Exploring the link between comorbid insomnia and sleep apnea (COMISA) and erectile dysfunction: implications for male sexual health.

INTRODUCTION: This review explores the interplay between comorbid insomnia and sleep apnea (COMISA) and erectile dysfunction (ED), 2 conditions that significantly impact men's health. COMISA, a recently recognized condition characterized by the coexistence of insomnia and obstructive sleep apnea, has been shown to disrupt sleep architecture and cause intermittent hypoxia. These disturbances are increasingly linked to the exacerbation of ED, a prevalent issue among men. Understanding the connection between COMISA and ED is crucial for developing integrated treatment approaches that address both sleep and sexual health. OBJECTIVES: We aim to explore the epidemiological, physiological, and potential therapeutic intersections of COMISA and ED. This review sets out to develop a better understanding of the relationship between these conditions and to emphasize the need for an integrated diagnostic and therapeutic approach that addresses both sleep and sexual health. METHODS: Through a comprehensive analysis, including a detailed examination of extant studies, we address the hormonal imbalances and alterations in neural pathways that collectively contribute to the complex pathophysiology of ED and how these are particularly susceptible to the concurrent presence of COMISA. RESULTS: Our analysis indicates that disruptions in sleep architecture and intermittent hypoxia associated with COMISA can exacerbate ED. Hormonal imbalances, endothelial dysfunction, autonomic imbalance, and increased inflammation and oxidative stress are key mechanisms through which COMISA influences ED. These factors collectively impair vascular health, reduce testosterone levels, disrupt neural control of erections, and contribute to the severity of ED. CONCLUSIONS: This review underscores the necessity for an integrated approach to diagnosis and therapy that considers both sleep and sexual health to improve overall outcomes. These insights should foster a deeper understanding of the relationship between COMISA and ED, encourage further research in this area, and potentially lead to the development of innovative treatment strategies to manage these closely intertwined health concerns.

Unlocking the role of Galectin-3: Implications for sleep disorders and health.

Galectin-3 is a member of the lectin family, and is an intriguing protein that is found in diverse tissues across the body. It is known for its multifaceted involvement in various physiological functions, including tissue repair, immune function and neuroinflammation in the central nervous system. It also serves as a paracrine signal, promoting the growth of certain cells and contributing to fibrosis, while higher levels of Galectin-3 in the bloodstream correlate with an increased risk of mortality and cardiovascular disease-related outcomes in the general population. Recent scientific studies have identified a potential link between Galectin-3 and sleep disorders. However, the precise mechanisms through which galectin-3 influences sleep disorders remain an active area of investigation. Although initial studies suggest a potential association between Galectin-3 and sleep disruptions, including conditions, such as insomnia, insufficient sleep time, and obstructive sleep apnea, further research is required to establish a more definitive relationship. This review explores recent findings regarding the potential connection between Galectin-3 and sleep patterns, and offers insights into the complex interplay between this protein and sleep. These discoveries present promising prospects for the development of innovative therapeutic approaches aimed at sleep disorder management, using Galectin-3 as a potential target for interventions or as a biomarker for sleep health.

The influence of phototherapy on circadian melatonin and sleep regulation and potential benefits of these pathways in the management of vitiligo: a narrative review : Vitiligo, phototherapy, sleep and melatonin.

Ultraviolet B narrow band (UVB-NB) phototherapy is the gold standard treatment for vitiligo, primarily due to its immunomodulatory effects. Additionally, it may influence circadian melatonin balance, that may indirectly induce sleep regulation, which in turn could potentially contribute to vitiligo improvement. The association between melatonin, vitiligo and phototherapy has been little investigated. The aim of this study was to evaluate the current evidence regarding the effects of circadian melatonin regulation and sleep, particularly during vitiligo treatment with phototherapy. We undertook a narrative review to synthetize the evidence on this association through the MEDLINE/PubMed database, using combined search terms: melatonin, vitiligo, phototherapy, and circadian rhythm (sleep). A total of 56 articles were included. There are few studies on this relationship, and conflicting findings. Some studies have suggested that UV exposure and phototherapy might benefit vitiligo by stimulating melanocytes, which have melatonin receptors, and this could potentially synchronize the circadian regulation of melatonin. This improved melatonin balance could result in better sleep quality further enhancing the antiinflammatory properties of melatonin and contributing to vitiligo improvement. Less is known about the possible effects of the use of topical melatonin, with or without phototherapy, to treat vitiligo lesions. In conclusion, there is some evidence that circadian melatonin regulation plays an important role in the course of vitiligo, both through sleep regulation and its anti-inflammatory properties. The evidence suggests that the systemic and physiological properties of melatonin, especially its circadian behavior regulated by phototherapy, may be more effective in respect of vitiligo improvement than the use of topical melatonin. However, the effects of the oral intake of melatonin are less clear. Phototherapy, as a potential modulator of circadian melatonin rhythm, that influences sleep and clinical improvement of vitiligo, needs further examination, as does the use of melatonin as an adjuvant treatment to UVB phototherapy in vitiligo.

