Effect of bottled fluoridated water to prevent dental caries in primary teeth: study protocol for a phase 2 parallel-group 3.5-year randomized controlled clinical trial (waterBEST).

BACKGROUND: Fluoridation of public water systems is known as a safe and effective strategy for preventing dental caries based on evidence from non-randomized studies. Yet 110 million Americans do not have access to a fluoridated public water system and many others do not drink tap water. This article describes the study protocol for the first randomized controlled trial (RCT) of fluoridated water that assesses its potential dental caries preventive efficacy when delivered in bottles. METHODS: waterBEST is a phase 2b proof-of-concept, randomized, quadruple-masked, placebo-controlled, parallel-group trial designed to estimate the potential efficacy of fluoridated versus non-fluoridated bottled water to prevent dental caries incidence in the first 4 years of life. Two hundred children living in eastern North Carolina, USA, and aged 2-6 months at screening are being allocated at random in a 1:1 ratio to receive fluoridated (0.7 mg/L F) or non-fluoridated bottled water sourced from two local public water systems. Throughout the 3.5-year intervention, study water is delivered monthly in 5-gallon bottles to each child's home with instructions to use it whenever the child consumes water as a beverage or in food preparation. Parents are interviewed quarterly to monitor children's water consumption and health. At annual visits, the presence of dental caries is evaluated with a dental screening examination. Clippings from fingernails and toenails are collected to quantify fluoride content as a biomarker of total fluoride intake. The primary endpoint is the number of primary tooth surfaces decayed, missing, or filled due to dental caries measured by the study dentist near the time of the child's fourth birthday. Tooth decay is assessed at the threshold of macroscopic enamel loss. For the primary aim, a least-squares, generalized linear model will estimate efficacy and its one-tailed, upper 80% confidence limit. DISCUSSION: waterBEST is the first evaluation of a randomized intervention of fluoridated drinking water in bottles to prevent dental caries in the primary dentition. This innovative method of delivering fluoridated water has the potential to prevent early childhood caries in a large segment of the US population that currently does not benefit from fluoridated public water. TRIAL REGISTRATION: ClinicalTrials.gov NCT04893681. Registered on March 2022. Last update posted on 10 October 2023. https://clinicaltrials.gov/study/NCT04893681?cond=Dental%20Caries%20in%20Children&term=fluoride&locStr=North%20Carolina,%20USA&country=United%20States&state=North%20Carolina&distance=50&rank=1.

Effect of bottled fluoridated water to prevent dental caries in primary teeth: study protocol for a phase 2 parallel group 3.5-year randomized controlled clinical trial (waterBEST).

Background: Fluoridation of public water systems is known as a safe and effective strategy for preventing dental caries based on evidence from non-randomized studies. Yet 110 million Americans do not have access to a fluoridated public water system and many others do not drink tap water. This article describes the study protocol for the first randomized controlled trial (RCT) of fluoridated water that assesses its potential dental caries preventive efficacy when delivered in bottles. Methods: waterBEST is a phase 2b proof-of-concept, randomized, quadruple-masked, placebo controlled, parallel group, trial designed to estimate the potential efficacy of fluoridated versus non-fluoridated bottled water to prevent dental caries incidence in the first four years of life. Two hundred children living in eastern North Carolina, USA, and aged 2-6 months at screening are being allocated at random in a 1:1 ratio to receive fluoridated (0.7 mg/L F) or non-fluoridated bottled water sourced from two local public water systems. Throughout the 3.5-year intervention, study water is delivered monthly in 5-gallon bottles to each child's home with instructions to use it whenever the child consumes water as a beverage or in food preparation. Parents are interviewed quarterly to monitor children's water consumption and health. At annual visits, the presence of dental caries is evaluated with a dental screening examination. Clippings from fingernails and toenails are collected to quantify fluoride content as a biomarker of total fluoride intake. The primary endpoint is the number of primary tooth surfaces decayed, missing, or filled due to dental caries measured by the study dentist near the time of the child's fourth birthday. Tooth decay is assessed at the threshold of macroscopic enamel loss. For the primary aim, a least-squares, generalized linear model will estimate efficacy and its one-tailed, upper 80% confidence limit. Discussion: waterBEST is the first evaluation of a randomized intervention of fluoridated drinking water in bottles to prevent dental caries in the primary dentition. This innovative method of delivering fluoridated water has potential to prevent early childhood caries in a large segment of the U.S. population that currently does not benefit from fluoridated public water.

