Port-Wine Stains and Intraoral Hemangiomas: A Case Series.

Port-wine stains (PWSs), also called port-wine birthmarks or nevus flammeus, are hamartomatous vascular capillary malformations that clinically appear as erythematous areas on the buccal mucosa, vermilion border of the lip, gingiva, or pink to port-wine-colored patches on skin since birth and persist throughout life. On the face, they occur in the area supplied by the trigeminal nerve. PWSs have structural abnormalities of the intradermal capillaries. PWSs on the skin and oral mucosa contain ectatic capillaries in the dermis and submucosa, respectively. PWSs occur anywhere, and the oral mucosa is no exception. PWSs on the facial skin lead to cosmetic disfigurement and create social stigma. Clinically, PWSs start as flat, pink, or red patches and may darken, thicken, and develop nodules over time. The diagnosis of PWSs is primarily clinical. PWSs are complex vascular malformations with significant clinical, psychosocial, and therapeutic challenges. This article enlightens a series of cases of PWSs on the facial skin and capillary hemangioma on the gingiva, buccal mucosa, and lip diagnosed by a diascopy test, etiopathogenesis, differential diagnosis, and management of PWSs.

Surgical Technique for Compartmental Resection of T4b Gingivobuccal Cancer.

Management of advanced gingivo-buccal complex cancers involving the masticatory space (T4b) is often managed by compartment resection. The oncological safety of the procedure is now clearly established. Based on the origin and epicenter of the tumor there are two classes of compartmental resection. Those tumors arising from the tuberosity of the maxilla and/or upper gingival sulcus region; the resection involves the tumor, posterior maxilla, and the ipsilateral infratemporal fossa. These tumors can be resected by mandibulotomy approach, preserving the mandible. This constitutes class-1 infratemporal fossa resection. The class-2 infratemporal fossa resection is applied for those tumors arising from the retromolar trigone and/or lower gingivo-buccal sulcus region. In this class, the mandible and often the overlying cheek skin needs to be sacrificed, in addition to the contents of the infratemporal fossa and the posterior maxilla. Both the classes of resections are carried out in an orderly fashion following well-defined steps. These sequential steps maximize the exposure of inaccessible structures, enables protection of critical structures as well as minimizes blood loss. This manuscript describes the surgical steps for the two classes of compartmental resection of the infratemporal fossa for advanced gingivo-buccal complex cancers involving the masticatory space.

Evaluating the role of amino acids and isothermal dry particle coating in modulating buccal permeation of large molecule drug vancomycin.

The formulation and delivery of macromolecules through the oral route pose considerable challenges due to factors such as large molecular weight, pH sensitivity, and limited formulation approaches. This challenge is compounded if the drug is poorly permeable, necessitating innovative drug delivery strategies. Vancomycin, a widely prescribed glycopeptide antibiotic, has an oral bioavailability of less than 10%, leading to predominantly intravenous administration and potential patient discomfort. This study explores the potential of the buccal route as a non-invasive, highly vascularised alternative route of administration, offering a rapid onset of action while bypassing the first-pass metabolism. In this study, vancomycin was coated with L-glutamic acid using an isothermal dry particle coater to modulate permeation through the buccal cell line, TR146. Results confirm significant impact of both amino acid concentration and dry particle coating on the rate and extent of drug permeability. With the introduction of L-glutamic acid and utilisation of the isothermal dry particle coater, vancomycin's permeation profile increased six-fold compared to the control due to the formation of drug ion-pair complex. Imaging studies showed the presence of layered micronized glutamic acid particles on the surface of dry coated vancomycin particles which confirms the role of dry coating and amino acid concentration in modulating drug permeation. Microbiology experiments in Staphylococcus aureus, minimum inhibitory concentration and biofilm disruption studies, provided confirmatory evidence of antimicrobial activity of dry coated glutamic acid-vancomycin ion pair particulate structure. This study demonstrates, for the first-time, buccal delivery of dry coated large molecule drug, vancomycin, through controlled deposition of amino acid using innovative particle coating strategy.

Beyond Infancy: Unveiling the Rarity of Buccal Cavernous Hemangioma in a Young Adult Male.

