[Show abstract][Hide abstract] ABSTRACT: Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.Molecular Psychiatry advance online publication, 2 December 2014; doi:10.1038/mp.2014.133.
[Show abstract][Hide abstract] ABSTRACT: Background:The advent of home sleep testing has allowed for the development of an ambulatory care model for obstructive sleep apnea (OSA) that is easily deployed by most healthcare providers. While automated algorithms that accompany home sleep monitors can identify and classify disordered breathing events, it is unclear if manual scoring followed by expert review of home sleep recordings is of any value. Thus, the current study examined the agreement between automated and manual scoring of home sleep recordings. Methods:Two type III monitors (ApneaLink Plus and Embletta) with distinct study samples were used. Data from manual and automated scoring were available for 200 subjects. Two thresholds for oxygen desaturation (≥3% and ≥4%) were used to define disordered breathing events. Agreement between manual and automated scoring was examined using Pearson's correlation coefficients and Bland-Altman analyses. Results:Automated scoring consistently underscored disordered breathing events compared with manual scoring for both sleep monitors irrespective of whether a ≥3% or ≥4% oxygen desaturation threshold was used to define the apnea-hypopnea index (AHI). Bland-Altman analyses revealed that for the ApneaLink Plus, the average AHI difference between the manual and automated scoring was 6.1 events/hr (95% CI: 4.9-7.3) and 4.6 events/hr (95% CI: 3.5-5.6) for the ≥3% and ≥4% oxygen desaturation threshold, respectively. Similarly, for the Embletta, the average difference between the manual and automated scoring was 5.3 events/hr (95% CI: 3.2-7.3) and 8.4 events/hr (95% CI: 7.2-9.6), respectively. Conclusions:While agreement between automated and manual scoring of home sleep recordings varies based on the device used, modest agreement was observed between the two approaches. However, manual review of HST recordings can decrease the misclassification of OSA severity, particularly for those with mild disease. Study Registration:http://www.clinicaltrials.gov (NCT01503164).
The advent of home sleep testing has allowed for the development of an ambulatory care model for obstructive sleep apnea (OSA) that is easily deployed by most healthcare providers. While automated algorithms that accompany home sleep monitors can identify and classify disordered breathing events, it is unclear if manual scoring followed by expert review of home sleep recordings is of any value. Thus, the current study examined the agreement between automated and manual scoring of home sleep recordings.
Two type III monitors (ApneaLink Plus and Embletta) with distinct study samples were used. Data from manual and automated scoring were available for 200 subjects. Two thresholds for oxygen desaturation (≥3% and ≥4%) were used to define disordered breathing events. Agreement between manual and automated scoring was examined using Pearson's correlation coefficients and Bland-Altman analyses.
Automated scoring consistently underscored disordered breathing events compared with manual scoring for both sleep monitors irrespective of whether a ≥3% or ≥4% oxygen desaturation threshold was used to define the apnea-hypopnea index (AHI). Bland-Altman analyses revealed that for the ApneaLink Plus, the average AHI difference between the manual and automated scoring was 6.1 events/hr (95% CI: 4.9-7.3) and 4.6 events/hr (95% CI: 3.5-5.6) for the ≥3% and ≥4% oxygen desaturation threshold, respectively. Similarly, for the Embletta, the average difference between the manual and automated scoring was 5.3 events/hr (95% CI: 3.2-7.3) and 8.4 events/hr (95% CI: 7.2-9.6), respectively.
While agreement between automated and manual scoring of home sleep recordings varies based on the device used, modest agreement was observed between the two approaches. However, manual review of HST recordings can decrease the misclassification of OSA severity, particularly for those with mild disease.
[Show abstract][Hide abstract] ABSTRACT: To determine the association between sleep-disordered breathing (SDB) and decline in instrumental activities of daily living (IADLs) and mobility in older women.
Journal of the American Geriatrics Society 11/2014; · 4.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Blood pressure (BP) may be adversely affected by a variety of sleep disturbances, including sleep fragmentation, hypoxemia, respiratory disturbances, and periodic limb movements. We aim to identify which polysomnography indices are most strongly and consistently associated with systolic and diastolic blood pressure (SBP, DBP) levels in a population-based sample.
