Pharmacokinetics, safety, and tolerability of BMS-986263, a lipid nanoparticle containing HSP47 siRNA, in participants with hepatic impairment.

BMS-986263 is a retinoid-conjugated lipid nanoparticle delivering small interfering RNA designed to inhibit synthesis of HSP47 protein, a collagen-specific chaperone protein involved in fibrosis development. This is a phase I, open-label, two-part study evaluating pharmacokinetics and safety of BMS-986263 in participants with hepatic impairment (HI). Part 1 (n = 24) of this study enrolled two cohorts with mild and moderate HI and a separate cohort of age- and body mass index (BMI)-matched participants with normal hepatic function. Part 2 enrolled eight participants with severe HI and eight age- and BMI-matched participants with normal hepatic function. All participants received a single intravenous 90 mg BMS-986263 infusion. Compared with normal-matched participants, geometric mean area under the plasma concentration-time curve time zero to the time of the last quantifiable concentration (AUC(0-T) ) and AUC from zero to infinity (AUC(INF) ) of HSP47 siRNA were similar in participants with mild HI and 34% and 163% greater in those with moderate and severe HI, respectively, whereas the maximum plasma concentration was ~25% lower in mild and moderate HI groups but 58% higher in the severe HI group than in the normal group. Adverse events were reported by two of eight, four of eight, and three of eight participants with mild, moderate, or severe HI, respectively; none were reported in the normal-matched group. Overall, single-dose BMS-986263 was generally safe and well-tolerated and dose adjustment is not considered necessary for participants with mild or moderate HI. Although available data do not indicate that dose adjustment should be performed in patients with severe HI; the optimal posology of BMS-986263 in patients with severe HI may be determined later in its clinical development when additional data to establish exposure-safety/efficacy relationship becomes available.

Effect of pegbelfermin on NASH and fibrosis-related biomarkers and correlation with histological response in the FALCON 1 trial.

Background & Aims: FALCON 1 was a phase IIb study of pegbelfermin in patients with non-alcoholic steatohepatitis (NASH) and stage 3 fibrosis. This FALCON 1 post hoc analysis aimed to further assess the effect of pegbelfermin on NASH-related biomarkers, correlations between histological assessments and non-invasive biomarkers, and concordance between the week 24 histologically assessed primary endpoint response and biomarkers. Methods: Blood-based composite fibrosis scores, blood-based biomarkers, and imaging biomarkers were evaluated for patients with available data from FALCON 1 at baseline through week 24. SomaSignal tests assessed protein signatures of NASH steatosis, inflammation, ballooning, and fibrosis in blood. Linear mixed-effect models were fit for each biomarker. Correlations and concordance were assessed between blood-based biomarkers, imaging, and histological metrics. Results: At week 24, pegbelfermin significantly improved blood-based composite fibrosis scores (ELF, FIB-4, APRI), fibrogenesis biomarkers (PRO-C3 and PC3X), adiponectin, CK-18, hepatic fat fraction measured by MRI-proton density fat fraction, and all four SomaSignal NASH component tests. Correlation analyses between histological and non-invasive measures identified four main categories: steatosis/metabolism, tissue injury, fibrosis, and biopsy-based metrics. Concordant and discordant effects of pegbelfermin on the primary endpoint vs. biomarker responses were observed; the most clear and concordant effects were on measures of liver steatosis and metabolism. A significant association between hepatic fat measured histologically and by imaging was observed in pegbelfermin arms. Conclusions: Pegbelfermin improved NASH-related biomarkers most consistently through improvement of liver steatosis, though biomarkers of tissue injury/inflammation and fibrosis were also improved. Concordance analysis shows that non-invasive assessments of NASH support and exceed the improvements detected by liver biopsy, suggesting that greater consideration should be given to the totality of available data when evaluating the efficacy of NASH therapeutics. Clinical trial number: Post hoc analysis of NCT03486899. Impact and implications: FALCON 1 was a study of pegbelfermin vs. placebo in patients with non-alcoholic steatohepatitis (NASH) without cirrhosis; in this study, patients who responded to pegbelfermin treatment were identified through examination of liver fibrosis in tissue samples collected through biopsy. In the current analysis, non-invasive blood- and imaging-based measures of fibrosis, liver fat, and liver injury were used to determine pegbelfermin treatment response to see how they compared with the biopsy-based results. We found that many of the non-invasive tests, particularly those that measured liver fat, identified patients who responded to pegbelfermin treatment, consistent with the liver biopsy findings. These results suggest that there may be additional value in using data from non-invasive tests, along with liver biopsy, to evaluate how well patients with NASH respond to treatment.

