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Background: Thyroid function tests are frequently requested, but manufacturer reference intervals often lack age- or sex-based stratification. This study established indirect reference intervals for thyroid stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) in a large adult population. We evaluated unsupervised algorithms and conventional partitioning to identify subgroups, compared multiple limit estimation methods, and assessed the diagnostic performance of the derived intervals against an independent, clinically defined external validation cohort. Methods: Data from 37,255 adults (age ≥ 18) collected between 2022 and 2024 were analyzed; a reference population of 5870 individuals was established following standardized exclusion criteria. Age-based subgroups were identified through hierarchical clustering with the Elbow method, and variable importance was assessed using Random Forest analysis. Reference intervals were calculated using non-parametric, Bhattacharya, refineR, and reflimR algorithms, applied to three population frameworks: (1) the total population without stratification, (2) subgroups derived from hierarchical clustering and (3) subgroups defined by the conventional Harris–Boyd partitioning method. Diagnostic performance was subsequently evaluated in an independent external cohort (National Health and Nutrition Examination Survey [NHANES]; N = 2297) for all estimated reference intervals. Three classification scenarios were assessed: TSH-only, fT4-only, and combined TSH + fT4, with sensitivity, specificity, Youden index, and decision curve analysis performed for each. Results: Random Forest analysis identified age as the dominant variable influencing TSH, fT4 and fT3 distributions (mean decrease in accuracy: TSH 41.62, fT4 44.18, fT3 43.7), while sex showed the lowest impact. Clustering yielded six age-based subgroups for analytes. Harris–Boyd partitioning yielded six age-based subgroups for TSH, two sex-based subgroups for fT4, and six combined age-and-sex subgroups for fT3. TSH limits were broadly concordant across all three approaches (six-subgroup partitioning: 0.36–0.68 to 4.75–5.67 mIU/L). For fT4, conventional (sex-based) and clustering (age-based) partitioning produced similar ranges (11.33–20.08 pmol/L), except reflimR’s notably lower limit (10.90 pmol/L). For fT3, conventional (age + sex) and clustering (age-only) partitioning showed comparable ranges (3.36–7.03 pmol/L), with clustering revealing a clearer age-related decline in the oldest group. Diagnostic performance varied markedly by analyte. TSH-only classification achieved positive discrimination across all 13 methods (Youden index: 0.173–0.239). In contrast, fT4-only and combined TSH + fT4 classifications performed at or below chance for most methods, with 75% of the cohort falling outside fT4 reference intervals, indicating an inter-platform harmonization issue rather than a partitioning failure. Decision curve analysis confirmed TSH-only classification’s superiority, exceeding universal testing from pt ≈ 0.20 onward across all methods. Conclusions: Age-stratified reference intervals combined with limit estimation showed potential diagnostic advantages over manufacturer and non-stratified intervals; however, an independent external validation using a clinically defined outcome indicated that this advantage was not consistently reproduced and was dependent on the clinical decision threshold considered. These results suggest that age stratification and algorithm choice merit further clinically adjudicated validation before broad clinical adoption, and that unsupervised clustering offers a practical, objective alternative to manual subgrouping for laboratories pursuing this approach.

