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Etiological insights and therapeutic target prioritization in multiple sclerosis using multi-omics and population data
No full textBackground: Multiple sclerosis (MS) is an immune-mediated chronic central nervous system disease, driven by inflammation and neurodegenerative processes, and characterized by demyelination and axonal injury. It affects nearly three million people worldwide, typically strikes young adults, and leads to progressive disabilities. Despite advances, the underlying causes and pathogenesis of MS remain elusive, limiting progress in early diagnosis and the development of effective treatments.Aims: This thesis aimed to elucidate the etiology and pathogenesis and to translate these insights into therapeutic and diagnostic opportunities. Specifically, these studies aimed to investigate (1) whether elevated testosterone levels influence the risk of MS; (2) whether MS risk increases among individuals with relatives affected by other immune-mediated inflammatory diseases (IMIDs), and whether shared genetic architecture plays a role; (3) potential causal proteins underlying MS susceptibility and opportunities for drug discovery and repurposing; (4) potential causal proteins underlying MS progression and opportunities for drug discovery and repurposing; and (5) clinically actionable diagnostic biomarkers in cerebrospinal fluid (CSF) and plasma.Methods: The combination of large-scale population-based observational studies with genome-wide cross-trait analyses was used to explore the links between polycystic ovary syndrome (serving as a proxy for elevated testosterone levels) and MS, as well as familial co-aggregation of MS with IMIDs. Multi-omics integrative analyses were conducted to identify potential causal proteins detected in plasma and the brain tissue for MS susceptibility and progression. Pathway annotation, protein interaction, and multi-omics verification analyses were performed to elucidate the underlying molecular mechanisms and provide evidence for drug development. Ultra-sensitive proteomic profiling technologies (Olink and NULISA) were applied to matched CSF and plasma samples to discover diagnostic biomarkers using multivariable linear regression. The diagnostic performances were evaluated.Results: No evidence was found suggesting a causal role of elevated testosterone in MS risk, while increased MS risk was identified among individuals with first- degree relatives affected by IMIDs, and demonstrated a shared genetic basis between MS and IMIDs. Integrative analyses identified 18 proteins exhibiting putative causal links with MS susceptibility and six with progression. These proteins interacted with known MS drug targets and linked with drugs currently indicated for other conditions, underscoring their potential for drug discovery and repurposing. In the diagnostic biomarker identification study, 39 CSF proteins were significantly associated with MS, and seven plasma proteins showed nominal associations. Several CSF proteins demonstrated excellent diagnostic performance (AUC up to 0.98), while the plasma panel consisting of seven proteins achieved an AUC of 0.92, highlighting the potential of minimally invasive biomarkers.Conclusions: The thesis established a translational pipeline linking observational findings with genetic and molecular insights, and ultimately providing evidence for clinical application, potentially advancing precise strategies for the prevention, treatment, and diagnosis of MS.List of scientific papersI. Exploring the relationship between polycystic ovarian syndrome, testosterone, and multiple sclerosis in women: A nationwide cohort study and genome-wide cross-trait analysis. Yuan Jiang, Carolyn E Cesta, Qianwen Liu, Elaine Kingwell, Pernilla Stridh, Klementy Shchetynsky, Tomas Olsson, Ingrid Kockum, Elisabet Stener-Victorin, Xia Jiang, Ali Manouchehrinia. Multiple Sclerosis Journal. 2024 Dec;30(14):1765-74.https://doi.org/10.1177/13524585241292802II. Shared aetiology underlying multiple sclerosis and other immune mediated inflammatory diseases: Swedish familial co-aggregation and large-scale genetic correlation analyses. Qianwen Liu, Yuan Jiang, Thomas Frisell, Pernilla Stridh, Klementy Shchetynsky, Lars Alfredsson, Ingrid Kockum, Ali Manouchehrinia, Xia Jiang. Journal of Autoimmunity. 2024 Sep 1;148:103294.https://doi.org/10.1016/j.jaut.2024.103294III. Multi-omics integration prioritizes potential drug targets for multiple sclerosis. Yuan Jiang, Qianwen Liu, Pernilla Stridh, Ingrid Kockum, Tomas Olsson, Lars Alfredsson, Lina-Marcela Diaz-Gallo, Xia Jiang. Proceedings of the National Academy of Sciences. 2025 Jul 1;122(26):e2425537122.https://doi.org/10.1073/pnas.2425537122IV. Multi-omics integration provides biological insight and prioritizes potential drug targets in multiple sclerosis progression. Yuan Jiang, Jinyu Xiao, Ingrid Kockum, Pernilla Stridh, Qianwen Liu, Tomas Olsson, Lars Alfredsson, Xia Jiang. [Submitted]V. Identifying diagnostic biomarkers for multiple sclerosis using multi-platform proteomic profiling of matched cerebrospinal fluid and plasma. Yuan Jiang, Cecilia Vuong, Mohsen Khademi, Fredrik Piehl, Tomas Olsson, Ingrid Kockum, Jesse Huang. [Manuscript]</p
Preterm Supraglottic Airways Succeed in Neonatal Resuscitation Simulations
No full textAim Advanced airway management for preterm infants is limited. Supraglottic airway devices may provide an alternative when face‐mask ventilation fails or intubation is not feasible. Preterm‐sized devices are now accessible. This study aimed to evaluate ventilation outcomes in manikins to determine whether progression to clinical testing is warranted. Methods This observational manikin study included healthcare workers at Sachs Children and Youth Hospital, Stockholm, Sweden, in March 2022. Insertion time, success rates, mask leakage, ventilatory rate, tidal volumes, and airway pressures were assessed using three manikins (2200, 950, 500 g) with one commercially available device (i‐gel size 1) and three prototype sizes (neo‐i‐gel 0.85, 0.75, 0.65). Mask leakage was categorised as good (< 25%), acceptable (25%–49%), or unacceptable (≥ 50%). Participant satisfaction was recorded using a Likert scale. Results Across 243 sessions conducted by nine physicians and 18 nurses, optimal device sizes were 0.85 for the 2200 g and 950 g manikins, and 0.75 for the 500 g manikin, based on mask leakage and tidal volume performance. High insertion success and consistent ventilatory rates were found. Participant satisfaction was positive. Conclusion Preterm‐sized supraglottic airway devices appeared feasible for simulated neonatal resuscitation. Further clinical studies are urgently needed to validate their safety and effectiveness in clinical practice.</p
Natural Selection of a Virus-Protective FUT2 Variant Following the Transition to Agriculture.
