Pub Date : 2024-08-01Epub Date: 2024-08-05DOI: 10.1177/00220345241259954
F V Bitencourt, A Andersen, L Bjerg, A Sandbæk, H Li, G G Nascimento, R Spin-Neto, M A Peres, F R M Leite
Conflicting evidence suggests a link between diabetes-related microvascular complications and periodontitis. Reliable estimates have been hindered by small sample sizes and residual confounding. Moreover, the combined effects of microvascular complications and dyslipidemia on periodontitis have not been explored. Therefore, this study aimed to investigate the association between individual and combined diabetic microvascular complications (i.e., neuropathy and retinopathy) and moderate/severe periodontitis in a Danish population-based study. In addition, we assessed whether dyslipidemia modified these associations. This study comprised 15,922 participants with type 2 diabetes from the Health in Central Denmark study. Multinomial logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for individual and joint microvascular diabetes complications. The models adjusted for potential confounders, including sociodemographic factors, lifestyle behaviors, and health conditions. Inverse probability of treatment weighting (IPTW) balanced measured confounders between periodontitis and nonperiodontitis participants. Sensitivity analyses tested the findings' robustness by estimating E-values for unmeasured confounding and varying microvascular complication definitions. After IPTW, adjusted models revealed that diabetic neuropathy (OR 1.36, 95% CI 1.14 to 1.63) and retinopathy (OR 1.21, 95% CI 1.03 to 1.43) were significantly associated with moderate/severe periodontitis. Moreover, the coexistence of microvascular complications increased the odds 1.5-fold for moderate/severe periodontitis (OR 1.51, 95% CI 1.23 to 1.85). An effect modification of dyslipidemia on an additive scale was found, indicated by a positive relative excess risk due to interaction of 0.24 for neuropathy, 0.11 for retinopathy, and 0.44 for both complications. Sensitivity analysis ruled out unmeasured confounders and microvascular complication definitions as explanatory factors. Diabetic neuropathy and retinopathy, individually and combined, were associated with moderate/severe periodontitis. In addition, dyslipidemia had an additive positive effect modification on diabetic microvascular complications, elevating the odds of moderate/severe periodontitis. These findings may aid in identifying at-risk subgroups for diabetes-related microvascular complications and periodontitis, optimizing efforts to mitigate disease burden.
相互矛盾的证据表明,糖尿病相关微血管并发症与牙周炎之间存在联系。由于样本量小和残余混杂因素,可靠的估计结果受到阻碍。此外,尚未探讨微血管并发症和血脂异常对牙周炎的综合影响。因此,本研究旨在通过一项基于丹麦人群的研究,探讨糖尿病微血管并发症(即神经病变和视网膜病变)与中度/重度牙周炎之间的关联。此外,我们还评估了血脂异常是否会改变这些关联。这项研究包括丹麦中部健康研究中的 15,922 名 2 型糖尿病患者。我们采用多叉逻辑回归法估算了单个和联合微血管糖尿病并发症的几率比(OR)和 95% 置信区间(CI)。模型调整了潜在的混杂因素,包括社会人口因素、生活方式行为和健康状况。反向治疗概率加权(IPTW)平衡了牙周炎和非牙周炎参与者之间的测量混杂因素。敏感性分析通过估算未测量混杂因素的 E 值和不同的微血管并发症定义来检验研究结果的稳健性。IPTW调整后的模型显示,糖尿病神经病变(OR 1.36,95% CI 1.14-1.63)和视网膜病变(OR 1.21,95% CI 1.03-1.43)与中度/重度牙周炎显著相关。此外,同时存在微血管并发症会使中度/重度牙周炎的几率增加 1.5 倍(OR 1.51,95% CI 1.23 至 1.85)。研究还发现,血脂异常对并发症的影响具有叠加效应,神经病变、视网膜病变和两种并发症的交互作用导致的正向相对超额风险分别为 0.24、0.11 和 0.44。敏感性分析排除了作为解释因素的未测量混杂因素和微血管并发症定义。糖尿病神经病变和视网膜病变单独或合并与中度/重度牙周炎有关。此外,血脂异常对糖尿病微血管并发症也有叠加的积极影响,提高了中度/重度牙周炎的几率。这些发现有助于确定糖尿病相关微血管并发症和牙周炎的高危亚群,从而优化减轻疾病负担的工作。
{"title":"Periodontitis and Diabetes Complications: A Danish Population-Based Study.","authors":"F V Bitencourt, A Andersen, L Bjerg, A Sandbæk, H Li, G G Nascimento, R Spin-Neto, M A Peres, F R M Leite","doi":"10.1177/00220345241259954","DOIUrl":"10.1177/00220345241259954","url":null,"abstract":"<p><p>Conflicting evidence suggests a link between diabetes-related microvascular complications and periodontitis. Reliable estimates have been hindered by small sample sizes and residual confounding. Moreover, the combined effects of microvascular complications and dyslipidemia on periodontitis have not been explored. Therefore, this study aimed to investigate the association between individual and combined diabetic microvascular complications (i.e., neuropathy and retinopathy) and moderate/severe periodontitis in a Danish population-based study. In addition, we assessed whether dyslipidemia modified these associations. This study comprised 15,922 participants with type 2 diabetes from the Health in Central Denmark study. Multinomial logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for individual and joint microvascular diabetes complications. The models adjusted for potential confounders, including sociodemographic factors, lifestyle behaviors, and health conditions. Inverse probability of treatment weighting (IPTW) balanced measured confounders between periodontitis and nonperiodontitis participants. Sensitivity analyses tested the findings' robustness by estimating E-values for unmeasured confounding and varying microvascular complication definitions. After IPTW, adjusted models revealed that diabetic neuropathy (OR 1.36, 95% CI 1.14 to 1.63) and retinopathy (OR 1.21, 95% CI 1.03 to 1.43) were significantly associated with moderate/severe periodontitis. Moreover, the coexistence of microvascular complications increased the odds 1.5-fold for moderate/severe periodontitis (OR 1.51, 95% CI 1.23 to 1.85). An effect modification of dyslipidemia on an additive scale was found, indicated by a positive relative excess risk due to interaction of 0.24 for neuropathy, 0.11 for retinopathy, and 0.44 for both complications. Sensitivity analysis ruled out unmeasured confounders and microvascular complication definitions as explanatory factors. Diabetic neuropathy and retinopathy, individually and combined, were associated with moderate/severe periodontitis. In addition, dyslipidemia had an additive positive effect modification on diabetic microvascular complications, elevating the odds of moderate/severe periodontitis. These findings may aid in identifying at-risk subgroups for diabetes-related microvascular complications and periodontitis, optimizing efforts to mitigate disease burden.