Poor oral health influences head and neck cancer patient survival: an International Head and Neck Cancer Epidemiology Consortium pooled analysis.

BACKGROUND: Poor oral health has been identified as a prognostic factor potentially affecting the survival of patients with head and neck squamous cell carcinoma. However, evidence to date supporting this association has emanated from studies based on single cohorts with small-to-modest sample sizes. METHODS: Pooled analysis of 2449 head and neck squamous cell carcinoma participants from 4 studies of the International Head and Neck Cancer Epidemiology Consortium included data on periodontal disease, tooth brushing frequency, mouthwash use, numbers of natural teeth, and dental visits over the 10 years prior to diagnosis. Multivariable generalized linear regression models were used and adjusted for age, sex, race, geographic region, tumor site, tumor-node-metastasis stage, treatment modality, education, and smoking to estimate risk ratios (RR) of associations between measures of oral health and overall survival. RESULTS: Remaining natural teeth (10-19 teeth: RR = 0.81, 95% confidence interval [CI] = 0.69 to 0.95; ≥20 teeth: RR = 0.88, 95% CI = 0.78 to 0.99) and frequent dental visits (>5 visits: RR = 0.77, 95% CI = 0.66 to 0.91) were associated with better overall survival. The inverse association with natural teeth was most pronounced among patients with hypopharyngeal and/or laryngeal, and not otherwise specified head and neck squamous cell carcinoma. The association with dental visits was most pronounced among patients with oropharyngeal head and neck squamous cell carcinoma. Patient-reported gingival bleeding, tooth brushing, and report of ever use of mouthwash were not associated with overall survival. CONCLUSIONS: Good oral health as defined by maintenance of the natural dentition and frequent dental visits appears to be associated with improved overall survival among head and neck squamous cell carcinoma patients.

Comprehensive evaluation of methods for differential expression analysis of metatranscriptomics data.

Understanding the function of the human microbiome is important but the development of statistical methods specifically for the microbial gene expression (i.e. metatranscriptomics) is in its infancy. Many currently employed differential expression analysis methods have been designed for different data types and have not been evaluated in metatranscriptomics settings. To address this gap, we undertook a comprehensive evaluation and benchmarking of 10 differential analysis methods for metatranscriptomics data. We used a combination of real and simulated data to evaluate performance (i.e. type I error, false discovery rate and sensitivity) of the following methods: log-normal (LN), logistic-beta (LB), MAST, DESeq2, metagenomeSeq, ANCOM-BC, LEfSe, ALDEx2, Kruskal-Wallis and two-part Kruskal-Wallis. The simulation was informed by supragingival biofilm microbiome data from 300 preschool-age children enrolled in a study of childhood dental disease (early childhood caries, ECC), whereas validations were sought in two additional datasets from the ECC study and an inflammatory bowel disease study. The LB test showed the highest sensitivity in both small and large samples and reasonably controlled type I error. Contrarily, MAST was hampered by inflated type I error. Upon application of the LN and LB tests in the ECC study, we found that genes C8PHV7 and C8PEV7, harbored by the lactate-producing Campylobacter gracilis, had the strongest association with childhood dental disease. This comprehensive model evaluation offers practical guidance for selection of appropriate methods for rigorous analyses of differential expression in metatranscriptomics. Selection of an optimal method increases the possibility of detecting true signals while minimizing the chance of claiming false ones.

Selenomonas sputigena acts as a pathobiont mediating spatial structure and biofilm virulence in early childhood caries.

