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Bleeding complications in cardiothoracic surgery and extracorporeal membrane oxygenation treatment
No full textBackgroundBleeding is a common complication in cardiothoracic surgical procedures and creates the need for blood transfusions and reexploration. After cardiac surgery and lung resections it has been associated with other postoperative complications and increased mortality. The long-term effects of bleeding complications on survival are less studied, and the impact on graft patency after coronary artery bypass grafting (CABG) is unknown. In patients on extracorporeal membrane oxygenation (ECMO), bleeding occurs even more frequently due to long exposure to antithrombotic heparin treatment and coagulopathy induced by both the circuit and underlying pathological processes. Major iatrogenic bleeding events have been reported in patients on ECMO support from both chest tube treatment and vascular cannulation, but the true incidence of these complications remains uncertain.This thesis investigates the incidence and both short- and long-term effects of bleeding in CABG, lung resection, and chest tube treatment during ECMO. It also compares complications between minimally invasive and standard techniques for both aortic valve replacement (AVR) and ECMO femoral cannulation.Methods and resultsStudy I - Within the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) registry, all isolated CABG operations using a single internal mammary artery and saphenous vein grafts in patients aged 40 to 80 years between year 2005 and 2015 were included. Patients who underwent reexploration for bleeding within 24 hours of the operation were identified and their future incidence of coronary angiographies, coronary reinterventions, and mortality were compared to patients not reexplored. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using multivariable Cox regression and adjusted for confounding variables associated to graft patency. Angiography events were analysed separately as early and late (within and beyond one year).Of 27 957 CABG patients, 1071 (3.8%) underwent reexploration. Ninety-day mortality was higher in reexplored patients. Mean follow-up was 6.5 ± 3.1 years, and within 1 year, the cumulative incidence of coronary angiography was 7.8% in reexplored versus 4.8% in non-reexplored patients (adjusted HR 1.64; 95% CI 1.31-2.06), and need for coronary reintervention within 1 year was 4.9% vs 2.6% respectively (adjusted HR 1.91; 95% CI 1.43-2.56). No statistically significant differences were seen beyond 1 year.Study II - In this randomised trial, 100 patients scheduled for AVR due to aortic stenosis were randomised in a 1:1 ratio to undergo either full sternotomy or ministernotomy. The primary composite outcome was severe or massive bleeding defined as at least one of the following criteria: delayed sternal closure; postoperative chest tube output >1000 mL, transfusion of >4 units of packed red blood cells or plasma, administration of recombinant activated factor VII or reexploration. Secondary outcomes included transfusion rates, chest tube output, and reexploration.Three patients in each group (6%) met the criteria for severe or massive bleeding (p=1.00). Mean 12-hour chest tube output was 350 ± 220 mL in the full sternotomy group and 270 ± 190 mL in the ministernotomy group (p=0.08). Packed red blood cell transfusion was administered in 28% of cases in the full sternotomy group vs 36% in the ministernotomy group (p=0.39). Two patients per group required reexploration.Study III - This was a nationwide cohort study including adult patients who underwent lung resections for malignant and non-malignant diagnoses between 2013 and 2021. All data were obtained from the Swedish National Registry for Thoracic Surgery (ThoR). Patients with and without bleeding complications, defined as requiring reexploration or receiving any blood transfusions, were compared regarding incidence of postoperative complications and long-term survival. Full matching was performed, and Cox regression was used for survival analysis.The cohort comprised 15 617 adult patients, of whom 646 (4.1%) had bleeding complications. The unadjusted 90-day mortality was 9.4% in patients with a bleeding complication versus 1.0% in the non-bleeding group. After matching, the odds ratio (OR) for 90-day mortality in the bleeding group was 3.66 (95% CI 2.17-6.17). Long-term overall survival was lower among patients in the bleeding group, with an adjusted HR of 1.47 (95% CI 1.29-1.69). Other postoperative complications were also more common (OR 3.00; 95% CI 2.38-3.79), including infections (OR 2.80; 95% CI 1.86-4.20). Bleeding complication rates declined during the study period (pStudy IV - This was a retrospective study of ECMO patients with iatrogenic bleeding events related to chest tube treatment. All consecutive paediatric and adult patients treated at the Karolinska University Hospital ECMO Centre from 2010 to 2024 with chest tubes for pneumothorax or pleural effusion during ECMO were included. Major bleeding was defined by the chest tube output (e.g. 800 mL/24 h for adult patients), transfusion requirement, or need for intervention with thoracotomy or angiography to stop the haemorrhage.A total of 168 out of 1158 ECMO patients (14.5%) underwent chest tube treatment for pneumothorax or pleural effusion, with a total of 279 chest tubes. Major bleeding occurred in 12.5% of patients (n=21) and from 8.1% of individual chest tubes. Emergency thoracotomy to control the blood loss was required in 14 patients. Bleeding occurred more frequently from tubes inserted during ECMO than with those inserted before ECMO (11.3% vs 4.7%, p=0.036). Patients with major chest tube-related bleeding had longer ECMO durations (median 42 vs 17 days, p=0.003) and lower in-hospital survival (47.6% vs 71.4%, p=0.043). No associations to ECMO mode or chest tube characteristics, including size and placement technique, were found.Study V - This was a retrospective cohort study of 384 consecutive adult venoarterial (VA) ECMO patients treated at the Karolinska University Hospital Cardiothoracic Unit between 2007 and 2022, comparing percutaneous (n=181) and surgical (n=203) femoral cannulation. Complications including bleeding, infection, and limb ischaemia were analysed. Cannulation-site bleeding was defined as requiring blood transfusion or resulting in at least one of the following: conversion to surgical cut-down, change in cannulation strategy, vascular repair, cannula relocation, or use of a mechanical compression device. Logistic regression was used for multivariable adjustment.Bleeding complications occurred in 29.3% of percutaneously and 40.9% of surgically cannulated patients (p = 0.02), while infections were observed in 8.3% and 31.0% of patients, respectively (p ConclusionsThe results of these studies confirm that bleeding