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-08-05DOI: 10.1177/00220345241261982
K L Adeleye, A R Li, Y Xie, S Pochampally, D Hamilton, F Garcia-Godoy, D D Miller, W Li
Effective management of head and neck cancer (HNC) poses a significant challenge in the field of oncology, due to its intricate pathophysiology and limited treatment options. The most common HNC malignancy is head and neck squamous cell carcinoma (HNSCC). HNSCC treatment includes a combination of surgery, radiation, and chemotherapy. While HNSCC is treatable if diagnosed early, this is often not the case and is considered incurable once in its late stages and metastatic disease has developed. Therapies are also limited once resistant disease has occurred. SP-1-39, a novel colchicine-binding site inhibitor (CBSI), has been recently reported for its potential efficacy in a variety of cancer cell lines including breast, melanoma, pancreatic, and prostate. SP-1-39 also shows abilities to overcome paclitaxel resistance in a paclitaxel-resistant prostate cancer xenograft model. To evaluate the potential of SP-1-39 as a new HNSCC treatment option, herein we systematically performed preclinical studies in HNSCC models using SP-1-39 and demonstrated that, in vitro, SP-1-39 inhibits the proliferation of 2 HNSCC cell lines with low nanomolar IC50 values (1.4 to 2.1 nM), induces HNSCC cell apoptosis in a dose-dependent manner, interferes with migration of HNSCC cells, and leads to HNSCC cell cycle arrest in the G2/M phase. In vivo, SP-1-39 suppresses the primary tumor growth of a Detroit 562 subcutaneous xenograft mouse model in 6- to 8-wk-old, male NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice, with no detectable cytotoxic effects at a low dose of 2.5 mg/kg. This efficacy of SP-1-39 is better when compared with the treatment using a reference chemotherapy drug, paclitaxel at 10 mg/kg. Collectively, these data demonstrate that SP-1-39 is a promising candidate for further development for more efficacious HNSCC treatment.
{"title":"Novel Antimitotic Agent SP-1-39 Inhibits Head and Neck Squamous Cell Carcinoma.","authors":"K L Adeleye, A R Li, Y Xie, S Pochampally, D Hamilton, F Garcia-Godoy, D D Miller, W Li","doi":"10.1177/00220345241261982","DOIUrl":"10.1177/00220345241261982","url":null,"abstract":"<p><p>Effective management of head and neck cancer (HNC) poses a significant challenge in the field of oncology, due to its intricate pathophysiology and limited treatment options. The most common HNC malignancy is head and neck squamous cell carcinoma (HNSCC). HNSCC treatment includes a combination of surgery, radiation, and chemotherapy. While HNSCC is treatable if diagnosed early, this is often not the case and is considered incurable once in its late stages and metastatic disease has developed. Therapies are also limited once resistant disease has occurred. SP-1-39, a novel colchicine-binding site inhibitor (CBSI), has been recently reported for its potential efficacy in a variety of cancer cell lines including breast, melanoma, pancreatic, and prostate. SP-1-39 also shows abilities to overcome paclitaxel resistance in a paclitaxel-resistant prostate cancer xenograft model. To evaluate the potential of SP-1-39 as a new HNSCC treatment option, herein we systematically performed preclinical studies in HNSCC models using SP-1-39 and demonstrated that, in vitro, SP-1-39 inhibits the proliferation of 2 HNSCC cell lines with low nanomolar IC<sub>50</sub> values (1.4 to 2.1 nM), induces HNSCC cell apoptosis in a dose-dependent manner, interferes with migration of HNSCC cells, and leads to HNSCC cell cycle arrest in the G2/M phase. In vivo, SP-1-39 suppresses the primary tumor growth of a Detroit 562 subcutaneous xenograft mouse model in 6- to 8-wk-old, male NSG (NOD.Cg-Prkdc<sup>scid</sup> Il2rg<sup>tm1Wjl</sup>/SzJ) mice, with no detectable cytotoxic effects at a low dose of 2.5 mg/kg. This efficacy of SP-1-39 is better when compared with the treatment using a reference chemotherapy drug, paclitaxel at 10 mg/kg. Collectively, these data demonstrate that SP-1-39 is a promising candidate for further development for more efficacious HNSCC treatment.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-06-24DOI: 10.1177/00220345241257866
P Huang, R X Jiang, F Wang, W W Qiao, Y T Ji, L Y Meng, Z Bian
