Melatonin-loaded bioactive microspheres accelerate aged bone regeneration by formation of tunneling nanotubes to enhance mitochondrial transfer.

The repair of bone defects in the elderly individuals is significantly delayed due to cellular senescence and dysfunction, which presents a challenge in clinical settings. Furthermore, there are limited effective methods available to promote bone repair in older individuals. Herein, melatonin-loaded mesoporous bioactive glasses microspheres (MTBG) were successfully prepared based on their mesoporous properties. The repair of bone defects in aged rats was significantly accelerated by enhancing mitochondrial function through the sustained release of melatonin and bioactive ions. MTBG effectively rejuvenated senescent bone marrow mesenchymal stem cells (BMSCs) by scavenging excessive reactive oxygen species (ROS), stabilizing the mitochondrial membrane potential (ΔΨm), and increasing ATP synthesis. Analysis of the underlying mechanism revealed that the formation of tunneling nanotubes (TNTs) facilitated the intercellular transfer of mitochondria, thereby resulting in the recovery of mitochondrial function. This study provides critical insights into the design of new biomaterials for the elderly individuals and the biological mechanism involved in aged bone regeneration.

Comprehensiveness of Large Language Models in Patient Queries on Gingival and Endodontic Health.

AIM: Given the increasing interest in using large language models (LLMs) for self-diagnosis, this study aimed to evaluate the comprehensiveness of two prominent LLMs, ChatGPT-3.5 and ChatGPT-4, in addressing common queries related to gingival and endodontic health across different language contexts and query types. METHODS: We assembled a set of 33 common real-life questions related to gingival and endodontic healthcare, including 17 common-sense questions and 16 expert questions. Each question was presented to the LLMs in both English and Chinese. Three specialists were invited to evaluate the comprehensiveness of the responses on a five-point Likert scale, where a higher score indicated greater quality responses. RESULTS: LLMs performed significantly better in English, with an average score of 4.53, compared to 3.95 in Chinese (Mann-Whitney U test, P < .05). Responses to common sense questions received higher scores than those to expert questions, with averages of 4.46 and 4.02 (Mann-Whitney U test, P < .05). Among the LLMs, ChatGPT-4 consistently outperformed ChatGPT-3.5, achieving average scores of 4.45 and 4.03 (Mann-Whitney U test, P < .05). CONCLUSIONS: ChatGPT-4 provides more comprehensive responses than ChatGPT-3.5 for queries related to gingival and endodontic health. Both LLMs perform better in English and on common sense questions. However, the performance discrepancies across different language contexts and the presence of inaccurate responses suggest that further evaluation and understanding of their limitations are crucial to avoid potential misunderstandings. CLINICAL RELEVANCE: This study revealed the performance differences of ChatGPT-3.5 and ChatGPT-4 in handling gingival and endodontic health issues across different language contexts, providing insights into the comprehensiveness and limitations of LLMs in addressing common oral healthcare queries.

An Osteoimmunomodulatory Biopatch Potentiates Stem Cell Therapies for Bone Regeneration by Simultaneously Regulating IL-17/Ferroptosis Signaling Pathways.

Currently, there are still great challenges in promoting bone defect healing, a common health problem affecting millions of people. Herein an osteoimmunity-regulating biopatch capable of promoting stem cell-based therapies for bone regeneration is developed. A totally biodegradable conjugate is first synthesized, which can self-assemble into bioactive nano micelles (PPT NMs). This nanotherapy effectively improves the osteogenesis of periodontal ligament stem cells (PDLSCs) under pathological conditions, by simultaneously regulating IL-17 signaling and ferroptosis pathways. Incorporation of PPT NMs into biodegradable electrospun nanofibers affords a bioactive patch, which notably improves bone formation in two rat bone defect models. A Janus bio patch is then engineered by integrating the bioactive patch with a stem cell sheet of PDLSCs. The obtained biopatch shows additionally potentiated bone regeneration capacity, by synergistically regulating osteoimmune microenvironment and facilitating stem cell differentiation. Further surface functionalization of the biopatch with tannic acid considerably increases its adhesion to the bone defect, prolongs local retention, and sustains bioactivities, thereby offering much better repair effects in rats with mandibular or cranial bone defects. Moreover, the engineered bioactive patches display good safety. Besides bone defects, this osteoimmunity-regulating biopatch strategy can be applied to promote stem cell therapies for spinal cord injury, wound healing, and skin burns.

