Dysregulation of the Long Noncoding RNA X-Inactive-Specific Transcript Expression in Male Patients with Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a sex-biased disease with female gender as a significant risk factor. Recently, we reported that increased expression of the long noncoding RNA X-inactive-specific transcript (Xist), as induced by an intersectin-1s protein fragment with proliferative potential (EHITSN), may explain the sexual dimorphism of female pulmonary artery endothelial cells (ECs) and at least in part, the imbalance sex/ratio of PAH. Xist is essential for X-chromosome inactivation and dosage compensation of X-linked genes. Increased Xist expression was also detected in a subset of ECs and lung tissue samples of male patients with PAH. The role of different Xist expression levels in ECs of male patients with PAH (ECPAH) was studied in several lines of male ECPAH in conjunction with molecular, biochemical, morphologic, and functional approaches. Male ECPAH showed on average 10.3-fold increase in high Xist versus low Xist, a significant association between Xist levels and their proliferative potential, and a heterogeneous methylation of the Xist/Tsix locus. Interestingly, Xist up-regulation in male ECPAH decreases the expression of Klf2, via EHITSN interaction with EZH2, the catalytic subunit of the polycomb repressive complex 2. Moreover, the studies demonstrate that EHITSN-triggered p38/Elk1/c-Fos signaling is a pathologic mechanism central to ECPAH proliferation and the dynamic crosstalk with cell cycle regulatory proteins cyclin A1/cyclin D2 and Xist-EZH2-Klf2 interaction participate directly and differentially in establishing the proliferative profile of male ECPAH.

The association of self-reported sleep and circadian measures with glycemic control and diabetes complications among young adults with type 2 diabetes.

We aim to examine the association of sleep duration, sleep quality, late chronotype, and circadian misalignment with glycemic control and risk of complications in young adults with youth-onset type 2 diabetes followed in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Self-reported sleep duration, quality, timing, and circadian misalignment were assessed via a modified Pittsburgh Sleep Quality Index (PSQI) questionnaire, and chronotype was assessed via the Morningness-Eveningness Questionnaire (MEQ). We examined diabetes complications including loss of glycemic control (defined as hemoglobin A1c ≥8%), hypertension, dyslipidemia, albuminuria, and diabetic peripheral neuropathy. Multivariable logistic regression models were constructed to assess associations between sleep and circadian measures with outcomes of interest, such as loss of glycemic control and diabetes complications. A total of 421 participants (34.2% male), mean age 23.6 ± 2.5 yr, mean body mass index (BMI) of 36.1 ± 8.3 kg/m2, and mean diabetes duration of 10.0 ± 1.5 yr were evaluated. Self-reported short sleep duration, daytime sleepiness, and sleep quality were not associated with loss of glycemic control or diabetes complications. Late self-reported bedtime (after midnight) on work/school nights, rather than self-expressed chronotype or circadian misalignment, was independently associated with loss of glycemic control. An association was seen between late bedtimes and albuminuria but was attenuated after adjusting for depression. In conclusion, late bedtime on work/school days, rather than short sleep duration, daytime sleepiness, or poor sleep quality, was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes.NEW & NOTEWORTHY The prevalence of type 2 diabetes in youth is increasing at an alarming rate. Identifying potentially modifiable factors modulating glycemic control is critically important to reduce micro and macrovascular complications. In a large cohort of youth-onset type 2 diabetes, self-reported late bedtime on work/school days was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes.