Liver Enlargement Predicts Obstructive Sleep Apnea-Hypopnea Syndrome in Morbidly Obese Women.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is frequently present in patients with severe obesity, but its prevalence especially in women is not well defined. OSAHS and non-alcoholic fatty liver disease are common conditions, frequently associated in patients with central obesity and metabolic syndrome and are both the result of the accumulation of ectopic fat mass. Identifying predictors of risk of OSAHS may be useful to select the subjects requiring instrumental sleep evaluation. In this cross-sectional study, we have investigated the potential role of hepatic left lobe volume (HLLV) in predicting the presence of OSAHS. OSAHS was quantified by the apnea/hypopnea index (AHI) and oxygen desaturation index in a cardiorespiratory inpatient sleep study of 97 obese women [age: 47 ± 11 years body mass index (BMI): 50 ± 8 kg/m2]. OSAHS was diagnosed when AHI was ≥5. HLLV, subcutaneous and intra-abdominal fat were measured by ultrasound. After adjustment for age and BMI, both HLLV and neck circumference (NC) were independent predictors of AHI. OSAHS was found in 72% of patients; HLLV ≥ 370 cm3 was a predictor of OSAHS with a sensitivity of 66%, a specificity of 70%, a positive and negative predictive values of 85 and 44%, respectively (AUC = 0.67, p < 0.005). A multivariate logistic model was used including age, BMI, NC, and HLLV (the only independent predictors of AHI in a multiple linear regression analyses), and a cut off value for the predicted probability of OSAHS equal to 0.7 provided the best diagnostic results (AUC = 0.79, p < 0.005) in terms of sensitivity (76%), specificity (89%), negative and positive predictive values (59 and 95%, respectively). All patients with severe OSAHS were identified by this prediction model. In conclusion, HLLV, an established index of visceral adiposity, represents an anthropometric parameter closely associated with OSAHS in severely obese women.

Cytokine Patterns in Healthy Adolescent Girls: Heterogeneity Captured by Variable and Person-Centered Statistical Strategies.

BACKGROUND: Little is known about variation in individual cytokines/cytokine profiles for a large healthy, pediatric population. When cytokines in a healthy group are not abnormally high as in a disease state, it is challenging to determine appropriate statistical strategies. The aims of the study were (1) to describe variation among cytokine concentrations and profiles in healthy adolescent girls, (2) to illustrate utility of data reduction approaches novel to cytokine research, (variable-centered [principal factor analysis, PFA], person-centered [latent profile analysis, LPA]), and (3) to demonstrate utility of such methods in linking cytokine profiles to health outcomes (e.g., depressive, anxiety symptoms). METHOD: Serum was analyzed for 13 cytokines representing adaptive and innate immune responses in 262 girls (age = 11, 13, 15, and 17 years). RESULTS: There was great variation in cytokine concentrations. PFA revealed a four-factor solution explaining 73.13% of the shared variance among 13 cytokines (e.g., factor 1 included interleukin [IL]-4, IL-13, IL-5, interferon gamma; 26.65% of the shared variance). The LPA supported classifying girls into subgroups characterized by "high overall" (7.3% of sample), "high adaptive" (26.7%), "high innate" (21%), or "low overall" (45%) cytokine levels. Factors and profiles were useful in describing individual differences in depressive/anxiety symptoms (e.g., factor 1 positively associated with depressive symptoms but negatively with trait anxiety; increased depressive symptoms or trait anxiety was associated with greater likelihood of being in the "high adaptive" group). CONCLUSIONS: Healthy girls showed differences in cytokine levels and patterns of variation and important associations with psychological variables. PFA and LPA offer novel approaches useful for examining cytokine panels in healthy populations.

