Tuva Boerresdatter Dahl

BACKGROUND: The bidirectional interaction between inflammation and thrombus formation plays an important role in myocardial infarction (MI) with IL (interleukin)-6 as a central mediator. If anti-inflammatory therapy modulates coagulation factors, and platelet activation in patients with MI is not clear. METHODS: We have shown that tocilizumab, a monoclonal antibody targeting IL-6R (IL-6 receptor), improves myocardial salvage index in patients with ST-elevation MI. Herein, we measured levels of soluble markers of platelet activation (P-selectin, sCD40L [soluble CD40 ligand]) and coagulation (TF [tissue factor], TFPI [TF pathway inhibitor], PAI [plasminogen activator inhibitor]-1, and D-dimer) in 136 patients with ST-segment–elevation MI (70 tocilizumab and 66 placebo). Platelet-poor EDTA plasma samples were obtained at admission and after 24 and 168 hours. Temporal changes were related to TnT (troponin T), as well as infarct size and myocardial salvage index, assessed by cardiac magnetic resonance imaging. RESULTS: Our major findings were given as follows: (1) patients had higher sCD40L, P-selectin, TFPI, and D-dimer than 28 healthy controls, and these increased during 1-week follow-up, while TFPI decreased; (2) tocilizumab attenuated P-selectin in patients with short symptom duration at 24 hours in particular in those with high C-reactive protein, and this change correlated positively with indices of myocardial damage; (3) tocilizumab augmented TF at 168 hours, and this change correlated positively with infarct size and negatively with myocardial salvage index; (4) change in D-dimer at 168 hours correlated positively with infarct size and negatively with myocardial salvage index in particular in those with long symptom durations or treated with placebo; tocilizumab attenuated these changes; and (5) the use of heparin attenuated sCD40L levels and increased TFPI levels in admission samples and TF levels after 168 hours. CONCLUSIONS: Our findings support attenuation of platelet activation/coagulation by tocilizumab in patients with ST-segment–elevation MI. The marked rise in TF could be a hereto unrecognized side effects of tocilizumab, which need further investigation.

Only few cases of human immunodeficiency virus (HIV) remission have been reported after allogeneic haematopoietic stem cell transplantation (HSCT), mostly involving stem cell donors with the homozygous CCR5Δ32 (CCR5Δ32/Δ32) mutation, which confers resistance to CCR5-tropic HIV-1. Here we report the case of a 63-year-old man in off-treatment HIV remission, 5 years after HSCT with a CCR5Δ32/Δ32 sibling donor for myelodysplastic syndrome. In-depth clinical characterization including virological and immunological analyses of peripheral blood, gut and bone marrow samples revealed that full donor chimerism was achieved. Antiretroviral therapy was discontinued after 24 months, and 48 months after HSCT, no intact HIV DNA was detected in blood or gut biopsies. Replication-competent virus and HIV-specific T cell responses were absent, and HIV antibody responses showed a gradual decline. Full donor chimerism in the gut, which is the primary viral reservoir, underscores the likelihood of a cure.

Background: The high prevalence of patients with post–COVID-19 condition, also called long COVID, even among those with mild initial disease, may have a large impact on both the individual and society. Disability in everyday life, reduced health-related quality of life and work capacity, strain on the health care system, and substantial socioeconomic costs are associated with long COVID. More research to investigate the effectiveness of rehabilitation services is warranted. Objective: This study aims to examine the effectiveness of tailored individual follow-ups versus a 1-day group course in patients with long COVID. Additionally, the feasibility and use of a mobile app for self-monitoring goal achievement will be assessed. Methods: This is a single-center, parallel-group, superiority randomized controlled trial with a 1:1 allocation ratio. A total of 62 outpatients aged 18‐65 years with long COVID will be randomized to either a rehabilitation program with individual follow-up consultations or a 1-day self-management group course. The individual intervention incorporates setting goals, teaching cognitive behavioral strategies, energy management (pacing), and a supervised gradual increase in both physical and cognitive activities tailored to individual tolerance levels. The primary outcome is the between-group difference in health-related quality of life, measured using the EQ-5D-5L index at 6 months. Secondary outcomes include improvements in symptoms, work participation, neurocognitive function, and app usability, assessed at 3, 6, and 12 months, depending on the outcome measure. Results: Data enrollment started in October 2023. A total of 62 participants were included by November 2024. Data collection is planned to be completed in November 2025. Conclusions: Long COVID poses substantial challenges for both individuals and society, underscoring the need for effective rehabilitation strategies. This study will provide valuable insights into the benefits of an individualized outpatient rehabilitation program. The results from this clinical trial will help guide future treatment recommendations and may improve long-term outcomes for affected patients. Additionally, the study will generate important knowledge about neuropsychological function and digital self-management tools in long COVID rehabilitation.

