Invasive candidiasis (IC) is a severe infection primarily affecting immunocompromised patients and is associated with high mortality and substantial hospital costs. Accurate regional data on epidemiology and antifungal resistance of IC are crucial for effective clinical management. The China Hospital Invasive Fungal Surveillance Net (CHIF-NET) study is a laboratory-based multicenter study initiated in August 2009. This report presented updated data from August 2017 to December 2021, involving 76 hospitals across 28 provincial regions in China, and included a 12-year longitudinal analysis. Isolates from patients with IC were assigned to species level by matrix-assisted laser desorption ionization-time of flight mass spectrometry and internal transcribed spacer rDNA sequencing. Susceptibility testing was performed for nine antifungal agents using the broth microdilution method. A total of 11,679 Candida isolates were collected. Candida albicans was the most common Candida species (46.0%), followed by Candida tropicalis (17.6%), Candida parapsilosis sensu stricto (15.6%), and Candida glabrata sensu stricto (11.2%). Antifungal resistance rates showed notable variations among different Candida species, with the highest azole resistance observed in C. tropicalis isolates causing candidemia (42.5% to fluconazole and 38.9% to voriconazole). Cross- and multi-drug resistance to azoles and echinocandins was observed in all predominant Candida species. The species distribution of major Candida pathogens causing IC remained stable in China, while antifungal resistance increased, especially among non-albicans Candida species. Enhanced surveillance, accurate species identification, and strengthened antifungal stewardship are needed to address the growing challenge of antifungal resistance.

ABSTRACT Purpose: To evaluate the role of ultra-widefield Fundus fluorescein angiography (UWF-FFA) in patients with Takayasu Arteritis (TA) and its superiority over conventional 7-field FFA in detecting Takayasu retinopathy (TR) changes.Methods: In this prospective observational study, TA patients with Takayasu Retinopathy (TR) who underwent UWF-FFA were enrolled. Standard 7 × 30° ETDRS fields representing conventional imaging were superimposed over the UWF-FFA images. Additional retinal findings captured by UWF-FFA beyond the 7 standard fields were recorded, and their impact on clinical management was noted.Results: Seventy-eight eyes of 39 patients (mean age: 31.31 ± 10 years; 87% female) were included. On UWF-FFA, TR was graded as stage 4 in 5(6.4%) eyes; stage 3 in 33(42.3%), stage 2 in 11(14.1%), stage 1 in 7(9%) eyes, and 22(28.2%) eyes showed no retinopathy. By comparison, conventional imaging detected stage 4 in 4(5.1%) eyes, stage 3 in 1(1.3%), stage 2 in 17(21.8%), stage 1 in 33(42.3%), and 23(29.5%) eyes were normal. UWF-FFA resulted in an increase in detected retinopathy stage in 41 eyes (52.6%, p < 0.05). Notably, UWF-FFA revealed peripheral capillary non-perfusion (CNP) in 28 (35.9%) eyes and neovascularization in 1(1.3%) eye, findings that were missed on conventional fields. These additional findings guided laser photocoagulation treatment in those 28 eyes(35.9%), interventions that would have been missed without UWF imaging.Conclusion: UWF-FFA provided significant additional diagnostic information in over one-half of eyes, enabling detection of advanced retinopathy and guiding timely treatment in 36% of eyes. UWF-FFA should be considered for all patients with TA to improve the detection and management of Takayasu retinopathy.

Effective myocardial regeneration following infarction remains a major clinical challenge due to the complex and dynamic pathological microenvironment. Current clinical management fails to adequately modulate the dynamic infarct microenvironment, where dysregulated inflammation and insufficient angiogenesis represent key therapeutic targets. To address this challenge, we developed a spatiotemporally coordinated microneedle (MN) patch based on curcumin-conjugated gelatin methacrylate (Cur-GelMA) hydrogel for co-delivery of curcumin and stromal cell-derived factor-1α (SDF-1α). The engineered Cur-GelMA network significantly enhanced curcumin solubility and bioavailability, while PDMS micromolding enabled fabrication of mechanically robust MN patches. This integrated system provides rapid, reactive oxygen species-responsive curcumin release along with sustained SDF-1α delivery, achieving spatially targeted penetration and localized drug deposition in the infarcted myocardium. In vitro studies demonstrated that curcumin-hydrogel effectively reprogrammed macrophage polarization from pro-inflammatory M1 to reparative M2 phenotype, downregulating pro-inflammatory cytokines while upregulating anti-inflammatory cytokine. Simultaneously, sustained SDF-1α release promoted endothelial cell proliferation, migration, and tube formation via VEGF pathway activation. In a rat MI model, the SDF-1α@Cur-MN patch significantly improved recovery of cardiac function, attenuated fibrosis, enhanced M2 macrophage infiltration, and promoted mature neovessel formation. This dual-target MN system provides a coordinated approach to regulating inflammation and angiogenesis, demonstrating therapeutic potential for myocardial repair.