No full textCommon enteric viruses rely on sugars mediated by the galactoside 2-alpha-L-fucosyltransferase 2 (FUT2) enzyme to infect host cells. Analyzing 4,343 ancient genomes, we map a premature stop codon in FUT2, which was introduced into Europe by migrating Anatolian farmers ∼6000 BC and provide evidence for positive selection. Using data from ∼700,000 present-day individuals, we confirm its protective effect against viral gastroenteritis. Experiments with intestinal organoids reveal that only homozygous carriers are protected against noroviruses and rotaviruses but not sapovirus. Our rotavirus findings resolve a long-standing contradiction between epidemiological data and experiments. Contrary to previous reports, we find no association between FUT2 loss of function and Helicobacter pylori infection. However, carriers exhibit an increased risk of gastric ulcers and gallbladder disease, associations replicated with an independent loss-of-function variant in East Asia. These findings suggest that the transition to agriculture and increased pathogen exposure drove positive selection of this allele.</p
Tissue specific regulation of human ILC2 in allergy and asthma
No full textAsthma is one of the most common non-communicable diseases, affecting over 300 million people worldwide. It is a heterogeneous condition comprising several endotypes, yet all share the hallmark of dysregulated immune responses driving airway inflammation. The most prevalent form, type 2-high asthma, is mediated by aberrant activation of type 2 immune cells, including type 2 innate lymphoid cells (ILC2), type 2 T helper (Th2), and type 2 cytotoxic T (Tc2) cells. We and others have previously shown that the phenotype and function of ILC2 are strongly shaped by their microenvironment, but how human ILC2 are regulated in asthma and allergy remains incompletely understood.In this thesis, we investigated how metabolic status, biologics therapy, lipid mediators, and epithelial-immune crosstalk shape ILC2 function in asthma. By combining patient cohorts with mechanistic studies, we aimed to clarify the factors that sustain or modulate type 2 airway inflammation. Although this work primarily focused on ILC2, related lymphocytes were also analyzed to capture the broader network of immune cells orchestrating airway inflammation.In Paper I, we studied how metabolic dysregulation affects ILC2 function in a cohort of asthmatic individuals with overweight or obesity, well-known risk factors for asthma. In those patients, ILC2 displayed an inflammatory phenotype characterized by elevated CD45RO expression, while IL-7Ra expression correlated with body-fat percentage, suggesting a link between metabolic status and ILC2 activation. Functionally, these ILC2 displayed features of corticosteroid resistance, the mainstay of asthma therapy, suggesting a mechanism underlying poor treatment response.In Paper II, we analyzed blood samples from patients with severe asthma before and after initiation of biologics therapy targeting IL-5 (mepolizumab) or IL-4Ra (dupilumab). Type 2 lymphocytes, including ILC2, Th2, and Tc2 cells, accumulated in the circulation during mepolizumab therapy, while ILC2 exhibited a similar trend in patients on dupilumab. ILC2 acquired a mature CD117low phenotype, while Th2 and Tc2 cells adopted a central memory profile in patients on mepolizumab. Single-cell RNA sequencing and stimulation assays of mepolizumab-treated patients further revealed altered expression of tissue-homing receptors and increased inflammatory potential, indicating that biologics may redistribute rather than eliminate pathogenic cells capable of reigniting inflammation once treatment ends.In Paper III, we examined how bioactive lipid mediators regulate ILCs. We found that ILC3 produce prostaglandin E2 (PGE2), which enhances their cytokine production, but inhibits ILC2, which instead produce and depend on prostaglandin D2 (PGD2). During ILC2-to-ILC3 transdifferentiation, PGD2 synthesis decreased while PGE2 increased alongside type 3 cytokine production. Despite this metabolic shift, transdifferentiated cells remained sensitive to PGE2 inhibition, indicating incomplete reprogramming and a hybrid ILC2/ILC3 phenotype. Such mixed effector profiles have been observed in chronic inflammatory diseases, including mixed granulocytic asthma, highlighting the need to better understand the regulators of this plasticity.In Paper IV, we developed a co-culture model combining both human bronchial epithelial cells (BECs) and ILC2 to study their reciprocal interactions. Rhinovirus (RV) infection of BECs induced TSLP release, which activated ILC2 to produce type 2 cytokines. Notably, BECs from asthmatic donors secreted TSLP even at baseline, sustaining chronic ILC2 activation. These findings highlight epithelial-immune crosstalk as a key driver of persistent airway inflammation in asthma and provide a model for future mechanistic studies.Collectively, our findings demonstrate that ILC2 function is dynamically regulated by metabolic, pharmacologic, and tissue-derived signals. The persistence and adaptability of ILC2 and related lymphocytes across different disease contexts may explain why certain asthma phenotypes are difficult to treat and point to new avenues for more precise and effective therapeutic intervention.List of scientific papersI. Sophia Björkander, Paul Maier, Maura Kere, Simon Kebede Merid, Lorenz Wirth, Whitney Weigel, Sandra Ekström, Inger Kull, Anna Bergström, Erik Melén, Jenny Mjösberg, Christopher Andrew Tibbitt. Innate lymphoid cells type 2 and CD8+ T cells are perturbed in overweight and obese individuals with asthma. Allergy 2023 Sep; 78(9):2533-2536. https://doi.org/10.1111/all.15728II. Lorenz Wirth, Whitney Weigel, Christoper T Stamper, Johan Kolmert, Sabrina de Souza Ferreira, Quirin Hammer, Maria Sparreman Mikus, Jakob Theorell, Lars | Andersson, Ann-Sofie Lantz, Eva Wallen- Nielsen, Anne Petrén, Craig E Wheelock, Apostolos Bossios, Nikolaos Lazarinis, Andrei Malinovschi, Christer Janson, Barbro