[Show abstract][Hide abstract] ABSTRACT: Obstructive sleep apnea causes intermittent hypoxia (IH) and is associated with insulin resistance and type 2 diabetes. IH increases plasma catecholamine levels, which may increase insulin resistance and suppress insulin secretion. The objective of this study was to determine if adrenal medullectomy (MED) prevents metabolic dysfunction in IH. MED or sham surgery was performed in 60 male C57BL/6J mice, which were then exposed to IH or control conditions (intermittent air) for 6 weeks. IH increased plasma epinephrine and norepinephrine levels, increased fasting blood glucose and lowered basal and glucose-stimulated insulin secretion. MED decreased baseline epinephrine and prevented the IH induced increase in epinephrine, whereas the norepinephrine response remained intact. MED improved glucose tolerance in mice exposed to IH, attenuated the impairment in basal and glucose-stimulated insulin secretion, but did not prevent IH-induced fasting hyperglycemia or insulin resistance. We conclude that the epinephrine release from the adrenal medulla during IH suppresses insulin secretion causing hyperglycemia.
[Show abstract][Hide abstract] ABSTRACT: Intermittent hypoxemia is a fundamental pathophysiological consequence of sleep-disordered breathing and may alter glucose metabolism. To characterize the association between sleep-related intermittent hypoxemia and glucose metabolism, overnight pulse-oximetry and an oral glucose tolerance test were completed in a cohort of middle-aged and older Japanese adults.
[Show abstract][Hide abstract] ABSTRACT: 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 .).
New England Journal of Medicine 06/2014; 370(24):2276-2285. · 54.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To examine pediatric intensivist sedation management, sleep promotion, and delirium screening practices for intubated and mechanically ventilated children.
An international, online survey of questions regarding sedative and analgesic medication choices and availability, sedation protocols, sleep optimization, and delirium recognition and treatment.
Member societies of the World Federation of Pediatric Intensive and Critical Care Societies were asked to send the survey to their mailing lists; responses were collected from July 2012 to January 2013.
Pediatric critical care providers.
The survey was completed by 341 respondents, the majority of whom were from North America (70%). Twenty-seven percent of respondents reported having written sedation protocols. Most respondents worked in PICUs with sedation scoring systems (70%), although only 42% of those with access to scoring systems reported routine daily use for goal-directed sedation management. The State Behavioral Scale was the most commonly used scoring system in North America (22%), with the COMFORT score more prevalent in all other countries (39%). The most commonly used sedation regimen for intubated children was a combination of opioid and benzodiazepine (72%). Most intensivists chose fentanyl as their first-line opioid (66%) and midazolam as their first-line benzodiazepine (86%) and prefer to administer these medications as continuous infusions. Propofol and dexmedetomidine were the most commonly restricted medications in PICUs internationally. Use of earplugs, eye masks, noise reduction, and lighting optimization for sleep promotion was uncommon. Delirium screening was not practiced in 71% of respondent's PICUs, and only 2% reported routine screening at least twice a day.
The results highlight the heterogeneity in sedation practices among intensivists who care for critically ill children as well as a paucity of sleep promotion and delirium screening in PICUs worldwide.
Critical care medicine 04/2014; · 6.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We hypothesized that untreated severe obstructive sleep apnea (OSA) is associated with elevated ambulatory blood pressure (BP) in subjects with high cardiovascular disease (CVD) risk despite medical management.
Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine 01/2014; 10(8):835-43. · 2.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We hypothesized increasing obstructive sleep apnea (OSA) severity would be associated with nondipping blood pressure (BP) in increased cardiovascular disease (CVD) risk.
Baseline data from 298 cardiology patients recruited for a multicenter randomized controlled trial were examined. Dipping was defined as a sleep-related BP or heart rate (HR) reduction of at least 10%. Logistic regression models were fit, adjusting for age, sex, race, BMI, CVD risk factors, CVD, and study site.
There was a statistically significant 4% increase in the odds of nondipping SBP per 1-unit increase in both apnea hypopnea index (AHI) and oxygen desaturation index (ODI). There was no significant relationship between AHI and nondipping mean arterial pressure (MAP); however, a 3% increase in the odds of nondipping MAP per 1-unit increase in ODI was observed [odds ratio (OR) = 1.03; 95% confidence interval (CI) 1.00-1.05]. At severe OSA levels, a 10 and 4% increase in odds of nondipping DBP per 1-unit increase in AHI and ODI were observed, respectively. A 6% [OR = 1.06; 95% CI (1.01-1.10)] increase in nondipping HR odds was observed with each increase in ODI until the upper quartile of ODI.
