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Addressing Selection and Confounding Biases in Dental Claims Data: A Causal Inference Framework for Periodontal–Systemic Disease Research 解决牙科索赔数据中的选择和混淆偏差:牙周系统疾病研究的因果推理框架
IF 7.6 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2025-11-26 DOI: 10.1177/00220345251387660
J.J. Wong, O. Urquhart, A. Carrasco-Labra, E.F. Schisterman, M. Glick
Administrative health care data offer unique opportunities to investigate relationships between oral and systemic diseases. However, these data sources introduce methodological challenges that can compromise causal inference. This article demonstrates how, in the context of claims databases, selection bias (i.e., arising from restricting analyses to individuals with both dental and medical insurance) creates a collider structure that can distort estimates of periodontal treatment effects on systemic disease outcomes. Drawing on causal inference theory, we distinguish between confounding (resulting from common causes) and selection bias (resulting from common effects) and demonstrate how directed acyclic graphs (DAGs) can identify these biases and inform rigorous analytical strategies. Therefore, the goal of this article is to demonstrate how selection and confounding biases in administrative health care claims data can compromise causal inference in periodontal–systemic disease research and to introduce methodological approaches for addressing these threats. Our review of 7 studies investigating periodontal–systemic disease associations using claims data reveals methodological gaps in addressing selection bias in the current literature. Moreover, through a numerical example, we illustrate how selection bias can not only distort but also potentially reverse observed associations, producing contradictory clinical recommendations. To address these methodological threats, we introduce established causal inference strategies, referencing implementation tutorials: for confounding, we reference G-methods (G-formula, inverse probability weighting) and stratification-based approaches (regression, matching); for selection bias, we reference inverse probability of selection weighting approaches when data on nonselected individuals are available. To improve methodological rigor in oral–systemic research, we advocate for (1) routine use of DAGs with freely available software, (2) application of bias-correction techniques using established statistical packages, and (3) transparent reporting of bias assessment procedures. Strengthening causal inference methodology in dental research is paramount to building a robust evidence base on periodontal–systemic relationships that supports clinical decision making and integration of oral health into broader health care frameworks.
行政卫生保健数据提供了独特的机会,调查口腔和全身性疾病之间的关系。然而,这些数据源带来了方法论上的挑战,可能会损害因果推理。这篇文章展示了在索赔数据库的背景下,选择偏差(即,由于对同时拥有牙科和医疗保险的个人进行限制分析而产生的)如何产生碰撞结构,从而扭曲对牙周治疗对全身性疾病结果的估计。根据因果推理理论,我们区分了混淆(由共同原因引起)和选择偏差(由共同影响引起),并展示了有向无环图(dag)如何识别这些偏差并为严格的分析策略提供信息。因此,本文的目的是展示行政卫生保健索赔数据中的选择和混淆偏差如何损害牙周系统疾病研究中的因果推断,并介绍解决这些威胁的方法学方法。我们回顾了7项使用索赔数据调查牙周系统疾病相关性的研究,揭示了当前文献中在解决选择偏倚方面的方法差距。此外,通过一个数值例子,我们说明了选择偏差如何不仅扭曲,而且可能逆转观察到的关联,产生相互矛盾的临床建议。为了解决这些方法学上的威胁,我们引入了既定的因果推理策略,参考了实现教程:对于混淆,我们参考了g方法(g公式,逆概率加权)和基于分层的方法(回归,匹配);对于选择偏差,当非选择个体的数据可用时,我们引用选择加权方法的逆概率。为了提高口腔系统研究方法的严谨性,我们提倡(1)使用免费软件常规使用dag,(2)使用已建立的统计软件包应用偏倚校正技术,以及(3)透明地报告偏倚评估程序。加强牙科研究中的因果推理方法对于建立关于牙周-系统关系的有力证据基础至关重要,从而支持临床决策和将口腔健康纳入更广泛的卫生保健框架。
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引用次数: 0
Understanding the Periodontitis–Diabetes Linkage: Mechanisms and Evidence 了解牙周炎与糖尿病的联系:机制和证据
IF 7.6 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2025-11-26 DOI: 10.1177/00220345251388340
D.T. Graves, M.A. Levine, S. Aldosary, R.T. Demmer
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.
