A comparative study of bronchodilator response: utilizing pre-bronchodilator versus predicted normal values.

BACKGROUND: A positive bronchodilator response has been defined as a 12% increase in the forced expiratory volume in one second (FEV1) or forced vital capacity (FVC) from their respective pre-bronchodilator values, combined with at least a 0.2 L absolute change. Recent recommendations suggested the use of the percent change in FEV1 and FVC relative to their predicted normal values without having applied them in patients with airflow obstruction. The aim of the current study was to compare the two approaches over a wide range of pre-bronchodilator FEV1 and FVC values. METHODS: A retrospective review of consecutive patients undergoing spirometry and bronchodilator testing was completed. The change in FEV1 and FVC with a bronchodilator was expressed relative to the pre-bronchodilator and predicted normal FEV1 and FVC. RESULTS: In 1,040 patients with a non-paradoxical change in FEV1, 19.0% had a ≥ 12% change in FEV1 using their pre-bronchodilator value compared to 5.7% using their predicted normal value. For FVC, the respective values were 12.7% vs. 5.8%. The difference was retained in patients with a ≥ 0.2 L change in FEV1 or FVC. In unobstructed patients, the upper threshold (two standard deviations above the mean) of the bronchodilator response was 14% for FEV1 and 10% for FVC using predicted normal values. CONCLUSIONS: Expressing the percent change in FEV1 and FVC relative to predicted normal values reduces the over-estimation of the bronchodilator response, especially in patients with a very low pre-bronchodilator FEV1, including in those with a ≥ 0.2 L change in FEV1. Irrespective of pre-bronchodilator values, a ≥ 14% change in FEV1 and ≥ 10% change in FVC relative to the predicted normal values could be considered a positive bronchodilator response.

Tumor MK2 transcript levels are associated with improved response to chemotherapy and patient survival in non-small cell lung cancer.

Non-small cell lung cancers (NSCLCs) demonstrate intrinsic resistance to cell death, even after chemotherapy. Previous work suggested defective nuclear translocation of active caspase-3 in observed resistance to cell death. We have identified mitogen-activated protein kinase-activated protein kinase 2 (MK2; encoded by the gene MAPKAPK2) is required for caspase-3 nuclear translocation in the execution of apoptosis in endothelial cells. The objective was to determine MK2 expression in NSCLCs and the association between MK2 and clinical outcomes in patients with NSCLC. Clinical and MK2 mRNA data were extracted from two demographically distinct NSCLC clinical cohorts, North American (The Cancer Genome Atlas, TCGA) and East Asian (EA). Tumor responses following first round of chemotherapy were dichotomized as clinical response (complete response, partial response, and stable disease) or progression of disease. Multivariable survival analyses were performed using Cox proportional hazard ratios and Kaplan-Meier curves. NSCLC exhibited lower MK2 expression than SCLC cell lines. In patients, lower tumor MK2 transcript levels were observed in those presenting with late-stage NSCLC. Higher MK2 expression was associated with clinical response following initial chemotherapy and independently associated with improved 2-yr survival in two distinct cohorts, 0.52 (0.28-0.98) and 0.1 (0.01-0.81), TCGA and EA, respectively, even after adjusting for common oncogenic driver mutations. Survival benefit of higher MK2 expression was unique to lung adenocarcinoma when comparing across various cancers. This study implicates MK2 in apoptosis resistance in NSCLC and suggests prognostic value of MK2 transcript levels in patients with lung adenocarcinoma.

MK2 nonenzymatically promotes nuclear translocation of caspase-3 and resultant apoptosis.

We have previously identified mitogen-activated protein kinase-activated protein kinase 2 (MK2) is required for caspase-3 nuclear translocation in the execution of apoptosis; however, little is known of the underlying mechanisms. Therefore, we sought to determine the role of kinase and nonkinase functions of MK2 in promoting nuclear translocation of caspase-3. We identified two non-small cell lung cancer cell lines for use in these experiments based on low MK2 expression. Wild-type, enzymatic and cellular localization mutant MK2 constructs were expressed using adenoviral infection. Cell death was evaluated by flow cytometry. In addition, cell lysates were harvested for protein analyses. Phosphorylation of caspase-3 was determined using two-dimensional gel electrophoresis followed by immunoblotting and in vitro kinase assay. Association between MK2 and caspase-3 was evaluated using proximity-based biotin ligation assays and co-immunoprecipitation. Overexpression of MK2 resulted in nuclear translocation of caspase-3 and caspase-3-mediated apoptosis. MK2 directly phosphorylates caspase-3; however, phosphorylation status of caspase-3 or MK2-dependent phosphorylation of caspase-3 did not alter caspase-3 activity. The enzymatic function of MK2 was dispensable in nuclear translocation of caspase-3. MK2 and caspase-3 associated together and a nonenzymatic function of MK2, chaperoned nuclear trafficking, is required for caspase-3-mediated apoptosis. Taken together, our results demonstrate a nonenzymatic role for MK2 in the nuclear translocation of caspase-3. Furthermore, MK2 may function as a molecular switch in regulating the transition between the cytosolic and nuclear functions of caspase-3.

