KI Open Archive Karolinska Institutet
Not a member yet
10598 research outputs found
Sort by
T cell immunity induced by SARS-CoV-2 and flavivirus vaccination
No full textEmerging viruses is a continued threat to global public health and vaccines is the most effective medical intervention to reduce viral infectious disease. This thesis contains clinical studies that were conducted to better understand T cell responses to vaccination against SARS-CoV-2 and flaviviruses. Multiple vaccine platforms have been studied, including mRNA-based vaccines against COVID-19 and live attenuated or inactivated whole flavivirus vaccines. This thesis presents studies in the chronological order they were conducted, with Papers I-III focusing on SARS-CoV-2 and Paper IV on flaviviruses.In Paper I, we studied the T cell response in patients with CLL after primary vaccination with the mRNA BNT162b2 vaccine. Using an IFN-y ELISpot assay, we longitudinally assessed an increased T cell response after two doses of mRNA BNT162b2. Compared to healthy individuals the T cell response was lower, indicating that a booster dose may be important to reach higher protective levels. In Paper II, a cohort of patients with CLL with hybrid immunity was studied to measure the adaptive immune response. Spike- and nucleocapsid-specific antibodies were measured in serum and saliva, and T cell responses were evaluated using an IFN-y ELISpot assay and AIM assay. A robust antibody response in serum and saliva, as well as in the T-cell compartment, was observed after three doses of mRNA vaccination in a hybrid setting of CLL patients. In Paper III, we studied the relationship between SARS-CoV-2 and HCoV-OC43 T cells in unexposed individuals to better understand pre-existing immunity to SARS-CoV-2. We mapped and identified several T cell epitopes in spike, nucleocapsid and membrane regions of SARS-CoV-2 and OC43 using a FluroSpot assay.In Paper IV, we longitudinally assessed the T cell response in a clinical cohort of healthy participants co-administrated with YFV vaccine and either TBEV or JEV vaccines. Using an AIM assay, we measured the frequency of activated CD4+ and CD8+ T cells specific for envelope (E), capsid (C) and non-structural (NS) 5 proteins. We detected robust T cell responses after flavivirus vaccination that was primarily directed against envelope. Comparing single vaccinated individuals with concomitant vaccinated participants revealed strikingly similar results. Across all vaccine cohorts, limited cross-reactivity between different flaviviruses, including Zika peptides, was observed. Detectable cross-reactive responses were more prominent for CD8+ T cells. In conclusion, this study demonstrates that co-vaccination elicits responses comparable to single administration and importantly, does not diminish the virus-specific T cell response.The clinical studies in this thesis have expanded our understanding of T cells in the viral vaccine response. These findings offer valuable insights into the immune mechanisms induced by infection with and vaccination against emerging viruses.List of scientific papersI. Blixt, L *. , Wullimann, D *. , Aleman, S., Lundin, J., Chen, P., Gao, Y., Cuapio, A., Akber, M., Lange, J., Rivera-Ballesteros, O., Buggert, M., Ljunggren, H. G., Hansson, L., & Österborg, A. (2022). T-cell immune responses following vaccination with mRNA BNT162b2 against SARS-CoV-2 in patients with chronic lymphocytic leukemia: results from a prospective open-label clinical trial. Haematologica, 107(4), 1000-1003. *Joint first authors.https://doi.org/10.3324/haematol.2021.280300II. Blixt, L., Gao, Y *. , Wullimann, D *. , Murén Ingelman-Sundberg, H., Muschiol, S., Healy, K., Bogdanovic, G., Pin, E., Nilsson, P., Kjellander, C., Grifoni, A., Sette, A., Sällberg Chen, M., Ljunggren, H. G., Buggert, M., Hansson, L., & Österborg, A. (2022). Hybrid immunity in immunocompromised patients with CLL after SARS-CoV-2 infection followed by booster mRNA vaccination. Blood, 140(22), 2403-2407. * Authors contributed equally.https://doi.org/10.1182/blood.2022016815III. Humbert, M., Olofsson, A., Wullimann, D., Niessl, J., Hodcroft, E. B., Cai, C., Gao, Y., Sohlberg, E., Dyrdak, R., Mikaeloff, F., Neogi, U., Albert, J., Malmberg, K. J., Lund-Johansen, F., Aleman, S., Björkhem- Bergman, L., Jenmalm, M. C., Ljunggren, H. G., Buggert, M., & Karlsson, A. C. (2023). Functional SARS-CoV-2 cross-reactive CD4+ T cells established in early childhood decline with age. Proceedings of the National Academy of Sciences of the United States of America, 120(12), e2220320120. https://doi.org/10.1073/pnas.2220320120IV. Wullimann, D., Sandberg, J. T., Akber, M., Löfling, M., Gredmark-Russ, S., Michaëlsson, J., Buggert, M., Blom, K., & Ljunggren, H. G. (2025). Antigen-specific T cell responses following single and co- administration of tick-borne encephalitis, Japanese encephalitis, and yellow fever virus vaccines: Results from an open-label, non- randomized clinical trial-cohort. PLoS neglected tropical diseases, 19(2), e0012693.https://doi.org/10.1371/journal.pntd.0012693</p
Female Genital Mutilation : obstetric outcomes and perceived health consequences among women affected
