European Journal of Clinical Investigation最新文献

Background

Controlled Human Infection Models (CHIMs) offer a powerful approach to expedite vaccine development by enabling early evaluation of vaccine candidate efficacy and immune responses. Their role is increasingly relevant for neglected tropical diseases (NTDs), where traditional trial approaches may be slow, costly, or unfeasible. This review explores the scientific, ethical and translational dimensions of CHIMs, with a focus on the recently developed Leishmania major CHIM for cutaneous leishmaniasis (CL).

Methods

A narrative synthesis of peer-reviewed literature and regulatory guidance documents published over the past two decades was conducted, with additional insights drawn from original fieldwork and the first-in-human sand fly-transmitted CHIM for CL. Considerations included CHIM design principles, immunological outcomes, safety considerations and translational utility, including integration with omics and early phase trials.

Results

CHIMs provide early efficacy data, help identify immune correlates of protection and facilitate the prioritisation of vaccine candidates. The Leishmania major CHIM demonstrated safety, high participant acceptability and revealed insights into lesion kinetics and host–parasite interactions. Ethical and regulatory frameworks remain heterogeneous across regions, limiting scalability. Barriers to CHIM deployment in low- and middle-income countries include infrastructure, governance and community engagement challenges.

Conclusions

CHIMs represent a critical translational tool for NTD vaccine research. Lessons from the CL CHIM underscore the potential and challenges of broader implementation. Harmonised regulation, ethical innovation and global collaboration will be essential for future impact.

Background

Alzheimer's disease (AD) is neuropathologically defined by the buildup of misfolded proteins such as extracellular amyloid-β (Aβ) and intracellular tau neurofibrillary tangles. AD also extends beyond these pathological processes, and additional mechanisms such as synaptic dysfunction, microglial activity, astrocytic neuroinflammation play an important role as biomarkers of AD progression. In vivo evaluation and quantification of these molecular processes are possible with positron emission tomography (PET) imaging. As disease-modifying therapies are entering clinical use, biomarkers' importance for early diagnosis and longitudinal monitoring of the disease increases.

Results

Aβ is the earliest signature of AD which can be measured with PET imaging, followed by tau-PET positivity, which is highly specific and central for staging and longitudinal monitoring. FDG-PET continues to serve as a gold standard for detecting neurodegeneration, challenged by emerging dual-phase PET protocols for amyloid and tau imaging, which integrate perfusion as a measure of neurodegeneration and pathology information in a single session, enhancing diagnostic efficiency. Synaptic density imaging reveals early synaptic loss linked to cognitive performance and decline. Neuroinflammation tracers can visualize microglial and astrocytic activation, contributing to disease onset and progression. Novel PET tracers targeting alpha-synuclein and TDP-43 show great promise for detecting co-pathologies which can contribute to AD clinical heterogeneity.

Conclusion

PET imaging has advanced the field by enabling visualization of AD-related changes and providing measurable outcomes for clinical trials and disease-modifying therapies. Imaging of related pathologies can further improve diagnostic accuracy and provide important insights into disease heterogeneity. Moving forward, integrating multiple PET biomarkers into personalized diagnostic approaches will be crucial.

Background

Interstitial lung diseases (ILDs) are characterized by progressive fibrosis, in which extracellular matrix remodelling is regulated by matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). The MMP-9/TIMP-1 balance has been implicated in fibrogenesis, but its role in human ILD remains incompletely defined. This study aimed to assess the MMP-9/TIMP-1 ratio in BAL fluids of ILD patients, its relationship with fibrotic severity, and the cellular contribution of fibroblasts/myofibroblasts.

Methods

BAL samples from 48 consecutive ILD patients (non-fibrotic ILD, fibrotic ILD, idiopathic pulmonary fibrosis [IPF]) were analysed. MMP-9 and TIMP-1 concentrations were quantified by enzyme-linked immunosorbent assay (ELISA), and MMP-9 activity assessed by gelatin zymography. Fibroblasts/myofibroblasts were isolated from BAL of ILD patients and tested for TIMP-1 and MMP-9 release by ELISA, or protein expression by immunofluorescence. Published single-cell RNA sequencing datasets were reanalyzed (DESeq2 model) to define the cellular source of MMP-9 and TIMP-1.

Results

The MMP-9/TIMP-1 ratio was significantly reduced in BAL of patients with more advanced fibrosis, correlating with a higher presence of fibroblastic foci (p = .002) and collagen deposition (p < .001). This reduction was driven by both decreased MMP-9 and increased TIMP-1 levels. Zymography confirmed declining MMP-9 enzymatic activity across ILD subgroups. Fibroblasts, derived from BAL of ILD patients, displayed high TIMP-1 secretion but minimal MMP-9 release, consistent with their expression in immunofluorescence. Reanalysis of two independent scRNA-seq datasets confirmed predominant TIMP-1 expression in fibroblast/myofibroblast clusters, with low but detectable MMP-9 expression.