Erectile dysfunction and sleep related bruxism: An exploratory review of an improbable association.

The World Health Organization recognizes sexual health as not merely the absence of disease, but a state of physical, mental, and social well-being in relation to one's sexuality. Achieving sexual satisfaction is pivotal for many individuals, as it significantly contributes to their quality of life. Among various sexual disorders, erectile dysfunction (ED) is notably prevalent, affecting an estimated 10-20 million men in the United States alone. This condition impacts not just the person experiencing it but also significantly influences their intimate connections with partners. Although the causes of ED are multifactorial, recent research highlights a compelling association between sleep disorders, such as sleep deprivation, obstructive sleep apnea (OSA), and insomnia, and the incidence of ED. Furthermore, engaging in night work has been observed to exacerbate the risk of developing ED. One common sleep disorder, sleep related bruxism (SRB), despite its prevalence, has not generally been associated with ED. However, there is some interesting evidence hinting at a potential relationship, including a few studies reporting a high prevalence of ED in individuals with SRB. This review delves into the epidemiological, etiological, and mechanistic links between ED and SRB, aiming to uncover potential intersections between these two conditions. These insights could pave the way for innovative research avenues, possibly exploring treatments like vasodilation medication, that might concurrently address both ED and SRB.

Sleep is associated with telomere shortening: A population-based longitudinal study.

As the chronological age increases, there is a decrease in the telomere length (TL). Associations between TL and age-related diseases have been described. Since the major pathophysiological factors related to inadequate sleep (including sleep complaints and sleep disorders) contribute to the exacerbation of inflammation and oxidative stress, an association of sleep and TL has been proposed. The aim of this study was to evaluate the association between sleep-related variables with TL in a longitudinal framework. We used data derived from the EPISONO cohort, which was followed over 8 years. All individuals answered sleep-related questionnaires, underwent a full-night polysomnography (PSG), and had their blood collected for DNA extraction. The TL was measured through a quantitative real time polymerase chain reaction. Age, sex, body mass index (BMI), smoking, physical activity status, and the 10 principal components (ancestry estimate) were considered covariables. Of the 1042 individuals in the EPISONO cohort, 68.3% agreed to participate in the follow-up study (n = 712). Baseline SpO2 (ß = 0.008, p = 0.007), medium SpO2 (ß = 0.013, p = 0.013), and total sleep time <90% (ß = -0.122, p = 0.012) had an effect on TL from the follow-up. The 8 year TL attrition was inversely associated with total sleep time, sleep efficiency, sleep architecture variables, wake after sleep onset, arousal index, oxygen-related variables baseline, and the presence of obstructive sleep apnea (OSA). We conclude that individuals with worse sleep quality, alterations in sleep architecture, and OSA had greater TL attrition over the 8 years. Using a longitudinal approach, these findings confirm previous cross-sectional evidence linking sleep with accelerated biological ageing.

Exploring the molecular pathways linking sleep phenotypes and POGZ-associated neurodevelopmental disorder.

