Heteroresistance has emerged as a clinically significant form of antimicrobial resistance that challenges microbiology laboratories, infectious disease management, and public health systems. It is defined by the presence of resistant subpopulations within an otherwise phenotypically susceptible bacterial population, capable of surviving high antibiotic concentrations. As conventional antimicrobial susceptibility testing methods frequently fail to detect these minor subpopulations, heteroresistance is associated with diagnostic uncertainty, treatment failure, recurrent infections, and the selection and expansion of resistant strains. Accumulating evidence across diverse bacterial species, particularly among Gram-negative pathogens, has highlighted the growing clinical relevance of this phenomenon. Despite this, its recognition and management remain hindered by the lack of standardized diagnostic methodologies, incomplete elucidation of underlying molecular mechanisms, and limited incorporation into clinical guidelines. This review provides a comprehensive overview of heteroresistance, emphasizing its definition, diagnostic challenges, and clinical implications, while aiming to increase awareness of its clinical significance. Furthermore, it addresses key knowledge gaps and outlines perspectives aimed at improving detection strategies and informing more effective therapeutic decision-making.
Androgenetic Alopecia (AGA) is the most prevalent hair disorder. Conventional topical minoxidil is limited by suboptimal follicular penetration, local adverse effects, and poor adherence; nanocarrier-based "nanominoxidil" systems may optimize delivery, but their clinical value remains uncertain. To synthesize experimental and clinical evidence on nanocarrier-based topical minoxidil for AGA. We systematically searched databases (2015-2024) for in vitro, ex-vivo, in vivo, and human studies evaluating nanocarriers < 1000 nm loaded with minoxidil versus conventional minoxidil, placebo, or no treatment. Primary outcomes were follicular and cutaneous penetration or retention; secondary outcomes included hair length, density and/or coverage, biomarker modulation, adverse events, and formulation stability. Risk of bias was assessed with SYRCLE and OHAT. Of 410 records, 20 studies met eligibility criteria, predominantly preclinical, and one evaluated cutaneous tolerability in healthy volunteers. Across platforms (lipid, polymeric, hybrid and deformable systems, nanoemulsions), nanominoxidil consistently increased follicular deposition and cutaneous retention (≈2- to > 7-fold vs conventional solutions) and improved hair growth surrogates and angiogenic or stem-cell markers. Local tolerability was generally acceptable and systemic exposure was negligible when reported. Evidence is preclinical, with a single non-therapeutic human study; heterogeneity across models, comparators, doses, follow-up, and outcomes, and frequent lack of randomization, blinding, and standardized safety reporting, precluded meta-analysis and limited internal validity and generalizability. Nanotechnology-based minoxidil formulations enhance follicular targeting and hair-growth surrogate outcomes in experimental models and appear locally safe, but randomized trials in patients with AGA are required before nanominoxidil can be recommended for routine clinical use.
Nonalcoholic fatty liver disease (NAFLD), also termed metabolic dysfunction‑associated fatty liver disease is a problem across the world. The most important factor of the increase in NAFLD prevalence is the insulin resistance. This study is the first clinical trial with the aim of determining the effect of Pistacia atlantica Sub. Kurdica gum on glycemic indices especially insulin resistance in patients with nonalcoholic fatty liver disease. In this double-blind randomized clinical trial 50 patients with nonalcoholic fatty liver disease were randomized into two groups: those given syrup containing Pistacia atlantica sub. Kurdica gum (Group A), those on placebo (Group B). Over a two-month period, Group A given syrup containing 500 mg of P. atlantica sub. Kurdica gum per each tablespoon and Group B given syrup without P. atlantica sub. Kurdica gum. Anthropometric measures, biochemical indices and physical activity were evaluated at the beginning and end of the intervention. We observed a significant decrease in fatty liver grade in group A (P = 0.03). The mean of fasting serum insulin and the insulin-resistance index (HOMA-IR) decreased significantly (P = 0.002, P < 0.001) and quantitative insulin sensitivity check index (QUICKI) increased from baseline in group A (P = 0.001). Fasting blood sugar (FBS) decreased significantly from baseline in group A (P = 0.019), but the mean changes between group not significant (P = 0.061). Weight had significant decrease in group A (P < 0.001). Pistacia atlantica sub. Kurdica gum can decrease insulin resistance, increase insulin sensitivity and subsequently improvement NAFLD in patient with nonalcoholic fatty liver disease. It is suggested that clinical trials be conducted in the long duration of the intervention, as well as a larger sample size. Registration number of Clinical trial: IRCT20231219060466N1 (https://irct.behdasht.gov.ir/).