糖尿病(DM)和牙周炎有着复杂的双向关系,每一种情况都会加剧另一种情况。糖尿病,特别是当控制不良时,会显著增加牙周炎的风险、严重程度和进展。所涉及的生物学机制是复杂和众多的。糖尿病患者的高血糖与口腔微生物生态失调有关,而口腔微生物生态失调又与炎症增加、上皮屏障功能障碍、中性粒细胞和巨噬细胞功能受损、t细胞谱改变和细胞因子失衡有关,共同促进慢性炎症和免疫失调。此外,糖尿病通过影响生长因子生成、间充质干细胞和成骨细胞来限制偶联骨形成,从而改变骨代谢,促进破骨细胞生成和减少修复性骨再生。相反,牙周炎与血糖控制不良密切相关。临床研究和纵向荟萃分析报告了一致的正相关,而随机对照试验显示牙周治疗可使HbA1c降低约0.43%。新出现的证据表明,牙周炎和口腔临床前生态失调有助于糖尿病的发生,尽管因果关系仍不确定。牙周炎可能通过几种生物学机制导致代谢功能障碍。口腔菌群失调和随后的牙周炎可促进全身性炎症和随后的胰岛素抵抗和葡萄糖耐受不良。此外,口腔生态失调可能会耗尽硝酸盐还原类群并损害一氧化氮途径,这与牙周和心脏代谢健康有关。因此,糖尿病人群的牙周治疗显示出潜在的保健节省。然而,评估牙周炎治疗对全身结果影响的试验一致显示出显著的治疗异质性,这需要在未来的研究中解释。这篇综述强调了牙周炎在糖尿病中的系统性影响,并强调了将牙周护理纳入糖尿病管理的价值。更好地理解这些疾病之间的共同病理生理学支持跨学科方法,并指出针对炎症,微生物平衡和宿主反应调节的新的预防和治疗策略,共同有益于牙周和心脏代谢健康。
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引用次数: 0
LinkMD: Linking Medical and Dental Records with 4 Linking Algorithms. LinkMD:链接医疗和牙科记录与4链接算法。
IF 7.6 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2025-11-18 DOI: 10.1177/00220345251383863
J S Patel,E Dinh
Despite well-established connections between oral and systemic health, electronic health records (EHRs) and electronic dental records (EDRs) remain largely siloed due to infrastructural and interoperability challenges. This separation limits interdisciplinary care and data-driven research to generate practice-based evidence. We developed and validated 4 algorithmic frameworks specifically designed to link EHR with EDR across nonintegrated systems. Using data from more than 1.7 million medical records and 222,480 dental records spanning a 10-y period at Temple University, we evaluated 4 linkage strategies: (1) direct Social Security number matching, (2) unweighted similarity scoring, (3) weighted average similarity scoring, and (4) a probabilistic expectation-conditional maximization classification model. We compared these approaches using expert-reviewed validation of 1,000 candidate record pairs and selected optimal similarity thresholds for high-fidelity linkages. Our weighted average similarity algorithm demonstrated the best performance with 100% specificity (correctly avoiding false matches), 99% sensitivity (correctly identifying all true matches), and 99% accuracy (proportion of all correct linkages out of total comparisons) at the threshold of 0.82 for successfully linking 121,771 unique patients and 144,229 patients' linkage with 96% sensitivity, 78% specificity, and 89% accuracy. After linking the datasets, the completeness of key patient demographic information significantly improved, with missing race data reduced from 79% to 11% and missing ethnicity data from 82% to 17%. We designed the algorithm to be transparent and vendor neutral, making it potentially adaptable to any institution or practice regardless of their existing EHR/EDR systems. This provides a foundation for developing a clinical decision support systems that facilitate real-time health information exchange, supporting safer dental procedures, timely medical referrals, and integrative research. Our findings provide a critical bridge between medicine and dentistry, which have remained largely divorced from each other. Future work will focus on multi-institutional validation, implementation, and integration into routine clinical workflows.
