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Aims To determine the relationship between hormonal contraceptive (HC) use and painful symptoms, particularly those associated with headache and painful temporomandibular disorders (TMD). Methods Data from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) prospective cohort study were used. During the 2.5-year median follow-up period, quarterly health update (QHU) questionnaires were completed by 1,475 women aged 18 to 44 years who did not have TMD, menopause, hysterectomy, or hormone replacement therapy use at baseline. QHU questionnaires evaluated HC use, symptoms of headache and TMD, and pain of ≥ 1 day duration in 12 body regions. Participants who developed TMD symptoms were examined to classify clinical TMD. Headache symptoms were classified based on the International Classification of Headache Disorders 3 (ICHD-3). Associations between HC use and pain symptoms were analyzed using generalized estimating equations and Cox models. Results HC use, endorsed in 33.7% of QHU questionnaires, was significantly associated with concurrent symptoms of TMD (odds ratio [OR]: 1.20, 95% CI: 1.06 to 1.35) and headache (OR: 1.26, 95% CI: 1.11 to 1.43). HC use was also significantly associated with concurrent pain of ≥ 1 day duration in the head (OR: 1.38, 95% CI: 1.16 to 1.63), face (OR: 1.44, 95% CI: 1.13 to 1.83), and legs (OR: 1.22, 95% CI: 1.01 to 1.47), but not elsewhere. Initiation of HC use was associated with increased odds of subsequent TMD symptoms (OR: 1.37, 95% CI: 1.13 to 1.66) and pain of ≥ 1 day in the head (OR: 1.37, 95% CI: 1.01 to 1.85). Discontinuing HC use was associated with lower odds of subsequent headache (OR: 0.82, 95% CI: 0.67 to 0.99). HC use was not significantly associated with subsequent onset of examiner-classified TMD. Conclusion These findings imply that HC influences craniofacial pain, and that this pain diminishes after cessation of HC use.

Traditional classification and prognostic approaches for chronic pain conditions focus primarily on anatomically based clinical characteristics not based on underlying biopsychosocial factors contributing to perception of clinical pain and future pain trajectories. Using a supervised clustering approach in a cohort of temporomandibular disorder cases and controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment study, we recently developed and validated a rapid algorithm (ROPA) to pragmatically classify chronic pain patients into 3 groups that differed in clinical pain report, biopsychosocial profiles, functional limitations, and comorbid conditions. The present aim was to examine the generalizability of this clustering procedure in 2 additional cohorts: a cohort of patients with chronic overlapping pain conditions (Complex Persistent Pain Conditions study) and a real-world clinical population of patients seeking treatment at duke innovative pain therapies. In each cohort, we applied a ROPA for cluster prediction, which requires only 4 input variables: pressure pain threshold and anxiety, depression, and somatization scales. In both complex persistent pain condition and duke innovative pain therapies, we distinguished 3 clusters, including one with more severe clinical characteristics and psychological distress. We observed strong concordance with observed cluster solutions, indicating the ROPA method allows for reliable subtyping of clinical populations with minimal patient burden. The ROPA clustering algorithm represents a rapid and valid stratification tool independent of anatomic diagnosis. ROPA holds promise in classifying patients based on pathophysiological mechanisms rather than structural or anatomical diagnoses. As such, this method of classifying patients will facilitate personalized pain medicine for patients with chronic pain.

Cross-sectional studies confirm, as expected, a positive association between jaw injury and painful temporomandibular disorders (TMDs), but prospective evaluations are lacking. We prospectively assessed incident jaw injury, injury type, and development of TMD in adults aged 18 to 44 years. Data were collected from 3258 individuals from communities surrounding 4 US academic institutes between 2006 and 2008. At enrollment, participants reported no TMD history and no facial injuries in the previous 6 months. Quarterly, follow-up questionnaires assessed incident jaw injury, which was classified as intrinsic (attributed to yawning or prolonged mouth opening) or extrinsic (attributed to other causes). Examiners classified incident TMD during a median follow-up period of 2.8 years (range 0.2-5.2 years). Cox regression models used jaw injury as a time-dependent covariate to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association with incident TMD. Among 1729 participants with complete data, 175 developed TMD. Eighty percent of injuries were intrinsic. Temporomandibular disorder annual incidence was nearly twice as high in those experiencing jaw injury (5.37%) compared with those who did not (3.44%). In the Cox model that accounted for timing of injury, the corresponding HR was 3.94 (95% CI = 2.82-5.50) after adjusting for study site, age, race, and sex. Hazard ratios did not differ (P = 0.91) for extrinsic injuries (HR = 4.03, 95% CI = 2.00-8.12) and intrinsic injuries (HR = 3.85, 95% CI = 2.70-5.49). Jaw injury was strongly associated with incident TMD. If surveillance and intervention after jaw injury is to be effective in preventing TMD, they should focus on both intrinsic and extrinsic injuries.

Cluster analysis is an unsupervised learning strategy that is exceptionally useful for identifying homogeneous subgroups of observations in data sets of unknown structure. However, it is challenging to determine if the identified clusters represent truly distinct subgroups rather than noise. Existing approaches for addressing this problem tend to define clusters based on distributional assumptions, ignore the inherent correlation structure in the data, or are not suited for high‐dimension low‐sample size (HDLSS) settings. In this paper we propose a novel method to evaluate the significance of identified clusters by comparing the explained variation due to the clustering from the original data to that produced by clustering a unimodal reference distribution which preserves the covariance structure in the data. The reference distribution is generated using kernel density estimation and thus does not require that the data follow a particular distribution. By utilizing sparse covariance estimation the method is adapted for the HDLSS setting. The approach can be used to test the null hypothesis that the data cannot be partitioned into clusters and to determine the optimal number of clusters. Simulation examples, theoretical evaluations, and applications to temporomandibular disorder research data and cancer microarray data illustrate the utility of the proposed method. This article is protected by copyright. All rights reserved

BACKGROUND Multiple risk factors predict temporomandibular disorders (TMD) onset, but temporal changes in risk factors and their contribution to risk of TMD have not been evaluated. The study aims were to (a) describe changes occurring in premorbid TMD risk factors when re-measured at TMD onset and 6 months later, and (b) determine if measures of change improve accuracy in predicting TMD incidence compared to premorbid measures alone. METHODS In this observational prospective cohort study at four university research clinics, 3,258 community-based, 18- to 44-year-olds without TMD were enrolled. During the 3-year median follow-up, 260 incident cases of first-onset TMD were identified, and 196 TMD-free subjects were selected as matched controls. Six-months later, 147 of 260 incident cases (56.6%) were re-examined revealing 72 (49%) with 'persistent TMD' and 75 (51%) whose condition had resolved ('transient TMD'). Virtually all (126) of the 127 re-examined controls remained without TMD. Questionnaires and clinical measurements evaluated risk factors from clinical, health, psychological and behavioural and neurosensory domains. RESULTS Most risk factors across all four domains increased with TMD onset, remained elevated in the persistent group and declined in the transient group (i.e., significant ANOVA interactions, p

In 2006, the OPPERA project (Orofacial Pain: Prospective Evaluation and Risk Assessment) set out to identify risk factors for development of painful temporomandibular disorder (TMD). A decade later, this review summarizes its key findings. At 4 US study sites, OPPERA recruited and examined 3,258 community-based TMD-free adults assessing genetic and phenotypic measures of biological, psychosocial, clinical, and health status characteristics. During follow-up, 4% of participants per annum developed clinically verified TMD, although that was a “symptom iceberg” when compared with the 19% annual rate of facial pain symptoms. The most influential predictors of clinical TMD were simple checklists of comorbid health conditions and nonpainful orofacial symptoms. Self-reports of jaw parafunction were markedly stronger predictors than corresponding examiner assessments. The strongest psychosocial predictor was frequency of somatic symptoms, although not somatic reactivity. Pressure pain thresholds measured at cranial sites only weakly predicted incident TMD yet were strongly associated with chronic TMD, cross-sectionally, in OPPERA’s separate case-control study. The puzzle was resolved in OPPERA’s nested case-control study where repeated measures of pressure pain thresholds revealed fluctuation that coincided with TMD’s onset, persistence, and recovery but did not predict its incidence. The nested case-control study likewise furnished novel evidence that deteriorating sleep quality predicted TMD incidence. Three hundred genes were investigated, implicating 6 single-nucleotide polymorphisms (SNPs) as risk factors for chronic TMD, while another 6 SNPs were associated with intermediate phenotypes for TMD. One study identified a serotonergic pathway in which multiple SNPs influenced risk of chronic TMD. Two other studies investigating gene-environment interactions found that effects of stress on pain were modified by variation in the gene encoding catechol O-methyltransferase. Lessons learned from OPPERA have verified some implicated risk factors for TMD and refuted others, redirecting our thinking. Now it is time to apply those lessons to studies investigating treatment and prevention of TMD.