Streptococcus mutans has been implicated as the primary pathogen in childhood caries (tooth decay). While the role of polymicrobial communities is appreciated, it remains unclear whether other microorganisms are active contributors or interact with pathogens. Here, we integrate multi-omics of supragingival biofilm (dental plaque) from 416 preschool-age children (208 males and 208 females) in a discovery-validation pipeline to identify disease-relevant inter-species interactions. Sixteen taxa associate with childhood caries in metagenomics-metatranscriptomics analyses. Using multiscale/computational imaging and virulence assays, we examine biofilm formation dynamics, spatial arrangement, and metabolic activity of Selenomonas sputigena, Prevotella salivae and Leptotrichia wadei, either individually or with S. mutans. We show that S. sputigena, a flagellated anaerobe with previously unknown role in supragingival biofilm, becomes trapped in streptococcal exoglucans, loses motility but actively proliferates to build a honeycomb-like multicellular-superstructure encapsulating S. mutans, enhancing acidogenesis. Rodent model experiments reveal an unrecognized ability of S. sputigena to colonize supragingival tooth surfaces. While incapable of causing caries on its own, when co-infected with S. mutans, S. sputigena causes extensive tooth enamel lesions and exacerbates disease severity in vivo. In summary, we discover a pathobiont cooperating with a known pathogen to build a unique spatial structure and heighten biofilm virulence in a prevalent human disease.

Optimizing donor tooth selection for autotransplantation in the anterior maxilla via CBCT-based root width and crown-root angle measurements.

BACKGROUND/AIM: The clinical management of growing patients with missing teeth in the anterior maxilla can be challenging due to limited treatment options and high esthetic demands. Tooth autotransplantation (AT) is a viable option for these cases. The selection of donor teeth has been reported to be driven by root development, existing malocclusion, and esthetics. The aim of this study was to add to the evidence base of tooth selection criteria for AT by examining candidate donor teeth root width and crown-root angles, two factors arguably important for surgical planning and esthetics. MATERIAL AND METHODS: Cementoenamel junction (CEJ) tooth width and crown-root angle measurements were made using cone-beam computed tomography (CBCT) images of 30 children and adolescents of European descent (mean age = 13 years, range = 10-17 years; 63% male) from a private orthodontic practice. Measurements of maxillary central and lateral incisors (index teeth) were compared with measurements of maxillary second premolars, mandibular central incisors, and mandibular first and second premolars (candidate donor teeth). Analyses relied on descriptive statistics of mean within-subject differences between index and donor teeth and the proportion of individuals without clinically important differences (i.e., >1.5 mm width deficit and > 15 degrees crown-root angle difference). RESULTS: Mandibular first premolars were the most compatible teeth for the replacement of maxillary central incisors based on both width (≥97% of individuals) and angle measurements (≥87% of individuals), followed closely by mandibular second premolars. Mandibular central incisors were the most compatible for the replacement of maxillary laterals, among all individuals based on width and ≥ 90% based on angle, whereas mandibular first premolars were somewhat less compatible. CONCLUSIONS: The study offers evidence of within-person, CBCT-based root width dimension and crown-root angle compatibilities. This information can be considered in addition to existing tooth selection criteria for AT including Angle's classification, midline deviation, crowding severity, root development, and esthetics.

BZINB Model-Based Pathway Analysis and Module Identification Facilitates Integration of Microbiome and Metabolome Data.

