However, risk increases were smaller than what was observed among nonautistic individuals, pointing to an already increased risk in autistic individuals, particularly for mental health problems. Similar patterns were observed for autistic females and males, and for individuals with and without intellectual disability, though there were differences in absolute risk between these groups.Together, the findings from this thesis enhance the understanding of etiological underpinnings of autism continuity into adulthood, highlighting the importance of genetic factors. Moreover, they illustrate the extensive mental and physical health challenges among autistic young adults, which appear to influence each other. In addition, our findings identify autistic females as a group with particularly elevated care needs, apparent at different time points and across secondary care levels. In conclusion, these insights underscore the importance of tailored interventions and long-term support strategies to address the complex and evolving needs of autistic females and males.List of scientific papersI. Martini, M. I., Butwicka, A., Du Rietz, E., Kanina, A., Rosenqvist, M. A., Larsson, H., Lichtenstein, P. & Taylor, M. J. (2024). Age effects on autism heritability and etiological stability of autistic traits. Journal of Child Psychology and Psychiatry. 65(9), 1135-1144.https://doi.org/10.1111/jcpp.13949II. Martini, M. I., Kuja-Halkola, R., Butwicka, A., Du Rietz, E., Kanina, A., Brikell, I., Chang, Z., Larsson, H., Lichtenstein, P., Bölte, S., Happé, F. & Taylor, M. J. Sex differences in psychiatric diagnoses preceding autism diagnosis and their stability post autism diagnosis. [Manuscript]III. Martini, M. I., Kuja-Halkola, R., Butwicka, A., Du Rietz, E., D'Onofrio, B. M., Happé, F., Kanina, A., Larsson, H., Lundström, S., Martin, J., Rosenqvist, M. A., Lichtenstein, P. & Taylor, M. J. (2022). Sex differences in mental health problems and psychiatric hospitalization in autistic young adults. JAMA psychiatry. 79(12), 1188-1198.https://doi.org/10.1001/jamapsychiatry.2022.3475IV. Martini, M. I., Kuja-Halkola, R., Butwicka, A., Du Rietz, E., Kanina, A., Larsson, H., Liu, S., Brikell, I., Chang, Z., Lichtenstein, P. & Taylor, M. J. The longitudinal bi-directional association between psychiatric and somatic conditions in autistic individuals. [Manuscript]</p
Post-migration and stigma-based factors influencing mental health among refugees and sexual minority migrants
No full textThis thesis investigated how experiences in the new country of residence influence mental health among two subgroups among migrants that have been shown to be at heightened risk of developing poor mental health: refugees and sexual minorities (i.e., individuals identifying as lesbian, gay, bisexual, or other non-heterosexual orientation).The first study showed that refugees from Syria recently resettled in Sweden had high levels of poor mental health, including depression, anxiety, posttraumatic stress disorder (PTSD), and low subjective wellbeing. More than half of the participants in the study met criteria for at least one of the studied types of poor mental health. A majority of the participants further had experienced several traumas in Syria and across the migration route, including war, loss of loved ones, and physical and sexual violence, including torture. Stressful experiences in Sweden, like feeling isolated or excluded, having financial difficulties, feeling disrespected because of oneŐs origin, and being sad because of not being reunited with family members, were also common. Those who had often had these types of stressful experiences were more likely to suffer from poor mental health compared to those who had not had these experiences often.The second study described the development of an instrument for assessing post-migration stress among refugees, the Refugee Post-Migration Stress Scale (RPMS). The RPMS was used in the first study, and data from that study was used to test whether the instrument assessed post-migration stress in the way that we intended. The second study showed that the RPMS is an instrument wellsuited for assessing post-migration stress among refugees.The third study showed that sexual minorities who had migrated to Sweden were at greater risk of poor mental health compared to heterosexuals born in Sweden. This risk was similar to that found among sexual minorities born in Sweden. Sexual minority migrants born outside of Europe were, however, no more likely