Dahlén, Thomas Hochdörfer, Christopher Andrew Tibbitt, Sven-Erik Dahlén, Valentyna Yasinska, Jenny Mjösberg. High-Dimensional Analysis of Type 2 Lymphocyte Dynamics During Mepolizumab or Dupilumab Treatment in Severe Asthma. Allergy 2025 Sep; 80(9):2541-2556 https://doi.org/10.1111/all.16633III. Lorenz Wirth, Whitney Weigel, Efthymia Kokkinou, Johan Kolmert, Anna-Karin Johnsson, Alessandro Quaranta, Craig E Wheelock, Mattias Jangard, Sven-Erik Dahlen, Christopher Andrew Tibbitt, Thomas Hochdorfer, Jenny Mjösberg. PGE2 Enhances Human ILC3 Function But Inhibits ILC2-to-ILC3 Transdifferentiation. [Manuscript]IV. Jelena Pesic, Lorenz Wirth, Annemarie Hasselberg, Thomas Hochdörfer, Oliwia Slettengren, Katerina Pardali, Stephen Delaney, Jenny Mjösberg, Henric Olsson and Lena Uller. Exploring Bronchial Epithelial and ILC2 Interactions: A Novel Co-Culture Model for Asthma and Viral Infections. [Manuscript]</p
Cone-beam computed tomography in assessment of alveolar clefts
No full textChildren born with an alveolar cleft receive a higher radiation dose compared to other children at the same age. In addition, children are more sensitive to radiation in comparison to adults. The aim of this thesis was to investigate potential dose reduction strategies in radiological examinations of alveolar clefts and to evaluate the outcome of bone grafting of bilateral alveolar clefts.Paper I evaluated whether the radiation dose could be reduced by applying a low-dose protocol instead of the standard protocol. The study assessed the visibility of anatomical structures adjacent to the alveolar cleft with a blinded study setup. The result showed no significant difference between the low-dose protocol and the normal dose protocol. Using a low-dose protocol in cone-beam computed tomography (CBCT) examinations of alveolar clefts reduced the dose by approximately 70%.In paper II, the outcome of two-step bone grafting in bilateral alveolar clefts was evaluated by calculation of bone fill through comparison of preoperative and postoperative cleft volumes. After bone grafting, no significant difference was observed when comparing the first and second operated alveolar cleft. The mean bone fill was 40% in the whole cleft. The bone fill in the nasal part was 12% and 52% in the dental part of the alveolar cleft. The cleft volume on the passive side did not change after bone grafting the cleft on the contralateral side.Paper III investigated possible dose reduction by decreasing the field of view (FOV) of the CBCT examination of unilateral alveolar clefts. The project assessed two FOV reduction protocols, one larger, which fully included the upper canines, incisors and the alveolar cleft. The smaller FOV reduction protocol fully included the central incisor and canine adjacent to the cleft, and the alveolar cleft. A FOV of 50 x 40 mm was suggested to depict the anatomical structures of the larger FOV reduction protocol with a 41% dose reduction. For the smaller dose reduction protocol, a FOV of 35 x 40 mm was suggested with a dose reduction of 56%.Paper IV assessed detection of dental anomalies between CBCT and two- dimensional (2D) radiological examinations of the maxilla and the alveolar cleft. Dental anomalies were found among 92% of the children with an alveolar cleft. PAN radiographs, CBCT, and a combination of PAN + IO radiographs. To reduce the radiation dose, 2D radiological examinations are recommended for assessment of dental anomalies. The most found dental anomalies were hypodontia followed by atypical morphology, microdontia, displaced teeth, and supernumerary teeth. The lateral incisor adjacent to the cleft was the tooth most frequently registered as missing.List of scientific papersI. Lemberger M, Regnstrand T, Karsten A, Benchimol D, Shi XQ. Low- Dose Cone-Beam Computed Tomography for Assessment of Alveolar Clefts: A Randomized Controlled Trial in Image Quality. Plast Reconstr Surg. 2024 Apr 1;153(4):897-903. doi: 10.1097/PRS.0000000000010588. Epub 2023 Apr 25. PMID: 37092973.https://doi.org/10.1097/PRS.0000000000010588II. Regnstrand T, Bousiou A, Karsten A, Benchimol D, Jacobs R. Volumetric Assessment of Resorption Patterns of Bilateral Alveolar Clefts in Cone-Beam Computed Tomography in Two- Stage Bone Graft. Orthod Craniofac Res. 2025 Jun;28(3):527-533. doi: 10.1111/ocr.12902. Epub 2025 Feb 4. PMID: 39905629; PMCID: PMC12056464.https://doi.org/10.1111/ocr.12902III. Regnstrand T, Top SK, Karsten A, Jacobs R, Benchimol D. Dose Reduction by Field of View Optimisation in Cone-Beam Computed Tomography of Unilateral Alveolar Clefts. Orthod Craniofac Res. 2025 Oct;28(5):820-825. doi: 10.1111/ocr.12938. Epub 2025 Apr 22. PMID: 40261632; PMCID: PMC12418059.https://doi.org/10.1111/ocr.12938IV. Regnstrand T, Karsten A, Jacobs R, Benchimol D. Radiological detection of dental anomalies in the anterior maxilla of patients with alveolar cleft, comparing 2D and 3D imaging modalities. [Submitted]</p
Spermatogonial stem cells populations in boys with haematological and oncological diseases
No full textWhile survival rates for paediatric patients with malignant and non-malignant diseases have improved considerably due to advances in treatment, intensive regimens frequently impair future fertility later in life. Subfertility or permanent infertility may emerge as lifelong consequences, yet these outcomes are frequently overlooked in clinical practice. This oversight arises from the necessity of prioritising survival in acute disease management, despite the potential long- term reproductive consequences of these treatments. The paradox is evident, advances in oncology have steadily increased childhood cancer survivorship over the past decades, but the same gonadotoxic therapies alkylating agents, radiation, and high-dose chemotherapy that cure disease frequently depletes SSCs and compromise future fertility. For adult patients, fertility preservation follows established protocols involving cryopreservation sperm before treatment initiation. Pre- and peripubertal boys face