The Impact of Sex Chromosomes in the Sexual Dimorphism of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a sex-biased disease with a poorly understood female prevalence. Emerging research suggests that nonhormonal factors, such as the XX or XY sex chromosome complement and sex bias in gene expression, may also lead to sex-based differences in PAH incidence, penetrance, and progression. Typically, one of females' two X chromosomes is epigenetically silenced to offer a gender-balanced gene expression. Recent data demonstrate that the long noncoding RNA X-inactive specific transcript, essential for X chromosome inactivation and dosage compensation of X-linked gene expression, shows elevated levels in female PAH lung specimens compared with controls. This molecular event leads to incomplete inactivation of the females' second X chromosome, abnormal expression of X-linked gene(s) involved in PAH pathophysiology, and a pulmonary artery endothelial cell (PAEC) proliferative phenotype. Moreover, the pathogenic proliferative p38 mitogen-activated protein kinase/ETS transcription factor ELK1 (Elk1)/cFos signaling is mechanistically linked to the sexually dimorphic proliferative response of PAECs in PAH. Apprehending the complicated relationship between long noncoding RNA X-inactive specific transcript and X-linked genes and how this relationship integrates into a sexually dimorphic proliferation of PAECs and PAH sex paradox remain challenging. We highlight herein new findings related to how the sex chromosome complement and sex-differentiated epigenetic mechanisms to control gene expression are decisive players in the sexual dimorphism of PAH. Pharmacologic interventions in the light of the newly elucidated mechanisms are discussed.

A new index, Respiratory Insufficiency index and Modified Early Warning Scores predict extubation failure.

Background: Extubation failure occurs in 5%-20% of patients and is associated with poor clinical outcomes. The primary aim of this project was to determine the predictive ability of the Respiratory Insufficiency (RI) index, Respiratory Oxygenation (ROX) index and Modified Early Warning Score (MEWS) in identifying extubation failure. Methods: This was a secondary analysis of a prior cross-sectional retrospective study conducted from February 2018 through December 2018 among adult subjects who received mechanical ventilation for more than 24 h. Extubation failure was defined as the need for reintubation or rescue non-invasive ventilation (NIV) within 48 h after planned extubation. Univariate analysis and logistic regression were used to identify the predictors and final model was validated using 10-fold cross validation. Nomogram was constructed based on the final model. Results: Of 216 enrolled subjects, 46 (21.3%) experienced extubation failure. The median RI index 1-h post extubation was 20 [interquartile range [IQR] 16.33-24.24] for success group and 27.02 [IQR 22.42-33.83] for the failure group (P<0.001). The median ROX index 1-h post extubation was 16.66 [IQR 12.57-19.84] for success group and 11.11 [IQR 8.09-14.67] for failure group (P<0.001). The median MEWS 1-h post extubation was 2 [IQR 1-3] for the success group and 4 [IQR 3-5] for the failure group (P<0.001). In multivariable analysis, age >60 years [OR 3.89 (95% CI 1.56-9.73); P=0.004], MEWS >4 [OR 4.01 (95% CI (1.59-10.14); P=0.003] and, RI index >20 [OR 4.50 (95% CI 1.43-14.21); P=0.010] were independently associated with extubation failure. Conclusion: In the present study, RI index and MEWS were independently associated with predicting extubation failure within 1 h of extubation. A prospective validation study is warranted to establish the role of these indices in predicting extubation outcome.

Taking to "heart" the proposed legislation for permanent daylight saving time.

In March 2022, the US Senate passed the Sunshine Protection Act that would abolish the biannual change in clocks each fall and spring and permanently adopt daylight saving time that aligns with the "spring forward" time change each March. A number of scientific and medical societies have endorsed the abolishment of the biannual clock change, but oppose the permanent adoption of daylight saving time. Instead, leading organizations such as the American Academy of Sleep Medicine (AASM) and the Society for Research on Biological Rhythms (SRBR) position statements highlight peer-reviewed evidence in favor of a permanent shift to standard time. The present perspectives will summarize some of the key AASM and SRBR recommendations, with a particular focus on the potential cardiovascular implications of a legislative change that would result in a permanent switch to either standard time or daylight saving time. Collectively, although there is building scientific consensus that abolishing the biannual time change has several sleep and circadian health benefits, the preponderance of evidence is opposite to the current legislation and instead suggests a permanent switch to standard time may offer the maximum health and safety benefits. This scientific evidence should be considered as the United States House of Representatives considers the Sunshine Protection Act.

Obesity and Obesity Hypoventilation, Sleep Hypoventilation, and Postoperative Respiratory Failure.

