Motor-evoked potentials in the human upper and lower limb do not increase after single 30-min sessions of acute intermittent hypoxia.

Acute intermittent hypoxia (AIH) can induce sustained facilitation of motor output in people with spinal cord injury (SCI). Most studies of corticospinal tract excitability in humans have used 9% fraction inspired oxygen ([Formula: see text]) AIH (AIH-9%), with inconsistent outcomes. We investigated the effect of single sessions of 9% [Formula: see text] and 12% [Formula: see text] AIH (AIH-12%) on corticospinal excitability of a hand and leg muscle in able-bodied adults. Ten naïve participants completed three sessions on separate days comprising 15 epochs of 1 min of AIH-9%, AIH-12%, or sham (SHAM-21%) followed by 1 min of room air (21% [Formula: see text]) in a randomized crossover design. Motor-evoked potentials (MEPs; n = 30, ∼1 mV) elicited at rest by transcranial magnetic stimulation and maximal M-waves (Mmax) evoked by peripheral nerve stimulation were measured from the first dorsal interosseous (FDI) and tibialis anterior (TA) muscles at baseline and at ∼0, 20, 40, and 60 min post intervention. AIH-9% induced the greatest reduction in peripheral oxygen saturation (to 85% vs. 93% and 100% in AIH-12% and SHAM-21%, respectively; P < 0.001) and the greatest increase in ventilation [by 22% vs. 12% and -3% in AIH-9%, AIH-12%, and SHAM-21%, respectively (P < 0.001)]. There was no difference in MEP amplitudes (%Mmax) after any of the three conditions (AIH-9%, AIH-12%, SHAM-21%) for both the FDI (P = 0.399) and TA (P = 0.582). Despite greater cardiorespiratory changes during AIH-9%, there was no evidence of corticospinal facilitation (tested with MEPs) in this study. Further studies could explore variability in response to AIH between individuals and other methods to measure motor facilitation in people with and without spinal cord injuries.NEW & NOTEWORTHY This is the first study that tests whether acute intermittent hypoxia (AIH) induces motor output facilitation in humans after two different doses of AIH (9% and 12% [Formula: see text]) and the reproducibility of participant responses after a repeat AIH intervention at 9% AIH. There was no motor output facilitation in response to either dose of AIH. The results question the effectiveness of a single 30-min session of AIH in inducing motor output facilitation, tested in this way.

Anti-racist interventions to reduce ethnic disparities in healthcare in the UK: an umbrella review and findings from healthcare, education and criminal justice.

OBJECTIVES: To assess the evidence for anti-racist interventions which aim to reduce ethnic disparities in healthcare, with a focus on implementation in the UK healthcare system. DESIGN: Umbrella review. DATA SOURCES: Embase, Medline, Social Policy and Practice, Social Care Online and Web of Science were searched for publications from the year 2000 up to November 2023. ELIGIBILITY CRITERIA: Only systematic and scoping reviews of anti-racist interventions reported in English were included. Reviews were excluded if no interventions were reported, no comparator interventions were reported or the study was primarily descriptive. DATA EXTRACTION AND SYNTHESIS: A narrative synthesis approach was used to integrate and categorise the evidence on anti-racist interventions for healthcare. Quality appraisal (including risk of bias) was assessed using the AMSTAR-2 tool. RESULTS: A total of 29 reviews are included in the final review. 26 are from the healthcare sector and three are from education and criminal justice. The most promising interventions targeting individuals include group-based health education and providing culturally tailored interventions. On a community level, participation in all aspects of care pathway development that empowers ethnic minority communities may provide an effective approach to reducing ethnic health disparities. Interventions to improve quality of care for conditions with disproportionately worse outcomes in ethnic minority communities show promise. At a policy level, structural interventions including minimum wage policies and integrating non-medical interventions such as housing support in clinical care has some evidence for improving outcomes in ethnic minority communities. CONCLUSIONS: Many of the included studies were low or critically low quality due to methodological or reporting limitations. For programme delivery, different types of pathway integration, and providing a more person-centred approach with fewer steps for patients to navigate can contribute to reducing disparities. For organisations, there is an overemphasis on individual behaviour change and recommendations should include a shift in focus and resources to policies and practices that seek to dismantle institutional and systemic racism through a multilevel approach.

