SUMMARY Patterns of daily human activity are controlled by an intrinsic circadian clock that promotes ~24 hour rhythms in many behavioral and physiological processes. This system is altered in Delayed Sleep Phase Disorder (DSPD), a common form of insomnia where sleep episodes are shifted to later times misaligned with the societal norm. Here, we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele has a frequency of up to 0.6% and reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers, suggesting that it affects sleep behavior in a sizeable portion of the human population.

ImportanceSARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals.ObjectiveTo develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections.Design, Setting, and ParticipantsProspective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling.ExposureSARS-CoV-2 infection.Main Outcomes and MeasuresPASC and 44 participant-reported symptoms (with severity thresholds).ResultsA total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months.Conclusions and RelevanceA definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

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Sleep bruxism (SB), primarily involving rhythmic grinding of the teeth during sleep, has been advanced as a causal or maintenance factor for a variety of orofacial problems, including temporomandibular disorders (TMD). Since laboratory polysomnographic (PSG) assessment is extremely expensive and time-consuming, most research testing this belief has relied on patient self-report of SB. The current case-control study examined the accuracy of those self-reports relative to laboratory-based PSG assessment of SB in a large sample of women suffering from chronic myofascial TMD (n=124) and a demographically matched control group without TMD (n=46). A clinical research coordinator administered a structured questionnaire to assess self-reported SB. Participants then spent two consecutive nights in a sleep laboratory. Audiovisual and electromyographic data from the second night were scored to assess whether participants met criteria for presence of 2 or more (2+) rhythmic masticatory muscle activity episodes accompanied by grinding sounds, moderate SB, or severe SB, using previously validated research scoring standards. Contingency tables were constructed to assess positive and negative predictive values, sensitivity and specificity, and 95% confidence intervals surrounding the point estimates. Results showed that self-report significantly predicted 2+ grinding sounds during sleep for TMD cases. However, self-reported SB failed to significantly predict presence or absence of either moderate or severe SB as assessed by PSG, for both cases and controls. These data show that self-report of tooth grinding awareness is highly unlikely to be a valid indicator of true SB. Studies relying on self-report to assess SB must be viewed with extreme caution.

Despite theoretical speculation and strong clinical belief, recent research using laboratory polysomnographic (PSG) recording has provided new evidence that frequency of sleep bruxism (SB) masseter muscle events, including grinding or clenching of the teeth during sleep, is not increased for women with chronic myofascial temporomandibular disorder (TMD). The current case-control study compares a large sample of women suffering from chronic myofascial TMD (n=124) with a demographically matched control group without TMD (n=46) on sleep background electromyography (EMG) during a laboratory PSG study. Background EMG activity was measured as EMG root mean square (RMS) from the right masseter muscle after lights out. Sleep background EMG activity was defined as EMG RMS remaining after activity attributable to SB, other orofacial activity, other oromotor activity and movement artifacts were removed. Results indicated that median background EMG during these non SB-event periods was significantly higher (p<.01) for women with myofascial TMD (median=3.31 μV and mean=4.98 μV) than for control women (median=2.83 μV and mean=3.88 μV) with median activity in 72% of cases exceeding control activity. Moreover, for TMD cases, background EMG was positively associated and SB event-related EMG was negatively associated with pain intensity ratings (0–10 numerical scale) on post sleep waking. These data provide the foundation for a new focus on small, but persistent, elevations in sleep EMG activity over the course of the night as a mechanism of pain induction or maintenance.

Study Objectives: Temporomandibular pain disorders (TMD) and myofascial pain were linked to increased prevalence of insomnia and obstructive sleep apnea (OSA) on clinical grounds. However, the literature lacks an accurate polysomnographic (PSG) characterization of sleep abnormalities associated with TMD, given that prior studies included small or uncontrolled samples of TMD patients. The present investigation aims to objectively evaluate measures of sleep and respiratory disturbance in a large representative sample of TMD cases in comparison with matched controls. Methods: Sleep, respiration, and limb movements were measured using a 2-night attended PSG protocol in 170 women-124 TMD cases with myofascial pain and 46 demographically matched controls. The second night data were compared between the groups using ANCOVAs. In TMD cases, the relationship between pain ratings and sleep parameters was analyzed using multiple regressions. Results: In comparison to healthy controls, TMD cased evidenced a signifi cant increase in stage N1 sleep (12.2% ± 7.6% vs. 9.2% ± 5.0%, p = 0.03), which was only mild relative to normative values. TMD cases also demonstrated mild but signifi cant elevations in arousals associated with all types of respiratory events (6.0/h ± 6.1 vs. 3.5/h ± 3. S C I E N T I F I C I N V E S T I G A T I O N ST emporomandibular disorders (TMD), most often characterized by painful musculoskeletal signs and symptoms in the masticatory region, is a pain syndrome estimated to affect approximately 5% to 15% of the population, predominantly women.1-4 Subjective sleep disturbance has been consistently reported in TMD patients. 5,6 Two earlier polysomnographic (PSG) studies failed to demonstrate objective differences in sleep or respiratory measures between TMD cases with myofascial pain and control participants free from myofascial pain and signs of TMD; however, the small sample sizes and restrictive selection criteria limit their interpretability. 7,8 A recent investigation employing PSG recordings and clinical sleep interviews in an uncontrolled sample of TMD cases showed that TMD is associated with primary sleep disorders, such as insomnia and obstructive sleep apnea (OSA): nearly 36% of TMD cases met diagnostic criteria for insomnia, and over 28% met criteria for OSA. 9 In the same sample of TMD cases, sleep effi ciency on PSG was directly related to a measure of pain threshold, suggesting an association between pain and sleep disturbance in TMD.9,10 Additionally, a high prevalence of TMD was reported in clinical patients with mild to moderate OSA referred for a clinical dental evaluation, lending further support to the association between TMD and OSA.11 It was BRIEF SUMMARYCurrent Knowledge/Study Rationale: A relationship between temporomandibular pain disorders (TMD) and sleep and respiratory disturbance has been suggested; however, large-scale controlled polysomnographic studies are lacking. The present investigation used two-night polysomnography to measure sleep architecture and respiration in a large...

Increasing recognition of sleep-disordered breathing (SDB) and its morbidity have prompted reevaluation of techniques to identify respiratory events during sleep. The present study was designed to evaluate the utility of various metrics of SDB and to identify the optimal respiratory metric that objectively correlates to symptoms of excessive daytime somnolence (EDS). Metrics were derived from combinations of conventional apnea/hypopnea, flow limitation events (transient elevated upper airway resistance identified by characteristic flattening on the flow/time tracing, using a noninvasive nasal cannula technique), desaturation, and arousal. A total of 137 subjects underwent clinical evaluation and nocturnal polysomnogram. In 34 randomly selected subjects, the best metrics for discriminating between 13 subjects with no EDS/snoring and 21 patients with EDS and snoring were identified by receiver operator curve analysis. Of the metrics and cut points tested, a total respiratory disturbance index (RDI(Total), sum of apneas, hypopnea, and flow limitation events) of 18 events/h was found to have the best discriminant ability (100% sensitivity and 96% specificity). Prospective testing of this metric was then performed with the remaining 103 subjects (14 nonsnoring non-EDS, 21 snoring non-EDS, 68 snoring with EDS). Using this cutoff of 18 events/h, we obtained 71% sensitivity and 60% specificity for identifying subjects with EDS. We conclude that, in subjects with upper airway dysfunction, an index that incorporates all respiratory events provides the best quantitative physiological correlate to EDS.