Search Results (1,389)

The clinical integration of artificial intelligence has outpaced the development of robust evaluative frameworks, raising critical safety concerns. This perspective establishes a clear taxonomy distinguishing probabilistic language models from deterministic classifiers and applies a multi-dimensional combinatorial model to calculate the requirements for complete diagnostic coverage. Our analysis demonstrates that comprehensive diagnostic coverage requires between 50,000 and 150,000 distinct, task-specific classifiers under subspecialty-level clinical granularity; conservative aggregated estimates (4500–18,750 binary classifiers) do not reflect the multiplicative expansion introduced by subtype differentiation, severity staging, temporal variants, demographic stratification, and equipment variation, whereas currently cleared devices cover less than one percent of this clinical space. More fundamentally, although population-trained models can generate conditional patient-specific risk estimates when predictors are informative and calibration is adequate, these statistical parameters optimized on population-scale data cannot provide the categorical certainty required for individual diagnostic decisions, which is a gap that clinical judgment must bridge. Because clinical AI tools are inherently statistical and perform reliably only on common, highly represented presentations while failing on rare, atypical cases rare in their training data, attempting to automate routine tasks leaves human clinicians with only the most challenging diagnostics. Furthermore, selective automation of these low-complexity cases introduces severe occupational hazards, including cognitive surrender, diagnostic complacency, and rapid expertise atrophy. Rather than pursuing the computationally and logistically unfeasible goal of complete diagnostic classification, developers should prioritize predictive, prognostic trajectory modeling. This paradigm shift aligns the probabilistic nature of machine learning with clinical utility, reinforcing clinical judgment as the irreplaceable diagnostic integrator. Full article

As a core organ responsible for metabolism and homeostatic regulation, the kidney performs physiological functions that encompass material excretion, fluid balance, electrolyte regulation, and endocrine control; and serves as a critical hub for maintaining the coordinated functioning of multiple organ systems. Kidney injury not only leads to disturbances in these core physiological functions but also generates systemic complications such as cardiovascular disease, hypertension, and diabetes mellitus through an “injury–inflammation–metabolic disorder” cascade. Epidemiologic studies and clinical statistics have revealed that acute kidney injury (AKI) may progress to chronic kidney disease (CKD) because of maladaptive repair, impaired regeneration, and other factors. During this process, macrophages—particularly certain functionally specialized macrophage subtypes—engage in complex intercellular communication with neighboring cells that include renal tubular epithelial cells, endothelial cells, fibroblasts, and platelets, thereby forming pathological signaling networks that collectively drive persistent inflammation and the progression of renal fibrosis. Macrophages thus play complex and dynamic dual regulatory roles throughout the initiation, progression, and repair of kidney injury, and their functional polarization and phenotypic transformation directly influence the pathological progression of kidney diseases. We herein aimed to elucidate the roles of AKI-to-CKD transition-associated macrophages, especially the subtypes with specialized functions in kidney diseases and to systematically review current research progress, thus to provide a reference for advancing basic research and clinical diagnostic and therapeutic strategies for kidney diseases. Full article

Background: Endometriosis-associated ovarian cancers (EAOCs), including ovarian clear cell (OCCC) and endometrioid ovarian carcinoma (EnOC) subtypes, frequently exhibit transcriptomic dysregulation of the PI3K/AKT/mTOR signalling axis. While genomic aberrations are well-documented, the coordinated microRNA (miRNA)-mediated networks governing post-transcriptional remodelling of this pathway across these subtypes remain poorly defined. Methods: We conducted an integrative in silico meta-analysis of independent mRNA and small RNA sequencing datasets. The mRNA analysis included 120 EAOC samples, of which 68 were OCCC and 52 were EnOC, compared with 149 normal ovarian tissues. The miRNA analysis included 170 samples comprising 55 OCCC, 82 EnOC and 33 normal ovarian tissues. Differential expression analysis, dimensionality reduction (UMAP), functional enrichment, and topologically unweighted miRNA–mRNA interaction networks were evaluated. Results: Both subtypes showed significant transcriptomic dysregulation of the core pathway machinery, including PIK3CB and mTOR, while preserving mTORC2 components. Post-transcriptional concurrent downregulation of IRS1, GRB10, DDIT4, and PIK3CD, which were identified as candidate targets of the hub miRNAs hsa-miR-30a-5p, hsa-miR-30d-5p, and hsa-miR-7-5p, suggests further refined control of the pathway. The identification of highly connected hub genes linking mTOR, MAPK, and Wnt signalling pathways within the mTOR-regulatory network suggests that pathway modulation occurs through extensive crosstalk across multiple oncogenic signalling pathways in EAOCs. Conclusions: Transcriptomic dysregulation of the mTOR pathway in EAOCs reflects not only genomic alterations but also potential post-transcriptional regulation. Despite subtype-specific transcriptomic differences, both exhibited transcriptional upregulation of components of the canonical PI3K/AKT/mTOR signalling axis. Pathway modulation through the miRNA regulatory network exhibited potential crosstalk across oncogenic pathways and hub genes. Full article