Obesity hypoventilation syndrome (OHS) is considered as a diagnosis in obese patients (body mass index [BMI] ≥30 kg/m2) who also have sleep-disordered breathing and awake diurnal hypercapnia in the absence of other causes of hypoventilation. Patients with OHS have a higher burden of medical comorbidities as compared to those with obstructive sleep apnea (OSA). This places patients with OHS at higher risk for adverse postoperative events. Obese patients and those with OSA undergoing elective noncardiac surgery are not routinely screened for OHS. Screening for OHS would require additional preoperative evaluation of morbidly obese patients with severe OSA and suspicion of hypoventilation or resting hypoxemia. Cautious selection of the type of anesthesia, use of apneic oxygenation with high-flow nasal cannula during laryngoscopy, better monitoring in the postanesthesia care unit (PACU) can help minimize adverse perioperative events. Among other risk-reduction strategies are proper patient positioning, especially during intubation and extubation, multimodal analgesia, and cautious use of postoperative supplemental oxygen.

Identification of Sleep Medicine and Anesthesia Core Topics for Anesthesia Residency: A Modified Delphi Technique Survey.

BACKGROUND: Sleep disorders affect up to 25% of the general population and are associated with increased risk of adverse perioperative events. The key sleep medicine topics that are most important for the practice of anesthesiology have not been well-defined. The objective of this study was to determine the high-priority sleep medicine topics that should be included in the education of anesthesia residents based on the insight of experts in the fields of anesthesia and sleep medicine. METHODS: We conducted a prospective cross-sectional survey of experts in the fields of sleep medicine and anesthesia based on the Delphi technique to establish consensus on the sleep medicine topics that should be incorporated into anesthesia residency curricula. Consensus for inclusion of a topic was defined as >80% of all experts selecting "agree" or "strongly agree" on a 5-point Likert scale. Responses to the survey questions were analyzed with descriptive statistical methods and presented as percentages or weighted mean values with standard deviations (SD) for Likert scale data. RESULTS: The topics that were found to have 100% agreement among experts were the influence of opioids and anesthetics on control of breathing and upper airway obstruction; potential interactions of wake-promoting/hypnotic medications with anesthetic agents; effects of sleep and anesthesia on upper airway patency; and anesthetic management of sleep apnea. Less than 80% agreement was found for topics on the anesthetic implications of other sleep disorders and future pathways in sleep medicine and anesthesia. CONCLUSIONS: We identify key topics of sleep medicine that can be included in the future design of anesthesia residency training curricula.

Echocardiographic Changes with Positive Airway Pressure Therapy in Obesity Hypoventilation Syndrome. Long-Term Pickwick Randomized Controlled Clinical Trial.

Rationale: Obesity hypoventilation syndrome (OHS) has been associated with cardiac dysfunction. However, randomized trials assessing the impact of long-term noninvasive ventilation (NIV) or continuous positive airway pressure (CPAP) on cardiac structure and function assessed by echocardiography are lacking.Objectives: In a prespecified secondary analysis of the largest multicenter randomized controlled trial of OHS (Pickwick Project; N = 221 patients with OHS and coexistent severe obstructive sleep apnea), we compared the effectiveness of three years of NIV and CPAP on structural and functional echocardiographic changes.Methods: At baseline and annually during three sequential years, patients underwent transthoracic two-dimensional and Doppler echocardiography. Echocardiographers at each site were blinded to the treatment allocation. Statistical analysis was performed using a linear mixed-effects model with a treatment group and repeated measures interaction to determine the differential effect between CPAP and NIV.Measurements and Main Results: A total of 196 patients were analyzed: 102 were treated with CPAP and 94 were treated with NIV. Systolic pulmonary artery pressure decreased from 40.5 ± 1.47 mm Hg at baseline to 35.3 ± 1.33 mm Hg at three years with CPAP, and from 41.5 ± 1.56 mm Hg to 35.5 ± 1.42 with NIV (P < 0.0001 for longitudinal intragroup changes for both treatment arms). However, there were no significant differences between groups. NIV and CPAP therapies similarly improved left ventricular diastolic dysfunction and reduced left atrial diameter. Both NIV and CPAP improved respiratory function and dyspnea.Conclusions: In patients with OHS who have concomitant severe obstructive sleep apnea, long-term treatment with NIV and CPAP led to similar degrees of improvement in pulmonary hypertension and left ventricular diastolic dysfunction.Clinical trial registered with www.clinicaltrials.gov (NCT01405976).