Buccal cavernous hemangiomas are uncommon vascular lesions, particularly in adult patients. We present a case of a 23-year-old male with a progressive left cheek swelling over three years. Clinical examination and radiographic imaging revealed a solid, multilobulated mass in the left buccal and masticator spaces. Surgical excision was performed, and histopathological analysis confirmed the diagnosis of a cavernous hemangioma. This case underscores the importance of recognizing and appropriately managing rare vascular lesions in adult patients.

Post-surgical complications of supernumerary teeth in the mandibular premolar area: A systematic review.

In the mandibular premolar area, supernumerary teeth are a rare disorder that are rarely documented in the literature. The purpose of this study was to evaluate the post-surgical problems associated with the buccal and lingual techniques used to treat the extra teeth in this area. Using PubMed, PubMed Central, Science Direct, Cochrane, Wiley, and manual search, a thorough search was done to locate and identify cases and case series with extra teeth in the mandibular premolar region. For every study that was included, data on the surgical technique and postoperative problems were documented. Seven studies involving 90 patients were included. Supernumerary teeth in the mandibular premolar region were predominantly found in male patients (65.55 %), with most cases occurring in the right mandibular region (77.16 %). Postoperative complications after removing supernumerary teeth using buccal and lingual approaches were similar, with only one complication reported among the 90 cases reviewed. Although the findings suggest that surgical management of supernumerary teeth in the mandibular premolar region is relatively safe, caution is advised due to the limited sample size. Detailed pre-operative evaluation, a comprehensive treatment plan, and regular follow-up can minimize postoperative complications.

The spatial distribution of intermediate fibroblasts and myeloid-derived cells dictate lymph node metastasis dynamics in oral cancer.

BACKGROUND: Oral cancer poses a significant health challenge due to limited treatment protocols and therapeutic targets. We aimed to investigate the invasive margins of gingivo-buccal oral squamous cell carcinoma (GB-OSCC) tumors in terms of the localization of genes and cell types within the margins at various distances that could lead to nodal metastasis. METHODS: We collected tumor tissues from 23 resected GB-OSCC samples for gene expression profiling using digital spatial transcriptomics. We monitored differential gene expression at varying distances between the tumor and its microenvironvent (TME), and performed a deconvulation study and immunohistochemistry to identify the cells and genes regulating the TME. RESULTS: We found that the tumor-stromal interface (a distance up to 200 µm between tumor and immune cells) is the most active region for disease progression in GB-OSCC. The most differentially expressed apex genes, such as FN1 and COL5A1, were located at the stromal ends of the margins, and together with enrichment of the extracellular matrix (ECM) and an immune-suppressed microenvironment, were associated with lymph node metastasis. Intermediate fibroblasts, myocytes, and neutrophils were enriched at the tumor ends, while cancer-associated fibroblasts (CAFs) were enriched at the stromal ends. The intermediate fibroblasts transformed into CAFs and relocated to the adjacent stromal ends where they participated in FN1-mediated ECM modulation. CONCLUSION: We have generated a functional organization of the tumor-stromal interface in GB-OSCC and identified spatially located genes that contribute to nodal metastasis and disease progression. Our dataset might now be mined to discover suitable molecular targets in oral cancer.

Silent Invader: Cardiac Metastasis From Buccal Squamous Cell Carcinoma.

​Head and neck squamous cell carcinomas (HNSCC) are common malignancies that can metastasize to various distant sites. Cardiac metastasis (CM) from a primary HNSCC is an extremely rare finding that presents a significant challenge due to its association with a poor prognosis and limited treatment options. Due to their rare occurrence, there is no clear consensus on how to diagnose and manage such cases. In this article, we review a patient with complicated CM from buccal squamous cell carcinoma, which was incidentally detected by fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT).

Tailored Sticky Solutions: 3D-Printed Miconazole Buccal Films for Pediatric Oral Candidiasis.

