Anxiety and Depression Associated With Increased Cardiovascular Disease Risk Through Accelerated Development of Risk Factors.

Background: Prior studies have incompletely assessed whether the development of cardiometabolic risk factors (CVDRF) (hypertension, hyperlipidemia, and diabetes mellitus) mediates the association between anxiety and depression (anxiety/depression) and cardiovascular disease (CVD). Objectives: The authors aimed to evaluate the following: 1) the association between anxiety/depression and incident CVDRFs and whether this association mediates the increased CVD risk; and 2) whether neuro-immune mechanisms and age and sex effects may be involved. Methods: Using a retrospective cohort design, Mass General Brigham Biobank subjects were followed for 10 years. Presence and timing of anxiety/depression, CVDRFs, and CVD were determined using ICD codes. Stress-related neural activity, chronic inflammation, and autonomic function were measured by the assessment of amygdalar-to-cortical activity ratio, high-sensitivity CRP, and heart rate variability. Multivariable regression and mediation analyses were employed. Results: Among 71,214 subjects (median age 49.6 years; 55.3% female), 27,048 (38.0%) developed CVDRFs during follow-up. Pre-existing anxiety/depression associated with increased risk of incident CVDRF (OR: 1.71 [95% CI: 1.59-1.83], P < 0.001) and with a shorter time to their development (ß = -0.486 [95% CI: -0.62 to -0.35], P < 0.001). The development of CVDRFs mediated the association between anxiety/depression and CVD events (log-odds: 0.044 [95% CI: 0.034-0.055], P < 0.05). Neuro-immune pathways contributed to the development of CVDRFs (P < 0.05 each) and significant age and sex effects were noted: younger women experienced the greatest acceleration in the development of CVDRFs after anxiety/depression. Conclusions: Anxiety/depression accelerate the development of CVDRFs. This association appears to be most notable among younger women and may be mediated by stress-related neuro-immune pathways. Evaluations of tailored preventive measures for individuals with anxiety/depression are needed to reduce CVD risk.

Dysregulated 24 h melatonin secretion associated with intrinsically photosensitive retinal ganglion cell function in diabetic retinopathy: a cross-sectional study.

AIMS/HYPOTHESIS: The aim of this study was to explore whether diabetic retinopathy is associated with alterations of the circadian system, and to examine the role of reduced intrinsically photosensitive retinal ganglion cell (ipRGC) function. METHODS: Participants with type 2 diabetes, with diabetic retinopathy (n=14) and without diabetic retinopathy (n=9) underwent 24 h blood sampling for melatonin and cortisol under controlled laboratory conditions. ipRGC function was inferred from the post-illumination pupil response (PIPR). Habitual sleep duration, efficiency and variability were assessed by actigraphy. RESULTS: Participants with diabetic retinopathy compared to participants without diabetic retinopathy had smaller PIPR (p=0.007), lower 24 h serum melatonin output (p=0.042) and greater day-to-day sleep variability (p=0.012). By contrast, 24 h cortisol profiles, sleep duration and efficiency were similar in both groups. Six individuals with diabetic retinopathy had no detectable dim-light melatonin onset. PIPR correlated with 24 h mean melatonin levels (r=0.555, p=0.007). CONCLUSIONS/INTERPRETATION: ipRCG dysfunction in diabetic retinopathy is associated with disruptions of the 24 h melatonin rhythm, suggesting circadian dysregulation in diabetic retinopathy.

PTSD increases risk for major adverse cardiovascular events through neural and cardio-inflammatory pathways.