尽管口腔和全身健康之间建立了良好的联系,但由于基础设施和互操作性方面的挑战,电子健康记录(EHRs)和电子牙科记录(EDRs)在很大程度上仍然是孤立的。这种分离限制了跨学科护理和数据驱动研究产生基于实践的证据。我们开发并验证了4个算法框架,专门设计用于跨非集成系统连接EHR和EDR。利用天普大学超过170万份医疗记录和222,480份牙科记录的数据,我们评估了4种关联策略:(1)直接社会保险号匹配,(2)未加权相似度评分,(3)加权平均相似度评分,以及(4)概率期望-条件最大化分类模型。我们使用专家审查的1,000个候选记录对验证来比较这些方法,并为高保真度联系选择最佳相似阈值。我们的加权平均相似度算法表现出最佳性能,在0.82的阈值下,100%特异性(正确避免错误匹配),99%敏感性(正确识别所有真实匹配)和99%准确性(所有正确链接占总比较的比例),成功连接121,771例独特患者和144,229例患者的链接,灵敏度为96%,特异性为78%,准确性为89%。连接数据集后,关键患者人口统计信息的完整性显著提高,缺失的种族数据从79%降至11%,缺失的种族数据从82%降至17%。我们设计的算法是透明和供应商中立的,使其潜在地适用于任何机构或实践,而不管他们现有的EHR/EDR系统。这为开发临床决策支持系统提供了基础,该系统可促进实时卫生信息交换,支持更安全的牙科手术、及时的医疗转诊和综合研究。我们的发现在医学和牙科之间架起了一座重要的桥梁,这两门学科在很大程度上是相互分离的。未来的工作将集中在多机构验证、实施和整合到常规临床工作流程中。
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引用次数: 0
Oral Lichen Planus and Systemic Diseases. 口腔扁平苔藓与全身疾病。
IF 7.6 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2025-11-18 DOI: 10.1177/00220345251385966
S Warnakulasuriya,P Ramos-García,M Á González-Moles
The mouth is referred to as "the mirror of health and disease in the body." This review critically examines the comorbidity between systemic diseases and oral lichen planus, an autoimmune disorder affecting the oral mucosa with malignant potential and of high worldwide prevalence. Research has indicated that patients with oral lichen planus are significantly predisposed to diabetes mellitus (pooled proportion [PP] = 9.77%, odds ratio [OR] = 1.64, P < 0.001), Hashimoto thyroiditis (PP = 8.60%, OR = 2.2, P < 0.001), hypothyroidism (PP = 8.14%, OR = 1.65, P = 0.02), hyperthyroidism (PP = 2.84%, OR = 2.11, P = 0.007), celiac disease (PP = 7.14%, OR = 4.09, P < 0.001), hepatitis C (PP = 7.14%, OR = 4.09, P < 0.001), hepatitis B (PP = 3.90%, OR = 1.62, P = 0.02), steatohepatitis (PP = 7.06%, OR = 5.71, P = 0.05), liver cirrhosis (PP = 4.27%, OR = 5.8, P = 0.002), depression (PP = 31.19%, OR = 6.15, P < 0.001), anxiety (PP = 54.76%, OR = 3.51, P < 0.001), and stress (PP = 41.10%, OR = 3.64, P = 0.005). A good knowledge of these associations may assist primary care physicians, dentists, and other oral health professionals involved in the management of patients with oral lichen planus since many patients may be unaware of these associations and could have an impact on their general health. Some of these diseases, such as diabetes, have a role in the development of oral lichen planus. In addition, most of these comorbidities act as risk factors for cancer of different locations: liver, thyroid, small intestine, and the oral cavity. Current evidence indicates a high prevalence and a higher risk of systemic diseases in patients with oral lichen planus compared with the general population. Future research is recommended to increase our knowledge of pathobiology and clinical management of these associations.