Performance of the Glucose Management Indicator (GMI) in Type 2 Diabetes.

BACKGROUND: The glucose management indicator (GMI) is an estimated measure of hemoglobin A1c (HbA1c) recommended for the management of persons with diabetes using continuous glucose monitoring (CGM). However, GMI was derived primarily in young adults with type 1 diabetes, and its performance in patients with type 2 diabetes is poorly characterized. METHODS: We conducted a prospective cohort study in 144 adults with obstructive sleep apnea and type 2 diabetes not using insulin (mean age: 59.4 years; 45.1% female). HbA1c was measured at the study screening visit. Participants simultaneously wore 2 CGM sensors (Dexcom G4 and Abbott Libre Pro) for up to 4 weeks (2 weeks at baseline and 2 weeks at the 3-month follow-up visit). GMI was calculated using all available CGM data for each sensor. RESULTS: Median wear time was 27 days (IQR: 23-29) for the Dexcom G4 and 28 days (IQR: 24-29) for the Libre Pro. The mean difference between HbA1c and GMI was small (0.12-0.14 percentage points) (approximately 2 mmol/mol). However, the 2 measures were only moderately correlated (r = 0.68-0.71), and there was substantial variability in GMI at any given value of HbA1c (root mean squared error: 0.66-0.69 percentage points [7 to 8 mmol/mol]). Between 36% and 43% of participants had an absolute difference between HbA1c and GMI ≥0.5 percentage points (≥5 mmol/mol), and 9% to 18% had an absolute difference >1 percentage points (>11 mmol/mol). Discordance was higher in the Libre Pro than the Dexcom G4. CONCLUSIONS: GMI may be an unreliable measure of glycemic control for patients with type 2 diabetes and should be interpreted cautiously in clinical practice.Clinicaltrials.gov Registration Number: NCT02454153.

Within-Person and Between-Sensor Variability in Continuous Glucose Monitoring Metrics.

BACKGROUND: The within-person and between-sensor variability of metrics from different interstitial continuous glucose monitoring (CGM) sensors in adults with type 2 diabetes not taking insulin is unclear. METHODS: Secondary analysis of data from 172 participants from the Hyperglycemic Profiles in Obstructive Sleep Apnea randomized clinical trial. Participants simultaneously wore Dexcom G4 and Abbott Libre Pro CGM sensors for up to 2 weeks at baseline and again at the 3-month follow-up visit. RESULTS: At baseline (up to 2 weeks of CGM), mean glucose for both the Abbott and Dexcom sensors was approximately 150 mg/dL (8.3 mmol/L) and time in range (70180 mg/dL [3.910.0 mmol/L]) was just below 80. When comparing the same sensor at 2 different time points (two 2-week periods, 3 months apart), the within-person coefficient of variation (CVw) in mean glucose was 17.4 (Abbott) and 14.2 (Dexcom). CVw for percent time in range: 20.1 (Abbott) and 18.6 (Dexcom). At baseline, the Pearson correlation of mean glucose from the 2 sensors worn simultaneously was r 0.86, root mean squared error (RMSE), 13 mg/dL (0.7 mmol/L); for time in range, r 0.88, RMSE, 8 percentage points. CONCLUSIONS: Substantial variation was observed within sensors over time and across 2 different sensors worn simultaneously on the same individuals. Clinicians should be aware of this variability when using CGM technology to make clinical decisions.ClinicalTrials.gov Identifier: NCT02454153.

Quantifying ventilation by X-ray velocimetry in healthy adults.