substantially greater complexity. Their only alternative is the surgical extraction and cryopreservation of immature testicular tissue including SSCs; this experimental approach relies on forthcoming technological advancements to induce these cells to become viable gametes. The urgency of this challenge is reflected in rising preservation rates recent surveys document more than 3,000 young males worldwide undergoing testicular tissue cryopreservation, with numbers doubling over five years. This rapid increase illustrates the urgent need to transform experimental approaches into clinically reliable strategies. The ultimate goal involves restoring reproductive function through laboratory-based spermatogenesis or tissue/cells transplantation approaches. Nevertheless, current methodologies for achieving fertility restoration from cryopreserved immature testicular tissue remain in experimental stages, and our ability to evaluate the impact of gonadotoxic treatments in prepubertal patients is still limited.Study I, Testicular tissue cryopreservation is increasingly offered to boys with sickle cell disease before potentially sterilizing hematopoietic stem cell transplantation HSCT. Hydroxyurea HU is the standard disease modifying therapy for sickle-cell disease SCD. It increases fetal haemoglobin, reduces vaso-occlusive crises, and improves survival, leading international guidelines to recommend its use in all infants with SCD from 9 months of age onwards. This study evaluated the effect of HU therapy, of SDC related complications. This study evaluated the effect of HU therapy, employed as a prevention of SCD related complications, on testicular function. By analysing clinical data from 29 males aged 2.8-15.1 years enrolled in fertility preservation programs Androprotect and Nordfertil, using Z- score comparisons against healthy reference values. immunostained for MAGEA4, and mean spermatogonia per round tubular cross-section (S/T) and fertility index (FI) were calculated; Z-scores were derived from age-matched reference values. Most patients (n=17) had S/T below reference, with four patients with totally depleted spermatogonia. Spermatogonial numbers showed a positive correlation with both S/T Z-score (P = 0.029, r = 0.476) and FI Z-score (P = 0.024, r = 0.490) when HU treatment initiated. Receiver operating characteristic analysis revealed that HU initiation at or before 2.4 years effectively predicted severely reduced spermatogonial numbers. There were no discernible correlations found between spermatogonial depletion and HU dosage, exposure time, iron load, or illness severity indicators. These results show that early exposure to HU may increase the risk of spermatogonial pool depletion during the first three years of a child's life, while the testicles are still developing. The results indicate that the potential risk of reduced fertility from early HU use must be weighed against its proven benefits in lowering morbidity and extending survival in SCD, while also underscoring the importance of counselling families on treatment decisions and considering fertility preservation strategies such as testicular tissue cryopreservation prior to HSCT therapy.Following this we shifted our focus toward study II, this study provides the groundwork for this research, focusing on sub-and infertility, which are among the most common and challenging long-term adverse effects faced by male childhood cancer survivors. This study examined the effects of alkylating and non-alkylating agents on SCCs numbers. Using current single-cell RNA sequencing investigations, several human spermatogonial cell clusters were identified, suggesting greater heterogeneity of SPG than previously thought. This study also included protein markers of these gene clusters, helping us understand the functional effects of this variability. Our findings indicate that depletion of the spermatogonial pool following chemotherapy results in different protein expression patterns. This comprehensive study employed previously generated single-cell RNA sequencing from six healthy testicular samples (ages 0-17 years) and reanalysed it. Combined with immunofluorescence analysis of key spermatogonial markers (UTF1, ID4, PIWIL4, FGFR3, and KIT) in 14 control samples and 31 prepubertal testicular tissues from paediatric cancer patients to investigate spermatogonial differentiation states and their sensitivity to chemotherapy-induced depletion. The research confirmed that prepubertal testes contain exclusively undifferentiated spermatogonia in states 0-1, while more advanced differentiated states (2-4) emerge only during pubertal development, with KIT protein expression showing positive correlation with patient age (PStudy III, builds on the findings from study II, in which SCCs subtypes, were evaluated based on the expression of five proteins at the time of tissue collection (day 0), and their variable responses towards treatments were reported. we then investigated how testicular tissue culture methodologies could be optimised to preserve and nurture these critical SCCs subpopulations. To this end, we applied an established organotypic culture system, previously shown to support spermatogenesis in rodents, in order to evaluate its applicability for human SSCs. By modifying the in vitro environment (supplements), we aimed to assess the ability of this approach to maintain human SSCs and support their differentiation. Supportive media formulations were used for the culture of testicular organoids, and antigen selection was informed by single-cell RNA sequencing data, with immunofluorescence and immunohistochemistry applied for characterisation. Prepubertal boys undergoing gonadotoxic cancer treatments can permanently lose spermatogonial stem cells SSCs, necessitating fertility preservation strategies. In vitro SSCs culture is a promising approach for regenerating the germline, especially when reimplantation of preserved testicular tissue is unsafe due to malignancy. However, maintaining undifferentiated human