complications are common and clinically significant adverse events in cardiothoracic procedures. Reexploration after CABG is associated with increased mortality and with a higher need for coronary reintervention within the first year. Minimally invasive aortic valve surgery via ministernotomy did not reduce bleeding compared to full sternotomy in a randomised trial. In lung resections, reexploration and blood transfusions are strongly associated with worse short- and long-term survival. In ECMO patients, chest tube-related major bleeding is common and often severe enough to require emergency thoracotomy for haemostasis. For ECMO femoral cannulation, local complications were common, and percutaneous access was associated with fewer bleeding events and infections than surgical cut-down.In summary, these findings support minimising perioperative bleeding to potentially reduce complications and improve survival. They also underscore the challenges in evaluating outcomes for new surgical methods, such as ministernotomy and percutaneous cannulation. Finally, knowing the incidence of bleeding for a procedure is useful for individualised risk-benefit assessments in clinical decision-making, for example, whether to place a chest tube or when selecting a cannulation method for an ECMO patient.List of scientific papersI. Re-exploration for bleeding associated with increased incidence of the need for reintervention after coronary artery bypass graft surgery. Dimberg A, Alström U, Janiec M. Interactive cardiovascular and thoracic surgery. 2019;28:214-21. https://doi.org/10.1093/icvts/ivy245II. Bleeding in minimally invasive versus conventional aortic valve replacement. Bratt S, Dimberg A, Kastengren M, Lilford RD, Svenarud P, Sartipy U, Franco-Cereceda A, Dalén M. Journal of cardiothoracic surgery. 2024;19:349. https://doi.org/10.1186/s13019-024-02667-1III. Bleeding and long-term survival after lung resections: nationwide observational cohort study. Dimberg A, Dalén M, Sartipy U. Journal of thoracic disease. 2024;16:4409-16. https://doi.org/10.21037/jtd-24-502IV. Bleeding complications from chest tube treatment in patients on extracorporeal membrane oxygenation support. Dimberg A, Dalen M, Broman L M, Sartipy U, Larsson M. [Submitted]V. Percutaneous cannulation for femoral veno-arterial ECMO associated with lower rates of cannulation site bleeding and infection than open surgical cut-down technique. Dimberg A, Dalén M, Franco-Cereceda A, Fux T. [Submitted]</p
Studies of the molecular anatomy of stroma vascular cells in murine adipose and renal tissues
No full textAdipose tissue plays a central role in metabolism and has during the last decades gained significant attention from the scientific community due the growing health concerns caused by the increased prevalence of obesity. Obesity-related diseases, including those affecting the vascular system, cancer, and diabetes, are among the most prevalent non-communicable diseases today. However, the issue may not solely lie within obesity itself since there are claims of metabolic "healthy" individuals with obesity, although the time for which one can live with obesity and still be health is limited. Nevertheless, this implies that the fundamental contributor to these diseases may rather be a dysfunctional adipose tissue rather than obesity. The primary contributors to associated morbidities to obesity may in fact be attributed to the enlarged adipocytes that are known to cause inflammation and reduced insulin sensitivity in adipose tissue. This, in turn, may redirect fatty acids from adipose tissue to other organs, leading to dyslipidemia, unhealthy systemic insulin resistance and elevated blood glucose levels.Current incretin-mimetic therapies, such as semaglutide and tirzepatide, aim to reduce food intake, thereby decreasing body weight and improving insulin sensitivity and blood glucose levels. The medicine possesses several physiological properties, and the reduction of blood glucose can be attributed to several mechanisms such as decreased production of glucose by the liver, increased secretion of insulin, and slowed down digestion of food, as well as the reduced food intake accompanied by body weight loss. However, the reduction of body weight comes with desirable reduction in fat mass and an undesired loss of lean mass, potentially increasing the risk of adverse effects. An alternative therapeutic strategy could therefore focus on enhancing the function and fat storage capacity of adipose tissue, thereby minimizing ectopic fat and improving insulin sensitivity. In this context, adipose stem cells could play a pivotal role, as they have the ability to differentiate into mature adipocytes and by so increasing the fat storage capacity of the tissue. Nonetheless, to develop medications aimed at enhancing the overall function of adipose tissue, such as by stimulating adipogenesis, a more detailed characterization of the cell types involved in adipogenic differentiation and adipose tissue homeostasis is needed. To this end, significant interest has been directed towards the single-cell RNA sequencing technology and for its potential to more accurately define cell types within adipose tissue. Previous methods, like bulk RNA sequencing of whole tissue or cells isolated by antibodies, have not fully captured the complexity and heterogeneity of tissue composition. Bulk RNA sequencing can overlook rare cell types, overshadowed by mRNA from more prevalent cell types, and the absence of specific cell-type markers suitable for antibody enrichment has made isolating certain cell populations nearly impossible.In this thesis, we utilized single-cell RNA sequencing to characterize cells within the stromal vascular fraction of white adipose tissue in lean healthy wild-type mice (Paper I), during obesity/diabetes and treatment (Paper II), and to study endothelial cells in kidney nephrons during disease progression of a common complication to diabetes, namely diabetic kidney disease (Paper III). Our work has led to a better characterization of adipose stem cells (Paper I) by comparing their gene expression profile to other cell types in adipose tissue and similar cell types from other organs. Our analysis identified adipose stem cells as fibroblast- like cells with a unique gene expression profile distinct from mural and endothelial cells. We found that the gene expression of adipose stem cells in mice is strongly influenced by anatomical location and sex, with male perivascular adipose stem cells showing a higher propensity for adipogenic differentiation than their female counterparts.In Paper II, we explored how the transcriptomic landscape of adipose tissue is affected by obesity/type-2-diabetes and treatment using a db/db mice model treated with the PPARG agonist pioglitazone. The treatment improved the metabolic profile, decreasing glucose and lipid levels in blood. Our analysis