Autofluorescence (AF) imaging enables label-free visualization of tissue metabolism and microenvironmental alterations, while deep learning (DL) provides powerful tools to decode its complex optical signatures. Their integration has emerged as a promising framework for functional and biologically informed disease assessment. Recent studies demonstrate that AF-DL approaches improve lesion detection, intraoperative guidance, and early therapeutic response evaluation across multiple organ systems. By leveraging multidimensional spectral, temporal, and spatial features, DL mitigates the intrinsic variability and limited specificity of standalone AF imaging. This review summarizes current diagnostic, prognostic, and surgical applications of AF-DL integration, with particular emphasis on model interpretability, generalizability, and biological relevance. Key challenges, including device dependence, dataset heterogeneity, annotation burden, and regulatory considerations, are critically discussed. Finally, future directions are proposed toward standardized acquisition, prospective multicenter validation, and clinically integrated workflows. By bridging intrinsic tissue biochemistry with data-driven intelligence, AF-DL integration offers a new class of functional imaging biomarkers with significant potential for precision diagnosis, surgery, and treatment monitoring.
Dopamine antagonists are the cornerstone of treatment for psychotic disorders, but long-term exposure may induce dopamine supersensitivity psychosis (DSP)-a syndrome characterized by psychotic relapse upon dose reduction or discontinuation, tolerance to antipsychotic effects, and co-occurrence of tardive dyskinesia. Despite decades of clinical observation and supporting preclinical evidence, the diagnostic validity of DSP and its relationship to treatment resistance remain incompletely understood. This systematized review evaluates clinical evidence supporting DSP as a distinct diagnostic entity using the standard framework of psychiatric diagnostic validators: delineation from other disorders, predictable clinical course, predictable treatment response, reliable biomarkers, and genetic susceptibility. A systematic search of MEDLINE and Embase identified 39 eligible clinical studies comprising case series, cross-sectional studies, cohort studies, and randomized controlled trials. Methodological quality was assessed using the Murad tool for case series and Joanna Briggs Institute critical appraisal checklists for remaining designs. Data were synthesized qualitatively due to heterogeneity in study designs, diagnostic criteria, and outcome measures. Evidence suggests predictable symptom worsening following dose reduction or switching to partial agonists, and points toward possible genetic susceptibility variants. Biomarker findings remain inconclusive, and differentiation of DSP from natural illness relapse is inherently difficult. Retrospective designs, small samples, absence of control groups, and inadequate confounder control preclude definitive conclusions. Standardized diagnostic criteria and prospective, well-controlled studies integrating clinical, genetic, and biomarker assessments are urgently needed to clarify the existence, mechanisms, and optimal management of DSP.
