Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss.

Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3aR878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.

Human oral mucosa cell atlas reveals a stromal-neutrophil axis regulating tissue immunity.

The oral mucosa remains an understudied barrier tissue. This is a site of rich exposure to antigens and commensals, and a tissue susceptible to one of the most prevalent human inflammatory diseases, periodontitis. To aid in understanding tissue-specific pathophysiology, we compile a single-cell transcriptome atlas of human oral mucosa in healthy individuals and patients with periodontitis. We uncover the complex cellular landscape of oral mucosal tissues and identify epithelial and stromal cell populations with inflammatory signatures that promote antimicrobial defenses and neutrophil recruitment. Our findings link exaggerated stromal cell responsiveness with enhanced neutrophil and leukocyte infiltration in periodontitis. Our work provides a resource characterizing the role of tissue stroma in regulating mucosal tissue homeostasis and disease pathogenesis.

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.

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.

"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.

Importance of Genetic Studies of Cardiometabolic Disease in Diverse Populations.

Genome-wide association studies have revolutionized our understanding of the genetic underpinnings of cardiometabolic disease. Yet, the inadequate representation of individuals of diverse ancestral backgrounds in these studies may undercut their ultimate potential for both public health and precision medicine. The goal of this review is to describe the imperativeness of studying the populations who are most affected by cardiometabolic disease, to the aim of better understanding the genetic underpinnings of the disease. We support this premise by describing the current variation in the global burden of cardiometabolic disease and emphasize the importance of building a globally and ancestrally representative genetics evidence base for the identification of population-specific variants, fine-mapping, and polygenic risk score estimation. We discuss the important ethical, legal, and social implications of increasing ancestral diversity in genetic studies of cardiometabolic disease and the challenges that arise from the (1) lack of diversity in current reference populations and available analytic samples and the (2) unequal generation of health-associated genomic data and their prediction accuracies. Despite these challenges, we conclude that additional, unprecedented opportunities lie ahead for public health genomics and the realization of precision medicine, provided that the gap in diversity can be systematically addressed. Achieving this goal will require concerted efforts by social, academic, professional and regulatory stakeholders and communities, and these efforts must be based on principles of equity and social justice.

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.

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.

Genomics of periodontal disease and tooth morbidity.

In this review we critically summarize the evidence base and the progress to date regarding the genomic basis of periodontal disease and tooth morbidity (ie, dental caries and tooth loss), and discuss future applications and research directions in the context of precision oral health and care. Evidence for these oral/dental traits from genome-wide association studies first emerged less than a decade ago. Basic and translational research activities in this domain are now under way by multiple groups around the world. Key departure points in the oral health genomics discourse are: (a) some heritable variation exists for periodontal and dental diseases; (b) the environmental component (eg, social determinants of health and behavioral risk factors) has a major influence on the population distribution but probably interacts with factors of innate susceptibility at the person-level; (c) sizeable, multi-ethnic, well-characterized samples or cohorts with high-quality measures on oral health outcomes and genomics information are required to make decisive discoveries; (d) challenges remain in the measurement of oral health and disease, with current periodontitis and dental caries traits capturing only a part of the health-disease continuum, and are little or not informed by the underlying biology; (e) the substantial individual heterogeneity that exists in the clinical presentation and lifetime trajectory of oral disease can be identified and leveraged in a precision medicine framework or, if unappreciated, can hamper translational efforts. In this review we discuss how composite or biologically informed traits may offer improvements over clinically defined ones for the genomic interrogation of oral diseases. We demonstrate the utility of the results of genome-wide association studies for the development and testing of a genetic risk score for severe periodontitis. We conclude that exciting opportunities lie ahead for improvements in the oral health of individual patients and populations via advances in our understanding of the genomic basis of oral health and disease. The pace of new discoveries and their equitable translation to practice will largely depend on investments in the education and training of the oral health care workforce, basic and population research, and sustained collaborative efforts..

Advances in precision oral health.