口腔被称为“身体健康和疾病的镜子”。口腔扁平苔藓是一种影响口腔黏膜的自身免疫性疾病,具有恶性潜能,在世界范围内具有很高的发病率。研究表明,口腔扁平苔癣患者明显倾向于糖尿病(池(PP) = 9.77%,比例优势比(或)= 1.64,P < 0.001),桥本甲状腺炎(PP = 8.60%,或= 2.2,P < 0.001),甲状腺功能减退(PP = 8.14%,或= 1.65,P = 0.02),甲状腺机能亢进(PP = 2.84%,或= 2.11,P = 0.007),乳糜泻(PP = 7.14%,或= 4.09,P < 0.001), C型肝炎(PP = 7.14%,或= 4.09,P < 0.001),乙型肝炎(PP = 3.90%,或= 1.62,P = 0.02),肝病(PP = 7.06%,或= 5.71,P = 0.05),肝硬化(PP = 4.27%,或= 5.8,P = 0.002),抑郁(PP = 31.19%,或= 6.15,P < 0.001),焦虑(PP = 54.76%,或= 3.51,P < 0.001)、压力(PP = 41.10%,或= 3.64,P = 0.005)。了解这些联系可以帮助初级保健医生、牙医和其他口腔卫生专业人员参与口腔扁平苔藓患者的管理,因为许多患者可能不知道这些联系,并可能对他们的整体健康产生影响。其中一些疾病,如糖尿病,在口腔扁平苔藓的发展中起作用。此外,这些合并症中的大多数是不同部位癌症的危险因素:肝癌、甲状腺癌、小肠癌和口腔癌。目前的证据表明,与一般人群相比,口腔扁平苔藓患者的患病率和全身性疾病的风险较高。建议未来的研究增加我们对这些关联的病理生物学和临床管理的知识。
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引用次数: 0
Letter to the Editor, “Early Childhood Exposures to Fluorides and Cognitive Neurodevelopment: A Population-Based Longitudinal Study” 致编辑的信,“儿童早期接触氟化物和认知神经发育:一项基于人群的纵向研究”
IF 7.6 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2025-11-14 DOI: 10.1177/00220345251368276
C. Neurath, H. Limeback, C.V. Howard
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引用次数: 0
Transcription Accuracy of Automatic Speech Recognition for Orthodontic Clinical Records 口腔正畸临床记录语音自动识别的转录准确性研究
IF 7.6 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2025-11-03 DOI: 10.1177/00220345251382452
R. O’Kane, D. Stonehouse-Smith, L.C.U. Ota, R. Patel, N. Johnson, C. Slipper, J. Seehra, S.N. Papageorgiou, M.T. Cobourne
Accurate clinical records are fundamental to dental practice. Automatic speech recognition (ASR) has the capacity to convert spoken clinical language into written text within the electronic health record; however, the accuracy of ASR in natural language processing for clinical dentistry remains uncertain. The aim of this study was to investigate the transcriptional accuracy of ASR systems using orthodontic clinical records as the experimental model. Specifically, we used 4 commercial ASR systems (Heidi Health, DigitalTCO, Dragon Medical One, Dragon Professional Anywhere), 5 application programming interfaces (Amazon, Google, Speechmatics, Whisper, GPT4oTranscribe), and a 2-stage pipeline coupling GPT4oTranscribe with the GPT4o large language model (LLM) for generative error correction (GPT4oTranscribeCorrected). Orthodontic diagnostic and treatment planning summaries ( <jats:italic toggle="yes">n</jats:italic> = 200; 10 subject domains; 43,408 words; 6 h of audio) were narrated and recorded for analysis. The primary outcome was domain word error rate (DWER), which investigates clinical terminological transcription errors against the Systematized Nomenclature of Medicine Clinical Terms (SNOMED-CT) database. Secondary outcomes included nondomain WER (N-DWER), lexical accuracy (Recall-Oriented Understudy for Gisting Evaluation [ROUGE] score), semantic similarity (Bidirectional Encoder Representations from Transformers [BERT] and Bidirectional and Auto-Regressive Transformer [BART] scores), hallucinations (transcribed text not in the spoken input), and qualitative error analysis. GPT4oTranscribeCorrected was transcriptionally most accurate (DWER = 3.5%; WER = 3.7%), with DWER decreasing by 54.9% versus GPT4oTranscribe. Heidi Health was the highest-performing commercial system (DWER = 6.2%; WER = 5.4%), with Dragon Professional Anywhere being the worst (WER = 33.9%). All systems were less accurate with technical vocabulary (DWER > N-DWER; <jats:italic toggle="yes">P</jats:italic> < 0.001), except GPT4oTranscribeCorrected. Significant differences were seen across systems for ROUGE, BERT, and BART scores ( <jats:italic toggle="yes">P</jats:italic> < 0.001). Based on post hoc pairwise comparisons, GPT4oTranscribeCorrected performed best and Dragon Professional Anywhere was consistently worst for lexical and semantic errors. Hallucinations were absent except for Whisper ( <jats:italic toggle="yes">n</jats:italic> = 57) and DigitalTCO ( <jats:italic toggle="yes">n</jats:italic> = 1). Across systems, background noise increased DWER and WER ( <jats:italic toggle="yes">P</jats:italic> < 0.001). Importantly, clinically significant errors were seen with all systems, ranging from 2% to 66% (GPT4oTranscribeCorrected clean; Dragon Medical One background noise, respectively). Variation in narrator accent had no effect in clean conditions ( <jats:italic toggle="yes">P</jats:italic> = 0.65) and a small effect with background noise ( <jats:italic toggle="y