A Systematic Review of Physical Activity and Sedentary Behavior Patterns in an Osteoarthritic Population.

OBJECTIVE: To explore physical activity (PA) and sedentary behaviors (SB) in individuals with lower limb (LL) Osteoarthritis (OA) and the influence of age, sex, and body mass index (BMI) on these behaviors. DESIGN: Systematic review search: PubMed, Cochrane Library, ScienceDirect, and CINAHL databases were searched from inception until July 2023. Study criteria: Studies that reported quantifiable device-based or self-reported data for PA and SB variables in adults clinically diagnosed with LL OA were included. DATA SYNTHESIS: A synthesis of PA and SB levels for those diagnosed with LL OA and the influence age, sex, and BMI have on these behaviors. RESULTS: From the 1930 studies identified through the electronic search process, 48 met the inclusion criteria. PA guidelines were met by 33% of the sample population that measured moderate and moderate to vigorous PA. No studies reported 75 minutes per week or more of vigorous PA. Additionally, 58% of the population reporting SB were sedentary for 8 hours per day or more. Also, increasing age, BMI, and the female sex were identified as negative influences on PA levels. There were numerous methodological inconsistencies in how data were collected and reported, such as various activity monitor cut points for PA and SB bout duration. CONCLUSION: Adults with LL OA may be at an increased risk of noncommunicable diseases due to low PA and high SB levels. It is important to consider age, sex, and BMI when investigating behavior patterns in those with LL OA.

Improved Physical Health in Middle-Older Aged Golf Caddies Following 24 Weeks of High-Volume Physical Activity.

BACKGROUND: The physical demands of golf caddying, including walking while carrying a golf bag, may potentially affect body composition, and markers of metabolic, cardiovascular, and musculoskeletal health. Therefore, this study examined the impact of 24 weeks of caddying on physical health in middle-older aged males. METHODS: Eleven full-time experienced male caddies (age: 59 [8] y; caddying experience: 14 [12] y) were recruited from a local golf course. The following were assessed at preseason and after 24 weeks of caddying (March-September 2022): body composition, heart rate, blood pressure, blood lipids, and performance tests (static and dynamic balance, strength, and submaximal fitness). Physical activity (PA) levels were assessed at preseason and at the mid-point of the caddying season. Across the caddying season, participants completed a monthly average of 24.0 (3.8) rounds. RESULTS: Following the caddying season, improvements in static balance (Δ = 13.5 s), dynamic balance (Δ = -1.8 s), and lower back absolute strength (Δ = 112.8 N), and muscle quality (Δ = 2.0 N·kg-1) were observed (all P < .05). Additionally, blood lipids, including total cholesterol (Δ = -0.6 mmol·L-1), high-density lipoprotein cholesterol (Δ = 0.1 mmol·L-1), low-density lipoprotein cholesterol (Δ = -0.6 mmol·L-1) (all P < .05), and body composition, including body mass (Δ = -2.7 kg), fat mass (Δ = -1.9 kg), fat percentage (Δ = -1.4%), fat-to-muscle ratio (Δ = -0.03), and body mass index (Δ = -0.9 kg·m-2) (all P < .05) improved. Caddying did not offer beneficial changes to cardiovascular variables or cardiorespiratory fitness (P > .05), while coronary heart disease risk score decreased (Δ = -3.3%) (P < .05). In relation to PA, light- (Δ = 145 min) and moderate-intensity (Δ = 71 min) PA, moderate to vigorous PA (Δ = 73 min), and total PA (Δ = 218 min) between preseason and the mid-point of the caddying season increased, while sedentary time (Δ = -172 min) decreased (all P < .05). CONCLUSION: Golf caddying can provide several physical health benefits such as improvements in various markers of cardiometabolic health, lower back absolute strength, and static and dynamic balance. The physical health improvements that caddying offers is likely contributed to by increased PA volume and intensity through walking on the golf course. Therefore, caddying may represent a feasible model for increasing PA volume and intensity and achieve physical health-related benefits.

The effect of a 2-week ischaemic preconditioning intervention on anaerobic performance in male academy football players: a randomized, single-blinded, SHAM-Controlled study.