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Behçet's disease is a chronic, inflammatory vasculitis affecting multiple systems. In addition to existing laboratory parameters used for the diagnosis and monitoring of Behçet's disease, new biomarkers are needed to improve diagnostic accuracy. The levels and activity of DNASE1L3, an enzyme that degrades chromatin released into circulation during apoptotic processes and can initiate autoimmune mechanisms, have been associated with autoimmune diseases. This study was designed to determine the levels of DNASE1L3 in patients with Behçet's disease, assess its relationship with clinical and inflammatory parameters, and evaluate its potential as a diagnostic biomarker. This study included 45 patients diagnosed with Behçet's disease and 45 age and sex-matched healthy controls. Serum DNASE1L3 levels were measured in both groups using the enzyme-linked immunosorbent assay (ELISA). Serum DNASE1L3 levels were significantly lower in patients with Behçet's disease (7.14 ± 1.81 ng/mL) compared to the healthy control group (15.79 ± 3.14 ng/mL) (p < 0.001). A statistically significant negative correlation was observed between serum DNASE1L3 levels and both CRP (r =  - 0.684, p < 0.001) and ESR (r =  - 0.524, p < 0.001). According to ROC curve analysis, a serum DNASE1L3 cutoff value of 9.53 ng/mL distinguished patients with Behçet's disease from healthy individuals with 96% sensitivity and 93% specificity. For this threshold, the positive predictive value was 95% and the negative predictive value was 93% (AUC = 0.983; p < 0.001; positive likelihood ratio, 21.13; negative likelihood ratio, 0.07). The findings of this preliminary study suggest that serum DNASE1L3 may represent a promising candidate biomarker for Behçet's disease. However, further validation in larger, independent cohorts is required before its potential clinical utility can be established. Key Points • Serum DNASE1L3 levels are significantly lower in patients with Behçet's disease compared to healthy individuals. • DNASE1L3 levels show a strong negative correlation with acute phase reactants, including CRP and ESR. • Low DNASE1L3 levels may reflect impaired extracellular DNA clearance and contribute to the inflammatory process in Behçet's disease. • Serum DNASE1L3 levels show potential as an exploratory biomarker for the clinical evaluation of Behçet's disease, providing a basis for further validation in larger clinical cohorts.
Antenatal hydronephrosis is the most common prenatal urinary tract abnormality, and some cases, mainly due to ureteropelvic junction obstruction, require surgery. Noninvasive biomarkers are needed to improve diagnosis and guide management. To evaluate urinary exosomal long non-coding RNAs, specifically MALAT1 and HOTAIR, as biomarkers for predicting surgical necessity in children with unilateral antenatal hydronephrosis, and to develop an AI-based predictive model. This retrospective case-control study included 88 children (38 requiring pyeloplasty, 26 non-obstructive dilatation, 24 controls). Urinary exosomes were isolated, and lncRNA expression was quantified by RT-qPCR. Clinical variables included anteroposterior pelvic diameter and split renal function. Diagnostic performance was assessed by ROC analysis and logistic regression. A SVM model was developed integrating biomarker and clinical data, with 5-fold cross-validation and an interactive Shiny web application for clinical translation. Preoperative MALAT1 and HOTAIR levels were significantly elevated compared to non-obstructive dilatation and controls and decreased after surgery (p < 0.001). MALAT1 remained an independent predictor of surgical intervention (OR = 1.272, p < 0.001) in multivariate analysis, alongside APD and SRF. MALAT1 showed an AUC of 0.745 (cut-off: 9.06), and HOTAIR an AUC of 0.685 (cut-off: 11.76). The SVM model achieved 91.9% accuracy, 89.5% sensitivity, 95.8% specificity, and an AUC of 0.951. Urinary exosomal MALAT1 and HOTAIR are promising noninvasive biomarker for predicting surgical need in pediatric ureteropelvic junction obstruction. Integration with clinical parameters in an SVM-based model enhances diagnostic precision, and the development of a freely accessible web application supports real-time individualized risk prediction.
Traditional and indigenous medical systems have a long history of using medicinal plants to treat conditions now understood as chronic inflammation. This ethnopharmacological knowledge provides a rich resource for discovering novel anti-inflammatory agents. This review critically evaluates the evidence for the modulation of the Receptor for Advanced Glycation End-products (RAGE) signaling pathway by natural products derived from traditional medicines, aiming to connect this traditional knowledge with modern molecular pharmacology. A comprehensive literature review was performed using the PubMed database. The search focused on keywords such as "RAGE," "natural products," and "traditional medicine" to identify studies detailing the mechanistic interactions between natural compounds and the RAGE pathway. Natural products, including polyphenols, terpenoids, and alkaloids, modulate the RAGE axis through several key mechanisms: (1) inhibiting the formation of Advanced Glycation End-products (AGEs); (2) directly blocking the RAGE-ligand interaction; (3) downregulating RAGE expression; and (4) suppressing downstream inflammatory signaling. Compounds like quercetin, ursolic acid, and berberine have demonstrated significant activity in various preclinical models. Natural products represent a profound source of multi-target RAGE modulators, offering a potential therapeutic advantage over synthetic single-target drugs. While challenges in bioavailability and clinical translation remain, the data strongly validates the ethnopharmacological approach. Future progress depends on integrating this traditional wisdom with modern technologies to unlock the full clinical potential of these compounds.