Hawthorne effect with transient behavioral and biochemical changes in a randomized controlled sleep extension trial of chronically short-sleeping obese adults: implications for the design and interpretation of clinical studies.

OBJECTIVE: To evaluate the effects of study participation per se at the beginning of a sleep extension trial between screening, randomization, and the run-in visit. DESIGN: Subjects were screened, returned for randomization (Comparison vs. Intervention) after 81 days (median), and attended run-in visit 121 days later. SETTING: Outpatient. PATIENTS: Obese (N = 125; M/F, 30/95; Blacks/Whites/Other, N = 73/44/8), mean weight 107.6±19.7 kg, <6.5 h sleep/night. INTERVENTION: Non-pharmacological sleep extension. MEASUREMENTS: Sleep duration (diaries and actigraphy watch), sleep quality (Pittsburgh Sleep Quality Index), daily sleepiness (Epworth Sleepiness Scale), fasting glucose, insulin and lipids. RESULTS: Prior to any intervention, marked improvements occurred between screening and randomization. Sleep duration increased (diaries: 357.4 ±51.2 vs. 388.1±48.6 min/night; mean±SD; P<0.001 screening vs. randomization; actigraphy: 344.3 ±41.9 vs. 358.6±48.2 min/night; P<0.001) sleep quality improved (9.1±3.2 vs. 8.2±3.0 PSQI score; P<0.001), sleepiness tended to improve (8.9±4.6 vs. 8.3±4.5 ESS score; P = 0.06), insulin resistance decreased (0.327±0.038 vs. 0.351±0.045; Quicki index; P<0.001), and lipids improved, except for HDL-C. Abnormal fasting glucose (25% vs. 11%; P = 0.007), and metabolic syndrome (42% vs. 29%; P = 0.007) both decreased. In absence of intervention, the earlier metabolic improvements disappeared at the run-in visit. LIMITATIONS: Relatively small sample size. CONCLUSIONS: Improvements in biochemical and behavioral parameters between screening and randomization changed the "true" study baseline, thereby potentially affecting outcome. While regression to the mean and placebo effect were considered, these findings are most consistent with the "Hawthorne effect", according to which behavior measured in the setting of an experimental study changes in response to the attention received from study investigators. This is the first time that biochemical changes were documented with respect to the Hawthorne effect. The findings have implications for the design and conduct of clinical research. TRIAL REGISTRATION: ClinicalTrials.gov NCT00261898.

Neck circumference is a predictor of metabolic syndrome and obstructive sleep apnea in short-sleeping obese men and women.

BACKGROUND: The constellation of metabolic syndrome, although controversial with regard to its clinical usefulness, is epidemiologically related to increased diabetes risk and cardiovascular mortality. Our goal was to investigate the associations among neck circumference (NC), obstructive sleep apnea syndromes (OSAS), and metabolic syndrome in obese men and women sleeping less than 6.5 hr per night. METHODS: This was a cross-sectional study of obese men and premenopausal obese women sleeping less than 6.5 hr per night. We enrolled 120 individuals (92 women), age 40.5±6.9 years and body mass index (BMI) 38.6±6.5 kg/m(2). Metabolic syndrome severity was assessed by a score and OSAS was defined as a respiratory disturbance index (RDI) ≥5. Metabolic end endocrine parameters were measured, and sleep duration was determined by actigraphy and validated questionnaires. RESULTS: Metabolic syndrome was found in 41% and OSAS in 58% (28% had both). Subjects with metabolic syndrome were 3 years older and more often Caucasian; they had higher RDI scores, larger NC, more visceral fat, lower serum adiponectin, higher 24-hr urinary norepinephrine (NE) excretion, and lower growth hormone concentrations. A NC of ≥38 cm had a sensitivity of 54% and 58% and a specificity of 70% and 79% in predicting the presence of metabolic syndrome and OSAS, respectively. RDI, adiponectin, and NC accounted for approximately 30% of the variability in the metabolic syndrome score, as estimated by an age-, gender-, and race-corrected multivariate model (R(2)=0.376, P<0.001). CONCLUSION: Greater NC is associated with OSAS and metabolic syndrome in short-sleeping obese men and premenopausal obese women. Addition of NC to the definition of metabolic syndrome should be considered and needs to be validated in future studies.

