Comparison of Awake Respiratory Control Versus Sleep Obstructive Sleep Apnea Endotypes.

Most approaches to advance simplified physiology-based precision medicine strategies for obstructive sleep apnea (OSA) focus on sleep parameters (i.e., OSA endotypes). However, wakefulness physiology measures can also provide prediction insight for certain OSA therapies yet their relationship with sleep parameters has not been extensively investigated. This study aimed to investigate potential relationships between awake ventilatory control parameters and sleep OSA endotypes and their potential to predict changes in OSA severity with morphine. Data were acquired from a randomised, cross-over trial that investigated effects of morphine versus placebo on OSA severity and underlying mechanisms. Here, awake ventilatory chemoreflex testing prior to overnight polysomnography was compared with direct measures of sleep respiratory control (e.g., hypercapnic ventilatory responses and loop gain) and OSA endotypes during a separate overnight physiology study (pharyngeal critical closure pressure-Pcrit, muscle responsiveness via genioglossus intramuscular electromyography and arousal threshold via epiglottic pressure catheter to transient continuous positive airway pressure reductions). Twenty-one men with OSA completed both study arms. During placebo, 1) awake chemosensitivity correlated with Pcrit (r=0.726, p=0.001), 2) arousal threshold correlated with awake CO2 ventilatory response threshold (r=-0.467, p=0.047) and basal ventilation (r=-0.500, p=0.029). Awake chemosensitivity and Pcrit also correlated with the apnea-hypopnea index (p<0.001) during placebo. Awake chemosensitivity was predictive of changes in OSA severity with morphine(r=-0.535, p=0.013). In conclusion, awake measures of respiratory control are related to physiological endotypes such as airway collapsibility and arousal threshold during sleep and OSA severity. Awake ventilatory chemosensitivity has the best potential to predict changes in OSA severity with morphine.

Hypoxemia during rapid eye movement sleep mediates memory impairment in older adults at risk for dementia via CA1 hippocampal volume loss.

BACKGROUND AND PURPOSE: Obstructive sleep apnea is associated with increased dementia risk. Nocturnal hypoxemia, which can be more severe during rapid eye movement (REM) sleep, may be a key mechanism. This study examines how REM hypoxemia affects memory and explores whether hippocampal vulnerability to hypoxemia mediates this effect in older adults at risk for dementia. METHODS: Older adults aged ≥50 years (N = 338) with subjective or mild cognitive impairment (i.e., objective impairment) underwent neuropsychological, mood, and medical assessment, magnetic resonance imaging scanning (n = 135), and overnight polysomnography. Verbal learning and memory were assessed with the Rey Auditory Verbal Learning Test. REM sleep hypoxemia was measured using the Oxygen Desaturation Index-3% (REM-ODI). Hippocampal subfield (CA1, CA3, subiculum, and dentate gyrus) volumes were derived from T1 and high-resolution hippocampus T2 scans. We determined whether the relationship between REM-ODI and learning and memory was mediated by hippocampal subfield volume. Analyses were repeated in non-REM sleep to determine whether the effects were REM-specific. RESULTS: Although there was not a direct effect of REM-ODI on verbal learning (p > 0.05) or memory (p > 0.05), mediation analyses showed a significant indirect effect of high REM-ODI on poorer verbal learning (ß = -0.09, 95% confidence interval [CI] = -0.238 to -0.005) and memory (ß = -0.100, 95% CI = -0.255 to -0.005), which was mediated by CA1 volume. These associations were absent in non-REM sleep (p > 0.05). CONCLUSIONS: Hypoxemia during REM sleep may impair memory in people at risk for dementia by reducing CA1 hippocampal volume. Research is needed to explore whether interventions targeting REM sleep hypoxemia are protective against memory decline.

Insights from a 10-year Australasian idiopathic hypersomnia patient data registry study.

