Search Results (68)

Background/Objectives: Brain death determination in children is clinically challenging. When standard clinical examination cannot be completed or reliably interpreted, ancillary testing is required—yet many established methods depend on infrastructure or patient transport that may not be feasible in critically ill pediatric patients. Orbital ultrasonography is bedside-applicable and non-invasive, but remains poorly characterized in children. Methods: We conducted a single-center retrospective study of 28 pediatric patients evaluated for suspected brain death between January 2021 and February 2025. Patients were classified as brain death-positive [BD(+), n = 20] or brain death-negative [BD(−), n = 8] based on clinical criteria independent of imaging findings. Orbital color Doppler parameters (ophthalmic artery, central retinal artery, posterior ciliary artery) and optic nerve sheath diameter (ONSD) were measured under a standardized protocol by a single experienced operator. Ophthalmic artery resistive index (OA-RI) was defined a priori as the primary outcome; ONSD was the secondary outcome. Group comparisons used the Mann–Whitney U test with Cliff’s delta effect sizes; false discovery rate correction was applied to secondary and exploratory comparisons. ROC analyses were performed to assess discriminative performance. The study was reported in accordance with the STARD 2015 guidelines for diagnostic accuracy research. Results: OA-RI was markedly higher in BD(+) patients (0.84 [IQR 0.80–0.90] vs. 0.65 [0.58–0.69]; p < 0.001; δ = 0.975). ROC analysis yielded an AUC of 0.99 (95% CI: 0.96–1.00); at a cut-off of ≥0.77, sensitivity was 95.0% and specificity 100.0%. ONSD also differed significantly between groups (4.75 [4.15–5.08] mm vs. 3.90 [3.40–4.15] mm; p = 0.012; δ = 0.619; AUC = 0.81, 95% CI: 0.62–1.00; cut-off ≥ 4.2 mm; sensitivity and specificity both 75.0%). Across all three orbital vessels, end-diastolic velocity was consistently reduced and resistive indices elevated in BD(+) patients. Systolic velocities did not differ meaningfully between groups. Cut-off values represent cohort-specific statistical optima and should be interpreted as exploratory. Conclusions: Orbital Doppler ultrasonography demonstrates a coherent high-resistance hemodynamic pattern in pediatric brain death. OA-RI showed strong discriminative performance and may serve as a useful bedside adjunct in selected cases where ancillary testing is indicated. ONSD provides complementary anatomical evidence. These findings are exploratory and require prospective validation in larger, multicenter pediatric cohorts. Full article

Colorectal cancer (CRC) develops through both conventional adenoma–carcinoma and serrated neoplasia pathways, yet noninvasive screening still under-detects the advanced precursor lesions that enable true cancer prevention. Stool-based screening reduces CRC mortality, but its preventive impact remains constrained by limited detection of advanced precancerous lesions (APLs), including advanced adenomas and sessile serrated lesions. Next-generation multitarget stool DNA assays (mt-sDNA; e.g., Cologuard Plus) have established high sensitivity for CRC and specificity approaching 94%, leaving improved APL detection as the principal opportunity for innovation. This review presents a consensus framework for a multi-omic stool screening paradigm that integrates host epigenetic markers (DNA methylation) with gut microbiome features using artificial intelligence (AI). Multi-omics capture complementary layers of early tumor biology: epithelial shedding and field effects reflected in host methylation signals together with luminal ecological and inflammatory changes represented by microbial features. Evidence from cross-cohort microbiome studies indicates that microbial signatures provide an additive—rather than standalone—axis of information for CRC and its precursor lesions. Because microbiome-based models are highly susceptible to batch effects arising from collection devices, extraction chemistry, sequencing platforms, and bioinformatic pipelines, practical mitigation strategies are outlined, including harmonized pre-analytics, batch-aware study design, leakage-resistant validation, and computational harmonization. A translational roadmap linking analytical validity, locked-model development, and prospective colonoscopy-verified clinical validation is proposed, aligned with TRIPOD + AI, STARD, PROBAST-AI, SPIRIT-AI, CONSORT-AI, and DECIDE-AI reporting standards. Scenario modeling using BLUE-C prevalence estimates suggests that improving APL sensitivity from approximately 43% to 55–65% at ~94% specificity could translate to detecting roughly 13–23 additional advanced precancerous lesions per 1000 individuals screened, highlighting the potential prevention impact of a multi-omic approach. This framework aims to guide developers and clinical investigators toward next-generation stool tests capable of materially improving precursor-lesion detection while maintaining clinically acceptable specificity. Full article