than heterosexuals born in Sweden to have received psychiatric treatment, despite the greater risk of mental health symptoms in this group. Interestingly, sexual minority migrants born outside of Europe were less likely to have experienced discrimination compared to Swedish-born sexual minorities, which impacted the risk of poor mental health.The fourth and final study showed that sexual minorities in Europe who had a migration background or identified as being ethnic minorities were at greater risk of depressive symptoms compared to sexual minorities with no migration background or ethnic minority status. They were also more likely to have been exposed to discrimination because of their sexual orientation, and to threats or violence, and they were more likely to conceal their sexual orientation. The study further showed that sexual minority individuals Đ both those with migration background or ethnic minority status and those without Đ residing in countries characterized by laws and policies that fail to protect or even discriminate against sexual minorities, and with negative population attitudes towards sexual minorities, were at greater risk of depressive symptoms and sexual orientation concealment compared to those living in countries with more favorable structural climate for sexual minorities.Taken together, the findings in this thesis show that factors in the new country of residence, including stressful experiences of discrimination, social isolation, financial difficulties and family separation, and stigma towards sexual minorities, including unfavorable laws and policies, negative social attitudes, and experiences of discrimination, have adverse effects on the mental health of refugees and sexual minority migrants. These findings point to the importance of reducing post-migration stress and stigma towards sexual minorities.List of scientific papersI. Tinghšg P, Malm A, Arwidsson C, Sigvardsdotter E, Lundin A & Saboonchi F. Prevalence of mental ill health, traumas and postmigration stress among refugees from Syria resettled in Sweden after 2011: a population-based survey. BMJ open. 2017;7. https://doi.org/10.1136/bmjopen-2017-018899 II. Malm A, Tinghšg P, Narusyte J & Saboonchi, F. The Refugee Post-Migration Stress Scale (RPMS) Đ development and validation among refugees from Syria recently resettled in Sweden. Conflict and Health. 2020. https://doi.org/10.1186/s13031-019-0246-5 III. Malm A, Tinghšg, P & BrŠnstršm, R. Differences in mental health symptoms and treatment for common mental disorders by sexual orientation and migration background in a population-based sample. [Submitted]IV. Malm A, Tinghšg, P & BrŠnstršm, R. Depressive symptoms and stigma among sexual minority individuals with migration background or ethnic minority status: an investigation of sexual orientation structural stigma and migrant structural stigma across 30 European countries. [Manuscript]</p
Multiomic modelling of schizophrenia using patient-derived brain organoids
No full textSchizophrenia (SCZ) is a highly heritable mental disorder characterized by disabling psychotic and cognitive symptoms, making a significant contribution to the global disease burden. The first symptoms typically appear in late adolescence and typically progress in a relapsing or chronic pattern. Existing treatments are only partially effective in restoring function, with many patients suffering from side effects and a lifelong disability. The growing number of identified genetic and environmental risk factors implicate deviation in early neurodevelopmental processes but despite this, the pathophysiology remains largely elusive. This is primarily due to the unavailability of diseased or "at-risk" brain tissue, as well as the absence of suitable experimental models to elucidate the mechanisms by which these risk factors affect the brain.However, recent studies have linked the genetic risk for SCZ to excessive microglia-mediated elimination of synapses, utilizing patient-derived cellular models based on induced pluripotent stem cells (iPSCs) from individuals with SCZ. Brain postmortem studies also confirm a loss of synapses in SCZ, and imaging studies suggest that this occurs already during the first psychotic episode.The main aim of this thesis was to investigate how risk factors for SCZ, genetic as well as environmental, influence early brain development and contribute to pathophysiology and clinical manifestations taking place much later in early adulthood. To do this, we used a