In patients at cardiovascular risk and moderate-to-severe OSA, increasing AHI and/or ODI were associated with increased odds of nondipping SBP and nondipping MAP. More severe levels of AHI and ODI also were associated with nondipping DBP. These results support progressive BP burden associated with increased OSA severity even in patients managed by cardiology specialty care.
Journal of Hypertension 12/2013; · 4.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Short and long sleep duration are associated with increased risk of type 2 diabetes. We aimed to investigate whether genetic variants for fasting glucose or type 2 diabetes associate with short or long sleep duration and whether sleep duration modifies the association of genetic variants with these traits.
We examined the cross-sectional relationship between self-reported habitual sleep duration and prevalence of type 2 diabetes in individuals of European descent participating in five studies included in the Candidate Gene Association Resource (CARe), totalling 1,474 cases and 8,323 controls. We tested for association of 16 fasting glucose-associated variants, 27 type 2 diabetes-associated variants and aggregate genetic risk scores with continuous and dichotomised (≤5 h or ≥9 h) sleep duration using regression models adjusted for age, sex and BMI. Finally, we tested whether a gene × behaviour interaction of variants with sleep duration had an impact on fasting glucose or type 2 diabetes risk.
Short sleep duration was significantly associated with type 2 diabetes in CARe (OR 1.32; 95% CI 1.08, 1.61; p = 0.008). Variants previously associated with fasting glucose or type 2 diabetes and genetic risk scores were not associated with sleep duration. Furthermore, no study-wide significant interaction was observed between sleep duration and these variants on glycaemic traits. Nominal interactions were observed for sleep duration and PPARG rs1801282, CRY2 rs7943320 and HNF1B rs4430796 in influencing risk of type 2 diabetes (p < 0.05).
Our findings suggest that differences in habitual sleep duration do not mediate or modify the relationship between common variants underlying glycaemic traits (including in circadian rhythm genes) and diabetes.
[Show abstract][Hide abstract] ABSTRACT: Aims: Obstructive sleep apnea (OSA) is associated with cardiovascular morbidity and mortality, although the underlying mechanisms are not well understood. We aimed to determine whether more severe OSA, measured by the respiratory disturbance index (RDI), is associated with subclinical myocardial injury and increased myocardial wall stress Methods and Results: 1,645 participants (62.5 ± 5.5 years and 54% women) free of coronary heart disease and heart failure and participating in both the Atherosclerosis Risk in the Communities and the Sleep Heart Health Studies underwent overnight polysomnography and measurement of high sensitivity Troponin T (hs-TnT) and N terminal pro B-type natriuretic peptide (NT-proBNP). OSA severity was defined using conventional clinical categories: none (RDI≤5), mild (RDI 5-15), moderate (RDI 15-30) and severe (RDI>30). Hs-TnT, but not NT-proBNP, was associated with OSA after adjusting for 17 potential confounders (p=0.02). Over a median of 12.4 [IQR 11.6-13.1] years follow up, hs-TnT was related to risk of death or incident heart failure in all OSA categories (p≤0.05 in each category). Conclusion: In middle aged to older individuals OSA severity is independently associated with higher levels of hs-TnT, suggesting that subclinical myocardial injury may play a role in the association between OSA and risk of heart failure. OSA was not associated with NT-proBNP levels after adjusting for multiple possible confounders.
American Journal of Respiratory and Critical Care Medicine 10/2013; · 11.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obstructive sleep apnoea and type 2 diabetes are common medical disorders that have important clinical, epidemiological, and public health implications. Research done in the past two decades indicates that obstructive sleep apnoea, through the effects of intermittent hypoxaemia and sleep fragmentation, could contribute independently to the development of insulin resistance, glucose intolerance, and type 2 diabetes. Conversely, type 2 diabetes might increase predisposition to, or accelerate progression of, obstructive and central sleep apnoea, possibly through the development of peripheral neuropathy and abnormalities of ventilatory and upper airway neural control. Although more research is needed to clarify the mechanisms underlying the bidirectional association between the two disorders, their frequent coexistence should prompt all health-care professionals to embrace clinical practices that include screening of a patient presenting with one disorder for the other. Early identification of obstructive sleep apnoea in patients with metabolic dysfunction, including type 2 diabetes, and assessment for metabolic abnormalities in those with obstructive sleep apnoea could reduce cardiovascular disease risk and improve the quality of life of patients with these chronic diseases.
The lancet. Respiratory medicine. 06/2013; 1(4):329-38.