There is good evidence that poor sleep quality increases risk of painful temporomandibular disorder (TMD). However, little is known about the course of sleep quality in the months preceding TMD onset, and whether the relationship is mediated by heightened sensitivity to pain. The Pittsburgh Sleep Quality Index was administered at enrollment into the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) prospective cohort study. Thereafter the Sleep Quality Numeric Rating Scale was administered every 3 months to 2,453 participants. Sensitivity to experimental pressure pain and pinprick pain stimuli was measured at baseline and repeated during follow-up of incident TMD cases (n = 220) and matched TMD-free controls (n = 193). Subjective sleep quality deteriorated progressively, but only in those who subsequently developed TMD. A Cox proportional hazards model showed that risk of TMD was greater among participants whose sleep quality worsened during follow-up (adjusted hazard ratio = 1.73, 95% confidence limits = 1.29, 2.32). This association was independent of baseline measures of sleep quality, psychological stress, somatic awareness, comorbid conditions, nonpain facial symptoms, and demographic characteristics. Poor baseline sleep quality was not significantly associated with baseline pain sensitivity or with subsequent change in pain sensitivity. Furthermore the relationship between sleep quality and TMD incidence was not mediated via baseline pain sensitivity or change in pain sensitivity. Perspective Subjective sleep quality deteriorates progressively before the onset of painful TMD, but sensitivity to experimental pain does not mediate this relationship. Furthermore, the relationship is independent of potential confounders such as psychological stress, somatic awareness, comorbid conditions, nonpain facial symptoms, and various demographic factors.

Catecholamine-O-methyltransferase (COMT) is a polymorphic gene whose variants affect enzymatic activity and pain sensitivity via adrenergic pathways. Although COMT represents one of the most studied genes in human pain genetics, findings regarding its association with pain phenotypes are not always replicated. Here, we investigated if interactions among functional COMT haplotypes, stress, and sex can modify the effect of COMT genetic variants on pain sensitivity. We tested these interactions in a cross-sectional study, including 2 cohorts, one of 2972 subjects tested for thermal pain sensitivity (Orofacial Pain: Prospective Evaluation and Risk Assessment) and one of 948 subjects with clinical acute pain after motor vehicle collision (post-motor vehicle collision). In both cohorts, the COMT high-pain sensitivity (HPS) haplotype showed robust interaction with stress and number of copies of the HPS haplotype was positively associated with pain sensitivity in nonstressed individuals, but not in stressed individuals. In the post-motor vehicle collision cohort, there was additional modification by sex: the HPS-stress interaction was apparent in males, but not in females. In summary, our findings indicate that stress and sex should be evaluated in association studies aiming to investigate the effect of COMT genetic variants on pain sensitivity.

Supplemental Digital Content is Available in the Text. A polymorphic locus associated with a protective effect against painful temporomandibular disorder in males regulates the expression of the muscle RAS oncogene homolog (MRAS) gene., Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02-4.27, P = 2.2 × 10−8). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio = 1.16, 95% confidence interval: 1.0-1.35, P = 2.3 × 10−2). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = −0.51, P = 2.43 × 10−5). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.

OBJECTIVES We evaluated the stability of the comorbidity between vulvodynia and orofacial pain (OFP) and its associated clinical characteristics over a 2-year follow-up period. MATERIALS AND METHODS In an earlier study of vestibulodynia patients, we administered questionnaires assessing demographic data, self-reported pain, anxiety, somatic awareness, and presence of signs and symptoms suggestive of clinical and subclinical OFP. The present study readministered the same surveys to a subset of the original cohort after a 2-year follow-up period. RESULTS Of the 138 women in the previous study, 71 (51%) agreed to participate in the present study. We confirmed our earlier findings that (1) OFP is a highly prevalent (66%) condition among women with vestibulodynia, and (2) compared with women with no OFP symptoms, those with OFP symptoms experience higher levels of anxiety (P=0.005) and somatic awareness (P

Subjective cognitive impairment negatively affects daily functioning, health-related quality of life, and health care consumption, and is predictive of future cognitive decline in many patient populations. However, no subjective measures of multidimensional cognitive functioning have been evaluated for dialysis patients. Our purposes were to examine (1) the association between patient-reported (subjective) cognitive functioning and objective cognitive functioning and (2) the relationships between subjective and objective cognitive functioning and everyday functioning of dialysis patients. We used baseline data from an ongoing longitudinal observational study of trajectories in dialysis patients' multidimensional quality of life. One hundred thirty-five patients completed a telephone-based neuropsychological battery (Brief Test of Adult Cognition by Telephone, a measure of objective cognitive functioning), a measure of subjective cognitive functioning (Patient's Assessment of Own Functioning Inventory), and measures of everyday functioning (Activities of Daily Living [ADL] and Instrumental Activities of Daily Living [IADL] scales). After controlling for age and education, there was a modest correlation (r = 0.33, P > 0.001) between subjective and objective cognitive functioning. Multivariate logistic regression models showed subjective, but not objective, cognitive functioning was a significant predictor of both ADLs and IADLs. The findings suggest the potential clinical value of subjective measures of cognitive functioning, not to replace objective measures or diagnostic tests, but rather to optimize the meaningfulness of clinical assessment and management.

Background When patients first develop a painful temporomandibular disorder (TMD) and seek care, 1 priority for clinicians is to assess prognosis. The authors aimed to develop a predictive model by using biopsychosocial measures from the Diagnostic Criteria for Temporomandibular Disorders (DC-TMD) to predict risk of developing TMD symptom persistence. Methods At baseline, trained examiners identified 260 participants with first-onset TMD classified by using DC-TMD–compliant protocols. After follow-up at least 6 months later, 72 (49%) had examiner-classified TMD (persistent cases), and 75 (51%) no longer had examiner-classified TMD (transient cases). For multivariable logistic regression analysis, the authors used blocks of variables selected using minimum redundancy maximum relevance to construct a model to predict the odds of TMD persistence. Results At onset, persistent cases had multiple worse TMD clinical measures and, among Axis II measures, only greater baseline pain intensity (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.04 to 2.2; P = .030) and more physical symptoms (OR, 1.8; 95% CI, 1.2 to 2.9; P = .004) than did transient cases. A multivariable model using TMD clinical measures showed greater discriminative capacity (area under the receiver operating characteristic curve, 0.74; 95% CI, 0.73 to 0.75) than did a model involving psychosocial measures (area under the receiver operating characteristic curve, 0.63; 95% CI, 0.62 to 0.64). Conclusions Clinical measures that clinicians can assess readily when TMD first develops are useful in predicting the risk of developing persistent TMD. Psychosocial measures are important predictors of onset but do not add meaningfully to the predictive capacity of clinical measures. Practical Implications When TMD first develops, clinicians usefully can identify patients at higher risk of developing persistence by using clinical measures that they logically also could use in treatment planning and for monitoring outcomes of intervention.