Background: We examined temporal trends in deaths mentioning both pancreatic cancer and renal failure in the United States. Methods: We analyzed CDC WONDER multiple-cause-of-death data for adults aged ≥25 years from 1999 to 2024. Age-adjusted mortality rates (AAMRs) were assessed using Joinpoint regression. Secondary analyses quantified renal-failure co-recording among pancreatic-cancer-involving deaths, renal-failure subtypes, disparities, and comparisons with lung and bronchus, colorectal, and liver and intrahepatic bile duct cancers. Results: Overall, 31,497 deaths mentioned both conditions. The AAMR increased from 0.37 per 100,000 in 1999 to 0.82 in 2024, with the most rapid increase during 2018–2024 (annual percentage change, 10.77%; 95% CI, 7.18–18.22%). Renal failure was co-recorded in 2.98% of pancreatic-cancer-involving deaths. Corresponding proportions were 2.37% for lung and bronchus, 4.75% for colorectal, and 5.77% for liver and intrahepatic bile duct cancer; recent trends did not differ significantly from pancreatic cancer. Acute kidney failure was the most frequently recorded renal subtype (43.22%). In 2024, AAMRs were higher among males and highest among non-Hispanic Black individuals. Conclusions: Renal-failure co-recording with pancreatic cancer increased markedly after 2018 but was not unique to pancreatic cancer. Death-certificate data do not establish temporal sequence or causality; linked clinical data are needed to clarify potentially modifiable kidney-related pathways. Full article

Background and Objectives: Basal cell carcinoma (BCC) is the most common non-melanoma skin cancer, and its global incidence rate constantly rises. However, there are no current epidemiological data for many regions, including Małopolska in southern Poland. This study aimed to characterize the clinical and histological profile of patients with BCC and to identify factors associated with local recurrence and the presence of multiple tumors. Materials and Methods: We performed a single-center, retrospective observational study consistent with STROBE guidelines at the Department of Dermatology and Allergology, University Hospital in Cracow. The included patients were adults with at least one histologically confirmed BCC treated between 2015 and 2025. Demographic, clinical, histopathological, and follow-up data were collected at patient and lesion levels. The results were evaluated using univariable tests, multivariable logistic regression, Kaplan–Meier survival analysis, and generalized estimating equations. Results: We included 108 patients (median age at first diagnosis, 73 years; 52% male) with 418 BCCs; the median follow-up duration was 84 months. Superficial BCC was the most common subtype among lesions with available histological subtype information (56%). The head and neck region was the most frequent anatomical site in this group (51%). Multiple BCCs were present in 62% of patients. Longer follow-up was independently associated with the presence of multiple BCCs. A history of actinic keratoses showed a positive but statistically nonsignificant association with multiple BCCs. Recurrence was observed in 15 lesions (3.6%). Female sex and H-zone involvement showed higher odds of recurrence. Conclusions: In this elderly cohort, multiple BCC tumors may reflect longer follow-up and cumulative actinic damage. Recurrence was relatively infrequent but associated with clinically relevant features, including H-zone involvement and female sex. These findings support an individualized, multifactorial approach to treatment and follow-up, taking into account age, sex, lesion burden, anatomical location, and histological subtype. Full article