Integration of multi-omics data is a challenging but necessary step to advance our understanding of the biology underlying human health and disease processes. To date, investigations seeking to integrate multi-omics (e.g., microbiome and metabolome) employ simple correlation-based network analyses; however, these methods are not always well-suited for microbiome analyses because they do not accommodate the excess zeros typically present in these data. In this paper, we introduce a bivariate zero-inflated negative binomial (BZINB) model-based network and module analysis method that addresses this limitation and improves microbiome-metabolome correlation-based model fitting by accommodating excess zeros. We use real and simulated data based on a multi-omics study of childhood oral health (ZOE 2.0; investigating early childhood dental caries, ECC) and find that the accuracy of the BZINB model-based correlation method is superior compared to Spearman's rank and Pearson correlations in terms of approximating the underlying relationships between microbial taxa and metabolites. The new method, BZINB-iMMPath, facilitates the construction of metabolite-species and species-species correlation networks using BZINB and identifies modules of (i.e., correlated) species by combining BZINB and similarity-based clustering. Perturbations in correlation networks and modules can be efficiently tested between groups (i.e., healthy and diseased study participants). Upon application of the new method in the ZOE 2.0 study microbiome-metabolome data, we identify that several biologically-relevant correlations of ECC-associated microbial taxa with carbohydrate metabolites differ between healthy and dental caries-affected participants. In sum, we find that the BZINB model is a useful alternative to Spearman or Pearson correlations for estimating the underlying correlation of zero-inflated bivariate count data and thus is suitable for integrative analyses of multi-omics data such as those encountered in microbiome and metabolome studies.

Barriers to oral health care for transgender and gender nonbinary populations.

BACKGROUND: Despite health disparities and barriers to medical care being well documented in the literature, transgender and gender nonbinary (TGNB) people's experiences and expectations with regard to oral health care remain understudied. The authors examined gender identity-related factors influencing experiences in the dental setting, aspects of subjective oral health, and avoidance of oral health care. METHODS: One-hundred eighteen TGNB people aged 13 through 70 years completed a 32-item questionnaire designed for this study. Data analysis relied on descriptive methods and bivariate comparisons using a conventional P < .05 statistical significance criterion. Qualitative description analysis was used to identify emerging themes from responses to an open-ended question. RESULTS: One-third of participants reported misgendering (that is, had been addressed by their incorrect name and pronouns in the dental setting). Although refusal of oral health care was rare in this sample of TGNB participants, more than one-half felt that their usual source of oral health care was not equipped to provide gender-appropriate care. Participants' avoidance due to gender identity was significantly associated with measures of self-reported suboptimal oral health. Common themes related to participants' oral health care experiences included gender insensitivity, awkward interactions, avoidance of care, and lack of gender-affirming providers. CONCLUSIONS: Discrepancies between TGNB patients' expectations and actual experiences suggest that their needs are often unmet in the dental setting, possibly contributing to gender identity-associated dental avoidance and oral health disparities. PRACTICAL IMPLICATIONS: Although these results need to be verified in larger and more diverse samples, they provide actionable information for improvement to this population's oral health and management.

BZINB model-based pathway analysis and module identification facilitates integration of microbiome and metabolome data.

Integration of multi-omics data is a challenging but necessary step to advance our understanding of the biology underlying human health and disease processes. To date, investigations seeking to integrate multi-omics (e.g., microbiome and metabolome) employ simple correlation-based network analyses; however, these methods are not always well-suited for microbiome analyses because they do not accommodate the excess zeros typically present in these data. In this paper, we introduce a bivariate zero-inflated negative binomial (BZINB) model-based network and module analysis method that addresses this limitation and improves microbiome-metabolome correlation-based model fitting by accommodating excess zeros. We use real and simulated data based on a multi-omics study of childhood oral health (ZOE 2.0; investigating early childhood dental disease, ECC) and find that the accuracy of the BZINB model-based correlation method is superior compared to Spearman’s rank and Pearson correlations in terms of approximating the underlying relationships between microbial taxa and metabolites. The new method, BZINB-iMMPath facilitates the construction of metabolite-species and species-species correlation networks using BZINB and identifies modules of (i.e., correlated) species by combining BZINB and similarity-based clustering. Perturbations in correlation networks and modules can be efficiently tested between groups (i.e., healthy and diseased study participants). Upon application of the new method in the ZOE 2.0 study microbiome-metabolome data, we identify that several biologically-relevant correlations of ECC-associated microbial taxa with carbohydrate metabolites differ between healthy and dental caries-affected participants. In sum, we find that the BZINB model is a useful alternative to Spearman or Pearson correlations for estimating the underlying correlation of zero-inflated bivariate count data and thus is suitable for integrative analyses of multi-omics data such as those encountered in microbiome and metabolome studies.