While posttraumatic stress disorder (PTSD) is known to associate with an elevated risk for major adverse cardiovascular events (MACE), few studies have examined mechanisms underlying this link. Recent studies have demonstrated that neuro-immune mechanisms, (manifested by heightened stress-associated neural activity (SNA), autonomic nervous system activity, and inflammation), link common stress syndromes to MACE. However, it is unknown if neuro-immune mechanisms similarly link PTSD to MACE. The current study aimed to test the hypothesis that upregulated neuro-immune mechanisms increase MACE risk among individuals with PTSD. This study included N = 118,827 participants from a large hospital-based biobank. Demographic, diagnostic, and medical history data collected from the biobank. SNA (n = 1,520), heart rate variability (HRV; [n = 11,463]), and high sensitivity C-reactive protein (hs-CRP; [n = 15,164]) were obtained for a subset of participants. PTSD predicted MACE after adjusting for traditional MACE risk factors (hazard ratio (HR) [95 % confidence interval (CI)] = 1.317 [1.098, 1.580], ß = 0.276, p = 0.003). The PTSD-to-MACE association was mediated by SNA (CI = 0.005, 0.133, p < 0.05), HRV (CI = 0.024, 0.056, p < 0.05), and hs-CRP (CI = 0.010, 0.040, p < 0.05). This study provides evidence that neuro-immune pathways may play important roles in the mechanisms linking PTSD to MACE. Future studies are needed to determine if these markers are relevant targets for PTSD treatment and if improvements in SNA, HRV, and hs-CRP associate with reduced MACE risk in this patient population.

Plasma Fibrinogen Change as a Predictor of Major Bleeding During Catheter-Directed Thrombolysis.

BACKGROUND: Our primary objective was to determine the relationship between plasma fibrinogen levels (PFLs) and major bleeding complications during catheter-directed thrombolysis, including final, nadir, and change over time. Furthermore, we sought to evaluate additional predictors of bleeding outcomes, including duration of lysis and total dose of tissue plasminogen activator received. METHODS: In this multicenter retrospective cohort study, we reviewed all patients undergoing catheter-directed thrombolysis between January 2016 and August 2021. Patients undergoing thrombolysis for management of peripheral arterial or venous thromboses, as well as for submassive pulmonary embolism, were included. We examined the relationships between PFLs during catheter-directed lysis and the incidence of major bleeding-that is significant hemorrhage requiring transfusion, intracranial hemorrhage, or hemorrhage requiring adjunctive procedures. We also examined the duration of lysis and total lytic agent dose received to assess for association with major bleeding. RESULTS: A total of 438 patients underwent catheter-directed lysis from January 1, 2016 through August 21, 2021, with a major bleeding rate of 16%. Patients who experienced major bleeding were more likely to be older (P = 0.022), experience in-stent thrombosis (P = 0.041), or have thrombosis in a lower extremity vessel (P = 0.011). There was no association between the incidence of major bleeding and a nadir PFL of <150 mg/dL (P = 0.194). Those who experienced major bleeding complications had a significantly greater decrease in PFL from baseline to nadir. This was true for both absolute (P = 0.029) and relative (P = 0.034) PFL decrease. Only percent decrease remained a significant predictor when adjusting for age, thrombosis type, and thrombosis location (P = 0.041). The PFL changes that were the best predictors of major bleeding complications were an absolute decrease of 146 mg/dL, or a relative decrease of 47%, giving a sensitivity and specificity of 71% and 48%, respectively. If neither were true, the negative predictive value for major bleeding was 89% regardless of absolute PFL. CONCLUSIONS: In this large, multicenter cohort, there does not appear to be an association between absolute PFL and major bleeding during catheter-directed lysis. Specifically, the typical absolute threshold of < 150 mg/dL was not an independent predictor of major bleeding. There was an association between percent-change in plasma fibrinogen and major bleeding, which aligns with the underlying physiologic mechanism of fibrinogen degradation coagulopathy. Applying a so-called "50-150 Rule" to catheter-directed lysis may decrease bleeding complications. That is, continued lysis should be re-evaluated if PFL drops by ≥150 mg/dL or by ≥50% from baseline regardless of absolute PFL.

Multidimensional sleep health and diabetic retinopathy: Systematic review and meta-analysis.