A triamcinolone acetonide palmitate nanoemulsion eye drop delivered by iontophoresis for the management of posterior uveitis.

Comparative Effect of Non-surgical Versus Surgical Therapy for Stage III/IV Periodontitis: A Retrospective Cohort Study.

High-Risk Human-AI Engagement: Clinical Assessment and Management Considerations.

To investigate alterations in brain pain-processing networks using resting-state functional magnetic resonance imaging (rs-fMRI) in women with endometriosis-associated chronic pelvic pain and to evaluate neurobiological evidence of central sensitization relevant to clinical management. This retrospective study included 30 women aged 18-45 years: 10 with deep infiltrating endometriosis (DIE) and chronic pelvic pain, 10 with ovarian endometriomas without pain, and 10 healthy controls. rs-fMRI data were analyzed using the SPM12 and the CONN toolbox. Seed-to-voxel functional connectivity analyses focused on predefined pain-related brain regions. Between-group differences were assessed using two-sample t tests with family-wise error (FWE) correction. Compared with controls, women with DIE and chronic pelvic pain demonstrated significantly increased connectivity between the amygdala and the right frontal pole (FWE-corrected P = 0.012 and 0.044), left paracingulate gyrus (FWE-corrected P = 0.036), right frontal operculum cortex (FWE-corrected P = 0.040), and anterior cingulate gyrus (FWE-corrected P = 0.044). Increased con was also observed between the posterior cingulate gyrus and the precuneus cortex (FWE-corrected P = 0.002), whereas decreased connectivity was detected between the anterior cingulate gyrus and the posterior left middle temporal gyrus (FWE-corrected P = 0.002). No significant differences were found in patients with ovarian endometriomas without pain. Endometriosis-associated chronic pelvic pain is associated with altered connectivity within key pain modulation networks, supporting central sensitization. Persistent pelvic pain may therefore reflect maladaptive central pain processing in addition to peripheral pathology. Recognition of these neurofunctional alterations may improve understanding of treatment-resistant pain and support earlier multidisciplinary and individualized management strategies.

Miller Fisher syndrome is a rare and challenging condition to diagnose. This article presents the case of a patient with severe and rapidly progressing symptoms who was initially misdiagnosed with cerebral infarction. Following methylprednisolone treatment, the patient's prognosis improved significantly. The patient was a 63-year-old east Asian female farmer who was admitted with complaints of "dizziness, double vision, and unsteady gait for 14hours." She subsequently developed respiratory distress, requiring ventilatory support and experienced a drop in blood pressure, which was managed with vasopressors. Initially misdiagnosed as having cerebral infarction, she received treatment with 3-butylphthalide, aspirin, and atorvastatin, but her symptoms did not improve. Serum tests were positive for anti-GQ1b and anti-GT1aIgG antibodies. This, combined with her history of a preceding infection and the presence of the clinical triad (ophthalmoplegia evidenced by diplopia and nystagmus, ataxia evidenced by unsteady gait and incoordination, and areflexia/hyporeflexia evidenced by absent pharyngeal reflex and diminished tendon reflexes), led to a final diagnosis of Miller Fisher syndrome (anti-GQ1b antibody-positive). Following treatment with methylprednisolone, her symptoms improved significantly. This report not only shares valuable clinical management experiences related to Miller Fisher syndrome, but also aims to enhance readers' understanding of the condition. Furthermore, this case is noteworthy as it documents the emergence of life-threatening symptoms such as respiratory distress and hypotension, which are atypical for Miller Fisher syndrome and highlight the potential for severe disease progression.

