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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.

Rationale: Although obstructive sleep apnea is associated with physiological perturbations that increase risk of hypertension and are proatherogenic, it is uncertain whether sleep apnea is associated with increased stroke risk in the general population.Objectives: To quantify the incidence of ischemic stroke with sleep apnea in a community-based sample of men and women across a wide range of sleep apnea.Methods: Baseline polysomnography was performed between 1995 and 1998 in a longitudinal cohort study. The primary exposure was the obstructive apnea-hypopnea index (OAHI) and outcome was incident ischemic stroke.Measurements and Main Results: A total of 5,422 participants without a history of stroke at the baseline examination and untreated for sleep apnea were followed for a median of 8.7 years. One hundred ninety-three ischemic strokes were observed. In covariate-adjusted Cox proportional hazard models, a significant positive association between ischemic stroke and OAHI was observed in men (P value for linear trend: P = 0.016). Men in the highest OAHI quartile (>19) had an adjusted hazard ratio of 2.86 (95% confidence interval, 1.1-7.4). In the mild to moderate range (OAHI, 5-25), each one-unit increase in OAHI in men was estimated to increase stroke risk by 6% (95% confidence interval, 2-10%). In women, stroke was not significantly associated with OAHI quartiles, but increased risk was observed at an OAHI greater than 25.Conclusions: The strong adjusted association between ischemic stroke and OAHI in community-dwelling men with mild to moderate sleep apnea suggests that this is an appropriate target for future stroke prevention trials. [ABSTRACT FROM AUTHOR]

The belief that integrated delivery systems offer better care at lower cost has contributed to growing interest in accountable care organizations. These provider-led delivery systems would accept responsibility for their primary care populations and would have financial incentives for improving care and reducing costs. We investigated this belief by comparing the costs and quality of care provided to Medicare beneficiaries in twenty-two health care markets by physicians who did and did not work within large multispecialty group practices affiliated with the Council of Accountable Physician Practices. In most markets, and after adjustment for patient factors, group physicians affiliated with the council provided higher-quality care at a 3.6 percent lower annual cost ($272 per patient). [ABSTRACT FROM AUTHOR]

Background: Most estimates of short- and long-term survival after hepatic resection of colorectal cancer metastases are derived from surgical case series. For the current report, the authors used Medicare data to investigate operative mortality and long-term survival in a national sample and examined the factors associated with survival.Methods: Data were analyzed from Medicare enrollees (age >or=65 years) who were admitted to hospital between January 1, 2000 and December 31, 2004 with a primary diagnosis of colorectal cancer with resection. The sample was restricted to patients who subsequently underwent hepatic resection for liver metastases. The Medicare Denominator File was used to determine operative mortality and long-term survival and the factors that were associated with those outcomes.Results: Of the 306,061 Medicare beneficiaries who were diagnosed with colorectal cancer, 3957 patients were identified who underwent hepatic resection for liver metastases. The crude 30-day and 90-day mortality rates were 4% and 8.2%, respectively, and the 5-year survival rate was 25.5%. Advancing age (hazards ratio [HR], 1.83; 95% confidence interval [95% CI], 1.32-2.53 for age >or=80 years vs ages 65-69 years), comorbid disease (HR, 1.40; 95% CI, 1.06-1.85 for Charlson >or=5 vs Charlson 0), and synchronous colon/hepatic resection (HR, 2.46; 95% CI, 1.89-3.20 for synchronous vs metachronous resection) were associated with worse 90-day mortality. Similarly, long-term mortality was associated with age (HR, 1.36; 95% CI, 1.18-1.56), comorbid disease (HR, 1.51; 95% CI, 1.36-1.69), and synchronous colon/hepatic resection (HR, 1.37; 95% CI, 1.24-1.51 for synchronous vs metachronous resection).Conclusions: In this national study, short- and long-term survival was worse than that reported in surgical case series. Subgroups at high risk for worse outcomes include the extreme elderly and those undergoing synchronous colon and hepatic resection. [ABSTRACT FROM AUTHOR]