Long-term clinical effectiveness of continuous positive airway pressure therapy versus non-invasive ventilation therapy in patients with obesity hypoventilation syndrome: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Obesity hypoventilation syndrome is commonly treated with continuous positive airway pressure or non-invasive ventilation during sleep. Non-invasive ventilation is more complex and costly than continuous positive airway pressure but might be advantageous because it provides ventilatory support. To date there have been no long-term trials comparing these treatment modalities. We therefore aimed to determine the long-term comparative effectiveness of both treatment modalities. METHODS: We did a multicentre, open-label, randomised controlled trial at 16 clinical sites in Spain. We included patients aged 15-80 years with untreated obesity hypoventilation syndrome and an apnoea-hypopnoea index of 30 or more events per h. We randomly assigned patients, using simple randomisation through an electronic database, to receive treatment with either non-invasive ventilation or continuous positive airway pressure. Both investigators and patients were aware of the treatment allocation. The research team was not involved in deciding hospital treatment, duration of treatment in the hospital, and adjustment of medications, as well as adjudicating cardiovascular events or cause of mortality. Treating clinicians from the routine care team were not aware of the treatment allocation. The primary outcome was the number of hospitalisation days per year. The analysis was done according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT01405976. FINDINGS: From May 4, 2009, to March 25, 2013, 100 patients were randomly assigned to the non-invasive ventilation group and 115 to the continuous positive airway pressure group, of which 97 patients in the non-invasive ventilation group and 107 in the continuous positive airway pressure group were included in the analysis. The median follow-up was 5·44 years (IQR 4·45-6·37) for all patients, 5·37 years (4·36-6·32) in the continuous positive airway pressure group, and 5·55 years (4·53-6·50) in the non-invasive ventilation group. The mean hospitalisation days per patient-year were 1·63 (SD 3·74) in the continuous positive airway pressure group and 1·44 (3·07) in the non-invasive ventilation group (adjusted rate ratio 0·78, 95% CI 0·34-1·77; p=0·561). Adverse events were similar between both groups. INTERPRETATION: In stable patients with obesity hypoventilation syndrome and severe obstructive sleep apnoea, non-invasive ventilation and continuous positive airway pressure have similar long-term effectiveness. Given that continuous positive airway pressure has lower complexity and cost, continuous positive airway pressure might be the preferred first-line positive airway pressure treatment modality until more studies become available. FUNDING: Instituto de Salud Carlos III, Spanish Respiratory Foundation, and Air Liquide Spain.

Cost-effectiveness of positive airway pressure modalities in obesity hypoventilation syndrome with severe obstructive sleep apnoea.

BACKGROUND: Obesity hypoventilation syndrome (OHS) is treated with either non-invasive ventilation (NIV) or CPAP, but there are no long-term cost-effectiveness studies comparing the two treatment modalities. OBJECTIVES: We performed a large, multicentre, randomised, open-label controlled study to determine the comparative long-term cost and effectiveness of NIV versus CPAP in patients with OHS with severe obstructive sleep apnoea (OSA) using hospitalisation days as the primary outcome measure. METHODS: Hospital resource utilisation and within trial costs were evaluated against the difference in effectiveness based on the primary outcome (hospitalisation days/year, transformed and non-transformed in monetary term). Costs and effectiveness were estimated from a log-normal distribution using a Bayesian approach. A secondary analysis by adherence subgroups was performed. RESULTS: In total, 363 patients were selected, 215 were randomised and 202 were available for the analysis. The median (IQR) follow-up was 3.01 (2.91-3.14) years for NIV group and 3.00 (2.92-3.17) years for CPAP. The mean (SD) Bayesian estimated hospital days was 2.13 (0.73) for CPAP and 1.89 (0.78) for NIV. The mean (SD) Bayesian estimated cost per patient/year in the NIV arm, excluding hospitalisation costs, was €2075.98 (91.6), which was higher than the cost in the CPAP arm of €1219.06 (52.3); mean difference €857.6 (105.5). CPAP was more cost-effective than NIV (99.5% probability) because longer hospital stay in the CPAP arm was compensated for by its lower costs. Similar findings were observed in the high and low adherence subgroups. CONCLUSION: CPAP is more cost-effective than NIV; therefore, CPAP should be the preferred treatment for patients with OHS with severe OSA. TRIAL REGISTRATION NUMBER: NCT01405976.