Anti-Müllerian hormone (AMH) is widely used as a clinical biomarker of ovarian reserve and is traditionallyinterpreted as a surrogate measure of remaining oocyte quantity. However, accumulating biological and clinicalevidence challenges this quantitative paradigm. AMH is exclusively produced by granulosa cells of growing folliclesrather than by primordial follicles themselves, suggesting that circulating AMH primarily refl ects somatic follicularactivity instead of dormant oocyte pool size. Here, we propose a conceptual framework redefi ning ovarian aging as aprocess that may be strongly infl uenced by progressive somatic ovarian dysfunction. In this model, granulosa cells, stromal integrity, vascular support, immune regulation, and metabolicenvironment collectively form a somatic support network that determines follicular survival and developmentalcompetence. Disruption of this somatic ecosystem, through aging, surgery, chemotherapy, autoimmunity,environmental toxicants, smoking, or metabolic stress, results in reduced granulosa cell functionality, declining AMHsecretion, impaired follicle maturation, and secondary oocyte loss. Evidence from granulosa cell biology, controlledovarian stimulation, ovarian surgery, autoimmune ovarian disease, chemotherapy exposure, and fertility outcomestudies consistently demonstrates that AMH responds dynamically to changes in somatic ovarian health and doesnot reliably predict natural fecundability or absolute follicle number. Primordial follicle depletion progresses continuously throughout life, yet circulating AMH levels often showabrupt declines in response to somatic ovarian injury such as surgery, chemotherapy, or metabolic stress.Continuous primordial follicle attrition therefore does not translate into continuous AMH decline, supporting the viewthat AMH represents the functional cohort of biologically supported follicles rather than the total ovarian reserve. It isimportant to recognize, however, that ovarian reserve markers including AMH have limited predictive value fornatural fecundability with area under the curve values ranging from 0.60 to 0.65. We introduce the concept of somatic ovarian function as an integrated framework for AMHinterpretation, proposing AMH as a biomarker of ovarian functional capacity. Reframing AMH from a purelyquantitative reserve marker to a functional systems biomarker that refl ects granulosa cell integrity, metabolichealth, and environmental infl uences may help reconcile longstanding clinical paradoxes and open new translationalavenues for fertility preservation, ovarian aging research, and therapeutic intervention.
We compared the analytical and clinical performance of MAGLUMI X3 (Snibe) and Elecsys (Roche) for measuring sFlt-1, PlGF, and their ratio in women hospitalized at the Department of Gynecology and Obstetrics, University Hospital in Pilsen. In a single-center, real-world cohort (192 samples from 164 patients), method comparison showed good agreement between analyzers. Diagnostic discrimination for preeclampsia (PE vs. non-PE) was similar across platforms (AUC early-onset 0.84-0.85; late-onset 0.95 each; no significant difference by DeLong). To compare the analytical and clinical performance of MAGLUMI X3 (Snibe) and Cobas e602 (Roche) assays for sFlt‐1, PlGF, and the sFlt‐1/PlGF ratio in women hospitalized at the Department of Gynecology and Obstetrics, University Hospital in Pilsen, and to evaluate diagnostic accuracy for early‐ and late‐onset preeclampsia (PE). This single‐center real‐world study analyzed 192 serum samples from 164 patients (mean age 31.8 ± 5.0 years). Routine testing was performed on Cobas e602; residual serum was measured on MAGLUMI X3 within 24 h. Precision followed CLSI EP05‐A3/EP15‐A3; agreement used Passing–Bablok and Bland–Altman. Diagnostic performance was evaluated by ROC curves with AUC and 95% confidence intervals (CI); AUCs were compared by the DeLong test. Repeatability and reproducibility were acceptable across levels (patient‐sample CVs ~0.7%–2.0% and 1.1%–1.5%; QC CVs ~2.0%–8.9%). Bland–Altman showed a mean bias for sFlt‐1 of −869.9 ng/L (95% CI −1035.6 to −704.2) and for PlGF +6.2 ng/L (−4.6 to 17.0). Spearman's r was 0.99 (sFlt‐1) and 0.97 (PlGF), p < 0.0001. For clinical classification, AUCs were high for both platforms—late‐onset PE: Roche 0.95 (95% CI 0.86–0.99) and Snibe 0.95 (0.87–0.99); early‐onset PE: Roche 0.85 (0.75–0.92) and Snibe 0.84 (0.75–0.91)—with no significant differences by DeLong (p = 0.71 late; p = 0.32 early). MAGLUMI X3 showed acceptable analytical performance and diagnostic discrimination comparable to Cobas e602. Although sFlt‐1 values were systematically higher on MAGLUMI, overall discrimination remained similar across platforms when platform‐specific cut‐offs were applied.