Pogo transposable element-derived protein with ZNF domain (POGZ) gene encodes a chromatin regulator and rare variants on this gene have been associated with a broad spectrum of neurodevelopmental disorders, such as White-Sutton syndrome. Patient clinical manifestations frequently include developmental delay, autism spectrum disorder and obesity. Sleep disturbances are also commonly observed in these patients, yet the biological pathways which link sleep traits to the POGZ-associated syndrome remain unclear. We screened for sleep implications among individuals with causative POGZ variants previously described. Sleep disturbances were observed in 52% of patients, and being obese was not observed as a risk factor for sleep problems. Next, we identified genes associated with sleep-associated traits among the POGZ regulatory targets, aiming to uncover the molecular pathways that, when disrupted by POGZ loss of function, contribute to the aetiology of sleep phenotypes in these patients. The intersect between POGZ targets and sleep-related genes was used in a pathway enrichment analysis. Relevant pathways among these overlapping genes are involved in the regulation of circadian rhythm, tau protein binding, ATPase activator activity. This study may represent the beginning for novel functional investigations on shared molecular mechanisms between sleep disturbances and rare developmental syndromes related to POGZ and its regulatory targets.

Understanding Sexual Parasomnias: A Review of the Current Literature on Their Nature, Diagnosis, Impacts, and Management.

Sexual behavior during sleep, known as sexual parasomnias, has captured the interest of researchers and clinicians. These parasomnias involve various sexual activities that occur unconsciously during sleep. Although relatively rare, they can profoundly affect well-being and relationships and can carry legal consequences. Understanding their nature, prevalence, and causes is crucial for advancing knowledge in this field. This article revisits the topic of sexsomnia, presenting new data and discussing cases published from 2007 to 2023. By analyzing these cases, we aim to enhance recognition, diagnosis, and management of sexsomnia, reducing stigma and providing better support for affected individuals.

The effects of social jetlag and sleep variability on sleepiness in a population-based study: The mediating role of sleep debt.

Sleepiness is a multicausal condition, and previous research has highlighted associations between this symptom and the circadian timing system, specifically concerning social jetlag and sleep variability. Recent inquiries have shown that the effects of social jetlag on sleepiness can be confounded with the consequences of sleep debt. In light of the current evidence, we aimed to assess the effects of social jetlag and sleep variability on sleepiness and the potential mediating role of sleep debt. We used data from the EPISONO study, a cross-sectional population-based study with a sample size of 1042 participants, representative of the city of Sao Paulo, Brazil. Participants completed the UNIFESP Sleep Questionnaire (self-reported bedtime and get-up time) and the Epworth Sleepiness Scale (subjective daytime sleepiness). Subsequently, sleep-corrected mid-sleep time (chronotype), total sleep time, social jetlag (absolute difference between the mid-sleep time on workdays and mid-sleep time on free days), sleep variability (standard deviation of mid-sleep time), and sleep debt (difference between total sleep time on workdays and free days) were calculated. Generalised linear models were used to test whether social jetlag and sleep variability affected sleepiness. Mediation models were used to determine if any observed significant effects were mediated by sleep debt. The prevalence of social jetlag was 23% for >1 h and 12% for >2 h. The mean sleep variability was 41 ± 30 min. Social jetlag had a significant effect on the Epworth Sleepiness Scale scores. This association was no longer statistically significant after controlling for age, sex, body mass index, work schedule, and chronotype. A significant indirect effect of social jetlag on sleep debt and subsequently on the Epworth Sleepiness Scale scores was found. No effect of sleep variability on sleepiness could be identified. In conclusion, the association between social jetlag and sleepiness was mediated by sleep debt but was not independent of demographic, work, and chronotype variables. This study provides new evidence on the importance of circadian misalignment and sleep debt for sleep health on a population level.

The role of upper airway and facial skeleton anatomy in the evolution of obstructive sleep apnea: an 8-year follow-up.

PURPOSE: To evaluate the role of anatomic alterations of the upper airway and facial skeleton in the evolution of obstructive sleep apnea (OSA) in a prospective population-based study with an 8-year follow-up. METHODS: This was a population-based, longitudinal, prospective study, which took place from 2007 to 2015 at the Instituto do Sono, Sao Paulo, Brazil. In 2007, type I polysomnography (PSG), otorhinolaryngological examination, and collection of anthropometric measurements of all volunteers were performed. Volunteers were classified according to their anatomical features of the upper airway and facial skeleton. After 8 years, volunteers were invited for reevaluation. The relationship between anatomical characteristics and polysomnographic evolution was evaluated. RESULTS: The study included 554 patients. After 8 years of follow-up, there was an increase in neck circumference and body mass index of the participants. There was a worsening in all polysomnographic parameters analyzed, with an increase in the apnea-hypopnea index, a decrease in minimum saturation values, and an increase in the percentage of sleep time with peripheral oxyhemoglobin saturation <90%. There was no statistical relationship between the anatomical findings considered unfavorable and the worsening of polysomnographic parameters. CONCLUSIONS: In a sample of the general population, after 8 years, we did not find any relationship between upper airway and facial skeleton characteristics and the progression of OSA.