No full textBackgroundFemale Genital Mutilation (FGM) involves the partial or total removal of the external female genitalia for non-medical reasons and is associated with serious health risks. The growing number of women from countries where FGM is practiced presents new challenges for healthcare systems in receiving countries. To improve care and promote health equity, it is essential to increase understanding of both the obstetric complications associated with FGM and the healthcare experiences of affected women.AimThis thesis aimed to investigate how FGM affects obstetric outcomes with a particular focus on obstetric anal sphincter injury (OASI) and emergency cesarean section (CS), and to explore the lived experiences of women with FGM and their experience of healthcare encounters in Sweden.Material, methods and resultsThe first study was a nationwide cohort study including 187 738 primiparous women with singleton term vaginal births in Sweden (2014-2018). It showed that women with a registered FGM diagnosis (n=1 444) had a nearly threefold increased risk of OASI (OR 2.69, 95%CI: 2.14-3.37) compared to women without FGM diagnosis (n= 186 294). FGM was also associated with a higher rate of instrumental deliveries and episiotomy.The second study was a qualitative interview study with eight women living in Sweden who had undergone FGM prior to migration. This study highlights the complexity of FGM, revealing a wide range of experiences and perceived health consequences among women affected. Additionally, women reported inadequate knowledge about FGM, disrespectful attitudes, and insensitive care when seeking healthcare, though some also reported positive encounters.The third study was a nationwide cohort study (2014-2020) that included 229 026 births and examined the risk of emergency CS for women born in FGM- practicing countries (n= 14 602) compared to women born in Sweden (n= 214 424). Women from FGM-practicing countries had a higher risk of emergency CS (aOR 1.23, 95% CI: 1.17-1.30) compared to Swedish-born women. However, when adding FGM diagnosis as a covariate in the regression model, FGM diagnosis did not change the risk.ConclusionsIn our study, women with FGM had an increased risk of OASI when having a vaginal delivery in Sweden. The increased risk of emergency CS among women from FGM- practicing countries appears to be attributed to factors other than the FGM diagnosis itself. Increasing healthcare providers' knowledge about obstetric complications associated with FGM is essential to ensure optimal care and prevent adverse obstetric outcomes. Since women affected by FGM perceive their health consequences in various ways, it is further important for healthcare professionals to acknowledge the diversity within this group. Adopting a sensitive, individualized approach and improving healthcare providers' understanding of FGM is key to enhancing women's experiences and perceptions of care.List of scientific papersI. Eshraghi B, Hermansson J, Berggren V, Marions LRisk of obstetric anal sphincter tear among primiparous women with a history of female genital mutilation, giving birth in Sweden. PLoS One. 2022 Dec 17(12): e0279295. https://doi.org/10.1371/journal.pone.0279295II. Eshraghi B, Marions L, Berger C, Berggren V."A part of my life". A qualitative study about perceptions of female genital mutilation and experiences of healthcare among affected women residing in Sweden. BMC Women's Health. 2024 May 22;24(1):304. https://doi.org/10.1186/s12905-024-03149-1III. Eshraghi B, Hermansson J, Marions L.Risk of emergency cesarean section when giving birth in Sweden. A nationwide cohort study comparing women born in countries practicing female genital mutilation, with Swedish-born women. [Submitted]</p
Life-course exposure to air pollution and the risk of dementia in the Lothian Birth Cohort 1936.
No full textBACKGROUND: Air pollution in later life has been associated with dementia; however, limited research has investigated the association between air pollution across the life course, either at specific life periods or cumulatively. The project investigates the association of air pollution with dementia via a life-course epidemiological approach. METHODS: Participants of the Lothian Birth Cohort, born in 1936, provided lifetime residential history in 2014. Participant's air pollution exposure for time periods 1935, 1950, 1970, 1980, 1990, 2001, and 2007 was modeled using an atmospheric chemistry transport model. Lifetime cumulative exposures were calculated as time-weighted mean exposure. Of 572 participants, 67 developed all-cause dementia [35 with Alzheimer's dementia (AD)] by wave 5 (~82 years). Cox proportional hazards and competing risk models assessed the association between all-cause dementia and AD with particulate matter (diameter of ≤2.5 µm) PM2.5 and nitrogen dioxide (NO2) exposure at specific life periods and cumulatively. False discovery rate (FDR) correction was applied for multiple testing. RESULTS: The mean follow-up was 11.26 years. One standard deviation (SD) higher exposure to air pollution in 1935 (PM2.5 = 14.03 μg/m3, NO2 = 5.35 μg/m3) was positively linked but not statistically significant to all-cause dementia [PM2.5 hazard ratio (HR) = 1.16, 95% confidence interval (CI) = 0.90, 1.49; NO2 HR = 1.13, 