The association between the Mediterranean Diet Score and death from cancer of the head and neck.

PURPOSE: The association between diet quality, captured by the Mediterranean Diet Score (MDS), and mortality was studied among 1184 individuals diagnosed with head and neck cancer (HNC) who reflected on the year preceding diagnosis about their usual diet using National Cancer Institute's Diet History Questionnaire (DHQ). METHODS: Intakes of nine dietary components were scored and summed to construct the MDS (sample: median = 4; range (0-9); lower MDS reflected poorer diet quality; 5-year survival probability = 0.62). Cox regression estimated 5-year hazard ratios (HR) and 95% confidence intervals (95CI) for all-cause mortality and for HNC-specific death for contrasts of MDS quintiles. Effect measure modification (EMM) by tumor features [human papillomavirus (HPV) positivity; anatomic site] and sociodemographic behavioral factors [race, body mass index (BMI), smoking, alcohol consumption] was explored. RESULTS: The 5-year [HR (95CI); P-trend] for all-cause mortality and HNC-specific mortality for highest versus lowest MDS quintile contrasts were [0.51 (0.33, 0.80); 0.014] and [0.43 (0.22, 0.85); 0.004], respectively. A unit increase in MDS adherence resulted in a 15% reduction of the 5-year HR for HNC-specific death for tumors located at the oral cavity [HR (95CI): 0.85 (0.75, 0.96)]. Poor diet quality (MDS ≤ 4) interacted with lower BMI (kg/m2 < 25) and separately with ever-using alcohol to produce 5-year HRs for all-cause and HNC-specific mortality that were statistically significantly larger than the sum of the individual HRs representing each combination (Poor diet quality + lower BMI; Poor diet quality + ever-using alcohol). CONCLUSION: Greater adherence to a Mediterranean diet pattern prior to HNC diagnosis may reduce post-diagnosis mortality.

Prevalence of painful temporomandibular disorders in endodontic patients with tooth pain.

BACKGROUND: Pain from temporomandibular disorders (TMDs) may mimic endodontic pain, but its prevalence in endodontic patients is unknown. OBJECTIVES: This cross-sectional study investigated the prevalence of painful TMDs in patients presenting for endodontic treatment of a painful tooth. Contribution of TMD pain to the chief complaint and characteristics associated with TMD prevalence were also assessed. METHODS: Patients reporting tooth pain in the 30 days before attending university clinics for nonsurgical root canal treatment or retreatment were enrolled. Before endodontic treatment, they completed questionnaires and a board-certified orofacial pain specialist/endodontic resident diagnosed TMD using published Diagnostic Criteria for TMD. Log-binomial regression models estimated prevalence ratios to quantify associations with patient characteristics. RESULTS: Among 100 patients enrolled, prevalence of painful TMDs was 54%. In 26% of patients, TMD pain was unrelated to endodontic pain; in 20%, TMD contributed to their chief pain complaint; and in 8%, TMD was a sole aetiology for pain. TMD prevalence was associated with greater intensity, frequency and duration of the chief pain complaint; pain in more than one tooth; tenderness to tooth percussion and palpation; a diagnosis of symptomatic apical periodontitis; pain medication use; and psychological distress. CONCLUSION: A majority of patients with tooth pain seeking endodontic treatment had painful TMDs; one quarter had TMD as a component or sole cause of their pain. TMD prevalence was associated with more severe symptoms and signs of tooth pain and with psychological factors. The high frequency of TMD comorbidity warrants consideration in management of endodontic patients with history of toothache.

A machine learning approach to determine the prognosis of patients with Class III malocclusion.