Timely recognition and monitoring of chronic kidney disease (CKD) is critical for improving patient outcomes. Non-coding RNAs (ncRNAs) are implicated in CKD pathophysiology. However, their clinical translation, particularly in patients on maintenance hemodialysis (MHD), and their association with erythropoiesis-stimulating agent (ESA) resistance remain under-investigated. This case-control study evaluated the signature of serum circ_DLGAP4, lncRNA KCNQ1OT1, and their targets miR-9/SOX7 in CKD across various stages, including MHD, and the clinical significance of their integration in diagnosis, staging, and ESA resistance. Overall, 180 individuals: 60 controls, 60 non-hemodialysis (non-HD) CKD G2-G4 patients, and 60 MHD patients with CKD G5, were enrolled. ncRNAs and SOX7 were measured using RT-qPCR and ELISA, respectively. Bioinformatics analysis revealed the interaction network of the investigated markers and their involvement in CKD pathophysiology. Serum circ_DLGAP4, KCNQ1OT1, and miR-9 were upregulated in CKD patients, with or without MHD, while SOX7 was downregulated in MHD patients compared to controls. circ_DLGAP4 and SOX7 were lower, and miR-9 was higher in MHD versus non-HD patients. circ_DLGAP4 and SOX7 were differentially expressed across CKD categories/stages. ROC analysis revealed diagnostic utility for circ_DLGAP4, KCNQ1OT1, and miR-9 and prognostic potential for circ_DLGAP4, miR-9, and SOX7. In multivariate analysis, KCNQ1OT1 was independently associated with CKD detection in non-HD patients. The circ_DLGAP4/SOX7 panel independently predicted CKD progression to MHD with high accuracy [Area under the curve (AUC) = 0.93, 95% confidence interval (CI) = 0.8823-0.9754]. We developed a simple nomogram for easier application in CKD progression prediction (AUC = 0.938, 95% CI = 0.8959-0.9808). circ_DLGAP4, miR-9, and SOX7 showed correlations with eGFR. miR-9 was associated with the ESA resistance index in MHD patients receiving epoetin alfa, independent of BMI. Conclusively, this study introduces serum KCNQ1OT1 as a potential candidate biomarker for CKD diagnosis, circ_DLGAP4/SOX7 as a novel panel useful for assessing CKD progression using a nomogram, and miR-9 as a potential candidate ESA resistance biomarker in MHD. Trial registration number: NCT07037953, date of registration: 10-6-2025.