indicated that adipose tissue was more affected by the disease than skeletal muscle and heart, with a gene expression profile suggesting inflammation in adipose tissue. The transcriptomic data suggested that the treatment resolved inflammation, potentially through increased adipogenic differentiation of adipose stem cells into mature adipocytes and/or improved function of the vascular system in adipose tissue.In Paper III, we aimed to identify endothelial cell subtypes in kidney nephrons using single-cell RNA sequencing technology and explore their transcriptomic changes during the progression of diabetic kidney disease using the BTBRob/ob mice model. We provided a single-cell RNA sequencing technology atlas covering major endothelial cell subtypes in kidney nephrons of lean mice as well as during the progression of the disease. Paper III highlights novel marker genes for endothelial cell subtypes and confirms their anatomical locations through tissue imaging. Our data suggest that glomerular endothelial cells and peritubular capillaries are most affected during diabetic kidney disease, with gene expression profile analysis indicating inactivation of oxidative phosphorylation pathways.In conclusion, our work underscores the utility of single-cell RNA sequencing in bridging previous knowledge gaps regarding the stromal vascular cell types of adipose tissue and renal endothelial cells, both in healthy and diseased states.List of scientific papersI. Uhrbom, M. Muhl, L. Genové, G. Liu, J. Palmgren, H. Alexandersson, I. Karlsson, F. Zhou A-X. Lunnerdal, S. Gustafsson, S. Buyandelger, B. Petkevicius, K. Ahlstedt, I. Karlsson, D. Aasehaug, L. He, L. Jeansson, M. Betsholtz, C. & Peng, X-R. Adipose stem cells are sexually dimorphic cells with dual roles as preadipocytes and resident fibroblasts. Nat Commun. 2024, 15, 7643. https://doi.org/10.1038/s41467-024-51867-9II. Uhrbom, M. Leke, R. Andréasson, A-C. Alexandersson, I. Collin, J. Ahlstedt, Xiang, Z, I. Aasehaug, L. Baker, T. Zarrouki, B. Betsholtz, C. and Peng, X-R. Single cell analysis of adipose tissue response to pioglitazone in a type-2 diabetes model. [Manuscript]III. Zhou, A-X. Jeansson, M. He, L. Wigge, L. Tonelius, P. Tati, R. Cederblad, L. Muhl, L. Uhrbom, M. Liu, J. Granqvist, AB. Lerman, L, O. Betsholtz, C. Hansen, P, B, L. Renal Endothelial Single-Cell Transcriptomics Reveals Spatiotemporal Regulation and Divergent Roles of Differential Gene Transcription and Alternative Splicing in Murine Diabetic Nephropathy. Int. J. Mol. Sci. 2024, 25, 4320. https://doi.org/10.3390/ijms25084320</p
Mental health in Central and Eastern Europe: a comprehensive analysis
No full textNo description supplied</p
Novel biomarkers in cardiovascular disease and dysglycaemia
No full textBackground. Cardiovascular disease (CVD) and dysglycaemia are closely interconnected. Dysglycaemia, defined as impaired glucose tolerance (IGT) or type 2 diabetes (T2DM), increases the risk of adverse cardiovascular events. Traditional glycaemic markers may not fully capture cardiometabolic risk and novel biomarkers reflecting early glucometabolic perturbations and their prognostic importance may improve risk stratification and management. Plasma mannose, a marker of insulin resistance (IR), and copeptin, a surrogate for vasopressin (AVP) activity, have emerged as potential candidates.Aims. The overall aim was to investigate novel biomarkers in the context of CVD and dysglycaemia, focusing on their associations with myocardial infarction (MI), glucometabolic profiles, and long-term outcomes, as well as their response to a cardioprotective glucose-lowering treatment such as empagliflozin, a sodium- glucose cotransporter 2 (SGLT2) inhibitors. Specifically, the four studies explored:The relationship between plasma mannose levels and risk of a first MI across glycaemic states (Study I).The association between mannose, IR indexes, and major adverse cardiovascular events (MACE) (Study II).The effects of the SGLT2-inhibitors empagliflozin on IR, B-cell function, and relevant biomarkers, including mannose (Study III).The effect of empagliflozin on copeptin levels, evaluating AVP signalling as a potential mediator of cardioprotection (Study IV).Methods. Study I and II were based on the population from the PAROKRANK Study, a cohort of 1,547 individuals, including patients with a first myocardial infarction (MI) and age and gender matched controls. Study participants were categorized by an oral glucose tolerance test (OGTT) as having normal glucose tolerance, IGT, or newly detected T2DM. The association between mannose, measured by high- performance liquid chromatography coupled with mass spectrometry, and MI was investigated across the glycaemic states by logistic regression. Multivariate regression models were used to explore mannose independent relationship with indexes of IR and insulin secretion derived during an OGTT. Multivariate Cox regression models were applied to assess the association between elevated (top quartile) and lower (lower three quartiles) mannose levels and the occurrence of MACE over a 10-year follow-up period. Study III and IV were based on the SOCOGAMI Trial, a randomized double-blind placebo-controlled study which enrolled 42 patients with IGT or T2DM detected in connection to a previous recent acute coronary syndrome (ACS). Study participants were randomized to receive 25 mg empagliflozin or placebo for 10 months in total, 7 on treatment and the last 3 off treatment. IR/insulin secretion, mannose (Study III) and copeptin, measured using an automated immunofluorescence assay (Study IV), were assessed before, during, and 3 months off treatment. The effects were primarily evaluated by repeated measures ANOVA and regression models.Results.Plasma mannose as a biomarker of cardiovascular risk. Study I found that plasma mannose levels increased with worsening glucose intolerance and were independently associated with a first MI, particularly in individuals with normal glucose tolerance (odds ratio - OR: 2.0; 95% confidence interval - CI: 1.2-3.6). Study II confirmed that mannose was associated with IR indexes and independently predicted MACE over 10 years (hazard ratio - HR: 1.54; 95% CI: 1.1-2.2), suggesting that mannose may serve as a marker of cardiometabolic risk.Biomarker responses to the SGLT2i empagliflozin in patients with ACS and dysglycaemia. Study III found that empagliflozin improved OGTT-based surrogate markers of IR but did not impact B-cell function, traditional IR indexes, or levels of mannose. The glucose-lowering effects were reversible after treatment discontinuation. In Study IV, copeptin correlated positively with arterial stiffness but empagliflozin did not significantly affect copeptin levels compared with placebo. Copeptin levels did not predict the glycaemic response to treatment.Conclusions. These studies suggest that: 1) plasma mannose is a potential biomarker