Tirzepatide for the treatment of obstructive sleep apnea: Rationale, design, and sample baseline characteristics of the SURMOUNT -OSA phase 3 trial.

BACKGROUND: Weight reduction is a standard recommendation for obstructive sleep apnea (OSA) treatment in people with obesity or overweight; however, weight loss can be challenging to achieve and maintain without bariatric surgery. Currently, no approved anti-obesity medication has demonstrated effectiveness in OSA management. This study is evaluating the efficacy and safety of tirzepatide for treatment of moderate to severe OSA in people with obesity. METHODS: SURMOUNT-OSA, a randomized, placebo -controlled, 52-week phase 3 trial, is investigating the efficacy and safety of tirzepatide for treatment of moderate to severe OSA (apnea hypopnea- index ≥15 events/h) in participants with obesity (body mass index ≥30 kg/m2) and an established OSA diagnosis. SURMOUNT-OSA is made of 2 intervention-specific appendices (ISAs): ISA-1 includes participants with no current OSA treatment, and ISA-2 includes participants using positive airway pressure therapy. Overall, 469 participants have been randomized 1:1 to receive tirzepatide or placebo across the master protocol (ISA-1, n = 234; ISA-2, n = 235). All participants are also receiving lifestyle intervention for weight reduction. RESULTS: The primary endpoint for the individual ISAs is the difference in apnea hypopnea- index response, as measured by polysomnography, between tirzepatide and placebo arms at week 52. Secondary endpoints include sleep apnea-specific hypoxic burden, functional outcomes, and cardiometabolic biomarkers. The trial employs digital wearables, including home sleep testing to capture time to improvement and accelerometry for daily physical activity assessment, to evaluate exploratory outcomes. CONCLUSION: SURMOUNT-OSA brings a novel design to investigate if tirzepatide provides clinically meaningful improvement in obesity-related OSA by targeting the underlying etiology. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05412004.

Predicting neurodegeneration from sleep related biofluid changes.

Sleep-wake disturbances are common in neurodegenerative diseases and may occur years before the clinical diagnosis, potentially either representing an early stage of the disease itself or acting as a pathophysiological driver. Therefore, discovering biomarkers that identify individuals with sleep-wake disturbances who are at risk of developing neurodegenerative diseases will allow early diagnosis and intervention. Given the association between sleep and neurodegeneration, the most frequently analyzed fluid biomarkers in people with sleep-wake disturbances to date include those directly associated with neurodegeneration itself, such as neurofilament light chain, phosphorylated tau, amyloid-beta and alpha-synuclein. Abnormalities in these biomarkers in patients with sleep-wake disturbances are considered as evidence of an underlying neurodegenerative process. Levels of hormonal sleep-related biomarkers such as melatonin, cortisol and orexin are often abnormal in patients with clinical neurodegenerative diseases, but their relationships with the more standard neurodegenerative biomarkers remain unclear. Similarly, it is unclear whether other chronobiological/circadian biomarkers, such as disrupted clock gene expression, are causal factors or a consequence of neurodegeneration. Current data would suggest that a combination of fluid biomarkers may identify sleep-wake disturbances that are most predictive for the risk of developing neurodegenerative disease with more optimal sensitivity and specificity.

Region-specific changes in brain activity and memory after continuous positive airway pressure therapy in obstructive sleep apnea: a pilot high-density electroencephalography study.

STUDY OBJECTIVES: Limited channel electroencephalography (EEG) investigations in obstructive sleep apnea (OSA) have revealed deficits in slow wave activity (SWA) and spindles during sleep and increased EEG slowing during resting wakefulness. High-density EEG (Hd-EEG) has also detected local parietal deficits in SWA (delta power) during NREM. It is unclear whether effective continuous positive airway pressure (CPAP) treatment reverses regional SWA deficits, and other regional sleep and wake EEG abnormalities, and whether any recovery relates to improved overnight memory consolidation. METHODS: A clinical sample of men with moderate-severe OSA underwent sleep and resting wake recordings with 256-channel Hd-EEG before and after 3 months of CPAP. Declarative and procedural memory tasks were administered pre- and post-sleep. Topographical spectral power maps and differences between baseline and treatment were compared using t-tests and statistical nonparametric mapping (SnPM). RESULTS: In 11 compliant CPAP users (5.2 ±â€…1.1 hours/night), total sleep time did not differ after CPAP but N1 and N2 sleep were lower and N3 was higher. Centro-parietal gamma power during N3 increased and fronto-central slow spindle activity during N2 decreased (SnPM < 0.05). No other significant differences in EEG power were observed. When averaged specifically within the parietal region, N3 delta power increased after CPAP (p = 0.0029) and was correlated with the change in overnight procedural memory consolidation (rho = 0.79, p = 0.03). During resting wakefulness, there were trends for reduced delta and theta power. CONCLUSIONS: Effective CPAP treatment of OSA may correct regional EEG abnormalities, and regional recovery of SWA may relate to procedural memory improvements in the short term.