INTRODUCTION: The conundrum of determining how to treat a patient with Class III malocclusion is significant, creating a burden on the patient and challenging the orthodontist. The objective of this study was to employ a statistical prediction model derived from our previous cephalometric data on 5 predominant subtypes of skeletal Class III malocclusion to test the hypothesis that Class III subtypes are associated with treatment modalities (eg, surgical vs nonsurgical) and treatment outcome. METHODS: Pretreatment lateral cephalometric records of 148 patients were digitized for 67 cephalometric variables, and measurements were applied to a mathematical equation to assign a Class III subtype. Subjects were assigned to either a surgical or nonsurgical group depending on the treatment received. Treatment outcome was determined by facial profile and clinical photographs. Log binomial models were used for statistical analysis. RESULTS: Subtype 1 (mandibular prognathic) patients were 3.5 × more likely to undergo orthognathic surgery than subtypes 2/3 (maxillary deficient) and 5.3 × more likely than 4/5 (combination). Subtype 1 patients were also 1.5 × more likely to experience treatment failure than subtypes 2/3 (maxillary deficient) and 4/5 (combination). CONCLUSIONS: This assessment of a systematic method to characterize patients with Class III malocclusion into subtypes revealed that subtype 1 (mandibular prognathic) showed a likelihood to undergo orthognathic surgery while subtypes 2/3 experienced significantly lower treatment failure (in response to orthodontics alone). Further refinement of the equation may yield a reliable prediction model for earlier identification of surgical patients and also provide predictive power of Class III treatment outcomes.

Effect of comorbid migraine on propranolol efficacy for painful TMD in a randomized controlled trial.

INTRODUCTION: The migraine-preventive drug propranolol is efficacious in reducing pain from temporomandibular disorder, suggesting potential modifying or mediating effects of comorbid migraine. METHODS: In this randomized controlled trial, myofascial temporomandibular disorder patients were treated with propranolol or placebo for 9 weeks. The primary endpoint was change in a facial pain index derived from daily symptom diaries. Linear and logistic regression models tested for a migraine × treatment-group interaction in reducing facial pain index. Counterfactual models explored changes in headache impact and heart rate as mediators of propranolol's efficacy. RESULTS: Propranolol's efficacy in reducing facial pain index was greater among the 104 migraineurs than the 95 non-migraineurs: For example, for the binary ≥ 30% reduction in facial pain index, odds ratios were 3.3 (95% confidence limits: 1.4, 8.1) versus 1.3 (0.5, 3.2), respectively, although the interaction was statistically non-significant (p = 0.139). Cumulative response curves confirmed greater efficacy for migraineurs than non-migraineurs (differences in area under the curve 26% and 6%, respectively; p = 0.081). While 9% of the treatment effect was mediated by reduced headache impact, 46% was mediated by reduced heart rate. CONCLUSIONS: Propranolol was more efficacious in reducing temporomandibular disorder pain among migraineurs than non-migraineurs, with more of the effect mediated by reduced heart rate than by reduced headache impact. STUDY IDENTIFICATION AND REGISTRATION: SOPPRANO; NCT02437383; https://clinicaltrials.gov/ct2/show/NCT02437383.

Clinical, psychological, and sensory characteristics associated with headache attributed to temporomandibular disorder in people with chronic myogenous temporomandibular disorder and primary headaches.

BACKGROUND: Headache attributed to Temporomandibular Disorder (HATMD) is a secondary headache that may have features resulting in diagnostic overlap with primary headaches, namely, tension-type (TTH) or migraine. This cross-sectional study of people with both chronic myogenous TMD and primary headaches evaluated characteristics associated with HATMD. METHODS: From a clinical trial of adults, baseline data were used from a subset with diagnoses of both TMD myalgia according to the Diagnostic Criteria for TMD (DC/TMD) and TTH or migraine according to the International Classification of Headache Disorders, 3rd edition. HATMD was classified based on the DC/TMD. Questionnaires and examinations evaluated 42 characteristics of facial pain, headache, general health, psychological distress, and experimental pain sensitivity. Univariate regression models quantified the associations of each characteristic with HATMD (present versus absent), headache type (TTH versus migraine), and their interaction in a factorial design. Multivariable lasso regression identified the most important predictors of HATMD. RESULTS: Of 185 participants, 114 (61.6%) had HATMD, while the numbers with TTH (n = 98, 53.0%) and migraine (n = 87, 47.0%) were similar. HATMD was more likely among migraineurs (61/87 = 70.1%) than participants with TTH (53/98 = 54.1%; odds ratio = 2.0; 95%CL = 1.1, 3.7). In univariate analyses, characteristics associated with HATMD included pain-free jaw opening and examination-evoked pain in masticatory muscles and temporomandibular joints (TMJ) as well as frequency and impact of headache, but not frequency or impact of facial pain. Lowered blood pressure but not psychological or sensory characteristics was associated with HATMD. Multiple characteristics of facial pain, headache, general health, and psychological distress differed between TTH or migraine groups. Few interactions were observed, demonstrating that most characteristics' associations with HATMD were consistent in TTH and migraine groups. The lasso model identified headache frequency and examination-evoked muscle pain as the most important predictors of HATMD. CONCLUSIONS: HATMD is highly prevalent among patients with chronic myogenous TMD and headaches and often presents as migraine. In contrast to primary headaches, HATMD is associated with higher headache frequency and examination-evoked masticatory muscle pain, but with surprisingly few measures of facial pain, general health, and psychological distress. A better understanding of HATMD is necessary for developing targeted strategies for its management. TRIAL IDENTIFICATION AND REGISTRATION: SOPPRANO; NCT02437383 . Registered May 7, 2015.