Located at the interface of the dentin-pulp complex, the odontoblasts are specialized cells responsible for dentin synthesis and nociceptive signal detection in response to external stimuli. Recent studies have shown that the mechanosensitive ion channel PIEZO1 is involved in bone formation and remodeling through the influx of calcium ions, and it is abundantly expressed in odontoblasts. However, the specific role of PIEZO1 in reactionary dentinogenesis and the underlying mechanisms remain elusive. In this study, we found intense PIEZO1 expression in the plasma membrane and cytoplasm of odontoblasts in healthy human third molars, mouse mandibular molars, and human odontoblast-like cells (hOBLCs). In hOBLCs, PIEZO1 positively regulated DSPP, DMP1, and COL1A1 expression through the Ca2+/PI3K-Akt/SEMA3A signaling pathway. In addition, exogenous SEMA3A supplementation effectively reversed reduced mineralization capacity in PIEZO1-knockdown hOBLCs. In vivo, Piezo1 expression peaked at day 7 and returned to baseline at day 21 in a wild-type mice dentin injury model, with Sema3a presenting a similar expression pattern. To investigate the specific role of PIEZO1 in odontoblast-mediated reactionary dentinogenesis, mice with a conditional knockout of Piezo1 in odontoblasts were generated, and no significant differences in teeth phenotypes were observed between the control and conditional knockout (cKO) mice. Nevertheless, cKO mice exhibited reduced reactionary dentin formation and decreased Sema3a and Dsp positive staining after dentin injury, indicating impaired dental pulp repair by odontoblasts. In summary, these findings suggest that PIEZO1 enhances the mineralization capacity of hOBLCs in vitro via the Ca2+/PI3K-Akt/SEMA3A signaling pathway and contributes to reactionary dentinogenesis in vivo.
{"title":"PIEZO1 Promotes Odontoblast-Mediated Reactionary Dentinogenesis via SEMA3A.","authors":"P Huang, R X Jiang, F Wang, W W Qiao, Y T Ji, L Y Meng, Z Bian","doi":"10.1177/00220345241257866","DOIUrl":"10.1177/00220345241257866","url":null,"abstract":"<p><p>Located at the interface of the dentin-pulp complex, the odontoblasts are specialized cells responsible for dentin synthesis and nociceptive signal detection in response to external stimuli. Recent studies have shown that the mechanosensitive ion channel PIEZO1 is involved in bone formation and remodeling through the influx of calcium ions, and it is abundantly expressed in odontoblasts. However, the specific role of PIEZO1 in reactionary dentinogenesis and the underlying mechanisms remain elusive. In this study, we found intense PIEZO1 expression in the plasma membrane and cytoplasm of odontoblasts in healthy human third molars, mouse mandibular molars, and human odontoblast-like cells (hOBLCs). In hOBLCs, PIEZO1 positively regulated DSPP, DMP1, and COL1A1 expression through the Ca<sup>2+</sup>/PI3K-Akt/SEMA3A signaling pathway. In addition, exogenous SEMA3A supplementation effectively reversed reduced mineralization capacity in <i>PIEZO1</i>-knockdown hOBLCs. In vivo, Piezo1 expression peaked at day 7 and returned to baseline at day 21 in a wild-type mice dentin injury model, with Sema3a presenting a similar expression pattern. To investigate the specific role of PIEZO1 in odontoblast-mediated reactionary dentinogenesis, mice with a conditional knockout of <i>Piezo1</i> in odontoblasts were generated, and no significant differences in teeth phenotypes were observed between the control and conditional knockout (<i>cKO</i>) mice. Nevertheless, <i>cKO</i> mice exhibited reduced reactionary dentin formation and decreased Sema3a and Dsp positive staining after dentin injury, indicating impaired dental pulp repair by odontoblasts. In summary, these findings suggest that PIEZO1 enhances the mineralization capacity of hOBLCs in vitro via the Ca<sup>2+</sup>/PI3K-Akt/SEMA3A signaling pathway and contributes to reactionary dentinogenesis in vivo.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141444002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-05-31DOI: 10.1177/00220345241255593
F C Setzer, J Li, A A Khan
Endodontics is the dental specialty foremost concerned with diseases of the pulp and periradicular tissues. Clinicians often face patients with varying symptoms, must critically assess radiographic images in 2 and 3 dimensions, derive complex diagnoses and decision making, and deliver sophisticated treatment. Paired with low intra- and interobserver agreement for radiographic interpretation and variations in treatment outcome resulting from nonstandardized clinical techniques, there exists an unmet need for support in the form of artificial intelligence (AI), providing automated biomedical image analysis, decision support, and assistance during treatment. In the past decade, there has been a steady increase in AI studies in endodontics but limited clinical application. This review focuses on critically assessing the recent advancements in endodontic AI research for clinical applications, including the detection and diagnosis of endodontic pathologies such as periapical lesions, fractures and resorptions, as well as clinical treatment outcome predictions. It discusses the benefits of AI-assisted diagnosis, treatment planning and execution, and future directions including augmented reality and robotics. It critically reviews the limitations and challenges imposed by the nature of endodontic data sets, AI transparency and generalization, and potential ethical dilemmas. In the near future, AI will significantly affect the everyday endodontic workflow, education, and continuous learning.
