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The combination of noradrenergic and anti-muscarinic agents has recently been shown to improve upper-airway function and reduce obstructive sleep apnea (OSA) severity in short-term (≤1 week) proof-of-concept studies.To determine the safety, tolerability, and potential efficacy of longer-term use of different doses of the noradrenergic agent atomoxetine combined with the anti-muscarinic oxybutynin.Thirty-nine people with predominantly severe OSA received either 80mg atomoxetine/5mg oxybutynin (ato-oxy), 40/5mg ato-oxy, 40/2.5mg ato-oxy or placebo nightly for 30 days in a double-blind, randomized, parallel design. Participants completed three in-laboratory sleep studies (baseline, night 1, night 30) to assess efficacy. Vital signs and objective measures of alertness and memory were assessed. In men, potential effects on prostate function were assessed using the International Prostate Symptom Score (IPSS) at baseline and night 30. Potential adverse events were assessed during in-lab visits and via weekly phone calls.Side effects were generally mild and consistent with known side-effect profiles of each individual drug (i.e., dose-dependent increases in dry mouth with oxybutynin). Heart rate increased by night 30 in two active drug arms (mean±SD: 8±10 beats/min, p=0.01, 80/5mg; 9±14 beats/min, p=0.02, 40/2.5mg; versus placebo). No clinically relevant changes to blood pressure, IPSS and measures of alertness and memory were observed between conditions. Apnoea-hypopnea index (4% oxygen desaturation: AHI4) and hypoxic burden decreased by ~50% with 80/5mg ato-oxy from baseline but not versus placebo (e.g., AHI3 and AHI4 difference [95%CI] at night 30= -8.2 [-22.5, 6.2] and -8.5 [-18.3, 1.3] events/h, respectively).1 month of nightly noradrenergic and anti-muscarinic combination therapy was generally well-tolerated with a side effect profile consistent with each agent alone and was associated with an ~50% reduction from baseline in a key OSA severity metric, the hypoxic burden with the highest dose combination. These findings highlight the potential to target noradrenergic and anti-muscarinic mechanisms for OSA pharmacotherapy development.ACTRN12619001153101.

STUDY OBJECTIVES: Sleep microarchitecture parameters determined by quantitative power spectral analysis of electroencephalograms have been proposed as potential brain-specific markers of cognitive dysfunction. However, data from community samples remain limited. This study examined cross-sectional associations between sleep microarchitecture and cognitive dysfunction in community-dwelling men. METHODS: Florey Adelaide Male Ageing Study participants (n = 477) underwent home-based polysomnography (2010–2011). All-night electroencephalogram recordings were processed using quantitative power spectral analysis following artifact exclusion. Cognitive testing (2007–2010) included the inspection time task, Trail-Making Tests A and B, and Fuld object memory evaluation. Complete case cognition, polysomnography, and covariate data were available in 366 men. Multivariable linear regression models controlling for demographic, biomedical, and behavioral confounders determined cross-sectional associations between sleep microarchitecture and cognitive dysfunction overall and by age-stratified subgroups. RESULTS: In the overall sample, worse Trail-Making Test A performance was associated with higher rapid eye movement (REM) theta and alpha and non-REM theta but lower delta power (all P

Objectives Exergame training is a promising method for delivering evidence-based fall prevention exercise as it can facilitate exercise adherence and can be tailored to address cognitive and motor risk factors for falls. This study examined the effectiveness of two home-based computer game interventions (seated brain training and step training; smart±step) in preventing falls in community-dwelling older people, compared to a minimal-intervention control group. Design Assessor-blinded, randomised controlled trial. Setting Research institute and homes of older people living in the community of Sydney, Australia. Participants 769 people aged 65+ years living independently in the community and free of cognitive impairment, progressive neurological disease, or any other unstable or acute medical condition that precludes exercise. Interventions Participants were randomised to one of three arms: brain training using a computerised touch pad while seated; exergame step training on a computerised mat; or control. The intervention groups were provided with a home-based training system and were asked to train for at least two hours per week over the 12-month trial. Main outcome measures The primary outcome was the rate of falls reported monthly over 12 months. Results Between October 2016 and May 2019, 769 participants were randomised (seated brain training =262, exergame step training=252, control=255) and all were included in the intention-to-treat analyses. The rate of falls over 12 months was significantly reduced in the exergame step training group compared to control (IRR=0.74, 95%CI=0.56 to 0.98) and was not statistically different between the seated brain training and control groups (IRR=0.86, 95%CI=0.65 to 1.12). No serious intervention-related adverse events were reported. Conclusions A home-based exergame step training program provides a safe and effective means for preventing falls in older people living in the community. As this intervention can be conducted at home and requires only minimal equipment, it has the potential for scalability as a public health intervention to address the increasing problem of falls and fall-related injuries. Trial registration Australian and New Zealand Clinical Trial Registry ACTRN12616001325493, registered 22 September 2016.