In this research, 3D-printed antifungal buccal films (BFs) were manufactured as a potential alternative to commercially available antifungal oral gels addressing key considerations such as ease of manufacturing, convenience of administration, enhanced drug efficacy and suitability of paediatric patients. The fabrication process involved the use of a semi-solid extrusion method to create BFs from zein-Poly-Vinyl-Pyrrolidone (zein-PVP) polymer blend, which served as a carrier for drug (miconazole) and taste enhancers. After manufacturing, it was determined that the disintegration time for all films was less than 10 min. However, these films are designed to adhere to buccal tissue, ensuring sustained drug release. Approximately 80% of the miconazole was released gradually over 2 h from the zein/PVP matrix of the 3D printed films. Moreover, a detailed physicochemical characterization including spectroscopic and thermal methods was conducted to assess solid state and thermal stability of film constituents. Mucoadhesive properties and mechanical evaluation were also studied, while permeability studies revealed the extent to which film-loaded miconazole permeates through buccal tissue compared to commercially available oral gel formulation. Histological evaluation of the treated tissues was followed. Furthermore, in vitro antifungal activity was assessed for the developed films and the commercial oral gel. Finally, films underwent a two-month drug stability test to ascertain the suitability of the BFs for clinical application. The results demonstrate that 3D-printed films are a promising alternative for local administration of miconazole in the oral cavity.

Occupations and the risk of buccal mucosa cancer in Indian men: A multi-centre case-control study.

OBJECTIVE: This study aimed to investigate the association between lifetime occupational history and risk of buccal mucosa cancer (BMC). METHODS: We utilized a multi-centric, hospital-based case-control study across five centres of Tata Memorial Centre, Mumbai, India. Cases included men aged 20-75-years with histological confirmed primary cancer of the buccal mucosa. Visitor controls were frequency matched to cases for age (10 years interval) and current residential zone. Study participants were interviewed face-to-face. Logistic regression was performed to estimate odds ratio (OR) and 95 % confidence intervals (CI). RESULTS: Among ever employed males, we identified 1969 BMC cases and 2145 controls. We observed an increased risk of BMC in 'Craft and Related Trades Workers' (OR 1.37; 95 % CI 1.13-1.65), 'Plant and Machine Operators and Assemblers' (OR: 1.26; 95 % CI 1.01-1.56), and 'Elementary Occupations' (OR:1.33; 95 % CI 1.12-1.58). More specifically, the increased risk was observed for 'Metal, Machinery and Related Trades Workers', 'Handicraft and Printing Workers', 'Drivers and Mobile Plant Operators', and 'Laborers in Mining, Construction, Manufacturing and Transport'. CONCLUSION: Our findings suggest that certain occupations may be at a higher risk of BMC. Some fraction of BMC can be prevented by reducing exposure to hazardous agents used in these occupations. Further research is needed to identify which exposures are responsible for the increased risk. Moreover, tobacco control and early detection activities can be focused towards these occupations as tobacco consumption is also high in them, which may also be the reason for increased risk observed in these groups.

Role of buccal mucosa graft ureteroplasty in the surgical management of pyeloplasty failure.

Objective: Secondary pyeloplasty for recurrent ureteropelvic junction obstructions may be a safe and feasible surgical option for patients. This study aimed to demonstrate outcomes of utilizing a non-transecting buccal mucosa graft ureteroplasty for management of recurrent ureteropelvic junction obstruction after prior failed pyeloplasty. Methods: We performed a retrospective review of our Collaborative of Reconstructive Robotic Ureteral Surgery database for all consecutive patients who underwent buccal mucosa graft ureteroplasty between April 2012 and June 2022 for management of recurrent ureteropelvic junction obstructions after prior failed pyeloplasty. The primary outcome included surgical success which was defined as the absence of flank pain and no obstruction on imaging. Results: Overall, ten patients were included in our analysis. The median stricture length was 2.5 (interquartile range [IQR] 1.8-4.0) cm. The median operative time was 230.5 (IQR 199.5-287.0) min and median estimated blood loss was 50.0 (IQR 28.8-102.5) mL. At a median follow-up of 10.3 (IQR 6.2-14.8) months, 80% of patients were surgically successful and there were no major (Clavien-Dindo Grade>2) complications. Conclusion: Buccal mucosa graft ureteroplasty is a valuable non-transecting surgical option for patients with recurrent ureteropelvic junction obstructions who failed prior pyeloplasty and has comparable outcomes to the literature regarding standard transecting techniques.

Effect of high-flow nasal and buccal oxygenation on safe apnea time in children with open mouth: A randomized controlled trial.