The association between diet quality and cancer incidence of the head and neck.

The association between diet quality and head and neck cancer (HNC) was explored using a population-based case-control study of 1170 HNC cases and 1303 age-, race-, and sex-matched controls from the United States. Diet quality was assessed with three diet quality scores (DQS): (a) Healthy Eating Index 2005 (HEI-2005), (b) Mediterranean Diet Score (MDS), and (c) HNC-specific Mediterranean Diet Score (MDS-HNC), a modified MDS that we developed to be more applicable to HNC. Logistic regression models estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) representing diet quality-incident HNC associations. We examined effect measure modification (EMM) by body mass index (BMI), race, cigarette smoking, and alcohol consumption and associational heterogeneity by HPV-positivity and tumor site. A one standard deviation summary DQS decrement suggested a consistent inverse association (ORs (CIs)) for the HEI-2005, MDS, and MDS-HNC: 1.35 (1.21, 1.50), 1.13 (1.02, 1.25), and 1.17 (1.06, 1.31), respectively. This association did not vary by tumor site or tumor HPV status, though additive EMM by alcohol use and by BMI was observed. Our findings suggest the Mediterranean diet can be used to study HNC in American populations, and that poor diet quality elevates HNC incidence, particularly among alcohol users.

A functional substitution in the L-aromatic amino acid decarboxylase enzyme worsens somatic symptoms via a serotonergic pathway.

OBJECTIVE: Heightened somatic symptoms are reported by a wide range of patients with chronic pain and have been associated with emotional distress and physical dysfunction. Despite their clinical significance, molecular mechanisms leading to their manifestation are not understood. METHODS: We used an association study design based on a curated list of 3,295 single nucleotide polymorphisms mapped to 358 genes to test somatic symptoms reporting using the Pennebaker Inventory of Limbic Languidness questionnaire from a case-control cohort of orofacial pain (n = 1,607). A replication meta-analysis of 3 independent cohorts (n = 3,189) was followed by functional validation, including in silico molecular dynamics, in vitro enzyme assays, and measures of serotonin (5-HT) plasma concentration. RESULTS: An association with the T allele of rs11575542 coding for an arginine to glutamine substitution in the L-aromatic amino acid decarboxylase (AADC) enzyme was replicated in a meta-analysis of 3 independent cohorts. In a combined meta-analysis of all cohorts, this association reached p = 6.43 × 10-8 . In silico studies demonstrated that this substitution dramatically reduces the conformational dynamics of AADC, potentially lowering its binding capacity to a cofactor. in vitro enzymatic assays showed that this substitution reduces the maximum kinetic velocity of AADC, hence lowering 5-HT levels. Finally, plasma samples from 90 subjects showed correlation between low 5-HT levels and heightened somatic symptoms. INTERPRETATION: Using functional genomics approaches, we identified a polymorphism in the AADC enzyme that contributes to somatic symptoms through reduced levels of 5-HT. Our findings suggest a molecular mechanism underlying the pathophysiology of somatic symptoms and opens up new treatment options targeting the serotonergic system. ANN NEUROL 2019;86:168-180.

Headache attributed to TMD Is Associated With the Presence of Comorbid Bodily Pain: A Case-Control Study.