Tongue and upper airway dilator muscle movement patterns during quiet breathing vary in people with obstructive sleep apnea (OSA). Many patients have inadequate or counterproductive responses to inspiratory negative airway pressure that likely contributes to their OSA. This may be due, at least in part, to inadequate or nonhomogeneous reflex drive to different regions of the largest upper airway dilator, genioglossus. To investigate potential regional heterogeneity of genioglossus reflex responses in OSA, brief suction pulses were applied via a nasal breathing mask and an electromyogram (EMG) was recorded in four regions (anterior oblique, anterior horizontal, posterior oblique, and posterior horizontal) using intramuscular fine wire electrodes in 15 people with OSA. Genioglossus short-latency reflex excitation amplitude had regional heterogeneity (horizontal vs. oblique regions) when expressed in absolute units but homogeneity when normalized as a percentage of the immediate (100 ms) prestimulus EMG. Regional variability in reflex morphology (excitation and inhibition) was present in one-third of the participants. The minimum cross-sectional area (CSA) of the pharyngeal airway was quantified using MRI and may be related to the amplitude of the short-latency reflex response to negative pressure as we found that people with a smaller CSA tended to have a greater reflex amplitude (e.g., horizontal region

Obstructive sleep apnea (OSA) is common in people with multiple sclerosis (MS). However, people with MS often do not have "typical" anatomical risk factors (i.e., nonobese and female predominance). Accordingly, nonanatomical factors such as impaired upper-airway muscle function may be particularly important for OSA pathogenesis in MS. Therefore, this study aimed to investigate genioglossus (largest upper-airway dilator muscle) reflex responses to brief pulses of upper-airway negative pressure in people with OSA and MS. Eleven people with MS and OSA and 10 OSA controls without MS matched for age, sex, and OSA severity were fitted with a nasal mask, pneumotachograph, choanal and epiglottic pressure sensors, and intramuscular electrodes into genioglossus. Approximately 60 brief (250 ms) negative pressure pulses (approximately -12 cmH

Introduction Upper airway sensory impairment may contribute to obstructive sleep apnea (OSA) for certain patients. However, the type of sensory impairment and its role in OSA pathogenesis remain unclear. This study aimed to: (1) evaluate methods of upper airway sensory testing in the OSA literature, (2) compare upper airway sensation in people with and without OSA and (3) investigate the relationship between OSA severity and upper airway sensory impairment. Methods Electronic databases were searched up to February 2020 for studies reporting methods of upper airway sensory testing in people with OSA (n=3,819). From the selected studies (n=38), information on the type of sensation, testing methods, validity and reliability were extracted. Meta-analyses were performed on case-controlled studies and studies reporting correlations between upper airway sensation and OSA severity. Results Seven types of upper airway sensation were reported: olfactory, gustatory, chemical, tactile, vibratory, thermal and neuro-sensation. Methods of upper airway sensory testing varied. No tests were validated or assessed for reliability in OSA populations. People with OSA had impaired sensation on airflow (p Conclusions People with OSA demonstrated impaired upper airway sensation, which related to increasing OSA severity. The extent to which upper airway sensation was impaired varied across testing methods. The findings suggest that development of valid and reliable upper airway sensory tests, that relate to upper airway function in people with OSA, are necessary for future clinical and research practices.

Impaired upper airway sensation may contribute to obstructive sleep apnea (OSA) pathophysiology and could represent a therapeutic target. However, the extent of impaired sensation and its functional role in OSA pathogenesis remains unclear. This study aimed to: 1) evaluate methods of upper airway sensory testing in people with OSA, 2) compare upper airway sensation in people with and without OSA and 3) investigate the potential relationship between upper airway sensation and OSA severity. Major electronic databases were searched for studies that reported methods of upper airway sensory testing in people with OSA (n = 3819). From the selected studies (n = 38), information on the type of sensation, testing methods, validity and test-retest reliability were extracted. Meta-analyses were performed on case-controlled studies and studies that investigated potential relationships between upper airway sensation and OSA severity. Seven categories of sensory tests were reported: olfactory, gustatory, chemical, tactile, vibratory, thermal and perioral neuro-sensation. Testing methods varied widely across studies. No tests were validated in OSA. People with OSA had impaired upper airway sensation to airflow (p = 0.0002), chemical (p = 0.0001), gustatory (p = 0.009), olfactory (p = 0.04), tactile (p = 0.0001) and vibratory (p = 0.005) stimuli. Upper airway sensory impairment increased with OSA severity (p 0.001). These findings suggest that, while variable across testing methods, people with OSA have impaired upper airway sensation, which is related to increased OSA severity. Development of valid and reliable upper airway sensory testing methods that relate to upper airway function in people with OSA are required to inform future clinical and research practices and identify potential therapeutic targets.