Background: Pemphigus is a rare group of autoimmune blistering diseases characterized by autoantibody-mediated loss of keratinocyte adhesion, resulting in intraepithelial blister formation involving the skin and mucous membranes. Pemphigus Vulgaris (PV) is the most common type of pemphigus, which usually presents in adulthood and has a prevalence rate of about 2.83 cases per million person years worldwide. The prevalence rate in children and adolescents is relatively uncommon; however, it accounts for about 1.4 to 3.7 percent of all cases of pemphigus vulgaris reported worldwide. The involvement of oral cavity is clinically significant since it can present prior to the disease or as its predominant feature. Hence, this narrative review seeks to review literature on pemphigus with involvement of oral cavity in children and adolescents. Objective: The objective of this study was to review the current literature regarding epidemiology, pathogenesis, clinical presentation, diagnosis, histopathological characteristics, treatment, and outcomes of pemphigus with oral involvement in children and adolescents. Materials and Methods: A literature search was conducted using the PubMed/MEDLINE, Scopus, and Cochrane Library databases to identify relevant studies published between 2015 and 2026. The search strategy included terms related to pemphigus, pediatric patients, and oral manifestations. Articles involving patients younger than 18 years of age with oral involvement were screened according to predefined inclusion criteria. Following database screening, duplicate removal, and full-text assessment, 25 studies comprising a total of 51 patients with documented oral or orofacial involvement were included in the final review. Results: Pemphigus vulgaris was the predominant subtype, with oral lesions representing the initial or sole manifestation in the majority of patients. The gingiva, mucosa, tongue, lip, and palate were the most common affected areas in the mouth. The lesions in these areas usually appeared as painful erosion, ulcers, and desquamative gingivitis. Histopathology with the presence of acantholysis in the suprabasal area and direct immunofluorescence was the most definitive test for diagnosis. Systemic corticosteroids were the mainstay of treatment in conjunction with steroid sparing agents in some cases, with good results in difficult cases using rituximab. Overall, most patients achieved partial or complete clinical remission following appropriate treatment, although relapses were occasionally reported. Conclusions: Pemphigus in children and adolescents is rarely encountered; however, it should be included as a differential diagnosis of erosive/ulcerative lesions. Early identification, diagnosis, and treatment through a collaborative approach from dental practitioners are critical. Further research is required at multiple centers to gain a better understanding of the disease and to develop evidence-based guidelines for diagnosis and treatment of pediatric patients. Full article

Neoadjuvant chemotherapy (NAC) is the standard of care for locally advanced breast cancer, yet the molecular predictors of pathological response remain incompletely defined, particularly regarding microRNA (miRNA) dynamics. We investigated paired pre- and post-NAC miRNA expression profiles in relation to molecular subtype, residual cancer burden (RCB), and clinical timing parameters. Seven patients with invasive breast cancer (Luminal A n = 3, Luminal B n = 1, TNBC n = 2, HER2+ n = 1) who received NAC (AC-T or TCHP) were included in this pilot study. Small-RNA sequencing (NovaSeq X Plus, CeGaT GmbH, project S17293) was performed on 14 FFPE specimens (7 pre-NAC core needle biopsies, 7 post-NAC surgical specimens). Differential expression analysis used the paired Wilcoxon signed-rank test with Benjamini–Hochberg correction. Spearman correlations assessed associations between miRNA expression, RCB score, and clinical timing intervals. Candidate miRNAs were subsequently annotated using experimentally validated miRNA–target interactions. After filtering (≥ three counts in ≥ three samples), 759 miRNAs were analysed. No miRNA reached strict significance (padj < 0.05, |log₂FC| > 1.0) after multiple testing correction, consistent with the limited statistical power (n = 7). Under exploratory criteria (p < 0.10, |log₂FC| > 0.5), 156 candidate miRNAs were identified: 70 upregulated and 86 downregulated post-NAC. Leading candidates included hsa-miR-139-3p (+2.60), hsa-miR-139-5p (+2.36), and hsa-miR-1323 (+1.55) as upregulated, and hsa-miR-429 (−2.53), hsa-miR-141-3p (−1.79), and hsa-miR-1277-5p (−1.25) as downregulated post-NAC. The single patient achieving the lowest residual disease burden (P3, Luminal B, RCB-I, score 1.32) displayed a distinct pre-treatment miRNA profile, separating from all other pre-NAC specimens on principal component analysis and characterised by higher baseline hsa-miR-139-3p/-5p and lower baseline hsa-miR-429 and hsa-miR-141-3p expression, suggesting that baseline miRNA expression patterns may contribute to differential chemotherapy response. RCB score showed a non-significant positive trend with post-NAC Ki-67 (ρ = +0.71, p = 0.07). This pilot study identifies NAC-modulated candidate miRNAs in breast cancer and establishes a paired FFPE-based small-RNA-sequencing workflow applicable in routine clinical settings. The distinct pre-treatment profile of the single best responder generates the testable hypothesis that baseline expression of tumour suppressor miRNAs of the miR-139 family, together with low miR-200-family expression, may track chemosensitivity. As no candidate reached statistical significance after multiple testing correction and none has been validated in an independent cohort or by an orthogonal method, all findings are exploratory and hypothesis-generating. The results support larger prospective validation studies examining miRNA signatures as predictive biomarkers of NAC response across breast cancer molecular subtypes. Full article