Headache attributed to temporomandibular disorders (TMDH) is defined as a secondary headache by the International Classification of Headache Disorders 3rd edition (ICHD-3). OBJECTIVE: The objective of this case-control study is to investigate the phenotypic characteristics of chronic TMD with and without TMDH. We hypothesize that chronic TMD with TMDH is associated with increased number of bodily pain conditions, more painful sites in the head and neck region, and greater TMD pain intensity. METHODS: This is a retrospective cross-sectional review of the medical records of consecutive patients who sought treatment at the University of North Carolina Orofacial Pain Clinic between 2013 and 2014. The inclusion criterion was a diagnosis of myalgia or arthralgia according to the Research Diagnostic Criteria for Temporomandibular Disorders. In addition, cases had a diagnosis of TMDH according to the ICHD-3 criteria. Data on the presence and the number of self-reported bodily pain conditions (such as fibromyalgia and low back pain), pain intensity, number of painful sites in the head and neck upon palpation, and TMD pain onset were analyzed. RESULTS: A total of 295 records were reviewed. Thirty-four (29.3%) patients fulfilled inclusion criteria for cases (TMD+TMDH) and 82 (70.7%) for controls (TMD-TMDH). Cases reported greater number of bodily pain conditions than controls, with a mean of 1.97 ± 1.50 and 1.26 ± 1.28 of bodily pain conditions, respectively (P = .012, OR = 1.43 [95% CI 1.07-1.92]). In fact, 55.9% of cases reported at least 2 comorbid pain conditions compared to 37.8% controls (P = .044). Compared to controls (8.65 ± 5.32), cases (13.05 ± 4.46) exhibited greater number of painful sites upon palpation in the head and neck region (P < .0001, OR = 1.18 [95% CI 1.09-1.30]), and greater TMD pain intensity, with a mean of 6.00 ± 2.17 for cases and 5.09 ± 2.14 for controls (P = .041, OR = 1.22 [95% CI 1.01-1.47]). CONCLUSION: In a population of patients with chronic TMD seeking pain management, TMDH was significantly associated with an increased number of self-reported bodily pain conditions, a greater number of painful sites in the head and neck regions, and higher TMD pain intensity.

Periodontitis and Non-alcoholic Fatty Liver Disease, a population-based cohort investigation in the Study of Health in Pomerania.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) affects 20%-30% of adults with risk factors like obesity and insulin resistance putatively acting through chronic low-grade inflammation. Because periodontitis elicits low-grade inflammation, we hypothesized that it could contribute to NAFLD occurrence. OBJECTIVE: To investigate epidemiologic associations between periodontitis and the incidence of NAFLD among 2,623 participants of the Study of Health in Pomerania. METHODS: Periodontitis at baseline was defined as the percentage of sites (0%, <30%, ≥30%) with (i) clinical attachment level (CAL) ≥3 mm; (ii) probing pocket depth (PD) ≥4 mm. Incident NAFLD was defined as a significant increase in liver echogenicity on ultrasound relative to the kidneys, with the diaphragm indistinct or the echogenic walls of the portal veins invisible. RESULTS: After a median 7.7 years of follow-up, 605 incident NAFLD cases occurred at a rate of 32.5 cases per 1,000 person-years. Relative to participants without CAL ≥3 mm, NAFLD incidence was elevated slightly in participants with <30% of sites affected and moderately in participants with ≥30% of sites affected (multivariable-adjusted incidence rate ratio = 1.28, 95% CI, 0.84, 1.95 and 1.60, 95% CI, 1.05-2.43), respectively. A similar dose-response relationship was not observed for PD. CONCLUSION: History of periodontitis may be a risk factor for NAFLD.

Systematic Review and Meta-analysis of the Association Between Exposure to Environmental Tobacco Smoke and Periodontitis Endpoints Among Nonsmokers.

OBJECTIVE: A systematic review was conducted to summarize the epidemiological evidence on environmental tobacco smoke (ETS) exposure and prevalent periodontitis endpoints among nonsmokers. METHODS: We searched PubMed, EMBASE, Web of Science, Pro-Quest dissertations, and conference proceedings of a dental research association. We included studies from which prevalence odds ratios (POR) could be extracted for periodontitis determined by examiner measurements of clinical attachment level (CAL) and/or probing pocket depth (PD) or self-report of missing teeth. Studies determined ETS exposure by self-report or biomarker (cotinine) levels. RESULTS: For studies reporting CAL and/or PD (n = 6), associations were stronger with cotinine-measured exposure (n = 3; random effects POR [95% prediction interval] = 1.63 (0.90, 2.96)) than self-reported exposure (n = 3; random effects POR = 1.15 (0.68, 1.96)). There was no meaningful difference in summary estimate for studies reporting CAL and/or PD endpoint (n = 6; random effects POR = 1.34 (0.93, 1.94)) as opposed to tooth loss (n = 2; random effects POR = 1.33 (0.52, 3.40)). CONCLUSIONS: There appears to be a positive association between exposure to ETS and prevalent periodontitis endpoints among nonsmokers, the magnitude of which depended mostly on the method of ETS assessment. IMPLICATIONS: The notoriety of ETS is often discussed in terms of its associations with cancer, chronic conditions like cardiovascular diseases, and respiratory illnesses in children. However, very little attention is paid to its association with oral diseases, especially periodontitis. Periodontitis affects a large proportion of the population and is a major cause of tooth loss. This study summarized the epidemiologic association between exposure to ETS and periodontitis among nonsmokers. Although the findings are consistent with a positive association, methodological weaknesses relating to study design, assessment of ETS, periodontitis, and adjustment covariates were highlighted and recommendations for improvement in future studies provided.