RATIONALE: X-ray velocimetry (XV) has been utilized in preclinical models to assess lung motion and regional ventilation, though no studies have compared XV-derived physiologic parameters to measures derived through conventional means. OBJECTIVES: To assess agreement between XV-analysis of fluoroscopic lung images and pitot tube flowmeter measures of ventilation. METHODS: XV- and pitot tube-derived ventilatory parameters were compared during tidal breathing and with bilevel-assisted breathing. Levels of agreement were assessed using the Bland-Altman analysis. Mixed models were used to characterize the association between XV- and pitot tube-derived values and optimize XV-derived values for higher ventilatory volumes. MEASUREMENTS AND MAIN RESULTS: Twenty-four healthy volunteers were assessed during tidal breathing and 11 were reassessed with increased minute ventilation with bilevel-assisted breathing. No clinically significant differences were observed between the two methods for respiratory rate (average Δ: 0.58; 95% limits of agreement: -1.55, 2.71) or duty cycle (average Δ: 0.02; 95% limits of agreement: 0.01, 0.03). Tidal volumes and flow rates measured using XV were lower than those measured using the pitot tube flowmeter, particularly at the higher volume ranges with bilevel-assisted breathing. Under these conditions, a mixed-model based adjustment was applied to the XV-derived values of tidal volume and flow rate to obtain closer agreement with the pitot tube-derived values. CONCLUSION: Radiographically obtained measures of ventilation with XV demonstrate a high degree of correlation with parameters of ventilation. If the accuracy of XV were also confirmed for assessing the regional distribution of ventilation, it would provide information that goes beyond the scope of conventional pulmonary function tests or static radiographic assessments.

A case study of glucose levels during sleep using multilevel fast function on scalar regression inference.

Continuous glucose monitors (CGMs) are increasingly used to measure blood glucose levels and provide information about the treatment and management of diabetes. Our motivating study contains CGM data during sleep for 174 study participants with type II diabetes mellitus measured at a 5-min frequency for an average of 10 nights. We aim to quantify the effects of diabetes medications and sleep apnea severity on glucose levels. Statistically, this is an inference question about the association between scalar covariates and functional responses observed at multiple visits (sleep periods). However, many characteristics of the data make analyses difficult, including (1) nonstationary within-period patterns; (2) substantial between-period heterogeneity, non-Gaussianity, and outliers; and (3) large dimensionality due to the number of study participants, sleep periods, and time points. For our analyses, we evaluate and compare two methods: fast univariate inference (FUI) and functional additive mixed models (FAMMs). We extend FUI and introduce a new approach for testing the hypotheses of no effect and time invariance of the covariates. We also highlight areas for further methodological development for FAMM. Our study reveals that (1) biguanide medication and sleep apnea severity significantly affect glucose trajectories during sleep and (2) the estimated effects are time invariant.

Cost-effectiveness of neuromuscular electrical stimulation for the treatment of mild obstructive sleep apnea: an exploratory analysis.

OBJECTIVES: To assess the potential cost-effectiveness of neuromuscular electrical stimulation (NMES) for treatment of mild obstructive sleep apnea (OSA). METHODS: A decision-analytic Markov model was developed to estimate health state progression, incremental cost, and quality-adjusted life year (QALY) gain of NMES compared to no treatment, continuous airway pressure (CPAP), or oral appliance (OA) treatment. The base case assumed no cardiovascular (CV) benefit for any of the interventions, while potential CV benefit was considered in scenario analyses. Therapy effectiveness was based on a recent multi-center trial for NMES, and on the TOMADO and MERGE studies for OA and CPAP. Costs, considered from a United States payer perspective, were projected over lifetime for a 48-year-old cohort, 68% of whom were male. An incremental cost-effectiveness ratio (ICER) threshold of USD150,000 per QALY gained was applied. RESULTS: From a baseline AHI of 10.2 events/hour, NMES, OA and CPAP reduced the AHI to 6.9, 7.0 and 1.4 events/hour respectively. Long-term therapy adherence was estimated at 65-75% for NMES and 55% for both OA and CPAP. Compared to no treatment, NMES added between 0.268 and 0.536 QALYs and between USD7,481 and USD17,445 in cost, resulting in ICERs between USD15,436 and USD57,844 per QALY gained. Depending on long-term adherence assumptions, either NMES or CPAP were found to be the preferred treatment option, with NMES becoming more attractive with younger age and assuming CPAP was not used for the full night in all patients. CONCLUSIONS: NMES might be a cost-effective treatment option for patients with mild OSA.

Non-pharmacological interventions for sleep promotion in hospitalized children.

