European Journal of Clinical Investigation最新文献

Objective

Our aim is to study proteomic and transcriptomic changes in the subcutaneous white adipose tissue (sWAT) from patients living with severe obesity at early term after bariatric surgery (BS).

Methods

Twenty-two sWAT biopsies were collected at the time of surgery and 3 months afterward (11 for each point and from the same patient). Clinical data and metabolic parameters were measured. Targeted proteomic profiling and RNA sequencing were conducted. Bioinformatic analyses were performed to identify differentially expressed proteins and genes and their associated pathways.

Results

Early-term after BS leads to significant reductions in some clinical parameters. Twenty inflammatory proteins, including cytokines, chemokines and immune-regulatory factors were increased after BS. Transcriptomic profiling revealed 277 significantly modulated genes (156 upregulated, 121 downregulated). ANGPTL8 was notably increased after BS and enrichment analyses highlighted its association with extracellular matrix remodelling, insulin signalling pathway, calcium metabolism and energy and lipid metabolism.

Conclusions

BS induces early immunological and transcriptomic modulations in sWAT, suggesting a transient pro-inflammatory state and tissue remodelling process. The ANGPTL8 upregulation could play a role in improving metabolic homeostasis at early term after BS. These findings offer new insights into adipose tissue remodelling after BS.

Background

Post-pandemic years are characterized by widespread previous population immunization against COVID-19. Whether and for whom COVID-19 vaccinations are still justified is unclear. We use nationwide estimates of IFR and literature-derived estimates of vaccine effectiveness (VE) to calculate numbers needed to vaccinate to prevent one COVID-19 death (NNV) and for one life-year saved (LYS) in Austria in 2024.

Methods

In this retrospective analysis, we calculate SARS-CoV-2 IFR during 2024 in Austria according to previously published wastewater-based infection estimates and available mortality data. Using literature-derived VE estimates, we calculate NNV to prevent one COVID-19 death and for one LYS in strata according to age groups, nursing home residency and vaccination in 2024. We repeat analyses with sensitivity range values of parameters.

Results

In 2024, total IFR was .048%. NNV (LYS) in the age groups 0–19, 20–39, 40–59, 60–74 and 75–84 years was very high: i.e. 5,497,526 (151,570), 2,432,498 (92,614), 415,714 (24,777), 35,925 (3748) and 4882 (1009), respectively, in community dwellers. In the 85+ years age group, IFRs of unvaccinated/vaccinated were .91%/.77% for community dwellers and 1.22%/1.04% for nursing home residents. The 85+ year age group had NNV estimates of 1215 and 907 (LYS: 525 and 1896) in community dwellers and nursing home residents, respectively. Sensitivity analyses yielded LYS < 1000 only under some favourable assumptions in the 75–84 and 85+ years old age strata.

Conclusions

In 2024 in Austria, SARS-CoV-2 IFR was low and NNV and LYS of COVID-19 vaccinations correspondingly non-favorably high, even for very old individuals.

Aims/Hypothesis

Type 2 diabetes is a multifactorial condition whose greatest impact comes from its complications. We hypothesized that distinct insulin-derived mechanisms and lipid profiles discriminate sex differences and can be used to identify subjects at higher risk to develop diabetes-related complications.

Methods

The PREVADIAB2 study evaluated metabolic alterations after 5 years in individuals initially free of Type 2 Diabetes (PREVADIAB1). In this analysis, 953 participants were stratified into clusters using hierarchical clustering based on insulinogenic index (IGI), fasting insulin secretion rate, HOMA-IR, and fasting insulin clearance. A subset of participants (n = 488) had their lipidome assessed using LC/MS-QTOF.

Results

Four clusters were identified: Liver Sensitive (LS), Pancreas Glucose Sensitive (PGS), Insulin Deficient (ID), and Insulin Resistant (IR), each with distinct dysglycemia risk. While metabolic features were similar across sexes, the parameter thresholds differed, resulting in sex-specific lipidomic profiles. Women exhibited higher levels of circulating dihydroceramides (5.3 ± 1.9 vs. 4.7 ± 1.8, p < .001), associated with de novo ceramide synthesis, and elevated sphingomyelins (SM), suggesting altered lipid metabolism. Conversely, the ceramide-to-SM ratio was higher in men (1.04 ± .21 vs. .90 ± .18, p < .001). Except for the LS cluster, all other clusters exhibit distinct lipid signatures associated with metabolic dysfunction, further accentuated by specific lipid profile sex differences.

Conclusions

Distinct insulin-related metabolic features and sex identify different phenotypes with distinct lipidome profiles, highlighting the need to place prediabetes in a broader context of metabolism beyond glucose.

Background

Tricuspid regurgitation (TR), defined as the failure of proper leaflet coaptation during systole, is a common but often underrecognized valvular disorder. TR continues to rise, primarily due to population aging and the broader application of advanced diagnostic imaging techniques. Recent studies have established a clear association between TR and increased morbidity and mortality, thereby challenging its historical perception as a benign condition.