The rising incidence of early-onset colorectal cancer has renewed attention to colorectal adenomas in adolescents and young adults (AYA), although these lesions remain rare and poorly characterized in adolescents. Lack of age-specific guidance creates uncertainty regarding genetic evaluation, surveillance intervals, and long-term management when these lesions are identified in adolescents. This narrative review synthesizes current evidence and expert perspective on epidemiology, evaluation, endoscopic management, surveillance, genetic considerations, and psychosocial implications of incidentally identified colorectal adenomas across the AYA spectrum, with emphasis on adolescents as a distinct clinical population. Available data largely derive from adults aged 20-49 years but suggest that adenomas in adolescents are uncommon and more likely to prompt evaluation for hereditary colorectal cancer syndromes. Accordingly, adolescents with incidental colorectal adenomas should be referred for genetic counseling, with consideration of multigene panel testing, even in the setting of isolated lesions. Endoscopic management generally parallels adult practice, and young age alone does not appear to increase risk of metachronous advanced neoplasia. These findings support guideline-concordant surveillance without routine interval shortening when accurate polyp size assessment and confident complete resection are achieved, although adolescent-specific evidence remains limited. We propose a pragmatic clinical management algorithm integrating adenoma features, genetic risk assessment, and surveillance planning to support consistent, evidence-informed care in this understudied population.

Female sterilization is one of the most commonly adopted permanent methods of contraception worldwide and is generally considered highly effective. Despite its low failure rate, pregnancy can occur following sterilization, and such pregnancies are associated with a disproportionately higher risk of ectopic implantation. Ectopic pregnancy after sterilization often presents diagnostic challenges, as prior sterilization may lead to a false sense of security and delayed clinical suspicion, thereby increasing the risk of tubal rupture and maternal morbidity. To describe the clinical presentation, diagnostic evaluation, management strategies, and maternal outcomes of ectopic pregnancies occurring after tubal sterilization. This case series includes four women with a previous history of tubal sterilization who were diagnosed with ectopic pregnancy at Vinayaka Mission's Kirupananda Variyar Medical College and Hospitals. Detailed clinical information, including age, parity, method and timing of sterilization, presenting symptoms, diagnostic findings, site of ectopic pregnancy, treatment approach, and outcomes, was collected and analyzed. Diagnosis was confirmed using urine pregnancy testing, serum beta human chorionic gonadotropin levels, and transvaginal ultrasonography. All cases were managed surgically and followed through the postoperative period. All four women presented with lower abdominal pain with or without amenorrhea. The interval between sterilization and occurrence of ectopic pregnancy ranged from 1 to 8 years. Tubal ectopic pregnancy was identified in all cases, with one patient presenting in a ruptured state requiring emergency surgical intervention. Timely diagnosis and appropriate surgical management resulted in favorable maternal outcomes in all cases, with no major postoperative complications. Ectopic pregnancy can occur even several years after tubal sterilization and should always be considered in women of reproductive age presenting with abdominal pain or menstrual irregularities, regardless of sterilization history. Maintaining a high index of clinical suspicion and ensuring early diagnostic evaluation are crucial for preventing maternal morbidity and achieving optimal outcomes.

Abstract Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that primarily affects the colon. Among its extraintestinal complications, cerebral venous sinus thrombosis (CVST) is a rare yet potentially life-threatening emergency that can manifest as headaches, seizures, and/or neurological deficits. This review aims to characterize the clinical presentation, diagnostic modalities, and management strategies for CVST in UC patients. A comprehensive search of case reports and series yielded 1,156 studies, of which 39 met the inclusion criteria. A total of 47 patients were identified; the majority of whom were adult males (33.3%) and commonly presented with headaches (67.4%). Multi-symptom presentations were more prevalent in adults (66%; p = 0.038) and were often associated with UC flare-ups (56.4%). Patients with multiple symptoms had a higher frequency of straight and sphenoid sinus involvement compared with those with an isolated symptom (p &lt; 0.001). Anemia was correlated with poorer clinical outcomes (p = 0.009). Computed tomography (CT) was the most frequently used initial imaging modality, whereas magnetic resonance imaging (MRI) was more sensitive. Anticoagulation therapy with low-molecular-weight heparin and warfarin, alongside endovascular thrombectomy in select cases, was effective in improving outcomes. This review underscores the importance of early recognition, MRI-based imaging, and timely anticoagulation to improve outcomes in UC-associated CVST.

