Adipokines in Sleep Disturbance and Metabolic Dysfunction: Insights from Network Analysis.

Adipokines are a growing group of secreted proteins that play important roles in obesity, sleep disturbance, and metabolic derangements. Due to the complex interplay between adipokines, sleep, and metabolic regulation, an integrated approach is required to better understand the significance of adipokines in these processes. In the present study, we created and analyzed a network of six adipokines and their molecular partners involved in sleep disturbance and metabolic dysregulation. This network represents information flow from regulatory factors, adipokines, and physiologic pathways to disease processes in metabolic dysfunction. Analyses using network metrics revealed that obesity and obstructive sleep apnea were major drivers for the sleep associated metabolic dysregulation. Two adipokines, leptin and adiponectin, were found to have higher degrees than other adipokines, indicating their central roles in the network. These adipokines signal through major metabolic pathways such as insulin signaling, inflammation, food intake, and energy expenditure, and exert their functions in cardiovascular, reproductive, and autoimmune diseases. Leptin, AMP activated protein kinase (AMPK), and fatty acid oxidation were found to have global influence in the network and represent potentially important interventional targets for metabolic and sleep disorders. These findings underscore the great potential of using network based approaches to identify new insights and pharmaceutical targets in metabolic and sleep disorders.

Sleep Disturbance and Metabolic Dysfunction: The Roles of Adipokines.

Adipokines are a growing group of peptide or protein hormones that play important roles in whole body metabolism and metabolic diseases. Sleep is an integral component of energy metabolism, and sleep disturbance has been implicated in a wide range of metabolic disorders. Accumulating evidence suggests that adipokines may play a role in mediating the close association between sleep disorders and systemic metabolic derangements. In this review, we briefly summarize a group of selected adipokines and their identified function in metabolism. Moreover, we provide a balanced overview of these adipokines and their roles in sleep physiology and sleep disorders from recent human and animal studies. These studies collectively demonstrate that the functions of adipokine in sleep physiology and disorders could be largely twofold: (1) adipokines have multifaceted roles in sleep physiology and sleep disorders, and (2) sleep disturbance can in turn affect adipokine functions that likely contribute to systemic metabolic derangements.

A Model for Sleep Apnea Management in Underserved Patient Populations.

INTRODUCTION: Obstructive sleep apnea (OSA) is a common condition in the United States that is strongly linked to metabolic disease, cardiovascular disease, and increased mortality. Uninsured populations experience sleep health disparities, including delayed recognition, diagnosis, and treatment of OSA due to barriers accessing and affording care. Partnerships between primary care clinics and sleep medicine specialists for sleep apnea management have the potential to increase screening, testing, and treatment among underserved populations. Here, we present an integrated and cost-effective model that is easier to navigate for patients while maintaining high quality care. METHODS: We designed and implemented a specialty sleep clinic at Shade Tree Clinic, Vanderbilt's student-run, free primary care clinic. Patients with signs and symptoms of OSA were identified at primary care appointments and screened using the STOP-BANG questionnaire. Clinic visits took place over telehealth with a medical student and sleep specialist. Patients were diagnosed using a home sleep test, and if indicated, were prescribed and given a CPAP device for treatment. CPAP adherence was monitored using a cloud-based remote monitoring system. RESULTS: From December 2020 through August 2021, we hosted 6 telehealth Sleep Clinics, seeing a total of 28 patients across these visits. We have received a total of 37 referrals and have coordinated sleep evaluations and diagnostic testing for 18 of these patients so far. Prior to initiation of the sleep clinic, there were 17 patients on our primary care panel at Shade Tree with a diagnosis of OSA. These patients were using donated equipment and many had been lost to follow-up or had broken parts. We were able to replace 10 of these patient's CPAP devices and plan to replace the remaining seven. CONCLUSIONS: We have created a model of integrated specialty care that is efficient and cost-effective. This paradigm can be replicated for the many specialties that are typically overlooked and undertreated when working with uninsured patients. As awareness of this sleep medicine program becomes more widespread at Shade Tree Clinic, we anticipate reaching more primary care patients with signs and symptoms of sleep apnea through student education, cost-effective diagnostics, and partnership with sleep specialists.

Vanderbilt University Medical Center Ambulatory Teleneurology COVID-19 Experience.