准确的临床记录是牙科实践的基础。自动语音识别(ASR)能够在电子健康记录中将口头临床语言转换为书面文本;然而,在临床牙科的自然语言处理中,ASR的准确性仍然不确定。本研究的目的是利用正畸临床记录作为实验模型来研究ASR系统的转录准确性。具体来说,我们使用了4个商业ASR系统(Heidi Health, DigitalTCO, Dragon Medical One, Dragon Professional Anywhere), 5个应用程序编程接口(Amazon, b谷歌,Speechmatics, Whisper, gpt40transcripte),以及一个2级管道耦合gpt40transcripte与gpt40large language model (LLM),用于生成纠错(gpt40transcribeccorrected)。对正畸诊疗计划总结(n = 200, 10个学科领域,43408个单词,6小时音频)进行叙述和记录以供分析。主要结果是领域词错误率(DWER),调查临床术语转录错误对医学临床术语系统化命名法(SNOMED-CT)数据库。次要结果包括非领域WER (N-DWER)、词汇准确性(面向记忆的替代评价评分[ROUGE])、语义相似性(来自变形金刚的双向编码器表征[BERT]和双向和自回归变形金刚[BART]评分)、幻觉(语音输入中没有转录的文本)和定性错误分析。gpt40transcribeccorrected在转录上最准确(DWER = 3.5%; WER = 3.7%),与gpt40transcribe相比,DWER降低了54.9%。Heidi Health是表现最好的商业系统(WER = 6.2%; WER = 5.4%), Dragon Professional Anywhere表现最差(WER = 33.9%)。所有系统在技术词汇方面的准确性都较低(DWER > N-DWER; P < 0.001),除了gpt40transcribe corrected。ROUGE、BERT和BART评分在不同系统之间存在显著差异(P < 0.001)。基于事后两两比较,gpt40transcribeccorrected表现最好,而Dragon Professional Anywhere在词汇和语义错误方面一直表现最差。除Whisper (n = 57)和DigitalTCO (n = 1)外,无幻觉。在各个系统中,背景噪声增加了DWER和WER (P < 0.001)。重要的是,所有系统的临床显著误差都在2%至66%之间(分别为gpt40、transcribeccorrected clean和Dragon Medical One背景噪声)。叙述者口音的变化在清洁条件下没有影响(P = 0.65),背景噪音的影响很小(P = 0.001)。ASR系统提供个位数的转录错误率,特别是当结合基于llm的校正时,但临床显著的错误仍然存在。当使用当前的ASR系统时,临床记录的验证是必不可少的。
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引用次数: 0
Vasculogenic Precedes Neurogenic Differentiation in Dental Pulp Stem Cells 牙髓干细胞的血管性分化先于神经性分化
IF 7.6 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2025-11-03 DOI: 10.1177/00220345251379776
R. Tsuboi, Z. Zhang, K. Warner, S. The, E.T. Keller, J.E. Nör
Dental pulp stem cells (DPSCs) are neural crest–derived stem cells endowed with multipotency and self-renewal. While processes orchestrating DPSC differentiation have been studied extensively, mechanisms underpinning the differentiation of human DPSCs in vivo remain unclear. Here, we induced vasculogenic, odontoblastic, or neurogenic differentiation of human DPSCs for 7 d in vitro and performed single-cell RNA sequencing. Then, human DPSCs tagged with green fluorescent protein (DPSC-GFP) seeded in human tooth slice/scaffolds were transplanted into the subcutaneous space of immunodeficient mice. DPSC-GFP were sorted by flow cytometry 7 and 21 d after transplantation, and single-cell RNA sequencing was performed. In addition, a time course study was performed to investigate the sequence of differentiation events triggered upon transplantation of DPSC-GFP into mice. Here, we observed 8 distinct clusters of DPSCs at baseline, indicating a high level of cell heterogeneity. When DPSCs were induced to undergo vasculogenic, odontoblastic, or neurogenic differentiation in vitro , we observed distinct shifts in patterns of gene expression. Although some DPSCs retained mesenchymal stem cell markers likely due to asymmetric cell division and self-renewal, each differentiation protocol resulted in a unique gene expression signature. Stem cell markers that were highly expressed in DPSCs pretransplantation were progressively downregulated after 7 and 21 d in vivo. In contrast, endothelial cell markers presented high expression levels 7 d after transplantation, while neuronal markers showed upregulation 21 d after transplantation. Notably, while DPSC-derived functional blood vessels (i.e., blood-carrying vessels) can be clearly seen 2 wk after transplantation, well-defined DPSC-derived neural structures can be observed only after 5 wk. In conclusion, DPSCs are heterogeneous stem cells with distinct cell clusters, all of which contain progenitor cells with unique differentiation potential. Furthermore, this work demonstrated that microenvironment cues generated within human root canals are sufficient to induce vasculogenic differentiation, followed by neurogenic differentiation of DPSCs in vivo .