Armodafinil to reduce the sleepiness related side-effects of sleep restriction therapy being used to treat insomnia disorder: An open label clinical trial pilot study compared with historical controls.

Sleep restriction therapy (SRT) is an effective stand-alone behavioural intervention for insomnia disorder. However, its daytime side effects, particularly sleepiness, may be troubling for patients and/or may be a necessary part of the patient's treatment journey. This pilot trial aims to explore the potential benefit of armodafinil, a wakefulness promoter. Patients were treated with SRT with open label adjunctive armodafinil (150 mg/day). Thirty-three patients from previous studies that have undergone exactly the same SRT intervention acted as controls. The primary outcome measure was the insomnia severity index (ISI), and secondary outcomes were the Epworth sleepiness scale, sleep restriction adherence scale (SRAS), and safety from baseline through to 12 weeks. We recruited 25 patients into the trial. Data for the primary end point (ISI at 12 weeks) was available for 20 of the participants. The baseline insomnia severity index was 20.2 (SD 3.3) and decreased to 9.1 (SE 1.1), with no change, to 10.2 and 11.2 at weeks 6 and 12 respectively (all p > 0.05 compared with baseline). The insomnia severity index values for armodafinil patients were statistically inferior to historical controls at the primary time point of 12 weeks (11.2 vs. 6.7, p < 0.01). Sleep restriction therapy plus armodafinil treatment was associated with frequent minor side effects but was generally safe and acceptable to patients. Sleep restriction therapy was associated with a robust clinical response in the insomnia severity index values for insomnia patients. Based upon historical control data, armodafinil does not appear to have beneficial adjunctive effects in addition to sleep restriction therapy alone.

Retrospective cohort study of hypersomnias of central origin from two Australian tertiary sleep disorders services.

BACKGROUND: Hypersomnias of central origin (HOCO) are diverse in origin and symptomatology and remain poorly described in an Australian population. We hypothesised that the rate of human leukocyte antigen (HLA) DQB1*0602 positivity in the Australian cohort would be comparable to international registries. AIMS: The current study aims to evaluate epidemiological and clinical characteristics of Australian patients with HOCO, including prevalence of HLA DQB1*0602 positivity, the most specific HLA marker associated with narcolepsy. METHODS: This is a retrospective study. Patients ≥ 16 years of age presenting with symptoms of hypersomnolence who attended one of two Australian sleep centres (New South Wales and Queensland) in the preceding 24 months and had undergone both HLA serology and multiple sleep latency tests (MSLTs) were included. Main outcome measures included demographics, HLA DQB1*0602 positivity, MSLT, and clinical parameters (presence of auxiliary narcolepsy symptoms, laboratory tests, relevant prescribed medications). RESULTS: Eighty-eight patients were included. HLA DQB1*0602 positivity was highest in those with type 1 narcolepsy (NT1) (95.7%) and lowest in those without a classifiable disorder (9.1%). Mean sleep latency was lowest and number of sleep-onset rapid eye movement periods (SOREMPs) highest in the NT1 group. Comorbid disorders, particularly depression and overweight/obesity, were prevalent in all cohorts. Across all diagnostic groups, dexamphetamine was the most commonly prescribed agent for excessive daytime sleepiness. CONCLUSIONS: Patients with HOCO assessed in two specialised Australian clinics demonstrate comparable clinical characteristics to other published cohorts internationally; however, available pharmacological agents in Australia do not reflect international standards of care.

The Effect of Light Therapy on Electroencephalographic Sleep in Sleep and Circadian Rhythm Disorders: A Scoping Review.