STUDY OBJECTIVES: Idiopathic hypersomnia (IH) is a disorder of central hypersomnolence that results in excessive daytime sleepiness in the absence of another identifying cause. Case studies from sleep clinic patients may not be a fair representation of the wider IH population. This study aims to better characterize patients diagnosed with IH in Australia and New Zealand using online patient-driven survey data. METHODS: A retrospective analysis of 686 participants from the Hypersomnolence Australia Patient Data Registry diagnosed with either IH (n = 554), narcolepsy type 1 (NT1, n = 54) or narcolepsy type 2 (NT2, n = 78) between January 2013 and October 2022 was performed. RESULTS: Participants with IH reported additional sleep disorders such as OSA (16.4%) and restless legs syndrome (7.9%) and notable comorbidities included depression (46.2%) and anxiety (50%). There was a mean delay in diagnosis of 10 years in participants with IH, when compared to symptom onset. IH presents with unique but also overlapping symptomatology with NT2, with similar reporting of long daytime naps, unrefreshed sleep and automatic behavior. Modafinil was the most common medication (45.5%) used by participants with IH followed by dexamphetamine (44.2%). Most participants with IH reported receiving physician advice regarding positive lifestyle changes but recommend that newly diagnosed patients be given more advice about medication use. CONCLUSIONS: This study demonstrates a delay in IH diagnosis when compared to symptom onset and overlapping features of IH and NT2. It also highlights the heterogeneous presentation of IH and the value of large patient registries in future research.

Cardio-metabolic health effects of CPAP treatment for sleep apnoea during weight loss: A randomised controlled pilot trial.

BACKGROUND AND AIMS: This study assessed whether the addition of continuous positive airway pressure (CPAP) during weight loss would enhance cardiometabolic health improvements in patients with obesity and Obstructive Sleep Apnoea (OSA). METHODS AND RESULTS: Patients with overweight or obesity, pre-diabetes and moderatesevere OSA were randomised to receive CPAP therapy with a weight loss programme (CPAP+WL) or a weight loss programme alone (WL alone). PRIMARY OUTCOME: 2-hour glucose assessed by an oral glucose tolerance test. SECONDARY OUTCOMES: 24 hr blood pressure, body composition (DEXA) and fasting blood markers. 17 patients completed 3-month follow-up assessments (8 CPAP+WL and 9 WL alone). Overall, participants in both groups lost ∼12 kg which reduced polysomnography determined OSA severity by ∼45 %. In the CPAP+WL group, CPAP use (compliance 5.29 hrs/night) did not improve any outcome above WL alone. There was no improvement in 2-hour glucose in either group. However, in the pooled (n = 17) analysis there were overall improvements in most outcomes including insulin sensitivity (.000965 units, p = .008), sleep systolic BP (- 16.2 mmHg, p = .0003), sleep diastolic BP (-9.8 mmHg, p = 0.02), wake diastolic BP (- 4.3 mmHg, p = .03) and sleepiness (Epworth Sleepiness Score -3.2, p = .0003). In addition, there were reductions in glucose area under the curve (-230 units, p = .009), total (-0.86 mmol/L, p = 0.006) and LDL cholesterol (-0.58 mmol/L, p = 0.007), triglycerides (-0.75 mmol/L, p = 0.004), fat mass (-7.6 kg, p < .0001) and abdominal fat (-310 cm3, p < .0001). CONCLUSION: Weight loss reduced OSA and improved sleepiness and cardiometabolic health. These improvements were not further enhanced by using CPAP. Results suggest weight loss should be the primary focus of treatment for patients with OSA and obesity.

Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity.