"The pediatric dentist is different": A qualitative study of young children's caregivers' experiences of oral health care in the Galapagos Islands.

BACKGROUND: Little is known about factors influencing children's access to and use of oral healthcare services in the Galapagos Islands, a resource-limited setting. AIM: We sought to understand caregivers' experiences and factors influencing their children's use of dental services on San Cristobal Island in the Galapagos Archipelago. DESIGN: A community-based qualitative interview study was carried out among 25 caregivers of children aged 6 months to 10 years. Participants were recruited via a random walk door-to-door approach in 10 neighborhoods, and interviews were conducted by a trained research assistant who is native of the Galapagos Islands. We employed a grounded theory-based qualitative data analysis based on inductive coding to identify and report major emerging themes and illustrative participant quotes. RESULTS: Two major themes emerged related to children's oral health care. Participants expressed their preference for care provided by paediatric versus general dentists and recognized the important role of school-based dental care programs, acknowledging their strengths and weaknesses. CONCLUSIONS: Participants' lived experiences were informative and helped improve our understanding of factors influencing children's use of dental services in the Galapagos Islands. Above and beyond their local relevance, these themes and insights are likely applicable to other global communities that experience similar barriers of access to oral healthcare services.

Subtypes of early childhood caries predict future caries experience.

OBJECTIVES: To test whether postulated subtypes of early childhood caries (ECC) are predictive of subsequent caries experience in a population-based cohort of Swedish children. METHODS: The study included children aged between 3 and 5 years at study entry with dental records available for at least 5 years of follow-up. Dental record data were retrieved from the Swedish Quality Registry for Caries and Periodontal disease (SKaPa) for the initial and follow-up visits. Participants who had ECC at study entry were assigned to one of five ECC subtypes (termed classes 1-5) using latent class modelling of tooth surface-level caries experience. Subsequent experience of caries was assessed using the decayed, missing and filled surfaces indices (dmfs/DMFS) at follow-up visits, and compared between ECC subtypes using logistic and negative binomial regression modelling. RESULTS: The study included 128 355 children who had 3 or more dental visits spanning at least 5 years post-baseline. Of these children, 31 919 had caries at the initial visit. Baseline ECC subtype was associated with differences in subsequent disease experience. As an example, 83% of children who had a severe form of ECC at age 5 went on to have caries in the permanent dentition by the end of the study, compared to 51% of children who were caries-free at age 5 (adjusted odds ratio of 4.9 for new disease at their third follow-up). CONCLUSIONS: ECC subtypes assigned at a baseline visit are associated with differences in subsequent caries experience in both primary and permanent teeth. This suggests that the development and future validation of an ECC classification can be used in addition to current prediction tools to help identify children at high risk of developing new caries lesions throughout childhood and adolescence.

Patterns of site-level periodontal disease and within-mouth correlation among older adults in the Hispanic Community Health Study/Study of Latinos.

OBJECTIVES: Clinical measures of periodontal disease such as attachment loss (CAL) and probing depth (PD) vary considerably between and within individuals with periodontitis and are known to be influenced by person-level factors (e.g. age and race/ethnicity) as well as intraoral characteristics (e.g. tooth type and location). This study sought to characterize site-level disease patterns and correlations using both person-level and intraoral factors through a model-based approach. METHODS: This study used full-mouth, six sites per tooth, periodontal examination data collected from 2301 Hispanic/Latino adults aged 60-74 years in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The presence of site-level CAL ≥3 mm and PD ≥4 mm was estimated using generalized estimating equations (GEE), explicitly modelling pairwise periodontal site correlations, while adjusting for number of teeth, sex and Hispanic/Latino background. Subsequently tooth- and tooth-site patterns of intraoral CAL ≥3 mm and PD ≥4 mm were estimated and visualized in the HCHS/SOL population. RESULTS: The findings showed that posterior sites had the highest odds of CAL ≥3 mm and PD ≥4 mm. Sites located in the interproximal space had higher odds of PD ≥4 mm but lower odds of CAL ≥3 mm than non-interproximal sites. Mexicans had the lowest odds of CAL ≥3 mm among all Hispanic/Latino backgrounds. While Mexicans had lower odds of PD ≥4 mm than Central Americans and Cubans, they had higher odds than Dominicans and Puerto Ricans. Site-level proportions and pairwise correlations of PD ≥4 mm were generally smaller than those of CAL ≥3 mm. CONCLUSIONS: The patterns of site-level probabilities of clinical measures of periodontal disease can be defined based on tooth, site and individual-level characteristics. Intraoral correlation patterns, while complex, are quantifiable. The risk factors for site-level CAL ≥3 mm may differ from those of PD ≥4 mm. Likewise, participant risk factors for site-level clinical measures of periodontal disease are distinct from those that affect individual-level periodontitis prevalence. Future epidemiological investigations should consider model-based approaches when examining site-level disease probabilities to identify intra-oral patterns of periodontal disease and make inferences about the larger population.