95% CI = 0.88, 1.47] and AD (PM2.5 HR = 1.38, 95% CI = 1.00, 1.91; NO2 HR = 1.35, 95% CI = 0.92, 1.99). In the competing risk model, one SD elevated PM2.5 exposure (1.12 μg/m3) in 1990 was inversely associated with dementia (subdistribution HR = 0.82, 95% CI = 0.67, 0.99) at P = 0.034 but not after FDR correction (P FDR = 0.442). Higher cumulative PM2.5 per one SD was associated with an increased risk of all-cause dementia and AD for all accumulation models except for the early-life model. CONCLUSION: The in-utero and early-life exposure to PM2.5 and NO2 was associated with higher AD and all-cause dementia risk, suggesting a sensitive/critical period. Cumulative exposure to PM2.5 across the life course was associated with higher dementia risk. Midlife PM2.5 exposure's negative association with all-cause dementia risk may stem from unaddressed confounders or bias.</p
Primary glomerular diseases and long-term adverse health outcomes : A nationwide cohort study
No full textBACKGROUND: Although glomerular diseases are the third most frequent cause of end-stage kidney disease worldwide, little is known about their long-term outcomes. METHODS: In patients with chronic kidney disease (CKD) stage 3-5 enrolled in the Swedish Renal Registry, we compared risks of hospitalization, kidney replacement therapy (KRT), major cardiovascular events (MACE), and death of the four most frequent primary glomerular diseases (IgA nephropathy [IgAN], focal segmental glomerulosclerosis [FSGS], minimal change disease [MCD], and membranous nephropathy [MN]), and patients with CKD due to the most common non-communicable diseases (control-CKD). RESULTS: We identified 2396 patients with glomerular disease (97% biopsy-proven, 69% men, 57 years, eGFR 29 mL/min/1.73 m2, uACR 88 mg/mmol, 1524 with IgAN, 398 FSGS, 94 MCD, and 380 MN) and 37,697 controls (64% men, 74 years, eGFR 25 mL/min/1.73 m2, uACR 23 mg/mmol), mainly with diabetic nephropathy and nephroangiosclerosis. The median follow-up was 6.3 (3.3; 9.9) years. Compared with control-CKD, patients with primary glomerular diseases generally had a lower risk of hospitalization, MACE (adjusted hazard ratios [HRs] ranging from 0.44 to 0.88 depending on the etiology) and death (HRs ranging 0.45-0.76). Patients with IgAN and FSGS had a faster eGFR decline and a higher rate of KRT (HRs 1.26 [95%CI: 1.15-1.37] and 1.34 [1.15-1.57], respectively). Conversely, patients with MN and MCD had a lower KRT rate and slower eGFR decline. CONCLUSION: Despite having a lower relative risk of hospitalization, cardiovascular events and mortality, patients with IgAN and FSGS are at higher risk of CKD progression than the most common etiologies of CKD, emphasizing the need for more stringent treatment strategies in these patients.</p
Tumour burden, thyroglobulin and Ki-67 as prognostic indicators in papillary thyroid cancer
No full textEach year, more than 700 patients in Sweden are diagnosed with thyroid cancer, with papillary thyroid cancer (PTC) being the most common type, accounting for approximately 80% of cases. The incidence of PTC has increased in high- and middle-income countries, doubling in Sweden over the past two decades. Despite this incidence rise, mortality rates remain low, highlighting concerns about overdiagnosis and overtreatment. While most patients have an excellent prognosis - demonstrating a 93% disease-specific survival rate over ten years - a subset of patients experience recurrence and poorer outcomes. Currently, treatment decisions for PTC rely on anatomical criteria, underscoring the need for additional prognostic biomarkers to identify high-risk patients. In recent years, the role of tumour biology and tumour microenvironment, particularly the tumour stroma, has gained recognition as a crucial factor in cancer progression and treatment resistance. Histopathological biomarkers are increasingly integrated into risk stratification and treatment planning for various cancers - yet their application in PTC remains limited.Aims: This thesis aimed to identify and evaluate potential histopathological biomarkers in primary PTC tumours and metastatic lymph nodes for improved prognostic risk stratification.Methods: Studies I, II and IV were retrospective analyses of patients surgically treated for PTC at Karolinska University Hospital (2006-2017). We examined the immunohistochemical expression of the Ki-67 labeling index, thyroglobulin, and the lymph node ratio (LNR) in relation to clinical data and PTC recurrence.Study III was a feasibility study on AI-assisted digital pathology, assessing thyroglobulin expression H-score and tumour-stroma ratio in primary tumours and their corresponding metastatic lymph nodes.Results: In study I, 165 patients were included. Lymph node metastases were significantly more common in younger patients, those with multifocal tumours, a Ki-67 index >3%, and extrathyroidal extension. The Ki-67 index in the primary tumour and LNR significantly correlated with tumour recurrence.In study II an expanded cohort of 327 patients was used. Findings from Study I were confirmed, with LNR ≥21% independently associated with tumour recurrence. The Ki-67 index was higher in the lymph node metastases (mean 4%) than in primary tumours (mean 