BACKGROUND: Obstructive sleep apnea is characterized by disordered breathing during sleep and is associated with major cardiovascular complications; excess adiposity is an etiologic risk factor. Tirzepatide may be a potential treatment. METHODS: We conducted two phase 3, double-blind, randomized, controlled trials involving adults with moderate-to-severe obstructive sleep apnea and obesity. Participants who were not receiving treatment with positive airway pressure (PAP) at baseline were enrolled in trial 1, and those who were receiving PAP therapy at baseline were enrolled in trial 2. The participants were assigned in a 1:1 ratio to receive either the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or placebo for 52 weeks. The primary end point was the change in the apnea-hypopnea index (AHI, the number of apneas and hypopneas during an hour of sleep) from baseline. Key multiplicity-controlled secondary end points included the percent change in AHI and body weight and changes in hypoxic burden, patient-reported sleep impairment and disturbance, high-sensitivity C-reactive protein (hsCRP) concentration, and systolic blood pressure. RESULTS: At baseline, the mean AHI was 51.5 events per hour in trial 1 and 49.5 events per hour in trial 2, and the mean body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) was 39.1 and 38.7, respectively. In trial 1, the mean change in AHI at week 52 was -25.3 events per hour (95% confidence interval [CI], -29.3 to -21.2) with tirzepatide and -5.3 events per hour (95% CI, -9.4 to -1.1) with placebo, for an estimated treatment difference of -20.0 events per hour (95% CI, -25.8 to -14.2) (P<0.001). In trial 2, the mean change in AHI at week 52 was -29.3 events per hour (95% CI, -33.2 to -25.4) with tirzepatide and -5.5 events per hour (95% CI, -9.9 to -1.2) with placebo, for an estimated treatment difference of -23.8 events per hour (95% CI, -29.6 to -17.9) (P<0.001). Significant improvements in the measurements for all prespecified key secondary end points were observed with tirzepatide as compared with placebo. The most frequently reported adverse events with tirzepatide were gastrointestinal in nature and mostly mild to moderate in severity. CONCLUSIONS: Among persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide reduced the AHI, body weight, hypoxic burden, hsCRP concentration, and systolic blood pressure and improved sleep-related patient-reported outcomes. (Funded by Eli Lilly; SURMOUNT-OSA ClinicalTrials.gov number, NCT05412004.).

Evaluating possible 'next day' impairment in insomnia patients administered an oral medicinal cannabis product by night: a pilot randomized controlled trial.

Cannabis and its major constituents, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are being widely used to treat sleep disturbances. However, THC can cause acute cognitive and psychomotor impairment and there are concerns that driving and workplace safety might be compromised the day after evening use. Here, we examined possible 'next day' impairment following evening administration of a typical medicinal cannabis oil in adults with insomnia disorder, compared to matched placebo. This paper describes the secondary outcomes of a larger study investigating the effects of THC/CBD on insomnia disorder. Twenty adults [16 female; mean (SD) age, 46.1 (8.6) y] with physician-diagnosed insomnia who infrequently use cannabis completed two 24 h in-laboratory visits involving acute oral administration of combined 10 mg THC and 200 mg CBD ('THC/CBD') or placebo in a randomised, double-blind, crossover trial design. Outcome measures included 'next day' (≥9 h post-treatment) performance on cognitive and psychomotor function tasks, simulated driving performance, subjective drug effects, and mood. We found no differences in 'next day' performance on 27 out of 28 tests of cognitive and psychomotor function and simulated driving performance relative to placebo. THC/CBD produced a small decrease (-1.4%, p=.016, d=-0.6) in accuracy on the Stroop-Colour Task (easy/congruent) but not the Stroop-Word Task (hard/incongruent). THC/CBD also produced a small increase (+8.6, p=.042, d=0.3) in self-ratings of Sedated at 10 h post-treatment, but with no accompanying changes in subjective ratings of Alert or Sleepy (p's>0.05). In conclusion, we found a lack of notable 'next day' impairment to cognitive and psychomotor function and simulated driving performance following evening use of 10 mg oral THC, in combination with 200 mg CBD, in an insomnia population who infrequently use cannabis.

A comparison of two obesity-related hypoventilation disorders: Impact on sleep, quality of life and neurocognitive outcomes and the effects of positive airway pressure therapy.