Tooth loss and obstructive sleep apnea signs and symptoms in the US population.

PURPOSE: The aim of this study is to investigate the relationship between tooth loss and signs and symptoms of obstructive sleep apnea (OSA) in a representative sample of the general US population. METHODS: Data were from 7305 men and women aged ≥25 years participating in the 2005-2008 National Health and Nutrition Examination Survey. Tooth loss, occlusal contacts, and denture use were determined by dental examination. Four cardinal OSA signs and symptoms were evaluated by questions based on American Academy of Sleep Medicine criteria. Adults with ≥2 signs/symptoms of OSA were classified at high-risk of OSA. Prevalence ratios (PR) and 95 % confidence limits (CL) from log binomial regression models estimated the strength of association between tooth loss and high-risk for OSA, adjusting for demographic characteristics, body mass index, dentures, and sleep duration. RESULTS: Prevalence of high-risk for OSA increased 2 % for each additional lost tooth (PR = 1.02, 95 % CL, 1.01, 1.03) among adults aged 25 to 65 years. When tooth loss was modeled as an ordinal variable with 0-4 lost teeth as the referent category, adjusted prevalence of high-risk for OSA was as follows: 25 % greater in those missing 5-8 teeth (PR = 1.25, 95 % CL, 1.07, 1.46); 36 % greater in those missing 9-31 teeth (PR = 1.36, 95 % CL, 1.06, 1.73); and 61 % greater in the edentulous (PR = 1.61, 95 % CL, 1.11, 2.33). CONCLUSION: Tooth loss may be an independent risk factor for OSA.

Parameter estimation in Cox models with missing failure indicators and the OPPERA study.

In a prospective cohort study, examining all participants for incidence of the condition of interest may be prohibitively expensive. For example, the "gold standard" for diagnosing temporomandibular disorder (TMD) is a physical examination by a trained clinician. In large studies, examining all participants in this manner is infeasible. Instead, it is common to use questionnaires to screen for incidence of TMD and perform the "gold standard" examination only on participants who screen positively. Unfortunately, some participants may leave the study before receiving the "gold standard" examination. Within the framework of survival analysis, this results in missing failure indicators. Motivated by the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study, a large cohort study of TMD, we propose a method for parameter estimation in survival models with missing failure indicators. We estimate the probability of being an incident case for those lacking a "gold standard" examination using logistic regression. These estimated probabilities are used to generate multiple imputations of case status for each missing examination that are combined with observed data in appropriate regression models. The variance introduced by the procedure is estimated using multiple imputation. The method can be used to estimate both regression coefficients in Cox proportional hazard models as well as incidence rates using Poisson regression. We simulate data with missing failure indicators and show that our method performs as well as or better than competing methods. Finally, we apply the proposed method to data from the OPPERA study.

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.

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.

Whole-genome methylation profiling reveals regions associated with painful temporomandibular disorders and active recovery processes.