Background: Telehealth has proliferated since the 1950s, but adoption and coverage of telehealth services for the U.S. public have been slow. In response to the coronavirus disease 2019 (COVID-19) pandemic, the federal government has implemented temporary policy changes that removed barriers and catalyzed the unprecedented adoption of telehealth. Methods: To assess ambulatory teleneurology satisfaction, we analyzed postvisit questionnaire data from patients and clinicians who completed teleneurology visits during the COVID-19 pandemic at Vanderbilt University Medical Center Department of Neurology (VUMC). Results: From March 18 to May 8, 2020, VUMC completed 3,935 teleneurology visits. More than 97% of patients were very highly or highly confident in the telehealth care they received, whereas almost 99% of clinicians were very likely or somewhat likely to recommend telehealth to other clinicians. Conclusions: Teleneurology satisfaction at VUMC has been positive, and going forward, we must advance upon this unprecedented adoption of telehealth and never revert to former restrictive policies.

Daylight saving time: an American Academy of Sleep Medicine position statement.

None: The last several years have seen intense debate about the issue of transitioning between standard and daylight saving time. In the United States, the annual advance to daylight saving time in spring, and fall back to standard time in autumn, is required by law (although some exceptions are allowed under the statute). An abundance of accumulated evidence indicates that the acute transition from standard time to daylight saving time incurs significant public health and safety risks, including increased risk of adverse cardiovascular events, mood disorders, and motor vehicle crashes. Although chronic effects of remaining in daylight saving time year-round have not been well studied, daylight saving time is less aligned with human circadian biology-which, due to the impacts of the delayed natural light/dark cycle on human activity, could result in circadian misalignment, which has been associated in some studies with increased cardiovascular disease risk, metabolic syndrome and other health risks. It is, therefore, the position of the American Academy of Sleep Medicine that these seasonal time changes should be abolished in favor of a fixed, national, year-round standard time.

Linking inhibition and anxiety symptoms following sleep restriction: The moderating role of prior sleep efficiency.

Although sleep loss increases state anxiety, the effects of partial sleep restriction on specific anxiety symptoms and mechanisms that may influence this relation remain unknown. It is also unknown whether prior sleep buffers the impact of sleep restriction on anxiety symptoms. Thus, the present study examined the relations between inhibition and repetitive negative thinking (RNT), obsessions, and other OCD symptoms following sleep restriction and the moderating role of prior night's sleep efficiency. Healthy sleeping adults (n = 73) completed measures of inhibition, anxiety symptoms, and sleep before and after one night of sleep restriction (4 h between 4:00am and 8:00am). Results indicate significant associations between decreased post-sleep restriction inhibition and increased post-sleep restriction RNT and obsessions. Prior night's subjective and objective sleep efficiency significantly moderated these relations, such that the highest post-sleep restriction anxiety symptoms were reported by those with the lowest post-sleep restriction inhibition and the lowest pre-sleep restriction sleep efficiency. These findings suggest decreased inhibition may be one mechanism by which sleep loss affects anxiety, and those with worse sleep prior to acute sleep loss may be particularly vulnerable. The implications for the prevention and treatment of anxiety-related disorders characterized by intrusive cognition are discussed.

What is the role of sleep in physician burnout?

None: The occurrence of physician burnout is widespread among clinicians and academic faculty, who report indicators such as low quality of life and poor work-life balance. Chronic insufficient sleep, whether due to extended work hours, circadian misalignment, or unrecognized sleep disorders, is a critically important risk factor for burnout that is overlooked and under-studied, and interventions to promote healthy sleep may reduce burnout susceptibility among attending physicians. While strategies to reduce burnout among resident and attending physicians have been under-evaluated, evidence suggests a need to address burnout at both individual and organizational levels. Solutions have been offered that are applicable to many stakeholders, including employers; payers; licensing and certification boards; state and federal regulatory agencies; and physicians and researchers. As more studies are undertaken to evaluate how these approaches impact burnout, two questions need to be addressed: (1) What is the role of sleep in the crisis of burnout, specifically among attendings, who are particularly under-studied? (2) Is restoration of healthy sleep the fundamental mechanism by which burnout interventions work? It is essential for key stakeholders to consider the role of sleep, sleepiness, and sleep disorders in order to optimize any efforts to mitigate the present crisis in physician burnout, particularly among attending physicians, an understudied group.

Sleep, fatigue and burnout among physicians: an American Academy of Sleep Medicine position statement.