Evaluation and Management of Obesity Hypoventilation Syndrome. An Official American Thoracic Society Clinical Practice Guideline.

Background: The purpose of this guideline is to optimize evaluation and management of patients with obesity hypoventilation syndrome (OHS).Methods: A multidisciplinary panel identified and prioritized five clinical questions. The panel performed systematic reviews of available studies (up to July 2018) and followed the Grading of Recommendations, Assessment, Development, and Evaluation evidence-to-decision framework to develop recommendations. All panel members discussed and approved the recommendations.Recommendations: After considering the overall very low quality of the evidence, the panel made five conditional recommendations. We suggest that: 1) clinicians use a serum bicarbonate level <27 mmol/L to exclude the diagnosis of OHS in obese patients with sleep-disordered breathing when suspicion for OHS is not very high (<20%) but to measure arterial blood gases in patients strongly suspected of having OHS, 2) stable ambulatory patients with OHS receive positive airway pressure (PAP), 3) continuous positive airway pressure (CPAP) rather than noninvasive ventilation be offered as the first-line treatment to stable ambulatory patients with OHS and coexistent severe obstructive sleep apnea, 4) patients hospitalized with respiratory failure and suspected of having OHS be discharged with noninvasive ventilation until they undergo outpatient diagnostic procedures and PAP titration in the sleep laboratory (ideally within 2-3 mo), and 5) patients with OHS use weight-loss interventions that produce sustained weight loss of 25% to 30% of body weight to achieve resolution of OHS (which is more likely to be obtained with bariatric surgery).Conclusions: Clinicians may use these recommendations, on the basis of the best available evidence, to guide management and improve outcomes among patients with OHS.

Risk of major cardiovascular and cerebrovascular complications after elective surgery in patients with sleep-disordered breathing: A retrospective cohort analysis.

BACKGROUND: There is limited and conflicting data on whether sleep-disordered breathing (SDB) is associated with postoperative major cardiovascular and cerebrovascular events (MACCE), and mortality. OBJECTIVES: To determine whether SDB is associated with increased risks of MACCE, mortality and length of hospital stay. DESIGN: Retrospective cohort analysis from the Nationwide Inpatient Sample. SETTING: Adults who underwent elective abdominal, orthopaedic, prostatic, gynaecological, thoracic, transplant, vascular or cardiac surgery in the United States of America between 2011 and 2014. PATIENTS: The study cohort included 1813 974 surgical patients, of whom 185 615 (10.2%) had SDB. Emergency or urgent surgical procedures were excluded. MAIN OUTCOME MEASURES: The incidences of MACCE, respiratory and vascular complications, in-hospital mortality and mean length of hospital stay were stratified by SDB. Linear and logistic regression models were constructed to determine the independent association between SDB and outcomes of interest. RESULTS: The incidences of MACCE [25.3 vs. 19.8%, odds ratio (OR) 1.20, P < 0.001] and respiratory complications (11.75 vs. 8.0%, OR 1.43, P < 0.001) were significantly higher in patients with SDB than in those without SDB. SDB was associated with higher rates of atrial fibrillation (14.7 vs. 10.8%, P < 0.001), other arrhythmias (6.0 vs. 5.4%, P < 0.001) and congestive heart failure (9.8 vs. 7.1%, P < 0.001). SDB patients had a lower rate of myocardial infarction (3.1 vs. 3.4%, OR 0.69, P < 0.001), lower mortality (0.6 vs. 1.3%, P < 0.001) and shorter length of hospital stay (4.8 vs. 5.2 days, P < 0.001). CONCLUSION: SDB was associated with increased risks of MACCE, and respiratory and vascular complications, but had a lower incidence of in-hospital mortality and shorter length of hospital stay.

Sympathetic neural responsiveness to sleep deprivation in older adults: sex differences.