{"title":"The Use of Artificial Intelligence in Endodontics.","authors":"F C Setzer, J Li, A A Khan","doi":"10.1177/00220345241255593","DOIUrl":"10.1177/00220345241255593","url":null,"abstract":"<p><p>Endodontics is the dental specialty foremost concerned with diseases of the pulp and periradicular tissues. Clinicians often face patients with varying symptoms, must critically assess radiographic images in 2 and 3 dimensions, derive complex diagnoses and decision making, and deliver sophisticated treatment. Paired with low intra- and interobserver agreement for radiographic interpretation and variations in treatment outcome resulting from nonstandardized clinical techniques, there exists an unmet need for support in the form of artificial intelligence (AI), providing automated biomedical image analysis, decision support, and assistance during treatment. In the past decade, there has been a steady increase in AI studies in endodontics but limited clinical application. This review focuses on critically assessing the recent advancements in endodontic AI research for clinical applications, including the detection and diagnosis of endodontic pathologies such as periapical lesions, fractures and resorptions, as well as clinical treatment outcome predictions. It discusses the benefits of AI-assisted diagnosis, treatment planning and execution, and future directions including augmented reality and robotics. It critically reviews the limitations and challenges imposed by the nature of endodontic data sets, AI transparency and generalization, and potential ethical dilemmas. In the near future, AI will significantly affect the everyday endodontic workflow, education, and continuous learning.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141186988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-08-05DOI: 10.1177/00220345241258459
H S Schuch, M Furtado, A D P Chiavegatto Filho, H W Elani
In 2020, the Brazilian federal government launched the "Prevent Brazil" program to incentivize cities to improve their performance across 7 health care indicators, including prenatal dental care. Our study examines the impact of this policy on the use of oral health care among pregnant women in Brazil. We used a series of cross-sectional data from the Brazilian Public Health System from 2018 to 2023. We linked publicly available data from the Brazilian Ministry of Health and the Brazilian Institute of Geography and Statistics. Our outcome was the proportion of pregnant women receiving prenatal care who had at least 1 dental visit during the past year. Covariates included city-level socioeconomic (income and literacy), demographic (gender, race, and urban areas), and workforce variables (number of dentists working in the public health system per city/year). We estimated the impact of the policy on prenatal dental visits nationwide and stratified by geographic region using interrupted time-series analysis. Our analyses included 99.9% of all Brazilian cities (n = 5,562). The use of oral health care among pregnant women increased from 15% in 2018 to 69% in 2023. Adjusted estimates show that, after initiation of the Prevent Brazil, dental care use among pregnant women increased nationally at a rate of 4.6 percentage points per 4-mo period (95% confidence interval [CI] 4.5; 4.7). The policy's largest impact was in the North and Northeast regions, which have the lowest socioeconomic profiles (adjusted time-series rate 5.7 [95% CI 5.3; 6.1] and 5.2 [5.0; 5.4] percent points, respectively). Our findings support the positive impact of the Prevent Brazil policy on prenatal dental care in Brazil. The policy was associated with a countrywide improvement in prenatal dental care use, with a greater impact in socioeconomically disadvantaged regions.
{"title":"Changes in Use of Prenatal Dental Care After Brazil's Incentive Policy.","authors":"H S Schuch, M Furtado, A D P Chiavegatto Filho, H W Elani","doi":"10.1177/00220345241258459","DOIUrl":"10.1177/00220345241258459","url":null,"abstract":"<p><p>In 2020, the Brazilian federal government launched the \"Prevent Brazil\" program to incentivize cities to improve their performance across 7 health care indicators, including prenatal dental care. Our study examines the impact of this policy on the use of oral health care among pregnant women in Brazil. We used a series of cross-sectional data from the Brazilian Public Health System from 2018 to 2023. We linked publicly available data from the Brazilian Ministry of Health and the Brazilian Institute of Geography and Statistics. Our outcome was the proportion of pregnant women receiving prenatal care who had at least 1 dental visit during the past year. Covariates included city-level socioeconomic (income and literacy), demographic (gender, race, and urban areas), and workforce variables (number of dentists working in the public health system per city/year). We estimated the impact of the policy on prenatal dental visits nationwide and stratified by geographic region using interrupted time-series analysis. Our analyses included 99.9% of all Brazilian cities (<i>n</i> = 5,562). The use of oral health care among pregnant women increased from 15% in 2018 to 69% in 2023. Adjusted estimates show that, after initiation of the Prevent Brazil, dental care use among pregnant women increased nationally at a rate of 4.6 percentage points per 4-mo period (95% confidence interval [CI] 4.5; 4.7). The policy's largest impact was in the North and Northeast regions, which have the lowest socioeconomic profiles (adjusted time-series rate 5.7 [95% CI 5.3; 6.1] and 5.2 [5.0; 5.4] percent points, respectively). Our findings support the positive impact of the Prevent Brazil policy on prenatal dental care in Brazil. The policy was associated with a countrywide improvement in prenatal dental care use, with a greater impact in socioeconomically disadvantaged regions.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-06-24DOI: 10.1177/00220345241256306
T Komori, V Kram, S Perry, H T Pham, P Jani, T M Kilts, K Watanabe, D G Kim, D Martin, M F Young
The periodontal ligament (PDL) is a fibrillar connective tissue that lies between the alveolar bone and the tooth and is composed of highly specialized extracellular matrix (ECM) molecules and a heterogeneous population of cells that are responsible for collagen formation, immune response, bone formation, and chewing force sensation. Type VI collagen (COL6), a widely distributed ECM molecule, plays a critical role in the structural integrity and mechanical properties of various tissues including muscle, tendon, bone, cartilage, and skin. However, its role in the PDL remains largely unknown. Our study shows that deficiency of COL6 impairs PDL fibrillogenesis and exacerbates tissue destruction in ligature-induced periodontitis (LIP). We found that COL6-deficient mice exhibited increased bone loss and degraded PDL in LIP and that fibroblasts expressing high levels of Col6α2 are pivotal in ECM organization and cell-ECM interactions. Moreover, COL6 deficiency in the PDL led to an increased number of fibroblasts geared toward the inflammatory response. We also observed that cultured COL6-deficient fibroblasts from the PDL exhibited decreased expression of genes related to collagen fiber turnover and ECM organization as well as migration and proliferation. Our findings suggest that COL6 plays a crucial role in the PDL, influencing fibroblast function in fibrillogenesis and affecting the immune response in periodontitis. These insights advance our understanding of the molecular mechanisms underlying PDL maturation and periodontal disease.