Diabetic retinopathy (DR) is one of the most prevalent microvascular diabetic complications. Poor sleep health and obstructive sleep apnea (OSA) are risk factors for diabetes and poor glycemic control. Recent studies have suggested associations between poor sleep health/OSA and DR. Furthermore, there have been suggestions of melatonin dysregulation in the context of DR. We conducted a systematic review and meta-analysis exploring the associations between multidimensional sleep health (duration, satisfaction, efficiency, timing/regularity and alertness), OSA and melatonin with DR. Forty-two studies were included. Long, but not short sleep, was significantly associated with DR, OR 1.41 (95%CI 1.21, 1.64). Poor sleep satisfaction was also significantly associated with DR, OR 2.04 (1.41, 2.94). Sleep efficiency and alertness were not associated with DR, while the evidence on timing/regularity was scant. Having OSA was significantly associated with having DR, OR 1.34 (1.07, 1.69). Further, those with DR had significantly lower melatonin/melatonin metabolite levels than those without DR, standardized mean difference -0.94 (-1.44, -0.44). We explored whether treating OSA with continuous positive airway pressure (CPAP) led to improvement in DR (five studies). The results were mixed among studies, but potential benefits were observed in some. This review highlights the association between poor multidimensional sleep health and DR.

Greater sleep variability is associated with higher systemic inflammation in type 2 diabetes.

Sleep irregularity and variability have been shown to be detrimental to cardiometabolic health. The present pilot study explored if higher day-to-day sleep irregularity and variability were associated with systemic inflammation, as assessed by high-sensitivity C-reactive protein, in type 2 diabetes. Thirty-five patients with type 2 diabetes (mean age 54.3 years, 54.3% female) who were not shift-workers participated. The presence of diabetic retinopathy was determined. The standard deviation of sleep duration and sleep midpoint across all recorded nights were used to quantify sleep variability and regularity, respectively, assessed by 14-day actigraphy. The presence and severity of sleep apnea were assessed using an overnight home monitor. Low-density lipoprotein, haemoglobin A1C and high-sensitivity C-reactive protein were collected. Multiple regression analysis using natural-log-transformed values was performed to establish an independent association between sleep variability and high-sensitivity C-reactive protein. Twenty-two (62.9%) patients had diabetic retinopathy. The median (interquartile range) of high-sensitivity C-reactive protein was 2.4 (1.4, 4.6) mg L-1 . Higher sleep variability was significantly associated with higher high-sensitivity C-reactive protein (r = 0.342, p = 0.044), as was haemoglobin A1C (r = 0.431, p = 0.010) and low-density lipoprotein (r = 0.379, p = 0.025), but not sleep regularity, sleep apnea severity or diabetic retinopathy. Multiple regression analysis showed that higher sleep variability (B = 0.907, p = 0.038) and higher HbA1c (B = 1.519, p = 0.035), but not low-density lipoprotein, contributed to higher high-sensitivity C-reactive protein. In conclusion, higher sleep variability in patients with type 2 diabetes who were not shift-workers was independently associated with higher systemic inflammation, conferring increased cardiovascular risk. Whether sleep interventions to reduce sleep variability can reduce systemic inflammation and improve cardiometabolic health should be investigated.

Research gaps and opportunities in precision nutrition: an NIH workshop report.

