Conformation of a Polyelectrolyte Complexed to a Like-Charged Colloid

We report results from a molecular dynamics (MD) simulation on the conformations of a long flexible polyelectrolyte complexed to a charged sphere, \textit{both negatively charged}, in the presence of neutralizing counterions in the strong Coulomb coupling regime. The structure of this complex is very sensitive to the charge density of the polyelectrolyte. For a fully charged polyelectrolyte the polymer forms a dense two-dimensional "disk", whereas for a partially charged polyelectrolyte the monomers are spread over the colloidal surface. A mechanism involving the \textit{overcharging} of the polyelectrolyte by counterions is proposed to explain the observed conformations.Comment: 4 pages, 4 figures (6 EPS files

The norepinephrine reuptake inhibitor reboxetine alone reduces obstructive sleep apnea severity: a double-blind, placebo-controlled, randomized crossover trial

Study objectives: Recent findings indicate that noradrenergic and muscarinic processes are crucial for pharyngeal muscle control during sleep. However, to date, reductions in obstructive sleep apnea (OSA) severity have only been detected when noradrenergic agents are combined with an antimuscarinic. Accordingly, this study aimed to determine if reboxetine alone and combined with oxybutynin reduces OSA severity. The pathophysiological mechanisms underpinning the effects of these agents were also investigated via endotyping analysis. Methods: Sixteen people (6 women) with OSA completed 3 polysomnograms (∼1-week washout) according to a double-blind, placebo-controlled, three-way crossover design across 2 sites. Single doses of 4 mg reboxetine, placebo, or 4 mg reboxetine + 5 mg oxybutynin were administered before sleep (order randomized). Results: Reboxetine reduced the apnea-hypopnea index (primary outcome) by 5.4 (95% confidence interval -10.4 to -0.3) events/h, P = .03 (-24 ± 27% in men; -0.7 ± 32% in women). Oxybutynin did not cause additional reductions in apnea-hypopnea index. Reboxetine alone reduced the 4% oxygen desaturation index by (mean ± standard deviation) 5.2 ± 7.2 events/h and reboxetine+oxybutynin by 5.1 ± 10.6 events/h vs placebo, P = .02. Nadir oxygen saturation also increased by 7 ± 11% with reboxetine and 5 ± 9% with reboxetine+oxybutynin vs placebo, P = .01. Mechanistically, reboxetine and reboxetine+oxybutynin improved pharyngeal collapsibility and respiratory control (loop gain). Larger reductions in apnea-hypopnea index with reboxetine in men were associated with higher baseline loop gain. Conclusions: These findings show the first evidence that reboxetine alone reduces OSA severity. The data provide novel insight into the role of norepinephrine reuptake inhibitors on upper airway stability during sleep and are important to inform future pharmacotherapy development for OSA.Thomas J. Altree, Atqiya Aishah, Kelly A. Loffler, Ronald R. Grunstein, Danny J. Ecker

The effect of acute morphine on sleep in male patients suffering from sleep apnea: Is there a genetic effect? An RCT study

Questionnaire-based studies have suggested genetic differences in sleep symptoms in chronic opioid users. The present study aims to investigate if there is a genetic effect on sleep architecture and quantitative electroencephalogram (EEG) in response to acute morphine. Under a randomized, double-blind, placebo-controlled, crossover design, 68 men with obstructive sleep apnea undertook two overnight polysomnographic studies conducted at least 1 week apart. Each night they received either 40 mg of controlled-release morphine or placebo. Sleep architecture and quantitative EEG were compared between conditions. Blood was sampled before sleep and on the next morning for genotyping and pharmacokinetic analyses. We analysed three candidate genes (OPRM1 [rs1799971, 118 A > G], ABCB1[rs1045642, 3435 C > T] and HTR3B [rs7103572 C > T]). We found that morphine decreased slow wave sleep and rapid eye movement sleep and increased stage 2 sleep. Those effects were less in subjects with HTR3B CT/TT than in those with CC genotype. Similarly, sleep onset latency was shortened in the ABCB1 CC subgroup compared with the CT/TT subgroup. Total sleep time was significantly increased in ABCB1 CC but not in CT/TT subjects. Sleep apnea and plasma morphine and metabolite concentration were not confounding factors for these genetic differences in sleep. With morphine, patients had significantly more active/unstable EEG (lower delta/alpha ratio) during sleep. No genetic effects on quantitative EEG were detected. In summary, we identified two genes (HTR3B and ABCB1) with significant variation in the sleep architecture response to morphine. Morphine caused a more active/unstable EEG during sleep. Our findings may have relevance for a personalized medicine approach to targeted morphine therapy.Luke Rowsell, Justin Guang-Ao Wu, Brendon J. Yee, Keith K.H. Wong, Sheila Sivam, Andrew A. Somogyi, Ronald R. Grunstein, David Wan