A cross-sectional analysis of the association between sleep disorders and cancer using data from the National Health and Nutrition Examination Survey (NHANES) 2005-2014.

STUDY OBJECTIVES: Cancer is one of the main causes of death in the world, and sleep disorders are a serious public health problem, especially in large cities; of these, insomnia and obstructive sleep apnea (OSA) are the most common. In the last decade, studies have pointed to a possible association between sleep disorders and cancer. The aim of this study is to evaluate whether there is any association between sleep disorders and cancer. METHODS: Five National Health and Nutrition Examination Surveys (NHANES) (2005-2014) from the United States were combined in order to obtain the sample. Two main sleep variables were assessed: having trouble sleeping and/or ever telling a doctor one had a sleep problem. The odds ratio of ever having a cancer diagnosis was the main outcome. Data were analyzed by binary logistic regression models in Jamovi. RESULTS: The final sample comprised 26,821 participants. Individuals who reported having trouble sleeping had an odds ratio of 1.48 (95% confidence interval = [1.336-1.646]; P < .001) of having been diagnosed with cancer, and those who had already been diagnosed with a sleep disorder had an odds ratio of 1.21 (95% confidence interval = [1.046-1.415]; P = .011), showing an increased chance of having been diagnosed with cancer. In men, these values were even greater, with an odds ratio of 1.56 (95% confidence interval = [1.321-1.843]; P < .001) and an odds ratio of 1.26 (95% confidence interval = [1.013-1.582]; P = .037), respectively, for having trouble sleeping and for having been diagnosed with a sleep disorder, in relation to having been diagnosed with cancer. CONCLUSIONS: Individuals who had trouble sleeping or who had been diagnosed with a sleep disorder at any time in their life were more likely to have been diagnosed with cancer. CITATION: Porcacchia AS, Pires GN, Andersen ML, Tufik S. A cross-sectional analysis of the association between sleep disorders and cancer using data from the National Health and Nutrition Examination Survey (NHANES) 2005-2014. J Clin Sleep Med. 2024;20(4):515-520.

Knowledge of elementary and high school students about experimental animal research / Conocimiento de los alumnos de la primaria y la secundaria sobre investigación experimentalen animales / Conhecimento de alunos dos ensinos fundamental e médio sobre pesquisa experimental em animais

Abstract Experimental research with the use of animal models to represent a specific reality is a target of criticism by the population. This study analyzed the knowledge of elementary and high school students on experimental/animal research methods, official ethical guidelines/laws, and regulatory institutions. In total, 35 students answered an informative questionnaire with objective questions about the subject. Only 18 students (Group 1), attended a lecture on the subject. The questionnaire was reapplied to all 35 students. The analysis of the first questionnaire round showed rejection by 51.4% of the students toward the methods used in experimental research. Significant changes in answer patterns between the first and second evaluations were observed, with a decrease in the number of students who strongly disagree with the methods used in experimental research in Group 1 (38.8%) compared to Group 2 (88.2%). These data suggest that educational activities could increase the acceptance of experimental research by the community.

Resumen La investigación experimental en animales para representar una realidad específica es criticada por la población. Este estudio analizó el conocimiento de los alumnos de la primaria y la secundaria sobre los métodos de investigación experimental/animal, los lineamientos/leyes éticas oficiales e instituciones que reglamentan. Un cuestionario con preguntas objetivas sobre el tema fue respondido por 35 alumnos. Solo 18 alumnos (Grupo 1) asistieron a una conferencia sobre el tema. El cuestionario se aplicó nuevamente a 35 alumnos. El primer cuestionario mostró que el 51,4% de los alumnos rechazaban los métodos utilizados en la investigación experimental. Hubo cambios significativos en las respuestas entre la primera y la segunda evaluación, con menor número de alumnos que estaban totalmente en desacuerdo con los métodos de la investigación experimental en el Grupo 1 (38,8%) en comparación con el Grupo 2 (88,2%). Por tanto, las actividades educativas pueden incrementar la aceptación comunitaria de la investigación experimental.