Study Objectives: Symptom impact and neurocognitive function have not been previously compared between patients with obesity-associated hypoventilation disorders (obesity hypoventilation syndrome [OHS]) and hypoventilation in the setting of obesity and obstructive airways disease (OHAD). The aim of this study is to compare baseline sleep-related symptoms, health-related quality of life, and neurocognitive function between OHS and OHAD and the impact of PAP therapy on these outcomes. Methods: Epworth Sleepiness Scale (ESS), Pittsburgh Sleepiness Quality Index (PSQI), SF36, and various neurocognitive tests, in addition to anthropometric, polysomnography, lung function, and blood gas data from participants with OHS and participants with OHAD, were included in the analysis. These data were originally collected in their respective randomized clinical trials, comparing the efficacy of different PAP modes (bilevel PAP vs. CPAP) in resolving hypercapnia. Between groups (OHS vs OHAD), pre- and post-treatment (with 3 months of positive airway pressure) comparisons were made using linear mixed modeling. Results: 45 OHS participants (mean age 51 years old, 33% female, BMI 52 kg/m2, FER 0.81, PaCO2 54 mmHg, AHI 87/h) and 32 OHAD participants (mean age 61years old, 31% female, BMI 43kg/m2, FER 0.60, PaCO2 54 mmHg, AHI 59/h) were included in the analysis. Both OHS and OHAD had similar baseline ESS (14(5.6) vs. 12(5.4)), Global PSQI (10(3.2) vs. 11(4.8)), SF36 and neurocognitive test performances (other than OHAD had lower digit symbol substitution test performance). Treatment with PAP therapy resulted in similar ESS, Global PSQI, and SF36 improvements in both groups. Neurocognitive performance did not significantly improve after PAP therapy in either group. Conclusions: The symptom impact between two separate hypoventilation disorders (OHS and OHAD), in terms of sleepiness, sleep quality, quality of life, and cognitive function, were similar. OHS and OHAD had similar treatment responses in these parameters after 3 months of PAP therapy.Nocturnal ventilatory support in OHS.

Detection of Δ9 -tetrahydrocannabinol (THC) in oral fluid using two point-of-collection testing devices following oral administration of a THC and cannabidiol containing oil.

Point-of-collection testing (POCT) devices are widely used in roadside and workplace drug testing to identify recent cannabis use by measuring the presence of Δ9 -tetrahydrocannabinol (THC) in oral fluid (OF). However, the performance of POCT devices with oral medicinal cannabis products remains poorly described. In a randomised, double-blinded, crossover trial, adults with insomnia disorder (n = 20) received a single (2 mL) oral dose of oil containing 10 mg THC + 200 mg cannabidiol, or placebo, prior to sleep. Participants were tested with the Securetec DrugWipe® 5S (10 ng/mL THC cut-off) and Dräger DrugTest® 5000 (25 ng/mL THC cut-off) POCT devices at baseline (pre-treatment) and then at 0.5, 10, and 18 h post-treatment. An OF sample, taken at each time point, was also analysed using liquid chromatography-tandem mass spectrometry. Large individual variability in OF THC concentrations was observed 0.5 h post-treatment (range: 0-425 ng/mL; mean (SD) 48.7 (107.5) ng/mL). Both the Securetec DrugWipe® 5S and DrugTest® 5000 demonstrated poor sensitivity to THC at 0.5 h post-treatment (25% and 50%, respectively). At 10 and 18 h post-treatment, all participant OF THC concentrations were below screening cut-offs, and all test results were negative. These findings highlight the relatively poor sensitivity of both devices in detecting recent use of an oral medicinal cannabis product. They also suggest a low probability of obtaining a positive THC result the morning after ('one-off') use. Further research is required to establish the probability of obtaining a positive THC result with regular medicinal cannabis use.

Obstructive sleep apnoea in obesity: A review.

Obstructive sleep apnea is a common comorbidity that occurs in individuals with obesity. It classically manifests with excessive daytime sleepiness, resulting in reduced quality of life, workplace productivity, and an increased risk of motor vehicle accidents. Weight gain plays an important role in its pathogenesis through worsening upper airway collapsibility, and current treatment options are targeted towards mechanically overcoming upper airway obstruction and weight loss. Continuous positive airway pressure therapy remains the most widely prescribed treatment for obstructive sleep apnea but poor tolerance is a common barrier to effective treatment. Sustainable weight loss is an important treatment option but can be difficult to achieve without bariatric surgery. The recent advances in incretin-based pharmacotherapies represent a promising avenue not only in achieving long-term weight loss but also in treating obstructive sleep apnoea and alleviating the burden of its symptoms and comorbidities.