{"title":"Type VI Collagen Deficiency Causes Enhanced Periodontal Tissue Destruction.","authors":"T Komori, V Kram, S Perry, H T Pham, P Jani, T M Kilts, K Watanabe, D G Kim, D Martin, M F Young","doi":"10.1177/00220345241256306","DOIUrl":"10.1177/00220345241256306","url":null,"abstract":"<p><p>The periodontal ligament (PDL) is a fibrillar connective tissue that lies between the alveolar bone and the tooth and is composed of highly specialized extracellular matrix (ECM) molecules and a heterogeneous population of cells that are responsible for collagen formation, immune response, bone formation, and chewing force sensation. Type VI collagen (COL6), a widely distributed ECM molecule, plays a critical role in the structural integrity and mechanical properties of various tissues including muscle, tendon, bone, cartilage, and skin. However, its role in the PDL remains largely unknown. Our study shows that deficiency of COL6 impairs PDL fibrillogenesis and exacerbates tissue destruction in ligature-induced periodontitis (LIP). We found that COL6-deficient mice exhibited increased bone loss and degraded PDL in LIP and that fibroblasts expressing high levels of <i>Col6α2</i> are pivotal in ECM organization and cell-ECM interactions. Moreover, COL6 deficiency in the PDL led to an increased number of fibroblasts geared toward the inflammatory response. We also observed that cultured COL6-deficient fibroblasts from the PDL exhibited decreased expression of genes related to collagen fiber turnover and ECM organization as well as migration and proliferation. Our findings suggest that COL6 plays a crucial role in the PDL, influencing fibroblast function in fibrillogenesis and affecting the immune response in periodontitis. These insights advance our understanding of the molecular mechanisms underlying PDL maturation and periodontal disease.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11377870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141444004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-08-05DOI: 10.1177/00220345241261980
B Srivichit, C Thonusin, R Aeimlapa, A Arinno, T Chunchai, N Charoenphandhu, N Chattipakorn, S C Chattipakorn
Evidence concerning the osteotoxic effects of chemotherapy (doxorubicin) has been previously described. Periodontitis also progressively increases in patients receiving chemotherapy; however, the beneficial effects of melatonin and metformin on the alleviation of doxorubicin-induced osteotoxicity have never been investigated. Therefore, we investigated the negative impact of doxorubicin on alveolar bone homeostasis and the benefits of melatonin and metformin on the attenuation of doxorubicin-induced alveolar bone toxicity. Male Wistar rats were divided into 4 groups to receive either 1 mL of normal saline solution as a control group, 3 mg/kg of doxorubicin, 3 mg/kg of doxorubicin plus 10 mg/kg of melatonin, or 3 mg/kg of doxorubicin plus 250 mg/kg of metformin. Doxorubicin treatment was given on days 0, 4, 8, 15, 22, and 29, while interventions were given daily on days 0 to 29. Following euthanasia, blood and alveolar bones were collected for evaluation of oxidative stress, bone remodeling, inflammation, microarchitecture, and periodontal condition. We found that doxorubicin increased systemic oxidative stress, decreased antioxidative capacity, increased inflammation, decreased bone formation, increased bone reabsorption, impaired microarchitecture, and impaired periodontal condition of the alveolar bone. Although cotreatment with melatonin or metformin resulted in some improvement in these parameters, cotreatment with melatonin was more effective than cotreatment with metformin in terms of decreasing oxidative stress, reducing bone resorption, and improving microarchitecture and periodontal condition. All of these findings highlight the potential for antioxidants, especially melatonin, to ameliorate doxorubicin-induced alveolar bone toxicity.