Recent studies have demonstrated a greater prevalence of coronary atherosclerosis in male masters endurance athletes, but the underlying contributors remain unclear. We explored the relationship between occult resting and exercise-induced hypertension with coronary atherosclerosis characteristics. 198 male masters endurance athletes with a low Framingham risk score (<10%) and no clinical diagnosis of hypertension underwent 24-hour ambulatory blood pressure (ABP) monitoring and exercise BP assessment. Coronary CT angiography assessed coronary artery calcification (CAC) score, luminal stenosis and high-risk plaque features. Seventy-eight (39%) athletes were hypertensive on ABP monitoring and 93 (47%) demonstrated a hypertensive response to exercise. A CAC score of 1-99 Agatston units (AU), 100-399 AU and ≥400 AU was present in 94 (47%), 32 (16%) and 15 (8%) athletes, respectively. Twenty-four (12%) athletes had coronary stenoses >50%. Sixty-two athletes (31%) had calcified plaque, 32 (16%) had mixed plaque, 2 (1%) had non-calcified plaque and 26 (13%) had markers of high-risk plaque. Hypertension on ABP monitoring was significantly associated with a CAC score ≥100 AU (OR: 2.56; 1.08 to 6.04) and coronary stenosis >50% (OR: 2.92; 1.17 to 7.33). A hypertensive response to exercise was significantly associated with coronary stenosis >50% (OR: 4.72; 1.65 to 13.5) and the presence of high-risk plaque (OR: 3.27; 1.27 to 8.43). Masters male endurance athletes have a high prevalence of occult hypertension, which is associated with high-risk features of coronary atherosclerosis. Both ambulatory and exercise-induced hypertension are associated with a higher prevalence of atherosclerotic coronary artery disease in male endurance athletes. Early identification and timely clinical management of this classic cardiovascular disease risk factor may reduce the burden of coronary atherosclerosis in athletes.

Sickle cell disease (SCD) is a hereditary hemoglobinopathy associated with various cerebrovascular complications. Although ischemic stroke is the most common manifestation, subarachnoid hemorrhage (SAH) secondary to ruptured intracranial aneurysms represents a rare but life-threatening condition in this population. Data regarding the optimal management of aneurysmal SAH in SCD patients remain limited. We retrospectively analyzed eight patients with confirmed SCD who were diagnosed with aneurysmal SAH and treated at a tertiary referral center. Clinical severity was assessed using the Glasgow Coma Scale (GCS), World Federation of Neurosurgical Societies (WFNS) grade, Hunt-Hess grade, and Fisher score. Aneurysm characteristics, including size, location, and multiplicity, were recorded. All patients underwent endovascular coil embolization. Hematologic parameters and peri-procedural multidisciplinary management strategies were reviewed. Aneurysm occlusion status was evaluated using the Raymond-Roy Occlusion Classification (RROC) at 6-month follow-up. A total of 11 aneurysms were identified in 8 patients (mean age: 34.5 years; 5 males, 3 females). Three patients (37.5%) had multiple aneurysms. Six aneurysms (54.5%) were located in the anterior circulation and five (45.5%) in the posterior circulation. Four patients (50%) developed clinical and radiological vasospasm requiring intra-arterial therapy. All aneurysms were successfully treated with endovascular coiling. At discharge, modified Rankin Scale (mRS) scores ranged from 0 to 6. At 6-month follow-up, complete occlusion (RROC Class I) was achieved in the majority of treated aneurysms. Multidisciplinary perioperative management, including hematology consultation and transfusion strategies, was applied in all cases. Ruptured intracranial aneurysms in patients with SCD require careful multidisciplinary management due to disease-specific hematologic and vascular risks. Endovascular coil embolization appears to be a safe and effective treatment modality in this population. Early aneurysm securing combined with optimized hematologic management may improve clinical outcomes and reduce procedure-related complications.

Acute limb ischemia (ALI) is a medical emergency that can be due to prolonged tourniquet application, peripheral arterial disease, arterial embolization, and/or arterial thrombosis. To prevent associated morbidity and mortality, ischemia time should be minimized by urgent or emergent revascularization. However, revascularization can lead to ischemia-reperfusion injury (IRI), a devastating complication that can cause limb loss, multi-organ failure, and/or death. Currently, management of IRI largely relies on preventative measures and supportive care. In Part 2 of this two-part review article, we will briefly review the pathophysiology of IRI discussed in Part 1, and then discuss contemporary interventions to perfuse an acutely ischemic limb, clinical strategies that have been used to reduce and/or prevent IRI, and lastly, randomized controlled trials that have investigated pharmacological interventions to neutralize or mitigate IRI toxicity.