Sepsis-induced acute lung injury (SI-ALI) is a severe complication of sepsis characterized by dysregulated inflammatory responses and impaired immune homeostasis. Growing evidence indicates that extracellular vesicles (EVs), particularly exosomes, are important mediators of intercellular communication. Despite the heterogeneity of infectious sources underlying sepsis, EVs can regulate macrophage polarization and functional reprogramming by transferring diverse bioactive cargo. Consequently, EVs are involved in the pathophysiological progression of SI-ALI arising from sepsis of different etiologies. However, the mechanisms through which distinct EV cargos regulate macrophage function and contribute to SI-ALI pathogenesis remain incompletely understood. To address these issues, this review summarizes how different EV subtypes and their cargos, including RNAs, proteins, lipids, and DNA, modulate macrophage functional states through multiple signaling pathways. The effect of such processes further contributes to inflammatory reaction, immune balance, and tissue regeneration in acute lung injury caused by damage to the SI-ALI. Particularly, the EV-mediated modulation of macrophage function goes beyond the rigid M1/M2 dichotomy, being rather based on the dynamic functional repertoire involving both pro-inflammatory response and immune regulation as well as tissue regeneration. The article finally concludes with EV-based treatment approaches aimed at cargo delivery or blocking and the main problems related to translational medicine. Overall, the review article identifies the macrophage regulatory network controlled by EVs, thus helping to understand immunopathogenesis of SI-ALI as well as laying the theoretical foundation for developing EV-based precision medicine. Full article

Roseofungin, a polyene macrolide antibiotic produced by Streptomyces roseoflavus, was evaluated for antiviral activity against Influenza A virus using complementary in vitro, in ovo, and preliminary in vivo toxicity models, supported by molecular docking and molecular dynamics simulations. The compound exhibited antiviral activity against multiple influenza A virus subtypes, including an oseltamivir-resistant H1N1 strain, with EC₅₀ values ranging from 2.0 to 2.5 μg/mL and selectivity indices of 20–25. Functional assays demonstrated that roseofungin interfered with early stages of the viral life cycle by reducing viral adsorption and partially inhibiting neuraminidase activity. In virucidal assays, treatment with roseofungin resulted in a 1.5–2.5 log₁₀ reduction in infectious viral titers. Acute toxicity studies in mice indicated low toxicity under the experimental conditions (LD₅₀ > 25 mg/kg). Molecular docking predicted favorable interactions of roseofungin with multiple influenza A virus proteins. Subsequent molecular dynamics simulations of the hemagglutinin–roseofungin complex maintained the stability of the predicted binding mode across three independent 50 ns simulations (150 ns cumulative). Collectively, these findings demonstrate that roseofungin possesses broad-spectrum antiviral activity against genetically diverse Influenza A virus strains and represents a promising lead compound for the development of novel membrane-active antiviral agents. Further studies are warranted to elucidate its molecular mechanism of action and to evaluate its therapeutic potential in vivo. Full article

Choroidal neovascularization (CNV) subtype classification from optical coherence tomography (OCT) images is clinically important because treatment response and disease prognosis vary across subtypes. However, automated classification remains challenging owing to subtle inter-class differences and considerable imaging noise. We propose an erasing–refining discriminative feature network (ERDF-Net) that mitigates noisy dominant activations and reveals fine-grained structural cues. The model perturbs salient regions to facilitate subtle feature learning, restores clean salient information, and fuses both representations via channel–spatial attention to form a coherent and discriminative embedding of CNV morphology. Experiments on a clinical OCT dataset show that ERDF-Net consistently surpasses state-of-the-art fine-grained and erasing-based methods across multiple metrics. Ablation and visualization analyses further confirm the benefit and interpretability of controlled salient suppression and refined feature fusion. ERDF-Net provides an effective and reliable solution for fine-grained medical image classification. Full article