for early identification of cardiovascular risk independently of glycaemic state and 2) while SGLT2-inhibitors offer metabolic benefits in patients with newly detected dysglycaemia post-ACS, their effects may not be mediated through changes in AVP activity.List of scientific papersI. Fortin E, Ferrannini G, Campi B, Mellbin L, Norhammar A, Näsman P, Saba A, Ferrannini E and Rydén L. Plasma mannose as a novel marker of myocardial infarction across different glycaemic states: a case control study. Cardiovascular Diabetology (2022) 21:195 https://doi.org/10.1186/s12933-022-01630-5I. Fortin E, Campi B, Ferrannini E, Mari A, Mellbin L, Norhammar A, Näsman P, Rydén L, Saba A, Ferrannini G. High Mannose Correlates with Surrogate Indexes of Insulin Resistance and Is Associated with an Increased Risk of Cardiovascular Events Independently of Glycemic Status and Traditional Risk Factors. Diabetes Care 2024;47(2):246-251 https://doi.org/10.2337/dc23-0870III. Fortin E, Lundin M, Mellbin L, Norhammar A, Näsman Per, Smetana S, Sörensson P, Ferrannini E, Rydén, Ferrannini G. Empagliflozin improves insulin sensitivity in patients with recent acute coronary syndrome and newly detected dysglycaemia Cardiovascular Diabetology (2023) 22:208 https://doi.org/10.1186/s12933-023-01950-0IV. Fortin E, Melander O, Ferrannini G, Näsman P, Norhammar A, Rydén L, Smetana S, Svensson M, Mellbin L. Response of Copeptin Levels to Empagliflozin in Patients with Recent Acute Coronary Syndrome and Newly Detected Dysglycaemia [Manuscript]</p
Targeting cytomegalovirus in brain tumor therapy : from bench to bedside
No full textBackgroundGlioblastoma (GBM) is the most aggressive primary brain tumor in adults, characterized by rapid progression, poor therapeutic response, and dismal prognosis. Despite advances in molecular understanding, the standard of care has remained largely unchanged since the introduction of the Stupp protocol in 2005, which combines surgery, radiotherapy, and temozolomide chemotherapy. Most tumors are recurring within 7 months, and the median overall survival (OS) remains approximately 15 months. Currently, there is no consensus or approved standard treatment for recurrent GBM. This highlights an urgent need for novel therapeutic approaches and actionable targets in neuro-oncology to help these patients to a better future.Human Cytomegalovirus in GBMThe presence of human cytomegalovirus (HCMV) in GBM was first reported by Cobbs et al. in 2002, opening new perspectives in tumor biology and treatment. Our group and others have since then demonstrated that HCMV infects the vast majority (89-99%) of GBM and other central nervous system tumors, where it is proposed to play an essential oncomodulatory role. Although HCMV is not classified as an oncogenic virus, it possesses the capacity to induce several hallmarks of cancer. Importantly, its presence and expression levels in GBM have been associated with patient survival outcomes. Like other herpesviruses, HCMV establishes lifelong latency and evades immune clearance. Furthermore, it can be reactivated during radiotherapy, occasionally resulting in life-threatening encephalitis. These findings suggest that antiviral therapy targeting HCMV could be a promising adjunctive approach in GBM management.AimsThe overall aim of this PhD project was to explore the clinical and biological significance of HCMV in brain tumors, with a particular focus on its translational potential. The long-term objective is to develop innovative therapeutic strategies incorporating antiviral treatment into neuro-oncological clinical practice.Summary of ProjectsProject I-III: Retrospective Clinical Cohort StudiesIn three retrospective studies, we analyzed survival outcomes in patients with (I) primary, (II) recurrent, and (III) secondary glioblastoma treated with the antiviral drug valganciclovir (VGCV) in addition to standard therapy at Karolinska University Hospital. Across all subgroups, patients who received VGCV demonstrated a trend toward longer survival compared to matched controls treated with standard therapy alone, suggesting a potential therapeutic benefit of antiviral intervention.Project IV: HCMV Expression, Survival and Epilepsy We examined the association between HCMV infection and survival in a cohort of GBM patients with tumor-related epilepsy (TRE). Our findings indicate that high levels of HCMV proteins were correlated to Focal-to-bilateral tonic-clonic (FBTCS) and to shorter survival.Project V: Mechanistic Insights into HCMV-Host Interactions We demonstrated that HCMV actively induces replication stress and DNA damage in host cells, creating a microenvironment favorable for viral gene expression. Simultaneously, HCMV hijacks the host stress response to upregulate its early gene expression. Simultaneously, HCMV hijacks the host stress response to upregulate its early gene expression. These findings suggest a feedback loop that may contribute both to tumor progression and viral persistence, providing a mechanistic rationale for antiviral therapy.Project VI: Prospective Randomized Trial of VGCVIn a prospective, randomized, double-blind study, we investigated HCMV reactivation in GBM patients undergoing radio-chemotherapy. Patients receiving prophylactic VGCV experienced no HCMV reactivation, while nearly 40% of those in the placebo group showed viral reactivation, which was associated with significantly worse prognosis. These clinical observations were corroborated by in vitro studies in HCMV-infected GBM cell lines and in vivo in a murine model, further supporting the hypothesis that HCMV reactivation negatively affects treatment outcomes and that VGCV may mitigate this risk.ConclusionCollectively, this thesis supports a clinically significant role for HCMV in glioblastoma pathophysiology. Our findings indicate that antiviral therapy with VGCV may improve survival outcomes in both primary and recurrent GBM settings The mechanistic studies suggest that HCMV contributes to tumor progression by exploiting the host stress response and inducing replication stress. We also found that a higher degree of CMV infection is associated with a clinical phenotype of FBTCS and poor survival; future study should be done to understand if HCMV can promote directly epileptogenesis. Overall, these insights pave the way for future clinical trials and suggest that targeting HCMV could become a novel adjunct strategy in the multimodal treatment of GBM.List of scientific papersI. Stragliotto G*, Pantalone MR*, Rahbar A, Bartek J, Söderberg-Naucler C. Valganciclovir as Add-on to Standard Therapy in Glioblastoma Patients. Clin Cancer Res. 2020;26(15):4031-4039. *shared first authorship https://doi.org/10.1158/1078-0432.ccr-20-0369II. Pantalone MR, Rahbar A, Söderberg-Naucler C, Stragliotto G. Valganciclovir as Add-on to Second-Line Therapy in Patients with Recurrent Glioblastoma. Cancers (Basel). 