Light therapy is used to treat sleep and circadian rhythm disorders, yet there are limited studies on whether light therapy impacts electroencephalographic (EEG) activity during sleep. Therefore, we aimed to provide an overview of research studies that examined the effects of light therapy on sleep macro- and micro-architecture in populations with sleep and circadian rhythm disorders. We searched for randomized controlled trials that used light therapy and included EEG sleep measures using MEDLINE, PubMed, CINAHL, PsycINFO and Cochrane Central Register of Controlled Trials databases. Five articles met the inclusion criteria of patients with either insomnia or delayed sleep−wake phase disorder (DSWPD). These trials reported sleep macro-architecture outcomes using EEG or polysomnography. Three insomnia trials showed no effect of the timing or intensity of light therapy on total sleep time, wake after sleep onset, sleep efficiency and sleep stage duration compared to controls. Only one insomnia trial reported significantly higher sleep efficiency after evening light therapy (>4000 lx between 21:00−23:00 h) compared with afternoon light therapy (>4000 lx between 15:00−17:00 h). In the only DSWPD trial, six multiple sleep latency tests were conducted across the day (09:00 and 19:00 h) and bright light (2500 lx) significantly lengthened sleep latency in the morning (09:00 and 11:00 h) compared to control light (300 lx). None of the five trials reported any sleep micro-architecture measures. Overall, there was limited research about the effect of light therapy on EEG sleep measures, and studies were confined to patients with insomnia and DSWPD only. More research is needed to better understand whether lighting interventions in clinical populations affect sleep macro- and micro-architecture and objective sleep timing and quality.

Narrow doorways alter brain connectivity and step patterns in isolated REM sleep behaviour disorder.

BACKGROUND: Motor impairments in those with isolated REM sleep behaviour disorder (iRBD) significantly increases the likelihood of developing Lewy body disease (e.g. Parkinson's disease and Dementia with Lewy Bodies). OBJECTIVE: This study sought to explore the prodromal process of neurodegeneration by examining the neural signature underlying motor deficits in iRBD patients. METHODS: A virtual reality (VR) gait paradigm (which has previously been shown to elicit adaptive changes in gait performance whilst navigating doorways in Parkinson's Disease - PD) was paired with fMRI to investigate whether iRBD patients demonstrated worsened motor performance and altered connectivity across frontoparietal, motor and basal ganglia networks compared to healthy controls. Forty participants (23 iRBD and 17 healthy controls) completed the virtual reality gait task whilst in the MRI scanner, and an additional cohort of 19 Early PD patients completed the behavioural virtual reality gait task. RESULTS: As predicted, iRBD patients demonstrated slower and more variable stepping compared to healthy control participants and demonstrated an exaggerated response when navigating narrow compared to wide doorways, a phenomenon characteristically seen in PD. The iRBD patients also demonstrated less BOLD signal change in the left posterior putamen and right mesencephalic locomotor region, as well as reduced functional connectivity between the frontoparietal network and the motor network, when navigating narrow versus wide doorways compared to healthy control participants. CONCLUSIONS: Taken together, this study demonstrates that iRBD patients have altered task-related brain connectivity, which may represent the neural underpinnings of early motor impairments that are evident in iRBD.

Single-channel EEG based insomnia detection with domain adaptation.

Insomnia is one of the most common sleep disorders which can dramatically impair life quality and negatively affect an individual's physical and mental health. Recently, various deep learning based methods have been proposed for automatic and objective insomnia detection, owing to the great success of deep learning techniques. However, due to the scarcity of public insomnia data, a deep learning model trained on a dataset with a small number of insomnia subjects may compromise the generalization capacity of the model and eventually limit the performance of insomnia detection. Meanwhile, there have been a number of public EEG datasets collected from a large number of healthy subjects for various sleep research tasks such as sleep staging. Therefore, to utilize such abundant EEG datasets for addressing the data scarcity issue in insomnia detection, in this paper we propose a domain adaptation based model to better extract insomnia related features of the target domain by leveraging stage annotations from the source domain. For each domain, two pairs of common encoder and private encoder are firstly trained to extract sleep related features and sleep irrelevant features, respectively. In order to further discriminate source domain and target domain, a domain classifier is introduced. Then, the common encoder of the target domain will be used together with the Long Short Term Memory (LSTM) network for insomnia detection. To the best of our knowledge, this is the first deep learning based domain adaptation model using single channel raw EEG signals to detect insomnia at subject level. We use the Montreal Archive of Sleep Studies (MASS) dataset which contains only healthy subjects as source domain and two datasets which contain both healthy and insomnia subjects as target domain to validate our model's generalizability. Experimental results on the two target domain datasets (a public one and an in-house one) demonstrate that our model generalizes well on two target domain datasets with different sampling rates. In particular, our proposed method is able to improve insomnia detection performance from 50.0% to 90.9% and 66.7%-79.2% in terms of accuracy on the two target domain datasets, respectively.