Supplemental Digital Content is Available in the Text., Background: Chronic facial pain often overlaps with pain experienced elsewhere in the body, although previous studies have focused on a few, selected pain conditions when assessing the degree of overlap. Aim: To quantify the degree of overlap between facial pain and pain reported at multiple locations throughout the body. Methods: Data were from a case–control study of US adults participating in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) project. They were interviewed to determine the presence of chronic facial pain (n = 424 cases) or its absence (n = 912 controls). A mailed questionnaire with a body drawing asked about pain at other locations. Odds ratios (ORs) and 95% confidence limits (95% CLs) quantified the degree of overlap between facial pain and pain at other locations. For replication, cross-sectional data were analyzed from the UK Biobank study (n = 459,604 participants) and the US National Health Interview Survey (n = 27,731 participants). Results: In univariate analysis, facial pain had greatest overlap with headache (OR = 14.2, 95% CL = 9.7–20.8) followed by neck pain (OR = 8.5, 95% CL = 6.5–11.0), whereas overlap decreased substantially (ORs of 4.4 or less) for pain at successively remote locations below the neck. The same anatomically based ranking of ORs persisted in multivariable analysis that adjusted for demographics and risk factors for facial pain. Findings were replicated in the UK Biobank study and the US National Health Interview Survey. The observed anatomical selectivity in the degree of overlap could be a consequence of neurosensory and/or affective processes that differentially amplify pain according to its location.

Case-control studies have documented clinical manifestations of chronic temporomandibular disorder (TMD), whereas clinical predictors of TMD development are largely unknown. We evaluated 41 clinical orofacial characteristics thought to predict first-onset TMD in a prospective cohort study of U.S. adults aged 18 to 44 years. During the median 2.8-year follow-up period, 2,737 people completed quarterly screening questionnaires. Those reporting symptoms were examined and 260 people were identified with first-onset TMD. Univariate and multivariable Cox regression models quantified associations between baseline clinical orofacial measures and TMD incidence. Significant predictors from baseline self-report instruments included oral parafunctions, prior facial pain and its life-impact, temporomandibular joint noises and jaw locking, and nonspecific orofacial symptoms. Significant predictors from the baseline clinical examination were pain on jaw opening and pain from palpation of masticatory, neck, and body muscles. Examiner assessments of temporomandibular joint noise and tooth wear facets did not predict incidence. In multivariable analysis, nonspecific orofacial symptoms, pain from jaw opening, and oral parafunctions predicted TMD incidence. The results indicate that only a few orofacial examination findings influenced TMD incidence, and only to a modest degree. More pronounced influences were found for self-reported symptoms, particularly those that appeared to reflect alterations to systems beyond the masticatory tissues. Perspective OPPERA's prospective cohort study identifies predictors of first-onset TMD comprising self-reported orofacial symptoms and examination findings. The results suggest a complex pattern of TMD etiology that is influenced by disorders locally, in masticatory tissues, and systemically, in pain-regulatory systems.

Case-control studies have consistently associated psychological factors with chronic pain in general and with temporomandibular disorder (TMD) specifically. However, only a handful of prospective studies have explored whether preexisting psychological characteristics represent risk factors for first-onset TMD. The current findings derive from the prospective cohort study of the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) cooperative agreement. For this study, 3,263 TMD-free participants completed a battery of psychological instruments assessing general psychological adjustment and personality, affective distress, psychosocial stress, somatic symptoms, and pain coping and catastrophizing. Study participants were then followed prospectively for an average of 2.8 years to ascertain cases of first-onset of TMD, and 2,737 provided follow-up data and were considered in the analyses of TMD onset. In bivariate and demographically adjusted analyses, several psychological variables predicted increased risk of first-onset TMD, including reported somatic symptoms, psychosocial stress, and affective distress. Principal component analysis of 26 psychological scores was used to identify latent constructs, revealing 4 components: stress and negative affectivity, global psychological and somatic symptoms, passive pain coping, and active pain coping. In multivariable analyses, global psychological and somatic symptoms emerged as the most robust risk factor for incident TMD. These findings provide evidence that measures of psychological functioning can predict first onset of TMD. Future analyses in the OPPERA cohort will determine whether these psychological factors interact with other variables to increase risk for TMD onset and persistence. Perspective This article reports that several premorbid psychological variables predict first-onset TMD in the OPPERA study, a large prospective cohort study designed to discover causal determinants of TMD pain. Measures of somatic symptoms were most strongly associated with TMD onset, but perceived stress, previous life events, and negative affect also predicted TMD incidence.

The authors tested the hypothesis that obstructive sleep apnea (OSA) signs/symptoms are associated with the occurrence of temporomandibular disorder (TMD), using the OPPERA prospective cohort study of adults aged 18 to 44 years at enrollment (n = 2,604) and the OPPERA case-control study of chronic TMD (n = 1,716). In both the OPPERA cohort and case-control studies, TMD was examiner determined according to established research diagnostic criteria. People were considered to have high likelihood of OSA if they reported a history of sleep apnea or ≥ 2 hallmarks of OSA: loud snoring, daytime sleepiness, witnessed apnea, and hypertension. Cox proportional hazards regression estimated hazard ratios (HRs) and 95% confidence limits (CL) for first-onset TMD. Logistic regression estimated odds ratios (OR) and 95% CL for chronic TMD. In the cohort, 248 individuals developed first-onset TMD during the median 2.8-year follow-up. High likelihood of OSA was associated with greater incidence of first-onset TMD (adjusted HR = 1.73; 95% CL, 1.14, 2.62). In the case-control study, high likelihood of OSA was associated with higher odds of chronic TMD (adjusted OR = 3.63; 95% CL, 2.03, 6.52). Both studies supported a significant association of OSA symptoms and TMD, with prospective cohort evidence finding that OSA symptoms preceded first-onset TMD.

INTRODUCTION: Literature concerning primary pulmonary sarcomas (PPS) is limited to small case series. This study examines, in a large cohort, the clinical characteristics and therapeutic strategies of PPS and their impact on overall survival (OS). METHODS: This was a retrospective analysis from the Surveillance, Epidemiology, and End Results database (1988-2008). Eligible patients had primary PPS and underwent local therapy. Survival estimates were obtained using the Kaplan-Meier method and the Cox regression model. OS of PPS patients were compared with a cohort of 10,909 patients with extremity soft-tissue sarcomas. RESULTS: The cohort included 365 PPS patients with a median follow-up of 21 months. Fifty-five percent of the patients had large tumors (>5 cm), 76% were high-grade, and 16% had node-positive disease. Seventy-five percent of the cohort underwent surgery alone, 14% underwent surgery and radiation therapy, and 11% underwent radiation therapy alone. Multivariate analysis showed reduced OS for patients with tumors more than 5 cm (hazard ratio [HR] 1.6, 95% confidence interval [CI] 1.25-2.19), high tumor grade (HR 3.1, 95% CI 1.26-3.62), and unresectable disease (HR 2.6, 95% CI 1.76-3.88. The 5-year OS for the cohort of pulmonary sarcomas versus sarcomas of the extremities was 35% versus 71% (p < 0.0001). CONCLUSION: This large study examining PPS patients reveals a high rate of nodal involvement and a markedly worse OS than patients with extremity soft-tissue sarcomas. Thus, given the poor overall prognosis, it is recommended that PPS patients undergo a thorough mediastinal nodal evaluation to rule out locoregional metastasis and proceed with aggressive treatment.