multi- pronged approach including patient-derived cellular modeling, with high-resolution sequencing techniques across molecular layers applied to human brain organoids, as well as clinical studies based on cerebrospinal fluid (CSF) collected from patients that experienced their first psychotic episode.In paper I, we exposed whole brain organoids with innately developing microglia to SARS- CoV-2, a virus linked to a neurodevelopmental spectrum diagnosis in young children and SCZ in adults. We discovered that SARS-CoV-2, despite a limited neurotropism, causes a loss of synaptic termini, similar to genetic risk factors for SCZ. Utilizing high-resolution imaging, we observed an increased uptake of synaptic material in microglia, while single cell transcriptomic profiling revealed an interferon-responsive state of microglia, promoting synapse elimination.Clinical studies of postmortem brain tissue and CSF obtained from patients with SCZ have revealed elevated levels of kynurenic acid, an endogenous metabolite of tryptophan with antagonistic properties on the N-methyl-D-aspartate (NMDA) and a7 nicotinic acetylcholine (a7nAch) receptors. In paper II, we demonstrated that extrinsic kynurenic acid decreased neuronal activity while leading to a loss of synapses in co-cultures of glutamatergic neurons and microglia-like cells from patients. Further using patient-derived forebrain organoids with innately developing microglia we show that pharmacological inhibition of kynurenic acid production caused a decreased internalization of synaptic structures in microglia. Our transcriptomic analyses also explored gene expression networks centered on the kynurenic acid-producing enzymes that enrich for common genetic SCZ risk variants and genes governing synaptic activity.In paper III, we focused on another complement factor, C1Q, that initiates the classical pathway used by microglia. The most strongly associated risk locus for SCZ can largely be explained by genomic elements that increase complement component 4A (C4A) expression and C4A proteins levels are elevated in patients first-episode SCZ. Experimental studies then show that C4A can bind synaptic structures and facilitate internalization of synaptic elements. In CSF obtained from patients with first-episode psychosis, we observed lower C1q levels while postmortem brain tissue gene expression data indicated lower C1Q mRNA expression.In paper IV, we utilized multi-lineage forebrain organoids derived from monozygotic twins discordant for SCZ and undertook an unbiased approach with combined single-cell transcriptomics and epigenomics. Our findings revealed early developmental disruptions in a cell type-specific manner across both modalities as well as an increased uptake of synaptic material in microglia within the patient-derived models.The work presented in this thesis suggest that different risk factors for SCZ can converge overlapping neurodevelopmental processes with the potential to influence pathophysiology observed in first-episode patients. Further, they strengthen the role of integrated multi- disciplinary approaches to study the causes of SCZ.List of scientific papersI. Samudyata*, Ana O. Oliveira*, Susmita Malwade*, Nuno Rufino de Sousa, Sravan K. Goparaju, Jessica Gracias, Funda Orhan, Laura Steponaviciute, Martin Schalling, Steven D. Sheridan, Roy H. Perlis, Antonio G. Rothfuchs & Carl M. Sellgren. SARS-CoV-2 promotes microglial synapse elimination in human brain organoids. Molecular Psychiatry. 27, 3939-3950 (2022). https://doi.org/10.1038/s41380-022-01786-2II. Funda Orhan, Susmita Malwade, Neda Khanlarkhani, Asimenia Gkoga, Oscar Jungholm, Marja Koskuvi, Šárka Lehtonen, Lilly Schwieler, Kent Jardemark, Jari Tiihonen, Jari Koistinaho, Sophie Erhardt, Göran Engberg, Samudyata, Carl M. Sellgren. Kynurenic acid promoted activity-dependent synaptic pruning in schizophrenia American Journal of Psychiatry. [Accepted]III. Marja Koskuvi*, Susmita Malwade*, Jessica Gracias Lekander, Elin Hörbeck, Sanna Bruno, Jessica Holmen Larsson, Aurimantas Pelanis, Anniella Isgren, Anneli Goulding, Helena Fatouros-Bergman, Samudyata, Martin Schalling, Fredrik Piehl, Sophie Erhardt, Mikael Landen, Simon Cervenka, Funda Orhan & Carl M. Sellgren. Lower complement C1q levels in first-episode psychosis and in schizophrenia. Brain Behaviour and Immunity. 117, 313-319 (2024). https://doi.org/10.1016/j.bbi.2024.01.219IV. Susmita Malwade, Samudyata, Jessica Gracias Lekander, Angelika Langeder, Katharina Weinberger, Marja Koskuvi, Luis Enrique Arroyo-García, Jari Koistinaho, Jari Tiihonen, Carl M. Sellgren. Developmental multi-omics of monozygotic twins discordant for schizophrenia. 2024. [Manuscript]*equal contribution; co-first authors</p