Precision nutrition is an emerging concept that aims to develop nutrition recommendations tailored to different people's circumstances and biological characteristics. Responses to dietary change and the resulting health outcomes from consuming different diets may vary significantly between people based on interactions between their genetic backgrounds, physiology, microbiome, underlying health status, behaviors, social influences, and environmental exposures. On 11-12 January 2021, the National Institutes of Health convened a workshop entitled "Precision Nutrition: Research Gaps and Opportunities" to bring together experts to discuss the issues involved in better understanding and addressing precision nutrition. The workshop proceeded in 3 parts: part I covered many aspects of genetics and physiology that mediate the links between nutrient intake and health conditions such as cardiovascular disease, Alzheimer disease, and cancer; part II reviewed potential contributors to interindividual variability in dietary exposures and responses such as baseline nutritional status, circadian rhythm/sleep, environmental exposures, sensory properties of food, stress, inflammation, and the social determinants of health; part III presented the need for systems approaches, with new methods and technologies that can facilitate the study and implementation of precision nutrition, and workforce development needed to create a new generation of researchers. The workshop concluded that much research will be needed before more precise nutrition recommendations can be achieved. This includes better understanding and accounting for variables such as age, sex, ethnicity, medical history, genetics, and social and environmental factors. The advent of new methods and technologies and the availability of considerably more data bring tremendous opportunity. However, the field must proceed with appropriate levels of caution and make sure the factors listed above are all considered, and systems approaches and methods are incorporated. It will be important to develop and train an expanded workforce with the goal of reducing health disparities and improving precision nutritional advice for all Americans.

Extended Absorption of Liothyronine from Poly-Zinc-Liothyronine: Results from a Phase 1, Double-Blind, Randomized, and Controlled Study in Humans.

Background: L-triiodothyronine (LT3) has been increasingly used in combination with levothyroxine in the treatment of hypothyroidism. A metal coordinated form of LT3, known as poly-zinc-liothyronine (PZL), avoided in rats the typical triiodothyronine (T3) peak seen after oral administration of LT3. Objectives: To evaluate in healthy volunteers (i) the pharmacokinetics (PK) of PZL-derived T3 after a single dose, (ii) the pharmacodynamics of PZL-derived T3, (iii) incidence of adverse events, and (iv) exploratory analysis of the sleep patterns after LT3, PZL, or placebo (PB) administration. Methods: Twelve healthy volunteers 18-50 years of age were recruited for a Phase 1, double-blind, randomized, single-dose PB-controlled, crossover study to compare PZL against LT3 or PB. Subjects were admitted three separate times to receive a randomly assigned capsule containing PB, 50 µg LT3, or 50 µg PZL, and were observed for 48 hours. A 2-week washout period separated each admission. Results: LT3-derived serum T3 levels exhibited the expected profile, with a Tmax at 2 hours and return to basal levels by 24-36 hours. PZL-derived serum T3 levels exhibited ∼30% lower Cmax that was 1 hour delayed and extended into a plateau that lasted up to 6 hours. This was followed by a lower but much longer plateau; by 24 hours serum T3 levels still exceeded ½ of Cmax. Thyrotropin levels were similarly reduced in both groups. Conclusion: PZL possesses the necessary properties to achieve a much improved T3 PK. PZL is on track to provide hypothyroid patients with stable levels of serum T3.

Sleep and circadian rhythms: pillars of health-a Keystone Symposia report.

The human circadian system consists of the master clock in the suprachiasmatic nuclei of the hypothalamus as well as in peripheral molecular clocks located in organs throughout the body. This system plays a major role in the temporal organization of biological and physiological processes, such as body temperature, blood pressure, hormone secretion, gene expression, and immune functions, which all manifest consistent diurnal patterns. Many facets of modern life, such as work schedules, travel, and social activities, can lead to sleep/wake and eating schedules that are misaligned relative to the biological clock. This misalignment can disrupt and impair physiological and psychological parameters that may ultimately put people at higher risk for chronic diseases like cancer, cardiovascular disease, and other metabolic disorders. Understanding the mechanisms that regulate sleep circadian rhythms may ultimately lead to insights on behavioral interventions that can lower the risk of these diseases. On February 25, 2021, experts in sleep, circadian rhythms, and chronobiology met virtually for the Keystone eSymposium "Sleep & Circadian Rhythms: Pillars of Health" to discuss the latest research for understanding the bidirectional relationships between sleep, circadian rhythms, and health and disease.

The human gut microbiome and health inequities.