We explored causal mediation of sleep quality and perceived stress in development of painful temporomandibular disorder (TMD). Sleep quality and perceived stress were assessed at baseline and quarterly intervals thereafter in 2,737 initially TMD-free adults in the Orofacial Pain Prospective Evaluation and Risk Assessment study (OPPERA) prospective cohort study. During follow-up, incident TMD cases were classified using research diagnostic criteria. Mediation analysis was conducted using a weighted Cox proportional hazards regression model that estimated hazard ratios (HRs) and 95% confidence limits (CL) of first-onset TMD. Models determined whether: 1) poor sleep quality during follow-up mediated the effect of baseline perceived stress on first-onset TMD, and 2) perceived stress during follow-up mediated the effect of baseline poor sleep quality on first-onset TMD. In both analyses, the total effect was decomposed into natural direct and indirect effects. Poor baseline sleep quality led to heightened perceived stress that then contributed to TMD development. When the total effect of poor sleep quality (HR = 2.10, CL = 1.76, 2.50) was decomposed, 34% of its effect was mediated by perceived stress (indirect effect HR = 1.29, CL = 1.06, 1.58). The effect of perceived stress on first-onset TMD was not mediated by sleep quality. Improving sleep may avert escalation of stress, limiting effects of both factors on TMD development. Perspective Causal mediation analysis highlights mechanisms by which poor sleep quality promotes development of TMD. First, poor sleep quality exerts a direct effect on pain. Second, it triggers a heightened perception of stress, which acts as an intermediate factor in the causal pathway between poor sleep quality and first-onset TMD pain.

It is not known to what extent residual infection may interfere with the success of pulp regeneration procedures. The aim of this study was to determine, radiographically and histologically, the effect of residual bacteria on the outcome of pulp regeneration mediated by a tissue-engineered construct as compared with traditional revascularization. Periapical lesions were induced in 24 canine teeth of 6 ferrets. After disinfection with 1.25% NaOCl and triple antibiotic paste, ferret dental pulp stem cells, encapsulated in a hydrogel scaffold, were injected into half the experimental teeth. The other half were treated with the traditional revascularization protocol with a blood clot scaffold. After 3 mo, block sections of the canine teeth were imaged radiographically and processed for histologic and histobacteriologic analyses. Associations between variables of interest were evaluated through mixed effects regression models. There were no significant differences between the 2 experimental groups in radiographic root development ( P > 0.05). There was a significant association between the presence of persistent periapical radiolucency and root wall thickness ( P = 0.02). There was also no significant difference in histologic findings between the 2 experimental groups ( P > 0.05). The presence of residual bacteria was significantly associated with lack of radiographic growth ( P < 0.001). The amount of dentin-associated mineralized tissue formed in teeth with residual bacteria was significantly less than in teeth with no residual bacteria ( P < 0.001). Residual bacteria have a critical negative effect on the outcome of regenerative endodontic procedures.

The demographic factors of sex, age, and race/ethnicity are well recognized as relevant to pain sensitivity and clinical pain expression. Of these, sex differences have been the most frequently studied, and most of the literature describes greater pain sensitivity for women. The other 2 factors have been less frequently evaluated, and current literature is not definitive. Taking advantage of the large Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study cohort, we evaluated the association of sex, age, and self-reported race with 34 measures of pressure, mechanical, and thermal pain sensitivity encompassing threshold and suprathreshold perception. Women were significantly more pain-sensitive than men for 29 of 34 measures. Age effects were small, and only significant for 7 of 34 measures, however, the age range was limited (18–44 years of age). Race/ethnicity differences varied across groups and pain assessment type. Non-Hispanic white individuals were less pain-sensitive than African-American (for 21 of 34 measures), Hispanic (19 of 34), and Asian (6 of 34) individuals. No pain threshold measure showed significant racial differences, whereas several suprathreshold pain measures did. This suggests that racial differences are not related to tissue characteristics or inherent nociceptor sensitivity. Rather, the differences observed for suprathreshold pain ratings or tolerance are more likely related to differences in central nociceptive processing, including modulation imposed by cognitive, psychological, and/or affective factors. Perspective The influence of sex, age, and race/ethnicity on various aspects of pain sensitivity, encompassing threshold and suprathreshold measures and multiple stimulus modalities, allows for a more complete evaluation of the relevance of these demographic factors to acute pain perception.

Vestibulodynia, the most common type of chronic vulvovaginal pain, impairs the psychological, physical health of nearly 10% of women at some point in their lifetime. The aim of this investigation was to establish reliable standardized methodologies for assessment of pain sensitivity in vulvar mucosa and pelvic musculature. We enrolled 34 women with vestibulodynia and 21 pain-free controls. The participants underwent a nuanced exam that consisted of palpation of precisely located vulvar mucosal and pelvic muscle sites. These measurements remained highly stable when participants were reexamined after 2 weeks, with high within-examiner correlation. Vestibulodynia patients reported greater sensitivity than pain-free controls at the majority of examination sites, particularly at mucosal sites on the lower vestibule. The pain threshold measures at the lower mucosal sites were also associated with the participants’ self-reported pain levels during intercourse. These mucosal pain threshold measurements were used to discriminate between vestibulodynia cases and controls with high sensitivity and specificity. This data supports the feasibility of contemporaneous assessment of vulvar mucosa and underlying musculature in the pelvic region, offering the hope of a more precise case definition for vestibulodynia and related disorders. Perspective This study describes performance characteristics of novel methodologies for assessing pelvic muscle and mucosal sensitivity. These pain sensitivity measures were reproducible and associated with subjective pain reports and vestibulodynia case status and represent an important step toward a more precise case definition for vestibulodynia and related disorders.

The classification of most chronic pain disorders gives emphasis to anatomical location of the pain to distinguish one disorder from the other (eg, back pain vs temporomandibular disorder [TMD]) or to define subtypes (eg, TMD myalgia vs arthralgia). However, anatomical criteria overlook etiology, potentially hampering treatment decisions. This study identified clusters of individuals using a comprehensive array of biopsychosocial measures. Data were collected from a case-control study of 1031 chronic TMD cases and 3247 TMD-free controls. Three subgroups were identified using supervised cluster analysis (referred to as the adaptive, pain-sensitive, and global symptoms clusters). Compared with the adaptive cluster, participants in the pain-sensitive cluster showed heightened sensitivity to experimental pain, and participants in the global symptoms cluster showed both greater pain sensitivity and greater psychological distress. Cluster membership was strongly associated with chronic TMD: 91.5% of TMD cases belonged to the pain-sensitive and global symptoms clusters, whereas 41.2% of controls belonged to the adaptive cluster. Temporomandibular disorder cases in the pain-sensitive and global symptoms clusters also showed greater pain intensity, jaw functional limitation, and more comorbid pain conditions. Similar results were obtained when the same methodology was applied to a smaller case-control study consisting of 199 chronic TMD cases and 201 TMD-free controls. During a median 3-year follow-up period of TMD-free individuals, participants in the global symptoms cluster had greater risk of developing first-onset TMD (hazard ratio = 2.8) compared with participants in the other 2 clusters. Cross-cohort predictive modeling was used to demonstrate the reliability of the clusters.

Chronic pain is a significant health care problem, ineffectively treated because of its unclear etiology and heterogeneous clinical presentation. Emerging evidence demonstrates that microRNAs (miRNAs) regulate the expression of pain-relevant genes, yet little is known about their role in chronic pain. Here, we evaluate the relationship among pain, psychological characteristics, plasma cytokines, and whole blood miRNAs in 22 healthy controls (HCs); 33 subjects with chronic pelvic pain (vestibulodynia, VBD); and 23 subjects with VBD and irritable bowel syndrome (VBD + IBS). VBD subjects were similar to HCs in self-reported pain, psychological profiles, and remote bodily pain. VBD + IBS subjects reported decreased health and function; and an increase in headaches, somatization, and remote bodily pain. Furthermore, VBD subjects exhibited a balance in proinflammatory and anti-inflammatory cytokines, whereas VBD + IBS subjects failed to exhibit a compensatory increase in anti-inflammatory cytokines. VBD subjects differed from controls in expression of 10 miRNAs of predicted importance for pain and estrogen signaling. VBD + IBS subjects differed from controls in expression of 11 miRNAs of predicted importance for pain, cell physiology, and insulin signaling. miRNA expression was correlated with pain-relevant phenotypes and cytokine levels. These results suggest that miRNAs represent a valuable tool for differentiating VBD subtypes (localized pain with apparent peripheral neurosensory disruption vs widespread pain with a central sensory contribution) that may require different treatment approaches.