Ischaemic preconditioning (IPC), brief periods of ischaemia immediately followed by reperfusion applied to a vascular bed, has emerged as a method to improve exercise performance. There is, however, a lack of research exploring repeated episodes of IPC on anaerobic performance. The aim of this study was to determine if a 2-week repeated IPC intervention could enhance anaerobic performance in male academy football players. Eight male academy football players completed two, 2-week intervention trials: six IPC episodes (4 × 5 min at 220 mmHg per episode), and six SHAM episodes (4 × 5 min at 20 mmHg per episode). Prior to and following each intervention trial, the participants completed assessments of anaerobic performance (Running Anaerobic Sprint Test [RAST]), and superficial femoral artery endothelial function (flow-mediated dilation [FMD]). IPC significantly enhanced peak and mean power output by 12% (p = 0.026) and 11% (p = 0.019) and significantly improved superficial femoral artery FMD (p = 0.049). The increase in endothelial function suggests that this may be a mechanism contributing to this enhancement of anaerobic performance. The present study supports the use of repeated IPC prior to matches and training sessions to enhance anaerobic performance.

Respiratory-related evoked potentials in chronic obstructive pulmonary disease and healthy aging.

Altered neural processing and increased respiratory sensations have been reported in chronic obstructive pulmonary disease (COPD) as larger respiratory-related evoked potentials (RREPs), but the effect of healthy-aging has not been considered adequately. We tested RREPs evoked by brief airway occlusions in 10 participants with moderate-to-severe COPD, 11 age-matched controls (AMC) and 14 young controls (YC), with similar airway occlusion pressure stimuli across groups. Mean age was 76 years for COPD and AMC groups, and 30 years for the YC group. Occlusion intensity and unpleasantness was rated using the modified Borg scale, and anxiety rated using the Hospital Anxiety and Depression Scale. There was no difference in RREP peak amplitudes across groups, except for the N1 peak, which was significantly greater in the YC group than the COPD and AMC groups (p = 0.011). The latencies of P1, P2 and P3 occurred later in COPD versus YC (p < 0.05). P3 latency occurred later in AMC than YC (p = 0.024). COPD and AMC groups had similar Borg ratings for occlusion intensity (3.0 (0.5, 3.5) [Median (IQR)] and 3.0 (3.0, 3.0), respectively; p = 0.476) and occlusion unpleasantness (1.3 (0.1, 3.4) and 1.0 (0.75, 2.0), respectively; p = 0.702). The COPD group had a higher anxiety score than AMC group (p = 0.013). A higher N1 amplitude suggests the YC group had higher cognitive processing of respiratory inputs than the COPD and AMC groups. Both COPD and AMC groups showed delayed neural responses to the airway occlusion, which may indicate impaired processing of respiratory sensory inputs in COPD and healthy aging.

The impact of age, sex, cardio-respiratory fitness, and cardiovascular disease risk on dynamic cerebral autoregulation and baroreflex sensitivity.

BACKGROUND: Humans display an age-related decline in cerebral blood flow and increase in blood pressure (BP), but changes in the underlying control mechanisms across the lifespan are less well understood. We aimed to; (1) examine the impact of age, sex, cardiovascular disease (CVD) risk, and cardio-respiratory fitness on dynamic cerebral autoregulation and cardiac baroreflex sensitivity, and (2) explore the relationships between dynamic cerebral autoregulation (dCA) and cardiac baroreflex sensitivity (cBRS). METHODS: 206 participants aged 18-70 years were stratified into age categories. Cerebral blood flow velocity was measured using transcranial Doppler ultrasound. Repeated squat-stand manoeuvres were performed (0.10 Hz), and transfer function analysis was used to assess dCA and cBRS. Multivariable linear regression was used to examine the influence of age, sex, CVD risk, and cardio-respiratory fitness on dCA and cBRS. Linear models determined the relationship between dCA and cBRS. RESULTS: Age, sex, CVD risk, and cardio-respiratory fitness did not impact dCA normalised gain, phase, or coherence with minimal change in all models (P > 0.05). cBRS gain was attenuated with age when adjusted for sex and CVD risk (young-older; ß = - 2.86 P < 0.001) along with cBRS phase (young-older; ß = - 0.44, P < 0.001). There was no correlation between dCA normalised gain and phase with either parameter of cBRS. CONCLUSION: Ageing was associated with a decreased cBRS, but dCA appears to remain unchanged. Additionally, our data suggest that sex, CVD risk, and cardio-respiratory fitness have little effect.