Light is a major environmental factor regulating circadian rhythms, sleep- wake cycles, and mood-related behaviors. Patients with Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often experience circadian disruption and poor sleep quality, which severely compromise their quality of life; however, the relationship between light exposure and illness severity remains largely unknown. An observational cross-sectional cohort secondary study used collected data from 100 ME/CFS patients and 56 healthy controls to explore the impact of spontaneous light exposure on multidimensional health status and circulating biochemical parameters. Demographic and clinical features were assessed using validated patient-reported outcome measures. Light intensity, wrist temperature, and physical activity were continuously monitored at home over one week using wrist-worn actigraphy. Light intensity during predefined intervals and rhythmic variables of light cycle were calculated. Principal component analysis (PCA) was applied to reduce dimensionality of light variables. Multivariable analysis was performed adjusting for age, sex, body mass index, and physical activity. Following PCA of the light patterns, two components emerged across groups with high consistency: PC1 (explaining 61.7% of the total variance) reflected higher daytime light and rhythm stability, and PC2 (explaining 16.1%) represented nocturnal/early-morning light and rhythm instability. In ME/CFS patients, light variables were more extensively associated with clinical outcomes measures (FIS-40, PSQI and SF-36) than in healthy controls (all p < 0.05). Furthermore, PC2 was associated with higher levels of VCAM-1 and triglycerides, and lower serotonin concentrations (all p < 0.05). Four distinct light patterns were identified based on PCA scores: nocturnal light, healthy, adverse, and low diurnal light. ME/CFS patients exhibiting the healthy light pattern showed significantly lower fatigue, fewer sleep complaints, reduced autonomic dysfunction, and higher quality of life compared to those with the adverse light pattern (all p < 0.05). No significant differences were observed among healthy controls. Light exposure patterns show distinct associations with symptom variability in ME/CFS compared to healthy controls. More stable daytime light appears to relate to better symptom profiles, whereas irregular exposure and nocturnal light are linked to poorer health outcomes. Although causality cannot be inferred, these findings highlight light exposure as a potentially modifiable, non-invasive target for behavioral interventions aimed at improving the quality of life in ME/CFS, representing a promising emerging for future translational research.
Efficient nucleic acid extraction and purification are fundamental to cellular and molecular biology research but remain challenging for large-scale clinical RNA sequencing and PCR assays. This chapter introduces BLADE-R, a novel magnetic bead-based protocol that streamlines the RNA extraction process. BLADE-R integrates cell lysis and nucleic acid binding into a single step, followed by an innovative on-bead rinse to achieve nuclease-free separation of genomic DNA and RNA. The protocol's adaptability to a 96-well plate format enables simultaneous RNA purification from up to 96 human blood samples, significantly reducing time compared with single-sample methods. In this high-throughput setup, BLADE-R demonstrated no cross-contamination between wells during RNA purification, cDNA synthesis, and PCR. BLADE-R's versatility, efficiency, and suitability for low- and high-throughput applications make it an ideal method for RNA preparation in clinical and research settings, particularly for detecting and measuring chimeric RNAs using RT-PCR and sequencing assays. This protocol is especially advantageous in resource-limited environments, facilitating robust and scalable RNA extraction workflows.
This study examined whether bempedoic acid (BPA) suppresses SEC progression through an integrated pharmacological framework with toxicological relevance, targeting metabolic, inflammatory, oxidative, angiogenic, proliferative, and apoptotic pathways. Fifty female Swiss albino mice were assigned to five groups (n = 10): normal control, untreated SEC control, SEC + bempedoic acid (10 or 30 mg/kg, orally), and SEC + doxorubicin (5 mg/kg, i.p.) three times weekly for two weeks as a reference chemotherapeutic comparator with established clinical toxicity relevance. After experiment completion, blood and tumor tissues were obtained for molecular assessment. SEC-bearing mice showed lipid dysregulation, with elevated ACLY, ACC, FASN, total cholesterol, and triglycerides, alongside suppressed AMPK. BPA counteracted these changes by inhibiting ACLY-driven lipogenesis and restoring AMPK-related signaling, thereby reducing NF-κB pathway activity and iNOS, IL-6, and TNF-α. It also attenuated oxidative stress, increasing SOD and lowering p-carbonyls. Moreover, BPA reduced VEGF, MMP-2, MMP-9, Hes-1, DLL4, Notch-1, and Jagged-1, indicating impaired angiogenic remodeling and endothelial differentiation. Decreased Cyclin-D1 and PCNA reflected reduced proliferation, while increased p53, Bax, and Caspase-3 indicated enhanced apoptosis. Histologically, BPA promoted dose-dependent tumor necrosis, reduced viable anaplastic cell clusters, and induced fibrovascular granulation tissue with peripheral inflammatory cell infiltration, indicating tumor regression and reparative remodeling. These findings provide preclinical evidence that BPA reduces SEC tumor burden by modulating the ACLY/AMPK-related metabolic pathway, accompanied by suppression of inflammatory, angiogenic, proliferative, survival, oxidative stress, and apoptosis-related dysregulation, supporting its repurposing potential as a multi-target therapeutic candidate for solid tumors.
