Emerging evidence demonstrates a J-shaped relationship between HDL-C levels and atherosclerotic cardiovascular disease (ASCVD) with very high HDL-C concentrations paradoxically associated with increased ASCVD events. This study aims to determine whether individuals with very high HDL-C (>80 mg/dL) and ASCVD exhibit altered HDL composition and impaired HDL functionality.
We investigated the HDL profile and functionality in 49 subjects (mean age: 62 ± 2 years, 83% female) with very high HDL-C levels (>80 mg/dL), including 23 with ASCVD. All ASCVD patients and 46% of those without ASCVD (non-ASCVD) were on lipid-lowering treatment.
Plasma atherogenic lipoprotein-cholesterol levels were significantly lower in ASCVD patients than in those without ASCVD, despite matched HDL-C levels. CEC differences were evident after tertile stratification, with ASCVD participants overrepresented in the lowest tertile and showing lower median [IQR] CEC than non-ASCVD (p = 0.030). Total radical-trapping antioxidative potential showed no significant group differences in HDL ability to inhibit copper-induced LDL oxidation. However, basal HDL oxidative level was significantly higher in the ASCVD compared with the non-ASCVD group (p = 0.007). Inflammatory glycoproteins were inversely associated with CEC and HDL-C levels in ASCVD patients, but not in non-ASCVD patients. By NMR, mean HDL particle diameter did not differ between groups, yet ASCVD patients had fewer percent of large HDL particles compared to the non-ASCVD (0.84 ± 0.02% vs. 0.91 ± 0.02%; p = 0.034) and a trend toward more small particles. HDL-C content increased with particle size in ASCVD (p = 0.008; r = 0.531), but not in non-ASCVD, while HDL-TG levels did not differ across tertiles. Functional cell-based assays showed attenuated endothelial proliferation (normalized Cell-Index) in ASCVD compared with non-ASCVD, most evident in the largest HDL particle tertile.
These findings suggest that HDL functionality and particle distribution may offer more clinically relevant insights into cardiovascular risk than plasma HDL-C concentrations alone, particularly in individuals with very high HDL-C levels.
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).
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.
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.
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.
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.
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.
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.
The emergence of real-world evidence (RWE) has significantly broadened the scope of clinical research in internal medicine, providing insights that extend beyond the constraints of randomized controlled trials (RCTs). RWE is generated from real-world data (RWD)—information collected outside experimental settings, such as routine clinical practice. Observational studies, including cohort, case–control and cross-sectional designs, are fundamental to RWE generation, enabling the examination of patient outcomes, treatment patterns and disease epidemiology as they naturally occur. The expanded use of registries and electronic health records (EHRs) has revolutionized data collection, offering both depth and breadth for large-scale, longitudinal studies. However, drawing causal inferences from observational research presents substantial methodological challenges, as confounding and bias arising from non-randomized treatment allocation and unmeasured variables can distort results. Data quality issues—such as missing data, exposure and outcome misclassification, and inconsistent variable definitions—further complicate analysis. Advanced statistical techniques, including propensity score matching and instrumental variable analysis, have been developed to mitigate the limitations due to confounding, yet cannot fully substitute for randomization. Transparent reporting, pre-registration of protocols, and adherence to standardized guidelines (e.g. STROBE) are essential to enhance rigor and reproducibility. Despite their challenges, observational studies remain indispensable for addressing clinical questions that cannot be answered by RCTs, informing practice and guiding healthcare policy. Careful study design, rigorous analysis and transparent reporting are crucial for maximizing the reliability and impact of real-world evidence in internal medicine.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
To clarify GLP-1RAs' effects on skeletal muscle tissue, body composition and physical function by reviewing preclinical and clinical evidence.
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.
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.
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.
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.
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.
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.
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：