The concept of precision dentistry as it relates to precision medicine is relatively new to the field of oral health. Precision dentistry is a contemporary, multifaceted, data-driven approach to oral health care that uses individual characteristics to stratify similar patients into phenotypic groups. The objective is to provide clinicians with the information that will allow them to improve treatment planning and a patient's response to treatment. Providers that use a precision oral health approach would move away from using an "average treatment" for all patients with a particular diagnosis and move toward more specific treatments for patients within each diagnostic subgroup. Precision dentistry requires a method or a model that places each individual in a subgroup where each member is the same as every other member in relation to the disease of interest. Precision dentistry is a paradigm shift that requires a new way of thinking about diagnostic categories. This approach uses patients' risk factor data (including, but not limited to, genetic, environmental, and health behavioral), rather than expert opinion or clinical presentation alone, to redefine traditional categories of health and disease. We review aspects of current efforts to allow precision dentistry to be realized and focus on one of the major innovations that may help precision dentistry to be practiced by periodontists, the World Workshop Model. Another approach is the Periodontal Profile Class system. These two approaches represent examples of supervised and unsupervised learning systems, respectively. This review compares and contrasts these two learning systems for their ability to classify patients into homogeneous disease and risk groups, as well as their feasibility at achieving the objective of enabling precision dentistry. We conclude that: (a) the World Workshop Model concept of stages and grades works as expected, in that periodontal status appears to be more serious in each successive stage. In addition, the seriousness and the complexity of the disease are greater as the grade increases within each stage. Stages and grades are important for precision dentistry because they consider the risk of future disease and the prognosis, and enable practitioners to use more signs, symptoms, and other associated factors when placing a patient in a diagnostic category; (b) the assignment of stages and grades using unsupervised learning systems is superior to using supervised learning systems for the prediction of 10-year tooth loss and 3-year attachment loss progression. In addition, the unsupervised learning approach (Periodontal Profile Class stages) results in stronger associations between the periodontal phenotypes and systemic diseases and conditions (prevalent diabetes, C-reactive protein, and incident stroke). This probably occurs because an unsupervised learning model produces more data-driven, mutually exclusive, homogeneous groups than a supervised learning model.

Development of a Greek Oral health literacy measurement instrument: GROHL.

BACKGROUND: Oral health literacy is an important construct for both clinical and public health outcomes research. The need to quantify and test OHL has led to the development of measurement instruments and has generated a substantial body of recent literature. A commonly used OHL instrument is REALD-30, a word recognition scale that has been adapted for use in several languages. The objective of this study was the development and testing of the Greek language oral health literacy measurement instrument (GROHL). METHODS: Data from 282 adult patients of two private dental clinics in Athens, Greece were collected via in-person interviews. Forty-four words were initially considered and tested for inclusion. Item response theory analysis (IRT) and 2-parameter logistic models assessing difficulty and discriminatory ability were used to identify an optimal scale composition. Internal consistency was examined using Cronbach's alpha and test-retest reliability was measured using intraclass correlation coefficient (ICC) in a subset of 20 participants over a two-week period. Convergent validity was tested against functional health literacy screening (HLS) items, dental knowledge (DK), oral health behaviors (OHBs), oral health-related quality of life (OHRQoL; OHIP-14 index), as well as self-reported oral and general health status. RESULTS: From an initial item pool of 44 items that were carried forward to IRT, 12 were excluded due to no or little variance, 10 were excluded due to low item-test correlation, and 2 due to insignificant contribution to the scale, i.e., difficulty parameter estimate with p > 0.05. The twenty remaining items composed the final index which showed favorable internal consistency (alpha = 0.80) and test-retest reliability (ICC = 0.95). The summary score distribution did not depart from normality (p = 0.32; mean = 11.5; median = 12; range = 1-20). GROHL scores were positively correlated with favorable oral hygiene behaviors and dental attendance, as well as HLS, DK and education level. CONCLUSION: The GROHL demonstrated good psychometric properties and can be used for outcomes research in clinical and public health settings.

Biologically Defined or Biologically Informed Traits Are More Heritable Than Clinically Defined Ones: The Case of Oral and Dental Phenotypes.