Conclusions

Fibroblast-driven MMP-9/TIMP-1 imbalance in BAL reflects fibrotic severity in ILD. The MMP-9/TIMP-1 ratio may represent a supportive biomarker for differential diagnosis and phenotyping of ILD, warranting validation in larger multicenter studies.

Backgorund

Adipose tissue has emerged as a prognostic factor in rectal cancer (RC), yet its metabolic role in tumour progression remains poorly understood. This study aims to characterise the metabolic profiles of subcutaneous (SAT) and visceral adipose tissue (VAT) in early and advanced tumours to investigate metabolic alterations that may influence tumour progression. Understanding these alterations could provide insights into mechanisms of rectal cancer and identify therapeutic targets.

Methods

Global metabolic profiles of 68 SAT and VAT samples from patients with RC were analyzed using high-performance chemical isotope labeling liquid chromatography mass spectrometry. Statistical analyses were stratified by clinical tumour invasion and disease stage.

Results

VAT exhibited distinct metabolic signatures between early and advanced tumour invasion. Advanced tumours (cT3-4) had a higher concentration of N-glycolylneuraminic acid and phenylacetylglutamine, whereas early invasive tumours (cT2) exhibited higher levels of dipeptides. Pathway enrichment analyses revealed dysregulations in taurine and hypotaurine metabolism, alanine, aspartate and glutamate metabolism, propanoate metabolism and cellular signalling pathways in advanced invasion. Propanoate metabolism emerged as a key pathway distinguishing early and advanced invasion stages. In SAT, metabolic changes aligned with overall disease stage. Early-stage disease was associated with a higher concentration of dipeptides, whereas advanced stages showed increased N-acetyl-agmatine and N-acetyl-L-noradrenaline.

Conclusions

Our study highlights significant metabolic alterations in adipose tissue associated with rectal cancer progression. VAT metabolism reflects tumour invasiveness, while SAT is more indicative of disease stage. Propanoate metabolism may serve as a biomarker for advanced invasion, offering potential for improved staging, reclassification and personalised therapeutic strategies.

Background

Interleukin-6 (IL-6), a pro-inflammatory cytokine and anti-inflammatory myokine, is involved in immune regulation and metabolic control. Persistent IL-6 activation, particularly via trans-signalling, is implicated in endothelial dysfunction, atherosclerosis, myocardial fibrosis, and adverse remodelling.

Methods

This review summarizes experimental, genetic, and clinical evidence on the role of IL-6 in cardiovascular disease (CVD), focusing on the molecular pathways, prognostic value, and its potential as a therapeutic target. Experimental and genome-wide association studies, as well as clinical trials—including IL-6–targeted interventions—are comprehensively reviewed.

Results

While acute activation of IL-6/STAT signalling, that is, before or during myocardial infarction, is protective, chronic activation leads to maladaptive changes in the myocardium. Mechanistically, IL-6 promotes vascular inflammation, monocyte recruitment, coagulation, and fibrosis. Mendelian randomization implies a causal role of IL-6 signalling in coronary artery disease, stroke, and atrial fibrillation. Simultaneously, elevated IL-6 levels predict adverse outcomes in acute coronary syndromes and heart failure. Pharmacological IL-6 inhibition reduces systemic inflammation, with pilot data implying acceptable safety profiles. Large phase III outcome trials are ongoing, shedding light on the impact of IL-6 blockade in high-risk populations, such as those with chronic kidney disease and heart failure with preserved or mildly reduced ejection fraction.

Conclusions

IL-6 plays a dual role-protective versus pathogenic and acute versus chronic. Chronic IL-6 links inflammation and metabolic dysregulation to structural cardiovascular damage. Chronic IL-6 activation requires therapeutic approaches tailored to disease context, timing and signalling mode. The results of ongoing trials will clarify whether IL-6–targeted interventions can be integrated into cardiovascular prevention and management strategies, complementing established therapies and addressing residual inflammatory risk.

Background

Intentional weight loss improves obesity-related outcomes but reduces lean body mass, raising concern about skeletal muscle mass, function and long-term health. GLP-1 receptor agonists (GLP-1RAs) produce clinically meaningful weight loss primarily by lowering energy intake and slowing gastric emptying, with additional benefits on insulin sensitivity and inflammation.

Objective

To clarify GLP-1RAs' effects on skeletal muscle tissue, body composition and physical function by reviewing preclinical and clinical evidence.

Findings

Across randomized and controlled studies, GLP-1RAs reduce fat mass more than lean body mass. Functional measures appear preserved. Preclinical and early clinical data suggest improvements in muscle quality (microvascular recruitment, mitochondrial efficiency, reduced intramuscular fat) rather than hypertrophy.

Conclusions

GLP-1RA-induced weight loss is largely fat mass with modest absolute lean body mass decline and no consistent deterioration in strength or function. Progressive resistance training, adequate/high-quality protein and periodic monitoring of body composition and performance should accompany therapy, especially in higher-risk patients.

Background

Transcatheter aortic valve implantation (TAVI) abruptly relieves aortic stenosis. The consequences for the peripheral vascular network, organ perfusion and postoperative organ dysfunction remain unclear. This study assessed hemodynamic and microcirculatory changes after TAVI, and their association with postoperative organ dysfunction.