[Show abstract][Hide abstract] ABSTRACT: Critically ill children in the pediatric intensive care unit (PICU) are exposed to multiple physical, environmental and pharmacologic factors which increase the propensity for sleep disruption and loss and may, in turn, play a role in short-term recovery from critical illness and long-term neurocognitive outcomes. Mechanically ventilated children receive sedative and analgesic medications, often at high doses and for long durations, to improve comfort and synchrony with mechanical ventilation. Sedatives and analgesics can decrease slow wave sleep and rapid eye movement sleep. Paradoxically, sedative medication doses are often increased in critically ill children to improve the subjective assessment of sedation and sleep, leading to further agitation and deterioration of sleep quality. The heterogeneity in age and critical illness encountered in the PICU pose several challenges to research on sleep in this setting. The present article reviews the available evidence on sleep in critically ill children admitted to the PICU, with an emphasis on subjective and objective methods of sleep assessment used and special populations studied, including mechanically ventilated children and children with severe burns.
Sleep Medicine Reviews 05/2013; · 9.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Cigarette smoking is the major cause of chronic obstructive pulmonary disease and emphysema. Recent studies suggest that susceptibility to cigarette smoke may vary by race/ethnicity; however, they were generally small and relied on self-reported race/ethnicity. OBJECTIVE: To test the hypothesis that relationships of smoking to lung function and per cent emphysema differ by genetic ancestry and self-reported race/ethnicity among Caucasians, African-Americans, Hispanics and Chinese-Americans. DESIGN: Cross-sectional population-based study of adults age 45-84 years in the USA. MEASUREMENTS: Principal components of genetic ancestry and continental ancestry estimated from one million genome-wide single nucleotide polymorphisms; pack-years of smoking; spirometry measured for 3344 participants; and per cent emphysema on computed tomography for 8224 participants. RESULTS: The prevalence of ever-smoking was: Caucasians, 57.6%; African-Americans, 56.4%; Hispanics, 46.7%; and Chinese-Americans, 26.8%. Every 10 pack-years was associated with -0.73% (95% CI -0.90% to -0.56%) decrement in the forced expiratory volume in 1 s to forced vital capacity (FEV1 to FVC) and a 0.23% (95% CI 0.08% to 0.38%) increase in per cent emphysema. There was no evidence that relationships of pack-years to the FEV1 to FVC, airflow obstruction and per cent emphysema varied by genetic ancestry (all p>0.10), self-reported race/ethnicity (all p>0.10) or, among African-Americans, African ancestry. There were small differences in relationships of pack-years to the FEV1 among male Chinese-Americans and to the FEV1 to FVC ratio with African and Native American ancestry among male Hispanics only. CONCLUSIONS: In this large cohort, there was little to no evidence that the associations of smoking to lung function and per cent emphysema differed by genetic ancestry or self-reported race/ethnicity.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Chitotriosidase (ChT) is secreted by chronically activated macrophages in Gaucher's disease. We hypothesize that circulating levels of ChT are altered with normal aging, reflecting age-related chronic macrophage activation. Potential sources that might contribute to altered levels were assessed by measuring systemic levels of ChT are α-naphthyl acetate esterase, a macrophage lysosomal enzyme; granulocyte-macrophage colony-stimulating factor (GM-CSF), which stimulates neutrophilic granule release of ChT; interleukin-6 (IL-6); and neopterin, a macrophage activation marker. METHODS: Serum was obtained from 315 healthy participants whose age ranged from 18 to 92 years. Anthropometric measures included percent body fat and body mass index. ChT and α-naphthyl acetate esterase levels were measured by enzyme activity assays. GM-CSF, IL-6, and neopterin concentrations were measured by commercial enzyme-linked immunosorbent assays. Serum marker values were statistically analyzed using nonparametric tests. RESULTS: Six percent of the participants had undetectable ChT levels. A positive association with age was observed for ChT and IL-6, whereas a negative correlation with age was seen for α-naphthyl acetate esterase and GM-CSF. ChT values were not associated with α-naphthyl acetate esterase or GM-CSF levels. ChT was independently associated with IL-6 and neopterin levels, but statistical significance was attenuated when controlled for age. CONCLUSIONS: The data are consistent with increased serum ChT activity not arising from altered macrophage lysosomal enzyme trafficking or GM-CSF-stimulated release of neutrophil granule stores. The association of ChT with age remains significant after controlling for neopterin and IL-6 changes with age, suggesting that ChT levels reflect a macrophage state distinct from acute macrophage activation or inflammatory state.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 03/2013; · 4.31 Impact Factor