BACKGROUND: Healthy sleep is an important component of childhood development. Changes in sleep architecture, including sleep stage composition, quantity, and quality from infancy to adolescence are a reflection of neurologic maturation. Hospital admission for acute illness introduces modifiable risk factors for sleep disruption that may negatively affect active brain development during a period of illness and recovery. Thus, it is important to examine non-pharmacologic interventions for sleep promotion in the pediatric inpatient setting. OBJECTIVES: To evaluate the effect of non-pharmacological sleep promotion interventions in hospitalized children and adolescents on sleep quality and sleep duration, child or parent satisfaction, cost-effectiveness, delirium incidence, length of mechanical ventilation, length of stay, and mortality. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, three other databases, and three trials registers to December 2021. We searched Google Scholar, and two websites, handsearched conference abstracts, and checked reference lists of included studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) or quasi-RCTs, including cross-over trials, investigating the effects of any non-pharmacological sleep promotion intervention on the sleep quality or sleep duration (or both) of children aged 1 month to 18 years in the pediatric inpatient setting (intensive care unit [ICU] or general ward setting). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility, evaluated risk of bias, extracted and synthesized data, and used the GRADE approach to assess certainty of evidence. The primary outcomes were changes in both objective and subjective validated measures of sleep in children; secondary outcomes were child and parent satisfaction, cost-effectiveness ratios, delirium incidence or delirium-free days at time of hospital discharge, duration of mechanical ventilation, length of hospital stay, and mortality. MAIN RESULTS: We included 10 trials (528 participants; aged 3 to 22 years) in inpatient pediatric settings. Seven studies were conducted in the USA, two in Canada, and one in Brazil. Eight studies were funded by government, charity, or foundation grants. Two provided no information on funding. Eight studies investigated behavioral interventions (massage, touch therapy, and bedtime stories); two investigated physical activity interventions. Duration and timing of interventions varied widely. All studies were at high risk of performance bias due to the nature of the intervention, as participants, parents, and staff could not be masked to group assignment. We were unable to perform a quantitative synthesis due to substantial clinical heterogeneity. Behavioral interventions versus usual care Five studies (145 participants) provided low-certainty evidence of no clear difference between multicomponent relaxation interventions and usual care on objective sleep measures. Overall, evidence from single studies found no clear differences in daytime or nighttime sleep measures (33 participants); any sleep parameter (48 participants); or daytime or nighttime sleep or nighttime arousals (20 participants). One study (34 participants) reported no effect of massage on nighttime sleep, sleep efficiency (SE), wake after sleep onset (WASO), or total sleep time (TST) in adolescents with cancer. Evidence from a cross-over study in 10 children with burns suggested touch therapy may increase TST (391 minutes, interquartile range [IQR] 251 to 467 versus 331 minutes, IQR 268 to 373; P = 0.02); SE (76, IQR 53 to 90 versus 66, IQR 55 to 78; P = 0.04); and the number of rapid eye movement (REM) periods (4.5, IQR 2 to 5 versus 3.5, IQR 2 to 4; P = 0.03); but not WASO, sleep latency (SL), total duration of REM, or per cent of slow wave sleep. Four studies (232 participants) provided very low-certainty evidence on subjective measures of sleep. Evidence from single studies found that sleep efficiency may increase, and the percentage of nighttime wakefulness may decrease more over a five-day period following a massage than usual care (72 participants). One study (48 participants) reported an improvement in Children's Sleep Habits Questionnaire scores after discharge in children who received a multicomponent relaxation intervention compared to usual care. In another study, mean sleep duration per sleep episode was longer (23 minutes versus 15 minutes), and time to fall asleep was shorter (22 minutes versus 27 minutes) following a bedtime story versus no story (18 participants); and children listening to a parent-recorded story had longer SL than when a parent was present (mean 57.5 versus 43.5 minutes); both groups reported longer SL than groups who had a stranger-recorded story, and those who had no story and absent parents (94 participants; P < 0.001). In one study (34 participants), 87% (13/15) of participants felt they slept better following massage, with most parents (92%; 11/12) reporting they wanted their child to receive a massage again. Another study (20 participants) reported that parents thought the music, touch, and reading components of the intervention were acceptable, feasible, and had positive effects on their children (very low-certainty evidence). Physical activity interventions versus usual care One study (29 participants) found that an enhanced physical activity intervention may result in little or no improvement in TST or SE compared to usual care (low-certainty evidence). Another study (139 participants), comparing play versus no play found inconsistent results on subjective measures of sleep across different ages (TST was 49% higher for the no play groups in 4- to 7-year olds, 10% higher in 7- to 11-year olds, and 22% higher in 11- to 14-year olds). This study also found inconsistent results between boys and girls (girls in the first two age groups in the play group slept more than the no play group). No study evaluated child or parent satisfaction for behavioral interventions, or cost-effectiveness, delirium incidence or delirium-free days at hospital discharge, length of mechanical ventilation, length of hospital stay, or mortality for either behavioral or physical activity intervention. AUTHORS' CONCLUSIONS: The included studies were heterogeneous, so we could not quantitatively synthesize the results. Our narrative summary found inconsistent, low to very low-certainty evidence. Therefore, we are unable to determine how non-pharmacologic sleep promotion interventions affect sleep quality or sleep duration compared with usual care or other interventions. The evidence base should be strengthened through design and conduct of randomized trials, which use validated and highly reliable sleep assessment tools, including objective measures, such as polysomnography and actigraphy.