Sleep health management in community pharmacy: Where are we and where should we be heading?

BACKGROUND: Poor sleep health is now recognised as a significant risk factor for chronic diseases and is associated with considerable comorbidity and mortality. Community pharmacists are primary care clinicians with an integral role in sleep health promotion and chronic sleep disorder management; however, it is unclear to what extent this is currently being undertaken or what the perspectives of Australian community pharmacists regarding their role in sleep health are. OBJECTIVES: To explore community pharmacists' current sleep health practice and perspectives on the potential future of sleep health care in community pharmacy. METHODS: Qualitative semi-structured interviews were carried out with a maximally varied, convenience-based purposive sample of community pharmacists. Interviews were audio-recorded, transcribed verbatim and subjected to, in sequence; an inductive analysis followed by a deductive approach where the inductively derived thematic structure was used as a framework. RESULTS: Twenty-five community pharmacists from two Australian states were interviewed. Insomnia and obstructive sleep apnea (OSA) were the most frequently encountered sleep disorders in community pharmacy presentations. Four key themes were derived from the data: 1) Preparedness, 2) Approach, 3) Capabilities and 4) What needs to change? All participants reported that their sleep health knowledge was insufficient and emphasized the need for more education and training. Although some were engaged in providing OSA services, none of the participants offered services for insomnia or other sleep disorders. Time/task pressures, low health system/health care professional sleep health recognition/awareness and the lack of standardised pharmacy-specific sleep health management guidelines were commonly cited barriers for sleep health service provision. CONCLUSION: Community pharmacists commonly manage day-to-day sleep health; however, most expressed a need for increased sleep health recognition/awareness by the health system, targeted education/training for pharmacists and support for the future provision of community pharmacy-delivered sleep health services. With the appropriate implementation strategies, community pharmacists could utilise their availability and accessibility to improve the future of primary care sleep health management.

The effect of cognitive behavioural therapy for insomnia on sedative-hypnotic use: A narrative review.

Although cognitive behavioural therapy for insomnia (CBTi) is the recommended 'first-line' treatment for insomnia, most patients are initially treated with sedative-hypnotic medications. Given the risk of impaired cognitive and psychomotor performance, serious adverse events, and long-term dependence associated with sedative-hypnotics, guidelines recommend that prescriptions should be limited to short-term use and that patients are provided with support for withdrawal where possible. CBTi is an effective insomnia treatment in the presence of sedative-hypnotic use. Furthermore, guidelines recommended that CBTi techniques are utilised to facilitate withdrawal from sedative-hypnotics. However, there is very little research evaluating the effect of CBTi on reduced medication use. The current narrative review integrates 95 studies including over 10,000 participants, investigating the effect of CBTi on reduced sedative-hypnotic use in different populations (e.g., hypnotic-dependent patients, older adults, military personnel), settings (e.g., primary care settings, psychiatric inpatients), CBTi modalities (e.g., self-administered reading/audio materials, digital, and therapist-administered), and in combination with gradual dose reduction programs. Based on this research, we discuss the theoretical mechanistic effects of CBTi in facilitating reduced sedative-hypnotic use, provide clear recommendations for future research, and offer pragmatic clinical suggestions to increase access to CBTi to reduce dependence on sedative-hypnotics as the 'default' treatment for insomnia.

Sleep and orexin: A new paradigm for understanding behavioural-variant frontotemporal dementia?

Behavioural variant frontotemporal dementia (bvFTD) is a complex and heterogeneous disorder with as yet unidentified unifying pathophysiological mechanism. There is emerging evidence that hypothalamic dysfunction, manifesting as disturbances in sleep and metabolism, is an integral component of neurodegeneration in bvFTD. Although sleep and metabolic disturbances and the behavioural abnormalities of bvFTD may appear disparate on the surface, there may be a common underlying hormonal mechanism involving orexin. Orexin is a hypothalamic neurotransmitter directly responsible for control of sleep and metabolism in healthy individuals and is implicated in many abnormal behaviours commonly seen in bvFTD - such as impulsive behaviour, hedonistic reinforcement and binge-consumption of ethanol. Further characterising orexin's role in pathophysiology of bvFTD could lead to a new paradigm for understanding this disease and may provide a new direction towards effective management and treatment.

