Citations

Background: Mandible contour significantly influences facial appearance, framing the lower facial silhouette. Redefining mandibular contour is key for facial and neck rejuvenation. Yet, there is limited facial aging research across different lifespans and sexes. Here, we utilize artificial intelligence and advanced 3-dimensional (3D) analysis to elucidate mandibular aging patterns in male and female subjects. Methods: A retrospective analysis of facial computed tomography scans in White patients was conducted, categorizing subjects into 3 age groups (20–79 y) and stratifying them by sex. Artificial intelligence–assisted segmentation into 3D mandibles was done in Mimics v.25, and statistical shape modeling was used to create an average mandible for each group. Volume and linear measurements were assessed via 3D overlays. Results: Analysis of 280 mandibles demonstrated statistically significant aging changes in both sexes. Ramus height showed a marked decrease with age, by approximately 5.3 mm in women and 4.2 mm in men (P < 0.001). Interrami and intercondylar widths increased by a mean of 4–5 mm (P < 0.01). Women exhibited an increase in mandibular angle (P < 0.01), and bony resorption over the chin compared to men, who exhibited concentrated bone resorption at the gonion projection. Conclusions: Mandibular aging, independent of tooth loss, exhibits specific bone remodeling patterns by sex. Posteriorly, mandibular widths increase in both sexes, whereas ramus height decreases. Women experience more resorption at the anterior alveolar surface and chin than men. Statistical shape modeling effectively visualizes these patterns on a population level, bridging the gap between traditional aging research and current understanding.

Background: Despite increased adoption of virtual surgical planning (VSP) in various craniofacial indications, the incorporation of VSP/3DP into facial trauma care remains limited. Therefore, Expedited Preoperative Point of Care for Fracture Reduction to Normalized Anatomy and 3DP to Improve Surgical Outcomes (EPPOCRATIS) was introduced in 2021. This study evaluates our experience with EPPORATIS in craniomaxillofacial trauma over 10 years. Methods: A retrospective review of patients who underwent facial trauma repair between September 2014 and September 2024 was conducted. For each VSP/3DP case, a patient with similar facial trauma patterns, who was treated without VSP, was selected. Evaluation metrics included operative time, blood loss, length of stay, complication rates, and fracture reduction accuracy through 3D heatmap analyses. Operative metrics were normalized by implant (i.e., fracture plates and screws) count to account for fracture complexity. A value of p < 0.05 was deemed statistically significant. Results: The VSP group presented with more complex injuries and higher involvement of various surgical specialties (p < 0.5) and demonstrated longer operative times (p < 0.03). Although the difference was not statistically significant (p = 0.4), when adjusted for implant count, the VSP group had shorter operative times (median: 15.4 vs. 19.3 min/implant) and reduced blood loss compared to non-VSP cases (median: 3.4 mL/implant vs. 4.2 mL/implant). Complications, revision rates, and length of stay showed no significant differences. Conclusions: The use of VSP/3DP (EPPOCRATIS) in craniomaxillofacial trauma reconstruction demonstrated operative efficiency and accurate fracture reduction in complex cases. Further studies are needed to examine the feasibility and cost-effectiveness of point-of-care VSP/3DP in trauma centers.

Abstract Background Recently, a model to predict 5-year recurrence-free survival (RFS) and melanoma-specific survival (MSS) after sentinel lymph node biopsy (SLNB) was published. The aim of this study was to validate that model in a large independent international cohort. Methods The database of the Sentinel Lymph Node Working Group (SLNWG) was analysed for patients with malignant melanoma who underwent SLNB. Patients with clinical stage III melanoma, a history of other malignancies, or receiving concomitant systemic therapies during follow-up were excluded. The model’s predictive performance was evaluated using discrimination and calibration metrics in the eligible cohort. Decision curve analysis was performed to assess the clinical value of the model. Results The external validation cohort consisted of 6174 patients of the SLNWG from the USA, Europe, and Israel. A positive sentinel node was found in 788 patients (12.8%). The area under the time-dependent receiver operating characteristic (ROC) curve of the external validation was 0.76 (95% c.i. 0.74 to 0.77) for RFS and 0.79 (95% c.i. 0.76 to 0.81) for MSS. The model was well calibrated, as the observed 5-year survival rates aligned closely with the predicted survival rates (calibration slope of 0.98 for RFS and calibration slope of 0.99 for MSS). The model provided a net benefit versus the ‘treat all’ and ‘treat none’ strategies at the predetermined probability threshold for recurrence of 45%. Conclusion The model demonstrated good performance in a large heterogeneous independent cohort, emphasizing its robustness. Decision curve analysis revealed a clear net benefit of the model over a treat all strategy, highlighting its potential for clinical use.