None: Physician burnout is a serious and growing threat to the medical profession and may undermine efforts to maintain a sufficient physician workforce to care for the growing and aging patient population in the United States. Burnout involves a host of complex underlying associations and potential for risk. While prevalence is unknown, recent estimates of physician burnout are quite high, approaching 50% or more, with midcareer physicians at highest risk. Sleep deprivation due to shift-work schedules, high workload, long hours, sleep interruptions, and insufficient recovery sleep have been implicated in the genesis and perpetuation of burnout. Maladaptive attitudes regarding sleep and endurance also may increase the risk for sleep deprivation among attending physicians. While duty-hour restrictions have been instituted to protect sleep opportunity among trainees, virtually no such effort has been made for attending physicians who have completed their training or practicing physicians in nonacademic settings. It is the position of the American Academy of Sleep Medicine that a critical need exists to evaluate the roles of sleep disruption, sleep deprivation, and circadian misalignment in physician well-being and burnout. Such evaluation may pave the way for the development of effective countermeasures that promote healthy sleep, with the goal of reducing burnout and its negative impacts such as a shrinking physician workforce, poor physician health and functional outcomes, lower quality of care, and compromised patient safety.

Automated sleep stage scoring of the Sleep Heart Health Study using deep neural networks.

STUDY OBJECTIVES: Polysomnography (PSG) scoring is labor intensive and suffers from variability in inter- and intra-rater reliability. Automated PSG scoring has the potential to reduce the human labor costs and the variability inherent to this task. Deep learning is a form of machine learning that uses neural networks to recognize data patterns by inspecting many examples rather than by following explicit programming. METHODS: A sleep staging classifier trained using deep learning methods scored PSG data from the Sleep Heart Health Study (SHHS). The training set was composed of 42 560 hours of PSG data from 5213 patients. To capture higher-order data, spectrograms were generated from electroencephalography, electrooculography, and electromyography data and then passed to the neural network. A holdout set of 580 PSGs not included in the training set was used to assess model accuracy and discrimination via weighted F1-score, per-stage accuracy, and Cohen's kappa (K). RESULTS: The optimal neural network model was composed of spectrograms in the input layer feeding into convolutional neural network layers and a long short-term memory layer to achieve a weighted F1-score of 0.87 and K = 0.82. CONCLUSIONS: The deep learning sleep stage classifier demonstrates excellent accuracy and agreement with expert sleep stage scoring, outperforming human agreement on sleep staging. It achieves comparable or better F1-scores, accuracy, and Cohen's kappa compared to literature for automated sleep stage scoring of PSG epochs. Accurate automated scoring of other PSG events may eventually allow for fully automated PSG scoring.

Signal-averaged P wave area increases during respiratory events in patients with paroxysmal atrial fibrillation and obstructive sleep apnea.

PURPOSE: P wave characteristics change during simulated apneic events in individuals with atrial fibrillation (AF). This study sought to assess whether similar changes occur during nocturnal respiratory events in patients with AF and obstructive sleep apnea (OSA). METHODS: Thirty-five individuals with severe OSA who underwent formal polysomnography and subsequent AF ablation were compared to a matched group without AF. Electrocardiographic segments from each polysomnogram corresponding to the following events were identified: period of wakefulness closest to the initial onset of sleep (baseline-awake), first respiratory event, respiratory event with the lowest nadir oxygen saturation, longest respiratory event, and last respiratory event. Signal-averaged P wave duration and signal-averaged positive P wave area (amplitude*duration for positive P wave amplitudes) were extracted using custom software. P wave characteristics during respiratory events and the baseline-awake condition were compared. RESULTS: Compared to the baseline-awake condition, the signal-averaged positive P wave area was significantly greater during the longest event and the event with the lowest oxygen saturation in those with AF, but not in those without AF. There were no significant differences in signal-averaged P wave duration for any respiratory event compared to the baseline-awake condition, regardless of AF status. CONCLUSION: In patients with paroxysmal AF and obstructive sleep apnea, the signal-averaged positive P wave area is greater during certain respiratory events than during wakefulness. This finding may reflect the acute impact on right atrial volume of increased venous return associated with respiratory events and could be useful to assess AF risk in sleep apnea and to monitor response to treatment.

Time of day effects on the relationship between daily sleep and anxiety: An ecological momentary assessment approach.