The genetic basis of oral health has long been theorized, but little information exists on the heritable variance in common oral and dental disease traits explained by the human genome. We sought to add to the evidence base of heritability of oral and dental traits using high-density genotype data in a well-characterized community-based cohort of middle-age adults. We used genome-wide association (GWAS) data combined with clinical and biomarker information in the Dental Atherosclerosis Risk In Communities (ARIC) cohort. Genotypes comprised SNPs directly typed on the Affymetrix Genome-Wide Human SNP Array 6.0 chip with minor allele frequency of >5% (n = 656,292) or were imputed using HapMap II-CEU (n = 2,104,905). We investigated 30 traits including "global" [e.g., number of natural teeth (NT) and incident tooth loss], clinically defined (e.g., dental caries via the DMFS index, periodontitis via the CDC/AAP and WW17 classifications), and biologically informed (e.g., subgingival pathogen colonization and "complex" traits). Heritability (i.e., variance explained; h2) was calculated using Visscher's Genome-wide Complex Trait Analysis (GCTA), using a random-effects mixed linear model and restricted maximum likelihood (REML) regression adjusting for ancestry (10 principal components), age, and sex. Heritability estimates were modest for clinical traits-NT = 0.11 (se = 0.07), severe chronic periodontitis (CDC/AAP) = 0.22 (se = 0.19), WW17 Stage 4 vs. 1/2 = 0.15 (se = 0.11). "High gingival index" and "high red complex colonization" had h2 > 0.50, while a periodontal complex trait defined by high IL-1ß GCF expression and Aggregatibacter actinomycetemcomitans subgingival colonization had the highest h2 = 0.72 (se = 0.32). Our results indicate that all GWAS SNPs explain modest levels of the observed variance in clinical oral and dental measures. Subgingival bacterial colonization and complex phenotypes encompassing both bacterial colonization and local inflammatory response had the highest heritability, suggesting that these biologically informed traits capture aspects of the disease process and are promising targets for genomics investigations, according to the notion of precision oral health.

Genome-wide association study of biologically informed periodontal complex traits offers novel insights into the genetic basis of periodontal disease.

Genome-wide association studies (GWAS) of chronic periodontitis (CP) defined by clinical criteria alone have had modest success to-date. Here, we refine the CP phenotype by supplementing clinical data with biological intermediates of microbial burden (levels of eight periodontal pathogens) and local inflammatory response (gingival crevicular fluid IL-1ß) and derive periodontal complex traits (PCTs) via principal component analysis. PCTs were carried forward to GWAS (∼2.5 million markers) to identify PCT-associated loci among 975 European American adult participants of the Dental ARIC study. We sought to validate these findings for CP in the larger ARIC cohort (n = 821 participants with severe CP, 2031-moderate CP, 1914-healthy/mild disease) and an independent German sample including 717 aggressive periodontitis cases and 4210 controls. We identified six PCTs with distinct microbial community/IL-1ß structures, although with overlapping clinical presentations. PCT1 was characterized by a uniformly high pathogen load, whereas PCT3 and PCT5 were dominated by Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, respectively. We detected genome-wide significant signals for PCT1 (CLEC19A, TRA, GGTA2P, TM9SF2, IFI16, RBMS3), PCT4 (HPVC1) and PCT5 (SLC15A4, PKP2, SNRPN). Overall, the highlighted loci included genes associated with immune response and epithelial barrier function. With the exception of associations of BEGAIN with severe and UBE3D with moderate CP, no other loci were associated with CP in ARIC or aggressive periodontitis in the German sample. Although not associated with current clinically determined periodontal disease taxonomies, upon replication and mechanistic validation these candidate loci may highlight dysbiotic microbial community structures and altered inflammatory/immune responses underlying biological sub-types of CP.

Prenatal Oral Health Counseling by Primary Care Physicians: Results of a National Survey.