Electroencephalographic slowing during REM sleep in older adults with subjective cognitive impairment and mild cognitive impairment.

STUDY OBJECTIVES: In older adults with Alzheimer's disease, slowing of electroencephalographic (EEG) activity during REM sleep has been observed. Few studies have examined EEG slowing during REM in those with mild cognitive impairment (MCI) and none have examined its relationship with cognition in this at-risk population. METHODS: Two hundred and ten older adults (mean age = 67.0, SD = 8.2 years) underwent comprehensive neuropsychological, medical, and psychiatric assessment and overnight polysomnography. Participants were classified as subjective cognitive impairment (SCI; n = 75), non-amnestic MCI (naMCI, n = 85), and amnestic MCI (aMCI, n = 50). REM EEG slowing was defined as (δ + θ)/(α + σ + ß) power and calculated for frontal, central, parietal, and occipital regions. Analysis of variance compared REM EEG slowing between groups. Correlations between REM EEG slowing and cognition, including learning and memory, visuospatial and executive functions, were examined within each subgroup. RESULTS: The aMCI group had significantly greater REM EEG slowing in the parietal and occipital regions compared to the naMCI and SCI groups (partial η2 = 0.06, p < 0.05 and 0.06, p < 0.05, respectively), and greater EEG slowing in the central region compared to SCI group (partial η2 = 0.03, p < 0.05). Greater REM EEG slowing in parietal (r = -0.49) and occipital regions (r = -0.38 [O1/M2] and -0.33 [O2/M1]) were associated with poorer visuospatial performance in naMCI. CONCLUSIONS: REM EEG slowing may differentiate older adults with memory impairment from those without. Longitudinal studies are now warranted to examine the prognostic utility of REM EEG slowing for cognitive and dementia trajectories.

Developing, Implementing, and Evaluating the Effectiveness of a Sleep Health Educational Module for Pharmacy Students.

OBJECTIVE: Pharmacists need sleep health knowledge and management skills to deliver evidence-based treatments to patients with sleep disorders/disturbances. This study aimed to develop, implement, and evaluate a pedagogically informed, interactive sleep health educational module for pharmacy students. METHODS: An educational module utilizing a flipped classroom approach, with an interactive lecture, student self-reflection of sleep patterns, case discussions, and pharmacist-patient role-play scenarios, was designed and implemented. A questionnaire assessing pre/post-module changes in knowledge about and attitudes toward sleep health as well as post-module learning satisfaction, was administered to all participating second-year pharmacy students at an Australian university. RESULTS: Mean total knowledge scores for participating students (n = 125, 70.4% female) improved significantly, from a baseline of 11.1 ± 3.8 to 17.1 ± 3.5 post-module (range: 0-25). Attitudes toward sleep health were moderately high at baseline (28.8 ± 3.2) and improved marginally post-module (29.4 ± 3.8) (range: 10-50); however, this increase was insignificant. Participants expressed high satisfaction with the module through subjective feedback, and post-module reflective statements indicated plans for changing sleep behaviors. CONCLUSION: The results of this study have shown that a targeted educational module for pharmacy students improved sleep health knowledge. It appeared that positive attitudes toward sleep health were not significantly increased which may reflect a ceiling effect. Future modules should focus on attitudinal aspects of positive sleep health to enhance pharmacists' skills in providing clinically related sleep health care to patients with sleep disturbance.

REducing Sleep Apnoea for the PrEvention of Dementia (REShAPED): Protocol for a multi-site feasibility randomised controlled trial.