Background/Objectives: Artificial intelligence (AI) tools for orthodontic diagnosis are increasingly used in clinical practice; however, there is limited evidence regarding their performance in CBCT-based assessments. In this study, we evaluated the diagnostic reliability of the Diagnocat platform for categorical orthodontic diagnoses obtained from CBCT examinations. Methods: Fifty-nine patients who underwent large-field CBCT (13 × 16 cm) and lateral cephalograms within 30 days were included, and CBCT scans were processed using Diagnocat (v1.0). The platform’s categorical outputs—sagittal skeletal class, vertical facial pattern, overbite category, and Dental Angle class—were compared with manual cephalometric analyses performed by an experienced orthodontist (reference standard). Standard thresholds were used to convert reference continuous measurements into categorical variables. Missing or ‘N/A’ index test outputs were treated as diagnostic failures in accordance with STARD recommendations. Agreement was assessed via Cohen’s kappa (κ), and the sensitivity, specificity, PPV, and NPV were calculated for angle classification. Results: The AI platform generated skeletal and vertical classifications in only 3/59 (5%) and 1/59 (1.7%) patients, respectively. Agreement was fair (κ = 0.324) for overbite categorization, and the Dental Angle class was provided for 34/59 (57.6%) patients. When “N/A” results were treated as diagnostic failures, the overall system usability was <10% for skeletal parameters. Conclusions: The platform demonstrated insufficient diagnostic reliability and failed to generate outputs for most patients. While the specificities for generated diagnoses were acceptable, the low data completeness rate renders the tool currently unsuitable for independent clinical decision-making. Full article

The introduction of domestic cattle to the Philippines is often attributed to Spanish and Chinese sources, yet the origins and adaptive history of Philippine Visayan native cattle remain unclear. This study examined the ancestry, structure, and putative selection signals of the Visayan native cattle from Panay and Siquijor islands (VNC) in a global context. Using genome-wide SNP data, population structure was assessed by PCA, IBS/Nei/F_ST trees, and ADMIXTURE; historical relationships were explored with migration, f-statistics, and an admixture graph; and positive selection was scanned using commonly used methods such as ROH, Tajima’s D, iHS/XP-EHH, and F_ST with cross-validation across methods and functional enrichment of the overlapping regions. VNC exhibited low-to-moderate genetic diversity (Ho and He ≈ 0.21; and FIS = 0.01 to 0.02) with Siquijor enriched for long ROH segments indicating recent inbreeding. Across multiple complementary analyses, VNC showed predominantly indicine ancestry and occupied an intermediate bridge-like position between indicine from mainland Southeast Asia and from Southeastern China, with additional components that were most similar to Iberian taurine cattle and South Asian indicine. Moreover, the current study identified putative selection signatures that would possibly provide insights to better understand the local adaptation of VNC under insular tropical conditions of the Philippines: (1) small stature (HOXC cluster, STAC3, NXPH4, STARD13, RTN1), (2) heat tolerance and immune robustness (NDUFA4L2, SHMT2, ATP5MC2, ATF7, R3HDM2, CALCOCO1); (3) early reproductive and maturity reproductive performance (IGF2BP2, KL, LRP1, PDS5B). Overall, the VNC in Panay and Siquijor showed a predominantly indicine ancestry with putatively island-adapted physiology, emphasizing the need for conservation and island-specific breeding that preserves local adaptation while managing inbreeding. Full article