Individuals who are minoritized as a result of race, sexual identity, gender, or socioeconomic status experience a higher prevalence of many diseases. Understanding the biological processes that cause and maintain these socially driven health inequities is essential for addressing them. The gut microbiome is strongly shaped by host environments and affects host metabolic, immune, and neuroendocrine functions, making it an important pathway by which differences in experiences caused by social, political, and economic forces could contribute to health inequities. Nevertheless, few studies have directly integrated the gut microbiome into investigations of health inequities. Here, we argue that accounting for host-gut microbe interactions will improve understanding and management of health inequities, and that health policy must begin to consider the microbiome as an important pathway linking environments to population health.

The Relationship between Sleep, Obesity, and Metabolic Health in Adolescents - a Review.

In this literature review, we discuss the importance of adequate sleep and the various effects of suboptimal sleep on weight maintenance and metabolic health specifically for adolescents. Two major contributors to adolescents experiencing decreased sleep duration and quality, and thus increasing the risk for developing metabolic syndrome in adolescence as well as later in adulthood, are increased electronic screen time particularly at night and early school start times. The less time adolescents spend sleeping, the less quality sleep they obtain, and the greater the disruption of endocrine hormone function. As another consequence, adolescents are more prone to making poor food choices, from choosing relatively nutrient-poor foods to consuming excess calories without necessarily increasing their energy expenditure. These choices put adolescents at greater risk for becoming obese throughout their lifespan.

Reduction of IL-6 gene expression in human adipose tissue after sleeve gastrectomy surgery.

OBJECTIVE: There is increasing evidence that immune cell interactions in adipose tissue contribute to the development of metabolic dysfunction. Pro-inflammatory cytokines have been shown to mediate insulin resistance, and the presence of macrophages is a salient feature in the development of obesity. The present study aimed to evaluate adipocyte size and macrophage activation in women before and 3 months after laparoscopic vertical sleeve gastrectomy (VSG). METHODS: Subcutaneous abdominal adipose tissue biopsies were obtained from women scheduled to undergo VSG. Histological evaluation of adipocytes and macrophages was performed as well as cytokine expression quantification before and after VSG-induced weight loss. RESULTS: Weight loss following VSG resulted in a reduction in adipocyte size as well as a decrease in interleukin (IL)-6 cytokine mRNA expression in subcutaneous adipose tissue. There was no change in the presence of crownlike structures after weight loss. CONCLUSIONS: Early weight loss after VSG is associated with a reduction in adipocyte size and a decline in IL-6 gene expression in local adipose tissue. Macrophage infiltration and crownlike density structures persist in adipose tissue from tissues impacted by excess body weight 3 months after VSG-induced weight loss.

Relationship between Intrinsically Photosensitive Ganglion Cell Function and Circadian Regulation in Diabetic Retinopathy.

BACKGROUND: Intrinsically photosensitive retinal ganglion cells (ipRGCs) control non-visual light responses (e.g. pupillary light reflex and circadian entrainment). Patients with diabetic retinopathy (DR) show reduced ipRGC function, as inferred by abnormalities in the post illumination pupil response (PIPR). We explored whether ipRGC function in DR is associated with circadian outputs and sleep/wake behavior. METHODS: Forty-five participants (15 without diabetes, 15 with type 2 diabetes (T2D) and no DR, 15 with T2D and DR) participated. ipRGC function was inferred from the PIPR (pupil size following stimulus offset). Circadian outputs were melatonin amplitude (overnight urinary 6-sulfatoxymelatonin (aMT6s)) and timing (dim light melatonin onset (DLMO)), and evening salivary cortisol levels. Sleep/wake patterns were measured with wrist actigraphy and insomnia symptoms were assessed subjectively. RESULTS: Patients with T2D and DR had smaller PIPR and lower urinary aMT6s than other groups (p < 0.001). In adjusted regression models, smaller PIPR was associated with lower urinary aMT6s (ß = 4.552, p = 0.005). Patients with DR were more likely to have no detectable DLMO (p = 0.049), higher evening salivary cortisol, greater insomnia symptoms and greater sleep variability compared to other groups. Sleep duration, efficiency and rest-activity rhythms were similar. CONCLUSION: Reduced ipRGC function in DR is associated with circadian dysregulation and sleep disturbances, although a causal relationship cannot be established in this cross-sectional study. Prospective mechanistic and intervention studies examining circadian and sleep health in these patients are warranted.