Consensus molecular subtype 4 (CMS4) colorectal cancer (CRC) is associated with an aggressive clinical course and poor survival, yet the biological basis of heterogeneity within this subtype remains incompletely understood. DNA methylation is an epigenetic mechanism involved in transcriptional regulation, cellular differentiation, and colorectal tumorigenesis. Here, we integrated single-cell RNA sequencing (scRNA-seq), bulk data, and promoter DNA methylation data to characterize CMS4-associated cancer cell states and methylation-related features. Using the scAB algorithm, we integrated scRNA-seq with bulk CMS4 data and identified CMS4-related cells distributed across multiple patients. Single-cell analyses of cell–cell communication and transcriptional regulation revealed a CMS4-related cancer cell population characterized by macrophage migration inhibitory factor (MIF)-centered intercellular communication, enhanced caudal type homeobox 1 (CDX1) and Kruppel-like factor 5 (KLF5) regulon activity, and gene modules enriched in differentiation-related pathways. CytoTRACE analysis further stratified CMS4 cancer cells into poorly and well-differentiated states, yielding 802 differentially expressed genes (DEGs). Linking these differentiation-associated DEGs with bulk expression and promoter methylation data identified 218 methylation-associated DEGs showing significant inverse methylation expression correlations, suggesting a link between differentiation-related heterogeneity and promoter methylation. Univariable Cox regression followed by LASSO regression further prioritized eight genes for construction of the methylation and differentiation-related prognostic model (MeDiff-PM). MeDiff-PM consistently stratified overall survival in the TCGA CMS4 cohort and two independent validation cohorts, with cutoff-independent continuous Cox analyses further supporting its prognostic association across cohorts. And MeDiff-PM remained prognostically significant after adjustment for available clinical variables. High MeDiff-PM risk scores were associated with activation of P53, WNT, and ubiquitin-mediated proteolysis pathways and with consistent predicted drug response differences for compounds across three CMS4 cohorts. While individual in silico knockout analysis suggested links between MeDiff-PM genes and metallothionein-related and immune-associated transcriptional responses. Collectively, these findings indicate that methylation-associated differentiation features represent a molecular dimension of intra-CMS4 heterogeneity and provide a biologically informed framework for prognostic stratification within CMS4 CRC. Full article

Social anxiety is a common and persistent mental health problem associated with substantial functional impairment. It comprises distinct subtypes, including social interaction anxiety and performance anxiety, which differ in their cognitive characteristics and may arise through different developmental pathways. Previous research has identified parental psychological control as an important risk factor for social anxiety and has linked rejection sensitivity and dysfunctional perfectionism to social anxiety symptoms. However, little is known about whether different forms of parental psychological control contribute to distinct social anxiety subtypes through different cognitive mechanisms. Addressing this gap, the present study examined whether rejection sensitivity and dysfunctional perfectionism differentially mediate the relationships between dependency-oriented and achievement-oriented psychological control and social interaction anxiety and performance anxiety. Using a cross-sectional design, 189 Korean college students completed validated self-report measures of parental psychological control, rejection n sensitivity, dysfunctional perfectionism, and social anxiety. Mediation effects were examined using regression analyses, Sobel tests, and multiple mediation analyses. The results indicated that rejection sensitivity partially mediated the relationship between dependency-oriented psychological control and social interaction anxiety. In contrast, achievement-oriented psychological control influenced performance anxiety through both dysfunctional perfectionism and rejection sensitivity, with dysfunctional perfectionism showing the stronger indirect effect. Furthermore, dependency-oriented psychological control was more strongly associated with rejection sensitivity, whereas achievement-oriented psychological control was more strongly associated with dysfunctional perfectionism, supporting distinct developmental pathways for the two social anxiety subtypes. These findings extend previous research by demonstrating that different forms of parental psychological control contribute to different cognitive vulnerabilities underlying social anxiety. The findings suggest that interventions may be more effective when tailored to social anxiety subtype by targeting rejection sensitivity in individuals with social interaction anxiety and dysfunctional perfectionism in those with performance anxiety. However, because the study employed a cross-sectional design and relied exclusively on self-report measures, causal inferences cannot be drawn, and the generalizability of the findings may be limited. Full article