Purpose: The minimal invasive extracorporeal circulation (MiECC) was developed as abiocompatible alternative to conventional cardiopulmonary bypass (cCPB), intending to mitigate haemodilution, lessen the systemic inflammatory response, and enhance organ protection. AQ2 Although the evidence base has grown over the past 30 years, there has been no systematic mappingof the evolution of research activity and its results. Methods: The objectives are to perform a detailed analysis of the temporal, geographical, methodological, and clinical trends within MiECC research published between 1990 and 2025. Studies involving original human clinical data (randomized controlled trials, cohort studies, observational reports, methodological or protocol papers) that reported perioperative or clinical outcomes of MiECC were included. Exclusion criteria comprised reviews, meta-analyses, editorials, letters, guidelines, animal studies, and conference abstracts lacking full text. A comprehensive search of PubMed/MEDLINE, Web of Science, Scopus, and Cochrane databases was conducted up to September 2025 to gather evidence. Reference lists of included articles and relevant reviews were also screened. Data were extracted on publication year, country, sample size, study design, surgical procedure, and reported outcomes. Two reviewers independently charted the data, and discrepancies were resolved by a third reviewer. Results: A total of 151 studies were identified, of which 128 met eligibility criteria. Publication activity increased substantially after 2002 and peaked in 2021, with major contributions from European centres (Germany, Italy, Switzerland, Greece, and the Netherlands). Methodological/protocol papers and Randomize Controlled Trials (RCT) predominated (respectively, n = 37, n = 36). Most studies focused on coronary artery bypass grafting (CABG), while valve surgery and paediatric populations were underrepresented. Reported outcomes shifted over time: early studies emphasised transfusion and inflammatory markers, whereas more recent investigations increasingly examined renal function, neurological complications, and survival. Subgroup analyses suggested notable benefits in elderly patients, those with renal dysfunction, and individuals with low ejection fraction (EF). Conclusion: MiECC research has progressed from feasibility series to large multicentre trials, generating evidence for reduced transfusion requirements, attenuated inflammatory response, and better organ protection, though no clear mortality benefit has been demonstrated.

Background: Reference intervals for 25-hydroxyvitamin D are significantly influenced by seasonal variations and population-specific factors. This study aimed to establish local, population-specific Vitamin D reference intervals using the refineR algorithm and to compare these results with the conventional non-parametric method using a hospital database. Methods: A total of 127,220 laboratory results from 2022 to 2025 were retrospectively analyzed. Data were filtered based on adult age, morning fasting specimens, outpatient status, and normal parathyroid hormone levels (14–72 ng/L). Following filtration, Wilcoxon and Kruskal–Wallis tests were employed to evaluate differences between potential subgroups. Consequently, 24,036 eligible results were stratified by age (18–40, 41–65, and >65 years) and sex (female and male). Reference intervals were calculated using the refineR algorithm and the non-parametric percentile method. Results: The distribution of vitamin D levels was found to be right-skewed [Median: 12.92 ng/mL (4.21–149)]. The upper reference limits obtained via refineR were consistently lower than those derived from the non-parametric method. Both methods showed a linear increase in median values and upper reference limits with advancing age. Females in the 18–40 age group exhibited the lowest vitamin D profile. The summer concentrations were significantly higher than those of other seasons (p <0.05). Conclusions: The refineR algorithm managed outliers and pathological results more effectively than the non-parametric method. Our findings highlight the clinical necessity for age- and sex-specific subgroups, rather than relying on the manufacturer’s single reference range. Implementing these population-specific intervals can enhance diagnostic accuracy and prevent misclassification, facilitating earlier identification of vitamin D-related metabolic and skeletal disorders.

Functional foods enriched with bioactive compounds have attracted increasing attention for their potential to improve metabolic health and reduce the risk of chronic diseases. White tea, a minimally processed tea rich in polyphenols and antioxidant constituents, may exert beneficial effects on obesity-related metabolic disturbances through multiple molecular pathways. In this study, we investigated the effects of white tea in a high-fat diet-induced obesity model in rats, with particular emphasis on metabolic regulation and adipokine signaling. Body weight, lipid profile, glucose homeostasis, insulin resistance-related parameters, and circulating levels of apelin and irisin were evaluated. High-fat diet feeding impaired metabolic balance and altered obesity-associated biochemical parameters, whereas white tea administration ameliorated several of these changes. White tea was associated with improvements in body weight gain and selected metabolic parameters, together with modulation of adipokine-related markers. These findings suggest that white tea may function as a bioactive-rich functional food with beneficial effects on pathways involved in obesity and metabolic homeostasis. Our results support the potential contribution of white tea-derived compounds to nutrition-based strategies for the prevention and management of obesity.