ABSTRACT: Temporomandibular disorders (TMDs), collectively representing one of the most common chronic pain conditions, have a substantial genetic component, but genetic variation alone has not fully explained the heritability of TMD risk. Reasoning that the unexplained heritability may be because of DNA methylation, an epigenetic phenomenon, we measured genome-wide DNA methylation using the Illumina MethylationEPIC platform with blood samples from participants in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Associations with chronic TMD used methylation data from 496 chronic painful TMD cases and 452 TMD-free controls. Changes in methylation between enrollment and a 6-month follow-up visit were determined for a separate sample of 62 people with recent-onset painful TMD. More than 750,000 individual CpG sites were examined for association with chronic painful TMD. Six differentially methylated regions were significantly ( P < 5 × 10 -8 ) associated with chronic painful TMD, including loci near genes involved in the regulation of inflammatory and neuronal response. A majority of loci were similarly differentially methylated in acute TMD consistent with observed transience or persistence of symptoms at follow-up. Functional characterization of the identified regions found relationships between methylation at these loci and nearby genetic variation contributing to chronic painful TMD and with gene expression of proximal genes. These findings reveal epigenetic contributions to chronic painful TMD through methylation of the genes FMOD , PM20D1 , ZNF718 , ZFP57 , and RNF39 , following the development of acute painful TMD. Epigenetic regulation of these genes likely contributes to the trajectory of transcriptional events in affected tissues leading to resolution or chronicity of pain.

Diagnostic Accuracy of a Temporomandibular Disorder Pain Screener in Patients Seeking Endodontic Treatment for Tooth Pain.

INTRODUCTION: This study assessed the accuracy of a TMD Pain Screener questionnaire in identifying patients with temporomandibular disorder (TMD) pain among those seeking endodontic treatment for tooth pain. It also investigated whether the screener accuracy could be improved by adding questions regarding putative predictors of TMD status. METHODS: One hundred patients seeking endodontic treatment for tooth pain were enrolled. Participants completed the 6-question TMD Pain Screener before treatment. A board-certified orofacial pain specialist/endodontic resident conducted endodontic and TMD examinations using validated Diagnostic Criteria for TMD (DC/TMD). The sensitivity (Se), specificity (Sp), and positive/negative predictive values (PPVs/NPVs) were calculated for the 6-question and 3-question versions of the TMD Pain Screener. Logistic regression and receiver operating characteristic curve (AUROC) analyses were performed to determine the screening accuracy. RESULTS: At the screening threshold of ≥3, TMD Pain Screener's sensitivity was 0.85, specificity 0.52, PPV 0.68, and NPV 0.75 for the 6-question version and 0.64, 0.65, 0.69, and 0.61, respectively, for the 3-question version. The AUROC was 0.71 (95% CL: 0.61, 0.82) and 0.60 (95% CL: 0.48, 0.71) for full and short versions, respectively. Adding a rating of current pain intensity of the chief complaint to the screener improved the AUROC to 0.81 (95% CL: 0.72, 0.89) and 0.77 (95% CL: 0.67, 0.86) for full and short versions, respectively, signifying useful overall accuracy. CONCLUSIONS: The 6-question TMD Pain Screener, combined with the patient's rating of current pain intensity of the chief complaint, could be recommended for use in endodontic patients with tooth pain for detecting painful TMD.

A mouse model of chronic primary pain that integrates clinically relevant genetic vulnerability, stress, and minor injury.

Chronic primary pain conditions (CPPCs) affect over 100 million Americans, predominantly women. They remain ineffectively treated, in large part because of a lack of valid animal models with translational relevance. Here, we characterized a CPPC mouse model that integrated clinically relevant genetic (catechol-O-methyltransferase; COMT knockdown) and environmental (stress and injury) factors. Compared with wild-type mice, Comt+/- mice undergoing repeated swim stress and molar extraction surgery intervention exhibited pronounced multisite body pain and depressive-like behavior lasting >3 months. Comt+/- mice undergoing the intervention also exhibited enhanced activity of primary afferent nociceptors innervating hindpaw and low back sites and increased plasma concentrations of norepinephrine and pro-inflammatory cytokines interleukin-6 (IL-6) and IL-17A. The pain and depressive-like behavior were of greater magnitude and longer duration (≥12 months) in females versus males. Furthermore, increases in anxiety-like behavior and IL-6 were female-specific. The effect of COMT genotype × stress interactions on pain, IL-6, and IL-17A was validated in a cohort of 549 patients with CPPCs, demonstrating clinical relevance. Last, we assessed the predictive validity of the model for analgesic screening and found that it successfully predicted the lack of efficacy of minocycline and the CB2 agonist GW842166X, which were effective in spared nerve injury and complete Freund's adjuvant models, respectively, but failed in clinical trials. Yet, pain in the CPPC model was alleviated by the beta-3 adrenergic antagonist SR59230A. Thus, the CPPC mouse model reliably recapitulates clinically and biologically relevant features of CPPCs and may be implemented to test underlying mechanisms and find new therapeutics.