The disparity in outcomes between preclinical and clinical studies supplementing coenzyme Q10 (CoQ10) in neurological disorders may be a reflection of the differences in the ability of supplemental CoQ10 to access the blood–brain barrier (BBB) in rodents and in humans, which is, in turn, a consequence of contrasting structures of the BBB. The applicability of in vivo animal models to study access of CoQ10 across the BBB and subsequent neuronal metabolism has, therefore, been questioned, and there is an argument, perhaps surprisingly, that in vitro model systems (particularly 3D cellular systems) may be more appropriate. In this article, we have, therefore, reviewed the role of model systems to study the access of CoQ10 across the BBB, as well as the role of such systems in studying the role of CoQ10 in aspects of neuronal metabolism, such as mitochondrial and lysosomal function. In addition, the use of such model systems to study the interactions of CoQ10 with vitamin E and selenium has been reviewed. Finally, the practical application of a neuronal model system to investigate the effect of CoQ10 supplementation on CoQ10 status and mitochondrial metabolism in a CoQ10 deficiency state has been described. Full article

46,XY gonadal dysgenesis, characterised by absent or defective testicular development in individuals with a 46,XY karyotype, results from disruptions in the genetic programme governing testis determination and differentiation during embryogenesis. While monogenic causes explain approximately 50% of cases, emerging evidence suggests an oligogenic basis in some patients. However, many cases remain without a definitive molecular diagnosis. In this study, we investigated a patient with 46,XY gonadal dysgenesis to explore the underlying genetic aetiology. Whole-exome sequencing in the patient did not reveal any pathogenic variants in genes previously associated with this condition. Instead, it detected rare variants in STARD9 and CDK5RAP2, which encode centrosomal proteins known to interact with each other. Gene expression analysis of embryonic gonads revealed that STARD9 is sexually dimorphic, with the highest expression in testis-specific Sertoli cells, while CDK5RAP2 is ubiquitously expressed, including in Sertoli cells. These findings suggest a role for both genes in Sertoli cell development, implicating them in the pathogenesis of 46,XY gonadal dysgenesis. To evaluate the functional relevance of the identified variants, we performed molecular dynamics simulations, which suggest that these variants may impair the individual and/or combined functions of STARD9 and CDK5RAP2 proteins. This study is the first to propose a role for STARD9 and CDK5RAP2 genes in human Sertoli cell development and highlights their potential contribution to 46,XY gonadal dysgenesis. Full article

Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a pivotal vulnerability in oral squamous cell carcinoma (OSCC). This review provides an overview of ferroptosis mechanisms and their implications for OSCC pathobiology and therapy. OSCC cells exhibit heightened reliance on anti-ferroptotic defenses such as GPX4, SLC7A11, FSP1, and Nrf2, and disrupting these pathways suppresses tumor growth and restores sensitivity to chemotherapy, radiotherapy, and immunotherapy. Genetic and epigenetic regulators, including p53, PER1, circ_0000140, and STARD4-AS1, critically modulate ferroptotic sensitivity, while metabolic enzymes such as ACSL4, LPCAT3, and TPI1 link ferroptosis to cellular plasticity and resistance. Preclinical studies highlight the promise of small-molecule inhibitors, repurposed agents (e.g., sorafenib, artesunate, trifluoperazine), natural compounds (e.g., piperlongumine, Evodia lepta, quercetin), and nanomedicine platforms for targeted ferroptosis induction. We further address ferroptosis within the tumor microenvironment, highlighting its immunogenic and context-dependent dual roles, and summarize genomic and transcriptomic evidence linking ferroptosis-related genes to patient prognosis. Beyond cancer, ferroptosis also contributes to non-malignant oral diseases, including pulpitis, periodontitis, and infection-associated inflammation, where inhibitors may protect tissues. Despite these advances, clinical translation is constrained by the lack of safe ferroptosis inducers and validated biomarkers. Future research should focus on developing pharmacologically viable GPX4 inhibitors, refining biomarker-driven patient stratification, and designing multimodal regimens that combine ferroptosis induction with standard therapies while preserving immune and tissue integrity. Ferroptosis therefore represents both a mechanistic framework and a translational opportunity to reshape oral oncology and broader oral disease management. Full article