Tunable Near-Field Radiative Heat Transfer between Graphene-Coated Magneto-Optical Metasurfaces.

The highly structured design of metasurfaces greatly facilitates the manipulation of near-field radiative heat transfer (NFRHT). In this study, we incorporate magneto-optical materials into metasurfaces to theoretically explore the mechanism for controlling NFRHT between anisotropic magneto-optical metasurfaces. Our findings indicate that the interaction between the magnetization-induced modes, arising from interband transitions of graphene, and the surface modes of InSb under a magnetic field leads to a transition in the heat transfer spectrum from a dual band to a triple band. The modification of the distribution and magnitude of transmission wave vectors in surface electromagnetic modes by magnetic fields serves to modulate the radiative heat flux. By combining active control by a magnetic field with passive structural design of metasurfaces, the regulation of heat flux can be increased by more than 8-fold compared with the planar configuration. Additionally, the magnetic field amplifies the anisotropy of the photon energy distribution induced by the symmetry breaking of the metasurface structure. This study is anticipated to provide a pathway for achieving flexible tuning of NFRHT by combining active and passive regulation. It also opens up possibilities for multiband information transmission and for improving the performance of energy conversion devices.

Treatment Patterns and Resource Use After Osimertinib Discontinuation in Patients with EGFR + Metastatic NSCLC.

INTRODUCTION: Current treatment guidelines for patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer (mNSCLC) recommend EGFR tyrosine kinase inhibitors (TKIs) as the standard of care for first-line treatment, with third-generation osimertinib the preferred choice. However, most patients develop resistance to targeted therapy, and subsequent systemic chemotherapy is recommended. The aim of this study was to characterize the subsequent line of therapy (LOT) following osimertinib in patients with EGFR-mNSCLC. METHODS: Medical and pharmacy claims of adults who initiated a subsequent LOT (index) after initial osimertinib discontinuation between November 2015 and September 2019 were analyzed retrospectively. RESULTS: A total of 135 patients met the inclusion criteria. After metastatic diagnosis, 22.2% and 49.6% of patients were treated with osimertinib in the first and second line, respectively. After osimertinib discontinuation, most patients were treated with a platinum-based chemotherapy regimen (57%), of which 40.3% included immuno-oncology therapy. Reuse or continuation of EGFR TKIs was also common (24%). Overall, the median time to treatment discontinuation for the index LOT was 2.4 months. Proportions of patients with ≥ 1 inpatient or emergency department visit were 31.9% and 35.6%, respectively. CONCLUSIONS: The duration of the LOT following osimertinib was short and associated with tolerability issues underscoring a high unmet need for new therapies to address EGFR TKI resistance.

A sono-responsive antibacterial nanosystem co-loaded with metformin and bone morphogenetic protein-2 for mitigation of inflammation and bone loss in experimental peri-implantitis.

Background: Dental implants have become an increasingly popular option for replacing missing teeth, and the prevalence of peri-implantitis has also increased, which is expected to become a public health problem worldwide and cause high economic and health burdens. This scenario highlights the need for new therapeutic options to treat peri-implantitis. Methods: In this study, we proposed a novel sono-responsive antibacterial nanosystem co-loaded with metformin (Met) and bone morphogenetic protein-2 (BMP-2) to promote efficacy in treating peri-implantitis. We introduced the zeolitic imidazolate framework-8 (ZIF-8) as a carrier for hematoporphyrin monomethyl ether (HMME) to enhance the antibacterial effect of sonodynamic antibacterial therapy and tested its reactive oxygen species (ROS) production efficiency and bactericidal effect in vitro. Afterward, HMME-loaded ZIF-8, BMP-2-loaded polylactic acid-glycolic acid (PLGA), and Met were incorporated into gelatin methacryloyl (GelMA) hydrogels to form HMME@ZIF-8/Met/BMP-2@PLGA/GelMA composite hydrogels, and the biocompatibility of which was determined in vitro and in vivo. A bacterial-induced peri-implantitis model in the maxilla of rats was established to detect the effects of the composite hydrogels with adjunctive use of ultrasound on regulating inflammation and promoting bone tissue repair in vivo. Results: The results indicated that HMME@ZIF-8 with ultrasound stimulation demonstrated more better ROS production efficiency and antimicrobial efficacy. The composite hydrogels had good biocompatibility. Ultrasound-assisted application of the composite hydrogels reduced the release of the inflammatory factors IL-6 and TNF-α and reduced bone loss around the implant in rats with bacterial-induced peri-implantitis. Conclusion: Our observations suggest that HMME@ZIF-8 may be a new good sonosensitizer material for sonodynamic antibacterial therapy. The use of HMME@ZIF-8/Met/BMP-2@PLGA/GelMA composite hydrogels in combination with ultrasound can provide a novel option for treating peri-implantitis in the future.