牙髓干细胞(DPSCs)是神经嵴来源的具有多能性和自我更新能力的干细胞。虽然调控DPSC分化的过程已被广泛研究,但支持人DPSCs在体内分化的机制仍不清楚。在这里,我们在体外诱导人DPSCs的血管源性、成牙细胞性或神经源性分化7天,并进行单细胞RNA测序。然后,将绿色荧光蛋白(DPSC-GFP)标记的人DPSCs植入人牙片/支架中,移植到免疫缺陷小鼠皮下。移植后7、21 d用流式细胞术对DPSC-GFP进行分选,并进行单细胞RNA测序。此外,我们还进行了时间过程研究,以研究DPSC-GFP移植小鼠后引发的分化事件的顺序。在这里,我们在基线上观察到8个不同的DPSCs簇,表明细胞异质性很高。当DPSCs在体外诱导进行血管源性、成牙性或神经源性分化时,我们观察到基因表达模式的明显变化。尽管一些DPSCs可能由于不对称的细胞分裂和自我更新而保留了间充质干细胞标记,但每种分化方案都导致了独特的基因表达特征。在DPSCs移植前高表达的干细胞标记物在体内7天和21天后逐渐下调。内皮细胞标志物在移植后第7天高表达,神经元标志物在移植后第21天表达上调。值得注意的是,虽然移植后2周可以清楚地看到dpsc衍生的功能血管(即载血血管),但只有在5周后才能观察到明确的dpsc衍生的神经结构。综上所述,DPSCs是具有不同细胞簇的异质干细胞,它们都含有具有独特分化潜力的祖细胞。此外,这项工作表明,在人类根管中产生的微环境线索足以诱导DPSCs在体内的血管源性分化,随后是神经源性分化。
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引用次数: 0
CaSR Activation Triggers Mandibular Overgrowth in Familial Mandibular Prognathism Patients and Mice. CaSR激活触发家族性下颌前伸症患者和小鼠的下颌过度生长。
IF 7.6 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2025-11-03 DOI: 10.1177/00220345251384290
H Fang,P Li,Y Wei,H Li,P Wang,X Yang,H Yu,Y Fan,S Zhu,R Bi
Mandibular prognathism (MP) is the most common type of dentomaxillofacial deformity in East Asian populations. Genetic studies have revealed several MP-associated loci, suggesting that MP could be inherited as familial MP (fMP). However, functional verifications and in-depth mechanistic investigations of these loci are limited. For this study, we recruited 5 fMP families with 17 fMP members and 7 normal members. We first compared the clinical features of the 17 fMP members with 31 nonfamilial MP patients, finding a stronger mandibular overgrowth phenotype in the fMP subjects. Next, we performed whole-exome sequencing analysis with members of the 5 fMP families and singled out a potential fMP-associated pathogenic variant in the CASR gene (namely, rs117375173); the mutation introduces an amino acid substitution (A601G) in exon 7 and confers gain of function in Calcium-Sensing Receptor (CaSR). The rs11735173 variant changes the CaSR protein structure toward a semiactive state, similar to CaSR activated by L-tryptophan (L-Trp). To verify the regulating roles of CASR in mandibular bone growth, we further generated different mouse models with abnormal CaSR function. L-Trp administration effectively activated CaSR/GNAQ expression in vivo and in vitro. The MC3T3-E1 cell line transfected with CaSR with rs117375173 (CaSRA601G) showed increased osteogenic differentiation and collagen synthesis at the transcriptional level. Local injection of L-Trp in the mandible of growing mice significantly increased the mandibular length and BMD, due to activated osteogenic activity and suppressed bone resorption. At the same time, loss of function of CaSR in osteogenic progenitors caused mandibular growth retardation in Gli1-CreER; Casrfl/fl; tdTomatofl/+ mice. In conclusion, our study reveals that abnormal functioning of CaSR affects mandibular bone development and may contribute to the pathogenesis of fMP, providing a theoretical and experimental basis for the early diagnosis of and therapeutic strategies for fMP in clinical practice.