2022;14(8):1958. Published 2022 Apr 13. doi:10.3390/cancers14081958https://doi.org/10.3390/cancers14081958III. Stragliotto G*, Pantalone MR*, Rahbar A, Söderberg-Nauclér C. Valganciclovir as Add-On to Standard Therapy in Secondary Glioblastoma. Microorganisms. 2020;8(10):1471. Published 2020 Sep 24. I. *shared first authorship https://doi.org/10.3390/microorganisms8101471IV. De la Cerda-Vargas MF, Pantalone MR, Söderberg Nauclér C, Medrano-Guzman R, Jauregui Renaud K, Nettel Rueda B, Reynoso- Sanchez MJ, Lopez-Quintana B, Rodriguez-Florido MA, Feria-Romero IA, Trejo-Rosales RR, Arreola-Rosales RL, Candelas-Rangel JA, Navarro-Dominguez P, Meza-Mata E, Muñoz-Hernandez MA, Segura- Lopez FK, Gonzalez-Martinez MDR, Delgado-Aguirre HA, Sandoval- Bonilla BA. Focal-to-bilateral tonic-clonic seizures and High-grade CMV-infection are poor survival predictors in Tumor-related Epilepsy Adult-type diffuse gliomas-A single-center study and literature review. Heliyon. 2024 Apr 2;10(7):e28555. https://doi.org/10.1016/j.heliyon.2024.e28555V. Merchut-Maya JM, Bartek J Jr, Bartkova J, Galanos P, Pantalone MR, Lee M, Cui HL, Shilling PJ, Brøchner CB, Broholm H, Maya-Mendoza A, Söderberg-Naucler C, Bartek J. Human cytomegalovirus hijacks host stress response fueling replication stress and genome instability. Cell Death Differ. 2022 Aug;29(8):1639-1653. https://doi.org/10.1038/s41418-022-00953-wVI. Pantalone MR, Stragliotto G, Martin-Almazan N, Lawler S, Bartek J, Söderberg-Naucler C Valganciclovir prevents Cytomegalovirus reactivationc upon chemoradiotheray in patients with Gliobalstoma. [Manuscript]</p
Uncovering metastasis biomarkers and molecular mechanisms in Merkel cell carcinoma
No full textMerkel cell carcinoma (MCC) is a rare but highly aggressive skin cancer with high metastatic potential and poor prognosis. Due to its nonspecific symptoms, MCC is often misdiagnosed or diagnosed late. At diagnosis, ~40% of patients present with regional or distant metastasis. These patients have poor 5-year overall survival (OS) rates, 35%-63% for regional and only 14-24% for distant metastases, compared to 51%-75% for those with localized disease. This thesis aims to deepen our understanding of MCC by characterizing molecular differences between primary MCC tumors and metastases, identifying metastasis biomarkers and potential treatment targets, and exploring the role of Merkel cell polyomavirus (MCPyV) in MCC.In Paper I, we investigated the role of Insulin-like growth factor 2 mRNA- binding protein 3 (IGF2BP3) in MCC and found its expression elevated in metastases compared to primary tumors. High levels of IGF2BP3 were associated with shorter MCC-specific survival. A xenograft model confirmed increased IGF2BP3 expression in lung metastases. Functional studies demonstrated that IGF2BP3 promotes cell migration and invasion. Through RNA immunoprecipitation, we identified 281 direct RNA targets of IGF2BP3, many of which are associated with metastasis-related processes and overlap with genes differentially expressed between primary MCC tumors and metastases. These findings suggest that IGF2BP3 and its targets contribute to tumor progression. Furthermore, we found that inhibiting or silencing the transcriptional coactivator bromodomain- containing protein 4 (BRD4) reduced IGF2BP3 expression, suggesting BRD4 as a potential regulator of IGF2BP3. Our results support IGF2BP3 as both a prognostic biomarker and a metastasis driver in MCC.In Paper II, we performed a combined transcriptomic analysis of publicly available bulk and single-cell RNA sequencing (RNA-seq) data from treatment- naïve, immunocompetent MCC patients. Bulk RNA-seq identified 708 differentially expressed genes (DEGs; fold change ≥ 2, adjusted p These findings suggest that primary MCC tumors exhibit a more immunologically active and mesenchymal phenotypes, which declines during tumor progression.In Paper III, we examined the role of KIT and revealed its direct role in autophagy regulation. We showed that truncated large T antigen (LT) of MCPyV stabilized and sequestered KIT in the paranuclear compartment via VPS39 binding. KIT interacts with phosphorylated BECN1, facilitating its binding to BCL2 while reducing its interaction with the PIK3C3 complex. This shift suppresses autophagy. Depletion of KIT induced both autophagy and apoptosis, and reduced LT expression. Conversely, inhibition of autophagy in KIT-depleted cells restored LT levels and rescued cells from apoptosis. In vivo, autophagy induction increased tumor cell death and significantly reduced tumor growth in MCC xenograft mouse models. These results identify KIT-mediated autophagy suppression as a key survival mechanism in MCC and suggest that autophagy-inducing agents hold therapeutic potential for advanced MCPyV-positive MCC.Together, this thesis advances our understanding of MCC biology by identifying IGF2BP3 as a key regulator of metastasis, elucidating molecular differences between primary tumors and metastases, and uncovering a viral strategy for autophagy suppression that is critical for tumor cell survival. These insights open new avenues for developing biomarkers, improving prognostic stratification, and advancing targeted therapies for patients with advanced MCC.List of scientific papersThis thesis is based on the following papers, which will be referred to in the text by their Roman numerals:I. Yajie Yang*, Jiwei Gao, Hao Shi, Harri Sihto, Sami Kilpinen, François Vilcot, Libuse Janská, Jakob Jeschonneck, Todor Cvetanovic, Anders Hoog, Jan Siarov, John Paoli, C. Christofer Juhlin, Lisa Villabona, Catharina Larsson and Weng-Onn Lui *. IGF2BP3 as a prognostic biomarker and regulator of metastasis in Merkel cell carcinoma. JID Innovations. 2025 Feb 12; 5(3):100355. https://doi.org/10.1016/j.xjidi.2025.100355 II. Yajie Yang*, Sami Kilpinen, Harri Sihto, Libuse Janská, Xiaohao Wang, Hao Shi, Lisa Villabona, Catharina Larsson and Weng-Onn Lui *. Discovery of prognostic biomarkers through transcriptomic differences between metastases and primary tumors in Merkel cell carcinoma. [Manuscript]III. Hao Shi*, Yajie Yang, Jiwei Gao, Satendra Kumar, Hong Xie, Ziqing Chen, Jiawen Lyu, Harri Sihto, Virve Koljonen, Silvia Vega-Rubin-de- Celis, Vladana Vukojevic, Filip Farnebo, Viveca Björnhagen, Anders Höög, C. Christofer Juhlin, Linkiat Lee, Malin Wickström, Jürgen C. Becker, John Inge Johnsen, Catharina Larsson and Weng-Onn Lui *. KIT mediated autophagy suppression driven by a viral oncoprotein emerges as a crucial survival mechanism in Merkel cell carcinoma. Autophagy. 2025 Jul; 21(7):1523-1543. https://doi.org/10.1080/15548627.2025.2477385*Corresponding author</p
Bridging genes and therapy : insights into CBT outcomes for OCD, anxiety and depression