Objectives Limited information exists on the extent oral health is addressed in the context of prenatal care. This study sought to investigate characteristics of primary care physicians (PCP) who provide oral health counseling to pregnant women. Methods The study relied upon data from the 2013 Survey of PCP on Oral Health. Provision of oral health counseling to pregnant women (sometimes vs. rarely/never) was the primary outcome. Covariates included respondents' demographic and practice characteristics, oral health-related training, knowledge, attitudes, preparedness and clinical behaviors. The analytical strategy included bivariate tests and multivariable Poisson regression modeling, accounting for the survey design; inference was based upon marginal effects estimation. Results Two-thirds of PCP (233 out of 366 respondents) reported providing oral health counseling to pregnant women. In bivariate comparisons, female PCP, PCP with oral health-specific instruction during medical training, favorable oral health-related attitudes, behaviors, preparedness, and knowledge were more likely to provide counseling (p < 0.05). Multivariable analyses confirmed the independent associations of female gender [marginal effect = + 9.7 percentage points (p.p.); 95% confidence interval (CI) = 0.0-19.0], years in practice (- 0.4 p.p. for each added year; 95% CI = - 0.09 to 0.0), oral health continuing education (+ 13.2 p.p.; 95% CI = 2.6-23.8), preparedness (+ 23.0 p.p.; 95% CI = 16.9-29.0) and oral health counseling of adult patients with other conditions (+ 8.8 p.p.; 95% CI = 4.6-13.3) with prenatal oral health counseling. Conclusions for Practice A considerable proportion of PCP nationwide counsel pregnant patients on oral health. Provider attributes including education and preparedness appear as promising targets for interventions aimed to enhance pregnant women's oral health and care.

Marginalized zero-inflated Poisson models with missing covariates.

Unlike zero-inflated Poisson regression, marginalized zero-inflated Poisson (MZIP) models for counts with excess zeros provide estimates with direct interpretations for the overall effects of covariates on the marginal mean. In the presence of missing covariates, MZIP and many other count data models are ordinarily fitted using complete case analysis methods due to lack of appropriate statistical methods and software. This article presents an estimation method for MZIP models with missing covariates. The method, which is applicable to other missing data problems, is illustrated and compared with complete case analysis by using simulations and dental data on the caries preventive effects of a school-based fluoride mouthrinse program.

Exploring the genomic basis of early childhood caries: a pilot study.

OBJECTIVE: A genetic component in early childhood caries (ECC) is theorized, but no genome-wide investigations of ECC have been conducted. This pilot study is part of a long-term research program aimed to: (1) determine the proportion of ECC variance attributable to the human genome and (2) identify ECC-associated genetic loci. METHODS: The study's community-based sample comprised 212 children (mean age=39 months; range = 30-52 months; males = 55%; Hispanic/Latino = 35%, African-American = 32%; American Academy of Pediatric Dentistry definition of ECC prevalence = 38%). Approximately 2.4 million single nucleotide polymorphisms (SNPs) were genotyped using DNA purified from saliva. A P < 5 × 10-8 criterion was used for genome-wide significance. SNPs with P < 5 × 10-5 were followed-up in three independent cohorts of 921 preschool-age children with similar ECC prevalence. RESULTS: SNPs with minor allele frequency ≥5% explained 52% (standard error = 54%) of ECC variance (one-sided P = 0.03). Unsurprisingly, given the pilot's small sample size, no genome-wide significant associations were found. An intergenic locus on 4q32 (rs4690994) displayed the strongest association with ECC [P = 2.3 × 10-6 ; odds ratio (OR) = 3.5; 95% confidence interval (CI) = 2.1-5.9]. Thirteen loci with suggestive associations were followed-up - none showed evidence of association in the replication samples. CONCLUSION: This study's findings support a heritable component of ECC and demonstrate the feasibility of conducting genomics studies among preschool-age children.

Trends and Characteristics of Pediatric Dentistry Patients Treated under General Anesthesia.