Virtual sketching-based dental anatomy module improves learners' abilities to use computer-aided design to create dental restorations and prostheses.

Dental anatomy education for dental technology students should be developed in alignment with digital dental laboratory practices. We hypothesized that a virtually assisted sketching-based dental anatomy teaching module could improve students' acquisition of skills essential for digital restoration design. The second-year dental technology curriculum included a novel virtual technology-assisted sketching-based module for dental anatomy education. Pre- and post-course assessments evaluated students' skill sets and knowledge bases. Computer-aided design (CAD) scores were analyzed after one year to assess how the skills students developed through this module impacted their subsequent CAD performance. Participants who undertook the dental sketching-based teaching module demonstrated significantly improved theoretical knowledge of dental anatomy, dental aesthetic perception, and spatial reasoning skills. A partial least squares structural equation model indicated that the positive effects of this module on subsequent CAD performance were indirectly mediated by dental aesthetic perception, spatial reasoning, and practice time. A virtually assisted sketching-based dental anatomy teaching module significantly improved students' acquisition of skills and knowledge and positively mediated dental technology students' CAD performance.

The association between diets and periodontitis: a bidirectional two-sample Mendelian randomization study.

Background: Periodontitis, a complex inflammatory condition, has been associated with dietary habits and antioxidants. While the association between certain dietary patterns and periodontitis has been documented, the bidirectional relationship remains unclear. This study utilizes Mendelian randomization (MR) analysis to investigate the bidirectional associations between dietary factors comprising dietary antioxidants, and periodontitis. Methods: Employing a two-sample MR approach, this study analyzed genome-wide association study (GWAS) data on diets and periodontitis from large databases and published literature. Instrumental variables (IVs) were selected and filtered based on genetic variants associated with dietary factors and periodontitis, respectively. Various MR methods, including Inverse Variance Weighted, MR-Egger, Weighted Median, Weighted Mode, and Simple Mode were applied to assess the bidirectional associations. Sensitivity analyses were conducted to validate the robustness of the findings. Results: Our analysis revealed significant associations between certain dietary factors and the risk of periodontitis. Specifically, higher intake of filtered coffee, low-calorie drinks, and other cereals, as well as increased metabolic circulating levels of gamma-tocopherol, were associated with an elevated risk of periodontitis. Conversely, consumption of cheese, white rice, chocolate bars, unsalted peanuts, and higher absolute circulating levels of vitamin C were linked to a reduced risk. Additionally, the study suggests that periodontitis may influence dietary habits, indicating a bidirectional relationship. Conclusion: This study provides additional evidence of a bidirectional association between dietary factors and periodontitis. It highlights the importance of dietary interventions in the prevention and management of periodontitis. The findings underscore the need for incorporating dietary counseling into periodontal disease management protocols and suggest the potential of personalized dietary strategies for periodontitis patients. Further research is warranted to explore the mechanisms underlying these associations and to confirm these findings in diverse populations.

Automated detection of anterior crossbite on intraoral images and videos utilizing deep learning.