HIV Infection Is Associated With Variability in Ventricular Repolarization: The Multicenter AIDS Cohort Study (MACS).

BACKGROUND: People living with human immunodeficiency virus (HIV+) have greater risk for sudden arrhythmic death than HIV-uninfected (HIV-) individuals. HIV-associated abnormal cardiac repolarization may contribute to this risk. We investigated whether HIV serostatus is associated with ventricular repolarization lability by using the QT variability index (QTVI), defined as a log measure of QT-interval variance indexed to heart rate variance. METHODS: We studied 1123 men (589 HIV+ and 534 HIV-) from MACS (Multicenter AIDS Cohort Study), using the ZioXT ambulatory electrocardiography patch. Beat-to-beat analysis of up to 4 full days of electrocardiographic data per participant was performed using an automated algorithm (median analyzed duration [quartile 1-quartile 3]: 78.3 [66.3-83.0] hours/person). QTVI was modeled using linear mixed-effects models adjusted for demographics, cardiac risk factors, and HIV-related and inflammatory biomarkers. RESULTS: Mean (SD) age was 60.1 (11.9) years among HIV- and 54.2 (11.2) years among HIV+ participants (P<0.001), 83% of whom had undetectable (<20 copies/mL) HIV-1 viral load (VL). In comparison with HIV- men, HIV+ men had higher QTVI (adjusted difference of +0.077 [95% CI, +0.032 to +0.123]). The magnitude of this association depended on the degree of viremia, such that in HIV+ men with undetectable VL, adjusted QTVI was +0.064 (95% CI, +0.017 to +0.111) higher than in HIV- men, whereas, in HIV+ men with detectable VL, adjusted QTVI was higher by +0.150 (95% CI, 0.072-0.228) than in HIV- referents. Analysis of QTVI subcomponents showed that HIV+ men had: (1) lower heart rate variability irrespective of VL status, and (2) higher QT variability if they had detectable, but not with undetectable, VL, in comparison with HIV- men. Higher levels of C-reactive protein, interleukin-6, intercellular adhesion molecule-1, soluble tumor necrosis factor receptor 2, and soluble cluster of differentiation-163 (borderline), were associated with higher QTVI and partially attenuated the association with HIV serostatus. CONCLUSIONS: HIV+ men have greater beat-to-beat variability in QT interval (QTVI) than HIV- men, especially in the setting of HIV viremia and heightened inflammation. Among HIV+ men, higher QTVI suggests ventricular repolarization lability, which can increase susceptibility to arrhythmias, whereas lower heart rate variability signals a component of autonomic dysfunction.

Long-Term Noninvasive Ventilation in Chronic Stable Hypercapnic Chronic Obstructive Pulmonary Disease. An Official American Thoracic Society Clinical Practice Guideline.

Background: Noninvasive ventilation (NIV) is used for patients with chronic obstructive pulmonary disease (COPD) and chronic hypercapnia. However, evidence for clinical efficacy and optimal management of therapy is limited.Target Audience: Patients with COPD, clinicians who care for them, and policy makers.Methods: We summarized evidence addressing five PICO (patients, intervention, comparator, and outcome) questions. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to evaluate the certainty in evidence and generate actionable recommendations. Recommendations were formulated by a panel of pulmonary and sleep physicians, respiratory therapists, and methodologists using the Evidence-to-Decision framework.Recommendations:1) We suggest the use of nocturnal NIV in addition to usual care for patients with chronic stable hypercapnic COPD (conditional recommendation, moderate certainty); 2) we suggest that patients with chronic stable hypercapnic COPD undergo screening for obstructive sleep apnea before initiation of long-term NIV (conditional recommendation, very low certainty); 3) we suggest not initiating long-term NIV during an admission for acute-on-chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2-4 weeks after resolution (conditional recommendation, low certainty); 4) we suggest not using an in-laboratory overnight polysomnogram to titrate NIV in patients with chronic stable hypercapnic COPD who are initiating NIV (conditional recommendation, very low certainty); and 5) we suggest NIV with targeted normalization of PaCO2 in patients with hypercapnic COPD on long-term NIV (conditional recommendation, low certainty).Conclusions: This expert panel provides evidence-based recommendations addressing the use of NIV in patients with COPD and chronic stable hypercapnic respiratory failure.