Atopic dermatitis (AD) is a prevalent inflammatory skin disease and a major source of disease burden in children. Biomarker studies in childhood AD span genetic, immune, microbial and metabolic domains, but prior reviews have often focused on single molecular layers, specific sample sites or clinical classification. As a result, the field lacks an integrated, systems-level synthesis that compares and contextualizes biomarkers across domains while clearly distinguishing evidence strength. The rapid growth of literature in this field also poses practical challenges for traditional manual review workflows. To address these gaps, we conducted an AI-augmented, multi-domain review of childhood AD biomarkers. ASReview supported title and abstract screening, while ChatGPT assisted structured data extraction with human validation. Across 526 studies, we identified 141 genome, 95 immunome, 57 microbiome and 75 metabolome childhood AD biomarkers. The most frequently reported biomarkers included Filaggrin, IgE, CCL17, Staphylococcus, Bifidobacterium and vitamin D. Using a structured evidence-grading framework, eight biomarkers were categorized as having strong evidence: IgE, CCL17, CCL27, eosinophil cationic protein, eosinophil, IL-18, IL-31 and Escherichia. By synthesizing evidence across biomarker domains, we developed a systems-level, conceptual AD model in which barrier defects, Th2 inflammation, microbial dysbiosis and metabolic imbalance drive a self-perpetuating cycle of inflammation and barrier dysfunction. We also developed a web app for exploration of the biomarker findings: https://leejw.shinyapps.io/eczema_review_526/. This review provides a broad synthesis of childhood AD biomarkers and frames the evidence within an integrated, multi-domain conceptual model. The findings support the rationale for approaches that consider multiple biological nodes, including barrier repair, immune modulation, microbiome-directed strategies and metabolic factors, while underscoring the need for further validation before clinical implementation. Methodologically, the study illustrates how a hybrid human-AI review workflow can support scalable biomedical evidence synthesis without replacing human oversight.
For over two centuries, natural enzymes have played essential roles in biochemistry and have found diverse applications in medicine, healthcare, food production, and the chemical industry. However, natural enzymes often face limitations such as high cost, limited stability, and challenging storage conditions. Artificial enzymes offer significant advantages including cost-effective and controllable synthesis, tunable catalytic properties, and enhanced stability under harsh conditions. In this work, iron and nitrogen co-doped carbon dots (Fe,N-CDs) were synthesized via a simple, rapid, and cost-effective pyrolysis method using glutamic acid as the carbon source, allantoin as the nitrogen source, and ferric chloride as the iron source. The synthesized Fe,N-CDs were characterized using scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), energy-dispersive X-ray spectroscopy (EDX), Fourier-transform infrared (FT-IR) spectroscopy, and fluorescence spectroscopy confirming successful doping and revealing excitation at 235.9 nm and emission at 325.0 nm. The Fe,N-CDs exhibited remarkable peroxidase-like activity catalyzing the oxidation of peroxidase substrates in the presence of hydrogen peroxide (H2O2). A linear response was observed for hydrogen peroxide in the range of 25-600 µM, while glucose detection coupled with glucose oxidase (Gox) showed proportional absorption changes in the range of 50-600 µM enabling indirect quantification of glucose. These results demonstrate that Fe,N-CDs provide a simple, robust, and cost-effective platform for colorimetric biosensing highlighting their potential applications in medical diagnostics, clinical evaluation, and home healthcare monitoring.