Background: Virtual reality (VR) and augmented reality (AR) have emerged as innovative tools in healthcare, particularly using diagnostic and interventional imaging methods, offering new avenues for enhancing patient care and procedural outcomes. Their applications range from improving preoperative planning and pain management to providing advanced procedural support and training. Despite their growing integration into clinical practice, evidence of their cost-effectiveness and specific clinical benefits when using radiological tools remains limited. This review aims to map the current landscape of VR and AR applications using radiological modalities and highlight areas for future research. Objective: This scoping review explores the clinical applications of VR and AR in different radiological fields, aiming at assessing target areas, cost-effectiveness, and benefits of these technologies. Methods: We conducted a comprehensive literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework. A total of 15 primary studies were included, covering diverse populations and applications of VR and AR. Results: In total, 15 studies (N = 781 patients) were included, with sample sizes ranging from 6 to 120. These studies highlighted various clinical applications of VR and AR, including imaging-guided preoperative planning, pain management, and procedural support. Although several studies demonstrated improvements in patient experiences and diagnostic accuracy, cost-effectiveness data were lacking. Notably, 47% of the studies focused exclusively on pediatric populations (N = 363), and 33% were randomized controlled trials. Quality assessment using the STARD criteria revealed that 60% of studies were rated as good (score > 12), 27% as fair (score 10–12), and 13% as suboptimal (score < 10), with inter-reader reliability showing substantial agreement (ICC = 0.76; 95% CI: 0.64–0.91). Out of 15 included studies, only 6 (40%) reported statistically significant improvements in patient experiences, with the remaining studies reporting positive trends (e.g., feasibility, usability, improved planning). Individual studies demonstrated significant benefits of VR interventions; for instance, one study reported a reduction in distress scores by a mean of 3.0 (95% CI: 1.0–5.0) and a decreased need for parental presence (risk ratio 0.3; 95% CI: 0.1–0.7; p < 0.001) compared to conventional methods. Conclusions: VR and AR technologies hold promise in enhancing patient care and procedural outcomes. Future research should focus on the cost-effectiveness of these technologies and identify specific target populations that would benefit the most. Additionally, adherence to the Standards for Reporting of Diagnostic Accuracy (STARD) guidelines should be encouraged to ensure transparent and comprehensive reporting in VR and AR studies. Full article

Background: Distinguishing between bacterial and viral infections in children remains a significant challenge for clinicians. Traditional biomarkers have limited utility, often leading to antibiotic overprescription due to clinician uncertainty. With rising antimicrobial resistance, novel biomarkers are needed to improve diagnosis. This scoping review examines current host miRNA biomarkers for acute bacterial and viral infections in children (0–18), focusing on study methods, diagnostic metrics, and research gaps to support clinical translation. Results: Of the 1147 articles identified, 36 studies were included. Notably, 72.2% of the studies originated from Asia, and the distribution across the paediatric age groups was relatively even. A total of 17 miRNAs were validated in at least two independent studies. Three miRNAs, hsa-miR-182-5p, hsa-miR-363-3p, and hsa-miR-206, were consistently associated with bacterial infection in children. Meanwhile, nine miRNAs were associated with viral infections: hsa-miR-155, hsa-miR-29a-3p, hsa-miR-155-5p, hsa-miR-150-5p, hsa-miR-140-3p, hsa-miR-142-3p, hsa-miR-149-3p, hsa-miR-210-3p, and hsa-miR-34a-5p. Across the 12 studies reporting diagnostic accuracy metrics, miRNA biomarkers exhibited a sensitivity ranging from 70% to 100%, and a specificity ranging from 72% to 100%. The area under the curve across the studies demonstrated a range from 0.62 to 0.99. Conclusions: This scoping review highlights the potential of miRNA targets for diagnosing paediatric infections when studied rigorously. However, clinical translation is limited by poor adherence to STARD guidelines, lack of robust diagnostic metrics, and study heterogeneity. Many studies were set up with a case–control design, a design that, while highlighting differences, is more likely to identify non-specific biomarkers rather than those that are useful for novel clinical diagnostics. Full article