Healthy children as stem cell donors to severely ill siblings : the experiences of donors, parents and health care professionals
No full textBackground: Advances in hematopoietic stem cell transplantation (HSCT) have expanded its application to a wider range of diseases in both adults and children and is a well- established treatment today. These advances have led to an increase in the number of transplantations and an increase in survival for children with cancer and hematological disorders. Finding an HLA-identical donor is crucial, and a biological sibling has a 25% likelihood of being a match.Aim: The primary objective of this thesis is to expand empirical knowledge regarding the experiences of children and adolescents in Sweden who donate stem cells to their seriously ill siblings. To gain a comprehensive perspective, the study also examines the experiences of their parents, focusing on decision-making and ethical considerations in the donation process. Additionally, the research explores the challenges and perceptions of healthcare professionals involved in caring for these young donors and their families, particularly during the informed consent process, and the moral dilemmas they may encounter.Methods: All four studies have a qualitative approach. Interviews have been conducted with children and adolescents, their parents and healthcare professionals at paediatric HSCT centers. The interviews of the healthcare professionals were preceded by observational studies of informational conversations with potential donors who are minors and their parents. The goal was to observe and interview at all HSCT centers in Sweden.Result: Healthy siblings experience that to donate was the presumed choice when a sibling is ill. They were proud to help the sibling, but it was not a choice situation. They were primarily focusing on the ill sibling and the outcome and downplayed their own efforts and were in need of more understandable information and support through play and talks.Parents lived with a threat of losing a child and an uncertain future but still had to managing family life amid the chaos. The parents did not experience dual loyalty at the time because they were completely focused on the cure for the ill child and had difficulty providing for the healthy children in the family. The healthcare staff tried to find practical solutions for the ethically difficult situation of obtaining good enough consent for the healthy child who is to donate stem cells. This takes place through child and proxy consent, but sometimes also pseudo-consent.Conclusions: These findings highlight the importance of providing age-appropriate information, engaging in dialogue with the child and describing available treatment options. Such informed decision-making ensures that potential donors can make choices they can live with, regardless of the transplantation outcome for their sibling. Many parents did not express their conflicting feelings, as they lived under the constant threat of losing a child. They continued to struggle on, often hiding their conflicting loyalties, which were not mentioned in the interviews. Their primary focus remained on curing the child with a life-threatening disease, which made it obvious that the healthy child would donate stem cells. The main concern of health professionals was to find a pragmatic solution to an ethically challenging situation. They endeavoured to obtain informed consent from both the parents and the donated child, using methods such as child consent, proxy-consent or pseudo-consent. They tried to create an environment that favoured information sharing with the minor child and his/her parents.List of scientific papersI. Rinaldo, C., Stenmarker, M., Frost, B. M., Øra, I., & Pergert, P. (2022). Is there a choice when a sibling is ill? Experiences of children and adolescents who donated stem cells to a sibling. European Journal of Oncology Nursing. 58, 102147. https://doi.org/10.1016/j.ejon.2022.102147II. Rinaldo, C., Stenmarker, M., Øra, I., & Pergert, P. (2024). Living with the threat of losing a child: Parents' experiences of the transplantation process with a severely ill child who received stem cells from a sibling. Journal of Pediatric Nursing. 77, e495-e502. https://doi.org/10.1016/j.pedn.2024.05.015III. Rinaldo, C., Stenmarker, M., Øra, I., & Pergert, P. No conflicting loyalties in parents when their healthy child donates stem cells to a severely ill sibling: An interview study. Journal of Pediatric Hematology/Oncology Nursing. [Accepted]IV. Rinaldo, C., Stenmarker, M., Øra, I., Pergert, P. (ND) Healthcare professionals' experiences of caring for children/adolescents who will donate stem cells to ill siblings - main concerns and potential dilemmas. [Manuscript]</p