Are acute sitting-induced changes in inflammation and cerebrovascular function related to impaired mood and cognition?

PURPOSE: Sedentary behaviour is negatively associated with mood and cognition, yet how acute sitting contributes to these overall associations is unknown. Since sitting heightens inflammation and impairs cerebrovascular function, this study investigated the hypothesis that these sitting-induced changes are related to impaired mood and cognition. METHODS: Twenty-five healthy desk workers (18 male, 28.3 ± 7.5 years, BMI: 24.2 ± 3.3 kg∙m-2) were recruited. During laboratory visit one, participants were familiarised with cognitive performance tests measuring executive function, attention and working memory. During laboratory visit two, participants completed 6 h of continuous, uninterrupted sitting. At baseline and after 6 h, serum markers of inflammation, middle cerebral artery blood flow velocity (MCAv), cerebrovascular carbon dioxide reactivity (CVR), dynamic cerebral autoregulation (CA), cognitive performance and mood (positive and negative affect, alert, contented and calm) were assessed. Data were analysed using paired-samples t tests and correlation analyses. RESULTS: Following sitting, C-reactive protein (∆-1.0 µg/ml) and tissue plasminogen activator (∆-360.4 pg/ml) decreased (p < 0.05), MCAv reduced (∆-2.9 cm∙s-1, p = 0.012) and normalised gain increased in the very low frequency range, indicating impaired CA (∆ + 0.22%·mmHg-1, p = 0.016). Positive affect (∆-4.6, p < 0.001), and alert (∆-10.6 p = 0.002) and contented (∆-7.4, p = 0.006) mood states also decreased following sitting. No significant changes in interleukin-6, tumour necrosis factor-alpha, von Willebrand factor, CVR or cognitive performance were observed (p > 0.05). The observed changes in inflammation and cerebrovascular function were not related to changes in mood (p > 0.05). CONCLUSION: Alterations in inflammation or cerebrovascular function following six hours of prolonged, uninterrupted sitting are not related to the observed reductions in mood, indicating other mechanisms underlie the relationship between acute sitting and mood disturbances.

Addition of zolpidem to combination therapy with atomoxetine-oxybutynin increases sleep efficiency and the respiratory arousal threshold in obstructive sleep apnoea: A randomized trial.

BACKGROUND AND OBJECTIVE: Atomoxetine combined with oxybutynin (Ato-Oxy) has recently been shown to reduce obstructive sleep apnoea (OSA) severity by >60%. However, Ato-Oxy also modestly reduced the respiratory arousal threshold, which may decrease sleep quality/efficiency. We sought to investigate the additional effect of zolpidem with Ato-Oxy on sleep efficiency (primary outcome), the arousal threshold, OSA severity, other standard polysomnography (PSG) parameters, next-day sleepiness and alertness (secondary outcomes). METHODS: Twelve participants with OSA received 10 mg zolpidem plus Ato-Oxy (80-5 mg, respectively) or Ato-Oxy plus placebo prior to overnight in-laboratory PSG according to a double-blind, randomized, crossover design (1-week washout). Participants were fitted with an epiglottic catheter, a nasal mask and pneumotachograph to quantify arousal threshold and airflow. Next-day sleepiness and alertness were assessed via the Karolinska Sleepiness Scale and a driving simulation task. RESULTS: The addition of zolpidem increased sleep efficiency by 9% ± 13% (80.9% ± 16.9% vs. 88.2% ± 8.2%, p = 0.037) and the respiratory arousal threshold by 17% ± 18% (-26.6 ± 14.5 vs. -33.8 ± 20.3 cm H2 O, p = 0.004) versus Ato-Oxy + placebo. Zolpidem did not systematically change OSA severity. Combination therapy was well tolerated, and zolpidem did not worsen next-day sleepiness. However, median steering deviation during the driving simulator task increased following the zolpidem combination. CONCLUSION: Zolpidem improves sleep efficiency via an increase in the respiratory arousal threshold to counteract potential wake-promoting properties of atomoxetine in OSA. These changes occur without altering the rate of respiratory events or overnight hypoxaemia. However, while the addition of zolpidem does not increase next-day perceived sleepiness, caution is warranted given the potential impact on next-morning objective alertness.

Developing and user testing new pharmacy label formats-A study to inform labelling standards.