3%). Thyroglobulin expression was generally higher in the primary tumour than in metastatic lymph nodes. Low thyroglobulin expression (0-25%) in lymph node metastases was associated with shorter recurrence-free survival and a higher risk of recurrence in PTC - likely due to reduced response to adjuvant radioiodine therapy.In study III, we found that AI-assisted digital image analysis was adequate for assessing tumour-stroma ratio and estimating thyroglobulin expression in primary tumours and lymph node metastases. However, the clinical significance of these biomarkers requires future investigation in a larger patient cohort.Study IV included a subgroup of patients (n=245) from the Study II cohort with clinically node-negative PTC - NO, Nx and Nla stage. We found that microscopic extrathyroidal extension (mETE) was associated with larger tumour size, a higher Ki-67 index, and a sixfold increased risk of recurrence compared to tumours without mETE. Tumours ≤2 cm had significantly fewer recurrences (2.8%) and longer recurrence-free survival than tumours >2 cm (12%). Tumours with a high Ki-67 index (>3%) had a worse prognosis, though neither the Ki-67 index nor tumour size were independent risk factors for recurrence.Conclusion: Our findings highlight the potential prognostic value of the Ki-67 index and thyroglobulin expression in primary tumours and lymph node metastasis for predicting PTC recurrence. A high metastatic burden (LNR ≥21 %) significantly impacts recurrence risk in N1b-stage PTC. In clinically node-negative PTC, microscopic ETE might be associated with recurrence. These insights reinforce the need to integrate histopathological biomarkers into risk stratification strategies for PTC, potentially improving individualised treatment decisions.List of scientific papersI. Lindfors H, Ihre Lundgren C, Zedenius J, Juhlin CC, Shabo I. The Clinical Significance of Lymph Node Ratio and Ki-67 Expression in Papillary Thyroid Cancer. World Journal of Surgery. 2021 Jul;45(7):2155-2164. https://doi.org/10.1007/s00268-021-06070-yII. Lindfors H, Karlsen M, Karlton E, Zedenius J, Larsson C, Ihre Lundgren C, Juhlin CC, Shabo I. Thyroglobulin expression, Ki-67 index, and lymph node ratio in the prognostic assessment of papillary thyroid cancer. Scientific Reports. 2023 Jan 19;13(1):1070. https://doi.org/10.1038/s41598-023-27684-3III. Lindfors H, Hellgren LS, Zedenius J, Ihre Lundgren C, Juhlin CC, Shabo I. Assessment of tumor-stroma ratio and thyroglobulin immunohistochemical staining intensity scoring in papillary thyroid cancer using automated digital image analysis: A feasibility study. [Manuscript]IV. Lindfors H, Zedenius J, Ihre Lundgren C, Juhlin CC, Shabo I. The roles of tumor size and biological criteria in estimating the treatment options in papillary thyroid cancer. [Manuscript]</p
Cluster headache : focus on sleep, treatment, and genetics
No full textThe main hypothesis of this thesis is that cluster headache (CH) has a genetic component and by investigating this genetic component we can get insights into pathophysiological mechanisms behind CH. Clinical data can help indicate which genes can be contributing to the disease. The genetic variants can in turn help us better understand the biological mechanisms which give rise to CH. In that way we lay a foundation for developing treatment which can alleviate the suffering of millions of people around the world. This thesis focused on three major areas within CH research: sleep, treatment usage/response, and genetic links to CH pathophysiology.Sleep has long been studied in connection to CH due to the strikingly rhythmic nature of CH attacks which regularly disrupt sleep. In Paper I, we studied sleep patterns of CH participants using actigraph units to record sleep and wake times, complemented with sleep diaries. Actigraphy data showed that, although sleep time did not differ between CH participants and controls, sleep latency and time in bed was increased in CH participants. Participants with CH scored worse in almost all subjective sleep scores. Interestingly, in objective sleep measurements, CH participants in an active bout did not significantly differ to participants in remission.In Paper II, a survey investigating sleep quality, dysfunctional beliefs regarding sleep, and insomnia symptoms was sent to >700 CH participants. The survey results further established that sleep is disturbed during an active bout as compared to participants in remission and even more so to the general population. The sleep scores were additionally correlated to years since last active bout, again indicating participants in remission are still disrupted by the disease. Paper III used a similar method to investigate extent of burnout in the CH cohort. As high as 67.6% of participants in an active bout were in the risk zone for burnout. Burnout symptoms were also present in remission, but to a lesser degree and correlated to the length of time since the last active bout.To study possible biological links to the observed sleep patterns and circadian rhythm of attacks we studied genetic variants in biological clock genes. PER, CRY, BMAL1, and CLOCK are the core clock genes which drives the 24-hour rhythm. In Paper IV six genetic variants were