Fungal endophthalmitis (FE) is a vision-threatening emergency that requires rapid pathogen identification. Conventional microbial culture demonstrates limited sensitivity in FE, warranting improved diagnostic approaches. We evaluated the detection performance of unbiased metagenomic next-generation sequencing (mNGS) in 31 clinically diagnosed FE cases, including 16 vitreous humor (VH) and 15 aqueous humor (AH) specimens. mNGS showed a positivity rate of 90.3% (28/31, 95% CI: 74.2%-98%), outperforming culture (9.1%, 2/22, 95% CI: 1.1%-29.2%). The positivity rates were 100% for endogenous FE and 85% for exogenous FE, while VH and AH specimens achieved 100% and 80% positivity, respectively. mNGS identified polymicrobial infections in 5 exogenous cases, and a total of 15 fungal species across 9 genera, dominated by Aspergillus flavus, Candida albicans, and Aspergillus niger. Candida albicans and Aspergillus flavus were the predominant pathogens in endogenous and exogenous FE, respectively. Notably, mNGS enabled detection of rare fungal species including Aspergillus niger, Aspergillus welwitschiae, Fusarium oxysporum, Memnoniella echinata, Rhizopus oryzae, Rhizopus microsporus, Chaetomium globosum, and Debaryomyces fabryi. Sequencing results were supported or supplemented by culture, beta-D-glucan, and galactomannan testing in selected cases. Among mNGS-positive cases, 82.1% (23/28) experienced clinical management changes guided by fungal identification. We further propose a laboratory workflow integrating mNGS with conventional assays, tailored to the obtained specimen volume of intraocular fluids.

Abstract Diffuse axonal injury (DAI) is a frequent and devastating form of traumatic brain injury (TBI) that requires prolonged intensive care and carries high morbidity and mortality. Early magnetic resonance imaging (MRI) lesion topography may offer crucial prognostic information to guide clinical management and family counseling. The objective of this is to evaluate the prognostic value of early MRI-based lesion location in DAI using the novel KASHI Classification and to correlate lesion topography with acute neurological severity, in-hospital mortality, and long-term functional recovery. In this single-center prospective cohort study, 91 patients with DAI (from 734 TBI admissions) underwent standardized MRI (T1, T2, FLAIR, diffusion-weighted imaging, gradient echo ± diffusion tensor imaging) on Day 1 postinjury. Lesions were graded 1–3C according to the KASHI schema based on their anatomical distribution. Clinical severity was assessed by the Glasgow Coma Scale (GCS) at admission, and outcomes included in-hospital mortality, duration of post-traumatic amnesia (PTA), and 6-month functional status measured by Glasgow Outcome Score and Rancho Los Amigos Scale. Higher KASHI grades were strongly associated with worse acute and long-term outcomes. Grade 3C lesions (pontine, medullary, cerebellar peduncle, or intraventricular hemorrhage) corresponded to the lowest mean GCS scores and a 68 % in-hospital mortality rate. Lesions of the thalamus and basal ganglia independently predicted prolonged PTA and poorer 6-month functional recovery. The KASHI Classification demonstrated high interrater reliability and outperformed total lesion volume models in early prognostication. Early MRI lesion topography, as stratified by the KASHI Classification, provides a simple, reliable framework for predicting neurological severity and recovery in DAI. Its application in acute TBI care can enhance prognostic accuracy and inform clinical decision-making. Further multicenter validation and integration with automated imaging analytics are warranted.

Pituitary neuroendocrine tumours (PitNETs) exhibit significant heterogeneity, posing challenges for clinical management. We developed a deep learning model to predict PitNET lineage, high-risk subtypes, and recurrence directly from routine H&E-stained whole-slide images. Trained on 925 patients from USTC and externally validated on cohorts from Taihe Hospital (n = 226) and Huashan Hospital (n = 193), the model achieved a micro-average AUC of 0.912 for lineage classification (SF1: 0.926, PIT1: 0.932, TPIT: 0.904; Without distinct lineage: 0.706). High-risk subtype prediction yielded AUCs of 0.805 (PIT1), 0.753 (TPIT), and 0.733 (null cell). Recurrence prediction reached an AUC of 0.641. Analysis of the tumour microenvironment revealed that compared with primary tumours, recurrence tumours were characterized by an increased density of M2 macrophages and decreased infiltration of CD8 + T cells. Spatial transcriptomics further elucidated distinct molecular pathways associated with recurrence, providing mechanistic insights into prognostic predictions. Our deep learning model accurately predicts PitNET characteristics from routine H&E slides, and spatial biology validation identified distinct immune and molecular features associated with recurrence.