In regression problems where the number of predictors greatly exceeds the number of observations, conventional regression techniques may produce unsatisfactory results. We describe a technique called supervised principal components that can be applied to this type of problem. Supervised principal components is similar to conventional principal components analysis except that it uses a subset of the predictors selected based on their association with the outcome. Supervised principal components can be applied to regression and generalized regression problems, such as survival analysis. It compares favorably to other techniques for this type of problem, and can also account for the effects of other covariates and help identify which predictor variables are most important. We also provide asymptotic consistency results to help support our empirical findings. These methods could become important tools for DNA microarray data, where they may be used to more accurately diagnose and treat cancer.

Background In patients with acute myeloid leukemia (AML), the presence or absence of recurrent cytogenetic aberrations is used to identify the appropriate therapy. However, the current classification system does not fully reflect the molecular heterogeneity of the disease, and treatment stratification is difficult, especially for patients with intermediate-risk AML with a normal karyotype. Methods We used complementary-DNA microarrays to determine the levels of gene expression in peripheral-blood samples or bone marrow samples from 116 adults with AML (including 45 with a normal karyotype). We used unsupervised hierarchical clustering analysis to identify molecular subgroups with distinct gene-expression signatures. Using a training set of samples from 59 patients, we applied a novel supervised learning algorithm to devise a gene-expression–based clinical-outcome predictor, which we then tested using an independent validation group comprising the 57 remaining patients. Results Unsupervised analysis identi...

The morbidity rate of cancer victims varies greatly for similar patients who receive similar treatments. It is hypothesized that this variation can be explained by the genetic heterogeneity of the disease. DNA Microarrays, which can simultaneously measure the expression level of thousands of different genes, have been successfully used to identify such genetic differences. However, microarray data typically has a large number of features and relatively few observations, meaning that conventional machine learning tools can fail when applied to such data. We describe a novel procedure called "nearest shrunken centroids" that has successfully detected clinically relevant genetic differences in cancer patients. This procedure has the potential to become a powerful tool for diagnosing and treating cancer.

Purpose We assessed a novel Food and Drug Administration–approved hydrogel, synthesized as absorbable iodinated particles, in gynecologic-cancer patients undergoing computed tomography (CT) or magnetic resonance (MR) based brachytherapy after external beam radiation. Methods and Materials Nineteen patients underwent CT-guided (n = 13) or MR-guided (n = 6) brachytherapy for gynecologic cancers. Seventy-seven hydrogel injections were placed. The hydrogel material was injected into gross residual disease and/or key anatomic landmarks in amounts ranging from 0.1 to 0.4 mL. The visibility of the tracer was scored on CT and on MR images using a 5-point scoring scale. A Cohen's kappa statistic was calculated to assess interobserver agreement. To assess the unadjusted effects of baseline parameters on hydrogel visibility, we modeled visibility using a linear mixed-effect model. Results Injections were without complication. The kappa statistic was 0.77 (95% confidence interval [CI], 0.68–0.87). The volume of hydrogel injected was significantly associated with visibility on both CT ( p = 0.032) and magnetic resonance imaging ( p = 0.016). We analyzed visibility by location, controlling for amount. A 0.1-cc increase in volume injected was associated with increases of 0.54 (95% CI = 0.05–1.03) in the CT visibility score and 0.83 (95% CI = 0.17–1.49) in the MR visibility score. Injection of 0.4 cc or more was required for unequivocal visibility on CT or MR. No statistically significant correlation was found between tumor type, tumor location, or anatomical location of injection and visibility on either CT or magnetic resonance imaging. Conclusions In this first report of an injectable radiopaque hydrogel, targets were visualized to assist with three-dimensional–based brachytherapy in gynecologic malignancies. This marker has potential for several applications, is easy to inject and visualize, and caused no acute complications.

Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs) have a well-established analgesic efficacy for inflammatory pain. These drugs exert their effect by inhibiting the enzyme cyclooxygenase (COX) and are commonly used for the management of pain after endodontic treatment. There are 2 distinct isoforms of COX: COX-1, which is constitutively expressed, and COX-2, which is primarily induced by inflammation. Previous studies have shown that functional human genetic variants of the COX-2 gene may explain individual variations in acute pain. The present study extends this work by examining the potential contribution of the 2 COX isoforms to pain after endodontic treatment. Methods Ninety-four patients treated by endodontic residents at the University of North Carolina School of Dentistry were enrolled into a prospective cohort study. Data on potential predictors of post-treatment pain were collected, and all patients submitted saliva samples for genetic analysis. Nonsurgical root canal therapy was performed, and participants recorded pain levels for 5 days after. Results In this study, 63% of patients experienced at least mild pain after root canal therapy, and 24% experienced moderate to severe pain. The presence of pretreatment pain was correlated with higher post-treatment pain (P = .01). Elevated heart rate (P = .02) and higher diastolic blood pressure (P = .024) were also correlated with decreased post-treatment pain. Finally, we identified genetic variants in COX-2 (haplotype composed of rs2383515 G, rs5277 G, rs5275 T, and rs2206593 A) associated with post-treatment pain after endodontic treatment (P = .025). Conclusions Understanding the genetic basis of pain after endodontic treatment will advance its prevention and management.

Central sensitization elicits pain hypersensitivity and is thought to be causally implicated in painful temporomandibular disorder (TMD). This causal inference is based on cross-sectional evidence that people with TMD have greater sensitivity than controls to noxious stimuli. We tested this inference in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) prospective cohort study of 3258 adults with no lifetime history of TMD when enrolled (visit 1). During 5 years of follow-up, 1 group labeled "persistent TMD cases" (n=72) developed first-onset TMD by visit 2 that persisted ⩾ 6 months until visit 3. Another group labeled "transient TMD cases" (n=75) developed first-onset TMD at visit 2, which resolved by visit 3. Randomly sampled "controls" (n=126) remained TMD-free throughout all 3 visits. At each visit, pressure pain thresholds (PPTs) were measured by algometry at 10 cranial and bodily sites. In persistent TMD case patients, mean PPTs reduced 43 kPa (P

We examined the incidence and predictors of peritraumatic distress and dissociation after one of the most common forms of civilian trauma exposure: motor vehicle collision (MVC).In this study, patients presenting to the emergency department after MVCs who were without serious injury and discharged to home after evaluation (n = 935) completed an emergency department interview evaluating sociodemographic, collision-related, and psychological characteristics.The incidence and predictors of distress (Peritraumatic Distress Inventory score ≥23) and dissociation (Michigan Critical Events Perception Scale score3) were assessed. Distress was present in 355 of 935 patients (38%), and dissociation was present in 260 of 942 patients (28%). These outcomes showed only moderate correlation (r = .45) and had both shared and distinct predictors. Female gender, anxiety symptoms prior to the MVC, and vehicle damage severity predicted both distress and dissociation. Higher socioeconomic status (higher education, higher income, full-time employment) had a protective effect against distress but not dissociative symptoms. Better physical health and worse overall mental health were associated with increased risk of dissociation but not distress. Distress but not dissociation was associated with lower patient confidence in recovery and a longer expected duration of recovery.There are unique predictors of peritraumatic distress and dissociation. Further work is needed to better understand the neurobiology of peritraumatic distress and dissociation and the influence of these peritraumatic outcomes on persistent psychological sequelae.