Circadian Misalignment of the 24-hour Profile of Endocannabinoid 2-Arachidonoylglycerol (2-AG) in Obese Adults.

CONTEXT: The endocannabinoid (eCB) system partly controls hedonic eating, a major cause of obesity. While some studies suggested an overactivation of the eCB system in obesity, peripheral levels of eCBs across the 24-hour cycle have not been characterized in obese individuals despite the fact that in lean adults, levels of the eCB 2-arachidonoylglycerol (2-AG) vary across the day. OBJECTIVE: We sought to examine 24-hour profiles of serum concentrations of 2-AG in healthy obese and nonobese adults, under well-controlled laboratory conditions. We also simultaneously assessed 24-hour profiles of 2-oleoylglycerol (2-OG), leptin, and cortisol in each participant. DESIGN: With fixed light-dark and sleep-wake cycles, blood sampling was performed over an entire 24-hour period, including identical meals at 0900, 1400, and 1900. PARTICIPANTS: Twelve obese (8 women, mean body mass index [BMI]: 39.1 kg/m2) and 15 nonobese (6 women; mean BMI: 23.6 kg/m2) healthy adults were studied. RESULTS: We observed a 24-hour variation of 2-AG levels in obese individuals but, relative to nonobese adults, the amplitude was dampened and the timings of the nadir and peak were delayed by 4 to 5 hours. The profile of 2-OG was similarly misaligned. In contrast, when expressed relative to the 24-hour mean level, the 24-hour rhythm of cortisol and leptin were similar in obese and nonobese participants. CONCLUSIONS: Obesity appears to be associated with a dampening and delay of the 24-hour variation of eCB activity relative to the central circadian signal as well as to the daily leptin rhythm. This misalignment may play a role in the pathophysiology of obesity.

Impact of circadian rhythmicity and sleep restriction on circulating endocannabinoid (eCB) N-arachidonoylethanolamine (anandamide).

OBJECTIVE: The endocannabinoid (eCB) system is involved in diverse aspects of human physiology and behavior but little is known about the impact of circadian rhythmicity on the system. The two most studied endocannabinoids, AEA (ananamide) and 2-AG (2-arachidonoylglycerol), can be measured in peripheral blood however the functional relevance of peripheral eCB levels is not clear. Having previously detailed the 24-h profile of serum 2-AG, here we report the 24-h serum profile of AEA to determine if these two endocannabinoids vary in parallel across the biological day including a nocturnal 8.5-h sleep period. Further, we assessed and compared the effect of a physiological challenge, in the form of sleep restriction to 4.5-h, on these two profiles. METHODS: In this randomized crossover study, we examined serum concentrations of AEA across a 24-h period in fourteen young adults. Congeners of AEA, the structural analogs oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were simultaneously assayed. Prior to 24-h blood sampling, each participant was exposed to two nights of normal (8.5 h) or restricted sleep (4.5 h). The two sleep conditions were separated by at least one month. In both sleep conditions, during the period of blood sampling, each individual ate the same high-carbohydrate meal at 0900, 1400, and 1900. RESULTS: Mean 24-h concentrations of AEA were 0.697 ±â€¯0.11 pmol/ml. A reproducible biphasic 24-h profile of AEA was observed with a first peak occurring during early sleep (0200) and a second peak in the mid-afternoon (1500) while a nadir was detected in the mid-morning (1000). The 24-h profiles for both OEA and PEA followed a similar pattern to that observed for AEA. AEA, OEA, and PEA levels were not affected by sleep restriction at any time of day, contrasting with the elevation of early afternoon levels previously observed for 2-AG. CONCLUSIONS: The 24-h rhythm of AEA is markedly different from that of 2-AG, being of lesser amplitude and biphasic, rather than monophasic. These observations suggest distinct regulatory pathways of the two eCB and indicate that time of day needs to be carefully controlled in studies attempting to delineate their relative roles. Moreover, unlike 2-AG, AEA is not altered by sleep restriction, suggesting that physiological perturbations may affect AEA and 2-AG differently. Similar 24-h profiles were observed for OEA and PEA following normal and restricted sleep, further corroborating the validity of the wave-shape and lack of response to sleep loss observed for the AEA profile. Therapeutic approaches involving agonism or antagonism of peripheral eCB signaling will likely need to be tailored according to time of day.