Background: Epitranscriptomics, with m⁶A as the most prevalent in mammals, is a novel treatment target for inflammatory diseases, including cardiovascular diseases. However, little is known about m⁶A RNA-regulation during myocardial infarction (MI).Methods: In this explorative sub-study of the ASSAIL-MI trial, we used whole blood samples from patients with acute ST-elevation MI (STEMI) (n=6) at admission and after 3–7 days, and from healthy control subjects (n=3). RNA was isolated, and m⁶A sites were analyzed using human m⁶A single nucleotide resolution microarray analysis. mRNA levels were analyzed using RNA sequencing analysis.Results: Compared with controls, patients with STEMI had a strikingly different pattern of m⁶A deposition. In total, 845 m⁶A methylation sites in whole blood RNA were hypomethylated and 36 were hypermethylated compared with controls. Of the hypomethylated transcripts, 194 transcripts were lower expressed, while 197 transcripts were higher expressed. The m⁶A pattern changed from an overall hypomethylation at admission to an overall hypermethylation 3–7 day after admission. Anti-inflammatory treatment with tocilizumab further altered the m⁶A deposition.Conclusions: In this hypothesis generating study, m⁶A deposition differs STEMI patients and healthy controls. The m⁶A pattern changes over the course of 3–7 days. This response is, at least to some degree, is modulated by blocking the IL-6 receptor. Our data may suggest that this post-transcriptional regulation of RNA is involved in the immune response during STEMI, highlighting its potential as a target for therapy in MI.

Men develop larger infarct sizes than women after a myocardial infarction (MI), but the mechanism underlying this sex difference is unknown. Here, we demonstrated that blood neutrophil counts post-MI were higher in male than female mice. Castration-induced testosterone deficiency reduced blood neutrophil counts to the level in females and increased survival post-MI. These effects were mimicked by Osterix-directed ablation of the androgen receptor in bone marrow (BM). Mechanistically, androgens downregulated the leukocyte retention factor CXCL12 in BM stromal cells. Post-hoc analysis of clinical trial data showed that neutrophilia was greater in men than women after reperfusion of first-time ST-elevation MI, and tocilizumab, an interleukin-6 receptor inhibitor, reduced blood neutrophil counts and infarct size to a greater extent in men than women. Our work reveals a previously unknown mechanism connecting testosterone with neutrophilia and MI injury via BM and identifies the importance of considering sex when developing anti-inflammatory strategies to treat MI.

Background: Complement activation may promote atherosclerosis. Yet, data on the to which extent complement, and more specifically the alternative complement pathway, is activated in patients with carotid atherosclerosis and related to adverse outcome in these patients, are scarce. Methods and Results: We measured, by ELISA, plasma levels of factor D, properdin, C3bBbP (C3 convertase), and factor H in patients with advanced carotid atherosclerosis in a Discovery (n=324) and in a Validation (n=206) cohort in relation to adverse outcome (mean follow‐up 7.8 and 6.6 years, respectively). Our major findings were as follows. Compared with healthy controls, patients with carotid atherosclerosis had increased plasma levels of factor D, properdin, and C3bBbP ( P Discovery (HR 2.31, P =0.019) and the Validation cohort (hazard ratio [HR], 2.81, P =0.014). In contrast to the low circulating levels, high intraplaque properdin levels (assessed by ELISA) correlated with markers of plaque vulnerability and symptomatology. Conclusions: We show a strong and independent association of low plasma properdin levels with cardiovascular mortality in 2 cohorts. Conversely, the plaque properdin levels linked to features of plaque vulnerability, potentially reflecting increased deposition at the site of inflammation or local production of properdin in the atherosclerotic lesion indicating local enhanced alternative complement pathway activation.

Background and objectives: New onset persistent headache has been reported following acute COVID-19 and to some degree also after SARS-CoV-2 vaccination. The mechanisms for these headache types are unclear. The purpose of this study was to assess levels of amyloid related biomarkers in patients with persistent headache after COVID-19 and SARS-CoV-2 vaccine. Methods: In this prospective observational cohort, patients with severe headache as the dominating symptom after COVID-19 (n=29) and SARS-CoV-2 vaccination (n=31), had neurological assessments with reassessments after 6 months. Plasma levels of amyloid precursor protein (APP), pregnancy zone protein (PZP), cathepsin L1 (CTSL) and serum Amyloid A (SAA1) were measured by ELISA in relation to levels in healthy controls (n=16). Results: We found a strong and persistent upregulation of APP in patients with headache after COVID-19 as compared to the two other groups. At both inclusion and after 6 months APP levels were also increased in those with accompanying cognitive symptoms. In contrast, plasma levels of PZP were elevated in patients with headache after SARS-CoV-2 vaccination at both inclusion and after 6 months as compared to healthy controls. CTSL was only elevated in those with COVID-19 associated as compared with those with vaccine associated headache at baseline, whereas SAA1 showed levels comparable in all groups. Conclusion: Altered plasma levels of soluble markers potentially reflecting changes in amyloid processing was found in patients with persistent headache after SARS-CoV-2 vaccine and particular in those with persistent headache after COVID-19 where we also found some association with cognitive symptoms. NCT04576351 NCT05235776 What is already known on this topic: New onset persistent headache occurs in a subset of individuals after COVID-19 and to some extent after SARS-CoV-2 vaccine. However, the pathophysiological mechanisms are unknown. What this study adds: Altered plasma levels of soluble markers that potentially could reflect changes in amyloid processing was found in patients with persistent headache after SARS-CoV-2 vaccine and particular in those with persistent headache after COVID-19 with association to cognitive symptoms. How this study might affect research, practice or policy: Our data underscore the need for more long-time follow-up of patients with new onset headache following COVID-19 or SARS-CoV-2 vaccination and this follow-up might also include blood tests for amyloid processing and neuroinflammation.