Association of novel measures of sleep disturbances with blood pressure: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Mechanisms underlying blood pressure (BP) changes in obstructive sleep apnoea (OSA) are incompletely understood. We assessed the associations between BP and selected polysomnography (PSG) traits: sleep depth, airflow limitation measurements and OSA-specific hypoxic burden. METHODS: This cross-sectional analysis included 2055 participants from the Multi-Ethnic Study of Atherosclerosis who underwent PSG and BP measurements in 2010-2013. Sleep depth was assessed using the 'OR product', a continuous measure of arousability. Airflow limitation was assessed by duty cycle (Ti/Tt) and % of breaths with flow limitation, and hypoxia by 'hypoxic burden'. Primary outcomes were medication-adjusted systolic BP (SBP) and diastolic BP (DBP). We used generalised linear models adjusted for age, sex, race/ethnicity, smoking, education, body mass index, alcohol use, periodic limb movements and alternative physiological disturbances. RESULTS: The sample had a mean age of 68.4 years and apnoea-hypopnoea index of 14.8 events/hour. Sleep depth was not significantly associated with BP. Every 1 SD increment in log-transformed non-rapid eye movement duty cycle was associated with 0.9% decrease in SBP (95% CI: 0.1% to 1.6%), even after adjusting for sleep depth and hypoxic burden. Every 1 SD increment in log-transformed hypoxic burden was associated with a 1.1% increase in SBP (95% CI: 0.1% to 2.1%) and 1.9% increase in DBP (95% CI: 1.0% to 2.8%) among those not using hypertension medications. CONCLUSIONS: Higher duty cycle was associated with lower SBP overall and hypoxic burden with higher SBP and DBP among non-BP medication users. These findings suggest changes in both respiratory effort and oxygenation during sleep influence BP.

Diagnosis and Management of Obstructive Sleep Apnea: A Review.

Importance: Obstructive sleep apnea (OSA) affects 17% of women and 34% of men in the US and has a similar prevalence in other countries. This review provides an update on the diagnosis and treatment of OSA. Observations: The most common presenting symptom of OSA is excessive sleepiness, although this symptom is reported by as few as 15% to 50% of people with OSA in the general population. OSA is associated with a 2- to 3-fold increased risk of cardiovascular and metabolic disease. In many patients, OSA can be diagnosed with home sleep apnea testing, which has a sensitivity of approximately 80%. Effective treatments include weight loss and exercise, positive airway pressure, oral appliances that hold the jaw forward during sleep, and surgical modification of the pharyngeal soft tissues or facial skeleton to enlarge the upper airway. Hypoglossal nerve stimulation is effective in select patients with a body mass index less than 32. There are currently no effective pharmacological therapies. Treatment with positive airway pressure lowers blood pressure, especially in patients with resistant hypertension; however, randomized clinical trials of OSA treatment have not demonstrated significant benefit on rates of cardiovascular or cerebrovascular events. Conclusions and Relevance: OSA is common and the prevalence is increasing with the increased prevalence of obesity. Daytime sleepiness is among the most common symptoms, but many patients with OSA are asymptomatic. Patients with OSA who are asymptomatic, or whose symptoms are minimally bothersome and pose no apparent risk to driving safety, can be treated with behavioral measures, such as weight loss and exercise. Interventions such as positive airway pressure are recommended for those with excessive sleepiness and resistant hypertension. Managing asymptomatic OSA to reduce cardiovascular and cerebrovascular events is not currently supported by high-quality evidence.

Obstructive Sleep Apnea during REM Sleep and Cardiovascular Disease.

RATIONALE: Obstructive sleep apnea (OSA) during REM sleep is a common disorder. Data on whether OSA that occurs predominantly during REM sleep is associated with health outcomes are limited. OBJECTIVES: The present study examined the association between OSA during REM sleep and a composite cardiovascular endpoint in a community sample with and without prevalent cardiovascular disease. METHODS: Full-montage home polysomnography was conducted as part of the Sleep Heart Health Study. The study cohort was followed for an average of 9.5 years, during which time cardiovascular events were assessed. Only participants with a non-REM apnea-hypopnea index (AHI) of less than 5 events/h were included. A composite cardiovascular endpoint was determined as the occurrence of nonfatal or fatal events, including myocardial infarction, coronary artery revascularization, congestive heart failure, and stroke. Proportional hazards regression was used to derive the adjusted hazards ratios for the composite cardiovascular endpoint. MEASUREMENTS AND MAIN RESULTS: The sample consisted of 3,265 subjects with a non-REM AHI of less than 5.0 events/h. Using a REM AHI of less than 5.0 events/h as the reference group (n = 1,758), the adjusted hazards ratios for the composite cardiovascular endpoint in those with severe REM OSA (≥30 events/h; n = 180) was 1.35 (95% confidence interval, 0.98-1.85). Stratified analyses demonstrated that the association was most notable in those with prevalent cardiovascular disease and severe OSA during REM sleep with an adjusted hazards ratio of 2.56 (95% confidence interval, 1.46-4.47). CONCLUSIONS: Severe OSA that occurs primarily during REM sleep is associated with higher incidence of a composite cardiovascular endpoint, but in only those with prevalent cardiovascular disease.