M2 macrophage activation contributes to pancreatitis pathophysiology and may drive progression from recurrent acute pancreatitis (RAP) to chronic disease. Evidence is mainly preclinical or cross-sectional, highlighting a need for prospective studies. This was an exploratory analysis of a multicenter, randomized, placebo-controlled trial, which included patients with RAP randomized to naldemedine (tablet 0.2 mg daily), a peripherally acting µ-opioid receptor agonist hypothesized to reduce RAP frequency, or placebo for 12 months. Biomarkers of M2 macrophage activation (plasma levels of sCD163 and sCD206) were measured at baseline and trial end. Linear mixed-effects models assessed biomarker changes within and between treatment groups. Spearman correlation assessed associations between biomarker changes and disease activity, defined by RAP attacks and pain flares. Fifty-six patients with paired plasma samples were included (32 naldemedine, 24 placebo) in this exploratory analysis. Despite a numerical reduction in RAP frequency with naldemedine (hazard ratio 0.49; 95% confidence interval: 0.23 to 1.08; p = 0.076), no differences in mean change of sCD163 (-0.07 mg/L, p = 0.652) or sCD206 (0.01 mg/L, p = 0.299) were observed compared to placebo. Change in plasma levels of sCD163 correlated with the frequency of RAP attacks (rho = 0.348, p = 0.009) and pain flares (rho = 0.318, p = 0.017). No associations between disease activity and plasma levels of sCD206 were observed. Naldemedine did not significantly affect M2 macrophage activation, suggesting limited immunomodulatory effects. However, changes in sCD163 plasma levels correlated with clinical disease activity, highlighting macrophage activation in RAP.
Heart transplantation remains the definitive therapy for end-stage heart failure; however, its clinical impact is constrained by donor availability and preservation-associated injury. Static cold storage (SCS) with cardioplegic solutions such as Custodiol is the current clinical standard of care, yet extended cold ischemia markedly increases the risk of primary graft dysfunction. There is therefore a critical need for advanced preservation strategies and solutions that maintain graft viability under both cold and normothermic conditions. This study is aimed at comparing the effects of Custodiol and the novel cell-free organ preservation solution Omnisol on contractile function, metabolic activity, and apoptosis in human cardiomyocytes under static cold and normothermic storage conditions. Human-induced pluripotent stem cell-derived cardiomyocytes were subjected to static cold or normothermic storage in standard culture medium, Custodiol, or Omnisol, followed by functional assessment after return to standard culture medium. Contractile function was quantified using video-based motion analysis (MuscleMotion), metabolic activity was quantified by MTT assay, and cell death-associated DNA fragmentation was assessed by TUNEL staining in combination with cell morphology. Following normothermic preservation in Omnisol, cardiomyocyte contractility was comparable to that observed with standard culture medium, whereas Custodiol-preserved cells showed markedly reduced beating frequency, impaired contraction profiles, and delayed functional recovery. After SCS, contractile function recovered to a similar extent in Omnisol- and Custodiol-treated cells upon return to standard medium. Importantly, Omnisol-treated cardiomyocytes displayed significantly higher metabolic activity than Custodiol-treated cells under both cold and normothermic storage conditions. Apoptosis rates were comparable between groups following cold storage; however, under normothermic conditions, Custodiol treatment was associated with a significant increase in apoptotic cell death. This proof-of-concept study demonstrates the preservation potential of the novel cell-free preservation solution Omnisol for human cardiomyocytes under static cold and normothermic conditions. These hypothesis-generating findings support further evaluation of Omnisol as a versatile preservation solution for dynamic organ perfusion strategies.
Gene fusions and their associated chimeric RNAs have historically been recognized for their roles in cancer. However, recent research has increasingly detected chimeric transcripts in normal tissues and noncancerous cell lines. Extensive efforts have begun to annotate genomic structural variation, revealing gene fusions capable of generating chimeric transcripts even in normal tissues. In this study, we present a bottom-up approach targeting population-specific chimeric RNAs, identifying 58 such instances in the GTEx cohort. Among these, notable examples include SUZ12P1-CRLF3, TFG-ADGRG7, and TRPM4-PPFIA3, each associated with ancestry. We present direct genomic evidence for 29 polymorphic chimeric RNAs associated with structural variants, including 13 previously unreported rare variants. Additionally, utilizing data from the All of Us research program alongside a substantial clinical cohort, we characterized the clinical relevance of the SUZ12P1-CRLF3-associated variant. Collectively, our findings highlight the effectiveness of leveraging population-specific chimeric transcripts, exemplified by SUZ12P1-CRLF3, as a method for uncovering otherwise elusive transcribed genomic structural variants.