Microplastics (MPs) are emerging environmental contaminants detected not only in water, soil, and air but also in human biological samples. To date, three main exposure routes have been identified. Currently, the principal exposure routes examined in scholarly works are oral, inhalational, and dermal. This paper explores iatrogenic microplastic exposure (IME) as an underrecognized healthcare-associated source of exposure and suggests that, in certain clinical contexts involving invasive, device-mediated, or direct systemic contact, IME may be considered a possible fourth route of exposure. IME is the introduction of microplastics into the human body through medical interventions. A literature-based conceptual review was conducted focusing on the materials and additives used in pharmaceutical formulations, intravenous systems, and medical devices. Particular attention was given to polymer-based excipients and plasticizers (e.g., phthalates, PEG, triacetin) found in enteric drug coatings and infusion packaging. Findings suggest that polymer-derived particles may enter systemic circulation via intravenous fluids, implantable devices, or oral medications, especially under conditions of heat, pressure, or prolonged contact. Such materials, though deemed biocompatible, may contribute to nanoplastic load and chronic exposure risks. Vulnerable groups such as neonates, oncology patients, and ICU populations may face disproportionate exposure. This calls for re-evaluation of plastic use in medical practice, improved regulatory oversight of pharmaceutical excipients, and innovation in plastic-free biomedical materials. Integrating this route into toxicological and epidemiological frameworks will enrich our understanding of microplastic-related health risks and broaden the scope of environmental health strategies.

Given the increasing burden of diet-induced metabolic dysregulation, preventive nutritional strategies targeting early insulin resistance are of growing interest. The aim of this study was to evaluate the effects of white tea supplementation on body weight gain, insulin resistance, and the Gremlin-1/Bone Morphogenetic Protein-4 (BMP-4) axis in visceral adipose tissue under high-fat diet conditions in a non-obese experimental model. Thirty-two male Sprague–Dawley rats were randomized into four groups (n = 8/group): standard diet (control), only high-fat diet (HFD), high-fat diet plus orlistat (ORL: 30 mg/kg/day), and high-fat diet plus white tea (WT: 5 mg/kg/day). Interventions were administered once daily by oral gavage for 12 weeks. Body weight was recorded weekly. At the end of the study, serum insulin, Gremlin-1, and BMP-4 and retroperitoneal adipose tissue Gremlin-1 and BMP-4 levels were measured by ELISA. Adipose tissue GREM1 gene expression was quantified by qRT-PCR. Insulin resistance was estimated using the HOMA-IR index. Appropriate statistical analyses were conducted in line with the study design and data distribution. High-fat feeding resulted in the highest HOMA-IR values, whereas white tea supplementation reduced HOMA-IR compared to the HFD group (p = 0.008). Body weight gain was increased in both the HFD and ORL groups compared to the control (p = 0.009 and p = 0.012, respectively). The lowest weight gain was observed in the WT group, which was lower than the HFD group (p = 0.044). GREM1 expression showed a 1.92-fold increase in the HFD group relative to the control, with smaller increases in the WT and ORL groups; however, intergroup differences did not reach statistical significance (p = 0.063). Serum BMP-4 levels were lower in the WT group compared to the control (p = 0.012), while tissue BMP-4 and Gremlin-1 levels did not differ between groups. Correlation analyses revealed a moderate inverse association between serum Gremlin-1 and serum BMP-4 (rho = −0.493, p = 0.011) and a moderate positive correlation between serum BMP-4 and HOMA-IR (rho = 0.564, p = 0.003). White tea supplementation attenuated body weight gain and preserved insulin sensitivity in a non-obese high-fat diet model, as evidenced by reduced weight gain and lower HOMA-IR values compared with high-fat feeding alone. These metabolic improvements were accompanied by coordinated changes in circulating components of the Gremlin-1/BMP-4 axis, including reduced serum BMP-4 levels and associations between BMP-4, Gremlin-1, and insulin resistance. Although tissue-level alterations were modest, the observed systemic patterns are consistent with an exploratory association between white tea intake and early metabolic signaling changes; however, definitive pathway modulation cannot be inferred from the present dataset. Collectively, these findings support white tea as a nutrient-derived bioactive with preventive metabolic potential during the early stages of diet-induced metabolic dysregulation, prior to the development of overt obesity.

