Citations

Diabetes mellitus (DM) and periodontitis share a complex, bidirectional relationship, with each condition exacerbating the other. Diabetes, particularly when poorly controlled, significantly increases the risk, severity, and progression of periodontitis. The biological mechanisms involved are complex and numerous. Hyperglycemia in diabetes is linked to oral microbial dysbiosis, which is in turn associated with increased inflammation, epithelial barrier dysfunction, impaired neutrophil and macrophage function, altered T-cell profiles, and cytokine imbalance, collectively fostering chronic inflammation and immune dysregulation. Moreover, diabetes alters bone metabolism, promoting osteoclastogenesis and reducing reparative bone regeneration by limiting coupled bone formation through an effect on growth factor production, mesenchymal stems cells, and osteoblasts. Conversely, periodontitis is strongly linked to poor glycemic control. Clinical studies and longitudinal meta-analyses report consistent positive associations, while randomized controlled trials show that periodontal therapy reduces HbA1c by ~0.43%. Emerging evidence suggests that periodontitis and oral preclinical dysbiosis contribute to diabetogenesis, although causality remains uncertain. Periodontitis may drive metabolic dysfunction through several biological mechanisms. The dysbiotic oral microbiome and subsequent periodontitis may promote systemic inflammation and subsequent insulin resistance and glucose intolerance. Moreover, oral dysbiosis may deplete nitrate-reducing taxa and impair nitric oxide pathways, which has relevance to both periodontal and cardiometabolic health. Accordingly, periodontal treatment in diabetic populations has shown potential health care savings. Nevertheless, trials assessing the influence of periodontitis treatment on systemic outcomes consistently show significant treatment heterogeneity, which requires explication in future studies. This review underscores the systemic implications of periodontitis in diabetes and highlights the value of integrating periodontal care into diabetes management. A better understanding of the shared pathophysiology between these diseases supports interdisciplinary approaches and points toward novel preventive and therapeutic strategies targeting inflammation, microbial balance, and host response modulation to jointly benefit periodontal and cardiometabolic health.

Abstract Background The prevalence of heart failure with preserved ejection fraction (HFpEF) increases with age, and older adults with HFpEF have worse physical function, quality of life, and clinical outcomes. Semaglutide demonstrated efficacy in the treatment of obesity-related HFpEF in the STEP-HFpEF trials. Some have speculated that older patients may have less to gain from incretin therapies (and perhaps more to lose) than younger patients. Aims In this pre-specified pooled subanalysis of the STEP-HFpEF trials, we evaluated the efficacy of semaglutide across the age spectrum. Methods The STEP-HFpEF and STEP-HFpEF DM trials enrolled participants with obesity-related HFpEF and randomized them to semaglutide 2.4 mg once weekly (n = 573) or placebo (n = 572) for 52 weeks. Dual primary outcomes (change in Kansas City Cardiomyopathy Questionnaire clinical summary score [KCCQ-CSS] and change in body weight) and secondary outcome measures (6-minute walk distance [6MWD], C-reactive protein, hierarchical composite endpoint containing all-cause death, heart failure events, changes in KCCQ-CSS and 6MWD) were compared across specific age groups; <55 years, 55–64 years, 65–74 years and ≥75 years. Results Among 1145 randomized participants, 8.8% (N = 101) were <55, 23.3% (N = 267) were aged between 55–64, 42.4% (N = 485) were between 65–74, and 25.5% (N = 292) were 75 years or over. The efficacy of semaglutide on the dual primary endpoints was consistent across the age spectrum, KCCQ-CSS (p-interaction = 0.80), and body weight (p-interaction = 0.41). Similar benefits were observed for the key secondary endpoints, with no treatment effect heterogeneity across age groups. Moreover, the safety of semaglutide was consistent across age groups. Conclusion In patients with HFpEF enrolled across the STEP-HFpEF and STEP-HFpEF DM trials, treatment with semaglutide improved disease-specific symptoms, physical function and reduced body weight across the age spectrum. The safety profile of semaglutide was consistent in older and younger patients.