Methods

The development of novel interventional therapies, combined with enhanced insight into the pathophysiology of right-sided heart failure, has prompted a shift towards earlier diagnosis and more proactive clinical management.

Aim

Several gaps between novel scientific advancements and clinical translation still make this disease deserving of further attention.

Discussion and Conclusion

In this review, we examine the most recent advances in understanding TR, which have enabled improved segmentation of affected patient populations. This progress has made it possible to identify key prognostic markers—particularly those related to disease progression—allowing for more accurate risk stratification and significantly more personalized treatment approaches.

Background

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder with potential progression to multiple myeloma (MM). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated potential anti-neoplastic properties. This study evaluated the association between GLP-1 RA use and clinical outcomes in individuals with MGUS and concurrent DM, overweight or obesity.

Methods

A retrospective cohort study was conducted using the TriNetX global health research network. Adults with MGUS and either DM or overweight/obesity were identified. Propensity score matching (1:1) was performed, resulting in two balanced cohorts. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), time to progression to multiple myeloma (MM) and major cardiovascular events, including myocardial infarction (MI), ischemic stroke, ischemic heart disease and heart failure (HF).

Results

Among 30,034 matched patients, 823 patients in the GLP-1 RA group and 2317 in the control group progressed to symptomatic MM or died. GLP-1 RA use was associated with significantly improved PFS [HR (95% CI): .63 (.58–.68)] and OS [HR (95% CI): .61 (.56–.66)]. A reduced risk of progression to symptomatic MM was also observed [HR (95% CI): .82 (.69–.98)]. GLP-1 RA users had lower cumulative incidence of MI, HF, ischemic heart disease, and stroke; however, these differences were not confirmed in time-to-event analyses.

Conclusions

GLP-1 RA therapy was associated with significantly improved PFS and OS in MGUS patients with metabolic comorbidities. While fewer cardiovascular events were observed, these findings were not statistically confirmed over time.

Background

Early diagnosis is pivotal for guiding the intensity of clinical monitoring, optimizing therapeutic strategies and preventing organ damage in inflammatory and autoimmune rheumatic diseases (IARDs). This review summarizes current evidence on early diagnostic and therapeutic approaches of some IARDs, including rheumatoid arthritis (RA), systemic sclerosis (SSc) and detection of large-vessel vasculitis (LVV) in polymyalgia rheumatica (PMR), representing distinct pathophysiological mechanisms of joint synovitis, tissue fibrosis and vasculitis, respectively.

Methods

A comprehensive narrative literature review was conducted focusing on early recognition strategies, searching PubMed and Scopus databases with emphasis on studies from the past 5 years and recent EULAR/ACR conference abstracts (2023–2025).

Results

In RA, clinically suspect arthralgia with seropositivity for rheumatoid factor and anti-citrullinated peptide antibodies significantly increases progression risk to definite RA. Musculoskeletal ultrasound detects subclinical synovitis in 44%–51% of high-risk individuals, while MRI identifies bone marrow edema predicting erosive progression. Abatacept significantly reduces RA development in seropositive individuals at high risk of RA.

In SSc, Raynaud's phenomenon combined with SSc-specific autoantibodies and abnormal nailfold capillaroscopy predicts progression to definite disease, with 79.5% developing SSc within 4.6 years. LeRoy's criteria, validated by Koenig, enables early identification, though evidence for disease-modifying interventions in preclinical stages remains limited.

For PMR, imaging reveals subclinical LVV in 16%–23% of patients without cranial symptoms. Subclinical LVV associates with higher relapse rates in retrospective studies, though optimal management approaches require prospective validation.

Conclusions

Advances in early IARD recognition through refined clinical criteria, enhanced biomarkers and imaging enable risk stratification and personalized management. While intervention strategies show promise, particularly in RA, optimal patient selection and treatment protocols require further research.

Background

Dysmenorrhea, a common gynaecological complaint, is often underdiagnosed, particularly in adolescents. The Developmental Origins of Health and Disease hypothesis suggests that maternal cardiometabolic conditions during pregnancy may influence offspring reproductive health. We investigated whether cardiometabolic risk (CCMR) is associated with dysmenorrhea risk in offspring and whether early-puberty BMI and menarcheal age mediate these associations.

Methods

Data was from the Amsterdam Born Children and their Development cohort. A total of 982 mother-daughter pairs were included. Maternal CCMR included pre-pregnancy body mass index (BMI), blood pressure, glucose, triglycerides and Apolipoprotein A1. Dysmenorrhea was defined as menstrual abdominal/back pain requiring analgesics. Inverse probability weighted multivariable logistic regression examined associations between maternal CCMR or its components and dysmenorrhea in offspring. Multiple imputation was used to handle missing data in the sensitivity analysis. Serial multiple mediation analysis tested the mediating role of offspring's BMI and menarcheal age.