No full textEffective psychological treatments exist for common psychiatric disorders, in form of cognitive behavior therapy (CBT), but a significant portion (30-50%) of patients do not respond sufficiently to CBT. Not enough is known about which patients will benefit from CBT, with reliable predictors of individual differences in symptom change currently lacking. Genetic differences have been suggested to play a role, but existing evidence is limited and inconclusive.Study I described the set-up of the unique MULTI-PSYCH cohort, including 2,668 participants with panic disorder, social anxiety disorder and major depressive disorder that received internet-delivered CBT (ICBT). MULTI-PSYCH also contains genetic information and data from several Swedish register with variables spanning from birth to up to 10 years post ICBT.Study II examined associations between polygenic scores (PGS) and symptom change following ICBT in 2,668 participants from the MULTI-PSYCH cohort. Symptom change was assessed from pre- to post-treatment. Linear mixed- effects models with repeated measures revealed a significant negative association between the PGS for educational attainment (PGS-EDU) and symptom severity in the adjusted analysis (B =-. 69, p =. 034). This suggests that individuals with a higher genetic predisposition for educational attainment improved more during CBT. Additionally, a significant interaction between PGS- EDU and time was observed, indicating that PGS-EDU also was associated to symptom change rate over the course of treatment.Study III included 1,598 adults and children diagnosed with obsessive-compulsive disorder (OCD) who underwent CBT, drawn from the NORDIC cohort. Linear mixed models, adjusted for age, sex, genotyping batch, and the first five ancestry principal components, were used to examine the association between PGS and change in symptom severity from pre- to post-treatment. The PGS for schizophrenia was modestly but significantly associated with symptom change (B =. 013, p =. 04), suggesting that individuals with a higher genetic risk for schizophrenia experienced a smaller reduction in symptoms following CBT. No other PGS showed significant associations with symptom change.Study IV was a genome-wide association study (GWAS) of symptom change following CBT using data from the MULTI-PSYCH and NORDIC cohorts. The sample included 3,113 adults and children who received CBT for anxiety, depression, or OCD. The primary aim was to estimate how much of the variation in symptom change could be explained by common genetic variants (SNPs) and to identify SNPs associated with treatment outcome. Secondary analyses explored associations with additional clinical outcomes, such as pre- and post-treatment symptom severity and remission status. While no individual SNPs reached genome-wide significance for any outcome, including symptom change and remission, we observed a moderate and statistically significant SNP-based heritability for symptom improvement (h2snp =. 221, SE =. 123, p =. 036). These findings suggest that common genetic variation plays a modest role in treatment response. However, identifying specific genetic markers will likely require much larger sample sizes.Study V investigated the role of rare genetic variants in individuals with OCD, utilizing data from the NORDIC cohort. We identified copy number variants (CNVs) using genotype array data from 2,248 individuals with OCD and 3,608 unaffected controls from Sweden and Norway. The study found that rare, large (>30 kb in size). CNVs were more prevalent in OCD cases compared to controls, dominated by CNVs overlapping protein coding regions. Secondary analyses revealed that individuals carrying neurodevelopmental duplications were significantly more likely to present with comorbid autism, and those with deletions overlapping neurodevelopmental genes exhibited a poorer response to treatment. These findings support the involvement of rare CNVs in OCD risk.Together, these studies contribute to the growing understanding of how genetic variation influences psychological CBT outcomes. This thesis adopted a comprehensive strategy by including multiple psychiatric conditions, age groups, and genetic methodologies. The findings highlight the complexity of predicting treatment response and indicate that, while genetic factors are not yet clinically actionable, they may eventually form part of a broader, multimodal strategy for personalized psychiatry. They also emphasize the value of large, high-quality datasets in psychiatric genetics. To enhance predictive accuracy and clinical relevance, future research should integrate genetic data with environmental, clinical, and neurobiological measures. As sample sizes grow and analytic methods improve, the field may progress toward more precise, individualized treatment recommendations.List of scientific papersThe following publications and manuscripts were included in the thesis:I. Boberg J, Kaldo V, Mataix-Cols D, Crowley JJ, Roelstraete B, Halvorsen M, Forsell E, Isacsson NH, Sullivan PF, Svanborg C, Andersson EH, Lindefors N, Kravchenko O, Mattheisen M, :unselected: Danielsdottir HB, Ivanova E, Boman M, Fernández de la Cruz L, Wallert J & Rück C. Swedish multimodal cohort of patients with anxiety or depression treated with internet-delivered psychotherapy (MULTI- PSYCH). BMJ Open. 2023 Oct 4;13(10):e069427. https://doi.org/10.1136/bmjopen-2022-069427II. Bäckman J, Wallert J, Halvorsen M, Crowley JJ, Mataix-Cols D & Rück C. Polygenic scores and symptom severity change after internet- delivered cognitive behaviour therapy for depression and anxiety. Discover Mental Health 5, 82 (2025). https://doi.org/10.1007/s44192-025-00213-6III. Bäckman J, Wallert J, Halvorsen M, Roelstraete B, de Schipper E, Strom NI, Eide TO, Höffler KD, Mattheisen M, Hansen B, Kvale G, Hagen K, Haavik J, Nordic OCD and Related Disorders Consortium (NORDIC); Mataix-Cols D, Rück C & Crowley JJ. Association Between Polygenic Risk and Symptom Severity Change After Cognitive Behavioral Therapy for Obsessive-Compulsive Disorder. American Journal of Medical Genetics Part B. 2025 Mar 7:e33026. https://doi.org/10.1002/ajmg.b.33026IV. Backman J Kravchenko O Halvorsen M de Schipper E Ivanova E Kaldo V Hentati Isacsson N Olsen Eide T Hoffler KD Mattheisen M Hansen B Kvale G Hagen K Haavik J Nordic OCD and Related Disorders Consortium (NORDIC) Mataix-Cols D Crowley JJ Wallert J & Rück C. Genome-Wide Association Study of Symptom Change following Cognitive Behavioral Therapy. [Manuscript]V. Halvorsen M, de Schipper E, Bäckman J, Strom NI, Hagen K, Nordic OCD and Related Disorders Consortium (NORDIC), Lindblad-Toh K, Karlsson EK, Pedersen NL, Wallert J, Bulik CM, Fundín B, Landen M, Kvale G, Hansen B, Haavik J, Mattheisen M, Rück C, Mataix-Cols D & Crowley JJ. A burden of rare copy number variants in obsessive- compulsive disorder. Molecular Psychiatry. 2025 Apr;30(4):1510- 1517. https://doi.org/10.1038/s41380-024-02763-7</p
Shiga Toxin-Producing <i>Escherichia coli</i> (STEC) in Developing Countries: A 10-Year Review with Global Perspective.