Abstract CDK12 is frequently deleted and/or mutated in human cancers, and CDK12 inactivation is associated with aggressive phenotypes, including the tendency to metastasis. In this study, we showed that CDK12 deficiency induced intronic polyadenylation (IPA) usage in BRD4 to upregulate expression of the bromodomain-containing protein 4 (BRD4) short isoform (BRD4S). BRD4S demonstrated an enhanced capacity to form phase separation despite lacking the intrinsically disordered region located in the C-terminal of full-length BRD4. Oligomerization of BRD4S mediated phase separation through a base-interacting structural domain. CUT&Tag and RNA sequencing analyses revealed that BRD4S preferentially bound to the promoters of TGFβ signaling genes, including TGFB2 and LTBP1, driving their expression. Consistently, BRD4S drove cancer cell dissemination in vitro and metastasis in vivo, which could be blocked by BET or TGFβ signaling pathway inhibitors. Overall, this study identifies IPA usage at the BRD4 gene locus induced by CDK12 deficiency as a mechanism responsible for BRD4S genesis, which represents an important mechanism driving cancer metastasis and a potential target for therapeutic intervention in CDK12-deficient cancers. Significance: The CDK12–BRD4S–TGFβ signaling axis represents a key regulatory module that promotes metastatic progression and can be targeted by BET or TGFβ pathway inhibitors for treating CDK12-deficient cancers.

Background: Scoliosis has various etiologies, ranging from idiopathic, congenital, to those with spinal cord abnormalities. Advanced imaging is not always feasible and limited by cost, low-yield, and anesthesia risks in children. Given artificial intelligence's potential, we hypothesize that a deep learning (DL)–based image classifier will demonstrate superior performance in radiographic classification of scoliosis etiology compared witht experienced spine surgeons based on spine radiographs. Methods: One thousand thirty-six pediatric patients from single institution with scoliosis diagnosis and paired anterior-posterior - lateral images were included. Patients were manually classified based on their scoliosis etiology from chart review, including previous spine imaging studies when available. Categories included idiopathic, congenital, and spinal cord pathology. Images were randomized and assigned for training, validation, and testing. A DL-classifier using EfficientNet B4 architecture was trained on the radiographs. Accuracy and positive predictive value as defined by precision, recall, and F1-score were calculated to assess final performance metrics. Results: The trained classifier performed well at identifying correct etiologies, with F1-Score (harmonic mean of precision-recall) of 0.97. Model precision was 0.99 for adolescent idiopathic scoliosis, 0.89 for congenital, and 0.78 for spinal cord pathology. Performance was higher on more common classes, with lower performance observed in class with fewer images. The algorithm has highest overall precision (0.96), recall (0.96), and F1 (0.96), while Surgeons 1 and 2 have lower accuracies (precision 0.80, recall 0.79, and F1 0.79 and precision 0.76, recall 0.67, and F10.71, respectively). There was no clear pattern identified regarding the surgeons' errors and poor agreement on which X-rays corresponded to underlying spinal cord pathology. Conclusion: A DL-convolutional-neural-network classifier has been trained to high degree of accuracy to distinguish between 3 scoliosis etiologies on pediatric spine radiographs. This model could provide a novel tool to clinicians to decide when to refer for axial imaging. It had superior diagnostic performance compared with experienced spine surgeons. After further validation and refinement, a clinician could put a patient's X-rays into the predictive tool for analysis and use the results to discuss with the family the risk of finding spinal cord pathology, helping them determine together the best timing for an MRI. Level of Evidence: Level III . See Instructions for Authors for a complete description of levels of evidence.

Abstract Background Children’s Oncology Group ACNS0333 treated atypical teratoid/rhabdoid tumor (ATRT) with surgery, chemotherapy (induction and consolidation) and radiation therapy (RT). M0 had focal RT and M+ had physician-selected focal RT or craniospinal (CSI). Methods Forty patients (29 M0, 11 M+) received RT. Pre-RT chemotherapy response was complete, partial, or stable disease. RT timing (age/stage-based) was pre-consolidation (RT-first) or post-consolidation (consolidation-first). Event-free survival (RT-EFS), overall survival (RT-OS), and cumulative incidence of local relapse (CILR) or distant relapse (RT-CIDR) were calculated. Analyses included log-rank tests and relative hazard rates with 95% confidence intervals to estimate proportional hazards regression. Results Four-year RT-EFS was 56.8% and 4-year RT-OS was 58.8% focal RT: 34 patients, CSI: 6 patients). A trend for superior RT-EFS for M+ compared to M0 (P = .0625, RHR 0.26; 95% CI 0.06-1.18) was shown. RT-EFS was improved for consolidation-first compared to RT-first timing (P = .037, RHR 0.43; 95% CI 0.13-1.37). Pre-RT chemotherapy response was associated with improved RT-EFS (P = .031) and RT-OS (P = .0069). Four-year RT-CILR was 7.84%; no differences in RT-CILR were shown for higher primary RT dose (≥5400 cGy, P = .38) or gross total resection (P = .80). 4-year RT-CIDR was 27.8% for M0 and 9.1% for M+ patients (P = .22). M+ had CSI (n = 6) or focal RT (n = 5). Fatal necrosis potentially-attributable to RT occurred in 3 RT-first patients (occuring either 1.6, 4.6, or 16.2 months post-treatment). Conclusions RT with intensive systemic therapy showed promising survival outcomes and effective primary disease control in ATRT. Sequencing RT prior to myeloblative chemotherapy, rather than post-consolidation, may be associated with increased risk of fatal radionecrosis.