BACKGROUND: High-flow nasal oxygenation is reported to prolong duration of apnea while maintaining adequate oxygen saturation with the mouth closed. Also, buccal oxygenation is known to have similar effects in obese adults. We compared the effect of these two methods on prolongation of acceptable apnea time in pediatric patients with their mouth open. METHODS: Thirty-eight patients, aged 0-10 years were randomly allocated to either the high-flow nasal oxygenation group (n = 17) or the buccal oxygenation group (n = 21). After induction of anesthesia including neuromuscular blockade, manual ventilation was initiated until the expiratory oxygen concentration reached 90%. Subsequently, ventilation was paused, and the patient's head was extended, and mouth was opened. The HFNO group received 2 L·min-1·kg-1 of oxygen, and the BO group received 0.5 L·min-1·kg-1 of oxygen. We set a target apnea time according to previous literature. When the apnea time reached the target, we defined the case as "success" in prolongation of safe apnea time and resumed ventilation. When the pulse oximetry decreased to 92% before the target apnea time, it was recorded as "failure" and rescue ventilation was given. RESULTS: The success rate of safe apnea prolongation was 100% in the high-flow nasal oxygenation group compared to 76% in the buccal oxygenation group (p = .04). Oxygen reserve index, end-tidal or transcutaneous carbon dioxide partial pressure, and pulse oximetry did not differ between groups. CONCLUSION: High-flow nasal oxygenation is effective in maintaining appropriate arterial oxygen saturation during apnea even in children with their mouth open and is superior to buccal oxygenation. Buccal oxygenation may be a good alternative when high-flow nasal oxygenation is not available.

IMMEDIATE SINGLE IMPLANT PLACEMENT WITH FLAPLESS SURGERY MAY BETTER PRESERVE BUCCAL BONE THAN FLAP SURGERY, BUT CLINICAL SIGNIFICANCE IS UNCLEAR.

ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Immediate implant placement with flap or flapless surgery: a systematic review and meta-analysis. Pitman J, Christiaens V, Callens J, Glibert M, Seyssens L, Blanco J, et al. J Clin Periodontol. 2023;50:755-64. SOURCE OF FUNDING: The present study was funded by the authors and their institutions. CONFLICT OF INTEREST: The authors have no actual or potential conflicts of interest. TYPE OF STUDY/DESIGN: Systematic review and meta-analysis.

Pre-vascular Facial Nodes: Sentinel Station for Metastasis in Gingivobuccal Complex Cancers.

BACKGROUND: Pre-vascular facial nodes (PV-FNs; perifacial lymph nodes) are supra-mandibular lymph nodes above the inferior border of the mandible. These are not part of routine neck dissection done for OCSCC. These lymph nodes can be sentinel station for metastatic lymph nodes from gingivobuccal complex cancers and are missed during routine neck dissection. It is imperative to include this sentinel station in routine neck dissection to prevent nodal recurrences. MATERIALS AND METHODS: One hundred thirty-seven patients with GBCC (T1-T4) were prospectively recruited between May 2020 and June 2022 with the intent to evaluate the incidence of PV-FN metastases and clinicopathological factors predicting them. RESULTS: PV-FN metastases were seen in 26 patients (18.9%; 26/137). The occult metastasis rate was 8.7% (12/137). On multivariate analysis, pathological T4 stage (pT4), LVE positivity, and intermediate-high BGS were statistically significant predictors of PV-FN metastases in our study. CONCLUSIONS: Incidence of PV-FN metastasis is high (18.9%) in GBCC, which can be potentially the first sentinel station in the lymphatic drainage pattern for this sub-site. Meticulous clearance of this nodal basin is of paramount importance during neck dissection to prevent nodal recurrences. LEVEL OF EVIDENCE: Level 2 (CEBM-Level of Evidence-2.1) Laryngoscope, 2024.

A Case of Oral-Buccal-Lingual Dyskinesia and Neuropsychiatric Symptoms After Prolonged Levetiracetam Exposure.

Tardive dyskinesia (TD) is a serious and often permanent complication usually seen after the long-term use of antipsychotic medications, and multiple other classes of medications have been reported to cause TD or TD-like syndromes. TD can affect any part of the body, but it most commonly affects the mouth, lips, and tongue. We present a case of oral-buccal-lingual dyskinesia in an 86-year-old female from the long-term use of levetiracetam for a seizure disorder. The patient was started on levetiracetam four years before admission and was noted to have an acute onset of oral-buccal-lingual dyskinesia that was so severe it interrupted the patient's speech and feeding. The patient's dyskinesias are completely resolved after cross-tapering levetiracetam 500 mg twice a day with valproic acid 750 mg daily. Additionally, there was a global recovery of the patient's mood and psychosis after the cross-taper. Our case highlights the potential implications of levetiracetam in dyskinetic movements and neuropsychiatric symptoms, and it warrants close monitoring of patients taking this medication especially elderly with multiple comorbidities and compromised renal function. Moreover, the case suggests the reversible nature of both neuropsychiatric symptoms and dyskinesias.