The Neural Signature of Impaired Dual-Tasking in Idiopathic Rapid Eye Movement Sleep Behavior Disorder Patients.

Dual-task gait can be a useful biomarker for cognitive decline and a sensitive predictor of future neurodegeneration in certain clinical populations, such as patients with idiopathic rapid eye movement sleep behavior disorder. OBJECTIVES: The objective of this cross-sectional study was to determine the neural signature of dual-tasking deficits in idiopathic rapid eye movement sleep behavior disorder using a validated gait paradigm. METHODS: Fifty-eight participants (28 controls; 30 idiopathic rapid eye movement sleep behavior disorder patients) were recruited; 52 participants had functional MRI scans as they performed a validated dual-task virtual reality gait paradigm using foot pedals. Forty-one participants completed single- and dual-task "overground walking" on a pressure sensor carpet. RESULTS: Idiopathic rapid eye movement sleep behavior disorder patients showed deficits in dual-tasking (i.e., greater mean step time) compared to controls during "overground walking." Functional MRI revealed that idiopathic rapid eye movement sleep behavior disorder patients had reduced blood-oxygen-level-dependent signal change in the dorsal caudate nucleus, and significantly different corticostriatal functional connectivity patterns from controls, when dual-tasking in high versus low cognitive load. While controls showed greater connectivity between frontoparietal and motor networks, idiopathic rapid eye movement sleep behavior disorder patients exhibited less change in this connectivity as a function of cognitive load. CONCLUSIONS: These findings demonstrate evidence of dual-task gait deficits in idiopathic rapid eye movement sleep behavior disorder patients, underpinned by disrupted corticostriatal connectivity. Minimal differences in the level of functional connectivity between dual-tasking conditions of high and low cognitive load suggest that idiopathic rapid eye movement sleep behavior disorder patients recruit cognitive networks to control gait even when the cognitive demands are low. This may indicate a compensatory strategy for early cognitive decline in idiopathic rapid eye movement sleep behavior disorder. © 2020 International Parkinson and Movement Disorder Society.

A Residual Based Attention Model for EEG Based Sleep Staging.

Sleep staging is to score the sleep state of a subject into different sleep stages such as Wake and Rapid Eye Movement (REM). It plays an indispensable role in the diagnosis and treatment of sleep disorders. As manual sleep staging through well-trained sleep experts is time consuming, tedious, and subjective, many automatic methods have been developed for accurate, efficient, and objective sleep staging. Recently, deep learning based methods have been successfully proposed for electroencephalogram (EEG) based sleep staging with promising results. However, most of these methods directly take EEG raw signals as input of convolutional neural networks (CNNs) without considering the domain knowledge of EEG staging. Apart from that, to capture temporal information, most of the existing methods utilize recurrent neural networks such as LSTM (Long Short Term Memory) which are not effective for modelling global temporal context and difficult to train. Therefore, inspired by the clinical guidelines of sleep staging such as AASM (American Academy of Sleep Medicine) rules where different stages are generally characterized by EEG waveforms of various frequencies, we propose a multi-scale deep architecture by decomposing an EEG signal into different frequency bands as input to CNNs. To model global temporal context, we utilize the multi-head self-attention module of the transformer model to not only improve performance, but also shorten the training time. In addition, we choose residual based architecture which makes training end-to-end. Experimental results on two widely used sleep staging datasets, Montreal Archive of Sleep Studies (MASS) and sleep-EDF datasets, demonstrate the effectiveness and significant efficiency (up to 12 times less training time) of our proposed method over the state-of-the-art.

Nocturnal Hypoxemia Is Associated with Altered Parahippocampal Functional Brain Connectivity in Older Adults at Risk for Dementia.