Unlabelled: This study was performed to determine whether patients who sustain an intertrochanteric fracture have better outcomes when stabilized using a sliding hip screw or an intramedullary nail. A 20% sample of Part A and B entitled Medicare beneficiaries 65 years or older was used to generate a cohort of patients who sustained intertrochanteric femur fractures between 1999 and 2001. Two fracture implant groups, intramedullary nail and sliding hip screw, were identified using Current Procedural Terminology and International Classification of Diseases, 9th Revision codes. The cohort consisted of 43,659 patients. Patients treated with an intramedullary nail had higher rates of revision surgery during the first year than those treated with a sliding hip screw (7.2% intramedullary nail versus 5.5% sliding hip screw). Mortality rates at 30 days (14.2% intramedullary nail versus 15.8% sliding hip screw) and 1 year (30.7% intramedullary nail versus 32.5% sliding hip screw) were similar. Adjusted secondary outcome measures showed significant increases in the intramedullary nail group relative to the sliding hip screw group for index hospital length of stay, days of rehabilitation services in the first 6 months after discharge, and total expenditures for doctor and hospital services.Level Of Evidence: Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Objective: To characterize the association between sleep-disordered breathing (SDB) and impaired fasting glucose (IFG), impaired glucose tolerance (IGT), combined IFG and IGT, and occult diabetes in individuals of different body habitus.Research Design and Methods: Cross-sectional analysis of 2,588 participants (aged 52-96 years; 46% men) without known diabetes. SDB was defined as respiratory disturbance index >or=10 events/h. IFG, IGT, occult diabetes, and body weight were classified according to recent accepted guidelines. Participants with and without SDB were compared on prevalence and odds ratios for measures of impaired glucose metabolism (IGM), adjusting for age, sex, race, BMI, and waist circumference.Results: SDB was observed in 209 nonoverweight and 1,036 overweight/obese participants. SDB groups had significantly higher adjusted prevalence and adjusted odds of IFG, IFG plus IGT, and occult diabetes. The adjusted odds ratio for all subjects was 1.3 (95% CI 1.1-1.6) for IFG, 1.2 (1.0-1.4) for IGT, 1.4 (1.1-2.7) for IFG plus IGT, and 1.7 (1.1-2.7) for occult diabetes.Conclusions: SDB was associated with occult diabetes, IFG, and IFG plus IGT, after adjusting for age, sex, race, BMI, and waist circumference. The magnitude of these associations was similar in nonoverweight and overweight participants. The consistency of associations across all measures of IGM and body habitus groups and the significant association between SDB and IFG plus IGT, a risk factor for rapid progression to diabetes, cardiovascular disease, and mortality, suggests the importance of SDB as a risk factor for clinically important levels of metabolic dysfunction. [ABSTRACT FROM AUTHOR]

Background Administration of expanded tumor-infiltrating lymphocytes in association with lymphodepleting chemotherapy is effective in some patients with advanced malignant melanoma. However, obtaining lymphocytes and subsequent expansion is labor intensive, making it impractical for broad clinical application. Allogeneic transplantation may have anti-melanoma efficacy because of a graft vs. tumor effect. The disappointing tumor control observed post-transplant suggests that adoptive immunotherapy using melanoma-reactive cells will be essential for sustained responses. Methods Melanoma cell lines were grown from two patients with advanced disease. High-level CD80 and CD86 expression was obtained in the tumor lines using a retroviral vector for gene transfer. Transduced melanoma and controls were cultured with mononuclear cells from HLA-identical sibling donors. Results Expression of CD80 and CD86, particularly the former, promoted marked expansion of lymphocytes from HLA-matched sibling donors. Proliferation of up to 300-fold after 4 weeks of culture was observed. Lymphocytes from cultures stimulated with CD80 demonstrated cytotoxicity against recipient-untransfected melanoma (45-75% specific lysis at an E:T ratio of 50:1). Although expanded lymphocytes were predominantly CD4+, cytotoxicity was greatest in the numerically smaller CD8+ subpopulation. Both CD4+ and CD8+ cells secreted IFN-γ (but not IL-4) on exposure to untransduced stimulator melanoma cells. Discussion Our strategy generates a large number of melanoma-reactive lymphocytes from HLA-identical siblings using a 4-week culture strategy. Lymphocytes expanded in this way offer an alternative to tumor-infiltrating lymphocytes for allogeneic cellular immunotherapy after stem cell transplantation in young patients. [ABSTRACT FROM AUTHOR]

Context: Comparisons of outcomes between patients treated and untreated in observational studies may be biased due to differences in patient prognosis between groups, often because of unobserved treatment selection biases.Objective: To compare 4 analytic methods for removing the effects of selection bias in observational studies: multivariable model risk adjustment, propensity score risk adjustment, propensity-based matching, and instrumental variable analysis.Design, Setting, and Patients: A national cohort of 122,124 patients who were elderly (aged 65-84 years), receiving Medicare, and hospitalized with acute myocardial infarction (AMI) in 1994-1995, and who were eligible for cardiac catheterization. Baseline chart reviews were taken from the Cooperative Cardiovascular Project and linked to Medicare health administrative data to provide a rich set of prognostic variables. Patients were followed up for 7 years through December 31, 2001, to assess the association between long-term survival and cardiac catheterization within 30 days of hospital admission.Main Outcome Measure: Risk-adjusted relative mortality rate using each of the analytic methods.Results: Patients who received cardiac catheterization (n = 73 238) were younger and had lower AMI severity than those who did not. After adjustment for prognostic factors by using standard statistical risk-adjustment methods, cardiac catheterization was associated with a 50% relative decrease in mortality (for multivariable model risk adjustment: adjusted relative risk [RR], 0.51; 95% confidence interval [CI], 0.50-0.52; for propensity score risk adjustment: adjusted RR, 0.54; 95% CI, 0.53-0.55; and for propensity-based matching: adjusted RR, 0.54; 95% CI, 0.52-0.56). Using regional catheterization rate as an instrument, instrumental variable analysis showed a 16% relative decrease in mortality (adjusted RR, 0.84; 95% CI, 0.79-0.90). The survival benefits of routine invasive care from randomized clinical trials are between 8% and 21%.Conclusions: Estimates of the observational association of cardiac catheterization with long-term AMI mortality are highly sensitive to analytic method. All standard risk-adjustment methods have the same limitations regarding removal of unmeasured treatment selection biases. Compared with standard modeling, instrumental variable analysis may produce less biased estimates of treatment effects, but is more suited to answering policy questions than specific clinical questions. [ABSTRACT FROM AUTHOR]