No full textIn the past two decades, Shiga toxin-producing Escherichia coli (STEC) has been responsible for multiple large-scale outbreaks worldwide, affecting thousands of individuals. While surveillance systems in developed countries such as the United States, the United Kingdom, Europe, Australia, Japan, and Canada are well-established, data on STEC prevalence in developing nations remain sparse, partly due to the absence of well-structured molecular diagnostic networks or surveillance systems. This review analyzed 250 studies published between 2014 and 2024 across 39 developing countries in Africa, Asia, Latin America, and the Caribbean, yielding 8986 STEC isolates. Detailed serogroup and serotype data were available for 55.9% of these, with O111, O157, and O26 being most common in humans. In animals, O157:H7 was most frequent, while food isolates mirrored global trends with O157 and O111 dominance. Notably, O145, a serogroup frequently reported in the U.S. and Europe, was absent from the ''Top Seven'' serogroups. Shiga toxin subtypes stx1a and stx2a were most prevalent in human cases. In animal isolates, stx2e was the most prevalent subtype, while stx2c was most commonly found in food samples. We recommend establishing reference laboratories in these regions to improve data quality, strengthen monitoring efforts, and reduce the burden of STEC infections globally.</p
Studies of structural variation in rare disease
No full textAs clinical genetics transitions towards clinical genomics an increasing number of variants are detected requiring clinical interpretation. This is particularly relevant for structural variants (SVs), where improved resolution methods continue to reveal novel variants as well as increasing levels of variant complexity. This thesis explores how short-read and long-read genome sequencing (GS) can detect and characterize SVs, both helping to diagnose individual patients and moving toward more comprehensive precision diagnostics for all.In Studies I and II, two clinical short-read GS cohorts were compiled and analyzed: 229 individuals with neurodevelopmental disorders (NDD) and 860 individuals with neuromuscular disorders (NMD). We show that short-read GS with comprehensive variant calling captures the broad spectrum of pathogenic variants with SVs and short tandem repeats (STRs) accounting for 13% and 15%, respectively. In Study III, the pathogenicity of an inversion disrupting MEIS2, initially detected in the NMD cohort, was confirmed using targeted long-read sequencing and RNA sequencing.In Study IV, 100 individuals with neurological disorders (79 NDD, 21 NMD) newly referred for short-read GS were investigated in parallel with long-read GS. Added diagnostic value was identified in 13 cases, including phasing of pseudogenes and biallelic variants in autosomal recessive genes, precise STR genotyping capturing both sequence and methylation patterns at these loci, as well as methylation profiling of imprinting regions. However, the superior ability to detect and resolve SVs proved particularly important, enabling improved assessment of pathogenicity and recurrence risk in nine cases.In Study V, we examined X-chromosome inactivation in 21 individuals with balanced X-autosome translocations, complemented by data from 80 cases from the literature. Using short-read and long-read GS and the human androgen receptor assay (HUMARA), we further refined the minimal regions of the X chromosome compatible with a viable functional disomy.Through these studies, we demonstrate that GS, particularly long-read GS, is a superior first-line test for individuals with neurological disorders, enabling improved SV detection, clinical interpretation, and the resolution of complex genetic variation.List of scientific papersI. Lindstrand A, Ek M, Kvarnung M, Anderlid BM, Björck E, Carlsten J, Eisfeldt J, Grigelioniene G, Gustavsson P, Hammarsjö A, Helgadóttir HT, Hellström-Pigg M, Kuchinskaya E, Lagerstedt-Robinson K, Levin L-Å, Lieden A, Lindelöf H, Malmgren H, Nilsson D, Svensson E, Paucar M, Sahlin E, Tesi B, Tham E, Winberg J, Winerdal M, Wincent J, Johansson Soller M, Pettersson M, Nordgren A. Genome sequencing is a sensitive first-line test to diagnose individuals with intellectual disability. Genet Med. 2022;24(11):2296-307.https://doi.org/10.1016/j.gim.2022.07.022II. Ek M, Nilsson D, Engvall M, Malmgren H, Thonberg H, Pettersson M, Anderlid BM, Hammarsjö A, Helgadottir HT, Arnardottir S, Naess K, Nennesmo I, Paucar M, Hjartarson HT, Press R, Solders G, Sejersen T, Lindstrand A, Kvarnung M. Genome sequencing with comprehensive variant calling identifies structural variants and repeat expansions in a large fraction of individuals with ataxia and/or neuromuscular disorders. Frontiers in Neurology. 2023;14.https://doi.org/10.3389/fneur.2023.1170005III. Ek M, Kvarnung M, Pettersson M, Soller M J, Anderlid B-M, Thonberg H, Eisfeldt J, Lindstrand A. Multi-omics analysis detail a submicroscopic inv(15)(q14q15) generating fusion transcripts and MEIS2 and NUSAP1 haploinsufficiency. Sci Rep. 2024;14(1):30343https://doi.org/10.1038/s41598-024-81507-7IV. Ek M, Kvarnung M, Ten Berk de Boer E, La Fleur L, Ljöstad L, Lyander A, Lejsted Færgeman S, Opstrup Drue S, Thonberg H, Nordgren A, Johansson Soller M, Wirta V, Eisfeldt J, Lindstrand A. Long-read genome sequencing enhances diagnostics of pediatric neurological disorders.https://doi.org/10.21203/rs.3.rs-6863124/v1V. Zeib Khan S, Ek M, Lowther C, ten Berk de Boer E, Mehrjouy MM, Rasmussen MB, Nazaryan-Petersen L, Bache I, Bak M, Nordgren A, Ottosson J, Lovmar L, Collins RL, Morton CC, Bybjerg-Grauholm J, Sønderby Pedersen J, Midyan S, Chatron N, Pons L, Harzallah I, Januel L, Fannemel M, Misceo D, Varilo T, Kokalj Vokač N, Sheth FJ, Schinzel A, Sismani C, Vermeesch JR, Angelova L, Kalscheuer VM, Lauridsen M, del Rey G, Guitart M, Terada Abe K, Daumer-Haas C, Õunap K, Roht L, Mekkawy M, Moreno Igoa M, Schluth Bolard C, Eisfeldt J, Lindstrand A, Talkowski ME, Tommerup N. Minimal regions for functional disomy in balanced X-autosome translocations.</p
HIV prevention and sexual health among men who have sex with men in Vietnam
No full textIntroduction:Men who have sex with men (MSM) in Vietnam remain a key population disproportionately affected by HIV and emerging infections such as mpox. Despite the availability of prevention tools such as pre-exposure prophylaxis (PrEP) and digital health technologies, uptake remains low due to complex psychosocial and structural barriers. In this context, understanding behavioral, informational, and systemic factors influencing prevention readiness is essential to strengthen Vietnam's public health response.Aim:This thesis aims to explore knowledge, perceptions, and access to HIV and mpox prevention among MSM in Vietnam. Using a multi-method approach, the research investigates the role of eHealth, behavioral predictors, stigma, and healthcare trust in shaping uptake and engagement with prevention strategies such as PrEP and vaccination.Methods:This thesis employed a multi-method research design, integrating systematic review, qualitative inquiry, and quantitative surveys to generate a comprehensive understanding of HIV and mpox prevention dynamics among MSM in Vietnam. Study I was a systematic review conducted following PRISMA guidelines, incorporating 54 eHealth interventions targeting HIV/STI prevention among MSM globally. These interventions were assessed using the ICROMS quality appraisal tool, with thematic synthesis used to analyze