Methodological Considerations in Longitudinal Analyses of Microbiome Data: A Comprehensive Review.

Biological processes underlying health and disease are inherently dynamic and are best understood when characterized in a time-informed manner. In this comprehensive review, we discuss challenges inherent in time-series microbiome data analyses and compare available approaches and methods to overcome them. Appropriate handling of longitudinal microbiome data can shed light on important roles, functions, patterns, and potential interactions between large numbers of microbial taxa or genes in the context of health, disease, or interventions. We present a comprehensive review and comparison of existing microbiome time-series analysis methods, for both preprocessing and downstream analyses, including differential analysis, clustering, network inference, and trait classification. We posit that the careful selection and appropriate utilization of computational tools for longitudinal microbiome analyses can help advance our understanding of the dynamic host-microbiome relationships that underlie health-maintaining homeostases, progressions to disease-promoting dysbioses, as well as phases of physiologic development like those encountered in childhood.

Age-specific associations with dental caries in HIV-infected, exposed but uninfected and HIV-unexposed uninfected children in Nigeria.

BACKGROUND: HIV infection and its management confer a substantial health burden to affected individuals and have been associated with increased risk of oral and dental diseases. In this study, we sought to quantify HIV-associated differences in the prevalence and severity of dental caries in the primary and permanent dentition of 4-11-year-old Nigerian Children. METHODS: We used clinical, laboratory, demographic, and behavioral data obtained from an ongoing cohort study of age-matched HIV-infected (HI, n = 181), HIV-exposed-but-uninfected (HEU, n = 177), and HIV-unexposed-and-uninfected (HUU, n = 186) children. Measures of dental caries experience (i.e., prevalence and severity) were based on dmft/DMFT indices recorded by trained and calibrated clinical examiners. Differences in primary and permanent dentition caries experience between HI, HEU, and HUU were estimated using multivariable logistic and negative binomial regression modeling. RESULTS: HI children had significantly higher caries experience (33%) compared to HEU (15%) and HUU (22%) children. This difference persisted in fully adjusted analyses [odds ratio (OR) = 1.6; 95% confidence interval (CI) = 1.0-2.6], was most pronounced in the permanent dentition (OR = 3.4; 95% CI = 1.2-9.5), and mirrored differences in caries severity. While molars were predominantly affected in both primary and permanent dentitions, caries lesion patterns differed between dentitions. Caries severity was significantly associated with hypoplastic primary teeth, gingival inflammation, and lower CD4 counts. CONCLUSIONS: We found that the higher prevalence and severity of dental caries among HI children was driven by increased burden of permanent dentition caries compared to their uninfected counterparts. The dentition-specific associations identified in this study highlight the need to design and implement age-specific caries prevention strategies. These may include intensified oral hygiene regimens aimed at mitigating the cariogenic impact of hyposalivation among HI children. Similarly, the long-lasting impacts of developmental defects of the enamel in the primary and permanent dentitions must not be ignored.

Patient and Caregiver Perceptions of Animal Assisted Activity in Orthodontics.