BACKGROUND: Obstructive sleep apnea is associated with an increased risk of developing mild cognitive impairment and dementia. Intermittent nocturnal hypoxemia in obstructive sleep apnea is associated with brain changes in key regions that underpin memory. OBJECTIVE: To determine whether older adults with severe nocturnal hypoxemia would exhibit reduced functional connectivity within these regions, with associated deficits in memory. METHODS: Seventy-two participants 51 years and over underwent polysomnography with continuous blood oxygen saturation recorded via oximetry. The oxygen desaturation index (ODI, 3% dips in oxygen levels per hour) was the primary outcome measure. ODI was split into tertiles, with analyses comparing the lowest and highest tertiles (N = 48). Thirty-five of the 48 participants from these two tertiles had mild cognitive impairment. Participants also underwent resting-state fMRI and comprehensive neuropsychological, medical, and psychiatric assessment. RESULTS: The highest ODI tertile group demonstrated significantly reduced connectivity between the left and right parahippocampal cortex, relative to the lowest ODI tertile group (t(42) = -3.26, p = 0.041, beta = -1.99).The highest ODI tertile group also had poorer working memory performance. In the highest ODI tertile group only, higher left-right parahippocampal functional connectivity was associated with poorer visual memory recall (between-groups z = -2.93, p = 0.0034). CONCLUSIONS: Older adults with severe nocturnal hypoxemia demonstrate impaired functional connectivity in medial temporal structures, key regions involved in sleep memory processing and implicated in dementia pathophysiology. Oxygen desaturation and functional connectivity in these individuals each relate to cognitive performance. Research is now required to further elucidate these findings.

Arterial stiffness relates to executive dysfunction in later life.

Cardiovascular disease in older people is often linked with cognitive impairment, particularly in domains of executive function and processing speed. Our aims examined whether carotid-femoral pulse wave velocity (PWV) related to subtle changes of executive function and processing speed. Fifty-six individuals with subjective mood and/or cognitive concerns underwent PWV and neuropsychological assessments of processing speed (Trail Making Test Part A) and executive functioning (Delis Kaplan Executive Function System Stroop Task; Trail Making Test Part B, TMT-B). Individuals with high PWV (≥12.0m/s) had poorer performance on TMT-B, compared to low PWV (<12.0m/s), and a moderate negative correlation (r = -0.38, p = .004) between PWV and TMT-B performance. Our results confirm that in older adults at-risk for cognitive decline, early markers of CVD are associated with subtle decrements in rapid set-shifting (executive function), supporting efforts towards early detection of CVD as a secondary prevention strategy for older individuals with cognitive decline.

Melatonin for rapid eye movement sleep behavior disorder in Parkinson's disease: A randomised controlled trial.

BACKGROUND: Melatonin may reduce REM-sleep behavior disorder (RBD) symptoms in Parkinson's disease (PD), though robust clinical trials are lacking. OBJECTIVE: To assess the efficacy of prolonged-release (PR) melatonin for RBD in PD. METHODS: Randomized, double-blind, placebo-controlled, parallel-group trial with an 8-week intervention and 4-week observation pre- and postintervention (ACTRN12613000648729). Thirty PD patients with rapid eye movement sleep behavior disorder were randomized to 4 mg of prolonged-release melatonin (Circadin) or matched placebo, ingested orally once-daily before bedtime. Primary outcome was the aggregate of rapid eye movement sleep behavior disorder incidents averaged over weeks 5 to 8 of treatment captured by a weekly diary. Data were included in a mixed-model analysis of variance (n = 15 per group). RESULTS: No differences between groups at the primary endpoint (3.4 events/week melatonin vs. 3.6 placebo; difference, 0.2; 95% confidence interval = -3.2 to 3.6; P = 0.92). Adverse events included mild headaches, fatigue, and morning sleepiness (n = 4 melatonin; n = 5 placebo). CONCLUSION: Prolonged-release melatonin 4 mg did not reduce rapid eye movement sleep behavior disorder in PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Magnesium supplementation for the treatment of restless legs syndrome and periodic limb movement disorder: A systematic review.

Magnesium supplementation is often suggested for restless legs syndrome (RLS) or period limb movement disorder (PLMD) based on anecdotal evidence that it relieves symptoms and because it is also commonly recommended for leg cramps. We aimed to review all articles reporting the effects of magnesium supplementation on changes in RLS and/or PLMD. We conducted a systematic search looking for all relevant articles and then two reviewers read all article titles and abstracts to identify relevant studies. Eligible studies were scored for their quality as interventional trials. We found 855 abstracts and 16 of these could not be definitively excluded for not addressing all aspects of our research question. Seven full-text articles were unlocatable and one was ineligible which left eight studies with relevant data. One was a randomised placebo-controlled trial, three were case series and four were case studies. The RCT did not find a significant treatment effect of magnesium but may have been underpowered. After quality appraisal and synthesis of the evidence we were unable to make a conclusion as to the effectiveness of magnesium for RLS/PLMD. It is not clear whether magnesium helps relieve RLS or PLMD or in which patient groups any benefit might be seen.