SSC subpopulations in culture remains challenging. We evaluated the effect of KnockOut Serum Replacement (KSR) supplementation on the maintenance of SSC subtypes in organotypic cultures of prepubertal human testes. We cultured testicular tissue fragments from prepubertal and peripubertal boys (ages 2.9–12.4 years) in a fertility preservation program for up to 14 days, with or without 10% KSR. We quantified SSC marker expression (UTF1, PIWIL4, ID4, FGFR3, KIT) by immunohistochemistry on days 0, 7, and 14. All spermatogonial markers declined over time in culture. KSR supplementation significantly improved the preservation of undifferentiated SSC subtypes compared to KSR-free conditions. Primitive SSC populations (UTF1⁺ and PIWIL4⁺ cells) were relatively resilient, showing partial recovery by day 14 in KSR cultures, whereas intermediate progenitors (ID4⁺ and FGFR3⁺ cells) were markedly depleted without recovery. KIT⁺ spermatogonia were absent at all time points under both conditions. Greater cumulative exposure to alkylating chemotherapy correlated with a higher fold-change in PIWIL4⁺ cells, whereas higher baseline SSC abundance (Z-score) inversely correlated with UTF1⁺ cell retention in KSR cultures. KSR supplementation is essential to sustain the most primitive SSC populations during extended in vitro culture. These results suggest that culture systems augmented with KSR provide a promising strategy for the maintenance of fertility and treatments using germline stem cells. This thesis brings together three studies that address one of the most difficult challenges faced by boys undergoing medical treatments for haematological and oncological disease: the loss of their future fertility. In Study I, we showed that the timing of HU therapy for SCD can influence the spermatogonial pool, emphasising the value of early counselling and timely cryopreservation before stem cell transplantation. In study II, we uncovered that not all spermatogonial cells respond to chemotherapy in the same way. Some subtypes, marked by UTF1 and PIWIL4, appear more resistant and may act as a reserve population critical for fertility recovery, while others are far more vulnerable. Finally, in study III, we established that the incorporation of KSR into culture systems aids in the preservation of these delicate cells in vitro, therefore providing a foundation for future fertility restoration strategies. Collectively, these results enhance our comprehension of how medical interventions influence the developing male germline and provide pragmatic methods for its protection. They emphasise the significance of including fertility preservation in child treatment planning and the ongoing improvement of cultures, systems, and biomarkers to inform therapeutic choices. Although much effort is still required before these methodologies achieve standardisation, this study advances us towards a future in which overcoming childhood illness does not require relinquishing the prospect of parenting.List of scientific papersI. Klara M. Benninghoven-Frey, Nina Neuhaus, Atte K. Lahtinen, Claudia Krallmann, Joana M.D. Portela, Andrea Jarisch, Verena Nordhoff, Armin Soave, HAJAR BA OMAR, Mikael Sundin, Cecilia Langenskiod, Sabine Kliesch, Jan-Bernd Stukenborg, Kirsi Jahnukainen Early testicular maturation is sensitive to depletion of spermatogonial pool in sickle cell disease. Haematologica, 2022 Apr 1;107(4): 975- 979. https://doi.org/10.3324/haematol.2021.279253II. HAJAR BA OMAR*, Justine Stevens*, Anu Haavisto, Yanhua Cui, Femke Harteveld, YifanYang, Ragnar Bjarnason, Patrik Romerius, Mikael Sundin, Ulrika Norén Nyström, CeciliaLangenskiöld, Hartmut Vogt, Per Frisk, Kaisa Vepsäläinen, Cecilia PetersenLina Cui, Jingtao Guo, Kirsi Jahnukainen#, Jan Bernd Stukenborg# * and # These authors contributed equally to this work and should be considered co-first or co-last authors., respectively Early transcriptional states of spermatogonia and marker expressions in the prepubertal human testis following chemotherapy-induced depletion. Human Reproduction, 2025 Aug 1;40(8):1467-1475. https://doi.org/10.1093/humrep/deaf103III. HAJAR BA OMAR, Anu Haavisto, Yifan Yang, Yanhua Cui, Femke Harteveld, Cecilia Langenskiöld, Hartmut Vogt, Per Frisk, Cecilia Petersen, Kirsi Jahnukainen, Jan-Bernd Stukenborg Expression profile of spermatogonial subtypes during organotypic cultures. [Manuscript]</p
Cleaning, disinfection, and hygiene practices : occupational exposures and health hazards
No full textOccupational exposure to water, cleaning and disinfection products, and hygiene practices is widespread across multiple sectors, often involving a diverse range of products and tasks. Workers can be exposed through various routes which may lead adverse health effects, such as respiratory and skin symptoms. However, the extent of total exposure, including cumulative and combined effects of water and product use, remains insufficiently understood, posing challenges for effective risk assessment and implementation of appropriate management in the workplace.This doctoral thesis aimed to investigate occupational exposures and health hazards associated with cleaning and disinfection products and hygiene practices in six different occupations. The overall aim was to generate knowledge and understanding that supports improved workplace prevention and protection strategies.In Study I, workplace observations, airborne exposure assessment and questionnaire-based approach was used to characterize the work environment of cleaning personnel. Although the developed measuring methodology estimated airborne levels to cleaning products to be low, in relation to applicable Swedish OELs, a broad variety of cleaning substances/chemicals, including asthmagens and skin sensitizers, were found.Study II and III used a questionnaire-based approach to study six different occupations, including frontline workers, to assess hand hygiene practices, exposure frequency and skin symptoms during the COVID-19 pandemic. These studies revealed higher exposure