Our laboratory has previously reported that total sleep deprivation (TSD) modifies muscle sympathetic neural activity (MSNA) differently in young men and women. Because postmenopausal women are among the highest risk for hypertension, this study compares MSNA responses with TSD in older men and women. We hypothesized that TSD would alter MSNA in older adults, with greater sympathoexcitation in postmenopausal women. Twenty-seven participants (14 men and 13 women) between the ages of 55 and 75 yr were tested twice, once after 24-h TSD and once after normal sleep (randomized, crossover design). Our primary outcome measure of MSNA (microneurography) was successful across both conditions in 20 participants (10 men and 10 women). Secondary outcome measures included seated blood pressure, heart rate, and fasting plasma testosterone, estradiol, and progesterone. Age (60 ± 1 vs. 61 ± 2 yr) and BMI (27 ± 1 vs. 26 ± 1 kg/m2) were not different between groups. TSD increased systolic blood pressure in both men (124 ± 5 to 130 ± 4 mmHg) and women (107 ± 5 to 116 ± 4 mmHg), but the increases were not different between groups (condition, P = 0.014; condition × sex, P > 0.05). In contrast, TSD elicited divergent MSNA responses in older men and women. Specifically, MSNA burst frequency increased in postmenopausal women (28 ± 3 to 34 ± 3 burst/min), but not older men (38 ± 3 to 35 ± 3 bursts/min; condition × sex, P = 0.032). In conclusion, TSD elicited sympathoexcitation in postmenopausal women but not age-matched men. These findings provide new mechanistic insight into reported links between sleep deprivation and hypertension.NEW & NOTEWORTHY Epidemiological studies report that sleep deprivation is more strongly associated with hypertension in women than in men. In the present study, 24-h total sleep deprivation (TSD) increased blood pressure in postmenopausal women and age-matched men. In contrast, only women demonstrated increases in muscle sympathetic nerve activity after TSD. The sympathoexcitation observed in postmenopausal women suggests a potential contributing mechanism for epidemiological observations and advances our understanding of the complex relations between sleep, sex, and hypertension.

The association of sleep disturbances with glycemia and obesity in youth at risk for or with recently diagnosed type 2 diabetes.

OBJECTIVE: Poor sleep may increase obesity and type 2 diabetes (T2D) risk in youth. We explored whether subjective sleep duration, sleep quality, or risk for obstructive sleep apnea (OSA) are associated with glycemia, body mass index (BMI), or blood pressure (BP) in overweight/obese youth. METHODS: Two-hundred and fourteen overweight/obese youth of 10 to 19 years of age at risk for or recently diagnosed with T2D who were screened for the Restoring Insulin Secretion (RISE) Study had a 2-hour oral glucose tolerance test (OGTT) and completed a Cleveland Adolescent Sleepiness questionnaire and a Sleep Disturbances Scale questionnaire. Independent associations between sleep variables and measures of glycemia, BMI, and BP were evaluated with regression models. RESULTS: The multiethnic cohort was 67% female, 14.1 ± 2.1 years, and BMI 35.9 ± 6.5 kg/m2 . Habitual sleep duration <8 hours was reported in 74%. Daytime sleepiness was reported in 51%, poor sleep quality in 26%, and 30% had high obstructive sleep apnea (OSA) risk. Daytime sleepiness was associated with higher HbA1c (0.2%, P = .02) and 2-hour glucose (13.6 mg/dL, P < .05). Sleep duration, sleep quality, and OSA risk were not associated with the evaluated outcomes. Poor sleep quality and OSA risk were associated with higher BMI (2.9 kg/m2 , P = .004 and 2.83 kg/m2 , P < .003, respectively). CONCLUSIONS: In overweight/obese youth with or at risk for T2D, daytime sleepiness was associated with higher HbA1c. In addition, poor sleep quality and OSA risk were associated with higher BMI. These findings support intervention studies aimed at improving sleep quality in obese youth.

REM obstructive sleep apnea: risk for adverse health outcomes and novel treatments.

