Associating sleep problems with advanced cancer diagnosis, and immune checkpoint treatment outcomes: a pilot study.

BACKGROUND: Sleep problems (SP) are common in cancer patients but have not been previously assessed in patients receiving immune checkpoint inhibitors (ICI). METHODS: We collected questionnaire data on sleep apnea risk, insomnia, and general sleep patterns. We used an adjusted multivariate Poisson regression to calculate prevalence ratios (PRs) and associated 95% confidence intervals (CIs) for associations between these SP and metastatic versus localized cancer stage (M1 vs. M0), and adjusted logistic regression models to calculate ORs for associations between SP with the number of ICI infusions completed (6 + vs. < 6). RESULTS: Among 32 patients who received ICI treatment, the prevalence of low, intermediate, and high-risk OSA risk was 36%, 42%, and 21%, respectively. Overall, 58% of participants reported clinically significant insomnia. We did not find a significant association between intermediate or high risk OSA (vs. low risk) and metastatic cancer status (PR = 1.01 (95% CI: 0.28, 3.67)). Patients in the cohort who reported taking > 15 min to fall asleep were 3.6 times more likely to be diagnosed with metastatic cancer compared to those reporting shorter sleep latency (95% CI (1.74, 7.35)). We did not find a significant association between SP and number of ICI infusions completed. CONCLUSION: Our data associating sleep apnea risk, insomnia, and sleep patterns with more advanced cancer encourages further exploration in larger-scale observational studies and suggests interventional clinical trials focused on sleep quality improvement that could result in better outcomes for these patients.

The pillars of health: influence of multiple lifestyle behaviors on body mass index and depressive symptoms in adult twins.

BACKGROUND: Guidelines promoting healthy lifestyles are cornerstones of chronic disease prevention and treatment. The purpose of this study is to investigate independent and joint associations of five key health behaviors with health outcomes (body mass index (BMI kg/m2) and depressive symptoms) in adult twins. METHODS: We included 6,048 twin pairs from a community-based registry. Five key health behaviors were: (1) ≥ 8 h of sleep per night, (2) ≥ 5 servings of fruits and vegetables daily, (3) ≤ 2 h sedentary time per day, (4) ≥ 150 min of moderate-to-vigorous physical activity (MVPA) per week, and (5) no smoking. We analyzed phenotypic associations between behaviors and outcomes; whether phenotypic associations were confounded by additive genetic and shared environmental factors within twin pairs ("quasi-causal" associations); and which behaviors, considered simultaneously, had the largest associations with outcomes. RESULTS: We found negative phenotypic associations between number of behaviors achieved with BMI and depressive symptoms score (ps < 0.05). Associations remained significant, though attenuated, when controlling for genetic and shared environmental factors, and demographics, for depressive symptoms score but not BMI (p < 0.05). Quantitative variable importance measures derived from regression tree models showed sedentary time and MVPA were the most important variables in partitioning twins with different BMI, and smoking and sedentary time for partitioning twins with different depressive symptoms score. CONCLUSIONS: Achievement of commonly endorsed health behaviors is associated with lower BMI (especially sedentary and MVPA targets) and depressive symptoms score (especially sedentary and smoking targets). This provides further support of health behavior promotion to improve health outcomes.

Predictive lifestyle markers for efficacy of cancer immune checkpoint inhibitors: a commentary.

Lifestyle factors could plausibly modulate the host immune system, the tumor microenvironment and, hence, immune checkpoint inhibitor (ICI) response. As such, these factors should be considered in ICI studies.

Wake up call for collegiate athlete sleep: narrative review and consensus recommendations from the NCAA Interassociation Task Force on Sleep and Wellness.