frequency to water, hand soap, and hand disinfection during the pandemic compared to before, alongside a high prevalence and newly debuting hand eczema 20.7% and 7.4%, respectively. Notably, 25.4% of the 434 ingredients found in these products were identified as skin sensitizers.In Study IV, an in vitro experimental model evaluated how intense hand hygiene practices would affect the skin barrier integrity and the retention of common contact allergens in the skin. The findings showed that such practices impair the skin barrier evaluated by TEWL and higher metal (i.e. nickel, cobalt and chromium) amounts were generally measured in SLS-treated skin than untreated. These findings suggest that intense hand hygiene practices may enhance the retention/uptake of allergenic metals.In Study V, the assessment of the hazard information provided in SDS of a selected professional cleaning and disinfection market products was done. A non-negligible fraction of SDSs were found to contain insufficient, inconsistent and not easily accessible hazard and precautionary information. Moreover, discrepancies in hazard identification between SDSs and other sources of information may undermine their role in occupational risk communication and management.Overall, this thesis shows that exposure to cleaning and disinfection products and hygiene practices occurs across multiple occupations and involves a broad variety of substances/ingredients, many of which were identified as skin and respiratory irritants and sensitizers. The frequent and intense hand hygiene practices in the workplace suggest that there are major skin health implications, potentially enhancing uptake of allergens into the skin. Additionally, the thesis indicates the importance of the implementation skin care guidelines, procurement of products with safer formulations and policy changes to improve hazard identification/classification and enhance hazard communication to protect workers' health.List of scientific papersThis thesis is based on the following studies and will be referred to in the text by their Roman numerals:I. Vilela, L., Blom, A., Runström Eden, G., Tinnerberg, H., Farbrot, A., Julander, A., & Schenk, L. (2025). Characterising cleaners' exposures to chemicals in cleaning products using gas chromatography mass spectrometry fingerprinting: A feasibility study. ACS Chemical Health & Safety. https://doi.org/10.1021/acs.chas.5c00088II. Vilela, L., Lagrelius, M., Berglind, I. A., Midander, K., Schenk, L., & Julander, A. (2024). Water, soap, and hand-disinfectant exposure during the COVID-19 pandemic and self-reported hand eczema in frontline workers: A cross-sectional study. Contact dermatitis, 91(1), 22-29. https://doi.org/10.1111/cod.14540III. Vilela, L., Schenk, L., Midander, K., Berglind, I. A., Lagrelius, M., & Julander, A. Skin hazards associated with hygiene and hand care practices in six occupations during the COVID-19 pandemic. [Manuscript]IV. Vilela, L., Schenk, L., Julander, A., & Midander, K. (2024). Retention of nickel, cobalt and chromium in skin at conditions mimicking intense hand hygiene practices using water, soap, and hand-disinfectant in vitro. Journal of occupational medicine and toxicology (London, England), 19(1), 44. https://doi.org/10.1186/s12995-024-00442-5V. Erfani, B., Vilela, L., Julander, A., & Schenk, L. (2023). Safety data sheets as an information pathway on hazards of occupationally used cleaning agents. Regulatory toxicology and pharmacology : RTP, 142, 105447. https://doi.org/10.1016/j.yrtph.2023.105447</p
Genetic epidemiology of treatment-resistant depression
No full textMajor depressive disorder (MDD) is one of the leading causes of global disability and disease burden. Although many patients improve with antidepressants, a substantial proportion do not remit after multiple adequate trials. This condition, termed treatment-resistant depression (TRD), is linked to higher risks of suicide, hospitalization, and morbidity. Despite its clinical importance, Progress in understanding TRD has been limited by inconsistent definitions and modest sample sizes. This thesis integrates genetic and epidemiological approaches using Swedish registers, clinical cohorts, and biobank data to improve our understanding of the genetic and environmental factors associated with TRD.Study I examined the genetic overlap between treatment resistance in MDD and pharmacological treatment response. By applying polygenic risk scores (PRS) for antidepressant and lithium response to approximately 4,500 MDD cases from three Swedish cohorts, we found that individuals with TRD had significantly higher PRS of lithium response than non-TRD cases. In contrast, PRS for antidepressant response showed no clear association. These findings suggest a genetically conferred sensitivity to lithium in TRD and support the heritable component of treatment-related phenotypes.Study II combined a genome-wide association meta-analysis with copy number variant (CNV) analyses in more than 2,000 TRD cases, compared to around 38,500 non-TRD cases and 441,000 controls across Nordic cohorts. We reported the SNP-based heritability of 26% for TRD risk (compared to healthy controls), identified one genome-wide significant locus mapped with SPATA16, and observed suggestive loci relevant to treatment resistance in MDD. TRD shared genetics with schizophrenia and bipolar disorder. TRD carried a higher burden of rare CNV deletions and was enriched for known neuropsychiatric CNVs. These findings indicate that both common and rare structural variants contribute to TRD.Study III used Swedish national registers to evaluate psychiatric and cardiometabolic comorbidities and familial risk. Individuals with TRD had substantially elevated risks for both co-morbid psychiatric disorders (e.g., anxiety, obsessive-compulsive disorder) and cardiometabolic diseases (e.g., diabetes, cardiovascular disease). Relatives of TRD cases had increased TRD risk, with attenuation by genetic distance, and there was evidence for shared familial liability