Brain mitochondrial dysfunction and driving simulator performance in untreated obstructive sleep apnea

First published: 15 September 2021 OnlinePublIt is challenging to determine which patients with obstructive sleep apnea (OSA) have impaired driving ability. Vulnerability to this neurobehavioral impairment may be explained by lower brain metabolites levels involved in mitochondrial metabolism. This study compared markers of brain energy metabolism in OSA patients identified as vulnerable vs resistant to driving impairment following extended wakefulness. 44 patients with moderate-severe OSA underwent 28hr extended wakefulness with three 90min driving simulation assessments. Using a two-step cluster analysis, objective driving data (steering deviation and crashes) from the 2nd driving assessment (22.5 h awake) was used to categorise patients into vulnerable (poor driving, n = 21) or resistant groups (good driving, n = 23). 1H magnetic resonance spectra were acquired at baseline using two scan sequences (short echo PRESS and longer echo-time asymmetric PRESS), focusing on key metabolites, creatine, glutamate, N-acetylaspartate (NAA) in the hippocampus, anterior cingulate cortex and left orbito-frontal cortex. Based on cluster analysis, the vulnerable group had impaired driving performance compared with the resistant group and had lower levels of creatine (PRESS p = ns, APRESS p = 0.039), glutamate, (PRESS p < 0.01, APRESS p < 0.01), NAA (PRESS p = 0.038, APRESS p = 0.035) exclusively in the left orbito-frontal cortex. Adjusted analysis, higher glutamate was associated with a 21% (PRESS) and 36% (APRESS) reduced risk of vulnerable classification. Brain mitochondrial bioenergetics in the frontal brain regions are impaired in OSA patients who are vulnerable to driving impairment following sleep loss. These findings provide a potential way to identify at risk OSA phenotype when assessing fitness to drive, but this requires confirmation in larger future studies.Andrew Vakulin, Michael A. Green, Angela L. D’Rozario, David Stevens, Hannah Openshaw, Delwyn Bartlett ... et al

One Month Dosing of Atomoxetine plus Oxybutynin in Obstructive Sleep Apnea: A Randomized, Placebo-controlled Trial.

RATIONALE: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: ACTRN12619001153101.Atqiya Aishah, Kelly A. Loffler, Barbara Toson, Sutapa Mukherjee, Robert J. Adams, Thomas J. Altree, Henry W. Ainge-Allen, Brendon J. Yee, Ronald R. Grunstein, Jayne C. Carberry, and Danny J. Ecker

Assessment, referral and management of obstructive sleep apnea by Australian general practitioners: a qualitative analysis