Debate continues regarding the influence of litigation on pain outcomes after motor vehicle collision (MVC). In this study we enrolled European Americans presenting to the emergency department (ED) in the hours after MVC (n = 948). Six weeks later, participants were interviewed regarding pain symptoms and asked about their participation in MVC-related litigation. The incidence and predictors of neck pain and widespread pain six weeks after MVC were compared among those engaged in litigation ("litigants") and those not engaged in litigation ("non-litigants"). Among the 859/948 (91%) participants completing six week follow-up, 711/849 (83%) were non-litigants. Compared to non-litigants, litigants were less educated and had more severe neck pain, overall pain, and a greater extent of pain at the time of ED evaluation. Among individuals not engaged in litigation, persistent pain six weeks after MVC was common: 199/711 (28%) had moderate or severe neck pain, 92/711 (13%) had widespread pain, and 29/711 (4%) had fibromyalgia-like symptoms. Incidence of all three outcomes was significantly higher among litigants. Initial pain severity in the ED predicted pain outcomes among both litigants and non-litigants. Markers of socioeconomic disadvantage predicted worse pain outcomes in litigants but not non-litigants, and individual pain and psychological symptoms were less predictive of pain outcomes among those engaged in litigation. These data demonstrate that persistent pain after MVC is common among those not engaged in litigation, and provide evidence for bidirectional influences between pain outcomes and litigation after MVC.

Temporomandibular disorder (TMD) overlaps with other health conditions, but no study has examined which of these conditions increase the risk of developing first-onset TMD. The authors prospectively evaluated the relationship between health status at enrollment and subsequent incidence of TMD in 2,722 men and women. Participants aged 18 to 44 years had no history of TMD and were clinically free of TMD when enrolled in 2006 to 2008 at 4 U.S. study sites in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) prospective cohort study. First-onset examiner-classified TMD developed in 260 people over a median 2.8 years of follow-up. Cox regression estimated the association between health conditions and TMD incidence while accounting for potential confounders. Incidence of first-onset TMD was 50% higher for people with low back pain (adjusted hazard ratio [AHR] = 1.50, 95% confidence limits [CLs]: 1.08, 2.10) and 75% higher for people with genital pain symptoms (AHR = 1.75, 95% CLs = 1.04, 2.93) than people without a history of these pain disorders. Digit ratio, a marker of intrauterine exposure to sex hormones, was significantly associated with TMD incidence. Other independent predictors of first-onset TMD were sleep disturbance and cigarette smoking. These findings reveal multiple influences of health status on incidence of first-onset TMD. Perspective This article examines health conditions that commonly overlap with TMD to determine which ones predict first-onset TMD. A history of low back pain and genital pain conditions at baseline were important predictors. Novel findings were that disrupted sleep and conditions in utero may increase incidence of first-onset TMD.

Incidence of temporomandibular disorder (TMD) was predicted with multivariable models that used putative risk factors collected from initially TMD-free individuals in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. The 202 baseline risk factors included sociodemographic and clinical characteristics, measures of general health status, experimental pain sensitivity, autonomic function, and psychological distress. Study participants (n = 2,737) were then followed prospectively for a median of 2.8 years to ascertain cases of first-onset TMD. Lasso regression and random forest models were used to predict incidence of first-onset TMD using all of the aforementioned measures. Variable importance scores identified the most important risk factors, and their relationship with TMD incidence was illustrated graphically using partial dependence plots. Two of the most important risk factors for elevated TMD incidence were greater numbers of comorbid pain conditions and greater extent of nonspecific orofacial symptoms. Other important baseline risk factors were preexisting bodily pain, heightened somatic awareness, and greater extent of pain in response to examiners' palpation of the head, neck, and body. Several demographic variables persisted as risk factors even after adjusting for other OPPERA variables, suggesting that environmental variables not measured in OPPERA may also contribute to first-onset TMD. Perspective Multivariable methods were used to identify the most important predictors of first-onset TMD in the OPPERA study. Important variables included comorbid pain conditions, preexisting pain, and somatic awareness. Demographic characteristics, which probably reflect environmental variables not measured in OPPERA, also appear to play an important role in the etiology of TMD.

Papers in this issue investigate when and how putative risk factors influence development of first-onset, painful temporomandibular disorder (TMD). The results represent first findings from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) prospective cohort study that monitored 2,737 men and women aged 18 to 44 years recruited at 4 U.S. study sites. During a median 2.8-year follow-up period, 260 participants developed TMD. The average incidence rate of 4% per annum was influenced by a broad range of phenotypic risk factors including sociodemographic characteristics, health status, clinical orofacial factors, psychological functioning, pain sensitivity, and cardiac autonomic responses. A novel method of multivariable analysis used random forest models to simultaneously evaluate contributions of all 202 phenotypic variables. Variables from the health status domain made the greatest contribution to TMD incidence, followed closely by psychological and clinical orofacial domains. However, only a few measures of pain sensitivity and autonomic function contributed to TMD incidence, and their effects were modest. Meanwhile, age and study site were independent predictors of TMD incidence, even after controlling for other phenotypes. Separate analysis of 358 genes that regulate pain found several novel genetic associations with intermediate phenotypes that, themselves, are risk factors for TMD, suggesting new avenues to investigate biological pathways contributing to TMD. Perspective Collectively, the papers in this issue demonstrate that TMD is a complex disorder with multiple causes consistent with a biopsychosocial model of illness. It is a misnomer and no longer appropriate to regard TMD solely as a localized orofacial pain condition.

PURPOSE/OBJECTIVES: To determine if intensity modulated radiation therapy (IMRT) in the post-operative setting for gastric cancer was associated with reduced toxicity compared to 3D conformal radiation therapy (3DCRT). MATERIALS/METHODS: This retrospective study includes 24 patients with stage IB-IIIB gastric cancer consecutively treated from 2001-2010. All underwent surgery followed by adjuvant chemoradiation. Concurrent chemotherapy consisted of 5-FU/leucovorin (n = 21), epirubicin/cisplatin/5FU (n = 1), or none (n = 2). IMRT was utilized in 12 patients and 3DCRT in 12 patients. For both groups, the target volume included the tumor bed, anastomosis, gastric stump, and regional lymphatics. RESULTS: Median follow-up for the entire cohort was 19 months (range 0.4-8.5 years), and 49 months (0.5-8.5 years) in surviving patients. The 3DCRT group received a median dose of 45 Gy, and the IMRT group received a median dose of 50.4 Gy (p = 0.0004). For the entire cohort, 3-year overall survival (OS) was 40% and 3-year disease free survival (DFS) was 41%. OS and DFS did not differ significantly between the groups. Acute toxicity was similar. Between 3DCRT and IMRT groups, during radiotherapy, median weight lost (3.2 vs. 3.3 kg, respectively; p = 0.47) and median percent weight loss were similar (5.0% vs. 4.3%, respectively; p = 0.43). Acute grade 2 toxicity was experienced by 8 patients receiving 3DCRT and 11 receiving IMRT (p = 0.32); acute grade 3 toxicity occurred in 1 patient receiving 3DCRT and none receiving IMRT (p = 1.0). No patients in either cohort experienced late grade 3 toxicity, including renal or gastrointestinal toxicity. At last follow up, the median increase in creatinine was 0.1 mg/dL in the IMRT group and 0.1 mg/dL in the 3DCRT group (p = 0.78). CONCLUSION: This study demonstrates that adjuvant chemoradiation for gastric cancer with IMRT to 50.4 Gy was well-tolerated and compared similarly in toxicity with 3DCRT to 45 Gy.