Considerable advances in the prevention and treatment of traumatic spinal cord injury (SCI) have been made in the last 3 decades; hence, it can be assumed that the groups at risk, etiology, and characteristics of SCI have evolved in tandem. The objective of this study was to analyze SCI data to discern changes in patient demographics, etiology, and characteristics of injury over the last 3 decades. Data from 5 multicenter, prospective sources were combined to create a dataset representing the period from 1991 to 2020. The data were divided into 3 decades; 1991-1999, 2000-2009, and 2010-2020. The analyzed variables included patient age, sex, etiology, baseline injury severity based on the American Spinal Injury Association Impairment Scale (AIS), surgery, and timing of surgery. One-way ANOVA was performed to examine the association between patient age and decade, whereas chi-square tests were used to assess the association of sex, etiology, surgery, timing of surgery, and baseline severity with decade. Further analyses were done using univariate and multivariate regression to evaluate the relationship between age and sex, etiology, and decade. The overall dataset included 2642 patients. From the 1990s to the 2010s, the mean age increased independent of changes in etiology (p < 0.001), the frequency of injuries related to falls increased from 20.6% to 42.1% (p < 0.0001), and the frequency of SCIs related to motor vehicle collision decreased from 50.4% to 39.1% (p < 0.0001). Significant changes were observed when examining injury severity between the 1990s and 2010s: the percentage of complete SCI (AIS grade A) decreased from 58.3% to 49.8%, the percentage of incomplete SCI (AIS grades B, C, and D) increased from 41.7% to 50.2%, and the percentage of central cord syndrome increased from 33.7% to 54.7%. The percentage of patients undergoing surgical treatment increased from 73.8% to 96.8% (p < 0.0001), and the proportion that underwent early surgery increased from 20.6% to 43.9% (p < 0.0001). The changes in the demographics, etiology, and characteristics of SCI reflect a combination of an aging population, an increased public awareness of neurotrauma, and enhanced clinical management of older patients. These findings have implications for further research and the optimization of primary and secondary injury prevention strategies.

This systematic review, the first in this field, aimed to evaluate if interventions for dentin hypersensitivity (DH) affect patient-reported oral health-related quality of life (OHRQoL). A systematic search was conducted across seven electronic databases and gray literature sources, focusing on interventional studies published from 2010 onward. Eligible studies included adult participants with DH and assessed OHRQoL using validated measures. Data extraction followed the PRISMA guidelines. Risk of bias was appraised using the JBI tool. Thirteen randomized controlled trials involving 616 participants were included. Interventions ranged from desensitizing agents, fluoride varnishes, and laser therapy to nonpharmacological approaches like behavioral techniques. QoL was measured primarily using OHIP-14 and DHEQ-15 tools. The certainty of evidence was rated as very low due to risks of bias, inconsistency, and imprecision. Key findings from this review can help shape the way we understand, quantify, and explore QoL in patients diagnosed with DH. Although several interventions showed promise in reducing DH symptoms and improving QoL, the current evidence base is methodologically limited and inconsistent. High-quality studies using standardized, validated patient-reported outcome measures are needed. Clinical management of DH should incorporate assessment of OHRQoL to guide holistic, patient-centred care.

Tobacco use, alcohol consumption, and infection with human papilloma virus (HPV) are well-established risk factors for head and neck squamous cell carcinomas (HNSCC). However, the incidence of oral cancer, particularly in the mobile tongue, has been rising in non-smoker/non-drinker and HPV-negative patients, suggesting the emergence of a new clinical entity. To understand in molecular terms this subtype of oral cavity squamous cell carcinomas (OCSCC) with no-identified risk factor (NIRF), we analyzed the available public head and neck cancer multi-omics data. We identified mutational signatures that stratified 253 OCSCC and 94 laryngeal cancer cases, used as tobacco-only-related controls, according to their clinico-pathological characteristics. We show that tobacco, depending on the anatomical site, triggers distinct mutational processes and further demonstrate that the single-base-substitution (SBS) signature SBS16 in OCSCC is associated with tobacco smoking, reflecting the combined effects of smoking and drinking. Importantly, we identified a tongue cancer-enriched NIRF OCSCC subgroup exhibiting significantly increased endogenous clock-like mutagenesis, while another NIRF subgroup manifested with elevated apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC)-associated mutagenesis. Both NIRF OCSCC subgroups harbored specific cancer driver mutations and distinct methylation patterns, which differed from those observed in OCSCC linked to traditional HNSCC risk factors, reflecting unique molecular programs underlying disease development. Specifically, NIRF-OSCC exhibited pronounced immune evasion strategies and antimicrobial transcriptomic responses. Our study presents the first molecular and genomic characterization of the emerging NIRF OCSCC subtype likely driven by increased endogenous mutagenesis and responses to microbial insults. These findings warrant future detailed investigations into etiology and have implications for clinical management and cancer prevention.