The role of thyroid hormone function and prokineticin-1 in pregnancy and offspring outcome in women with polycystic ovary syndrome
No full textThyroid disorders are common in women with polycystic ovary syndrome (PCOS) and both conditions are associated with adverse pregnancy outcomes, such as intrauterine growth restriction, preterm delivery, and gestational diabetes (GDM). Furthermore, increased serum levels of prokineticin-1 (PROK1) are associated with similar complications. However, data is scarce on how pregnancy and neonatal outcomes are associated with maternal thyroid function and PROK1 in PCOS. Two similar randomized controlled studies, in which pregnant women with PCOS were treated with metformin or placebo and followed longitudinally during pregnancy, provided the data for papers I-IV. In this thesis, we aimed to study the role of thyroid hormone function and PROK1 for pregnancy and offspring outcomes in PCOS, as well as the effect of metformin.In paper I, we studied thyroid status longitudinally in association with pregnancy complications, and in relation to metformin treatment in pregnant women with PCOS. Metformin treatment resulted in less decrease in free thyroxine (fT4) compared to placebo without affecting thyroid stimulating hormone (TSH). Moreover, a smaller decrease in fT4 correlated to less maternal weight gain and tended to be associated with a lower risk of GDM.In paper II, we analyzed the contribution of PROK1 in the development of pregnancy complications, and in relation to metformin treatment and the PCOS phenotypes. Maternal serum-PROK1 in the second trimester was not predictive of pregnancy complications. Women using metformin at conception and/or during pregnancy had lower PROK1 levels, as well as women with hyperandrogenic PCOS phenotypes.In paper III, we aimed to study associations between maternal thyroid function and offspring’s anthropometry. Higher maternal fT4 in early pregnancy and a greater decrease in fT4 during pregnancy was associated with lower offspring birthweight and shorter birth length. Higher TSH by mid-gestation and smaller increase in TSH during pregnancy were associated with less risk of large for gestational age (LGA) neonates.In paper IV, we examined associations of maternal thyroid function during pregnancy with measures of insulin resistance. We found that lower maternal fT4 levels and smaller TSH increase during pregnancy were associated with higher subsequent insulin/homeostatic model assessment for insulin resistance (HOMA-IR) and glucose levels, respectively.In summary, metformin treatment during pregnancy in women with PCOS induces less decrease in fT4 compared to placebo, without affecting TSH. This change in fT4 tends to be associated with a lower risk of GDM. PROK1 in the second trimester does not predict complications. Even subclinical variations in maternal thyroid function might play a role for birth anthropometrics of PCOS offspring and predict metabolic profile later in pregnancy.List of scientific papersI. Thyroid Status During Pregnancy in Women with Polycystic Ovary Syndrome and the Effect of Metformin. Trouva A, Alvarsson M, Calissendorff J, Åsvold BO, Vanky E*, Hirschberg AL*. Front Endocrinol (Lausanne). 2022 Feb 21;13:772801. *Shared last authorship. https://doi.org/10.3389/fendo.2022.772801 II. Maternal serum levels of prokineticin-1 related to pregnancy complications and metformin use in women with polycystic ovary syndrome: a post hoc analysis of two prospective, randomised, placebo-controlled trials. Ujvari D, Trouva A, Hirschberg AL*, Vanky E*. BMJ Open. 2023 Nov 21;13(11):e073619. *Shared last authorship. https://doi.org/10.1136/bmjopen-2023-073619 III. Maternal thyroid function and offspring birth anthropometrics in women with polycystic ovary syndrome. Trouva A, Alvarsson M, Calissendorff J, Åsvold BO, Ujvari D, Hirschberg AL* and Vanky E*. *Shared last authorship. [Submitted]IV. Maternal thyroid function as predictor of markers of insulin resistance in pregnant women with PCOS. Trouva A, Vanky E, Alvarsson M, Calissendorff J, Åsvold BO, Ujvari D* and Hirschberg AL*. *Shared last authorship. [Manuscript]</p