{"title":"Melatonin and Metformin Mitigate Doxorubicin-Induced Alveolar Bone Toxicity.","authors":"B Srivichit, C Thonusin, R Aeimlapa, A Arinno, T Chunchai, N Charoenphandhu, N Chattipakorn, S C Chattipakorn","doi":"10.1177/00220345241261980","DOIUrl":"10.1177/00220345241261980","url":null,"abstract":"<p><p>Evidence concerning the osteotoxic effects of chemotherapy (doxorubicin) has been previously described. Periodontitis also progressively increases in patients receiving chemotherapy; however, the beneficial effects of melatonin and metformin on the alleviation of doxorubicin-induced osteotoxicity have never been investigated. Therefore, we investigated the negative impact of doxorubicin on alveolar bone homeostasis and the benefits of melatonin and metformin on the attenuation of doxorubicin-induced alveolar bone toxicity. Male Wistar rats were divided into 4 groups to receive either 1 mL of normal saline solution as a control group, 3 mg/kg of doxorubicin, 3 mg/kg of doxorubicin plus 10 mg/kg of melatonin, or 3 mg/kg of doxorubicin plus 250 mg/kg of metformin. Doxorubicin treatment was given on days 0, 4, 8, 15, 22, and 29, while interventions were given daily on days 0 to 29. Following euthanasia, blood and alveolar bones were collected for evaluation of oxidative stress, bone remodeling, inflammation, microarchitecture, and periodontal condition. We found that doxorubicin increased systemic oxidative stress, decreased antioxidative capacity, increased inflammation, decreased bone formation, increased bone reabsorption, impaired microarchitecture, and impaired periodontal condition of the alveolar bone. Although cotreatment with melatonin or metformin resulted in some improvement in these parameters, cotreatment with melatonin was more effective than cotreatment with metformin in terms of decreasing oxidative stress, reducing bone resorption, and improving microarchitecture and periodontal condition. All of these findings highlight the potential for antioxidants, especially melatonin, to ameliorate doxorubicin-induced alveolar bone toxicity.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-08-05DOI: 10.1177/00220345241259417
K L Kirkwood, T E Van Dyke, C L Kirkwood, L Zhang, J Panezai, A E Duran-Pinedo, E L Figgins, L K Ryan, J J Frias-Lopez, G Diamond
There is a strong association between vitamin D levels and periodontal disease based on numerous epidemiological studies. We have previously shown that experimental deficiency of serum vitamin D in mice leads to gingival inflammation and alveolar bone loss. Treatment of cultured oral epithelial cells with the active form of vitamin D, 1,25(OH)2 vitamin D3 (1,25(OH)2D3), inhibits the extracellular growth and intracellular invasion of bacteria associated with periodontal disease. Maintenance of periodontal health may be due in part to the anti-inflammatory activities of vitamin D. Furthermore, this hormone can induce the expression of an antimicrobial peptide in cultured oral epithelial cells. We have shown that oral epithelial cells are capable of converting inactive vitamin D to the active form, suggesting that topical treatment of the oral epithelium with inactive vitamin D could prevent the development of periodontitis. We subjected mice to ligature-induced periodontitis (LIP), followed by daily treatment with inactive vitamin D or 1,25(OH)2D3. Treatment with both forms led to a reduction in ligature-induced bone loss and inflammation. Gingival tissues obtained from vitamin D-treated LIP showed production of specialized proresolving mediators (SPM) of inflammation. To examine the mechanism, we demonstrated that apical treatment of 3-dimensional cultures of primary gingival epithelial cells with vitamin D prevented lipopolysaccharide-induced secretion of proinflammatory cytokines and led to a similar production of SPM. Analysis of the oral microbiome of the mice treated with vitamin D showed significant changes in resident bacteria, which reflects a shift toward health-associated species. Together, our results show that topical treatment of oral tissues with inactive vitamin D can lead to the maintenance of periodontal health through the regulation of a healthy microbiome and the stimulation of resolution of inflammation. This strongly supports the development of a safe and effective vitamin D-based topical treatment or preventive agent for periodontal inflammation and disease.