BACKGROUND: Dispensed prescription medicine labels (prescription labels) are important information sources supporting safe and appropriate medicines use. OBJECTIVE: To develop and user test patient-centred prescription label formats. METHODS: Five stages: developing 12 labels for four fictitious medicines of varying dosage forms; diagnostic user testing of labels (Round 1) with 40 consumers (each testing three labels); iterative label revision, and development of Round 2 labels (n = 7); user testing of labels (Round 2) with 20 consumers (each testing four labels); labelling recommendations. Evaluated labels stated the active ingredient and brand name, using various design features (eg upper case and bold). Dosing was expressed differently across labels: frequency of doses/day, approximate times of day (eg morning), explicit times (eg 7 to 9 AM), and/or explicit dosing interval. Participants' ability to find and understand medicines information and plan a dosing schedule were assessed. RESULTS: Participants demonstrated satisfactory ability to find and understand the dosage for all label formats. Excluding active ingredient and dosing schedule, 14/19 labels (8/12 in Round 1; 6/7 in Round 2) met industry standard on performance. Participants' ability to correctly identify the active ingredient varied, with clear medicine name sign-posting enabling all participants evaluating these labels to find and understand the active ingredient. When planning a dosing schedule, doses were correctly spaced if the label stated a dosing interval, or frequency of doses/day. Two-thirds planned appropriate dosing schedules using a dosing table. CONCLUSIONS: Effective prescription label formatting and sign-posting of active ingredient improved communication of information on labels, potentially supporting safe medicines use. PATIENT AND PUBLIC INVOLVEMENT: Consumers actively contributed to the development of dispensed prescription medicine labels. Feedback from consumers following the first round was incorporated in revisions of the labels for the next round. Patient and public involvement in this study was critical to the development of readable and understandable dispensed prescription medicine labels.

Effects of hypnotics on obstructive sleep apnea endotypes and severity: Novel insights into pathophysiology and treatment.

Impaired upper airway anatomy is the main cause of obstructive sleep apnea (OSA). However, there are other important non-anatomical contributors or "endotypes" including ventilatory control instability, poor pharyngeal dilator muscle responsiveness and waking up too easily to minor respiratory events (low arousal threshold). Recent studies have focused on the potential to target specific OSA causes with novel treatments to reduce OSA severity and improve efficacy with existing non-CPAP therapies which are often suboptimal (e.g., mandibular advancement splints). One novel target is pharmacotherapy with hypnotics to increase the threshold for arousal and reduce OSA severity in the approximately 30% of patients who have a low arousal threshold endotype. This increasing body of work has produced varied and at times unexpected findings which have challenged previous knowledge on the effects of hypnotics on upper airway physiology and breathing during sleep in people with OSA. This review provides a concise overview of the latest research that has investigated the effects of common hypnotics/sedative agents on upper airway physiology and OSA severity and potential implications for OSA pathophysiology, treatment and safety. This includes a summary of the latest knowledge on the effects of hypnotics on OSA endotypes. Priorities for future research are also highlighted.

Sit less and move more for cardiovascular health: emerging insights and opportunities.

Sedentary behaviour - put simply, too much sitting, as a distinct concept from too little exercise - is a novel determinant of cardiovascular risk. This definition provides a perspective that is complementary to the well-understood detrimental effects of physical inactivity. Sitting occupies the majority of the daily waking hours in most adults and has become even more pervasive owing to the COVID-19 pandemic. The potential for a broad cardiovascular health benefit exists through an integrated approach that involves 'sitting less and moving more'. In this Review, we first consider observational and experimental evidence on the adverse effects of prolonged, uninterrupted sitting and the evidence identifying the possible mechanisms underlying the associated risk. We summarize the results of randomized controlled trials demonstrating the feasibility of changing sedentary behaviour. We also highlight evidence on the deleterious synergies between sedentary behaviour and physical inactivity as the underpinnings of our case for addressing them jointly in mitigating cardiovascular risk. This integrated approach should not only reduce the specific risks of too much sitting but also have a positive effect on the total amount of physical activity, with the potential to more broadly benefit the health of individuals living with or at risk of developing cardiovascular disease.

Impact of green tea on the deleterious cardiometabolic effects of 7-days unhealthy lifestyle in young healthy males.