Objective To assess the relationship in ratings of velopharyngeal closure between connected speech and sustained speech, as visualized on nasopharyngoscopy. Design Prospective observational study. Setting Craniofacial clinics in the United States and Canada. Participants Fifty-two participants with velopharyngeal insufficiency (VPI) who underwent nasopharyngoscopy and produced both connected speech and sustained speech of either /i/or /s/ during the procedure. Main outcome measure(s) Correlations and differences between connected speech and sustained speech for velopharyngeal closure percentage, velar movement, lateral pharyngeal wall movement, and velopharyngeal closure pattern. Results There were moderate to very strong correlations observed between connected speech and sustained /i/ for velopharyngeal closure percentage ( P < .01); extent of velar movement ( P < .01), and left ( P < .01) and right ( P < .01) lateral pharyngeal wall movement. Findings were similar between connected speech and sustained /s/. Differences between ratings made during connected and sustained speech were small: for velopharyngeal closure percentage, there was a 5% difference in the mean between connected speech and sustained /i/ (77.5% vs 72.5%) and a 7% difference for /s/ (79.3% vs 86.7%). Overall differences across ratings ranged from 2% to 12%. Closure pattern was rated the same for both connected speech and sustained /i/ in 90% of videos (n = 44/49; P = .38) and the same for connected speech and sustained /s/ in 95% of videos (n = 42/44; P = 1.00). Conclusions Ratings of velopharyngeal movement during nasopharyngoscopy are similar between connected speech and sustained /i/ and /s/ suggesting elicitation of only sustained /i/ and /s/ may be adequate in most cases when assessment of connected speech is not possible.

Background: Pericarotid adipose tissue (PCAT) characteristics and systemic inflammation may play an important role in carotid endarterectomy (CEA) outcomes. This study explores the association between PCAT Hounsfield Unit (HU) ranges, radiomic features, and systemic inflammatory markers in patients undergoing carotid endarterectomy (CEA). Methods: Twenty patients undergoing CEA were included in this cross-sectional study. PCAT was analyzed using preoperative computed tomography angiography (CTA) images, with regions of interest defined around the carotid arteries. PCAT was categorized into three HU ranges: −190 to −120, −119 to −70, and −69 to −30. Radiomics features were extracted using PyRadiomics. The primary outcome was the correlation of PCAT imaging with preoperative neutrophil-to-lymphocyte ratios (NLRs). The secondary outcome was the association of PCAT imaging with the red cell distribution width (RDW-CV). Linear regression was used to evaluate associations between PCAT characteristics and inflammatory markers. Results: Distinct HU ranges in PCAT imaging showed strong correlations with the preoperative NLR. The −190 to −120 HU range demonstrated a negative association (β = −3.809, p < 0.001), whereas the −119 to −70 HU range showed a positive correlation (β = 3.814, p < 0.001). PCAT uniformity was positively associated with RDW-CV (β = 0.494, p = 0.027). Other radiomics features, such as contrast, showed trends but did not reach statistical significance. A larger outer area of PCAT was inversely associated with the NLR (β = −0.677, p < 0.001). Conclusions: Specific PCAT HU ranges and radiomics features are significantly associated with systemic inflammatory markers in CEA patients. These findings suggest that HU-based segmentation and radiomics analysis of PCAT may offer valuable insights into the relationship between local adipose tissue characteristics and systemic inflammation.