Resumo A pesquisa experimental com uso de modelos animais para representar uma realidade específica é alvo de críticas por parte da população. Este estudo analisou o conhecimento de alunos do ensino fundamental e médio sobre métodos de pesquisa experimental/animal, diretrizes/leis éticas oficiais e instituições reguladoras. Ao todo, 35 alunos responderam a um questionário informativo com perguntas objetivas sobre o assunto. Apenas 18 alunos (Grupo 1) assistiram a uma palestra sobre o tema. O questionário foi aplicado novamente aos 35 alunos. A análise do primeiro questionário mostrou rejeição por 51,4% dos estudantes em relação aos métodos utilizados na pesquisa experimental. Observaram-se mudanças significativas nos padrões de resposta entre a primeira e a segunda avaliação, com diminuição do número de alunos que discordam totalmente dos métodos utilizados na pesquisa experimental no Grupo 1 (38,8%) em relação ao Grupo 2 (88,2%). Esses dados sugerem que atividades educativas podem aumentar a aceitação da pesquisa experimental pela comunidade.

Methods for REM Sleep Density Analysis: A Scoping Review.

Rapid eye movements (REM) sleep density is the parameter proposed to explain the variability in the amount of eye movements during REM sleep. Alterations in REM sleep density have been proposed as a screening criterion for individuals with depression and other mental health conditions, but its accuracy has not been properly evaluated. The lack of consensus and the variability of the methods used to score it reduces the external validity of the results, hindering an adequate analysis of its diagnostic accuracy and clinical applicability. This scoping review aimed to identify and quantify the methods used to score REM sleep density, describing their main characteristics. A literature search was conducted in PubMed, Scopus, PsycInfo, and Web of Science. Only studies with objective measures for REM sleep density analysis in individuals with depression were considered eligible. The final sample comprised 57 articles, covering 64 analyses of REM sleep density. The relative frequency methods were the predominant measurement parameter for analyzing REM sleep density across studies. The most frequently adopted REM estimation unit was the number of REM events followed by mini-epochs containing REM. The most common unit of measurement were frequency/time measures. The results demonstrate that there is no consistency in the methods used to calculate REM sleep density in the literature, and a high percentage of studies do not describe their methods in sufficient detail. The most used method was the number of REM episodes per minute of REM sleep, but its use is neither unanimous nor consensual. The methodological inconsistencies and omissions among studies limit the replicability, comparability, and clinical applicability of REM sleep density. Future guidelines should discuss and include a specific methodology for the scoring of REM sleep density, so it can be consensually implemented in clinical services and research.

Emergence of different dimensions of sleepiness in a general population sample: An EPISONO study.

INTRODUCTION: Recent evidence supports the idea that sleepiness has several dimensions, comprising psychophysiological phenomena, such as sleep propensity and sleepiness perception. The Epworth Sleepiness Scale (ESS) is among one of the most used sleepiness assessment tools, but recent data suggest that it might not detect problematic impairments in sleep health. More research is warranted investigating sleepiness dimensions with large sample sizes, using both objective and subjective methods of analyzing sleep. METHODS: We used data from the Epidemiological Sleep Study (EPISONO), a major study carried out in Brazil using a representative sample of 1042 participants of the general population of Sao Paulo city, who completed questionnaires and underwent type I polysomnography. Sleepiness was measured by the ESS (sleep propensity) and the UNIFESP Sleep Questionnaire, which asked about the frequency of feeling sleepy during the day (sleepiness perception). The participants were distributed into 4 groups in respect of excessive daytime sleepiness (EDS) according to the following criteria: 1) having an ESS score >10 (ESS group). 2) feeling sleepy ≥3 times per week (Frequent EDS group). 3) the combined criteria (Combined EDS group). 4) having no evidence of EDS (no EDS group). The UNIFESP Sleep Questionnaire was used to obtain self-reported sleep duration, sleep debt, and sleep duration variability. Participants also completed the Pittsburgh Sleep Quality Index, the Insomnia Severity Index, and a pre-polysomnography sleep questionnaire. RESULTS: After removing participants with missing data, there were 620 participants with no EDS, 255 individuals in the ESS group, 68 in the Frequent EDS group, and 73 in the Combined EDS group. Compared to the no EDS group, the ESS and Combined EDS groups had significantly increased sleep efficiency, diminished sleep latency, wake after sleep onset, and self-reported weekly sleep duration. The Frequent and Combined EDS groups had significantly higher scores in the Insomnia Severity Index and Pittsburgh Sleep Quality Index. All EDS groups had an increased likelihood of nonrestorative sleep. EDS frequency and the ESS scores were significantly correlated. CONCLUSIONS: Participants with a high sleep propensity had a profile suggesting prior sleep deprivation, while high sleepiness perception was associated with impaired sleep quality. These findings indicated that, in the general population, these instruments evaluated separate sleepiness dimensions with different associations, highlighting that screening using a combination of instruments might be more effective in detecting impairments in sleep health.