Background and Clinical Significance: Hemophagocytic lymphohistiocytosis (HLH) and autoimmune hemolytic anemia (AIHA) are both life-threatening hematologic syndromes that rarely present together outside of malignancy. Advanced acquired immunodeficiency syndrome (AIDS) creates a milieu of profound immune dysregulation and hyperinflammation, predisposing patients to atypical overlaps of these disorders. Case Presentation: A 30-year-old woman with poorly controlled AIDS presented with three weeks of jaundice, fever, and fatigue. Initial labs revealed pancytopenia, hyperbilirubinemia, and elevated ferritin level. Direct anti-globulin testing confirmed warm AIHA (IgG⁺/C3d⁺) with transient cold agglutinins. Despite intravenous immunoglobulin (IVIG), rituximab, and transfusions, she developed hepatosplenomegaly, extreme hyperferritinemia, and sIL-2R > 10,000 pg/mL, meeting HLH-2004 criteria. Bone marrow biopsy excluded malignancy; further work-up revealed Epstein–Barr virus (EBV) viremia and cytomegalovirus (CMV) reactivation. Dexamethasone plus reduced-dose etoposide transiently reduced soluble interleukin-2 receptor (sIL-2R) but precipitated profound pancytopenia, Acute respiratory distress syndrome (ARDS) from CMV/parainfluenza pneumonia, bilateral deep vein thrombosis (DVT), and an ST-elevation myocardial infarction (STEMI). She ultimately died of hemorrhagic shock after anticoagulation despite maximal supportive measures. Conclusions: This case underscores the diagnostic challenges of HLH-AIHA overlap in AIDS, where cytopenias and hyperferritinemia mask the underlying cytokine storm. Pathogenesis likely involved IL-6/IFN-γ overproduction, impaired cytotoxic T-cell function, and molecular mimicry. While etoposide remains a cornerstone of HLH therapy, its myelotoxicity proved catastrophic in this immunocompromised host, highlighting the urgent need for cytokine-targeted agents to mitigate treatment-related mortality. Full article

Background and Objectives: General-purpose multimodal large language models (LLMs) are increasingly used for medical image interpretation despite lacking clinical validation. This study evaluates the diagnostic reliability of ChatGPT-4o and Claude 2 in photographic assessment of adolescent idiopathic scoliosis (AIS) against radiological standards. This study examines two critical questions: whether families can derive reliable preliminary assessments from LLMs through analysis of clinical photographs and whether LLMs exhibit cognitive fidelity in their visuospatial reasoning capabilities for AIS assessment. Materials and Methods: A prospective diagnostic accuracy study (STARD-compliant) analyzed 97 adolescents (74 with AIS and 23 with postural asymmetry). Standardized clinical photographs (nine views/patient) were assessed by two LLMs and two orthopedic residents against reference radiological measurements. Primary outcomes included diagnostic accuracy (sensitivity/specificity), Cobb angle concordance (Lin’s CCC), inter-rater reliability (Cohen’s κ), and measurement agreement (Bland–Altman LoA). Results: The LLMs exhibited hazardous diagnostic inaccuracy: ChatGPT misclassified all non-AIS cases (specificity 0% [95% CI: 0.0–14.8]), while Claude 2 generated 78.3% false positives. Systematic measurement errors exceeded clinical tolerance: ChatGPT overestimated thoracic curves by +10.74° (LoA: −21.45° to +42.92°), exceeding tolerance by >800%. Both LLMs showed inverse biomechanical concordance in thoracolumbar curves (CCC ≤ −0.106). Inter-rater reliability fell below random chance (ChatGPT κ = −0.039). Universal proportional bias (slopes ≈ −1.0) caused severe curve underestimation (e.g., 10–15° error for 50° deformities). Human evaluators demonstrated superior bias control (0.3–2.8° vs. 2.6–10.7°) but suboptimal specificity (21.7–26.1%) and hazardous lumbar concordance (CCC: −0.123). Conclusions: General-purpose LLMs demonstrate clinically unacceptable inaccuracy in photographic AIS assessment, contraindicating clinical deployment. Catastrophic false positives, systematic measurement errors exceeding tolerance by 480–1074%, and inverse diagnostic concordance necessitate urgent regulatory safeguards under frameworks like the EU AI Act. Neither LLMs nor photographic human assessment achieve reliability thresholds for standalone screening, mandating domain-specific algorithm development and integration of 3D modalities. Full article