Previous research has linked sleep disturbance to anxiety. However, evidence for this relation has been inconsistent, largely limited to retrospective reports that do not account for daily variability, and silent on when the association is most pronounced. Thus, the present study utilized ecological momentary assessment (EMA) to examine the effects of daily deviations in total sleep time (TST) and person-average TST on anxiety and whether these effects varied as a function of time of day in a sample of unselected adults (N = 138). Results indicate that the amount of TST on a given night, relative to personal average TST, negatively predicted anxiety, and this relation was significant in the morning and afternoon, but not evening. In contrast, person-average TST was unrelated to average anxiety. Relations between TST and anxiety did not differ across objective (e.g., actigraphy) and subjective (e.g., sleep diary) measures. Furthermore, the pattern of results remained the same when controlling for previous day's anxiety and were not bidirectional. These findings suggest that getting less sleep than is typical for the individual predicts subsequent anxiety, and this effect is particularly strong in the morning. Average sleep duration may be less important to the experience of anxiety than deviations from that average. These findings highlight the importance of EMA to examine how and when variability in sleep confers vulnerability for anxiety symptoms.

Improvement in Sleep-Disordered Breathing Indices Downloaded From a Positive Airway Pressure Machine Following Conversion of Atrial Fibrillation to Sinus Rhythm.

ABSTRACT: Sleep-disordered breathing (SDB) is a contributor to atrial fibrillation (AF) and treatment of obstructive sleep apnea can reduce the recurrence of AF following catheter ablation. However, the effect of AF therapies on measures of SDB severity is less robustly described. We present the case of a middle-aged man with SDB and persistent AF who exhibited improvement in SDB metrics, as characterized by data downloaded from his auto-titrating continuous positive airway pressure (AutoCPAP) machine, very shortly following procedures that restored sinus rhythm. Between procedures, when his rhythm reverted to AF, the downloaded parameters suggested more SDB events. After catheter ablation, the patient maintained sinus rhythm and the improvement in SDB metrics was sustained as well. This case provides support in favor of a bidirectional relationship between SDB and AF and suggests that data available from PAP machines may be useful in serial assessment of SDB status relative to heart rhythm.

Relation of Obstructive Sleep Apnea and a Common Variant at Chromosome 4q25 to Atrial Fibrillation.

Obstructive sleep apnea (OSA) and single nucleotide polymorphisms (SNPs) at the 4q25 locus are associated with increased risk of atrial fibrillation (AF). Whether these associations are independent of traditional risk factors for AF remains unknown. Using billing code queries and manual chart review, we assembled a cohort of adults that underwent overnight polysomnography and at least 1 12-lead electrocardiogram. Case status was defined by electrocardiographic data in support of AF or documentation of AF by a staff cardiologist. Controls were defined by a lack of primary evidence of AF and absence of a diagnosis of AF in the medical record. OSA severity was categorized based on Apnea-Hypopnea Index. Genotyping for a key 4q25 SNP (rs2200733) was performed using the Sequenom platform. Logistic regression was used to test for associations of AF with OSA category and 4q25 SNP genotype while adjusting for age, gender, body mass index, ancestry, hypertension status, and heart failure status. The cohort consisted of 674 subjects (62 ± 13 years; 44% women), including 132 patients with AF. After adjustment for established risk factors, the association between AF and OSA severity was borderline significant (odds ratio 1.2, 95% CI 1.0 to 1.5). The association between AF and 4q25 SNP status remained significant in a fully adjusted model that included OSA severity (odds ratio 1.5, 95% CI 1.3 to 5.7). In conclusion, OSA severity and the chromosome 4q25 SNP genotype were associated with AF status independent of clinical risk factors. Knowledge of AF-related SNPs may enhance AF risk stratification for those undergoing polysomnography.

Effective Apnea-Hypopnea Index ("Effective AHI"): A New Measure of Effectiveness for Positive Airway Pressure Therapy.