PURPOSE: The aims of this study were to describe the demographic characteristics of pediatric dentistry patients undergoing dental rehabilitation under general anesthesia (DRGA) at UNC-Chapel Hill during the last 13 years and identify factors associated with multiple (1 versus 2 or more) DRGA visits during that timeframe. STUDY DESIGN: Administrative claims data were used to identify children and adolescents (age <18 years) who underwent DRGA between 1/1/2002 and 12/31/2014 at the UNC Hospitals system. Information on children's age, sex and all treatment-associated CDT codes were collected. Descriptive statistics and bivariate tests of association were used for data analyses. RESULTS: There were 4,413 DRGAs among 3,973 children (median age=4 years 8 months, males=55%) during the study period. The annual rate of DRGAs increased over time, peaking (n=447) in 2013. Overall, 9% of children had ≥2 visits with repeat rates up to 18%. There was no association between children's sex and receipt of one versus multiple DRGAs; however, craniofacial cases were more likely (p<0.0005) to have multiple DRGAs compared to non-craniofacial ones. CONCLUSION: DRGAs are on the increase-with the exception of craniofacial and special health care needs patients, multiple DRGAs may be reflective of sub-optimal adherence to preventive and continuing care recommendations.

Oral health and human papillomavirus-associated head and neck squamous cell carcinoma.

BACKGROUND: Indicators of poor oral health, including smoking, have been associated with increased risk of head and neck squamous cell carcinoma, especially oropharyngeal squamous cell carcinoma (OPSCC), yet few studies have examined whether this association is modified by human papillomavirus (HPV) status. METHODS: Data from interviews and tumor HPV status from a large population-based case-control study, the Carolina Head and Neck Cancer Study (CHANCE), were used to estimate the association between oral health indicators and smoking among 102 HPV-positive patients and 145 HPV-negative patients with OPSCC and 1396 controls. HPV status was determined by p16INK4a (p16) immunohistochemistry. Unconditional, multinomial logistic regression was used to estimate odds ratios (ORs) for all oral health indictors adjusting for important covariates. RESULTS: Routine dental examinations were associated with a decreased risk of both HPV-negative OPSCC (OR, 0.52; 95% confidence interval [CI], 0.35-0.76) and HPV-positive OPSCC (OR, 0.55; 95% CI, 0.36-.86). Tooth mobility (a proxy for periodontal disease) increased the risk of HPV-negative disease (OR, 1.70; 95% CI, 1.18-2.43) slightly more than the risk for HPV-positive disease (OR, 1.45; 95% CI, 0.95-2.20). Ten or more pack-years of cigarette smoking were strongly associated with an increased risk of HPV-negative OPSCC (OR, 4.26; 95% CI, 2.85-6.37) and were associated less with an increased risk of HPV-positive OPSCC (OR, 1.62; 95% CI, 1.10-2.38). CONCLUSIONS: Although HPV-positive and HPV-negative HNSCC differ significantly with respect to etiology and tumorigenesis, the current findings suggest a similar pattern of association between poor oral health, frequency of dental examinations, and both HPV-positive and HPV-negative OPSCC. Future research is required to elucidate interactions between poor oral health, tobacco use, and HPV in the development of OPSCC. Cancer 2017;71-80. © 2016 American Cancer Society.

A haplotype block downstream of plasminogen is associated with chronic and aggressive periodontitis.

AIM: The intronic variant rs4252120 in the plasminogen gene (PLG) is known to be associated with aggressive periodontitis (AgP) and atherosclerosis. Here, we examined the chromosomal region spanning PLG for associations with both chronic periodontitis (CP) and AgP. MATERIALS AND METHODS: The association of PLG candidate rs4252120 was tested in a German case-control sample of 1,419 CP cases using the genotyping assay hCV11225947 and 4,562 controls, genotyped with HumanOmni BeadChips. The German and Dutch sample of AgP cases (N = 851) and controls (N = 6,836) were genotyped with HumanOmni BeadChips. The North American CP sample (N = 2,681 cases, 1,823 controls) was previously genotyped on the Genome-Wide Human SNP Array 6.0. Genotypes were imputed (software Impute v2), and association tests were performed using an additive genetic model adjusting for sex and smoking. RESULTS: Rs4252120 was not associated with CP. However, a haplotype block downstream of PLG and not in linkage disequilibrium with rs4252120 (r2  = .08) was associated with both AgP (rs1247559; p = .002, odds ratio [OR] = 1.33) and CP (p = .02, OR = 1.15). That locus was also significantly associated with PLG expression in osteoblasts (p = 6.9 × 10-5 ). CONCLUSIONS: Our findings support a role of genetic variants in PLG in the aetiology of periodontitis.