Sleep extension improves neurocognitive functions in chronically sleep-deprived obese individuals.

BACKGROUND: Sleep deprivation and obesity, are associated with neurocognitive impairments. Effects of sleep deprivation and obesity on cognition are unknown, and the cognitive long-term effects of improvement of sleep have not been prospectively assessed in short sleeping, obese individuals. OBJECTIVE: To characterize neurocognitive functions and assess its reversibility. DESIGN: Prospective cohort study. SETTING: Tertiary Referral Research Clinical Center. PATIENTS: A cohort of 121 short-sleeping (<6.5 h/night) obese (BMI 30-55 kg/m(2)) men and pre-menopausal women. INTERVENTION: Sleep extension (468±88 days) with life-style modifications. MEASUREMENTS: Neurocognitive functions, sleep quality and sleep duration. RESULTS: At baseline, 44% of the individuals had an impaired global deficit score (t-score 0-39). Impaired global deficit score was associated with worse subjective sleep quality (p = 0.02), and lower urinary dopamine levels (p = 0.001). Memory was impaired in 33%; attention in 35%; motor skills in 42%; and executive function in 51% of individuals. At the final evaluation (N = 74), subjective sleep quality improved by 24% (p<0.001), self-reported sleep duration increased by 11% by questionnaires (p<0.001) and by 4% by diaries (p = 0.04), and daytime sleepiness tended to improve (p = 0.10). Global cognitive function and attention improved by 7% and 10%, respectively (both p = 0.001), and memory and executive functions tended to improve (p = 0.07 and p = 0.06). Serum cortisol increased by 17% (p = 0.02). In a multivariate mixed model, subjective sleep quality and sleep efficiency, urinary free cortisol and dopamine and plasma total ghrelin accounted for 1/5 of the variability in global cognitive function. LIMITATIONS: Drop-out rate. CONCLUSIONS: Chronically sleep-deprived obese individuals exhibit substantial neurocognitive deficits that are partially reversible upon improvement of sleep in a non-pharmacological way. These findings have clinical implications for large segments of the US population. TRAIL REGISTRATION: www.ClinicalTrials.gov NCT00261898. NIDDK protocol 06-DK-0036.

Challenging recruitment of youth with type 2 diabetes into clinical trials.

PURPOSE: To better understand and overcome difficulties with recruitment of adolescents with type 2 diabetes into clinical trials at three United States institutions, we reviewed recruitment and retention strategies in clinical trials of youth with various chronic conditions. We explored whether similar strategies might be applicable to pediatric patients with type 2 diabetes. METHODS: We compiled data on recruitment and retention of adolescents with type 2 diabetes at three centers (National Institutes of Health, Bethesda, Maryland; Baylor College of Medicine, Houston, Texas; and Children's National Medical Center, Washington, DC) from January 2009 to December 2011. We also conducted a thorough literature review on recruitment and retention in adolescents with chronic health conditions. RESULTS: The number of recruited patients was inadequate for timely completion of ongoing trials. Our review of recruitment strategies in adolescents included monetary and material incentives, technology-based advertising, word-of-mouth referral, and continuous patient-research team contact. Cellular or Internet technology appeared promising in improving participation among youths in studies of various chronic conditions and social behaviors. CONCLUSIONS: Adolescents with type 2 diabetes are particularly difficult to engage in clinical trials. Monetary incentives and use of technology do not represent "magic bullets," but may presently be the most effective tools. Future studies should be conducted to explore motivation in this population. We speculate that (1) recruitment into interventional trials that address the main concerns of the affected youth (e.g., weight loss, body image, and stress management) combined with less tangible outcomes (e.g., blood glucose control) may be more successful; and (2) study participation and retention may be improved by accommodating patients' and caregivers' schedules, by scheduling study visits before and after working hours, and in more convenient locations than in medical facilities.

Obstructive sleep apnea is a predictor of abnormal glucose metabolism in chronically sleep deprived obese adults.