with both psychiatric and cardiometabolic conditions, suggesting shared genetic or environmental influences.Study IV investigated the association between adverse childhood experiences (ACEs) and TRD in a population-based twin register including over 21,000 Swedish twins. ACEs were associated with increased risk of TRD, with a 76% higher odds per additional ACE. The association remained after accounting for shared familial factors, suggesting an independent environmental contribution. Subtype-specific analyses showed particularly strong associations for physical neglect and sexual abuse, each conferring more than a 5-fold higher risk of TRD.In summary, this thesis presents new evidence on the genetic architecture of TRD, including contributions from polygenic and rare structural variants, and it highlights the roles of psychosocial adversity and comorbid health conditions. These findings highlight TRD as a distinct and complex phenotype, supporting the need for personalized treatment strategies and preventative efforts targeting early-life adversity.List of scientific papersI. Xiong Y, Karlsson R, Song J, Kowalec K, Rück C, Sigström R, Jonsson L, Clements CC, Andersson E, Boberg J, Lewis CM, Sullivan PF, Landén M, Lu Y. Polygenic risk scores of lithium response and treatment resistance in major depressive disorder. Translational Psychiatry. 2023 Sep 28;13(1):301. https://doi.org/10.1038/s41398-023-02602-3II. Xiong Y, Krebs K, Jermy B, Karlsson R, Pasman JA, Nguyen TD, Gong T, Kowalec K, Rück C, Sigström R, Jonsson L, Clements CC, Hörbeck E, Andersson E, Bäckman J; FinnGen; Estonian Biobank Research Team; Ganna A, German J, Sullivan PF, Landen M, Lehto K, Lu Y. Genome-wide association meta-analysis and rare copy number variant analysis of treatment-resistant depression. Molecular Psychiatry. 2025 Jun 26. https://doi.org/10.1038/s41380-025-03084-zIII. Ying Xiong, Shengxin Liu, Thuy-Dung Nguyen, Tong Gong, Ralf Kuja- Halkola, Henrik Larsson, Brian D'Onofrio, Zheng Chang, Isabell Brikell, Paul Lichtenstein, Yi Lu. Association and familial liability of treatment-resistant depression with psychiatric and cardiometabolic comorbidities. [Manuscript]IV. Ying Xiong, Philip Daniel Javier Lindersten, Tong Gong, Patrik Magnusson, Shengxin Liu, Yi Lu. Association between adverse childhood experiences and treatment-resistant depression - Evidence from Cohort and Co-Twin control Analyses. [Submitted]</p
Violence against children in sub-Saharan Africa and Mozambique : burden and prevention mechanisms in Mozambique
No full textBackground: Violence against children undermines children's rights and their development into autonomous people. Public health agendas must prioritise our understanding of this preventable health threat and inform its prevention. The Sub-Saharan African (SSA) region has some of the highest prevalences of child violence-related injuries globally. Yet, knowledge of its burden and prevention is scarce in the region, including in Mozambique.Aim: The thesis aims are twofold: to increase knowledge of the burden of violence- related injuries among children in the SSA region and Mozambique and to shed light on whether the prerequisites are in place for Mozambican stakeholders to engage and succeed in the prevention of all forms of violence against children. Each aim is addressed by two complementary studies.Methods: The first two papers are register-based, and the following two are based on primary data gathered through interviews. Paper I is a cross-country (SSA region), ecological study based on data from the Global Burden of Disease 2019 study (latest data available at the time of the study). The outcome was the trend in child violence-related death and DALYs and its correlation with risk factors. Descriptive statistics compiled trends over the past 30 years and Spearman's rank correlation test for the association with alcohol consumption per capita. Paper II was cross-sectional and hospital-based. Outcomes were forms of child violence-related injuries presented at the paediatric emergency and forensic unit of the Maputo Central Hospital in Mozambique. Data were extracted from medical records (2019) using a standardised Case Report Form. Descriptive analysis and chi-square tests were performed. Paper III addressed community readiness to prevent child maltreatment based on the WHO Readiness Assessment for the Prevention of Child Maltreatment-Individual questionnaire with stakeholders from national agencies and in Maputo. The questionnaire-specific scoring system and descriptive analysis were performed. Paper IV was qualitative descriptive research exploring frontline practitioners' experiences with the implementation and enforcement of child protection laws in local services in Maputo City. An inductive approach and thematic analysis by Braun and Clarke were used.Results: The SSA region registered a decline in child violence-related deaths and DALYs rates between 1990 and 2019, 22.5% and 22.3%, respectively. In Mozambique, death and DALYs rates declined 22.7% and 25.3%, respectively, that the country in 2019 to match the regional average rates in 2019. A significant correlation was seen between alcohol consumption and child interpersonal violence for both death and DALYs in 2019 (r=0.446, pConclusion: Findings from this thesis indicate that, albeit declining, the rates of child violence-related injuries remain higher both in SSA and in Mozambique than the global average, despite the significant reduction in death and DALYs rates in the past three decades. Sexual violence, typically sustained by girls, was the most frequent form of violence among child victims seeking hospital care in Maputo Central Hospital. Mozambique is in early stages of readiness to prevent child maltreatment. Child protection services in Maputo lack the capacity to implement and enforce child protection laws to protect children from violence, mainly at the local level.List of scientific papersI. Trends and demographic differences in interpersonal violence against children in sub-Saharan Africa: findings from the 1990-2019 Global Burden of Disease Study. Sergio Nhassengo, Lucie Laflamme, Mathilde Sengoelge, GBD 2019 SSA Child Interpersonal Violence. BMJ Open. 2025;15:e083070. https://doi.org/10.1136/bmjopen-2023-083070II. Circumstances and Consequences of Violence-Related Injuries Presenting at Hospital. A Study at the Pediatric Emergency and Forensic Medicine Units of Maputo Central Hospital, Mozambique. Sérgio Keita Nhassengo, Stela Ocuane Matsinhe, Eunice Jethá and Lucie Laflamme. Int. J. Environ. Res. Public Health. 