Obesity is a major global health concern, being associated with insulin resistance and multiple metabolic disorders. Gremlin 1 (GREM1), a bone morphogenetic protein (BMP) antagonist, is increasingly recognized as a key regulator of adipose tissue dysfunction and impaired thermogenesis in obesity. Orlistat, a lipase inhibitor that reduces dietary fat absorption, is one of the most commonly used pharmacological agents for obesity management. White tea has demonstrated antioxidant and anti-obesity properties in experimental models. The aim of this study was to evaluate the effects of white tea on metabolic parameters (HOMA-IR, BMP4, Gremlin1) and GREM1 expression in rats made obese by a high-fat diet (HFD). A total of 40 male Sprague-Dawley rats were randomized into five groups: a standard diet group (STD); a high-fat diet group (HFD); an HFD + orlistat group (ORL); an HFD + 50 mg/kg white tea group (WT50); and an HFD + 150 mg/kg white tea group (WT150). Obesity was induced by feeding the rats a 45% high-fat diet for 3 weeks. Serum insulin, glucose and HOMA-IR levels were measured. Levels of GREM1 and BMP4 in serum and retroperitoneal adipose tissue were assessed. White tea supplementation significantly reduced weight gain and HOMA-IR compared to the HFD group. GREM1 mRNA expression in visceral adipose tissue decreased markedly in the WT50 and WT150 groups (p = 0.002 and p = 0.017, respectively). Serum GREM1 levels were significantly lower in the white tea-treated groups than in the HFD group (p = 0.011). Tissue BMP4 levels were only significantly reduced in the WT50 group (p = 0.005), indicating a non-linear dose–response pattern. There was a negative correlation between serum BMP4 levels and weight gain (rho = −0.440, p = 0.015). White tea was associated with improvements in metabolic parameters in an HFD-induced obesity model. These observations suggest a potential association between white tea bioactives and adipose tissue-related molecular pathways implicated in obesity. Given the short intervention duration and the exploratory design of this animal study, the findings should be interpreted with caution.

Background: Obesity is a major global health concern, being associated with insulin resistance and multiple metabolic disorders. Gremlin 1(GREM1), a bone morphogenetic protein(BMP) antagonist, is increasingly recognised as a key regulator of adipose tissue dysfunction and impaired thermogenesis in obesity. White tea has demonstrated antioxidant and anti-obesity properties in experimental models. The aim of this study was to evaluate the effects of white tea on metabolic parameters and GREM1 expression in rats made obese by a high-fat diet (HFD). Methods: A total of 40 male Sprague-Dawley rats were randomised into five groups: a standard diet group (STD); a high-fat diet group (HFD); an HFD + orlistat group (HFD + ORL); an HFD + 50 mg/kg white tea group (HFD + WT50); and an HFD + 150 mg/kg white tea group (HFD + WT150). Obesity was induced by feeding the rats a 45% high-fat diet for 3 weeks. Serum insulin, glucose and HOMA-IR levels were measured. Levels of GREM1 and BMP4 in serum and retroperitoneal adipose tissue were assessed. Results: White tea supplementation, significantly reduced weight gain and HOMA-IR compared to the HFD group. GREM1 mRNA expression in visceral adipose tissue decreased markedly in the WT50 and WT150 groups (p = 0.002 and p = 0.017, respectively). Serum GREM1 levels were significantly lower in the white tea-treated groups than in the HFD group (p = 0.011). Tissue BMP4 levels were only significantly reduced in the WT50 group (p = 0.005). There was a negative correlation between serum BMP4 levels and weight gain (rho = –0.440, p = 0.015). Conclusion: White tea has been shown to have a protective metabolic effect in obese rats, suppressing GREM1 expression and improving insulin sensitivity. White tea could therefore serve as both a dietary antioxidant and a molecular regulator of adipose tissue function in obesity management.