Dental anxiety affects up to 21% of children and 80% of adults and is associated with lifelong dental avoidance. Animal assisted activity (AAA) is widely used to reduce anxiety and pain in medical settings and has promise in dentistry. The primary objective of this study was to evaluate caregiver and patient perceptions of canine AAA in orthodontics. A cross-sectional survey consisting of pre-tested and validated questions was conducted (n = 800) including orthodontic patients (n = 352 minors, n = 204 adults) and parents/caregivers (n = 244) attending university orthodontic clinics. In this study, AAA and dog therapy were not used or tested for dental anxiety management. More than a third of orthodontic patients (37%) had moderate or greater anxiety related to care. Participants believed that therapy animals would make dental experiences more enjoyable (75%) and reduce anxiety (82%). There was little to no concern expressed regarding cleanliness (83%), allergies (81%), and safety (89%) with a therapy animal in dental settings. Almost half of the participants would preferentially select an orthodontic office offering AAA. In light of the COVID-19 pandemic, we assessed whether perceptions of AAA changed before and after the shutdown of dental offices, with no significant differences. Across patients and caregivers, the responses support the use of AAA in orthodontic settings with minimal concerns.

Interferon activated gene 204 protects against bone loss in experimental periodontitis.

BACKGROUND: Periodontal destruction can be the result of different known and yet-to-be-discovered biological pathways. Recent human genetic association studies have implicated interferon-gamma inducible protein 16 (IFI16) and absent in melanoma 2 (AIM2) with high periodontal interleukin (IL)-1ß levels and more destructive disease, but mechanistic evidence is lacking. Here, we sought to experimentally validate these observational associations and better understand IFI16 and AIM2's roles in periodontitis. METHODS: Periodontitis was induced in Ifi204-/- (IFI16 murine homolog) and Aim2-/- mice using the ligature model. Chimeric mice were created to identify the main source cells of Ifi204 in the periodontium. IFI16-silenced human endothelial cells were treated with periodontal pathogens in vitro. Periodontal tissues from Ifi204-/- mice were evaluated for alveolar bone (micro-CT), cell inflammatory infiltration (MPO+ staining), Il1b (qRT-PCR), and osteoclast numbers (cathepsin K+ staining). RESULTS: Ifi204-deficient mice> exhibited >20% higher alveolar bone loss than wild-type (WT) (P < 0.05), while no significant difference was found in Aim2-/- mice. Ifi204's effect on bone loss was primarily mediated by a nonbone marrow source and was independent of Aim2. Ifi204-deficient mice had greater neutrophil/macrophage trafficking into gingival tissues regardless of periodontitis development compared to WT. In human endothelial cells, IFI16 decreased the chemokine response to periodontal pathogens. In murine periodontitis, Ifi204 depletion elevated gingival Il1b and increased osteoclast numbers at diseased sites (P < 0.05). CONCLUSIONS: These findings support IFI16's role as a novel regulator of inflammatory cell trafficking to the periodontium that protects against bone loss and offers potential targets for the development of new periodontal disease biomarkers and therapeutics.

PARTITIONING AROUND MEDOIDS CLUSTERING AND RANDOM FOREST CLASSIFICATION FOR GIS-INFORMED IMPUTATION OF FLUORIDE CONCENTRATION DATA.

Community water fluoridation is an important component of oral health promotion, as fluoride exposure is a well-documented dental caries-preventive agent. Direct measurements of domestic water fluoride content provide valuable information regarding individuals' fluoride exposure and thus caries risk; however, they are logistically challenging to carry out at a large scale in oral health research. This article describes the development and evaluation of a novel method for the imputation of missing domestic water fluoride concentration data informed by spatial autocorrelation. The context is a state-wide epidemiologic study of pediatric oral health in North Carolina, where domestic water fluoride concentration information was missing for approximately 75% of study participants with clinical data on dental caries. A new machine-learning-based imputation method that combines partitioning around medoids clustering and random forest classification (PAMRF) is developed and implemented. Imputed values are filtered according to allowable error rates or target sample size, depending on the requirements of each application. In leave-one-out cross-validation and simulation studies, PAMRF outperforms four existing imputation approaches-two conventional spatial interpolation methods (i.e., inverse-distance weighting, IDW and universal kriging, UK) and two supervised learning methods (k-nearest neighbors, KNN and classification and regression trees, CART). The inclusion of multiply imputed values in the estimation of the association between fluoride concentration and dental caries prevalence resulted in essentially no change in PAMRF estimates but substantial gains in precision due to larger effective sample size. PAMRF is a powerful new method for the imputation of missing fluoride values where geographical information exists.