Background: Cotton, a key global economic crop, suffers yield and quality losses due to salt stress. This study aims to analyze the cotton STARD gene family and its role in salt stress responses. Methods: We conducted a genome-wide analysis of the STARD gene family in four cotton species, using phylogenetic trees, chromosomal mapping, and collinearity analyses to explore their evolutionary relationships and expansion mechanisms. We also examined gene structures, conserved motifs, and promoter cis-elements. Results: STARD genes are evenly distributed across the four cotton species. Segmental duplication was found to be the main driver of gene expansion, with most pairs undergoing purifying selection. Distinct structural features and potential roles in plant growth and stress responses were identified. Notably, 11 GhSTARD genes showed significant expression changes under salt stress, especially GhSTARD45 in root tissues. Conclusions: This study provides new insights into the function and salt stress response mechanisms of the cotton STARD gene family, suggesting GhSTARD45 plays a key role in root-mediated salt tolerance and highlighting the potential of STARD genes in enhancing cotton’s salt tolerance. Full article

Heart rate variability (HRV) has been established as a measure for the variation in time intervals between successive cardiac actions as a marker of the autonomic nervous system. However, despite many efforts in this field, there are no reference values that are generally accepted. The objective of this systematic review is, therefore, to present an overview of the studies on HRV normal values published to date, with due consideration of any influencing factors. A systematic database query was carried out in PubMed, Scopus, Ovid Medline, and PsychInfo using the search string “((hrv) or (heart rate variability)) and ((reference values) or (reference range) or (normal values))”. Of the 6640 studies yielded by the query, 58 were used for this systematic review. The STARD-HRV procedure was used to assess the quality of the studies. The studies considered date from 1989 to 2022. The number of subjects examined was between 20 and 84,772. The age of the subjects was between 1 day and 99 years. A total of 51 of the studies examined both male and female subjects. In total, 19 studies used long-term measurements, 22 studies used short-term measurements, and 17 studies used intermediate measuring periods. Many different HRV parameters were analyzed, most often traditional time-domain and frequency-domain ones. Nine studies described the subjects as “healthy” without giving more detailed explanations. There are no generally accepted HRV normal values (yet). Some large studies provide values that may be used for orientation purposes. However, further studies are required to collect HRV normal values. It was not possible to merge the results of the studies in terms of a meta-analysis; this would also not be practical since, among other reasons, the consideration of confounders as well as recording and measuring modalities sometimes vary to a large extent and impede the comparability of the studies. Generally, HRV seems to be influenced by various mechanisms and external factors that are still not fully understood. An exploration of these factors will ultimately allow HRV normal values to be obtained in a manner that is generally accepted. Full article