BACKGROUND: The high and increasing demand for obstructive sleep apnea (OSA) care has exceeded the capacity of specialist sleep services prompting consideration of whether general practitioners could have an enhanced role in service delivery. However, little is known about the current involvement, experiences and attitudes of Australian general practitioners towards OSA. The purpose of this study was to provide an in-depth analysis of Australian general practitioners' experiences and opinions regarding their care of patients with OSA to inform the design and implementation of new general practice models of care. METHODS: Purposive sampling was used to recruit participants with maximum variation in age, experience and location. Semi-structured interviews were conducted and were analysed using Thematic Analysis. RESULTS: Three major themes were identified: (1) General practitioners are important in recognising symptoms of OSA and facilitating a diagnosis by others; (2) Inequities in access to the assessment and management of OSA; and (3) General practitioners currently have a limited role in the management of OSA. CONCLUSIONS: When consulting with patients with symptoms of OSA, general practitioners see their primary responsibility as providing a referral for diagnosis by others. General practitioners working with patients in areas of greater need, such as rural/remote areas and those of socio-economic disadvantage, demonstrated interest in being more involved in OSA management. Inequities in access to assessment and management are potential drivers for change in future models of care for OSA in general practice.Nicole Grivell, Jenny Haycock, Anne Redman, Andrew Vakulin, Nicholas Zwar, Nigel Stocks ... et al

Predictors of weight loss in obese patients with obstructive sleep apnea

Vol. 26 pp 753-762Purpose: Consistent predictors of weight loss outcomes with very low-energy diets (VLEDs) in obstructive sleep apnea (OSA) have not been identified. This study aimed to identify variables predictive of weight loss success in obese patients with OSA undertaking an intensive weight loss programme. Methods: We analysed biological, psychological, and behavioural variables as potential predictors of weight loss in obese patients with OSA after a 2-month VLED followed by one of two 10-month weight loss maintenance diets. Actigraphy, in-lab polysomnography, urinary catecholamines, and various psychological and behavioural variables were measured at baseline, 2, and 12 months. Spearman’s correlations analysed baseline variables with 2-month weight loss, and 2-month variables with 2–12 month-weight change. Results: Forty-two patients completed the VLED and thirty-eight completed the maintenance diets. Actigraphy data revealed that late bedtime (rs =  − 0.45, p =  < 0.01) was correlated with 2-month weight loss. The change in the time that participants got out of bed (rise-time) from baseline to two months was also correlated with 2-month weight loss (rs = 0.36, p = 0.03). The Impact of Weight on Quality of Life-Lite questionnaire (IWQOL) Public Distress domain (rs =  − 0.54, p =  < 0.01) and total (rs =  − 0.38, p = 0.02) scores were correlated with weight loss maintenance from 2 to 12 months. Conclusions: Results from this small patient sample reveal correlations between actigraphy characteristics and weight loss in obese patients with OSA. We suggest the IWQOL may also be a useful clinical tool to identify OSA patients at risk of weight regain after initial weight loss.Thomas J. Altree, Delwyn J. Bartlett, Nathaniel S. Marshall, Camilla M. Hoyos, Craig L. Phillips, Callum Birks, Aran Kanagaratnam, Anna Mullins, Yasmina Serinel, Keith K.H. Wong, Brendon J. Yee, Ronald R. Grunstein, Elizabeth A. Cayana

Light-based methods for predicting circadian phase in delayed sleep–wake phase disorder

Methods for predicting circadian phase have been developed for healthy individuals. It is unknown whether these methods generalize to clinical populations, such as delayed sleep-wake phase disorder (DSWPD), where circadian timing is associated with functional outcomes. This study evaluated two methods for predicting dim light melatonin onset (DLMO) in 154 DSWPD patients using ~ 7 days of sleep-wake and light data: a dynamic model and a statistical model. The dynamic model has been validated in healthy individuals under both laboratory and field conditions. The statistical model was developed for this dataset and used a multiple linear regression of light exposure during phase delay/advance portions of the phase response curve, as well as sleep timing and demographic variables. Both models performed comparably well in predicting DLMO. The dynamic model predicted DLMO with root mean square error of 68 min, with predictions accurate to within ± 1 h in 58% of participants and ± 2 h in 95%. The statistical model predicted DLMO with root mean square error of 57 min, with predictions accurate to within ± 1 h in 75% of participants and ± 2 h in 96%. We conclude that circadian phase prediction from light data is a viable technique for improving screening, diagnosis, and treatment of DSWPD.Jade M. Murray, Michelle Magee, Tracey L. Sletten, Christopher Gordon, Nicole Lovato, Krutika Ambani ... et al