Sleep is an important determinant of collegiate athlete health, well-being and performance. However, collegiate athlete social and physical environments are often not conducive to obtaining restorative sleep. Traditionally, sleep has not been a primary focus of collegiate athletic training and is neglected due to competing academic, athletic and social demands. Collegiate athletics departments are well positioned to facilitate better sleep culture for their athletes. Recognising the lack of evidence-based or consensus-based guidelines for sleep management and restorative sleep for collegiate athletes, the National Collegiate Athletic Association hosted a sleep summit in 2017. Members of the Interassociation Task Force on Sleep and Wellness reviewed current data related to collegiate athlete sleep and aimed to develop consensus recommendations on sleep management and restorative sleep using the Delphi method. In this paper, we provide a narrative review of four topics central to collegiate athlete sleep: (1) sleep patterns and disorders among collegiate athletes; (2) sleep and optimal functioning among athletes; (3) screening, tracking and assessment of athlete sleep; and (4) interventions to improve sleep. We also present five consensus recommendations for colleges to improve their athletes' sleep.

Sleep apnea and subsequent cancer incidence.

PURPOSE: In vitro and animal models suggest that the physiological effects of sleep apnea could contribute to cancer risk, yet epidemiologic studies have been inconsistent. METHODS: We identified a cohort of adults diagnosed with sleep apnea between 2005 and 2014 using regional administrative databases. Linking this cohort to a population-based cancer registry, we identified first incident cancers diagnosed after sleep apnea diagnosis through 2015. We calculated age-sex standardized cancer incidence ratios (SIRs) to compare the observed number of cancers among those with sleep apnea with expected population estimates over a comparable period. RESULTS: Among 34,402 individuals with sleep apnea, 1,575 first incident cancers were diagnosed during follow-up (mean ± SD; 5.3 ± 2.0 years). Compared to the general population, cancer incidence (SIR 1.26, 95% CI 1.20-1.32) was elevated among sleep apnea patients. We observed significantly elevated incidence for kidney (SIR 2.24, 95% CI 1.82-2.72), melanoma (SIR 1.71, 95% CI 1.42-2.03), breast (SIR 1.43, 95% CI 1.76-2.00), and corpus uteri (SIR 2.80, 95% CI 2.24-2.47) while risk for lung (SIR 0.66, 95% CI 0.54-0.79) and colorectal cancer (SIR 0.71, 95% CI 0.56-0.89) was lower. CONCLUSION: These findings suggest an elevated cancer burden, particularly at certain sites, among individuals with diagnosed sleep apnea. Results should be interpreted with caution due to unmeasured confounders (e.g., BMI, diabetes).

Awake at the wheel: how auto technology innovations present ongoing sleep challenges and new safety opportunities.

Individuals and society are dependent on transportation. Individuals move about their world for work, school, healthcare, social activities, religious and athletic events, and so much more. Society requires the movement of goods, food, medicine, etc. for basic needs, commerce, cultural and political exchanges, and all of its dynamic, complex elements. To meet these critical daily demands, the transportation system operates globally and around the clock. Regardless of their role, a basic requirement for the individuals operating the transportation system is that they are awake and at optimal alertness. This applies to individuals driving their own cars, riding a bike or motorcycle, as well as pilots of commercial aircraft, train engineers, long-haul truck drivers, and air traffic controllers. Alert operators are a basic requirement for a safe and effective transportation system. Decades of scientific and operational research have demonstrated that the 24/7 scheduling demands on operators and passengers of our transportation system create sleep and circadian disruptions that reduce alertness and performance and cause serious safety problems. These challenges underly the longstanding interest in transportation safety by the sleep and circadian scientific community. An area currently offering perhaps the most significant opportunities and challenges in transportation safety involves vehicle technology innovations. This paper provides an overview of these latest innovations with a focus on sleep-relevant issues and opportunities. Drowsy driving is discussed, along with fatigue management in round-the-clock transportation operations. Examples of cases where technology innovations could improve or complicate sleep issues are discussed, and ongoing sleep challenges and new safety opportunities are considered.

Insomnia and Death Anxiety: A Theoretical Model with Therapeutic Implications.

Insomnia is common, growing in prevalence [...].

Quasi-causal associations between chronotype and post-traumatic stress disorder symptoms: A twin study.