To examine pain and biopsychosocial correlates over time for women with persistent postsurgical pain after surgery for endometriosis.Cross-sectional study of women who underwent any endometriosis surgery between 2003 and 2006. Following surgery, patients completed validated questionnaires (Short-Form McGill Pain Questionnaire, 12-item Short-Form Health Survey, Beck Depression Inventory, Coping Strategies Questionnaire catastrophizing subscale). The primary outcome was pelvic pain intensity, measured by the McGill total pain score. Bivariate comparisons between each potential predictor and pain intensity were performed using the χ(2) and t tests, 1-way analysis of variance, and simple linear regression.In total, 79 completed the questionnaires and were included in the present analysis. The McGill affective pain score was negatively correlated with age (β-coefficient -0.12, P=0.002) and positively correlated with catastrophization (β-coefficient 0.66, P=0.01). Women with a history of dyspareunia scored significantly higher on the McGill total pain score (P0.001); there was no association between pain intensity and endometriosis severity.Younger age and catastrophization are correlated with persistent pain following surgery for endometriosis. The severity of endometriosis does not predict persistent pain. Further evaluation of psychosocial factors may identify patients who are least likely to benefit from surgeries for endometriosis-associated pelvic pain.

The course of preclinical pain symptoms sheds light on the etiology and prognosis of chronic pain. We aimed to quantify rates of developing initial and recurrent symptoms of painful temporomandibular disorder (TMD) and to evaluate associations with health behaviors. In the OPPERA prospective cohort study, 2,719 individuals aged 18 to 44years with lifetime absence of TMD when enrolled completed 25,103 quarterly (3-monthly) questionnaires during a median 2.3-year follow-up period. Questionnaires documented TMD symptom episodes, headache, other body pain, health care attendance, and analgesic use, and. Kaplan-Meier methods for clustered data estimated symptom-free survival time. Multivariable models assessed demographic variation in TMD symptom rates and evaluated associations with health care and analgesic use. One-third of the study subjects developed TMD symptoms and for a quarter of symptomatic episodes, pain intensity was severe. Initial TMD symptoms developed at an annual rate of 18.8 episodes per 100 persons. The annual rate more than doubled for first-recurrence and doubled again for second or subsequent recurrence such that, 1year after first recurrence, 71% of study subjects experienced a second recurrence. The overall rate increased with age and was greater in African Americans and lower in Asians relative to those of white race/ethnicity. The probability of TMD symptoms was strongly associated with concurrent episodes of headache and body pain and with past episodes of TMD symptoms. Episodes of TMD symptoms, headache, and body pain were associated with increases of ∼10% in probability of analgesic use and health care attendance. Yet, even when TMD, headache, and body pain occurred concurrently, 27% of study subjects neither attended health care nor used analgesics.

When studying incidence of pain conditions such as temporomandibular disorder (TMD), repeated monitoring is needed in prospective cohort studies. However, monitoring methods usually have limitations and, over a period of years, some loss to follow-up is inevitable. The OPPERA prospective cohort study of first-onset TMD screened for symptoms using quarterly questionnaires and examined symptomatic participants to definitively ascertain TMD incidence. During the median 2.8-year observation period, 16% of the 3,263 enrollees completed no follow-up questionnaires, others provided incomplete follow-up, and examinations were not conducted for one third of symptomatic episodes. Although screening methods and examinations were found to have excellent reliability and validity, they were not perfect. Loss to follow-up varied according to some putative TMD risk factors, although multiple imputation to correct the problem suggested that bias was minimal. A second method of multiple imputation that evaluated bias associated with omitted and dubious examinations revealed a slight underestimate of incidence and some small biases in hazard ratios used to quantify effects of risk factors. Although “bottom line” statistical conclusions were not affected, multiply-imputed estimates should be considered when evaluating the large number of risk factors under investigation in the OPPERA study. Perspective These findings support the validity of the OPPERA prospective cohort study for the purpose of investigating the etiology of first-onset TMD, providing the foundation for other papers investigating risk factors hypothesized in the OPPERA project.

Purpose Three-dimensional (3D) surface matching is a novel method to administer deep inspiration breath-hold (DIBH) radiation therapy for left-sided breast cancer to reduce cardiac exposure. We analyzed port (x-ray) films to assess patient setup accuracy and treatment times to assess the practical workflow of this system. Methods and materials The data from 50 left-sided breast cancer patients treated with DIBH were studied. AlignRT (London, UK) was used. The distance between the field edge and the anterior pericardial shadow as seen on the routine port films (d PORT ), and the corresponding distance seen on the digitally reconstructed radiographs (DRR) from the planning (d DRR ) were compared as a quantitative measure of setup accuracy. Variations of d PORT – d DRR over the treatment course were assessed. In a subset of 21 patients treated with tangential beams alone, the daily treatment durations were analyzed to assess the practical workflow of this system. Results Considering all 50 patients, the mean absolute systematic uncertainty between d PORT and d DRR was 0.20 cm (range, 0 to 1.22 cm), the mean systematic uncertainty was −0.07 cm (range, −1.22 to 0.67 cm), and their mean random uncertainty was 0.19 cm (range, 0 to 0.84 cm). There was no significant change in d PORT – d DRR during the course of treatment. The mean patient treatment duration for the 21 patients studied was 11 minutes 48 seconds. On intrapatient assessments, 15/21 had nonsignificant trends toward reduced treatment durations during their course of therapy. On interpatient comparisons, the mean treatment times declined as we gained more experience with this technique. Conclusions The DIBH patient setup appears to provide a fairly reproducible degree of cardiac sparing with random uncertainties of ≈ 0.2 cm. The treatment durations are clinically acceptable and appear not to change significantly over time on an intrapatient basis, and to improve over time on an interpatient basis.

Although cross-sectional studies of temporomandibular disorder (TMD) often report elevated prevalence in young women, they do not address the risk of its development. Here we evaluate sociodemographic predictors of TMD incidence in a community-based prospective cohort study of U.S. adults. Symptoms and pain-related disability in TMD cases are also described. People aged 18 to 44 years with no history of TMD were enrolled at 4 study sites when they completed questionnaires about sociodemographic characteristics. During the median 2.8-year follow-up period, 2,737 participants completed quarterly screening questionnaires. Those reporting symptoms were examined clinically and 260 had first-onset TMD. Additional questionnaires asked about severity and impact of their symptoms. Univariate and multivariable Cox regression models quantified associations between sociodemographic characteristics and TMD incidence. First-onset TMD developed in 3.9% of participants per annum, typically producing mild to moderate levels of pain and disability in cases. TMD incidence was positively associated with age, whereas females had only slightly greater incidence than males. Compared to whites, Asians had lower TMD incidence whereas African Americans had greater incidence, although the latter was attenuated somewhat after adjusting for satisfaction with socioeconomic circumstances. Perspective In this study of 18- to 44-year-olds, TMD developed at a higher rate than reported previously for similar age groups. TMD incidence was positively associated with age but weakly associated with gender, thereby differing from demographic patterns of prevalence found in some cross-sectional studies. Experiences related to aging merit investigation as etiologic influences on development of TMD.

Genetic risk factors are believed to combine with environmental exposures and contribute to the risk of developing temporomandibular disorder (TMD). In this prospective cohort study, 2,737 people without TMD were assessed for common genetic variation in 358 genes known to contribute to nociceptive pathways, inflammation, and affective distress. During a median follow-up period of 2.8 years, 260 people developed first-onset TMD. Hazard ratios were computed as measures of association between 2,924 single-nucleotide polymorphisms and TMD incidence. After correction for multiple testing, no single single-nucleotide polymorphism was significantly associated with risk of onset TMD. However, several single-nucleotide polymorphisms exceeded Bonferroni correction for multiple comparison or false discovery rate thresholds (.05, .1, or .2) for association with intermediate phenotypes shown to be predictive of TMD onset. Nonspecific orofacial symptoms were associated with voltage-gated sodium channel, type I, alpha subunit ( SCN1A , rs6432860, P = 2.77 × 10 −5 ) and angiotensin I–converting enzyme 2 ( ACE2 , rs1514280, P = 4.86 × 10 −5 ); global psychological symptoms with prostaglandin-endoperoxide synthase 1 ( PTGS1 , rs3842803, P = 2.79 × 10 −6 ); stress and negative affectivity with amyloid-β (A4) precursor protein ( APP , rs466448, P = 4.29 × 10 −5 ); and heat pain temporal summation with multiple PDZ domain protein ( MPDZ , rs10809907, P = 3.05 × 10 −5 ). The use of intermediate phenotypes for complex pain diseases revealed new genetic pathways influencing risk of TMD. Perspective This article reports the findings of a large candidate gene association study of first-onset TMD and related intermediate phenotypes in the OPPERA Study. Although no genetic markers predicted TMD onset, several genetic risk factors for clinical, psychological, and sensory phenotypes associated with TMD onset were observed.