STUDY OBJECTIVES: To assess a new measure of positive airway pressure (PAP) effectiveness, the Effective AHI, which accounts for sleep disordered breathing events during the time PAP is (PAP On) and is not (PAP Off) being used. A secondary aim was to test the accuracy of the Watch-PAT 200 (WP) portable monitor for measurement of the Effective AHI. METHODS: A prospective two-center cohort study design was used to evaluate patients who had been prescribed PAP therapy for ≥ 2 months. The primary outcome measure was the Effective AHI as determined by an in-laboratory polysomnogram (PSG) where patients used their PAP machine as they did at home, and concomitantly wore the WP. The Effective AHI equals the sum of apneas and hypopneas with PAP On and PAP Off divided by hours of total sleep time. RESULTS: Twenty-eight adult patients (75% men, age 51.4 ± 10.8 years [mean ± SD]) comprised the study sample. The mean Effective AHI of 18.3, was significantly lower than the mean Diagnostic AHI of 67.9 (P < 0.0001). All patients using PAP ≥ 6 h had an Effective AHI < 5. For patients using PAP < 6 h, Effective AHI scores < 5 only occurred in patients who slept in a non-supine position during PAP Off time; leaving 63.6% of patients with residual moderate-to-severe OSA. There was a high correlation between the PSG and WP for the Effective AHI (r = 0.871). CONCLUSIONS: Significant disease burden, as objectively measured by the Effective AHI, may still exist in many patients with severe OSA in whom PAP therapy is not utilized for the entire sleep period. The WP is a reasonably accurate device to measure the Effective AHI.

Severity of obstructive sleep apnea influences the effect of genotype on response to anti-arrhythmic drug therapy for atrial fibrillation.

STUDY OBJECTIVES: To examine the impact of genotype on the relationship between obstructive sleep apnea (OSA) and anti-arrhythmic drug (AAD) efficacy in atrial fibrillation (AF). DESIGN: Registry based. SETTING: Clinic-based. PARTICIPANTS: Eighty-four individuals from Vanderbilt AF registry who had polysomnography, genotyping, and serial comprehensive evaluations of AF status. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Response to AADs was defined as a decrease in AF burden score by ≥ 75% or the combination of sinus rhythm on follow-up EKGs, stable AAD therapy for at least 6 months, objective AF burden below an established threshold, and the absence of non-pharmacologic therapies. Participants were genotyped for common AF susceptibility alleles at chromosomes 4q25 (near PITX2), 16q22 (in ZFHX3), and 1q21 (in KCNN3), and common SNPs in the ß1-adrenergic receptor (ARDB1). Wild-type status for rs10033464 at 4q25 was associated with increased success of AAD therapy in patients with no or mild OSA (odds ratio: 10.0, 95% confidence interval: 1.03 to 97.5; p < 0.05), but did not influence response to AAD therapy in those with moderate-severe OSA. A similar trend was observed for rs1801252 on ARDB1. CONCLUSION: In this hypothesis-generating pilot study of predominantly Caucasian men, the effect on AF response to AAD therapy of rs10033464 at 4q25 varied based on OSA status. The impact of genotype on AAD efficacy may be greatest in mild OSA and attenuated in more severe disease.

Medical evaluation and treatment of diabetic peripheral neuropathy.

Diabetes mellitus is a major health concern that is only expected to become more prevalent over the next few decades. It causes much morbidity and mortality through various macro- and microvascular complications, including diabetic neuropathy. Currently, there is no treatment that directly affects the natural course of diabetic neuropathy except for rigorous glycemic control, a goal that is not always achievable. Despite these therapeutic limitations, the morbidity caused by diabetic neuropathy can be minimized by early and accurate diagnosis. A detailed history and physical examination, along with carefully selected laboratory tests will confirm the presence of diabetic neuropathy while excluding other etiologies that may require alternative management strategies. Treatment is always tailored to the patient's symptoms. In addition to improved glycemic control, health care providers can provide education, support, and symptomatic relief. There are many pain modulating therapies that are effective in diabetic neuropathy as discussed above. Nortriptyline at low doses is an inexpensive well-tolerated medication that is effective. Gabapentin is an excellent choice when nortriptyline is ineffective or not tolerated. Other anticonvulsants, such as lamotrigine, carbamazepine, oxycarbazepine, and topiramate, may also provide benefit. Judicious use of narcotics is appropriate when other treatment modalities fail. The importance of treating underlying depression cannot be overemphasized. When gait becomes impaired as a result of neuropathy, appropriate prescription of assistive devices will prevent injuries from falls. Ankle-foot orthoses and other orthotic devices may allow patients to remain ambulatory and independent for a longer period. Despite the challenges ahead, the future holds the promise of more effective treatments for diabetes mellitus and its complications.