根据大量流行病学研究,维生素 D 水平与牙周病之间存在密切联系。我们以前的研究表明,小鼠实验性血清维生素 D 缺乏会导致牙龈炎症和牙槽骨流失。用维生素 D 的活性形式--1,25(OH)2 维生素 D3(1,25(OH)2D3)处理培养的口腔上皮细胞,可抑制与牙周病相关的细菌的胞外生长和胞内侵袭。此外,这种激素还能诱导培养的口腔上皮细胞表达一种抗菌肽。我们已经证明,口腔上皮细胞能够将非活性维生素 D 转化为活性形式,这表明用非活性维生素 D 局部治疗口腔上皮细胞可以预防牙周炎的发生。我们对小鼠进行了结扎诱导的牙周炎(LIP)治疗,然后每天用非活性维生素 D 或 1,25(OH)2D3进行治疗。这两种维生素都能减少结扎诱发的骨质流失和炎症。从经维生素 D 处理的 LIP 中获得的牙龈组织显示,产生了专门的炎症促溶解介质(SPM)。为了研究其机理,我们证明了用维生素 D 对原代牙龈上皮细胞的三维培养物进行根尖处理可防止脂多糖诱导的促炎细胞因子的分泌,并导致产生类似的 SPM。对接受维生素 D 治疗的小鼠口腔微生物组的分析表明,常驻细菌发生了显著变化,这反映出小鼠口腔微生物组向与健康相关的菌种转变。总之,我们的研究结果表明,用非活性维生素 D 局部治疗口腔组织可通过调节健康的微生物群和刺激炎症消退来维持牙周健康。这有力地支持了以安全有效的维生素 D 为基础的牙周炎症和疾病局部治疗或预防剂的开发。
{"title":"Topical Vitamin D Prevents Bone Loss and Inflammation in a Mouse Model.","authors":"K L Kirkwood, T E Van Dyke, C L Kirkwood, L Zhang, J Panezai, A E Duran-Pinedo, E L Figgins, L K Ryan, J J Frias-Lopez, G Diamond","doi":"10.1177/00220345241259417","DOIUrl":"10.1177/00220345241259417","url":null,"abstract":"<p><p>There is a strong association between vitamin D levels and periodontal disease based on numerous epidemiological studies. We have previously shown that experimental deficiency of serum vitamin D in mice leads to gingival inflammation and alveolar bone loss. Treatment of cultured oral epithelial cells with the active form of vitamin D, 1,25(OH)<sub>2</sub> vitamin D<sub>3</sub> (1,25(OH)<sub>2</sub>D<sub>3</sub>), inhibits the extracellular growth and intracellular invasion of bacteria associated with periodontal disease. Maintenance of periodontal health may be due in part to the anti-inflammatory activities of vitamin D. Furthermore, this hormone can induce the expression of an antimicrobial peptide in cultured oral epithelial cells. We have shown that oral epithelial cells are capable of converting inactive vitamin D to the active form, suggesting that topical treatment of the oral epithelium with inactive vitamin D could prevent the development of periodontitis. We subjected mice to ligature-induced periodontitis (LIP), followed by daily treatment with inactive vitamin D or 1,25(OH)<sub>2</sub>D<sub>3</sub>. Treatment with both forms led to a reduction in ligature-induced bone loss and inflammation. Gingival tissues obtained from vitamin D-treated LIP showed production of specialized proresolving mediators (SPM) of inflammation. To examine the mechanism, we demonstrated that apical treatment of 3-dimensional cultures of primary gingival epithelial cells with vitamin D prevented lipopolysaccharide-induced secretion of proinflammatory cytokines and led to a similar production of SPM. Analysis of the oral microbiome of the mice treated with vitamin D showed significant changes in resident bacteria, which reflects a shift toward health-associated species. Together, our results show that topical treatment of oral tissues with inactive vitamin D can lead to the maintenance of periodontal health through the regulation of a healthy microbiome and the stimulation of resolution of inflammation. This strongly supports the development of a safe and effective vitamin D-based topical treatment or preventive agent for periodontal inflammation and disease.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-08-05DOI: 10.1177/00220345241258990
A Soundia, N Elzakra, D Hadaya, I Gkouveris, O Bezouglaia, S Dry, T Aghaloo, S Tetradis
Macrophages are important regulators of bone remodeling, and M1 polarization is observed in the setting of medication-related osteonecrosis of the jaws (MRONJ). Here, we characterize the phenotype of macrophages during early stages of MRONJ development in zoledronate (ZA)-treated mice with periodontal disease and explore the role of rosiglitazone, a drug that has been reported to lower the M1/M2 macrophage ratio, in MRONJ burden. Mice received ZA, and experimental periodontal disease (EPD) was induced around their second left maxillary molar. The mice were euthanized 1, 2, or 4 wk later. Micro-computed tomography and histologic and immunohistochemical analyses were carried out. In a separate experiment, mice were treated with ZA in the absence or presence of rosiglitazone, EPD was induced for 5 wk, and the MRONJ burden was assessed. An M1 predilection was noted in ZA versus vehicle (Veh) mice at 1, 2, or 4 wk after ligature placement. M1 cells were found to be positive for MMP-13, and their presence coincided with disruption of the surrounding collagen network in ZA mice. Rosiglitazone caused a reversal in the M1/M2 polarization in Veh and ZA mice. Rosiglitazone did not cause significant radiographic changes 5 wk after EPD in Veh or ZA animals. Importantly, percentage osteonecrosis and bone exposure were decreased in the rosiglitazone-treated versus nontreated ZA sites 5 wk after EPD. Our data point to an important role of M1 macrophage polarization with an overexpression of MMP-13 in the early phases of MRONJ development and provide insight into the use of interventional approaches promoting an M2 phenotype as a preventative means to alleviate MRONJ burden.