下颌前突症是东亚人群中最常见的牙颌面畸形。遗传学研究发现了几个与MP相关的位点,提示MP可能作为家族性MP (fMP)遗传。然而,这些基因座的功能验证和深入的机制研究是有限的。在本研究中,我们招募了5个fMP家庭,其中17个fMP成员和7个正常成员。我们首先比较了17名fMP成员与31名非家族性MP患者的临床特征,发现fMP受试者的下颌过度生长表型更强。接下来,我们对5个fMP家族的成员进行了全外显子组测序分析,并在CASR基因中筛选出了一个潜在的与fMP相关的致病变异(即rs117375173);该突变在第7外显子引入氨基酸取代(A601G),并赋予钙敏感受体(CaSR)功能的增益。rs11735173变异将CaSR蛋白结构改变为半活性状态,类似于l -色氨酸(L-Trp)激活的CaSR。为了验证CASR在下颌骨生长中的调节作用,我们进一步制作了不同CASR功能异常的小鼠模型。L-Trp有效激活CaSR/GNAQ在体内和体外的表达。用rs117375173 (CaSRA601G)转染CaSR的MC3T3-E1细胞系在转录水平上显示出成骨分化和胶原合成的增加。生长小鼠下颌骨局部注射l -色氨酸,由于激活成骨活性,抑制骨吸收,显著增加下颌骨长度和骨密度。同时,成骨祖细胞中CaSR功能缺失导致Gli1-CreER的下颌生长迟缓;Casrfl / fl;tdTomatofl / +老鼠。综上所述,我们的研究揭示了CaSR功能异常影响下颌骨骼发育,并可能参与fMP的发病机制,为临床fMP的早期诊断和治疗策略提供了理论和实验依据。
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引用次数: 0
CD300lf Regulates Neutrophil Aging and Periodontal Immune Homeostasis CD300lf调节中性粒细胞老化和牙周免疫稳态
IF 7.6 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2025-11-03 DOI: 10.1177/00220345251382572
Z. Zou, J. Guo, J. Li, Y. Bao, W. Xie, Q. Hu, L. Wen, H. Lu, X. Liu, Q. Dong, J. Fang, Q. Hu, Y. Cao, Z. Wang, L. Yang, X. Wang
Immune alterations, such as neutrophil dysfunction, significantly affect the progression and outcome of periodontitis, a prevalent inflammatory disease. Despite this, the molecular mechanisms driving neutrophil dysregulation in periodontitis remain poorly understood. In this study, we demonstrate that CD300lf, a critical immune regulator, is markedly downregulated in neutrophils from a periodontitis mouse model and human patients. The loss of CD300lf accelerates neutrophil aging, as evidenced by increased reactive oxygen species production, the senescence-associated secretory phenotype with elevated IL-1β and S100A8/A9 levels, and heightened neutrophil extracellular trap formation. Mechanistically, CD300lf deficiency leads to MyD88 upregulation, indicating a shift toward a proinflammatory state. Inhibition of MyD88 effectively reduces periodontal inflammation in CD300lf-deficient mice. Furthermore, targeting CD300lf with its known ligand ceramide alleviates periodontitis and mitigates the aging phenotype of neutrophils. These findings underscore the critical role of the CD300lf/MyD88 axis in neutrophil homeostasis and suggest that modulation of CD300lf through ceramide presents a promising therapeutic strategy for periodontitis.