Reference Gene Optimization for Circadian Gene Expression Analysis in Human Adipose Tissue.

A hallmark of biology is the cyclical nature of organismal physiology driven by networks of biological, including circadian, rhythms. Unsurprisingly, disruptions of the circadian rhythms through sleep curtailment or shift work have been connected through numerous studies to positive associations with obesity, insulin resistance, and diabetes. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) measures oscillation in messenger RNA expression, an essential foundation for the study of the physiological circadian regulatory network. Primarily, measured oscillations have involved the use of reference gene normalization. However, the validation and identification of suitable reference genes is a significant challenge across different biological systems. This study focuses on adipose tissue of premenopausal, otherwise healthy, morbidly obese women voluntarily enrolled after being scheduled for laparoscopic sleeve gastrectomy surgery. Acquisition of tissue was accomplished by aspiratory needle biopsies of subcutaneous adipose tissue 1 to 2 weeks prior to surgery and 12 to 13 weeks following surgery and an in-surgery scalpel-assisted excision of mesenteric adipose tissue. Each biopsy was sterile cultured ex vivo and serially collected every 4 h over approximately 36 h. The candidate reference genes that were tested were 18S rRNA, GAPDH, HPRT1, RPII, RPL13α, and YWHAZ. Three analytic tools were used to test suitability, and the candidate reference genes were used to measure oscillation in expression of a known circadian clock element (Dbp). No gene was deemed suitable as an individual reference gene control, which indicated that the optimal reference gene set was the geometrically averaged 3-gene panel composed of YWHAZ, RPL13α, and GAPDH. These methods can be employed to identify optimal reference genes in other systems.

Reduced length of stay and 30-day readmission rate on an inpatient vascular surgery service.

As the cost of care for patients with specific diagnoses becomes fixed, hospitals must develop systems to reduce length of stay and optimize the use of hospital resources while maintaining a high quality of care. The goal of this study is to evaluate the implementation and efficacy of a system designed to reduce average length of stay on a vascular surgery service. To effectively reduce the average length of stay in our center, we restructured patient rounds, implemented multidisciplinary rounds, introduced clinical pathways to postoperative care, and expanded outpatient management of postoperative patients. A total of 1697 adult vascular surgery patients discharged while under the medical direction of a vascular surgeon between July 1, 2013, and June 30, 2016, were included in the study. Improving communication with critical staff and using procedural space outside of the main operating rooms led to a 2.8-day reduction in the length of stay (10.8 vs 8.0, P < .001). There was a trend toward a reduction in the 30-day readmission rate (12% vs 10%, respectively; P = .01) and no significant difference in the case-mix index as a measure of illness severity (2.5 vs 2.4, respectively; P = .15). Length of stay reductions were heterogeneous among the types of vascular diseases studied, with greater improvements seen in patients undergoing lower extremity amputation, lower extremity angiogram, and endovascular aneurysm repair for nonruptured abdominal aortic aneurysms. Less pronounced differences were observed in patients undergoing carotid artery endarterectomy or stenting and lower extremity bypasses. In conclusion, restructuring team rounds and instituting a multidisciplinary approach to discharge planning produced significant reductions in length of stay without a deleterious effect on patient care which may impact hospital profitability.