AIM: Malocclusion has emerged as a burgeoning global public health concern. Individuals with an anterior crossbite face an elevated risk of exhibiting characteristics such as a concave facial profile, negative overjet, and poor masticatory efficiency. In response to this issue, we proposed a convolutional neural network (CNN)-based model designed for the automated detection and classification of intraoral images and videos. MATERIALS AND METHODS: A total of 1865 intraoral images were included in this study, 1493 (80%) of which were allocated for training and 372 (20%) for testing the CNN. Additionally, we tested the models on 10 videos, spanning a cumulative duration of 124 seconds. To assess the performance of our predictions, metrics including accuracy, sensitivity, specificity, precision, F1-score, area under the precision-recall (AUPR) curve, and area under the receiver operating characteristic (ROC) curve (AUC) were employed. RESULTS: The trained model exhibited commendable classification performance, achieving an accuracy of 0.965 and an AUC of 0.986. Moreover, it demonstrated superior specificity (0.992 vs. 0.978 and 0.956, P < 0.05) in comparison to assessments by two orthodontists. Conversely, the CNN model displayed diminished sensitivity (0.89 vs. 0.96 and 0.92, P < 0.05) relative to the orthodontists. Notably, the CNN model accomplished a perfect classification rate, successfully identifying 100% of the videos in the test set. CONCLUSION: The deep learning (DL) model exhibited remarkable classification accuracy in identifying anterior crossbite through both intraoral images and videos. This proficiency holds the potential to expedite the detection of severe malocclusions, facilitating timely classification for appropriate treatment and, consequently, mitigating the risk of complications.

Expert consensus on pediatric orthodontic therapies of malocclusions in children.

Malocclusion, identified by the World Health Organization (WHO) as one of three major oral diseases, profoundly impacts the dental-maxillofacial functions, facial esthetics, and long-term development of ~260 million children in China. Beyond its physical manifestations, malocclusion also significantly influences the psycho-social well-being of these children. Timely intervention in malocclusion can foster an environment conducive to dental-maxillofacial development and substantially decrease the incidence of malocclusion or reduce the severity and complexity of malocclusion in the permanent dentition, by mitigating the negative impact of abnormal environmental influences on the growth. Early orthodontic treatment encompasses accurate identification and treatment of dental and maxillofacial morphological and functional abnormalities during various stages of dental-maxillofacial development, ranging from fetal stages to the early permanent dentition phase. From an economic and societal standpoint, the urgency for effective early orthodontic treatments for malocclusions in childhood cannot be overstated, underlining its profound practical and social importance. This consensus paper discusses the characteristics and the detrimental effects of malocclusion in children, emphasizing critical need for early treatment. It elaborates on corresponding core principles and fundamental approaches in early orthodontics, proposing comprehensive guidance for preventive and interceptive orthodontic treatment, serving as a reference for clinicians engaged in early orthodontic treatment.

Efficacy of a Virtual 3D Simulation-Based Digital Training Module for Building Dental Technology Students' Long-Term Competency in Removable Partial Denture Design: Prospective Cohort Study.

Background: Removable partial denture (RPD) design is crucial to long-term success in dental treatment, but shortcomings in RPD design training and competency acquisition among dental students have persisted for decades. Digital production is increasing in prevalence in stomatology, and a digital RPD (D-RPD) module, under the framework of the certified Objective Manipulative Skill Examination of Dental Technicians (OMEDT) system reported in our previous work, may improve on existing RPD training models for students. Objective: We aimed to determine the efficacy of a virtual 3D simulation-based progressive digital training module for RPD design compared to traditional training. Methods: We developed a prospective cohort study including dental technology students at the Stomatology College of Chongqing Medical University. Cohort 1 received traditional RPD design training (7 wk). Cohort 2 received D-RPD module training based on text and 2D sketches (7 wk). Cohort 3 received D-RPD module pilot training based on text and 2D sketches (4 wk) and continued to receive training based on 3D virtual casts of real patients (3 wk). RPD design tests based on virtual casts were conducted at 1 month and 1 year after training. We collected RPD design scores and the time spent to perform each assessment. Results: We collected the RPD design scores and the time spent to perform each assessment at 1 month and 1 year after training. The study recruited 109 students, including 58 (53.2%) female and 51 male (56.8%) students. Cohort 1 scored the lowest and cohort 3 scored the highest in both tests (cohorts 1-3 at 1 mo: mean score 65.8, SD 21.5; mean score 81.9, SD 6.88; and mean score 85.3, SD 8.55, respectively; P<.001; cohorts 1-3 at 1 y: mean score 60.3, SD 16.7; mean score 75.5, SD 3.90; and mean score 90.9, SD 4.3, respectively; P<.001). The difference between cohorts in the time spent was not statistically significant at 1 month (cohorts 1-3: mean 2407.8, SD 1370.3 s; mean 1835.0, SD 1329.2 s; and mean 1790.3, SD 1195.5 s, respectively; P=.06) but was statistically significant at 1 year (cohorts 1-3: mean 2049.16, SD 1099.0 s; mean 1857.33, SD 587.39 s; and mean 2524.3, SD 566.37 s, respectively; P<.001). Intracohort comparisons indicated that the differences in scores at 1 month and 1 year were not statistically significant for cohort 1 (95% CI -2.1 to 13.0; P=.16), while cohort 3 obtained significantly higher scores 1 year later (95% CI 2.5-8.7; P=.001), and cohort 2 obtained significantly lower scores 1 year later (95% CI -8.8 to -3.9; P<.001). Conclusions: Cohort 3 obtained the highest score at both time points with retention of competency at 1 year, indicating that progressive D-RPD training including virtual 3D simulation facilitated improved competency in RPD design. The adoption of D-RPD training may benefit learning outcomes.