Reboxetine and hyoscine butylbromide improve upper airway function during nonrapid eye movement and suppress rapid eye movement sleep in healthy individuals.

STUDY OBJECTIVES: Recent findings indicate that noradrenergic and antimuscarinic processes are crucial for sleep-related reductions in pharyngeal muscle activity. However, there are few human studies. Accordingly, this study aimed to determine if a combined noradrenergic and antimuscarinic intervention increases pharyngeal dilator muscle activity and improves airway function in sleeping humans. METHODS: Genioglossus (GG) and tensor palatini electromyography (EMG), pharyngeal pressure, upper airway resistance, and breathing parameters were acquired in 10 healthy adults (5 female) during two overnight sleep studies after 4 mg of reboxetine (REB) plus 20 mg of hyoscine butylbromide (HBB) or placebo using a double-blind, placebo-controlled, randomized, cross-over design. RESULTS: Compared with placebo, peak and tonic GG EMG were lower (Mean ± SD: 83 ± 73 vs. 130 ± 75, p = 0.021 and 102 ± 102 vs. 147 ± 123 % wakefulness, p = 0.021, respectively) but the sleep-related reduction in tensor palatini was less (Median [25th, 75th centiles]: 53[45, 62] vs. 34[28, 38] % wakefulness, p = 0.008) with the drug combination during nonrapid eye movement (non-REM) sleep. These changes were accompanied by improved upper airway function including reduced pharyngeal pressure swings, airway resistance, respiratory load compensation, and increased breathing frequency during N2. REB and HBB significantly reduced rapid eye movement sleep compared with placebo (0.6 ± 1.1 vs. 14.5 ± 6.8 % total sleep time, p < 0.001). CONCLUSIONS: Contrary to our hypothesis, GG muscle activity (% wakefulness) during non-REM sleep was lower with REB and HBB. However, sleep-related reductions in tensor palatini activity were less and upper airway function improved. These findings provide mechanistic insight into the role of noradrenergic and antimuscarinic processes on upper airway function in humans and have therapeutic potential for obstructive sleep apnea. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, https://www.anzctr.org.au, trial ID: ACTRN12616000469415.

No association between sleep apnoea and macular telangiectasia type 2 and its markers of severity and progression: a case-control study and retrospective cohort study.

IMPORTANCE: Idiopathic Macular Telangiectasia Type 2 (MacTel) is an uncommon, progressive retinal disease usually affecting both eyes. Currently there is no know treatment however with similar comorbidities to Obstructive Sleep Apnoea (OSA) there is plausibility of an association which may accelerate disease progression. BACKGROUND: To identify an association between MacTel and OSA and whether OSA may result in increased disease progression. DESIGN: Matched case-control study and retrospective cohort analysis. PARTICIPANTS: Fifty-seven patients with MacTel and 165 matched controls from the Busselton Health Study. METHODS: MacTel participants were matched based on age, gender and body mass index (BMI) (and where possible hypertension and diabetes) on a 3:1 ratio with controls from the Busselton Health Study. Participants undertook a sleep questionnaire using a previously validated questionnaire. In a subset sleep apnoea severity was objectively measured via overnight ambulatory polygraphy (30 cases and 83 matched controls; ApneaLink device; ResMed, Sydney, Australia). In a retrospective analysis of the suspected MacTel cases we assessed whether major markers of OSA severity and MacTel progression were associated. MAIN OUTCOME MEASURES: Apnoea Hypopnea Index along with key markers of MacTel progression. RESULTS: MacTel patients did not have a higher risk of sleep apnoea when compared to age, sex and BMI -matched controls (mean ± SD Apnoea hypopnea index [AHI] cases 9.6 ± 14.7 vs. controls 9.7 ± 10.8, P = 0.95). No markers of disease progression in the cases were associated with any marker of OSA severity. CONCLUSIONS AND RELEVANCE: Sleep apnoea does not increase the risk or accelerate the progression of MacTel.