There is accumulating evidence that has linked OSA with increased risk of cognitive decline and dementia. Here we present the protocol for an Australian, multi-site randomised controlled, parallel open-label trial which will evaluate the feasibility for a full-scale trial investigating the effects of treating OSA on cognitive decline in older adults at risk of dementia within memory clinic settings. We will randomise 180 older adults to either the treatment intervention group or control group for 2 years. Inclusion criteria include: 50-85 years; mild-severe OSA (defined average ODI ≥ 10 with 3% oxygen desaturation determined by wrist oximetry over two nights); and subjective cognitive complaints or mild cognitive impairment. The treatment intervention arm aims to achieve an optimal treatment response based on reducing hypoxic burden with either CPAP, mandibular advancement splint, positional therapy, or oxygen therapy. Furthermore, participants will receive up to 8 sessions which involve motivational interviewing, collaborative goal setting, and behavioural sleep management. The control arm will not receive OSA treatment as part of this trial, however there will be no OSA treatment restrictions, and any treatment will be documented. Primary outcomes are 1) acceptability based upon willingness of participants to be randomised; 2) alleviating hypoxic burden by reducing OSA severity; 3) tolerability of the trial burden based upon collection of outcomes over the 2-year follow-up. Secondary outcomes include safety and cognitive function. Outcomes will be collected at 0, 6 and 24-months. This feasibility study aims to will provide the basis for a larger longer-term trial of dementia prevention.

Comparative short-term safety and efficacy of hypnotics: A quantitative risk-benefit analysis.

Several professional societies have provided recommendations for prescribing medications for insomnia. None has provided an integrative analysis that concurrently quantifies safety and efficacy (e.g., risk-benefit ratios). This represents an important gap for informing clinician decision-making. Accordingly, the aim of the present review is to provide such an analysis for five classes of sleep-promoting medications. Adverse event data values were extracted from the most recent FDA-approved package inserts and converted to an integer before being placebo-adjusted and standardized as a rate per 1000 (AEr). Efficacy data, pre-to-post self-reported data for active and placebo conditions were acquired from pivotal trials identified in "white papers" and systematic reviews/meta-analyses. Weighted effect sizes were calculated for subjective sleep latency, wake time after sleep onset and total sleep time, and then were averaged by medication class for each sleep continuity variable. Overall efficacy was represented by a single variable, SWT (sleep latency + wake time after sleep onset + total sleep time). Risk-benefit was represented using a simple ratio value. For safety, it was found that melatonin receptor agonists had the lowest adverse event rate (AEr = 43.1), and non-benzodiazepine benzodiazepine receptor agonists had the highest rate (AEr = 255.0). For efficacy, it was found that the pre-to-post placebo adjusted effect sizes were largest for benzodiazepines (effect size = 1.94) and smallest for melatonin receptor agonists (effect size = 0.109). For risk-benefit, histamine antagonist had the most favourable profile (risk-benefit = 69.5), while melatonin receptor agonist had the least favourable profile (risk-benefit = 395.7). Overall, the combined metric for risk-benefit suggests that treatment with a histamine antagonist is optimal and potentially represents the best first-line therapy for the medical management of insomnia.

Giving weight to incretin-based pharmacotherapy for obesity-related sleep apnea: a revolution or a pipe dream?

Obesity is a chronic disease affecting over 670 million adults globally, with multiple complications including obstructive sleep apnea (OSA). Substantial weight loss in patients with obesity-related OSA can reduce or even eliminate OSA as well as reduce sleepiness and improve cardio-metabolic health. Evidence suggests that these improvements exceed those that occur with device-based OSA therapies like continuous positive airway pressure which continue to be the first-line of therapy. Resistance to weight management as a first-line strategy to combat OSA could arise from the complexities in delivering and maintaining adequate weight management, particularly in sleep clinic settings. Recently, incretin-based pharmacotherapies including glucagon-like peptide 1 (GLP-1) receptor agonists alone or combined with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been developed to target glycemic control in type 2 diabetes. These medications also slow gastric emptying and reduce energy intake. In randomized, placebo-controlled trials of these medications in diabetic and non-diabetic populations with obesity, participants on active medication lost up to 20% of their body weight, with corresponding improvements in blood pressure, lipid levels, physical functioning, and fat mass loss. Their adverse effects are predominantly gastrointestinal-related, mild, and transient. There are trials currently underway within individuals with obesity-related OSA, with a focus on reduction in weight, OSA severity, and cardio-metabolic outcomes. These medications have the potential to substantially disrupt the management of OSA. Pending coming data, we will need to consider pharmacological weight loss as a first-line therapy and how that influences training and management guidelines.

