European Journal of Clinical Investigation最新文献

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: Molecular expression of meningiomas has become increasingly important for predicting their biological behaviour. However, the factors influencing tumour recurrence and progression after surgery remain unclear. Recent studies suggest that programmed death-ligand 1 (PD-L1) could be a key predictive and therapeutic factor in these tumours.

Methods: This single-center retrospective study included 96 patients who underwent Simpson Grade I resection of intracranial meningiomas between 2001 and 2022. PD-L1 expression was assessed immunohistochemically (clone SP142) and categorized as overall (OE), membranous (mb), granular cytoplasmic (gr) and perinuclear dot-like. Associations with WHO grade, recurrence, mitotic count and Ki-67 index were analysed using univariate and multivariate statistics.

Results: 118 samples were analysed. Grade 2 meningiomas showed significantly higher mitotic count (4.0 ± 5.5 vs. 1.0 ± 1.0 n/mm², p < .001) and Ki-67 index (7.6 ± 2.1% vs. 3.5 ± .2%, p < .001) than Grade 1. PD-L1 OE (2.0 ± 5.0% vs. .0 ± 1.0%, p < .001), gr (1.0 ± 2.5% vs. .0 ± 1.0%, p < .001) and mb (1.0 ± 1.0% vs. .0 ± .0%, p = .003) expressions were also higher in Grade 2. At recurrence, Grade 1 tumours progressing to Grade 2 showed increased PD-L1 OE (p = .025), gr (p = .024) and mb (p = .037). Multivariate analysis confirmed PD-L1 gr and mb as independent markers of high-grade tumours.

Conclusions: Granular cytoplasmic and membranous PD-L1 expression patterns are significantly associated with tumour grade, recurrence and progression, suggesting their potential role as prognostic biomarkers in meningiomas.

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: This study investigates the prognostic impact of albumin, the urea-to-albumin ratio (UAR), and albumin-to-creatinine ratio (ACR) in patients with heart failure with mildly reduced ejection fraction (HFmrEF), since hypoalbuminemia, renal disease and malnutrition often coincide with heart failure (HF).

Methods: Consecutive patients hospitalized with HFmrEF at one university medical centre were retrospectively included from 2016 to 2022. Patients were stratified into quartiles based on albumin, the UAR, and ACR. The primary endpoint was all-cause mortality at 30 months (median follow-up), key secondary endpoint was long-term HF-related rehospitalization.

Results: The study cohort comprised 2,061 patients with HFmrEF with a median albumin level of 32.4 g/L. Albumin levels, the UAR and ACR were predictive for the risk of long-term all-cause mortality, which was still observed after multivariable adjustment (albumin Q1 vs. Q4: HR = 2.260; 95% CI 1.623-3.148; p = .001 / UAR Q4 vs. Q1: HR = 1.507; 95% CI 1.071-2.119; p = .019/ACR Q1 vs. Q4: HR = 2.208; 95% CI 1.528-3.190; p = .001). However, neither albumin nor the UAR or ACR predicted the risk of HF-related rehospitalization (albumin Q1 vs. Q4: HR = 1.117; 95% CI .678-1.842; p = .664 / UAR Q4 vs. Q1: HR = 1.589; 95% CI .922-2.738; p = .095 / ACR Q1 vs. Q4: HR = 1.112; 95% CI .624-1.981; p = .720).

Conclusions: Hypoalbuminemia is common in hospitalized HFmrEF patients. Low albumin levels, ACRs, and elevated UARs independently predicted long-term all-cause mortality, but not HF-related rehospitalization. The UAR and ACR did not provide a clinically significant predictive advantage over albumin levels alone.

Trial registration: ClinicalTrials.gov Identifier: NCT05603390 (date of registration: 10.10.2020).

Background: Giant cell arteritis (GCA) and (PMR) are inflammatory rheumatic disorders whose pathogenesis are unclear. The interleukin (IL)-6 receptor inhibitor is the first approved biologic agent for GCA and PMR, reducing relapse rates and cumulative glucocorticoid (GC) doses. Notably, IL-6, also a key pro-inflammatory factor secreted by senescent cells, contributes to tissue aging and chronic inflammation. We aim to explore the role of senescence-associated secretory phenotype (SASP) in the pathogenesis of GCA and PMR.

Methods: A narrative synthesis of literature published in the last 10 years was conducted utilizing keywords such as "Giant cell arteritis," "Polymyalgia rheumatica," "cellular senescence," "senescence-associated secretory phenotype," or "aging".

Results: Evidence links cellular senescence and SASP to the pathogenesis of GCA and PMR, with key components like IL-6, IL-1β, and matrix metalloproteinases (MMPs) driving inflammation and tissue damage. We highlight how key SASP components, such as IL-6, IL-1β, and MMPs promote inflammation and tissue damage in GCA and PMR. Targeting SASP factors (senomorphics) or selectively eliminating senescent cells (senolytics) offers therapeutic potential. Further research into the mechanisms linking senescence to disease phenotypes is needed to develop effective therapies that mitigate disease progression and improve clinical outcomes.

Conclusion: We demonstrated age-related stress and senescence in the pathogenesis of GCA and PMR. We provide an overview of senomorphics, which have shown promise in clinical trials, and emphasize the need for further research to develop effective therapies.

Background: Elderly frailty is a multifaceted clinical condition with diminished physiological reserves and increased stress susceptibility. It increases disability, hospitalization and mortality rates, requiring multidomain therapy. Structured physical-activity-based medical treatment can reduce frailty in physical, mental and emotional areas. This assessment distinguishes outcomes among validated frailty models (phenotype-based vs. deficit-accumulation) to highlight model-specific effects.

Objectives: The present systematic review assesses the efficacy of structured physical-activity-based physiotherapy in reducing frailty and enhancing physical, cognitive and emotional outcomes in persons aged ≥60. It highlights a critical data gap neglected by past studies by distinguishing intervention effects across proven frailty models (phenotype-based and deficit-accumulation frameworks).

Methodology: The review used PRISMA criteria and the PICOS framework to find relevant papers published between January 2002 and December 2025. PubMed, Scopus, Cochrane Library and Embase were searched. RCTs and longitudinal cohort studies on physiotherapy or structured physical-activity therapies (e.g. resistance training, aerobic conditioning, balance exercises, multimodal programs) for individuals aged ≥60 years were eligible. Frailty, physical performance and quality of life were evaluated. Cochrane Risk of Bias 2.0 was used for randomised studies and ROBINS-I for non-randomised designs.

Results: 36 trials covered varied physiotherapy and structured physical-activity regimens. Participants, mostly aged ≥60, were mostly women (approximately two-thirds of the sample). The majority of investigations found that resistance training increased muscle strength and decreased frailty by 20%-35%. Exercises involving balance reduced fall risk by 25%-35%, while aerobic workouts improved gait and cardiovascular fitness. Multimodal interventions reversed frailty in 41%-50% of individuals and improved cognitive and emotional outcomes the highest. Physical performance, quality of life and functional independence improved across frailty models in weighted summaries.

Conclusion: Structured physical-activity-based physiotherapy therapies, especially multimodal programs, reduce frailty and enhance physical, cognitive and emotional resilience in older persons, highlighting their value in comprehensive geriatric care.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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.

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.