behavioral, psychosocial, and technological outcomes. Particular attention was paid to the duration, mode of delivery, and sustainability of behavior change effects.Studies II and III utilized qualitative focus group discussions (FGDs) in Hanoi, Vietnam. Study II explored eHealth preferences with 35 MSM across five stratified FGDs, while Study III examined PrEP acceptability, perceived barriers, and service design preferences among 30 HIV-negative or status-unknown MSM. The FGDs were transcribed, translated, and analyzed using directed content analysis to identify themes related to digital engagement, privacy, stigma, and trust. Studies IV and V were nationwide online cross-sectional surveys conducted between August and November 2022. Study IV involved 1,422 MSM and focused on awareness, access, and willingness to use PrEP. Study V involved 1,549 MSM and assessed mpox-related knowledge, misconceptions, and vaccine willingness. Participants were recruited using a snowball sampling strategy via trusted MSM community leaders. Surveys were administered anonymously using structured online questionnaires covering sociodemographic, behavioral, and psychosocial domains. Multivariable logistic and Tobit regression models were applied to identify predictors of prevention behavior and knowledge.Findings:The systematic review (Study I) synthesized 54 eHealth interventions for HIV/STI prevention among MSM globally. Most were randomized controlled trials conducted in high-income countries, predominantly web-based, and aimed at reducing sexual risk behaviors and increasing HIV/STI testing. About two-thirds employed behavioral theories, but methodological quality varied. The review highlighted that sustained behavior change remains a challenge, with limited long- term follow-up and a lack of booster interventions. Interventions integrating interactivity, personalization, and multi-platform access were associated with higher engagement and effectiveness.Qualitative studies (Study II and III) conducted in Hanoi provided contextual depth on MSM's preferences for digital tools and perceptions of PrEP. MSM preferred smartphone-based, interactive, and discreet eHealth platforms, favoring private channels such as Facebook groups or encrypted chat over SMS, which was viewed as spam-like or privacy-threatening. Participants emphasized trust in content source, short and engaging formats, and integration with real-time services such as booking and counseling. Regarding PrEP, while participants acknowledged its value in reducing HIV risk and enhancing sexual agency, concerns about daily adherence, side effects, stigma, and cost were common. PrEP was seen as a complement-not a replacement-for condoms, and participants favored accessing PrEP through MSM-friendly CBOs or trusted clinics.Survey findings (Study IV and V) reinforced and extended these insights. Among 1,422 MSM across 62 provinces (Study IV), 56.1% were aware of PrEP, and 67.2% expressed willingness to use it. Willingness was higher among younger, better- educated MSM, those with higher income, and those open about their sexual orientation. However, recent experiences of sexual violence and stigma significantly reduced willingness, indicating psychological and structural barriers. Notably, inconsistent condom users and those engaging in group sex were more likely to express PrEP interest-suggesting risk-awareness as a motivating factor. In the context of emerging infections, Study V surveyed 1,549 MSM and found low mpox awareness despite high vaccine willingness (72.4%). Misconceptions about transmission were widespread, and only one in four participants knew where to get tested for mpox. Higher awareness was associated with youth, education, risk behaviors, and social support. Predictors of vaccine acceptance included general mpox knowledge, perceived necessity of vaccination, group sex engagement, and perceived HIV risk. These results emphasize the need for integrated communication strategies that align sexual health education with outbreak preparedness, particularly using trusted digital and peer-based channels.Together, the five studies revealed that while prevention interest among MSM in Vietnam is high-especially for PrEP and mpox vaccination-significant gaps in digital engagement, structural access, and trust must be addressed to translate willingness into action.Conclusion:This thesis provides an integrated understanding of HIV and emerging infectious disease prevention among MSM in Vietnam, drawing on findings from a systematic review, two qualitative studies, and two national surveys. Together, the studies highlight the readiness of MSM to engage with digital and biomedical prevention tools-such as eHealth platforms, PrEP, and vaccines-while also revealing substantial barriers related to stigma, disclosure, service trust, and knowledge gaps. The systematic review affirmed the short-term effectiveness of eHealth interventions when grounded in behavioral theory, but also pointed to limitations in long-term impact and sustainability. Qualitative findings showed that MSM valued credible, interactive, and private online interventions, yet remained concerned about information overload and inadvertent disclosure. Surveys confirmed a high willingness to use PrEP and accept mpox vaccination but revealed low awareness and structural obstacles to access. Psychosocial factors such as stigma, mental health distress, and sexual violence were consistently associated with lower prevention engagement. To close the gap between willingness and action, future health programs must prioritize integrated, stigma- free, and community-centered service models. This thesis offers key recommendations for designing inclusive digital and biomedical interventions, improving policy, and ensuring that MSM in Vietnam are equitably reached by national HIV and infectious disease prevention strategies.List of scientific papersI. A systematic review of eHealth interventions addressing HIV/STI prevention among men who have sex with men. Long Hoang Nguyen, Bach Xuan Tran, Luis EC Rocha, Huong Lan Thi Nguyen, Cui Yang, Carl A Latkin, Anna Thorson, Susanne Strömdahl. AIDS and behavior, 23(9), 2253-2272. https://doi.org/10.1007/s10461-019-02626-1II. An exploratory assessment of the preference for eHealth interventions to prevent HIV and sexually transmitted infections among men who have sex with men in Hanoi, Vietnam. Long Hoang Nguyen, Huong Lan Thi Nguyen, Mattias Larsson, Bach Xuan Tran, Mart L. Stein, Luis EC Rocha, Susanne Strömdahl. BMC public health, 20(1), 1387. https://doi.org/10.1186/s12889-020-09449-zIII. A qualitative assessment in acceptability and barriers to use pre- exposure prophylaxis (PrEP) among men who have sex with men: implications for service delivery in Vietnam. Long Hoang Nguyen, Huong Lan Thi Nguyen, Bach Xuan Tran, Mattias Larsson, Luis EC Rocha, Anna Thorson, Susanne Strömdahl. BMC infectious diseases, 21(1), 472. https://doi.org/10.1186/s12879-021-06178-5IV. Empowering Wellness: Exploring PrEP Access, Utilization, and Willingness among Men Who Have Sex With Men in Vietnam. Long Hoang Nguyen, Huong Lan Thi Nguyen, Tham Thi Nguyen, Mattias Larsson, Luis E. C. Rocha, Anna Thorson, and Susanne Strömdahl. [Manuscript]V. Exploring Awareness of the Disease, Attitude, and Acceptance Towards Vaccine against Monkeypox among Men Who Have Sex With Men in Vietnam. Long Hoang Nguyen, Huong Lan Thi Nguyen, Mattias Larsson, Luis E. C. Rocha, Anna Thorson, Susanne Strömdahl. [Manuscript]</p