Maladaptive trained immunity and clonal hematopoiesis as potential mechanistic links between periodontitis and inflammatory comorbidities.

Periodontitis is bidirectionally associated with systemic inflammatory disorders. The prevalence and severity of this oral disease and linked comorbidities increases with aging. Here, we review two newly emerged concepts, trained innate immunity (TII) and clonal hematopoiesis of indeterminate potential (CHIP), which together support a potential hypothesis on how periodontitis affects and is affected by comorbidities and why the susceptibility to periodontitis and comorbidities increases with aging. Given that chronic diseases are largely triggered by the action of inflammatory immune cells, modulation of their bone marrow precursors, the hematopoietic stem and progenitor cells (HSPCs), may affect multiple disorders that emerge as comorbidities. Such alterations in HSPCs can be mediated by TII and/or CHIP, two non-mutually exclusive processes sharing a bias for enhanced myelopoiesis and production of innate immune cells with heightened proinflammatory potential. TII is a state of elevated immune responsiveness based on innate immune (epigenetic) memory. Systemic inflammation can initiate TII in the bone marrow via sustained rewiring of HSPCs, which thereby display a skewing toward the myeloid lineage, resulting in generation of hyper-reactive or "trained" myeloid cells. CHIP arises from aging-related somatic mutations in HSPCs, which confer a survival and proliferation advantage to the mutant HSPCs and give rise to an outsized fraction of hyper-inflammatory mutant myeloid cells in the circulation and tissues. This review discusses emerging evidence that supports the notion that TII and CHIP may underlie a causal and age-related association between periodontitis and comorbidities. A holistic mechanistic understanding of the periodontitis-systemic disease connection may offer novel diagnostic and therapeutic targets for treating inflammatory comorbidities.

Guardians' Self-Reported Fair/Poor Oral Health Is Associated with Their Young Children's Fair/Poor Oral Health and Clinically Determined Dental Caries Experience.

In this cross-sectional, community-based study among a multi-ethnic sample of preschool-age children in North Carolina, United States, we sought to quantify the association between guardians' self-reported oral health and their children's oral health and determine whether race/ethnicity and education level modify these associations. We used questionnaire (n = 7852) responses about caregivers' and their children's oral health and clinical examination-derived (n = 6243) early childhood caries (ECC) status defined at the ICDAS ≥ 3 caries lesion detection threshold. We used multi-level mixed-effects generalized linear models to examine the associations between the guardians' reported oral health and their children's reported and clinically determined oral health among the entire sample and within strata of race/ethnicity, guardians' education, and children's dental home. The guardians' and their children's reported fair/poor oral health (FPOH) were 32% and 15%, respectively, whereas 54% of the children had ECC and 36% had unrestored disease. The guardians' FPOH was strongly associated with their children's FPOH (average marginal effect (AME) = +19 percentage points (p.p.); 95% CI = 17-21), and this association was most pronounced among Hispanics, lower-educated guardians, and children without a dental home. Similar patterns, but smaller-in-magnitude associations, were found for the guardians' FPOH and their children's clinically determined ECC (AME = +9 p.p.; 95% CI = 6-12) and unrestored disease (AME = +7 p.p.; 95% CI = 4-9). The study's findings support a strong association between guardians' and their children's reported and clinically determined oral health and implicate ethnicity, education, and having a dental home as factors possibly modifying the magnitude of these associations.