IRE1α regulates macrophage polarization in type 2 diabetic periodontitis through promoting endoplasmic reticulum stress.

OBJECTIVES: The aim of this study was to investigate the effect of 4µ8c, an inhibitor targeting the endoplasmic reticulum stress-associated factor IRE1α, on macrophage polarization in an experimental model of diabetic periodontitis through ex vivo experiments. MATERIALS AND METHODS: Local alveolar bone parameters were evaluated using Micro-CT following intraperitoneal administration of 4µ8c in mice with experimental diabetic periodontitis. Surface markers indicating macrophage polarization were identified using immunofluorescence. In vitro experiments were performed employing bone marrow-derived macrophages and gingival fibroblasts. Macrophage polarization was determined using flow cytometry. Principal impacted signaling pathways were identified through Western blot analysis. RESULTS: Results from both in vitro and in vivo experiments demonstrated that 4µ8c mitigated alveolar bone resorption and inflammation in mice with diabetic periodontitis. Furthermore, it modulated macrophage polarization towards the M2 phenotype and augmented M2 macrophage polarization through the MAPK signaling pathway. CONCLUSIONS: These findings suggest that inhibiting IRE1α can modulate macrophage polarization and alleviate ligature-induced diabetic periodontitis via the MAPK signaling pathway. This unveils a novel mechanism, offering a scientific foundation for the treatment of experimental diabetic periodontitis.

Integrated analyses revealed the potential role and immune link of mitochondrial dysfunction between periodontitis and type 2 diabetes mellitus.

There is a reciprocal comorbid relationship between periodontitis and type 2 diabetes mellitus (T2DM). Recent studies have suggested that mitochondrial dysfunction (MD) could be the key driver underlying this comorbidity. The aim of this study is to provide novel understandings into the potential molecular mechanisms between MD and the comorbidity, and identify potential therapeutic targets for personalized clinical management. MD-related differentially expressed genes (MDDEGs) were identified. Enrichment analyses and PPI network analysis were then conducted. Six algorithms were used to explore the hub MDDEGs, and these were validated by ROC analysis and qRT-PCR. Co-expression and potential drug targeting analyses were then performed. Potential biomarkers were identified using LASSO regression. The immunocyte infiltration levels in periodontitis and T2DM were evaluated via CIBERSORTx and validated in mouse models. Subsequently, MD-related immune-related genes (MDIRGs) were screened by WGCNA. The in vitro experiment verified that MD was closely associated with this comorbidity. GO and KEGG analyses demonstrated that the connection between periodontitis and T2DM was mainly enriched in immuno-inflammatory pathways. In total, 116 MDDEGs, eight hub MDDEGs, and two biomarkers were identified. qRT-PCR revealed a distinct hub MDDEG expression pattern in the comorbidity group. Altered immunocytes in disease samples were identified, and their correlations were explored. The in vivo examination revealed higher infiltration levels of inflammatory immunocytes. The findings of this study provide insight into the mechanism underlying the gene-mitochondria-immunocyte network and provide a novel reference for future research into the function of mitochondria in periodontitis and T2DM.

An ultrasound-triggered injectable sodium alginate scaffold loaded with electrospun microspheres for on-demand drug delivery to accelerate bone defect regeneration.