OBJECTIVE: The evening ("night owl") chronotype is associated with greater severity and lifetime prevalence of post-traumatic stress disorder (PTSD) symptoms compared to morning or intermediate chronotypes. This twin study investigated the gene-environment relationships between chronotype, recent PTSD symptoms, and lifetime intrusive symptoms. METHODS: We used the reduced Horne-Östberg Morningness-Eveningness Questionnaire (rMEQ) to assess chronotype in a sample of 3777 same-sex adult twin pairs raised together (70.4% monozygotic, 29.6% dizygotic) in the community-based Washington State Twin Registry. PTSD symptoms were reported on the Impact of Events Scale (IES) and a single item for lifetime experience of intrusive symptoms after a stressful or traumatic event. RESULTS: Genetic influences accounted for 50% of chronotype variance, 30% of IES score variance, and 14% of lifetime intrusive symptom variance. Bivariate twin models showed a phenotypic association (bp) between evening chronotype and more severe PTSD symptoms (bp = -0.16, SE = 0.02, p < .001) that remained significant even after adjusting for shared genetic and environmental influences (bp = -0.10, SE = 0.04, p = .009), as well as age, sex, and self-reported sleep duration (bp = -0.11, SE = 0.04, p = .004). An association was found between evening chronotype and lifetime intrusive symptoms (bp = -0.11, SE = 0.03, p < .001) that was no longer significant after adjusting for shared genetic and environmental influences (bp = 0.04, SE = 0.06, p = .558). CONCLUSIONS: Our results suggest a "quasi-causal" relationship between evening chronotype and PTSD symptoms that is not purely attributable to genetic or shared environmental factors. Evening chronotype may increase vulnerability to pathologic stress responses in the setting of circadian misalignment, providing potential avenues of prevention and treatment using chronobiological strategies.

Alliance for Sleep Clinical Practice Guideline on Switching or Deprescribing Hypnotic Medications for Insomnia.

Determining the most effective insomnia medication for patients may require therapeutic trials of different medications. In addition, medication side effects, interactions with co-administered medications, and declining therapeutic efficacy can necessitate switching between different insomnia medications or deprescribing altogether. Currently, little guidance exists regarding the safest and most effective way to transition from one medication to another. Thus, we developed evidence-based guidelines to inform clinicians regarding best practices when deprescribing or transitioning between insomnia medications. Five U.S.-based sleep experts reviewed the literature involving insomnia medication deprescribing, tapering, and switching and rated the quality of evidence. They used this evidence to generate recommendations through discussion and consensus. When switching or discontinuing insomnia medications, we recommend benzodiazepine hypnotic drugs be tapered while additional CBT-I is provided. For Z-drugs zolpidem and eszopiclone (and not zaleplon), especially when prescribed at supratherapeutic doses, tapering is recommended with a 1-2-day delay in administration of the next insomnia therapy when applicable. There is no need to taper DORAs, doxepin, and ramelteon. Lastly, off-label antidepressants and antipsychotics used to treat insomnia should be gradually reduced when discontinuing. In general, offering individuals a rationale for deprescribing or switching and involving them in the decision-making process can facilitate the change and enhance treatment success.

Long-Term Use of Insomnia Medications: An Appraisal of the Current Clinical and Scientific Evidence.

While evidence supports the benefits of medications for the treatment of chronic insomnia, there is ongoing debate regarding their appropriate duration of use. A panel of sleep experts conducted a clinical appraisal regarding the use of insomnia medications, as it relates to the evidence supporting the focus statement, "No insomnia medication should be used on a daily basis for durations longer than 3 weeks at a time". The panelists' assessment was also compared to findings from a national survey of practicing physicians, psychiatrists, and sleep specialists. Survey respondents revealed a wide range of opinions regarding the appropriateness of using the US Food and Drug Administration (FDA)-approved medications for the treatment of insomnia lasting more than 3 weeks. After discussion of the literature, the panel unanimously agreed that some classes of insomnia medications, such as non-benzodiazepines hypnotics, have been shown to be effective and safe for long-term use in the appropriate clinical setting. For eszopiclone, doxepin, ramelteon and the newer class of dual orexin receptor antagonists, the FDA label does not specify that their use should be of a limited duration. Thus, an evaluation of evidence supporting the long-term safety and efficacy of newer non-benzodiazepine hypnotics is timely and should be considered in practice recommendations for the duration of pharmacologic treatment of chronic insomnia.