Genetic factors play a role in the etiology of persistent pain conditions, putatively by modulating underlying processes such as nociceptive sensitivity, psychological well-being, inflammation, and autonomic response. However, to date, only a few genes have been associated with temporomandibular disorders (TMD). This study evaluated 358 genes involved in pain processes, comparing allelic frequencies between 166 cases with chronic TMD and 1,442 controls enrolled in the OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment) study cooperative agreement. To enhance statistical power, 182 TMD cases and 170 controls from a similar study were included in the analysis. Genotyping was performed using the Pain Research Panel, an Affymetrix gene chip representing 3,295 single nucleotide polymorphisms, including ancestry-informative markers that were used to adjust for population stratification. Adjusted associations between genetic markers and TMD case status were evaluated using logistic regression. The OPPERA findings provided evidence supporting previously reported associations between TMD and 2 genes: HTR2A and COMT. Other genes were revealed as potential new genetic risk factors for TMD, including NR3C1, CAMK4, CHRM2, IFRD1, and GRK5. While these findings need to be replicated in independent cohorts, the genes potentially represent important markers of risk for TMD, and they identify potential targets for therapeutic intervention. Perspective Genetic risk factors for TMD pain were explored in the case-control component of the OPPERA cooperative agreement, a large population-based prospective cohort study. Over 350 candidate pain genes were assessed using a candidate gene panel, with several genes displaying preliminary evidence for association with TMD status.

To examine long-term reports of pain and psychologic correlates of pain in women after vestibulectomy.In a retrospective cross-sectional exploratory study, 37 women who had undergone vestibulectomy between January 1989 and January 2008 completed questionnaires assessing demographic information, self-reported levels of pain, anxiety, somatization, psychologic distress, and sexual function.Eight women reported being completely pain free after surgery. The remaining 29 women reported various levels of pain during intercourse (as measured by the Gracely pain scale) and decreased sexual function (as measured by a sexual functioning questionnaire). Various measures of psychologic distress were associated with average intercourse-related pain, including brief symptom inventory (P=0.002), Pennebaker inventory of limbic languidness (P=0.002), perceived stress scale (P=0.04), and Spielberger trait-anxiety inventory (P=0.01). These same measures of psychological distress were similarly associated with general, unprovoked vaginal pain.The present data suggest that the pathophysiology of localized vulvodynia may be more complex in some women, leading to a suboptimal response to surgical treatment.

This paper describes methods used in the project “Orofacial Pain Prospective Evaluation and Risk Assessment” (OPPERA) and evaluates sociodemographic characteristics associated with temporomandibular disorders (TMD) in the OPPERA case-control study. Representativeness was investigated by comparing sociodemographic profiles of OPPERA participants with population census profiles of counties near study sites and by comparing age and gender associations with TMD in OPPERA and the 2007 to 2009 US National Health Interview Survey. Volunteers aged 18 to 44 years were recruited at 4 US study sites: 3,263 people without TMD were enrolled into the prospective cohort study; 1,633 of them were selected as controls for the baseline case-control study. Cases were 185 volunteers with examiner-classified TMD. Distributions of some demographic characteristics among OPPERA participants differed from census profiles, although there was less difference in socioeconomic profiles. Odds of TMD was associated with greater age in this 18 to 44 year range; females had 3 times the odds of TMD as males; and relative to non-Hispanic-Whites, other racial groups had one-fifth the odds of TMD. Age and gender associations with chronic TMD were strikingly similar to associations observed in the US population. Assessments of representativeness in this demographically diverse group of community volunteers suggest that OPPERA case-control findings have good internal validity. Perspective Demographic associations with TMD were consistent with population benchmarks and with other studies, suggesting broad applicability of these OPPERA findings. Greater occurrence of TMD in non-Hispanic-Whites than in other racial/ethnic groups and the lack of a socioeconomic gradient contradicts the disparities seen in many other health conditions.

Many studies report that people with temporomandibular disorders (TMD) are more sensitive to experimental pain stimuli than TMD-free controls. Such differences in sensitivity are observed in remote body sites as well as in the orofacial region, suggesting a generalized upregulation of nociceptive processing in TMD cases. This large case-control study of 185 adults with TMD and 1,633 TMD-free controls measured sensitivity to painful pressure, mechanical cutaneous, and heat stimuli, using multiple testing protocols. Based on an unprecedented 36 experimental pain measures, 28 showed statistically significantly greater pain sensitivity in TMD cases than controls. The largest effects were seen for pressure pain thresholds at multiple body sites and cutaneous mechanical pain threshold. The other mechanical cutaneous pain measures and many of the heat pain measures showed significant differences, but with lesser effect sizes. Principal component analysis (PCA) of the pain measures derived from 1,633 controls identified 5 components labeled: 1) heat pain ratings; 2) heat pain aftersensations and tolerance; 3) mechanical cutaneous pain sensitivity; 4) pressure pain thresholds; and 5) heat pain temporal summation. These results demonstrate that compared to TMD-free controls, chronic TMD cases are more sensitive to many experimental noxious stimuli at extracranial body sites, and provide for the first time the ability to directly compare the case-control effect sizes of a wide range of pain sensitivity measures. Perspective This article describes experimental pain sensitivity differences between a large sample of people with chronic TMD and non-TMD controls, using multiple stimulus modalities and measures. Variability in the magnitude and consistency of case-control differences highlight the need to consider multiple testing measures to adequately assess pain processing alterations in chronic pain conditions.

Case-control studies have consistently associated psychosocial factors with chronic pain in general, and with temporomandibular disorders (TMD) specifically. Moreover, a handful of prospective studies suggest that preexisting psychosocial characteristics represent risk factors for new onset TMD. The current study presents psychosocial findings from the baseline case-control study of the Orofacial Pain Prospective Evaluation and Risk Assessment (OPPERA) cooperative agreement. For this study, 1,633 TMD-free controls and 185 TMD cases completed a battery of psychosocial instruments assessing general psychosocial adjustment and personality, affective distress, psychosocial stress, somatic awareness, and pain coping and catastrophizing. In bivariate and demographically adjusted analyses, odds of TMD were associated with higher levels of psychosocial symptoms, affective distress, somatic awareness, and pain catastrophizing. Among controls, significant gender and ethnic group differences in psychosocial measures were observed, consistent with previous findings. Principal component analysis was undertaken to identify latent constructs revealing 4 components: stress and negative affectivity, global psychosocial symptoms, passive pain coping, and active pain coping. These findings provide further evidence of associations between psychosocial factors and TMD. Future prospective analyses in the OPPERA cohort will determine if the premorbid presence of these psychosocial factors predicts increased risk for developing new onset TMD. Perspective This article reports baseline psychosocial findings from the OPPERA Study, a large prospective cohort study designed to discover causal determinants of TMD pain. Findings indicate significant differences between TMD cases and TMD-free controls across multiple psychosocial constructs, and future analyses will determine whether these psychosocial factors increase risk for new onset TMD.