Biological processes, such as bone defects healing are precisely controlled in both time and space. This spatiotemporal characteristic inspires novel therapeutic strategies. The sustained-release systems including hydrogels are commonly utilized in the treatment of bone defect; however, traditional hydrogels often release drugs at a consistent rate, lacking temporal precision. In this study, a hybrid hydrogel has been developed by using sodium alginate, sucrose acetate isobutyrate, and electrospray microspheres as the base materials, and designed with ultrasound response, and on-demand release properties. Sucrose acetate isobutyrate was added to the hybrid hydrogel to prevent burst release. The network structure of the hybrid hydrogel is formed by the interconnection of Ca2+ with the carboxyl groups of sodium alginate. Notably, when the hybrid hydrogel is exposed to ultrasound, the ionic bond can be broken to promote drug release; when ultrasound is turned off, the release returned to a low-release state. This hybrid hydrogel reveals not only injectability, degradability, and good mechanical properties but also shows multiple responses to ultrasound. And it has good biocompatibility and promotes osteogenesis efficiency in vivo. Thus, this hybrid hydrogel provides a promising therapeutic strategy for the treatment of bone defects.

Craniocervical posture in patients with skeletal malocclusion and its correlation with craniofacial morphology during different growth periods.

The association between craniocervical posture and craniofacial structures in the various sagittal skeletal malocclusion during different growth stages has been the focus of intense interest in fields of orthodontics, but it has not been conclusively demonstrated. Thus, this study aimed to investigate the association between craniofacial morphology and craniocervical posture in patients with sagittal skeletal malocclusion during different growth periods. A total of 150 from a large pool of cephalograms qualified for the inclusion and exclusion were evaluated and classified into three groups according to the Cervical Vertebral Maturation (CVM) by examining the morphological modifications of the second through fourth cervical vertebrae, each group consisted of 50 cephalograms. In each growth period, for the comparison of head and cervical posture differences among various skeletal classes, the radiographs were further subdivided into skeletal Class I (0° < ANB < 5°, n = 16), skeletal Class II (ANB ≥ 5°, n = 18), and skeletal Class III (0° ≤ ANB, n = 16) on the basis of their ANB angle. There was no significant difference in gender (P > 0.05). Some variables were found to be significant during pubertal growth and later in patients with sagittal skeletal malocclusion (P < 0.05). Most indicators describing craniocervical posture were largest in skeletal Class II and smallest in skeletal Class III during the peak growth periods and later. Cervical inclination variables were greater in skeletal Class III than in skeletal Class II. Variables of craniofacial morphology and craniocervical posture are more correlated during the pubertal growth period and later in patients with sagittal skeletal malocclusion. A tendency is an indication of the close interrelationship that a more extended head was in skeletal Class II while a flexed head was in skeletal Class III. Nevertheless, with the considerations of some limitations involved in this study, further longitudinal studies with large samples are required to elucidate the relationship clearly.

A Nature-Derived, Hetero-Structured, Pro-Healing Bioadhesive Patch for High-Performance Sealing of Wet Tissues.

Tissue adhesives are promising alternatives to sutures and staples to achieve wound closure and hemostasis. However, they often do not work well on tissues that are soaked in blood or other biological fluids, and organs that are typically exposed to a variety of harsh environments such as different pH values, nonhomogeneous distortions, continuous expansions and contractions, or high pressures. In this study, a nature-derived multilayered hetero-bioadhesive patch (skin secretion of Andrias davidianus (SSAD)-Patch) based on hydrophilic/hydrophobic pro-healing bioadhesives derived from the SSAD is developed, which is designed to form pressure-triggered strong adhesion with wet tissues. The SSAD-Patch is successfully applied for the sealing and healing of tissue defects within 10 s in diverse extreme injury scenarios in vivo including rat stomach perforation, small intestine perforation, fetal membrane defect, porcine carotid artery incision, and lung lobe laceration. The findings reveal a promising new type of self-adhesive regenerative SSAD-Patch, which is potentially adaptable to broad applications (under different pH values and air or liquid pressures) in sutureless wound sealing and healing.

Cytochrome P450 inhibitor/inducer treatment patterns among patients in the United States with advanced ovarian cancer who were prescribed or were eligible for poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors in the first-line maintenance setting.

Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) are metabolized either via carboxylesterase (niraparib) or cytochrome P450 (CYP) enzymes (olaparib and rucaparib). Patients with advanced epithelial ovarian cancer (aOC) who receive concomitant medication metabolized by the CYP system may be at risk of drug-drug interactions impacting PARPi efficacy and tolerability. This study investigated CYP inhibitor/inducer treatment patterns in the first-line maintenance (1Lm) setting for patients with aOC. This retrospective cohort study used de-identified databases of US patients with aOC. Eligible patients were aged ≥18 years, diagnosed with aOC between January 2015-March 2021, and received CYP inhibitors/inducers during 1Lm PARPi initiation or the eligibility window (90 days before to 120 days after first-line platinum-based therapy ended [index]). Patients were either prescribed 1Lm PARPi monotherapy (PARPi cohort) or were not prescribed any 1Lm therapy within 120 days post-index (PARPi-eligible cohort). Strong/moderate CYP inhibitors/inducers were defined as area under the plasma concentration-time curve ratio (AUCR) ≥2 or clearance ratio (CL) ≤0.5 (inhibitors), and AUCR ≤0.5 or CL ratio ≥2 (inducers). Of 1411 patients (median age 63), 158 were prescribed PARPis and 1253 were PARPi-eligible. Among the PARPi cohort, 46.2%, 48.7%, and 5.1% were prescribed niraparib, olaparib, and rucaparib, respectively. For patients prescribed olaparib or rucaparib, 42.4% also received strong and/or moderate CYP inhibitors/inducers. This real-world study indicated a considerable proportion of patients received strong and/or moderate CYP inhibitors/inducers and were prescribed PARPis metabolized by the CYP system. Understanding potential impacts of concomitant CYP inhibitors/inducers on PARPi efficacy and safety is warranted.

Lipotoxicity: The missing link between diabetes and periodontitis?

Lipotoxicity refers to the accumulation of lipids in tissues other than adipose tissue (body fat). It is one of the major pathophysiological mechanisms responsible for the progression of diabetes complications such as non-alcoholic fatty liver disease and diabetic nephropathy. Accumulating evidence indicates that lipotoxicity also contributes significantly to the toxic effects of diabetes on periodontitis. Therefore, we reviewed the current in vivo, in vitro, and clinical evidence of the detrimental effects of lipotoxicity on periodontitis, focusing on its molecular mechanisms, especially oxidative and endoplasmic reticulum stress, inflammation, ceramides, adipokines, and programmed cell death pathways. By elucidating potential therapeutic strategies targeting lipotoxicity and describing their associated mechanisms and clinical outcomes, including metformin, statins, liraglutide, adiponectin, and omega-3 PUFA, this review seeks to provide a more comprehensive and effective treatment framework against diabetes-associated periodontitis. Furthermore, the challenges and future research directions are proposed, aiming to contribute to a more profound understanding of the impact of lipotoxicity on periodontitis.

An Automatic Grading System for Orthodontically Induced External Root Resorption Based on Deep Convolutional Neural Network.

Orthodontically induced external root resorption (OIERR) is a common complication of orthodontic treatments. Accurate OIERR grading is crucial for clinical intervention. This study aimed to evaluate six deep convolutional neural networks (CNNs) for performing OIERR grading on tooth slices to construct an automatic grading system for OIERR. A total of 2146 tooth slices of different OIERR grades were collected and preprocessed. Six pre-trained CNNs (EfficientNet-B1, EfficientNet-B2, EfficientNet-B3, EfficientNet-B4, EfficientNet-B5, and MobileNet-V3) were trained and validated on the pre-processed images based on four different cross-validation methods. The performances of the CNNs on a test set were evaluated and compared with those of orthodontists. The gradient-weighted class activation mapping (Grad-CAM) technique was used to explore the area of maximum impact on the model decisions in the tooth slices. The six CNN models performed remarkably well in OIERR grading, with a mean accuracy of 0.92, surpassing that of the orthodontists (mean accuracy of 0.82). EfficientNet-B4 trained with fivefold cross-validation emerged as the final OIERR grading system, with a high accuracy of 0.94. Grad-CAM revealed that the apical region had the greatest effect on the OIERR grading system. The six CNNs demonstrated excellent OIERR grading and outperformed orthodontists. The proposed OIERR grading system holds potential as a reliable diagnostic support for orthodontists in clinical practice.