Cannabinol (CBN; 30 and 300 mg) effects on sleep and next-day function in insomnia disorder ('CUPID' study): protocol for a randomised, double-blind, placebo-controlled, cross-over, three-arm, proof-of-concept trial.

OBJECTIVE: Insomnia is the most prevalent sleep disorder, with few effective pharmacotherapies. Anecdotal reports and recent preclinical research suggest that cannabinol (CBN), a constituent of Cannabis sativa derived from delta-9-tetrahydrocannabinol, could be an effective treatment. Despite this, the isolated effects of CBN on sleep have yet to be systematically studied in humans. METHODS: The present protocol paper describes a randomised, double-blind, placebo-controlled, single-dose, three-arm, cross-over, proof-of-concept study which investigates the effects of CBN on sleep and next-day function in 20 participants with clinician-diagnosed insomnia disorder and an Insomnia Severity Index Score ≥15. Participants receive a single fixed oral liquid dose of 30 mg CBN, 300 mg CBN and matched placebo, in random order on three treatment nights; each separated by a 2-week wash-out period. Participants undergo overnight sleep assessment using in-laboratory polysomnography and next-day neurobehavioural function tests. The primary outcome is wake after sleep onset minutes. Secondary outcomes include changes to traditional sleep staging, sleep-onset latency and absolute spectral power during non-rapid eye movement (NREM) sleep. Tertiary outcomes include changes to sleep spindles during NREM sleep, arousal indices, absolute spectral power during REM sleep and subjective sleep quality. Safety-related and exploratory outcomes include changes to next-day simulated driving performance, subjective mood and drug effects, postural sway, alertness and reaction time, overnight memory consolidation, pre and post-sleep subjective and objective sleepiness; and plasma, urinary, and salivary cannabinoid concentrations. The study will provide novel preliminary data on CBN efficacy and safety in insomnia disorder, which will inform larger clinical trials. ETHICS AND DISSEMINATION: Human Research Ethics Committee approval has been granted by Bellberry (2021-08-907). Study findings will be disseminated in a peer-reviewed journal and at academic conferences. TRIAL REGISTRATION NUMBER: NCT05344170.

Melatonin use in children and adolescents: A scoping review of caregiver perspectives.

Despite melatonin's popularity as a pediatric sleep-aid, little has been investigated around caregivers' understanding and perception of melatonin use for their dependent. This scoping review analyzes the current literature on pediatric melatonin use, to understand how caregivers' perceptions around melatonin are shaped by their illness/medication-related beliefs, treatment experience and preferences. A literature search was conducted across Embase, Medline, PsycINFO, PubMed and Scopus, generating 184 results for screening against the inclusion criteria. Nineteen studies were retrieved, comprising of 1561 children and adolescents, aged 8.7 ± 2.3 years (range: 0-44 years), conducted primarily in the United States of America (n = 6), Canada (n = 3) and the Netherlands (n = 3). Studies were evaluated for their study design and caregiver-centered outcomes, encompassing: 1) illness/treatment-related beliefs, 2) treatment satisfaction/effectiveness, 3) treatment preference/acceptability, and 4) impact of child's sleep disturbance on caregivers' quality-of-life. Sleep disturbances necessitating melatonin use occurred alongside congenital/neurodevelopmental comorbidities in 18 studies (95%). Melatonin was commonly associated with "naturalness" and "safety". Concepts of treatment satisfaction versus effectiveness were minimally differentiated within included studies. Caregivers preferred concurrent use of melatonin and behavioral interventions for management of their dependents' sleep. Improved sleep in the dependent generally led to better quality-of-life for caregivers and their family.