Do Insomnia Treatments Improve Daytime Function?

A scientific advisory panel of seven U.S. and Canadian sleep experts performed a clinical appraisal by comparing general medical opinion, assessed via a survey of practicing clinicians, regarding insomnia treatment, with the available scientific evidence. This clinical appraisal focuses on the specific statement, "Treatments for insomnia have uniformly been shown to significantly improve the associated daytime impairment seen with insomnia." The advisory panel reviewed and discussed the available body of evidence within the published medical literature to determine what discrepancies may exist between the currently published evidence base and general medical opinion. The advisory panels' evaluation of this statement was also compared with the results of a national survey of primary care physicians, psychiatrists, nurse practitioners, physician assistants, and sleep specialists in the United States. Contrary to general medical opinion, the expert advisory panel concluded that the medical literature did not support the statement. This gap highlights the need to educate the general medical community regarding insomnia treatment efficacy in pursuit of improved treatment outcomes.

What Should Be the Focus of Treatment When Insomnia Disorder Is Comorbid with Depression or Anxiety Disorder?

Insomnia is a significant, highly prevalent, persistent public health problem but often remains undiagnosed and untreated. Current treatment practices are not always evidence-based. When insomnia is comorbid with anxiety or depression, treatment often targets that comorbid condition with the expectation that improvement of the mental health condition will generalize to sleep symptoms. An expert panel of seven members conducted a clinical appraisal of the literature regarding the treatment of insomnia when comorbid anxiety or depression are also present. The clinical appraisal consisted of the review, presentation, and assessment of current published evidence as it relates to the panel's predetermined clinical focus statement, "Whenever chronic insomnia is associated with another condition, such as anxiety or depression, that psychiatric condition should be the only focus of treatment as the insomnia is most likely a symptom of the condition". The results from an electronic national survey of US-based practicing physicians, psychiatrists, and sleep (N = 508) revealed that >40% of physicians agree "at least somewhat" that treatment of comorbid insomnia should focus solely on the psychiatric condition. Whereas 100% of the expert panel disagreed with the statement. Thus, an important gap exists between current clinical practices and evidence-based guidelines and more awareness is needed so that insomnia is treated distinctly from comorbid anxiety and depression.

A Narrative Review of the Association between Post-Traumatic Stress Disorder and Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) and post-traumatic stress disorder (PTSD) are often co-morbid with implications for disease severity and treatment outcomes. OSA prevalence is higher in PTSD sufferers than in the general population, with a likely bidirectional effect of the two illnesses. There is substantial evidence to support the role that disturbed sleep may play in the pathophysiology of PTSD. Sleep disturbance associated with OSA may interfere with normal rapid eye movement (REM) functioning and thus worsen nightmares and sleep-related movements. Conversely, hyperarousal and hypervigilance symptoms of PTSD may lower the arousal threshold and thus increase the frequency of sleep fragmentation related to obstructive events. Treating OSA not only improves OSA symptoms, but also nightmares and daytime symptoms of PTSD. Evidence suggests that positive airway pressure (PAP) therapy reduces PTSD symptoms in a dose-dependent fashion, but also presents challenges to tolerance in the PTSD population. Alternative OSA treatments may be better tolerated and effective for improving both OSA and PTSD. Further research avenues will be introduced as we seek a better understanding of this complex relationship.

Chronic insomnia in the setting of MTHFR polymorphism.