Circadian rhythms and metabolism: from the brain to the gut and back again.

This paper focuses on the relationship between the circadian system and glucose metabolism. Research across the translational spectrum confirms the importance of the circadian system for glucose metabolism and offers promising clues as to when and why these systems go awry. In particular, basic research has started to clarify the molecular and genetic mechanisms through which the circadian system regulates metabolism. The study of human behavior, especially in the context of psychiatric disorders, such as bipolar disorder and major depression, forces us to see how inextricably linked mental health and metabolic health are. We also emphasize the remarkable opportunities for advancing circadian science through big data and advanced analytics. Advances in circadian research have translated into environmental and pharmacological interventions with tremendous therapeutic potential.

Peripheral circadian misalignment: contributor to systemic insulin resistance and potential intervention to improve bariatric surgical outcomes.

Thirteen percent of the world's population suffers from obesity and 39% from being overweight, which correlates with an increase in numerous secondary metabolic complications, such as Type 2 diabetes mellitus. Bariatric surgery is the most effective treatment for severe obesity and results in significant weight loss and the amelioration of obesity-related comorbidities through changes in enteroendocrine activity, caloric intake, and alterations in gut microbiota composition. The circadian system has recently been found to be a critical regulatory component in the control of metabolism and, thus, may potentially play an important role in inappropriate weight gain. Indeed, some behaviors and lifestyle factors associated with an increased risk of obesity are also risk factors for misalignment in the circadian clock system and for the metabolic syndrome. It is thus possible that alterations in peripheral circadian clocks in metabolically relevant tissues are a contributor to the current obesity epidemic. As such, it is plausible that postsurgical alterations in central circadian alignment, as well as peripheral gene expression in metabolic tissues may represent another mechanism for the beneficial effects of bariatric surgery. Bariatric surgery may represent an opportunity to identify changes in the circadian expression of clock genes that have been altered by environmental factors, allowing for a better understanding of the mechanism of action of surgery. These studies could also reveal an overlooked target for behavioral intervention to improve metabolic outcomes following bariatric surgery.

Sleep Restriction Enhances the Daily Rhythm of Circulating Levels of Endocannabinoid 2-Arachidonoylglycerol.

STUDY OBJECTIVES: Increasing evidence from laboratory and epidemiologic studies indicates that insufficient sleep may be a risk factor for obesity. Sleep curtailment results in stimulation of hunger and food intake that exceeds the energy cost of extended wakefulness, suggesting the involvement of reward mechanisms. The current study tested the hypothesis that sleep restriction is associated with activation of the endocannabinoid (eCB) system, a key component of hedonic pathways involved in modulating appetite and food intake. METHODS: In a randomized crossover study comparing 4 nights of normal (8.5 h) versus restricted sleep (4.5 h) in healthy young adults, we examined the 24-h profiles of circulating concentrations of the endocannabinoid 2-arachidonoylglycerol (2-AG) and its structural analog 2-oleoylglycerol (2-OG). We concomitantly assessed hunger, appetite, and food intake under controlled conditions. RESULTS: A robust daily variation of 2-AG concentrations with a nadir around the middle of the sleep/overnight fast, followed by a continuous increase culminating in the early afternoon, was evident under both sleep conditions but sleep restriction resulted in an amplification of this rhythm with delayed and extended maximum values. Concentrations of 2-OG followed a similar pattern, but with a lesser amplitude. When sleep deprived, participants reported increases in hunger and appetite concomitant with the afternoon elevation of 2-AG concentrations, and were less able to inhibit intake of palatable snacks. CONCLUSIONS: Our findings suggest that activation of the eCB system may be involved in excessive food intake in a state of sleep debt and contribute to the increased risk of obesity associated with insufficient sleep. COMMENTARY: A commentary on this article appears in this issue on page 495.