PURPOSE: The aim of this study was to examine if catechin-rich green tea abrogates the negative effects of 7-days of physical inactivity and excessive calorie-intake on insulin homeostasis and peripheral vascular function. METHODS: Using a randomized, double-blind, crossover design, twelve healthy men (29 ± 6 yrs) underwent 7-days unhealthy lifestyle (UL), including physical inactivity (-50% steps/day) and overfeeding (+50% kcal/day). This was combined with green tea consumption (UL-tea; 3 doses/day) or placebo (UL-placebo). Before and after each intervention, we examined postprandial blood glucose and insulin (3-h after a 1,202 kcal meal) and upper and lower limb vascular function (flow-mediated dilation (FMD%)) and carotid artery reactivity (CAR%). RESULTS: UL-placebo increased postprandial glucose and insulin, while UL-tea decreased postprandial glucose and insulin (Time*Intervention interaction effects: both p < 0.05). UL-placebo decreased CAR% and femoral FMD%, while UL-tea prevented these effects (Time*Intervention interaction effects of p < 0.04 and p < 0.001, respectively). There was no main effect of Time or Time*Intervention interaction (both p > 0.05) for brachial FMD%. CONCLUSION: Seven days of physical inactivity and overfeeding impair insulin homeostasis and vascular function. These effects were mitigated by a daily intake of catechin-rich green tea.

Using an e-Health Intervention to Reduce Prolonged Sitting in UK Office Workers: A Randomised Acceptability and Feasibility Study.

Low-cost workplace interventions are required to reduce prolonged sitting in office workers as this may improve employees' health and well-being. This study aimed to assess the acceptability and feasibility of an e-health intervention to reduce prolonged sitting among sedentary UK-based office workers. Secondary aims were to describe preliminary changes in employee health, mood and work productivity after using an e-health intervention. Healthy, university office workers (n = 14) completed this study. An 8 week randomised crossover design was used, consisting of two trials: Intervention (computer-based prompts) and Control. Eligibility and retention rates were recorded to assess the feasibility of the trial and interviews were conducted following the intervention to explore its acceptability. Sitting, standing and stepping were objectively assessed prior to and during week 8 of each trial. Before and after each trial, measurements of vascular function, cerebrovascular function, mood and work productivity were obtained. This study had eligibility and retention rates of 54.5% and 77.8%, respectively. Participants expressed a lack of autonomy and disruption to their workflow when using the e-health intervention, raising concerns over its acceptability and long-term implementation. Preliminary data indicate that the intervention may improve the patterning of activity accrued during work hours, with increases in the number of standing and stepping bouts completed, in addition to improving vascular function. This e-health intervention is feasible to deliver in a cohort of university office workers. However, adaptations to its implementation, such as personalised settings, are needed to increase acceptability before larger trials can be conducted.

Relationship Between Sedentary Behavior and Physical Activity at Work and Cognition and Mood.

BACKGROUND: Sedentary behavior is negatively associated with cognition and mood. Adults often engage in high levels of sedentary behavior at work through sitting, which may impact productivity. Consequently, replacing sitting with standing and physical activity (PA) is recommended. However, the associations between sitting, standing, and PA at work and cognition and mood are unknown; this study, therefore, aimed to explore these relationships. METHODS: A total of 75 healthy full-time workers (33 male, mean [SD]; 33.6 [10.4] y, 38 [7] work hr/wk) wore sedentary behavior (activPAL) and PA (SenseWear Pro) monitors for 7 days and recorded their work hours. The day after this monitoring period, participants completed cognitive tests (executive function, attention, and working memory) and mood questionnaires (affect, alert, content, and calm). Multiple linear regression analyses examined the associations between cognition and mood and the time spent sitting, standing, and in each PA intensity during work hours, weekday leisure time, and weekends. RESULTS: Workplace sitting, standing, or PA were not significantly associated with cognition or mood (P > .05). No significant associations were observed between these variables during weekday leisure time or weekends (P > .05). CONCLUSIONS: In a cohort of healthy workers, workplace sitting, standing, and PA are not associated with cognition or mood. Further research in this population is needed, examining the influence of workplace behaviors on cognition and mood, because this will contribute to evidence-based workplace guidelines to increase productivity.

Zolpidem increases sleep efficiency and the respiratory arousal threshold without changing sleep apnoea severity and pharyngeal muscle activity.