Diffuse large B-cell lymphoma (DLBCL), the most prevalent subtype of non-Hodgkin lymphoma (NHL), is an aggressive and fairly heterogeneous group with diverse clinical, pathological, and molecular features. Despite the success of first-line immunochemotherapy, relapsed or treatment-resistant forms remain a clinical challenge. Consequently, minimally invasive markers are needed to predict refractoriness. Recently, circulating microRNAs (miRNAs) have emerged as highly stable, promising biomarkers. MiRNAs such as miR-21, miR-155, miR-222-3p, and the miR-17~92 cluster act as oncogenes that promote tumor survival, while others, such as miR-34, miR-181a, miR-144, miR-101, miR-10a, and miR-320, act as tumor suppressors. Despite multiple recent publications that have correlated dysregulated miRNAs with diagnostic and prognostic importance, the clinical translation has not been fully addressed. Overall, this review provides an updated perspective on the potential of miRNAs in DLBCL and outlines key challenges and future directions for their integration into precision oncology, as miRNAs can remodel the clinical management of DLBCL by enabling earlier diagnosis, improved prognostication, and personalized treatment approaches. Full article

Fatty acid-binding proteins (FABPs) are a family of intracellular lipid chaperones that transport fatty acids and other hydrophobic molecules, playing essential roles in cellular lipid metabolism, signaling, and brain function. Within the central nervous system, FABP3, FABP5, and FABP7 facilitate the trafficking of long-chain polyunsaturated fatty acids and endocannabinoids, thereby modulating key regulatory pathways including the endocannabinoid system (ECS), peroxisome proliferator-activated receptor (PPAR) signaling, and dopaminergic neurotransmission. Peripherally, FABP1 and FABP4 contribute to hepatic drug metabolism, kidney excretion, and inflammatory processes in both tissues, with implications for the pharmacokinetics of substances of abuse. This narrative review synthesizes the current literature on FABPs and their involvement in substance use and addiction-related behaviors. Evidence from transgenic knockout models, pharmacological inhibition studies, and adeno-associated virus vector approaches demonstrates that manipulation of FABP subtypes can alter reward-related behaviors across multiple substances, including THC, ethanol, nicotine, and cocaine. Reduction or knockout of FABP7 alters THC metabolite levels in a sex-dependent manner. FABP3 shows involvement with dopamine receptor expression; however, interaction between FABP3 modulation and specific substances has sparsely been investigated. FABP5 has vastly diverging interactions with addictive behavior and appears to be substance dependent, as downregulation reduces cocaine self-administration, but knockout enhances nicotine conditioned place preference (CPP) and increases brain uptake of THC. Combined deletion of FABP5 and 7 additionally reduces cocaine CPP and reinstatement, while showing promising decreases in ethanol consumption paradigms. FABPs may be a potential therapeutic target for treating substance use disorders and underlying reward deficiency mechanisms underlying addiction and further research is required to elucidate specific mechanistic effects and eliminate potential adverse consequences of chronic FABP modulation. Full article

Background/Objectives: Functional outcomes after digitally planned mandibular fracture repair remain incompletely characterized. This study estimated the 12-month frequency of clinician-recorded temporomandibular disorder (TMD) and examined its associations with condylar injury and clinical findings documented at 3 months. Methods: This single-center retrospective cohort included patients treated between September 2021 and June 2023. Of 139 patients eligible after criterion review, 18 (12.9%) lacked an observed 12-month outcome and 121 were analyzed. The endpoint was the treating-team clinical diagnosis after structured symptom review and examination; preserved records did not support full Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) Axis I decision rules, subtype assignment, or Axis II instruments. Associations with condylar involvement were estimated using modified-Poisson regression with robust variance; the adjusted model included age, sex, and displacement grade. Associations with 3-month findings were exploratory and multiplicity-controlled. Results: Thirty-three of 121 patients had clinician-recorded TMD at 12 months (27.3%; 95% confidence interval [CI], 20.1–35.8%). TMD occurred in 27 of 47 patients with condylar involvement (57.4%) and 6 of 74 without it (8.1%; risk ratio [RR], 7.09; 95% CI, 3.17–15.86). The adjusted RR was 6.87 (95% CI, 3.06–15.41), with similar results when displacement grade was categorical. Malocclusion, TMJ clicking, TMJ pain, abnormal opening pattern, limited mouth opening, and unilateral chewing at 3 months remained associated after correction (all q ≤ 0.003). Conclusions: Clinician-recorded TMD was concentrated among patients with condylar injury. Associations with early functional abnormalities may reflect persistence or recurrence because several findings overlap with the later endpoint. These data support closer functional surveillance but do not establish causality, independent prediction, or the comparative effectiveness of digital planning. Full article