genotyped in PER1, PER2, and PER3 which had previous links to diurnal preference or sleep. No significant difference between CH participants and controls was found. In Paper V, genetic variants in BMAL1, and NPAS2, a paralog to CLOCK, were investigated. Variants in BMAL1 (rs3789327) and NPAS2 (rs3768984) were associated with CH. Significant or trending genetic variants in the core clock genes from this study and previous studies were combined in a multi allele risk analysis. This analysis showed that CH participants carried more risk alleles than controls further strengthening the possible role of the biological clock in CH.Treatment response can vary greatly between different individuals and treatment options, and is not fully understood. In Paper VI a survey was sent out to investigate treatment response in a Swedish CH cohort. It confirmed the previously reported wide range of treatment responses observed for CH. Surprisingly, a considerable number of CH participants didn’t take any preventative medication. Side effects were common and prevented some participants with continuing their otherwise effective treatment.Since treatment response varied between participants, Paper VII investigated if genetics could partially explain this variation in the first line treatment, triptans. Five genetic variants which had previously been linked to triptan response in other diseases were genotyped and the allelic distribution was compared between triptan users and non-users. One single nucleotide polymorphism (SNP) previously linked to triptan response in migraine was significantly associated with CH triptan usage, meaning the mechanisms of action behind triptan non-response could be similar.Anecdotally, some CH patients have reported taking vitamin D supplements to improve their CH. To investigate if this was reflected in genetics, a SNP in the VDR gene was genotyped in Paper VIII. We pooled the data from the genotyped SNP and two other VDR SNPs from our previous genome-wide association study (GWAS) with data from a Greek CH cohort into a meta-analysis. No significant associations were found to CH for any of the SNPs.In the last few years genetics have increasingly shown to play an important role in CH pathology. In Paper IX, a meta-GWAS was performed on genetic material from 11 cohorts comparing CH participants to controls. When only including the 10 European cohorts, the four significant loci from previous CH GWAS were replicated, in proximity to the genes MERTK, DUSP10, FTCDNL1, and FHL5. Three new loci reached genome wide significance: WNT2, PLCE1, and LRP1.The next step was to translate the genetic findings to possible biological pathways which can contribute to the disease. MERTK is a cell-surface receptor mostly present on immune cells which plays a role in immune suppression, efferocytosis, and a range of other functions. Paper X investigated its potential role in CH. Trigeminal nerves from rats were stained with MERTK antibodies. MERTK was found to be present in Satellite cells and in Schwann cells close to the nodes of Ranvier which would allow MERTK to bind to its ligands if they were released during neuronal activation. Additionally, the protein expression levels of three of MERTK’s ligands were measured in serum. Protein levels of Galectin-3 were significantly higher in CH participants compared to controls.To further investigate a possible immunological mechanism in CH, in Paper XI cerebral spinal fluid (CSF) and serum samples were sent for an immunoassay which allowed us to look at concentrations of dozens of proteins. Eleven immune system related proteins were elevated in the CSF of CH participants compared to controls. Only two cytokines showed differentiated protein expression in the serum. These data indicate increased inflammatory markers in CH participants both in an active bout and in remission, mostly isolated to the central nervous system.List of scientific papersI. Ran C, Jennysdotter Olofsgård F, Steinberg A, Sjöstrand C, Waldenlind E, Dahlgren A, Belin AC. Patients with cluster headache show signs of insomnia and sleep related stress: results from an actigraphy and self-assessed sleep study. J Headache Pain. 2023 Aug 18;24(1):114.https://doi.org/10.1186/s10194-023-01650-wII. Jennysdotter Olofsgård F, Ran C, Steinberg A, Sjöstrand C, Waldenlind E, Lantz M, Sundholm A, Söderström M, Dahlgren A, Belin AC. Characterization of insomnia and sleep quality in a cluster headache population. [Manuscript]III. Jennysdotter Olofsgård F, Ran C, Steinberg A, Sjöstrand C, Waldenlind E, Lantz M, Sundholm A, Söderström M, Dahlgren A, Belin AC. Evidence of High Rates of Burnout in a Cluster Headache Cohort. [Manuscript]IV. Jennysdotter Olofsgård F, Ran C, Fourier C, Wirth C, Sjöstrand C, Waldenlind E, Steinberg A, Belin AC. PER gene family polymorphisms in relation to cluster headache and circadian rhythm in Sweden. Brain Sci. 2021 Aug 23;11(8):1108.https://doi.org/10.3390/brainsci11081108V. Deborgies Sanches C, Jennysdotter Olofsgård F, Fourier C, Sundholm A, Lantz M, Sjöstrand C, Waldenlind E, Steinberg A, Ran C, Belin AC. Genetic variability within molecular core clock genes in cluster headache. [Manuscript]VI. Smedfors G, Jennysdotter Olofsgård F, Steinberg A, Waldenlind E, Ran C, Belin AC. Use of prescribed and non-prescribed treatments for cluster headache in a Swedish cohort. Brain Sci. 2024 Mar 31;14(4):348.https://doi.org/10.3390/brainsci14040348VII. Jennysdotter Olofsgård F, Ran C, Qin Y, Fourier C, Waldenlind E, Steinberg A, Sjöstrand C, Belin AC. Genetic and phenotypic profiling of triptan users in a Swedish cluster headache cohort. J Mol Neurosci. 