CONTEXT: Sleep abnormalities, including obstructive sleep apnea (OSA), have been associated with insulin resistance. OBJECTIVE: To determine the relationship between sleep, including OSA, and glucose parameters in a prospectively assembled cohort of chronically sleep-deprived obese subjects. DESIGN: Cross-sectional evaluation of a prospective cohort study. SETTING: Tertiary Referral Research Clinical Center. MAIN OUTCOME MEASURES: Sleep duration and quality assessed by actigraphy, sleep diaries and questionnaires, OSA determined by a portable device; glucose metabolism assessed by oral glucose tolerance test (oGTT), and HbA1c concentrations in 96 obese individuals reporting sleeping less than 6.5 h on a regular basis. RESULTS: Sixty % of subjects had an abnormal respiratory disturbance index (RDI≥5) and 44% of these subjects had abnormal oGTT results. Severity of OSA as assessed by RDI score was associated with fasting glucose (R = 0.325, p = 0.001) and fasting insulin levels (ρ = 0.217, p = 0.033). Subjects with moderate to severe OSA (RDI>15) had higher glucose concentrations at 120 min than those without OSA (RDI<5) (p = 0.017). Subjects with OSA also had significantly higher concentrations of plasma ACTH (p = 0.009). Several pro-inflammatory cytokines were higher in subjects with OSA (p<0.050). CRP levels were elevated in this sample, suggesting increased cardiovascular risk. CONCLUSIONS: OSA is associated with impaired glucose metabolism in obese, sleep deprived individuals. Since sleep apnea is common and frequently undiagnosed, health care providers should be aware of its occurrence and associated risks. TRIAL REGISTRATION: This study was conducted under the NIDDK protocol 06-DK-0036 and is listed in ClinicalTrials.gov NCT00261898.

Evening chronotype is associated with changes in eating behavior, more sleep apnea, and increased stress hormones in short sleeping obese individuals.

BACKGROUND: Short sleep duration and decreased sleep quality are emerging risk factors for obesity and its associated morbidities. Chronotype, an attribute that reflects individual preferences in the timing of sleep and other behaviors, is a continuum from morningness to eveningness. The importance of chronotype in relation to obesity is mostly unknown. Evening types tend to have unhealthy eating habits and suffer from psychological problems more frequently than Morning types, thus we hypothesized that eveningness may affect health parameters in a cohort of obese individuals reporting sleeping less than 6.5 hours per night. METHODOLOGY AND PRINCIPAL FINDINGS: BASELINE DATA FROM OBESE (BMI: 38.5±6.4 kg/m(2)) and short sleeping (5.8±0.8 h/night by actigraphy) participants (n = 119) of the Sleep Extension Study were analyzed (www.ClinicalTrials.gov, identifier NCT00261898). Assessments included the Horne and Ostberg Morningness-Eveningness questionnaire, a three-day dietary intake diary, a 14-day sleep diary, 14 days of actigraphy, and measurements of sleep apnea. Twenty-four hour urinary free cortisol, 24 h urinary norepinephrine and epinephrine levels, morning plasma ACTH and serum cortisol, fasting glucose and insulin, and lipid parameters were determined. Eveningness was associated with eating later in the day on both working and non-working days. Progression towards eveningness was associated with an increase in BMI, resting heart rate, food portion size, and a decrease in the number of eating occasions and HDL-cholesterol. Evening types had overtly higher 24 h urinary epinephrine and morning plasma ACTH levels, and higher morning resting heart rate than Morning types. In addition, Evening types more often had sleep apnea, independent of BMI or neck circumference. CONCLUSIONS: Eveningness was associated with eating later and a tendency towards fewer and larger meals and lower HDL-cholesterol levels. In addition, Evening types had more sleep apnea and higher stress hormones. Thus, eveningness in obese, chronically sleep-deprived individuals compounds the cardiovascular risk associated with obesity.

The Hypothalamic-Pituitary-Adrenal Axis, Obesity, and Chronic Stress Exposure: Sleep and the HPA Axis in Obesity.