Common variants in DRD2 are associated with sleep duration: the CARe consortium.

Sleep duration is implicated in the etiologies of chronic diseases and premature mortality. However, the genetic basis for sleep duration is poorly defined. We sought to identify novel genetic components influencing sleep duration in a multi-ethnic sample. Meta-analyses were conducted of genetic associations with self-reported, habitual sleep duration from seven Candidate Gene Association Resource (CARe) cohorts of over 25 000 individuals of African, Asian, European and Hispanic American ancestry. All individuals were genotyped for ∼50 000 SNPs from 2000 candidate heart, lung, blood and sleep genes. African-Americans had additional genome-wide genotypes. Four cohorts provided replication. A SNP (rs17601612) in the dopamine D2 receptor gene (DRD2) was significantly associated with sleep duration (P = 9.8 × 10(-7)). Conditional analysis identified a second DRD2 signal with opposite effects on sleep duration. In exploratory analysis, suggestive association was observed for rs17601612 with polysomnographically determined sleep latency (P = 0.002). The lead DRD2 signal was recently identified in a schizophrenia GWAS, and a genetic risk score of 11 additional schizophrenia GWAS loci genotyped on the IBC array was also associated with longer sleep duration (P = 0.03). These findings support a role for DRD2 in influencing sleep duration. Our work motivates future pharmocogenetics research on alerting agents such as caffeine and modafinil that interact with the dopaminergic pathway and further investigation of genetic overlap between sleep and neuro-psychiatric traits.

Sleep characteristics and risk of dementia and Alzheimer's disease: The Atherosclerosis Risk in Communities Study.

INTRODUCTION: This study tested the hypotheses that late-midlife obstructive sleep apnea (OSA) and short and long sleep duration are associated with dementia over 15 years of follow-up. METHODS: A total of 1667 Atherosclerosis Risk in Communities Study participants underwent in-home polysomnography (1996-1998) and were followed for dementia. Dementia was defined by (1) hospitalization diagnosis codes (1996-2012) and (2) a comprehensive neurocognitive examination (2011-2013) with adjudication. RESULTS: OSA and sleep duration were not associated with risk of incident dementia. When using adjudicated outcomes, severe OSA (≥30 vs. <5 apnea-hypopnea events/hour) was associated with higher risk of all-cause dementia (risk ratio [95% confidence interval], 2.35 [1.06-5.18]) and Alzheimer's disease dementia (1.66 [1.03-2.68]); associations were attenuated with cardiovascular risk factor adjustment. Sleeping <7 versus 8 to ≤9 hours was associated with higher risk of all-cause dementia (2.00 [1.03-3.86]). DISCUSSION: When adjudicated outcome definitions were used, late-midlife OSA and short sleep duration were associated with all-cause and Alzheimer's disease dementia in later life.

CPAP versus oxygen in obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea is associated with hypertension, inflammation, and increased cardiovascular risk. Continuous positive airway pressure (CPAP) reduces blood pressure, but adherence is often suboptimal, and the benefit beyond management of conventional risk factors is uncertain. Since intermittent hypoxemia may underlie cardiovascular sequelae of sleep apnea, we evaluated the effects of nocturnal supplemental oxygen and CPAP on markers of cardiovascular risk. METHODS: We conducted a randomized, controlled trial in which patients with cardiovascular disease or multiple cardiovascular risk factors were recruited from cardiology practices. Patients were screened for obstructive sleep apnea with the use of the Berlin questionnaire, and home sleep testing was used to establish the diagnosis. Participants with an apnea-hypopnea index of 15 to 50 events per hour were randomly assigned to receive education on sleep hygiene and healthy lifestyle alone (the control group) or, in addition to education, either CPAP or nocturnal supplemental oxygen. Cardiovascular risk was assessed at baseline and after 12 weeks of the study treatment. The primary outcome was 24-hour mean arterial pressure. RESULTS: Of 318 patients who underwent randomization, 281 (88%) could be evaluated for ambulatory blood pressure at both baseline and follow-up. On average, the 24-hour mean arterial pressure at 12 weeks was lower in the group receiving CPAP than in the control group (-2.4 mm Hg; 95% confidence interval [CI], -4.7 to -0.1; P=0.04) or the group receiving supplemental oxygen (-2.8 mm Hg; 95% CI, -5.1 to -0.5; P=0.02). There was no significant difference in the 24-hour mean arterial pressure between the control group and the group receiving oxygen. A sensitivity analysis performed with the use of multiple imputation approaches to assess the effect of missing data did not change the results of the primary analysis. CONCLUSIONS: In patients with cardiovascular disease or multiple cardiovascular risk factors, the treatment of obstructive sleep apnea with CPAP, but not nocturnal supplemental oxygen, resulted in a significant reduction in blood pressure. (Funded by the National Heart, Lung, and Blood Institute and others; HeartBEAT ClinicalTrials.gov number, NCT01086800 .).