Intranasal Versus Buccal Versus Intramuscular Midazolam for the Home and Emergency Treatment of Acute Seizures in Pediatric Patients: A Randomized Controlled Trial.

BACKGROUND: Benzodiazepines are the recommended first-line treatment of acute seizures. We wished to compare the efficacy, side effects, and satisfaction after midazolam administration by the buccal, intranasal, or intramuscular route in the treatment of acute seizures in children at homes and in emergency room (ER). METHODS: A prospective, randomized, controlled trial was performed in children aged one month to 17 years with acute seizures lasting longer than five minutes. The primary end point was seizure cessation within 10 minutes of drug administration and no seizure recurrence within 30 minutes. RESULTS: In the home group, 67 patients received midazolam via buccal route, 60 via intranasal route, and 69 via intramuscular route, whereas in the ER group, 37 patients received buccal, 34 received intranasal, and 34 received intramuscular midazolam. The primary end point was achieved in 94.2% and 85.3% after intramuscular midazolam in the home and ER groups, respectively. The intranasal midazolam was successful in stopping seizures in 93.3% in the home group and 88.2% in the ER group. The buccal route was effective in 91% in the home group and 78.4% in the ER group. There were no significant differences in efficacy between all groups (P = 0.763 and P = 0.509) among the home and ER groups, respectively. There were no significant cardiorespiratory events in all groups. CONCLUSIONS: Intramuscular, intranasal, and buccal doses of midazolam resolved most seizures in prehospital and emergency settings. Our results indicate that there is no statistically significant difference detected between different routes of midazolam. Intranasal route showed the highest satisfaction rate among caregivers.

Buccal Administration of a Zika Virus Vaccine Utilizing 3D-Printed Oral Dissolving Films in a Mouse Model.

Over the years, research regarding the Zika virus has been steadily increasing. Early immunization for ZIKV is a priority for preventing complications such as microencephaly and Guillain-Barré syndrome (GBS). Unlike traditional vaccination approaches, oral dissolving films (ODFs) or mucoadhesive film technology is an emerging, exciting concept that can be used in the field of pharmaceuticals for vaccine design and formulation development. This attractive and novel method can help patients who suffer from dysphagia as a complication of a disease or syndrome. In this study, we investigated a microparticulate Zika vaccine administered via the buccal route with the help of thin films or oral dissolving films (ODFs) with a prime dose and two booster doses two weeks apart. In vitro, the ODFs displayed excellent physiochemical properties, indicating that the films were good carriers for vaccine microparticles and biocompatible with the buccal mucosa. In vivo results revealed robust humoral (IgG, subtypes IgG1 and IgG2a) and T-cell responses (CD4+/CD8+) for ZIKV-specific immunity. Both the Zika MP vaccine and the adjuvanted Zika MP vaccine affected memory (CD45R/CD27) and intracellular cytokine (TNF-α and IL-6) expression. In this study, ZIKV vaccination via the buccal route with the aid of ODFs demonstrated great promise for the development of pain-free vaccines for infectious diseases.

Increased infiltration of M2-polarized tumour-associated macrophages is highly associated with advanced disease stage and high expression of PD-L1 in buccal mucosa carcinoma.

OBJECTIVE: To assess the infiltration characteristics of tumour-associated macrophages (TAMs) in buccal mucosa carcinoma (BMC) and the correlation of these features with clinicopathological factors. MATERIALS AND METHODS: Immunohistochemistry was used to detect the expression of TAM-related markers (CD68, CD163, CD206), CD8+ T cell markers, PD-L1, and epidermal growth factor receptor (EGFR) in 46 patients with mucosal cancer after radical surgery. In addition, the correlation between TAM infiltration and clinical characteristics, PD-L1 expression, and EGFR expression was analysed. RESULTS: A high infiltration level of M2-polarized (CD206+) TAMs and M2-polarized (CD163+) TAMs was more common in stage T3-T4, N+, III-IV patients than in other patient groups (P < 0.05). The infiltration degree of M2-polarized (CD68+) TAMs was positively correlated with the PD-L1 TPS (P = 0.0331). The infiltration level of M2-polarized (CD206+) TAMs was higher in the EGFR high expression group than in the EGFR low expression group (P = 0.040). CONCLUSION: High infiltration of M2-polarized TAMs is highly associated with advanced disease stage and higher expression of PD-L1 and EGFR in BMCs, suggesting that M2-polarized TAMs infiltration can serve as a potential therapeutic target.