Rapid eye movement (REM) sleep was discovered nearly 60 years ago. This stage of sleep accounts for approximately a quarter of total sleep time in healthy adults, and it is mostly concentrated in the second half of the sleep period. The majority of research on REM sleep has focused on neurocognition. More recently, however, there has been a growing interest in understanding whether obstructive sleep apnea (OSA) during the two main stages of sleep (REM and non-REM sleep) leads to different cardiometabolic and neurocognitive risk. In this review, we discuss the growing evidence indicating that OSA during REM sleep is a prevalent disorder that is independently associated with adverse cardiovascular, metabolic, and neurocognitive outcomes. From a therapeutic standpoint, we discuss limitations of continuous positive airway pressure (CPAP) therapy given that 3 or 4 h of CPAP use from the beginning of the sleep period would leave 75% or 60% of obstructive events during REM sleep untreated. We also review potential pharmacologic approaches to treating OSA during REM sleep. Undoubtedly, further research is needed to establish best treatment strategies in order to effectively treat REM OSA. Moreover, it is critical to understand whether treatment of REM OSA will translate into better patient outcomes.

Echocardiographic changes with non-invasive ventilation and CPAP in obesity hypoventilation syndrome.

RATIONALE: Despite a significant association between obesity hypoventilation syndrome (OHS) and cardiac dysfunction, no randomised trials have assessed the impact of non-invasive ventilation (NIV) or CPAP on cardiac structure and function assessed by echocardiography. OBJECTIVES: We performed a secondary analysis of the data from the largest multicentre randomised controlled trial of OHS (Pickwick project, n=221) to determine the comparative efficacy of 2 months of NIV (n=71), CPAP (n=80) and lifestyle modification (control group, n=70) on structural and functional echocardiographic changes. METHODS: Conventional transthoracic two-dimensional and Doppler echocardiograms were obtained at baseline and after 2 months. Echocardiographers at each site were blinded to the treatment arms. Statistical analysis was performed using intention-to-treat analysis. RESULTS: At baseline, 55% of patients had pulmonary hypertension and 51% had evidence of left ventricular hypertrophy. Treatment with NIV, but not CPAP, lowered systolic pulmonary artery pressure (-3.4 mm Hg, 95% CI -5.3 to -1.5; adjusted P=0.025 vs control and P=0.033 vs CPAP). The degree of improvement in systolic pulmonary artery pressure was greater in patients treated with NIV who had pulmonary hypertension at baseline (-6.4 mm Hg, 95% CI -9 to -3.8). Only NIV therapy decreased left ventricular hypertrophy with a significant reduction in left ventricular mass index (-5.7 g/m2; 95% CI -11.0 to -4.4). After adjusted analysis, NIV was superior to control group in improving left ventricular mass index (P=0.015). Only treatment with NIV led to a significant improvement in 6 min walk distance (32 m; 95% CI 19 to 46). CONCLUSION: In patients with OHS, medium-term treatment with NIV is more effective than CPAP and lifestyle modification in improving pulmonary hypertension, left ventricular hypertrophy and functional outcomes. Long-term studies are needed to confirm these results. TRIAL REGISTRATION NUMBER: Pre-results, NCT01405976 (https://clinicaltrials.gov/).

Educational video to improve CPAP use in patients with obstructive sleep apnoea at risk for poor adherence: a randomised controlled trial.

BACKGROUND: Suboptimal adherence to CPAP limits its clinical effectiveness in patients with obstructive sleep apnoea (OSA). Although rigorous behavioural interventions improve CPAP adherence, their labour-intensive nature has limited widespread implementation. Moreover, these interventions have not been tested in patients at risk of poor CPAP adherence. Our objective was to determine whether an educational video will improve CPAP adherence in patients at risk of poor CPAP adherence. METHODS: Patients referred by clinicians without sleep medicine expertise to an urban sleep laboratory that serves predominantly minority population were randomised to view an educational video about OSA and CPAP therapy before the polysomnogram, or to usual care. The primary outcome was CPAP adherence during the first 30 days of therapy. Secondary outcomes were show rates to sleep clinic (attended appointment) and 30-day CPAP adherence after the sleep clinic visit date. RESULTS: A total of 212 patients met the eligibility criteria and were randomised to video education (n=99) or to usual care (n=113). There were no differences in CPAP adherence at 30 days (3.3, 95% CI 2.8 to 3.8 hours/day video education; vs 3.5, 95% CI 3.1 to 4.0 hours/day usual care; p=0.44) or during the 30 days after sleep clinic visit. Sleep clinic show rate was 54% in the video education group and 59% in the usual care group (p=0.41). CPAP adherence, however, significantly worsened in patients who did not show up to the sleep clinic. CONCLUSIONS: In patients at risk for poor CPAP adherence, an educational video did not improve CPAP adherence or show rates to sleep clinic compared with usual care. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT02553694.