2024 Apr 18;74(2):45.https://doi.org/10.1007/s12031-024-02219-1VIII. Jennysdotter Olofsgård F, Ran C, Qin Y, Fourier C, Sjöstrand C, Waldenlind E, Steinberg A, Belin AC. Investigating vitamin D receptor genetic markers in a cluster headache meta-analysis. Int J Mol Sci. 2023 Mar 21;24(6):5950.https://doi.org/10.3390/ijms24065950IX. Winsvold BS, Harder AVE, Ran C, Chalmer MA, Dalmasso MC, Ferkingstad E, Tripathi KP, Bacchelli E, Børte S, Fourier C, Petersen AS, Vijfhuizen LS, Magnusson SH, O'Connor E, Bjornsdottir G, Häppölä P, Wang YF, Callesen I, Kelderman T, Gallardo VJ, de Boer I, Jennysdotter Olofsgård F, Heinze K, Lund N, Thomas LF, Hsu CL, Pirinen M, Hautakangas H, Ribasés M, Guerzoni S, Sivakumar P, Yip J, Heinze A, Küçükali F, Ostrowski SR, Pedersen OB, Kristoffersen ES, Martinsen AE, Artigas MS, Lagrata S, Cainazzo MM, Adebimpe J, Quinn O, Göbel C, Cirkel A, Volk AE, Heilmann-Heimbach S, Skogholt AH, Gabrielsen ME, Wilbrink LA, Danno D, Mehta D, Guðbjartsson DF; HUNT All-In Headache, The International Headache Genetics Consortium, DBDS Genomic Consortium; Rosendaal FR, Willems van Dijk K, Fronczek R, Wagner M, Scherer M, Göbel H, Sleegers K, Sveinsson OA, Pani L, Zoli M, Ramos-Quiroga JA, Dardiotis E, Steinberg A, Riedel-Heller S, Sjöstrand C, Thorgeirsson TE, Stefansson H, Southgate L, Trembath RC, Vandrovcova J, Noordam R, Paemeleire K, Stefansson K, Fann CS, Waldenlind E, Tronvik E, Jensen RH, Chen SP, Houlden H, Terwindt GM, Kubisch C, Maestrini E, Vikelis M, Pozo-Rosich P, Belin AC, Matharu M, van den Maagdenberg AMJM, Hansen TF, Ramirez A, Zwart JA; International Consortium for Cluster Headache Genetics. Cluster headache genomewide association study and meta-analysis identifies eight loci and implicates smoking as causal risk factor. Ann Neurol. 2023 Oct;94(4):713-726.https://doi.org/10.1002/ana.26743X. Edvinsson JCA, Ran C, Jennysdotter Olofsgård F, Steinberg A, Edvinsson L, Belin AC. MERTK in the rat trigeminal system: a potential novel target for cluster headache? J Headache Pain. 2024 May 23;25(1):85.https://doi.org/10.1186/s10194-024-01791-6XI. Ran C, Jennysdotter Olofsgård F, Wellfelt K, Steinberg A, Belin AC. Elevated cytokine levels in the central nervous system of cluster headache patients in bout and in remission. J Headache Pain. 2024 Jul 23;25(1):121.https://doi.org/10.1186/s10194-024-01829-9</p
Advancement in human neuroimaging based on proximity ligation assay in brain disease
No full textIn this article we highlights the use of in situ proximity ligation assay (PLA) method to study protein-protein interactions in brain diseases. PLA enables high-sensitivity detection of protein complexes, such as G protein-coupled receptor (GPCR) heterocomplexes, in post-mortem human brains. This approach has facilitated the visualization of A2AR-D2R heterocomplexes in the striatum and contributed to understanding neuropsychiatric and neurodegenerative disorders. PLA has been instrumental in identifying pathological protein interactions in Alzheimer’s disease (AD) and Parkinson’s disease (PD). For AD, it revealed tau-ubiquitin interactions, providing insights into tau pathology. In PD, PLA demonstrated alpha-synuclein (AS) oligomers and their interactions with dopamine transporters and synapsin-III, shedding light on neurodegenerative mechanisms. It also detected AS oligomers in multiple system atrophy (MSA), offering new perspectives on disease pathology. Despite challenges such as antibody variability and post-mortem tissue degradation, PLA has significantly enhanced molecular imaging, enabling early detection of protein aggregation. This method provides a powerful tool for studying brain disorders, improving molecular understanding, and identifying potential therapeutic targets.</p
Challenges in fertility preservation for patients with cervix cancer : clinical experiences and experimental developments
No full textCervical cancer is fairly prevalent among young women, with approximately one- third of patients being under 40 at the time of diagnosis. Despite most of cervical cancers in early stages can be resolved with conservative surgery including conization and trachelectomy, in more advanced stages, treatments including radiotherapy, chemotherapy and major surgery are required. These treatments will affect fertility chances and the opportunity to build a biologically related future family.In Study I, the challenges that pose cervical cancer and its treatment to young women's fertility were explored in a prospective cohort of 91 patients diagnosed with stages I, II, III, or IV (67%, 25%, 7%, and 1%, respectively). Sixty-eight women underwent procedures for fertility preservation. During a follow-up of 8.3 years, 25 women (37%) returned to the center aiming at fertility treatments and five achieved conceptions either naturally or with assisted reproduction. This