Background: Colonic diverticulosis is a common condition, particularly in the elderly population. While dietary habits, obesity, smoking, and physical inactivity contribute to its pathogenesis, emerging evidence highlights a genetic predisposition affecting extracellular matrix (ECM) remodeling, inflammation, and connective tissue integrity. The aim of this systematic review was to summarize genetic determinants of colonic diverticulosis. Methods: The PubMed^® database was searched for original studies in humans. The inclusion criteria were named genetic factor and confirmed diverticulosis. Patients with diverticulitis and diverticular diseases were excluded from this review. Results: Out of 137 publications, 10 articles met the inclusion criteria: six large association studies (GWAS) and four cross-sectional studies. The genes regulating ECM turnover, including TIMP1, MMP3, and MMP9, are involved in diverticulosis development. The TIMP1 (rs4898) T allele has been associated with increased susceptibility, potentially due to its role in ECM remodeling. Similarly, MMP3 (rs3025058) and MMP9 (rs3918242) polymorphisms contribute to altered collagen degradation. The COL3A1 (rs3134646) variant coding modified collagen type III may promote diverticular formation. Other genes, such as ARHGAP15 (rs4662344, rs6736741), affect cytoskeletal dynamics. Identified in GWAS studies, gene candidates may be grouped into blood group and immune system-related genes (ABO, HLA-DQA1, HLA-H, OAS1, TNFSF13, FADD), extracellular matrix and connective tissue genes (COL6A1, COLQ, EFEMP1, ELN, HAS2, TIMP2), signaling and cell communication (BMPR1B, WNT4, RHOU, PHGR1, PCSK5), nervous system and neurodevelopment (BDNF, CACNB2, GPR158, SIRT1, SCAPER, TRPS1), metabolism and transporters (SLC25A28, SLC35F3, RBKS, PPP1R14A, PPP1R16B), lipids and cholesterol (LDAH, LYPLAL1, STARD13), transcription and gene regulation (ZBTB4, UBTF, TNRC6B), apoptosis (FADD, PIAS1), and poorly characterized genes (C1TNF7, ENSG00000224849, ENSG00000251283, LINC01082, DISP2, SNX24, THEM4, UBL4B, UNC50, WDR70, SREK1IP1). Conclusions: There are a number of gene variants that probably predispose to colonic diverticulosis. Detailed characterization of the multigene background of diverticulosis will enable appropriate therapeutic or preventive interventions in the future. Full article

Background/Objectives: Bariatric surgery (BS), drugs approved for type-2-diabetes (T2D), obesity, and liver fibrosis (resmetirom) announce the widespread use of fibrosis tests in patients with metabolic liver disease (MASLD). An unmet need is to reduce the uncertainty of biomarkers for the diagnosis of the early stage of clinically significant fibrosis (eF). This can be achieved if three essential but neglected STARD methods (3M) are used, which have a more sensitive histological score than the standard comparator (five-tiers), the weighted area under the characteristic curve (wAUROC) instead of the binary AUROC, and biopsy length. We applied 3M to FibroTest-T2D to demonstrate this reduction of uncertainty and constructed proxies predicting eF in large populations. Methods: For uncertainty, seven subsets were analyzed, four included biopsies (n = 1903), and to assess eF incidence, three MASLD-populations (n = 299,098). FibroTest-T2D classification rates after BS and in outpatients-T2D (n = 402) were compared with and without 3M. In MASLD, trajectories of proxies and incidence against confounding factors used hazard ratios. Results: After BS (110 biopsies), reversal of eF was observed in 16/29 patients (84%) using seven-tier scores vs. 3/20 patients (47%) using five-tier scores (p = 0.005). When the biopsy length was above the median, FibroTest-T2D wAUROC was 0.90 (SD = 0.01), and the wAUROC was 0.88 (SD = 0.1) when the length was below the median (p < 0.001). For the first time, obesity was associated with eF before T2D (p < 0.001), and perimenopausal age with apoA1 and haptoglobin increases (p < 0.0001). Conclusions: Validations of circulating biomarkers need to assess their uncertainty. FibroTest-T2D predicts fibrosis regression after BS. Applying 3M and adjustments could avoid misinterpretations in MASLD surveillance. Full article