Obesity, exposure to stress and inadequate sleep are prevalent phenomena in modern society. In this review we focus on their relationships and critically evaluate causality. In obese individuals, one of the main stress systems, the hypothalamic-pituitary-adrenal axis, is altered, and concentrations of cortisol are elevated in adipose tissue due to elevated local activity of 11ß-hydroxysteroid dehydrogenase (HSD) type 1. Short sleep and decreased sleep quality are also associated with obesity. In addition, experimental sleep curtailment induces HPA-axis alterations which, in turn, may negatively affect sleep. These findings implicate that obesity, stress and sleep loss are all related in a vicious circle. Finally, we discuss new strategies to combat obesity through modulating cortisol levels in adipose tissue by 11ß-HSD(1) inhibitors or by improving sleep duration.

Do premenopausal women with major depression have low bone mineral density? A 36-month prospective study.

BACKGROUND: An inverse relationship between major depressive disorder (MDD) and bone mineral density (BMD) has been suggested, but prospective evaluation in premenopausal women is lacking. METHODS: Participants of this prospective study were 21 to 45 year-old premenopausal women with MDD (n = 92) and healthy controls (n = 44). We measured BMD at the anteroposterior lumbar spine, femoral neck, total hip, mid-distal radius, trochanter, and Ward's triangle, as well as serum intact parathyroid hormone (iPTH), ionized calcium, plasma adrenocorticotropic hormone (ACTH), serum cortisol, and 24-hour urinary-free cortisol levels at 0, 6, 12, 24, and 36 months. 25-hydroxyvitamin D was measured at baseline. RESULTS: At baseline, BMD tended to be lower in women with MDD compared to controls and BMD remained stable over time in both groups. At baseline, 6, 12, and 24 months intact PTH levels were significantly higher in women with MDD vs. controls. At baseline, ionized calcium and 25-hydroxyvitamin D levels were significantly lower in women with MDD compared to controls. At baseline and 12 months, bone-specific alkaline phosphatase, a marker of bone formation, was significantly higher in women with MDD vs. controls. Plasma ACTH was also higher in women with MDD at baseline and 6 months. Serum osteocalcin, urinary N-telopeptide, serum cortisol, and urinary free cortisol levels were not different between the two groups throughout the study. CONCLUSION: Women with MDD tended to have lower BMD than controls over time. Larger and longer studies are necessary to extend these observations with the possibility of prophylactic therapy for osteoporosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00006180.

Interacting epidemics? Sleep curtailment, insulin resistance, and obesity.

In the last 50 years, the average self-reported sleep duration in the United States has decreased by 1.5-2 hours in parallel with an increasing prevalence of obesity and diabetes. Epidemiological studies and meta-analyses report a strong relationship between short or disturbed sleep, obesity, and abnormalities in glucose metabolism. This relationship is likely to be bidirectional and causal in nature, but many aspects remain to be elucidated. Sleep and the internal circadian clock influence a host of endocrine parameters. Sleep curtailment in humans alters multiple metabolic pathways, leading to more insulin resistance, possibly decreased energy expenditure, increased appetite, and immunological changes. On the other hand, psychological, endocrine, and anatomical abnormalities in individuals with obesity and/or diabetes can interfere with sleep duration and quality, thus creating a vicious cycle. In this review, we address mechanisms linking sleep with metabolism, highlight the need for studies conducted in real-life settings, and explore therapeutic interventions to improve sleep, with a potential beneficial effect on obesity and its comorbidities.

Poor sleep quality and sleep apnea are associated with higher resting energy expenditure in obese individuals with short sleep duration.