study highlights the significant gap in effective fertility preservation options for women diagnosed with cervical cancer.In study II fertility-related distress was investigated in women treated for cervical cancer in the population-based Fex-Can prospective cohort. Women were classified according to maintenance or loss of uterine functionality due to the treatment received (PreservUt or LossUt, respectively) and questionnaires at study baseline approximately 1.5 years post diagnosis (T1) were collected, as well as during follow-up at 3- and 5-years post diagnosis (T2 and T3). After adjustment for sociodemographic covariates, women in the PreservUt group showed lower fertility-related distress in one of the six dimensions, partner disclosure, compared to LossUt group (adjusted OR 0.26, 95% CI 0.07-0.96) at T1. At T2, women in PreservUt group showed higher fertility related distress in becoming pregnant compared to LossUt group (adjusted OR, 11.6, 95% confidence interval CI 1.29-104.3). At T3, women in the PreservUt group were less likely (adjusted OR 0.10, 95% CI 0.17-0.57) as than those in the LossUt group to experience fertility related distress concerning partner disclosure. Conversely, women in PreservUt group were more likely (adjusted OR 5.00, 95% CI 1.02-24.7) than those in the LossUt group to report fertility-related distress concerning child's health at T3.In study III and IV we explored experimental methods that could help developing novel treatments for patients losing endometrial and uterine functionality, a common consequence of the treatment of cervical cancer.In Study III, the feasibility of endometrial tissue cryopreservation was evaluated using two methods: passive slow freezing (PSF) and vitrification (VT). Cells derived from both PSF and VT biopsies demonstrated sustained viability and retained their ability to generate functional epithelial organoids. However, post- thaw alterations were highlighted during histological assessments in epithelial cells in VT samples. Additionally, electron microscopy analysis revealed ultrastructural alterations in the mitochondria of both epithelial and stromal cells within the PSF samples. Overall, these findings suggest that despite minor ultrastructural changes, both PSF and VT techniques effectively preserved endometrial tissue morphology and maintained the ability to generate functional epithelial organoids.In study IV, human endometrial organoids were generated to evaluate their hormonal responses along a 28 days cycle, modelling a menstrual cycle. Three hormone strategies were applied to stimulate human endometrial organoids: (1) estrogen (E) to replicate the proliferative phase, (2) Estrogen plus progesterone (EP) to induce the secretory phase (3) Estrogen, progesterone, and cAMP (EPC) to mimic the secretory phase in vivo. Gene and protein expression were thoroughly evaluated using RT-qPCR, IHC and ELISA to assess the organoids' hormonal responsiveness. The endometrial organoids exhibited appropriate hormonal responses, demonstrating increased expression of estrogen receptor (ESR1), progesterone receptor (PR), 17 ß -hydroxysteroid dehydrogenase (HSD17B1), Mucin 1 (MUC1), progesterone-associated endometrial protein (PAEP), and secreted phosphoprotein 1 (SPP1)-closely reflecting in vivo physiological processes. Notably, the most pronounced changes were detected in the EPC- treated hEOs at week 4, with significantly increased expression of glycodelin (PAEP) and osteopontin (SPP1), hallmark markers of the mid- to late-secretory phase. This organoid model effectively recapitulated the dynamic hormonal environment of the human menstrual cycle, providing a powerful platform for advancing research on endometrial disorders and supporting the development of personalized treatments in gynecology.List of scientific papersI. Marklund, A., Jiang, Y., Röjlar, H., Sergonioutis, F., Nilsson, H., Lundberg, F. E., & Rodriguez-Wallberg, K. A .. The complexity and challenges of fertility preservation in women with cervix cancer-A prospective cohort study reporting on reproductive outcome and overall survival. Acta Obstet Gynecol Scand. Nov 20 2024. https://doi.org/10.1111/aogs.15007II. Jiang, Y., Rodriguez-Wallberg, K. A., Hellman K., Ullemar V., Wettergren L., Lampic C. Fertility-related distress following treatment for cervix cancer and the impact of maintaining or losing uterine functionality - a longitudinal population-based study. [Manuscript]III. Saare, M .* , Wróbel, M .* , Jiang, Y.,* Rodriguez-Wallberg, K. A., Palomares, A. R., Kask, K., Kalinina, A., Apostolov, A., Minajeva, A., Kiisholts, K., Pathare, A. D. S., Laudański, P., Peters, M., & Salumets, A .. Biopsy vitrification: New tool for endometrial tissue cryopreservation for research applications. Cryobiology. Nov 14 2024;117:105161. *Equal contribution as first authors. https://doi.org/10.1016/j.cryobiol.2024.105161IV. Jiang, Y., Palomares, A. R., Munoz, P., Nalvarte, I., Acharya, G., Inzunza, J., Varshney, M., & Rodriguez-Wallberg, K. A .. Proof-of-Concept for Long-Term Human Endometrial Epithelial Organoids in Modeling Menstrual Cycle Responses. Cells. Nov 2 2024;13(21). https://doi.org/10.3390/cells13211811</p
Minimally invasive techniques for heart valve procedures