KEY POINTS: A decreased respiratory arousal threshold is one of the main contributors to obstructive sleep apnoea (OSA) pathogenesis. Several recent studies have sought to find a drug capable of increasing the respiratory arousal threshold without impairing pharyngeal muscle activity to reduce OSA severity, with variable success. Here we show that zolpidem increases the respiratory arousal threshold by ∼15%, an effect size which was insufficient to systematically decrease OSA severity as measured by the apnoea-hypopnoea index. Unlike recent physiological findings that showed paradoxical increases in pharyngeal muscle responsiveness during transient manipulations of airway pressure, zolpidem did not alter pharyngeal muscle responsiveness during natural sleep. It did, however, increase sleep efficiency without changing apnoea length, oxygen desaturation, next-day perceived sleepiness and alertness. These novel findings indicate that zolpidem was well tolerated and effective in promoting sleep in people with OSA, which may be therapeutically useful for people with OSA and comorbid insomnia. ABSTRACT: A recent physiology study performed using continuous positive airway pressure (CPAP) manipulations indicated that the hypnotic zolpidem increases the arousal threshold and genioglossus responsiveness in people with and without obstructive sleep apnoea (OSA). Thus, zolpidem may stabilise breathing and reduce OSA severity without CPAP. Accordingly, we sought to determine the effects of zolpidem on OSA severity, upper airway physiology and next-day sleepiness and alertness. Nineteen people with OSA with low-to-moderate arousal threshold received 10 mg zolpidem or placebo according to a double-blind, randomised, cross-over design. Participants completed two overnight in-laboratory polysomnographies (1-week washout), with an epiglottic catheter, intramuscular genioglossus electromyography, nasal mask and pneumotachograph to measure OSA severity, arousal threshold and upper airway muscle responsiveness. Next-morning sleepiness and alertness were also assessed. Zolpidem did not change the apnoea-hypopnoea index versus placebo (40.6 ± 12.3 vs. 40.3 ± 16.4 events/h (means ± SD), p = 0.938) or nadir oxyhaemoglobin saturation (79.6 ± 6.6 vs. 79.7 ± 7.4%, p = 0.932), but was well tolerated. Zolpidem increased sleep efficiency by 9 ± 14% (83 ± 11 vs. 73 ± 17%, p = 0.010). Arousal threshold increased by 15 ± 5% with zolpidem throughout all sleep stages (p = 0.010), whereas genioglossus muscle responsiveness did not change. Next-morning sleepiness and alertness were not different between nights. In summary, a single night of 10 mg zolpidem is well tolerated and does not cause next-day impairment in alertness or sleepiness, or overnight hypoxaemia in OSA. However, despite increases in arousal threshold without any change in pharyngeal muscle responsiveness, zolpidem does not alter OSA severity. It does, however, increase sleep efficiency by ∼10%, which may be beneficial in people with OSA and insomnia.

Temporal dynamics of sitting behavior at work.

Sitting for prolonged periods of time impairs people's health. Prior research has mainly investigated sitting behavior on an aggregate level, for example, by analyzing total sitting time per day. By contrast, taking a dynamic approach, here we conceptualize sitting behavior as a continuous chain of sit-to-stand and stand-to-sit transitions. We use multilevel time-to-event analysis to analyze the timing of these transitions. We analyze ∼30,000 objectively measured posture transitions from 156 people during work time. Results indicate that the temporal dynamics of sit-to-stand transitions differ from stand-to-sit transitions, and that people are quicker to switch postures later in the workday, and quicker to stand up after having been more active in the recent hours. We found no evidence for associations with physical fitness. Altogether, these findings provide insights into the origins of people's stand-up and sit-down decisions, show that sitting behavior is fundamentally different from exercise behavior, and provide pointers for the development of interventions.

Randomized Trial on the Effects of High-Dose Zopiclone on OSA Severity, Upper Airway Physiology, and Alertness.