State cigarette excise tax, secondhand smoke exposure, and periodontitis in US nonsmokers.

OBJECTIVES: We assessed the relationship of state cigarette excise tax with cigarette sales, secondhand smoke (SHS) exposure, and periodontitis among US lifetime nonsmokers. METHODS: Cigarette excise tax and per capita sales data from 1983 to 1998 were obtained for 50 states and the District of Columbia. Periodontal data were analyzed for 3137 adults in 28 states from 3 National Health and Nutrition Examination Survey cycles (1999-2004). Measures of periodontal pocket depth and attachment level were used to classify people with moderate or severe periodontitis. SHS exposure was classified according to gender- or race/ethnicity-specific thresholds of serum cotinine concentration. Statistical analysis adjusted for the complex survey design. RESULTS: For each additional $0.10 in excise tax, predicted sales decreased by 0.74 packs per person per month and adjusted odds of moderate or severe periodontitis decreased 22% (odds ratio [OR] = 0.78; 95% confidence interval [CI] = 0.62, 0.97). For each pack sold per person per month, adjusted odds of SHS exposure increased 28% (95% CI = 1.17, 1.40) and adjusted odds of periodontitis increased 15% (95% CI = 1.03, 1.29). Odds of periodontitis for those exposed to SHS were elevated 2-fold relative to those who were unexposed (OR = 2.03; 95% CI = 1.30, 3.20). CONCLUSIONS: Cigarette excise tax may protect nonsmokers against periodontitis.

Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia.

OBJECTIVE: Fibromyalgia (FM) represents a complex disorder that is characterized by widespread pain and tenderness and is frequently accompanied by additional somatic and cognitive/affective symptoms. Genetic risk factors are known to contribute to the etiology of the syndrome. The aim of this study was to examine >350 genes for association with FM, using a large-scale candidate gene approach. METHODS: The study group comprised 496 patients with FM (cases) and 348 individuals with no chronic pain (controls). Genotyping was performed using a dedicated gene array chip, the Pain Research Panel, which assays variants characterizing >350 genes known to be involved in the biologic pathways relevant to nociception, inflammation, and mood. Association testing was performed using logistic regression. RESULTS: Significant differences in allele frequencies between cases and controls were observed for 3 genes: GABRB3 (rs4906902; P = 3.65 × 10(-6)), TAAR1 (rs8192619; P = 1.11 × 10(-5)), and GBP1 (rs7911; P = 1.06 × 10(-4)). These 3 genes and 7 other genes with suggestive evidence for association were examined in a second, independent cohort of patients with FM and control subjects who were genotyped using the Perlegen 600K platform. Evidence of association in the replication cohort was observed for TAAR1, RGS4, CNR1, and GRIA4. CONCLUSION: Variation in these 4 replicated genes may serve as a basis for development of new diagnostic approaches, and the products of these genes may contribute to the pathophysiology of FM and represent potential targets for therapeutic action.

Effects of full-mouth scaling on the periodontal health of Indigenous Australians: a randomized controlled trial.

BACKGROUND: Simplified periodontal therapy might be a pragmatic strategy for public health programmes targeting Indigenous Australian adults. The objective of this randomized controlled trial was to evaluate oral health effects of single-visit, non-surgical periodontal therapy compared to no treatment. METHODS: This parallel-group, randomized, open label clinical trial enrolled 273 Indigenous Australians aged ≥18 years with periodontitis. Intervention participants received full-mouth periodontal scaling and root planing during a single visit while the control group received no treatment. Endpoints were summary variables derived from clinical assessments of probing depth, clinical attachment loss, plaque, calculus and gingival bleeding before treatment and 3 months later. RESULTS: Endpoints could be calculated for 169 participants with follow-up data. Compared to the control group, there were statistically significant reductions in extent of shallow pockets: PD ≥4 mm (mean difference -2.86, [95% CI -5.01 to -0.71], p = 0.009) and gingival bleeding (mean difference -0.25, [95% CI -0.43 to -0.08], p = 0.005) but not deeper pockets PD ≥5 mm (mean difference -0.48, [95% CI -1.78 to 0.82], p = 0.468) or plaque scores. CONCLUSIONS: Periodontal therapy produced improvements in shallow periodontal pockets and measures of gingival bleeding in these Indigenous Australians.