Lung Function and Incident Kidney Disease: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Reduced lung function is associated with clinical outcomes such as cardiovascular disease. However, little is known about its association with incident end-stage renal disease (ESRD) and chronic kidney disease (CKD). STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 14,946 participants aged 45 to 64 years at baseline (1987-1989) in the Atherosclerosis Risk in Communities (ARIC) Study (45.0% men and 25.2% black), with follow-up through 2012. PREDICTORS: Race- and sex-specific quartiles of percent-predicted forced vital capacity (FVC) and the proportion of forced expiratory volume in 1 second of expiration to FVC (FEV1/FVC) at baseline determined with spirometry. OUTCOMES: Incident ESRD (defined here as renal replacement therapy or death due to CKD) as the primary outcome and incident CKD (defined here as ESRD, ≥25% decline in estimated glomerular filtration rate to a level <60mL/min/1.73m2, or CKD-related hospitalizations/deaths) as the secondary outcome. RESULTS: During a median follow-up of 23.6 years, 526 (3.5%) participants developed ESRD. After adjusting for potential confounders, the cause-specific HR of incident ESRD for the lowest (vs highest) quartile was 1.72 (95% CI, 1.31-2.26) for percent-predicted FVC and 1.33 (95% CI, 1.03-1.73) for FEV1/FVC. Compared to a high-normal lung function pattern, a mixed pattern (ie, percent-predicted FVC<80% and FEV1/FVC<70%; 3.4% of participants) demonstrated the highest adjusted cause-specific HR of ESRD at 2.28 (95% CI, 1.50-3.45), followed by the restrictive pattern (ie, percent-predicted FVC<80% and FEV1/FVC≥70%; 4.8% of participants) at 2.03 (95% CI, 1.47-2.81), obstructive pattern (ie, percent-predicted FVC≥80% and FEV1/FVC<70%; 18.9% of participants) at 1.47 (95% CI, 1.09-1.99), and low-normal pattern (ie, percent-predicted FVC 80%-<100% and FEV1/FVC≥70%, or percent-predicted FVC≥80% and FEV1/FVC 70%-<75%; 44.3% of participants) at 1.21 (95% CI, 0.94-1.55). Similar associations were seen with incident CKD. LIMITATIONS: Limited number of participants with moderate/severe lung dysfunction and spirometry only at baseline. CONCLUSIONS: Reduced lung function, particularly lower percent-predicted FVC, is independently associated with CKD progression. Our findings suggest a potential pathophysiologic contribution of reduced lung function to the development of CKD and a need for monitoring kidney function in persons with reduced lung function.

Influence of Lung Function and Sleep-disordered Breathing on All-Cause Mortality. A Community-based Study.

RATIONALE: Whether sleep-disordered breathing (SDB) severity and diminished lung function act synergistically to heighten the risk of adverse health outcomes remains a topic of significant debate. OBJECTIVES: The current study sought to determine whether the association between lower lung function and mortality would be stronger in those with increasing severity of SDB in a community-based cohort of middle-aged and older adults. METHODS: Full montage home sleep testing and spirometry data were analyzed on 6,173 participants of the Sleep Heart Health Study. Proportional hazards models were used to calculate risk for all-cause mortality, with FEV1 and apnea-hypopnea index (AHI) as the primary exposure indicators along with several potential confounders. MEASUREMENTS AND MAIN RESULTS: All-cause mortality rate was 26.9 per 1,000 person-years in those with SDB (AHI ≥5 events/h) and 18.2 per 1,000 person-years in those without (AHI <5 events/h). For every 200-ml decrease in FEV1, all-cause mortality increased by 11.0% in those without SDB (hazard ratio, 1.11; 95% confidence interval, 1.08-1.13). In contrast, for every 200-ml decrease in FEV1, all-cause mortality increased by only 6.0% in participants with SDB (hazard ratio, 1.06; 95% confidence interval, 1.04-1.09). Additionally, the incremental influence of lung function on all-cause mortality was less with increasing severity of SDB (P value for interaction between AHI and FEV1, 0.004). CONCLUSIONS: Lung function was associated with risk for all-cause mortality. The incremental contribution of lung function to mortality diminishes with increasing severity of SDB.