Rationale: Sleep-disordered breathing recurrent intermittent hypoxia and sympathetic nervous system activity surges provide the milieu for cardiac arrhythmia development.Objective: We postulate that the prevalence of nocturnal cardiac arrhythmias is higher among subjects with than without sleep-disordered breathing.Methods: The prevalence of arrhythmias was compared in two samples of participants from the Sleep Heart Health Study frequency-matched on age, sex, race/ethnicity, and body mass index: (1) 228 subjects with sleep-disordered breathing (respiratory disturbance index>or=30) and (2) 338 subjects without sleep-disordered breathing (respiratory disturbance index<5).Results: Atrial fibrillation, nonsustained ventricular tachycardia, and complex ventricular ectopy (nonsustained ventricular tachycardia or bigeminy or trigeminy or quadrigeminy) were more common in subjects with sleep-disordered breathing compared with those without sleep-disordered breathing: 4.8 versus 0.9% (p=0.003) for atrial fibrillation; 5.3 versus 1.2% (p=0.004) for nonsustained ventricular tachycardia; 25.0 versus 14.5% (p=0.002) for complex ventricular ectopy. Compared with those without sleep-disordered breathing and adjusting for age, sex, body mass index, and prevalent coronary heart disease, individuals with sleep-disordered breathing had four times the odds of atrial fibrillation (odds ratio [OR], 4.02; 95% confidence interval [CI], 1.03-15.74), three times the odds of nonsustained ventricular tachycardia (OR, 3.40; 95% CI, 1.03-11.20), and almost twice the odds of complex ventricular ectopy (OR, 1.74; 95% CI, 1.11-2.74). A significant relation was also observed between sleep-disordered breathing and ventricular ectopic beats/h (p<0.0003) considered as a continuous outcome.Conclusions: Individuals with severe sleep-disordered breathing have two- to fourfold higher odds of complex arrhythmias than those without sleep-disordered breathing even after adjustment for potential confounders. [ABSTRACT FROM AUTHOR]

Clinic-based studies suggest that sleep-disordered breathing (SDB) is associated with glucose intolerance and insulin resistance. However, in the available studies, researchers have not rigorously controlled for confounding variables to assess the independent relation between SDB and impaired glucose metabolism. The objective of this study was to determine whether SDB was associated with glucose intolerance and insulin resistance among community-dwelling subjects (n=2,656) participating in the Sleep Heart Health Study (1994-1999). SDB was characterized with the respiratory disturbance index and measurements of oxygen saturation during sleep. Fasting and 2-hour glucose levels measured during an oral glucose tolerance test were used to assess glycemic status. Relative to subjects with a respiratory disturbance index of less than 5.0 events/hour (the reference category), subjects with mild SDB (5.0-14.9 events/hour) and moderate to severe SDB (> or =15 events/hour) had adjusted odds ratios of 1.27 (95% confidence interval: 0.98, 1.64) and 1.46 (95% confidence interval: 1.09, 1.97), respectively, for fasting glucose intolerance (p for trend < 0.01). Sleep-related hypoxemia was also associated with glucose intolerance independently of age, gender, body mass index, and waist circumference. The results of this study suggest that SDB is independently associated with glucose intolerance and insulin resistance and may lead to type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background: Continuous positive airway pressure (CPAP) is an effective therapy for obstructive sleep apnea syndrome (OSAS), although many patients have difficulty adhering to this therapy. The purpose of this study was to investigate the effectiveness of totally automated telephone technology in improving adherence to prescribed CPAP therapy.Research Design: This pilot study was a randomized clinical trial in 30 patients being started on CPAP therapy for OSAS. Patients were randomly assigned to use of a computer telephone system designed to improve CPAP adherence (telephone-linked communications for CPAP [TLC-CPAP]) in addition to usual care (n = 15) or to usual care alone (n = 15) for a period of 2 months. TLC-CPAP is a computer-based system that monitors patients' self-reported behavior and provides education and reinforcement through a structured dialogue.Measures: A sleep symptoms checklist and the Functional Outcomes of Sleep Questionnaire were administered at study entry and at 2-month follow up. Hours of CPAP use at effective mask pressure were measured by the CPAP device, stored in its memory, and retrieved at the 2-month visit.Results: At 2 months, patients randomized to TLC-CPAP had fewer reported sleep-related symptoms (9.4 vs. 13.4, P = 0.047) than those receiving usual care. The average nightly CPAP use in the TLC-CPAP group was 4.4 hours compared with 2.9 hours (P = 0.076) in the usual-care group.Conclusions: This pilot study suggests that patients with OSAS started on CPAP and a concurrently administered automated education and counseling system had better CPAP adherence and better control of OSAS symptoms. [ABSTRACT FROM AUTHOR]