BACKGROUND: Studies indicate that standard doses of hypnotics reduce or do not change the apnea-hypopnea index (AHI) or pharyngeal muscle activity. A 1-month trial of nightly zopiclone (7.5 mg) modestly reduced the AHI vs baseline without changing other sleep parameters or next-day sleepiness. RESEARCH QUESTION: This study aimed to determine the effects of high-dose zopiclone (15 mg) on AHI, arousal threshold, genioglossus muscle responsiveness, and next-day alertness in selected people with OSA (low to moderate arousal thresholds without major overnight hypoxemia). We hypothesized that high-dose zopiclone would yield greater increases in arousal threshold and therefore larger reductions in AHI but may come at the expense of increased hypoxemia and next-day impairment. STUDY DESIGN AND METHODS: Twenty-eight participants (AHI = 29 ± 20 events/h) suspected to have low to moderate arousal thresholds were studied during two in-laboratory polysomnographies, separated by 1 week, with an epiglottic pressure catheter and genioglossus intramuscular electrodes. Participants received 15 mg of zopiclone or placebo at each visit according to a double-blind, randomized, crossover design. Each morning, subjective sleepiness and alertness via a driving simulator task were assessed. RESULTS: The AHI did not change from placebo to zopiclone (-1.5 events/h; 95% CI, -6.6 to 3.5 events/h; P = .54). Arousal threshold, genioglossus muscle responsiveness, and most other sleep parameters and measures of next-day sleepiness and alertness also did not change with zopiclone. INTERPRETATION: A single night of treatment with high-dose zopiclone does not systematically reduce the AHI or increase the arousal threshold in selected people with OSA. The mechanisms for these unexpected findings require further investigation. TRIAL REGISTRY: Australian New Zealand Clinical Trials Registry; No.: ACTRN12617000988358; URL: https://www.anzctr.org.au.

Versatile and robust genome editing with Streptococcus thermophilus CRISPR1-Cas9.

Targeting definite genomic locations using CRISPR-Cas systems requires a set of enzymes with unique protospacer adjacent motif (PAM) compatibilities. To expand this repertoire, we engineered nucleases, cytosine base editors, and adenine base editors from the archetypal Streptococcus thermophilus CRISPR1-Cas9 (St1Cas9) system. We found that St1Cas9 strain variants enable targeting to five distinct A-rich PAMs and provide a structural basis for their specificities. The small size of this ortholog enables expression of the holoenzyme from a single adeno-associated viral vector for in vivo editing applications. Delivery of St1Cas9 to the neonatal liver efficiently rewired metabolic pathways, leading to phenotypic rescue in a mouse model of hereditary tyrosinemia. These robust enzymes expand and complement current editing platforms available for tailoring mammalian genomes.

Cerebral and peripheral vascular differences between pre- and postmenopausal women.

OBJECTIVE: Menopause is associated with lower peripheral vascular function; however, cerebrovascular responses to this time-period are unclear. We aimed to describe peripheral vascular and cerebrovascular differences between pre- and postmenopausal women. METHODS: Fifty pre- and postmenopausal women (N = 100) underwent assessments of cerebral blood flow; cerebrovascular reactivity and autoregulation; carotid artery reactivity; brachial and femoral artery flow-mediated dilation; and carotid, brachial, and femoral artery intima-media thickness. Comparisons were made between pre- and postmenopausal women followed by a secondary analysis (N = 20) between late premenopausal women and those within 5 years of menopause using a general linear model. RESULTS: Cerebral blood flow (-11 [-17, -4 cm/s]; P = 0.03) and carotid reactivity (-2.3 [-4.3, -0.3%] P = 0.03) were lower postmenopause compared to premenopause, whereas cerebrovascular reactivity and autoregulation did not differ (P > 0.05). Postmenopausal women had a larger carotid (0.16 [0.13, 0.20 mm] P < 0.001), brachial (0.07 [0.03, 0.11 mm] P = 0.004), and femoral artery intima-media thickness (0.09 [0.05, 0.14 mm] P = 0.04), alongside lower brachial (-2.3 [-3.9, -0.7%] P = 0.004) and femoral artery flow-mediated dilation (-3.0 [-4.3, -1.8%] P < 0.001). In the secondary-analysis, early postmenopausal women had a lower femoral artery flow-mediated dilation (-1.9 [-3.9, -0.0%] P = 0.05) and larger carotid intima-media thickness (0.07 [0.00, 0.14 mm] P = 0.03) compared to late premenopausal women. CONCLUSIONS: Cerebral blood flow, carotid artery reactivity, peripheral vascular function, and structure are negatively affected by age. Preliminary data indicate that femoral artery function and carotid artery structure may be potentially impaired in early postmenopause compared with late premenopause. These findings suggest that conduit arteries susceptible to atherosclerosis may be important targets for lifestyle intervention in early menopause.