Results

Dysmenorrhea was reported in 49.2% of daughters. In the model adjusted for maternal age, socioeconomic status, smoking, alcohol use, anxiety and depressive symptoms, CCMR was not significantly associated with dysmenorrhea (OR: 1.03, 95% CI: .72–1.48). However, higher maternal pre-pregnancy BMI was associated with increased dysmenorrhea risk in offspring (OR: 1.20, 95% CI: 1.02–1.42). A partial mediation via BMI and menarcheal age was observed (indirect effect: 1.01, 95% CI: 1.00–1.03).

Conclusion

No evidence was found of maternal CCMR and dysmenorrhea in offspring. However, higher maternal pre-pregnancy BMI increased dysmenorrhea risk, partly mediated by heavier BMI and earlier pubertal timing in offspring. These findings align with the hypothesis of a possible intrauterine origin of menstrual disorders and highlight the importance of early life factors in dysmenorrhea research.

Background

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a leading cause of chronic liver disease worldwide, driven by the increasing prevalence of obesity and insulin resistance (IR). IR, a central feature of the metabolic syndrome, promotes hepatic lipid accumulation, inflammation and mitochondrial dysfunction, fostering the transition from steatosis to advanced liver injury and hepatocellular carcinoma (HCC). This review summarizes current evidence on the molecular mechanisms linking MASLD, IR and HCC, highlighting the role of insulin resistance in liver carcinogenesis and disease progression.

Methods

A comprehensive literature search was conducted to identify experimental, clinical and epidemiological studies addressing the interplay between MASLD, IR and HCC. Key molecular pathways and risk profiles were synthesised and compared across etiologies.

Results

IR contributes to hepatic lipid deposition, oxidative stress and chronic inflammation through activation of PI3K/Akt and mTOR signalling. The coexistence of MASLD and IR enhances pro-inflammatory and pro-fibrotic pathways, accelerating the evolution to HCC. Patients with MASLD-associated HCC exhibit distinct metabolic and molecular characteristics compared with those with viral or alcohol-related HCC. Novel biomarkers and advanced imaging modalities show promise for identifying high-risk individuals at earlier disease stages.

Conclusions

Although substantial progress has been made in understanding the MASLD–IR–HCC axis, critical gaps remain regarding genetic, environmental and metabolic determinants. A multidisciplinary approach integrating metabolic, molecular and oncologic research is essential for improving early detection, risk stratification and the development of targeted therapies against metabolic liver cancer.

Background

Preeclampsia is a disorder with complex pathophysiology, which underscores the need to study various biomarkers for its early prediction, accurate diagnosis, better understanding of underlying mechanisms and potential links to other diseases. A growing body of research has explored the potential of established and emerging cardiovascular biomarkers in the context of preeclampsia. The overlap in risk factors between preeclampsia and cardiovascular disease, along with findings from numerous epidemiological studies, suggests that cardiovascular biomarkers may play a key role in predicting preeclampsia, assessing its severity and determining the long-term risk of cardiovascular disease.

Aim

To explore the role of cardiovascular biomarkers in the prediction, diagnosis and management of preeclampsia, while investigating their ability to improve insights into disease mechanisms and their connection to long-term cardiovascular risk.

Methods and Discussion

This review summarizes findings from existing research on cardiovascular biomarkers in preeclampsia, including studies examining their predictive and diagnostic capabilities, their role in elucidating disease pathophysiology, and their relevance for long-term cardiovascular risk assessment. Furthermore, it highlights emerging cardiovascular biomarkers, outlining their technical limitations and the need for further studies to clarify their utility in routine clinical practice.

Conclusion

Cardiovascular biomarkers are becoming essential for diagnosing, monitoring and predicting outcomes in preeclampsia, enabling early detection and treatment. While some are already in clinical use, emerging biomarkers show promise for more precise and individualized care. Advancing research in this area offers significant potential to improve maternal and fetal outcomes.

Background

Lipoprotein(a) [Lp(a)] is a primarily genetically determined, causal and independent risk factor for atherosclerotic cardiovascular disease (ASCVD). Lp(a) levels are stable, unaffected by lifestyle, and best measured using isoform-insensitive, molar-based assays. Current guidelines from the European Atherosclerosis Society and U.S. National Lipid Association recommend a one-time Lp(a) measurement in all adults. Cascade testing is advised in affected families.

Results

Elevated Lp(a) levels are associated with increased risk of coronary artery disease, myocardial infarction incidence and recurrence, and aortic stenosis onset and progression. In cerebrovascular disease, high Lp(a) is linked to large artery ischemic stroke incidence and recurrence, as well as poor functional outcomes. Associations with venous thromboembolism are limited to prothrombotic states and extreme Lp(a) concentrations. Elevated levels (≥50 mg/dL or ≥125 nmol/L) should prompt intensified risk factor modification.

Conclusion

There are no currently approved lipid-lowering therapies that substantially reduce Lp(a) levels. Novel agents to lower Lp(a) include antisense oligonucleotides, small interfering ribonucleic acid and small molecules, all of which have shown promising results in phase 2 trials. Ongoing phase 3 trials will evaluate the causal relationship between Lp(a) and ASCVD, and whether lowering Lp(a) reduces cardiovascular outcomes.