Impact of the early months of the COVID-19 pandemic on the sleep patterns of a Brazilian population sample.

Humanitarian and health crisis have drastic effects on the physical and mental well-being of people. The COVID-19 pandemic forced many countries to impose containment measures on its population to halt the spread of the new coronavirus (SARS-CoV-2). This aim of this study was to explore self-reported sleep quality and insomnia symptoms in a sample of the Brazilian population before and during the COVID-19 quarantine period. Our data was collected through online questionnaires, including the Pittsburgh Sleep Quality Index, the Insomnia Severity Index, and the Sleep Hygiene Index. The final sample comprised 1,109 volunteers. Generalized estimating equations (GEE) revealed that during the initial months of the COVID-19 pandemic, alterations in self-reported sleep parameters were observed in the participants. Sleep efficiency and sleep duration increased, but there was a worsening in sleep quality and an increase in symptoms related to insomnia.

Exploring the potential relationships among obstructive sleep apnea, erectile dysfunction, and gut microbiota: a narrative review.

INTRODUCTION: Poor sleep quality is closely associated with comorbidities affecting a multitude of organ systems. Among the sleep disorders in the population, there has recently been an increase in the prevalence of obstructive sleep apnea (OSA), which has particularly affected men. The intermittent hypoxia and sleep fragmentation associated with OSA can result in the manifestation or aggravation of a number of pathophysiologic conditions, including the impairment of reproductive function in men and women. In this context, erectile dysfunction (ED) is of particular concern. Other consequences of OSA are changes in the gastrointestinal microbiota, with the resultant dysbiosis having potentially harmful consequences that promote downstream exacerbation of various comorbidities. OBJECTIVES: This narrative review aims to explore the potential relationships among ED, gut microbiota, and OSA. METHODS: A search of the relevant literature was performed in the PubMed, Embase, Medline, and Web of Science databases. RESULTS: Sleep is important for regulating the body's functions, and sleep deprivation can negatively affect health. OSA can damage organic functions, including reproductive function, and can lead to ED. Restoring the microbiota and improving sleep can help to improve sexual function or reverse ED and enhance other associated conditions mediated through the gut-brain axis relationship. Probiotics and prebiotics can be used as supportive strategies in the prevention and treatment of OSA, as they help to reduce systemic inflammation and improve intestinal barrier function. CONCLUSION: A good diet, a healthy lifestyle, and proper bowel function are essential in controlling depression and several other pathologies. Modulating the gut microbiota through probiotics and prebiotics can provide a viable strategy for developing new therapeutic options in treating many conditions. A better understanding of these a priori unrelated phenomena would foster our understanding of the effects of OSA on human fertility and how changes in gut microbiota may play a role.

Insomnia is associated with symptoms of central sensitization in patients with painful temporomandibular disorders.

BACKGROUND: Central sensitization (CS) and temporomandibular disorder (TMD) are both associated with insomnia. Therefore, the authors aimed to investigate whether insomnia was associated with more symptoms of CS in patients with TMD. METHODS: In 82 volunteers with TMD, insomnia was clinically assessed, allowing sample stratification according to its presence. The Central Sensitization Inventory questionnaire was self-applied to assess the clinical symptoms of CS. RESULTS: Participants with insomnia had significantly higher mean (SD) scores of CS according to the Central Sensitization Inventory than participants without insomnia (43.10 [12.57] vs 26.59 [13.66]; P = < .001). CONCLUSIONS: Insomnia was associated with higher scores of CS symptoms in patients with TMD. PRACTICAL IMPLICATIONS: Insomnia influences TMD as well as its relationship with CS, and, therefore, it is critical to the clinical management of TMD.