The urethra is considered a passive conduit for urine. Here, we reveal a surprising multicellular signaling pathway guiding the urethra’s dynamic response to an invading pathogen. Using a genetic approach in female mice, we deposited uropathogenic Escherichia coli into the distal urethra to establish a model of ascending urinary tract infection that progresses to the bladder within 4 h. We show that urethral neuroendocrine cells (UNECs), and the serotonin they synthesize, protect the bladder from bacterial colonization. We tested the hypothesis that serotonin initiates urethral contraction to expel ascending bacteria. We identified transient receptor potential cation channel subfamily A member 1, a noncanonical lipopolysaccharide receptor, in human and mouse UNECs and localized the serotonin receptors (HTR) 2B and 3, as well as the calcium-activated chloride channel anoctamin 1 (ANO1) to the pacemaker cells of the human and mouse urethra, the interstitial cells of Cajal (ICCs). HTR2B or ANO1 activation is sufficient for urethral contraction and is required for serotonin-induced mouse urethral contraction. Our results support the hypothesis that the urethra actively surveils its environment and responds to an ascending pathogen by evoking UNECs and ICC to induce urethral contraction and pathogen expulsion.

Mitral regurgitation (MR) in lung transplant (LTx) recipients is a rare but complex cardiopulmonary phenomenon. The overlap between symptoms of MR and post-LTx complications, such as primary graft dysfunction, complicates its diagnosis and management. This systematic review aims to characterize the incidence, pathophysiology, presentation, and management of MR in LTx patients. We conducted a literature search in PubMed, Web of Science, Scopus, and Embase. The search yielded 133 studies, of which 11 were included. Data regarding MR development, clinical presentation, echocardiographic findings, and management strategies were extracted and analyzed. Perioperative MR, occurring during or immediately post-LTx, was frequently attributed to the systolic anterior motion of the mitral valve (MV) occurring in the setting of hypovolemia and/or inotrope usage. Later postoperative MR, on the other hand, was associated with reverse ventricular remodeling and mitral annular dilation, although some variability in the literature was present. Preexisting MR or ventricular dysfunction, elongated MV leaflets, and bilateral LTx procedure appeared to be risk factors for MR development. Management was dependent on the timing of MR and its pathophysiology, where systolic anterior motion–related MR was treated with medical therapy, whereas postoperative MR often required MV interventions. In conclusion, the diagnosis of MR in LTx patients is complicated by its symptomatic overlap with other post-LTx complications. Echocardiographic monitoring in patients with preexisting MR, regardless of severity, is essential for early identification and management. Further research is needed to better understand the underlying mechanisms and refine management strategies for MR in this population.

Abstract Purpose/Background Clozapine was approved in the United States (US) using 1989 regulations and knowledge. After 30 years, many sections of the US package insert (PI) are outdated. Methods We comprehensively reviewed the literature to propose PI updates. We present the information in 2 articles. In Part I, we focus on basic pharmacology based on 407 relevant articles. Part II focuses on clinical aspects and pharmacovigilance. Findings/Results Based on more recent expectations of Food and Drug Administration regulations, we reviewed clozapine basic pharmacology including the following: 1) clearance, 2) pharmacokinetics and pharmacodynamics, and 3) monitoring tools. We identified 9 major problems in the basic pharmacological sections of the PI including the following: 1) in vivo studies indicate that clozapine is dependent on CYP1A2 for its metabolism, 2) the minor role of CYP2D6 in clozapine metabolism requires removing the PI recommendation to lower clozapine doses in CYP2D6 poor metabolizers, 3) in nontoxic concentrations CYP3A4 has a minor role in clozapine metabolism and potent CYP3A4 inhibitors lack clinically relevant effects, 4) several drug-drug interactions need to be updated based on recent literature, 5) systemic inflammation may decrease clozapine metabolism and increase the risk of clozapine intoxication, 6) obesity may decrease clozapine metabolism, 7) patients of Asian and Indigenous American ancestry need lower clozapine doses, 8) personalized titration and c-reactive protein monitoring should be considered until prospective studies are available, and 9) the half-life section needs to be modified to acknowledge that single dosing at night is frequent in the US. Implications/Conclusions An improvement in the US clozapine PI may lead to improvement in PIs worldwide.

Abstract Purpose/Background This is the second part of a 2-part article that proposes improving the United States (US) clozapine package insert. Part II focuses on fatal outcomes and the 5 boxed warnings, 4 specifically for clozapine: severe neutropenia, seizure, orthostatic hypotension and myocarditis, and 1 for all antipsychotics (elderly with dementia). Methods US reports to the World Health Organization's global pharmacovigilance database were analyzed from clozapine's introduction to January 15, 2023. Findings/Results The US was the top reporter worldwide for clozapine with 56,003 reports and 9587 associated fatal outcomes. The 4 clozapine boxed warnings were associated with 534 fatal outcomes (218 with severe neutropenia, 131 with seizures, 125 with orthostasis, 36 with myocarditis, 24 with cardiomyopathy, and 0 with mitral valve prolapse). With no boxed warnings, pneumonia was associated with 674 fatal outcomes and increased white blood cell count (a sign of infection) with 596 fatal outcomes. After considering overlaps, pneumonia and increases in white blood cell count explained 900 fatalities, or 9.4% of 9587 fatal outcomes. The Food and Drug Administration continues to focus on severe neutropenia which was associated with only 218 or 2.3% of fatal outcomes, whereas 97.7% of fatal outcomes reported in US clozapine-treated patients had another cause. Implications/Conclusions To help prevent future deaths in clozapine-treated patients, the clozapine package insert should focus on fatal outcomes during infections. Part II offers detailed solutions regarding current boxed warnings and lack of a warning for pneumonia and other infections. The Supplementary Material includes letters of support from 124 non-US clozapine experts from 44 countries/regions who support Parts I and II.