No full textBackgroundMinimally invasive cardiac surgery (MICS) has emerged as an alternative to conventional sternotomy, offering potential benefits due to reduced surgical trauma. This thesis evaluates the clinical outcomes, safety, and efficacy of MIMVS and the use of percutaneous femoral access and plug-based VCD in MIMVS and transcatheter aortic valve replacement (TAVR).Methods and ResultsStudy I: This single-center study analyzed patients who underwent mitral valve surgery at Karolinska University Hospital between January 2012 and May 2019, treated either via sternotomy or MIMVS. A total of 605 patients (294 sternotomy, 311 minimally invasive) were included. Propensity score matching was performed, resulting in 251 matched pairs. In the matched analysis, minimally invasive procedures had a shorter aortic occlusion duration (97+36 vs. 105+40 min; p=0.03) but a longer extracorporeal circulation duration (149+52 vs. 133+57 min; p=0.001). Minimally invasive procedures were associated with a lower incidence of reoperation for bleeding (2.4% vs. 7.2%; p=0.012), reduced need for transfusion (19.1% vs. 30.7%; p=0.003), and a shorter in-hospital stay (5.0+2.7 vs. 7.2+4.6 days; pStudy II: This single-center prospective study compared patients undergoing MIMVS with femoral cannulation, performed either via surgical cut-down or percutaneously with access site closure using a plug-based VCD (MANTA, Teleflex/Essential Medical Inc., Malvern, Pennsylvania, USA) between 2016 and 2018. A total of 268 patients (147 surgical cut-down, 121 percutaneous) were included, with 109 matched pairs after propensity score matching. The primary outcome was vascular complications according to Valve Academic Research Consortium (VARC)-2 criteria. The VCD group had a significantly higher rate of major vascular complications (4.6% vs. 0%; p=0.024). No bleeding occurred in either group. In the full series, patients in the surgical cut-down group had a significantly higher incidence of seroma (10.9% vs. 0%, pStudy III: A single-center observational study evaluated 1000 consecutive patients undergoing transfemoral TAVR between May 2017 and September 2020. Patients received a MANTA VCD for arterial access management, and outcomes were assessed using VARC-2 criteria. The primary endpoint was VCD- related major vascular complications. Major vascular complications occurred in 4.2% of patients. Complications included the need for a covered stent (1.7%), surgical repair (1.7%), and vascular surgery post-discharge (0.3%). A significant risk factor for vascular complications was a larger sheath outer diameter relative to the femoral artery's inner diameter (p=0.028).Study IV: This single-center study included 650 patients undergoing MICS between August 2017 and September 2022. The early group (207 patients) did not undergo intraoperative ultrasound assessment after VCD placement, while the late group (443 patients) did. The primary outcome was vascular complications according to VARC-2 criteria. Six patients (2.9%) in the early group experienced vascular complications, while no complications were reported in the ultrasound-assessed group (pConclusions[I] MIMVS was associated with comparable short-term outcomes to sternotomy mitral valve surgery. MIMVS had lower rates of bleeding, blood transfusions, and shorter hospital stays. The initiation of an MIMVS program, when managed appropriately, proved safe and effective. [II] The use of the MANTA VCD in MIMVS eliminated wound complications seen with surgical cut-down, such as seromas and infections, but was associated with a higher risk of major vascular complications. [IV] By introducing intraoperative ultrasound to assess proper positioning of the VCD, vascular complications were reduced, particularly femoral artery stenosis. [III] Also, the MANTA VCD was effective for large-bore arterial access management during transfemoral TAVR with a low rate of complications. A larger sheath-to-femoral artery diameter ratio increased the risk of complications. The studies confirm the safety and efficacy of the MANTA device in a broad patient population, although vascular risks must be carefully managed.List of scientific papersI. Kastengren M, Svenarud P, Källner G, Franco-Cereceda A, Liska J, Gran I, Dalén M. Minimally invasive versus sternotomy mitral valve surgery when initiating a minimally invasive programme. Eur J Cardiothorac Surg. 2020;58:1168-1174. https://doi.org/10.1093/ejcts/ezaa232II. Kastengren M, Svenarud P, Källner G, Settergren M, Franco- Cereceda A, Dalén M. Percutaneous Vascular Closure Device in Minimally Invasive Mitral Valve Surgery. Ann Thorac Surg. 2020;110:85-91. https://doi.org/10.1016/j.athoracsur.2019.10.038III. Kastengren M, Settergren M, Rück A, Feldt K, Saleh N, Linder R, Verouhis D, Meduri CU, Bager J, Dalén M. Percutaneous plug-based vascular closure device in 1000 consecutive transfemoral transcatheter aortic valve implantations. Int J Cardiol. 2022;359:7-13. https://doi.org/10.1016/j.ijcard.2022.04.033IV. Ma K, Kastengren M, Svenarud P, Green R, Dalen M. Routine use of percutaneous femoral cannulation in minimally invasive cardiac surgery. Eur J Cardiothorac Surg. 2023;63:ezad020. https://doi.org/10.1093/ejcts/ezad020</p