We present a patient with chronic insomnia resistant to traditional pharmacologic (eg, sedative-hypnotics) and nonpharmacologic (eg, cognitive behavioral therapy for insomnia) therapy. A finding of elevated serum homocysteine triggered a whole-genome sequencing analysis which revealed a homozygous methylenetetrahydrofolate reductase (MTHFR) gene polymorphism (C677T/C677T; dbSNP rs1801133). Interventions targeting her polymorphism-dependent loss of function successfully resolved her insomnia. This case demonstrates a genomic approach for insomnia whereby successful treatment was focused on optimizing the patient's metabolome, which was altered as a result of a missense single-nucleotide polymorphism. CITATION: Kapoor V, Watson NF, Ball L. Chronic insomnia in the setting of MTHFR polymorphism. J Clin Sleep Med. 2022;18(4):1215-1218.

Sleep problems and risk of cancer incidence and mortality in an older cohort: The Cardiovascular Health Study (CHS).

BACKGROUND: Sleep problems (SP) can indicate underlying sleep disorders, such as obstructive sleep apnea, which may adversely impact cancer risk and mortality. METHODS: We assessed the association of baseline and longitudinal sleep apnea and insomnia symptoms with incident cancer (N = 3930) and cancer mortality (N = 4580) in the Cardiovascular Health Study. We used Cox proportional hazards regression to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI) to evaluate the associations. RESULTS: Overall, 885 incident cancers and 804 cancer deaths were identified over a median follow-up of 12 and 14 years, respectively. Compared to participants who reported no sleep apnea symptoms, the risk of incident cancer was inversely associated [(HR (95%CI)] with snoring [0.84 (0.71, 0.99)]. We noted an elevated prostate cancer incidence for apnea [2.34 (1.32, 4.15)] and snoring [1.69 (1.11, 2.57)]. We also noted an elevated HR for lymphatic or hematopoietic cancers [daytime sleepiness: 1.81 (1.06, 3.08)]. We found an inverse relationship for cancer mortality with respect to snoring [0.73 (0.62, 0.8)] and apnea [(0.69 (0.51, 0.94))]. We noted a significant inverse relationship between difficulty falling asleep and colorectal cancer death [0.32 (0.15, 0.69)] and snoring with lung cancer death [0.56 (0.35, 0.89)]. CONCLUSIONS: The relationship between SP and cancer risk and mortality was heterogeneous. Larger prospective studies addressing more cancer sites, molecular type-specific associations, and better longitudinal SP assessments are needed for improved delineation of SP-cancer risk dyad.

Artificial intelligence and sleep: Advancing sleep medicine.

Artificial intelligence (AI) allows analysis of "big data" combining clinical, environmental and laboratory based objective measures to allow a deeper understanding of sleep and sleep disorders. This development has the potential to transform sleep medicine in coming years to the betterment of patient care and our collective understanding of human sleep. This review addresses the current state of the field starting with a broad definition of the various components and analytic methods deployed in AI. We review examples of AI use in screening, endotyping, diagnosing, and treating sleep disorders and place this in the context of precision/personalized sleep medicine. We explore the opportunities for AI to both facilitate and extend providers' clinical impact and present ethical considerations regarding AI derived prognostic information. We cover early adopting specialties of AI in the clinical realm, such as radiology and pathology, to provide a road map for the challenges sleep medicine is likely to face when deploying this technology. Finally, we discuss pitfalls to ensure clinical AI implementation proceeds in the safest and most effective manner possible.

Faradization for insomnia: a sleep neurology history.

NONE: Insomnia is highly prevalent and challenging to treat. We typically regard insomnia as a disorder of the modern world, but physicians and patients have been struggling with this malady for millennia. Here we present the curious historical practice of using electrization or faradization to treat insomnia. We present methods of application, hypotheses regarding mechanism of action, and historical case reports and case series to better understand this phenomenon. We put faradization for insomnia in the context of the modern use of electrical therapies to support and facilitate human health in multiple different health care arenas. Last, we examine current efforts to use these antiquated concepts to address insomnia through transcranial direct current stimulation and cranial electrical stimulation.

Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline.