2021, 18, 12125. https://doi.org/10.3390/ijerph182212125III. Community readiness to prevent child maltreatment in Mozambique: An investigation among key informants at country level and from Maputo city. Sergio Nhassengo, Lucie Laflamme, Mathilde Sengoelge. Children and Youth Services Review. 176 (2025) 108400. https://doi.org/10.1016/j.childyouth.2025.108400IV. Frontline practitioners' perspective of the implementation of child protection laws and prevention of violence against children in Maputo, Mozambique. Sergio Nhassengo, Stela Ocuane Matsinhe, Eunice Jetha, Mathilde Sengoelge, Lucie Laflamme and Asli Kulane. [Submitted]</p
Clinical evaluation after incontinence surgery and dehisced perineal tears : effects on women's pelvic floor health
No full textIntroductionThe prevalence of symptoms resulting from pelvic floor dysfunction are high and urinary incontinence in particular is a burden for the individual as well as for society. Stress urinary incontinence (SUI), which is the most common type of incontinence in women, has since the late 1990s been treated with mid-urethral slings (MUS). Rising concern about risks, complications, and long-term outcome have guided research in this direction. With obesity emerging as a growing global health issue, a known risk factor for urinary incontinence, alongside the aging population in many countries, the need for a clear rationale for treating various types of urinary incontinence is evident. Additionally, the awareness of consequences of a dehisced perineal tear after childbirth has increased. The need for evidence-based best clinical practices is essential to prevent more women from experiencing pelvic floor dysfunction.The aims of this thesis were to evaluate dyspareunia and pelvic pain following MUS surgery, to investigate the impact of BMI on long-term outcome after MUS surgery, and to compare these findings with a control group of women who had not undergone the procedure. Another objective was to explore optimal treatment strategies for dehisced second-degree perineal tears after childbirth.Methods and resultsStudies I, II, and III were registry-based investigations that included all women who underwent MUS surgery in Sweden and were registered in the Swedish National Quality Register of Gynecological Surgery (GynOp) between 2006 and 2010. In total 2421 women were analysed, 1562 women after retropubic MUS and 859 women after transobturator MUS. In study I dyspareunia, pelvic pain and sexual function, assessed by PISQ-12 were compared between the two surgical techniques, no differences were found. Study II investigated the impact of BMI at the time of MUS surgery on long-term outcomes, specifically focusing on subjective SUI. A higher BMI was significantly associated with lower cure rates both one year and ten years postoperatively. In study III a reference group was added to the GynOp cohort. The comparison of pelvic pain and lower urinary tract symptoms (LUTS) revealed that women aged 50 years or older who had undergone MUS surgery reported significantly more pelvic pain and LUTS than women who had never received a MUS.Study IV was a multicentre randomised controlled trial that examined the treatment of dehisced second-degree perineal tears. Early resuturing was compared to conventional conservative management with secondary healing. 141 women were included within 14 days after childbirth. In the final analysis 134 women were included, follow-ups were performed after two and four weeks and healing was significantly faster in the resuturing group. While no differences were observed between the groups in terms of pain or breastfeeding, the resuturing group demonstrated significantly better psychological well-being, as measured by the EPDS scale, at the first follow-up.ConclusionsDyspareunia, pelvic pain, and sexual function after MUS surgery do not differ between retropubic and transobturator MUS techniques.An elevated BMI at the time of MUS surgery is associated with a lower cure rate.Pelvic pain and LUTS appear to be more prevalent in women over the age of 50 who have undergone MUS surgery at least ten years earlier, compared to those who have not.In the treatment of dehisced second-degree perineal tears after childbirth, early resuturing appears to be more effective than conservative management in reducing healing time, without adversely affecting pain levels, breastfeeding, or psychological well-being.List of scientific papersI. Lundmark Drca A, Alexandridis V, Andrada Hamer M, Teleman P, Westergren Söderberg M, Ek M. Dyspareunia and pelvic pain: comparison of mid-urethral sling methods 10 years after insertion. Int Urogynecol J. 2024 Jan;35(1). Epub 2023 Jul 10. https://doi.org/10.1007/s00192-023-05585-3II. Lundmark Drca A, Westergren Söderberg M, Ek M. Obesity as an independent risk factor for poor long-term outcome after mid-urethral sling surgery. Acta Obstet Gynecol Scand. 2024 Aug. Epub 2024 Jun 11. https://doi.org/10.1111/aogs.14883III. Lundmark Drca A, Alexandridis V, Teleman P, Westergren Söderberg M, Ek M. Pelvic pain and lower urinary tract symptoms; long-term comparison between women with and without mid-urethral sling insertion. Acta Obstet Gynecol Scand. 30 September 2025. [Accepted]IV. Lundmark Drca A and Golmann D, Bergman I, Strindfors G, Westergren Söderberg M, Ek M. A randomised trial of resuturing versus expectancy for dehisced second-degree perineal tears: Early Healing, Pain, and Depressive Symptoms. [Manuscript]</p