免疫改变,如中性粒细胞功能障碍,显著影响牙周炎的进展和结果,这是一种普遍的炎症性疾病。尽管如此,在牙周炎中驱动中性粒细胞失调的分子机制仍然知之甚少。在这项研究中,我们证明了CD300lf,一个关键的免疫调节因子,在来自牙周炎小鼠模型和人类患者的中性粒细胞中显着下调。CD300lf的缺失加速了中性粒细胞的衰老,这可以通过活性氧产生的增加、衰老相关的分泌表型(IL-1β和S100A8/A9水平升高)以及中性粒细胞胞外陷阱形成的增加来证明。从机制上讲,CD300lf缺乏导致MyD88上调,表明向促炎状态转变。抑制MyD88可有效减轻cd300lf缺失小鼠的牙周炎症。此外,靶向CD300lf及其已知的配体神经酰胺可缓解牙周炎并减轻中性粒细胞的衰老表型。这些发现强调了CD300lf/MyD88轴在中性粒细胞稳态中的关键作用,并表明通过神经酰胺调节CD300lf是治疗牙周炎的一种有希望的策略。
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引用次数: 0
TMD Diagnosis Using a Masked Self-Supervised Tabular Transformer. 用掩模自监督表格变压器诊断TMD。
IF 7.6 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Pub Date : 2025-10-24 DOI: 10.1177/00220345251376974
Y-H Lee,J H Lee,Q-S Auh,S Lee,D Nixdorf,A Chaurasia
Temporomandibular disorders (TMDs) encompass a heterogeneous group of musculoskeletal conditions involving the temporomandibular joint (TMJ), masticatory muscles, and associated structures. Diagnosis remains challenging due to overlapping symptoms, multifactorial etiology, and variability across clinical settings. To address these limitations, we developed the Gated Attention Tabular Transformer (GATT), a novel deep-learning model that uses masked self-supervised learning and gated attention mechanisms, to classify TMD subgroups based on the diagnostic criteria for TMD (DC/TMD). A total of 4,644 structured clinical records from a university-based registry were analyzed, comprising 3,524 female and 1,120 male patients (mean age 36.9 ± 14.7 y), across 12 core TMD subgroups. GATT achieved robust diagnostic performance with area under the receiver-operating characteristic curve values ranging from 0.815 to 1.000, sensitivity from 0.652 to 1.000, and specificity from 0.773 to 1.000. The model significantly outperformed conventional machine-learning methods including logistic regression, random forest, support vector machine, and XGBoost as well as advanced tabular deep-learning models such as TabNet, TabTransformer, AutoGluon Tabular Predictor, and FT-Transformer. Shapley additive explanations (SHAP) analysis revealed "pain-free opening" (SHAP = 6.78, P < 0.001) and "current TMJ noise" (SHAP = 2.87, P = 0.003) as key features of mechanical TMJ disorders. Co-occurrence network analysis uncovered side-specific clustering and potential time-lagged progression between bilateral TMJs. These findings demonstrate the feasibility of using deep learning to classify heterogeneous TMD subgroups using only structured clinical data, without the need for imaging. The GATT model offers an accurate, explainable, and scalable tool to support clinician-assisted diagnosis and reduce variability in TMD management in real-world practice. These results support the integration of AI-driven tools such as GATT into clinical workflows for standardized, efficient, and patient-specific TMD diagnosis.
颞下颌关节疾病(TMDs)包括一组异质性的肌肉骨骼疾病,涉及颞下颌关节(TMJ)、咀嚼肌和相关结构。由于症状重叠、多因素病因和临床环境的可变性,诊断仍然具有挑战性。为了解决这些限制,我们开发了门控注意表转换器(GATT),这是一种新型的深度学习模型,使用屏蔽自监督学习和门控注意机制,根据TMD的诊断标准(DC/TMD)对TMD子组进行分类。研究人员分析了来自大学注册中心的4644份结构化临床记录,包括3524名女性和1120名男性患者(平均年龄36.9±14.7岁),涵盖12个核心TMD亚组。GATT具有较强的诊断能力,患者工作特征曲线下面积为0.815 ~ 1.000,灵敏度为0.652 ~ 1.000,特异度为0.773 ~ 1.000。该模型明显优于传统的机器学习方法,包括逻辑回归、随机森林、支持向量机和XGBoost,以及先进的表格深度学习模型,如TabNet、TabTransformer、AutoGluon tabular Predictor和FT-Transformer。Shapley加性解释(SHAP)分析显示,“无痛开口”(SHAP = 6.78, P < 0.001)和“当前TMJ噪声”(SHAP = 2.87, P = 0.003)是机械性TMJ障碍的主要特征。共发生网络分析揭示了两侧tmj之间的侧特异性聚类和潜在的时滞进展。这些发现表明,仅使用结构化临床数据,而无需成像,就可以使用深度学习对异质TMD亚组进行分类。GATT模型提供了一个准确的、可解释的、可扩展的工具,以支持临床辅助诊断,并减少现实世界实践中TMD管理的可变性。这些结果支持将GATT等人工智能驱动的工具整合到临床工作流程中,以实现标准化、高效和针对患者的TMD诊断。
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引用次数: 0
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Journal of Dental Research
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