{"title":"Macrophage Polarization during MRONJ Development in Mice.","authors":"A Soundia, N Elzakra, D Hadaya, I Gkouveris, O Bezouglaia, S Dry, T Aghaloo, S Tetradis","doi":"10.1177/00220345241258990","DOIUrl":"10.1177/00220345241258990","url":null,"abstract":"<p><p>Macrophages are important regulators of bone remodeling, and M1 polarization is observed in the setting of medication-related osteonecrosis of the jaws (MRONJ). Here, we characterize the phenotype of macrophages during early stages of MRONJ development in zoledronate (ZA)-treated mice with periodontal disease and explore the role of rosiglitazone, a drug that has been reported to lower the M1/M2 macrophage ratio, in MRONJ burden. Mice received ZA, and experimental periodontal disease (EPD) was induced around their second left maxillary molar. The mice were euthanized 1, 2, or 4 wk later. Micro-computed tomography and histologic and immunohistochemical analyses were carried out. In a separate experiment, mice were treated with ZA in the absence or presence of rosiglitazone, EPD was induced for 5 wk, and the MRONJ burden was assessed. An M1 predilection was noted in ZA versus vehicle (Veh) mice at 1, 2, or 4 wk after ligature placement. M1 cells were found to be positive for MMP-13, and their presence coincided with disruption of the surrounding collagen network in ZA mice. Rosiglitazone caused a reversal in the M1/M2 polarization in Veh and ZA mice. Rosiglitazone did not cause significant radiographic changes 5 wk after EPD in Veh or ZA animals. Importantly, percentage osteonecrosis and bone exposure were decreased in the rosiglitazone-treated versus nontreated ZA sites 5 wk after EPD. Our data point to an important role of M1 macrophage polarization with an overexpression of MMP-13 in the early phases of MRONJ development and provide insight into the use of interventional approaches promoting an M2 phenotype as a preventative means to alleviate MRONJ burden.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-06-13DOI: 10.1177/00220345241253526
H M Wang, K X Li, Z L Tian, Y L Zhu, X Y Liu, S H Yang, S W Qiao, S Zhu, Z S Shi
The water-rich nature of the dentin bonding microenvironment, coupled with the stresses on the bonding interface, contributes to the hydrolytic degradation of the hybrid layer, resulting in a decline in bonding durability and, ultimately, restoration failure. Currently, the 3-step etch-and-rinse technique remains the gold standard for dentin bonding, and the bonding mechanism mainly involves a physical interaction with little chemical bonding. In this study, we have developed a siloxane-modified polyurethane monomer (SPU) with acrylate and siloxane modifications that chemically binds to both collagen and hydroxyapatite in dentin. Formulated as a bisphenol A-glycidyl methacrylate alternative, the SPU monomer-based adhesive was designed to improve dentin bonding quality and durability. Attenuated total reflection Fourier transform infrared spectroscopy, thermogravimetric analysis, X-ray photoelectron spectroscopy, scanning electron microscopy, transmission electron microscope, and hydroxyproline release assays were performed on SPU-treated collagen, hydroxyapatite, and acid-etched dentin slices to dentin. The physicochemical properties of the configured SPU adhesives were profiled for polymerization behavior, water contact angle, and tensile strain and strength. The bonding effectiveness was assessed through micro-tensile strength, nano-leakage tests conducted on the bonded samples before and after thermal cycle aging. Finally, we further conducted in vivo and in vitro experiments to assess the biocompatibility of adhesives. The results showed that the siloxane groups of SPU monomer could covalently bind to dentin collagen and hydroxyapatite. The incorporation of SPU in the adhesive led to a significant increase in adhesive polymerization (P < 0.05) and tensile strain at break up to 134.11%. Furthermore, the SPU adhesive significantly improved dentin bond strength (P < 0.05), reduced interfacial nano-leakage (P < 0.05), and displayed good biocompatibility. In conclusion, the application of SPU, which achieves dual chemical bonding with dentin, can improve the quality of the hybrid layer, buffer the interfacial stresses, enhance the interfacial resistance to hydrolysis, and provide a feasible strategy to extend the service life of adhesive restorations.
{"title":"New Monomer Capable of Dual Chemical Binding with Dentin to Improve Bonding Durability.","authors":"H M Wang, K X Li, Z L Tian, Y L Zhu, X Y Liu, S H Yang, S W Qiao, S Zhu, Z S Shi","doi":"10.1177/00220345241253526","DOIUrl":"10.1177/00220345241253526","url":null,"abstract":"<p><p>The water-rich nature of the dentin bonding microenvironment, coupled with the stresses on the bonding interface, contributes to the hydrolytic degradation of the hybrid layer, resulting in a decline in bonding durability and, ultimately, restoration failure. Currently, the 3-step etch-and-rinse technique remains the gold standard for dentin bonding, and the bonding mechanism mainly involves a physical interaction with little chemical bonding. In this study, we have developed a siloxane-modified polyurethane monomer (SPU) with acrylate and siloxane modifications that chemically binds to both collagen and hydroxyapatite in dentin. Formulated as a bisphenol A-glycidyl methacrylate alternative, the SPU monomer-based adhesive was designed to improve dentin bonding quality and durability. Attenuated total reflection Fourier transform infrared spectroscopy, thermogravimetric analysis, X-ray photoelectron spectroscopy, scanning electron microscopy, transmission electron microscope, and hydroxyproline release assays were performed on SPU-treated collagen, hydroxyapatite, and acid-etched dentin slices to dentin. The physicochemical properties of the configured SPU adhesives were profiled for polymerization behavior, water contact angle, and tensile strain and strength. The bonding effectiveness was assessed through micro-tensile strength, nano-leakage tests conducted on the bonded samples before and after thermal cycle aging. Finally, we further conducted in vivo and in vitro experiments to assess the biocompatibility of adhesives. The results showed that the siloxane groups of SPU monomer could covalently bind to dentin collagen and hydroxyapatite. The incorporation of SPU in the adhesive led to a significant increase in adhesive polymerization (<i>P</i> < 0.05) and tensile strain at break up to 134.11%. Furthermore, the SPU adhesive significantly improved dentin bond strength (<i>P</i> < 0.05), reduced interfacial nano-leakage (<i>P</i> < 0.05), and displayed good biocompatibility. In conclusion, the application of SPU, which achieves dual chemical bonding with dentin, can improve the quality of the hybrid layer, buffer the interfacial stresses, enhance the interfacial resistance to hydrolysis, and provide a feasible strategy to extend the service life of adhesive restorations.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141312638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}