Serious treatment-emergent adverse events in chronic low back pain patients treated with buprenorphine or oral opioids: a retrospective commercial claims analysis.

Aim: Explore the safety of Belbuca® (buprenorphine buccal film), buprenorphine transdermal patches and oral opioids for chronic low back pain (cLBP) treatment. Methods: The retrospective analysis of the MarketScan Commercial database (2018-2021) included treatment-naive cLBP adults. The first date of buprenorphine (Belbuca and transdermal patch) or opioid prescription was index date. Cohorts were defined based on the index medication. Observation included a 6-month pre-index period, while post-index lasted until the end of continuous insurance coverage. There were 44 relevant treatment-emergent adverse events (TEAEs) identified in the literature. Incidence rate ratio (IRR) and incidence rate difference (IRD) were used to compare serious TEAE rates (in 1000 person-years) between cohorts. Propensity-score matching minimized the selection bias. Results: Buprenorphine had lower rates of 15 serious TEAEs than oral opioids (all p ≤ 0.037), while higher rates only for serious dizziness (IRR 2.44, p = 0.011; driven by Belbuca), opioid abuse/dependence (IRR 3.13, p = 0.004; driven by patches) and cholecystitis (IRD 20.25, p = 0.044; an outlier). Additionally, a comparison between Belbuca and oral opioids showed lower rates of 13 serious TEAEs (all p ≤ 0.024) and a higher serious dizziness rate (IRR 3.17, p = 0.024). Although the rates of serious opioid abuse/dependence were similar (24.60 vs 26.93, p = 0.921), all Belbuca patients and none of the opioid patients had a positive history of these events. Belbuca also had lower rates of five serious TEAEs than transdermal patches (all p ≤ 0.018), including a serious opioid abuse/dependence (IRR 0.04, p < 0.001), but higher rates of serious cholecystitis (IRD 52.17, p = 0.035; an outlier) and suicidal ideation (IRD 156.50, p < 0.001; an outlier). Conclusion: Buprenorphine had a better safety profile than oral opioids in cLBP treatment. Belbuca showed a more favorable TEAE profile than buprenorphine transdermal patches and oral opioids.

The Impact of Early Life Adversity on Peripubertal Accelerated Epigenetic Aging and Psychopathology.

OBJECTIVE: To examine longitudinal associations between early life threat and deprivation on epigenetic age acceleration at ages 9 and 15 years, and to examine associations of age acceleration on later internalizing and externalizing symptoms. METHOD: The study examines a large (n = 2,039) and racially diverse (Black/African American = 44%, Latino = 18%, White = 5%) sample from a national dataset. Epigenetic age acceleration was estimated using the pediatric buccal epigenetic clock. Early life threat and deprivation were measured using composites from the Parent-Child Conflict Tactics Scale and county-level violent and property crime rate data. Internalizing and externalizing symptoms came from parent-reported Child Behavior Checklist. Path analysis models examined associations of threat and deprivation at age 3 years on epigenetic age acceleration at ages 9 and 15. Experiences of threat were further broken down into threat experienced in the home and in the community. RESULTS: Home threat experienced at age 3 years predicted age acceleration at 9 and 15, and community threat experienced at 3 predicted age acceleration at 15, but not at 9. Deprivation was not a significant predictor of accelerated aging. Age acceleration at age 9 predicted externalizing, but not internalizing, symptoms at age 15. Community threat had a direct effect on externalizing. No association emerged with internalizing. CONCLUSION: Findings revealed that threat, not deprivation, was predictive of age acceleration, demonstrating support for this pattern longitudinally, using an epigenetic clock that is accurate in children. The findings provide critical nuance to the examination of threat, and highlight associated risks and possible intervention points for externalizing symptoms.