Methods

This prospective, single-center physiological study included 20 patients with severe aortic stenosis undergoing transfemoral TAVI at Geneva University Hospitals (January–June 2024). Hemodynamic and microcirculatory assessment included arterial stiffness (tonometry), temperature gradients (T grad), reactive hyperemia (near-infrared spectroscopy and photoplethysmography) and plasma vascular endothelium growth factor (VEGF) concentrations before and after TAVI. The primary outcome was perioperative changes in macro- and microcirculatory parameters; secondary outcomes were organ dysfunction within 7 days.

Results

TAVI immediately increased aortic pressures and amplified pressure waves. By day 1, central-peripheral T grad decreased, perfusion index rose (from 2.5 [0.9–4.2] to 3.9 [1.9–5.5]; p < 0.05), and tissue oxygen re-saturation slope increased (from 2.6 [1.5–3.4] to 3.9 [2.8–4.7] %/s; p < 0.05), independent of macrocirculatory parameters. Large artery stiffness decreased, despite a reduction in the total arterial compliance, without changes in small-vessel resistance. Cardiac index changes showed wide interindividual variability and correlated with vascular and VEGF dynamics. Patients with postoperative organ dysfunction had higher baseline VEGF (52.9 vs. 28.7 pg/mL, p = 0.033) and greater postoperative increases.

Conclusion

TAVI induces rapid macro- and microcirculatory changes, with early tissue perfusion improvement despite transient microcirculatory reserve impairment. VEGF dynamics were associated with postoperative complications, suggesting endothelial activation as a marker of vulnerability and linking baseline endothelial status to vascular adaptation and outcomes.

Background and Aims

Chest radiography (CXR) is the gold standard tool for early mechanical complications' detection after cardiac implantable electronic devices (CIED) procedures, along with CIED electrical parameters control for the diagnosis of early catheter dislodgement. However, the detection of thoracic complications using CXR is limited, and it requires radiation exposure. Thoracic ultrasound (TUS) is a more versatile and quicker alternative for the diagnosis of thoracic pathologies, although its use in cardiac electrophysiology is not yet validated.

Aim of this study was to compare the diagnostic power of CXR and TUS in the diagnosis of non-infective early complications of CIED implantation.

Methods

A total of 397 patients who underwent CIED implantation were prospectively enrolled from 1 November 2021, to 30 September 2022. Following surgery, all patients underwent CXR and TUS at the patient's bed and the electrical parameters were tested before discharge.

Results

21 patients experienced mechanical complications (5.3%), of which the most common were pneumothorax (3.3%) and pericardial effusion (2%). TUS demonstrated non-inferior accuracy in diagnosing early mechanical complications, with increased sensitivity when compared to CXR. When associated with device interrogation, TUS was at least as accurate as CXR and device control in diagnosing lead dislodgment.

Conclusions

TUS has a non-inferior diagnostic power compared to the CXR to detect early mechanical complications of CIED implantation, avoiding x-ray exposure. Our results suggest that TUS could be employed as a primary technique in association with standard electrical control to diagnose postoperative complications.

Background

Obesity and atherogenic dyslipidemias are interrelated disorders that substantially contribute to the development of atherosclerotic cardiovascular disease (ASCVD) and the broader cardiovascular–kidney–metabolic (CKM) syndrome. The heterogeneity of obesity, particularly the role of visceral, ectopic and dysfunctional adipose tissue, drives the dyslipidemia phenotype characterized by hypertriglyceridemia, reduced high-density lipoprotein cholesterol and elevated apolipoprotein B–containing lipoproteins.

Methods

We review the epidemiological studies, imaging analyses, genetic data and clinical trial evidence linking obesity phenotypes with dyslipidemias and cardiovascular outcomes. We further evaluated lifestyle, pharmacological and surgical strategies targeting obesity-related lipid abnormalities.

Results

Visceral and ectopic fat accumulation, rather than body mass index alone, strongly predicts adverse lipid patterns, insulin resistance and cardiovascular events. Atherogenic dyslipidemias contribute to substantial residual ASCVD risk despite low-density lipoprotein cholesterol lowering. Lifestyle interventions—including diet modification, physical activity and improved cardiorespiratory fitness—demonstrate favourable effects on lipid metabolism independent of weight loss. Traditional pharmacotherapies such as statins, fibrates and omega-3 fatty acids offer partial benefits, while novel incretin-based agents and dual or triple receptor agonists provide robust weight loss and metabolic improvements. Metabolic and bariatric surgery remains an effective approach for sustained weight reduction and remission of dyslipidemias in the appropriate patient and is increasingly integrated with pharmacotherapy.

Conclusions

Atherogenic dyslipidemias are a hallmark of high-risk obesity phenotypes and a major contributor to ASCVD within the CKM framework. Precision medicine approaches that incorporate obesity phenotyping, targeted treatment strategies and population-level interventions are needed to reduce the burden of dyslipidemias and their cardiovascular sequelae.