Improvement of microbiological diagnostics in sepsis
No full textSepsis, a life-threatening condition characterized by a dysregulated host response to infection, poses significant diagnostic and therapeutic challenges, contributing to high morbidity and mortality rates worldwide. The overall objective of this thesis is to provide an insight in how to improve the microbiological diagnosis of sepsis both by optimizing current blood culture (BC) practices and by evaluating novel diagnostic methods. The thesis also explores the impact on microbiological diagnosis imposed by two major recent events; the change of clinical sepsis criteria and the COVID-19 pandemic. The thesis consists of the four following projects:Study I was a prospective non-inferiority study, assessing the utility of implementing a single-sampling strategy (SSS) versus multi-sampling strategy (MSS) for BCs in sepsis. The study group consisted of 549 suspected BSI episodes. The outcomes were detection of pathogens and occurrence of sample contamination. We found no significant difference in pathogen detection rates, and a tendency toward less contamination using SSS, thereby suggesting a potential simplification of the BC sampling protocol without compromising diagnostic yield.In Study II, we described microbiological findings when using different sepsis criteria (Sepsis-2 versus Sepsis-3) in 514 patients with suspected sepsis. There were 357/514 (79.5%) Sepsis-3 and 411/514 (80.0%) Sepsis-2 episodes, with twothirds of patients fulfilling both definitions. The BC positivity rate was 130/357 (36.1%) and 145/411 (35.3%) in Sepsis-2 and Sepsis-3, respectively. The study shows that even with the improved definition, the frequency of BC positivity remains largely consistent.Study III explored the changes in bacteremia rates during the COVID-19 pandemic, comparing BCs from patients with COVID-19 (n = 3,027) with two control groups without COVID-19, consisting of a contemporary group (n = 6,663) during the same period, as well as historical group (n = 8,175) from a year prior. Clinically relevant growth was found in 6.5% of the BC episodes in the COVID-19 group compared to 10.8% and 10.4% in the control groups respectively. Contamination was present in 8.4% in the COVID-19 group compared to 5.0% and 4.3% in the control groups. The study concluded that in COVID-19 patients, frequency of relevant growth was lower and contamination rates were higher.Study IV retrospectively evaluated the diagnostic performance of T2Bacteria, a rapid molecular-based tool, against traditional BCs. We compared 640 T2Bacteria results to all BCs sampled within ± 72 hours of the T2Bacteria sampling. In total, 46/101 (45.5%) episodes were T2Bacteria positive/BC negative and 26/101 (25.7%) were T2Bacteria negative/BC positive. Only 29 (28.7%) episodes were positive using both methods. Total turn-around time was 27 hours and 33 minutes for T2Bacteria and 36 hours and 48 minutes for BCs (p Collectively, the findings from these studies adds to the understanding of microbiological diagnosis in sepsis, and highlights the need of both improving established methods, as well as the judicious implementation of novel techniques.List of scientific papersI. Single-sampling strategy versus multi-sampling strategy for blood cultures in sepsis: a prospective non-inferiority study. David Yu, Anna Ekwall-Larson, Åsa Parke, Christian Unge, Claes Henning, Jonas Sundén-Cullberg, Anna Somell, Kristoffer Strålin*, Volkan Özenci*. Front Microbiol. (2020) 11:1639. *Equal contribution. https://doi.org/10.3389/fmicb.2020.01639 II. Correlation of clinical sepsis definitions with microbiological characteristics in patients admitted through a sepsis alert system; a prospective cohort study. David Yu, David Unger, Christian Unge, Åsa Parke, Jonas Sundén-Cullberg, Kristoffer Strålin, Volkan Özenci. Ann Clin Microbiol Antimicrob. (2022) 21:7. https://doi.org/10.1186/s12941-022-00498-3 III. Low prevalence of bloodstream infection and high blood culture contamination rates in patients with COVID-19. David Yu, Karolina Ininbergs, Karolina Hedman, Christian G. Giske, Kristoffer Strålin, Volkan Özenci. PLoS ONE. (2020) 15(11). https://doi.org/10.1371/journal.pone.0242533 IV. Performance of T2Bacteria in relationship to Blood Cultures: a retrospective comparative study. David Yu, Anna Ekwall-Larson, Volkan Özenci. [Submitted]</p