INTRODUCTION: This guideline establishes clinical practice recommendations for the treatment of central disorders of hypersomnolence in adults and children. METHODS: The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine to develop recommendations and assign strengths to each recommendation, based on a systematic review of the literature and an assessment of the evidence using the GRADE process. The task force provided a summary of the relevant literature and the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations. RECOMMENDATIONS: The following recommendations are intended to guide clinicians in choosing a specific treatment for central disorders of hypersomnolence in adults and children. Each recommendation statement is assigned a strength ("strong" or "conditional"). A "strong" recommendation (ie, "We recommend…") is one that clinicians should follow under most circumstances. A "conditional" recommendation (ie, "We suggest…") is one that requires that the clinician use clinical knowledge and experience and strongly consider the individual patient's values and preferences to determine the best course of action. Under each disorder, strong recommendations are listed in alphabetical order followed by the conditional recommendations in alphabetical order. The section on adult patients with hypersomnia because of medical conditions is categorized based on the clinical and pathological subtypes identified in ICSD-3. The interventions in all the recommendation statements were compared to no treatment. 1: We recommend that clinicians use modafinil for the treatment of narcolepsy in adults. (STRONG). 2: We recommend that clinicians use pitolisant for the treatment of narcolepsy in adults. (STRONG). 3: We recommend that clinicians use sodium oxybate for the treatment of narcolepsy in adults. (STRONG). 4: We recommend that clinicians use solriamfetol for the treatment of narcolepsy in adults. (STRONG). 5: We suggest that clinicians use armodafinil for the treatment of narcolepsy in adults. (CONDITIONAL). 6: We suggest that clinicians use dextroamphetamine for the treatment of narcolepsy in adults. (CONDITIONAL). 7: We suggest that clinicians use methylphenidate for the treatment of narcolepsy in adults. (CONDITIONAL). 8: We recommend that clinicians use modafinil for the treatment of idiopathic hypersomnia in adults. (STRONG). 9: We suggest that clinicians use clarithromycin for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). 10: We suggest that clinicians use methylphenidate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). 11: We suggest that clinicians use pitolisant for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). 12: We suggest that clinicians use sodium oxybate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). 13: We suggest that clinicians use lithium for the treatment of Kleine-Levin syndrome in adults. (CONDITIONAL). 14: We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to dementia with Lewy bodies in adults. (CONDITIONAL). 15: We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). 16: We suggest that clinicians use sodium oxybate for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). 17: We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). 18: We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). 19: We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to myotonic dystrophy in adults. (CONDITIONAL). 20: We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to multiple sclerosis in adults. (CONDITIONAL). 21: We suggest that clinicians use modafinil for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). 22: We suggest that clinicians use sodium oxybate for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). CITATION: Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2021;17(9):1881-1893.

Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment.

INTRODUCTION: This systematic review provides supporting evidence for the accompanying clinical practice guideline on the treatment of central disorders of hypersomnolence in adults and children. The review focuses on prescription medications with U.S. Food & Drug Administration approval and nonpharmacologic interventions studied for the treatment of symptoms caused by central disorders of hypersomnolence. METHODS: The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine to perform a systematic review. Randomized controlled trials and observational studies addressing pharmacological and nonpharmacological interventions for central disorders of hypersomnolence were identified. Statistical analyses were performed to determine the clinical significance of all outcomes. Finally, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process was used to assess the evidence for the purpose of making specific treatment recommendations. RESULTS: The literature search identified 678 studies; 144 met the inclusion criteria and 108 provided data suitable for statistical analyses. Evidence for the following interventions is presented: armodafinil, clarithromycin, clomipramine, dextroamphetamine, flumazenil, intravenous immune globulin (IVIG), light therapy, lithium, l-carnitine, liraglutide, methylphenidate, methylprednisolone, modafinil, naps, pitolisant, selegiline, sodium oxybate, solriamfetol, and triazolam. The task force provided a detailed summary of the evidence along with the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations. CITATION: Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2021;17(9):1895-1945.