Effect of one week of CPAP treatment of obstructive sleep apnoea on 24-hour profiles of glucose, insulin and counter-regulatory hormones in type 2 diabetes.

Studies examining the impact of CPAP treatment on glycaemic control have yielded conflicting results, partly because of insufficient nightly CPAP use. We examined the 24-hour profiles of glucose, insulin and counter-regulatory hormones in 12 subjects with type 2 diabetes and OSA before and after 1 week of effective in-laboratory CPAP therapy over an entire 8-hour night thus ensuring optimal CPAP compliance. Blood samples were collected every 15 to 30 minutes for 24 hours under controlled conditions. The 24-hour mean glucose decreased from 153.2 ± 33.0 to 139.7 ± 24.2 mg/dL with CPAP (-13.5 ± 13.5 mg/dL; P = .005) without change in insulin levels. Morning fasting glucose levels decreased by 14.6 ± 3 mg/dL (P = .001) and the dawn phenomenon decreased by 7.8 ± 9.8 mg/dL (P = .019). CPAP treatment decreased norepinephrine levels while the 24-hour profiles of growth hormone and cortisol remained unchanged. In conclusion, 1 week of effective treatment of OSA over an entire 8-hour night results in a clinically significant improvement in glycaemic control via an amelioration of evening fasting glucose metabolism and a reduction in the dawn phenomenon, a late-night glucose increase that is not adequately treated by oral medications. Clinical Trials Information: ClinicalTrials.gov Identifier: NCT01136785.

Non-invasive ventilation in obesity hypoventilation syndrome without severe obstructive sleep apnoea.

BACKGROUND: Non-invasive ventilation (NIV) is an effective form of treatment in patients with obesity hypoventilation syndrome (OHS) who have concomitant severe obstructive sleep apnoea (OSA). However, there is a paucity of evidence on the efficacy of NIV in patients with OHS without severe OSA. We performed a multicentre randomised clinical trial to determine the comparative efficacy of NIV versus lifestyle modification (control group) using daytime arterial carbon dioxide tension (PaCO2) as the main outcome measure. METHODS: Between May 2009 and December 2014 we sequentially screened patients with OHS without severe OSA. Participants were randomised to NIV versus lifestyle modification and were followed for 2 months. Arterial blood gas parameters, clinical symptoms, health-related quality of life assessments, polysomnography, spirometry, 6-min walk distance test, blood pressure measurements and healthcare resource utilisation were evaluated. Statistical analysis was performed using intention-to-treat analysis. RESULTS: A total of 365 patients were screened of whom 58 were excluded. Severe OSA was present in 221 and the remaining 86 patients without severe OSA were randomised. NIV led to a significantly larger improvement in PaCO2 of -6 (95% CI -7.7 to -4.2) mm Hg versus -2.8 (95% CI -4.3 to -1.3) mm Hg, (p<0.001) and serum bicarbonate of -3.4 (95% CI -4.5 to -2.3) versus -1 (95% CI -1.7 to -0.2 95% CI)  mmol/L (p<0.001). PaCO2 change adjusted for NIV compliance did not further improve the inter-group statistical significance. Sleepiness, some health-related quality of life assessments and polysomnographic parameters improved significantly more with NIV than with lifestyle modification. Additionally, there was a tendency towards lower healthcare resource utilisation in the NIV group. CONCLUSIONS: NIV is more effective than lifestyle modification in improving daytime PaCO2, sleepiness and polysomnographic parameters. Long-term prospective studies are necessary to determine whether NIV reduces healthcare resource utilisation, cardiovascular events and mortality. TRIAL REGISTRATION NUMBER: NCT01405976; results.