Embedding digital sleep health into primary care practice: A triangulation of perspectives from general practitioners, nurses, and pharmacists.

Introduction: While digital health interventions (DHIs) can potentially address the unmet needs for sleep health services, little is known about their implementation in practice. The current study aimed to explore primary care health providers' attitudes and beliefs towards DHIs for sleep and implementation into practice. Methods: A cross-sectional online survey was administered to Australian primary care health professionals: general practitioners (GPs), community nurses, and community pharmacists. Semi-structured interviews were conducted within a sub-sample of participants exploring their experiences with DHIs and perceived barriers/facilitators for embedding DHIs into primary care. Semi-structured interviews were thematically analysed using the framework approach to contextualise survey findings. Results: Ninety-six surveys were returned (GPs = 36, nurses = 30, and pharmacists = 30) and 45 interviews conducted (GPs = 17, nurses = 14, and pharmacists = 14). From the survey, GPs were more likely to endorse familiarity (p = 0.009) and use (p < 0.001) of sleep DHIs in clinical practice than pharmacists and nurses. GPs were more interested in utilising the diagnostic features within a sleep DHI (p = 0.009) compared to other professionals. Thematic analysis of the interviews revealed three major themes, contextualised by profession: (1) Scope for DHIs in Current Practice, (2) Practice Gaps and Training Needs, and (3) Envisioning a Model of Care Using Sleep DHIs. While DHIs can potentially improve care, greater clarity of care pathways and reimbursement structures are needed for integration into practice. Conclusion: Primary care health professionals highlighted the training, care pathway and financial models required to realise the potential for translating findings from efficacy studies for DHIs into primary care to optimise sleep health.

Heart rate variability during slow wave sleep is linked to functional connectivity in the central autonomic network.

Reduced heart rate variability can be an early sign of autonomic dysfunction in neurodegenerative diseases and may be related to brain dysfunction in the central autonomic network. As yet, such autonomic dysfunction has not been examined during sleep-which is an ideal physiological state to study brain-heart interaction as both the central and peripheral nervous systems behave differently compared to during wakefulness. Therefore, the primary aim of the current study was to examine whether heart rate variability during nocturnal sleep, specifically slow wave (deep) sleep, is associated with central autonomic network functional connectivity in older adults 'at-risk' of dementia. Older adults (n = 78; age range = 50-88 years; 64% female) attending a memory clinic for cognitive concerns underwent resting-state functional magnetic resonance imaging and an overnight polysomnography. From these, central autonomic network functional connectivity strength and heart rate variability data during sleep were derived, respectively. High-frequency heart rate variability was extracted to index parasympathetic activity during distinct periods of sleep, including slow wave sleep as well as secondary outcomes of non-rapid eye movement sleep, wake after sleep onset, and rapid eye movement sleep. General linear models were used to examine associations between central autonomic network functional connectivity and high-frequency heart rate variability. Analyses revealed that increased high-frequency heart rate variability during slow wave sleep was associated with stronger functional connectivity (F = 3.98, P = 0.022) in two core brain regions within the central autonomic network, the right anterior insular and posterior midcingulate cortex, as well as stronger functional connectivity (F = 6.21, P = 0.005) between broader central autonomic network brain regions-the right amygdala with three sub-nuclei of the thalamus. There were no significant associations between high-frequency heart rate variability and central autonomic network connectivity during wake after sleep onset or rapid eye movement sleep. These findings show that in older adults 'at-risk' of dementia, parasympathetic regulation during slow wave sleep is uniquely linked to differential functional connectivity within both core and broader central autonomic network brain regions. It is possible that dysfunctional brain-heart interactions manifest primarily during this specific period of sleep known for its role in memory and metabolic clearance. Further studies elucidating the pathophysiology and directionality of this relationship should be conducted to determine if heart rate variability drives neurodegeneration, or if brain degeneration within the central autonomic network promotes aberrant heart rate variability.