CONTEXT: Epidemiological studies reported an inverse or U-shaped relationship between sleep duration and weight. The relationship between sleep and resting energy expenditure (REE) has not been well characterized. OBJECTIVE: The aim of the study was to determine the relationship between sleep, REE, and stress hormones. DESIGN AND SETTING: We conducted a cross-sectional evaluation of a prospective cohort study at a tertiary referral research clinical center. SUBJECTS: Subjects included 126 obese individuals (30 males, 96 females; age, 40.5 ± 6.9 yr; body mass index, 38.6 ± 6.5 kg/m(2); sleep duration, 360 ± 50 min/night; and sleep efficiency, 79.5 ± 7.5%). MAIN OUTCOME MEASURE(S): REE and respiratory quotient (RQ) were assessed by indirect calorimetry. Sleep duration and sleep efficiency were assessed by actigraphy. Sleep quality was estimated by questionnaires, and sleep apnea was evaluated by respiratory disturbance index (RDI). Morning plasma ACTH, serum cortisol, and 24-h urinary free cortisol and catecholamines were also measured. RESULTS: RDI was positively correlated with REE adjusted by fat-free mass (r = 0.307; P = 0.003) and RQ (r = 0.377; P < 0.001). Sleep efficiency was inversely correlated with RQ (r = -0.200; P = 0.033). The relationship of RDI score and REE was stronger in men than women (P = 0.03). In women, serum cortisol was positively correlated (r = 0.407; P < 0.001), and Epworth sleepiness score tended to be inversely (r = -0.190; P = 0.086) correlated with adjusted REE. The RQ was positively related to RDI in women, whereas subjective sleep time was related to RQ in men. In a multiple regression model, RDI, serum cortisol, and urinary norepinephrine were directly related to REE, whereas serum cortisol also directly related to adjusted REE. CONCLUSION: Poor sleep quality was associated with increased REE, a higher RQ indicating a shift from fat toward carbohydrate oxidation, and activation of the stress system.

Predictors of sleep-disordered breathing in obese adults who are chronic short sleepers.

BACKGROUND: Sleep disordered breathing (SDB) is common in obese adults, but not all obese adults have SDB. The aim of these analyses was to determine what predicted SDB in a sample of obese adults. METHODS: We conducted cross-sectional analysis of 139 obese men and women aged 18-50 years who are chronic short sleepers. Habitual sleep duration and sleep efficiency were estimated using two weeks of wrist actigraphy. Respiratory disturbance index (RDI) was assessed by a portable screening device. SDB was defined as RDI ≥15 events h(-1). Subjective sleep quality, sleepiness, and sociodemographic characteristics were evaluated by questionnaires. RESULTS: Increased sleep duration from actigraphy was associated with reduced odds of SDB (OR 0.44 per hour, p=0.043). Neither subjective sleep quality nor sleepiness was associated with SDB. Male sex, older age, and increased waist circumference were associated with increased odds of SDB. CONCLUSIONS: In this sample of obese adults, subjective measures of sleep quality and sleepiness were not indicators of SDB. These results suggest that, in obese patients, physicians should not rely on subjective measures to determine who should be referred for a clinical sleep study. A wider use of portable apnea screening devices should be considered in nonsymptomatic, non-Hispanic white males.

Clinical subtypes of depression are associated with specific metabolic parameters and circadian endocrine profiles in women: the power study.

BACKGROUND: Major depressive disorder (MDD) has been associated with adverse medical consequences, including cardiovascular disease and osteoporosis. Patients with MDD may be classified as having melancholic, atypical, or undifferentiated features. The goal of the present study was to assess whether these clinical subtypes of depression have different endocrine and metabolic features and consequently, varying medical outcomes. METHODS: Premenopausal women, ages 21 to 45 years, with MDD (N = 89) and healthy controls (N = 44) were recruited for a prospective study of bone turnover. Women with MDD were classified as having melancholic (N = 51), atypical (N = 16), or undifferentiated (N = 22) features. Outcome measures included: metabolic parameters, body composition, bone mineral density (BMD), and 24 hourly sampling of plasma adrenocorticotropin (ACTH), cortisol, and leptin. RESULTS: Compared with control subjects, women with undifferentiated and atypical features of MDD exhibited greater BMI, waist/hip ratio, and whole body and abdominal fat mass. Women with undifferentiated MDD characteristics also had higher lipid and fasting glucose levels in addition to a greater prevalence of low BMD at the femoral neck compared to controls. Elevated ACTH levels were demonstrated in women with atypical features of depression, whereas higher mean 24-hour leptin levels were observed in the melancholic subgroup. CONCLUSIONS: Pre-menopausal women with various features of MDD exhibit metabolic, endocrine, and BMD features that may be associated with different health consequences. TRIAL REGISTRATION: ClinicalTrials.gov NCT00006180.