Search

We aimed to identify the minimum number of ambulatory blood pressure (ABP) measures to accurately determine daytime and nighttime systolic blood pressure (BP) averages and nocturnal dipping status (i.e., relative daytime:nighttime change). A total of 43 midlife participants wore an ABP monitor for 24 h with measurements every 20/30 min during the daytime/nighttime, as identified by a sleep diary. We calculated daytime/nighttime systolic BP average and dipping status from all available measurements per participant (i.e., normative data). We then calculated daytime and nighttime BP per participant based on a random selection of 8–20 and 4–10 measurements and replicated random selections 1,000 times. We calculated accuracy by checking the proportion from 1,000 different randomly selected samples for a particular number of measurements that systolic BP was ±5 mmHg of normative data, and dipping status remained unchanged for each participant compared with the normative value. The best fit for the regression model estimated the minimal number of measurements for an accuracy of 95% in BP averages. For a 95% accuracy in estimating daytime and nighttime systolic BP, 11 daytime and 8 nighttime measurements were required. The highest accuracy for dipping status was 91.6 ± 13.4% using 20 daytime and 10 nighttime measures, while the lowest was (83.4 ± 15.1%) using 8 daytime and 4 nighttime measures. In midlife adults, 11 daytime and 8 nighttime measurements are likely enough to calculate average systolic BPs accurately. However, no minimum number is suggested to accurately calculate dipping status. NEW & NOTEWORTHY: We found that a minimum of 11 blood pressure (BP) measures are necessary to calculate an accurate average daytime BP, and 8 nighttime measures are necessary to calculate an accurate nighttime average if 95% accuracy is acceptable. Regarding BP dipping status, the current recommendations (20 daytime/7 nighttime) inaccurately classified the dipping status 10.5% of the time, suggesting that guidelines may need to be updated to classify patients as nocturnal dippers or nondippers correctly. [ABSTRACT FROM AUTHOR]

Objective: Given the complex interaction among the circadian system, energy metabolism, and obesity, the authors tested whether having obesity impacts the circadian variation in energy and glucose metabolism in humans. Methods: Participants with BMI either in the healthy weight or obesity ranges were studied in a 5‐day, in‐laboratory protocol that equally distributed behaviors (i.e., sleep, eating, exercise) across 24 h. Energy metabolism was measured at rest and during a standardized exercise bout and blood was sampled before and after each identical study meal to assess glucose and insulin levels. Results: In those with a healthy weight, the circadian nadir of energy expenditure, during both rest and exercise, occurred when participants would normally be asleep. However, in those with obesity, this nadir appears to occur during the habitual wake period. Differences in glucose regulation also depended on the circadian phase, such that individuals with obesity appeared to have relatively greater glucose intolerance during the circadian day and produced less insulin during the circadian night. Conclusions: Obesity is associated with altered circadian energy and glucose metabolism. Understanding and addressing these associations could lead to strategies that improve body weight and metabolic health in people with obesity. [ABSTRACT FROM AUTHOR]

Averaged nighttime blood pressure (BP) is superior to daytime BP for cardiovascular risk stratification, and the relative change between daytime/nighttime BP (dipping percentage) significantly predicts cardiovascular risk. Newer reports suggest that four measurements at night may be enough for cardiovascular risk stratification. Since BP oscillates across the night, the temporal distribution of measurements across the night may impact nighttime BP and dipping percentage. Therefore, we compared average nighttime BP and dipping percentage when using measurements in the first half (1st half), second half (2nd half), and a combination of both (combined). Forty-three (17 females and 26 males) midlife adults aged 50 ± 10 yr old wore an ambulatory BP monitor for 24 h at home, programmed to measure BP every 20 min when scheduled for daytime and every 30 min during a self-selected 8-h nighttime for time in bed. We compared the nighttime BP averages and dipping percentages when using either the first four measurements from the first half or second half of the nighttime and combined. Nighttime systolic BP was significantly different across first half, second half, and combined (111 ± 9 vs. 107 ± 11 vs. 109 ± 9 mmHg, P < 0.01), respectively, with significant pairwise differences across all categories (P < 0.01 for each). Systolic BP dipping percentage was significantly different across first half, second half, and combined (9.9 ± 5.5 vs. 13.5 ± 6.4 vs. 11.7 ± 5.0%, P < 0.01), respectively, with significant pairwise differences across all categories (P < 0.01 for each). Diastolic BP and diastolic dipping percentage were similar across the three different bins. In midlife adults, systolic nighttime BP and dipping percentage may depend upon when BP measurements are taken during the night. [ABSTRACT FROM AUTHOR]

Background: In humans, circulating cortisol usually peaks 30-60 min after awakening from nocturnal sleep, this is commonly referred to as the cortisol awakening response (CAR). We examined the extent to which the CAR is influenced by the circadian system, independent of behaviors including sleep. Materials and methods: We examined the CAR in 34 adults (20 female) using two complementary multiday in-laboratory circadian protocols performed in dim light, throughout which behavioral factors were uniformly distributed across the 24-hour circadian cycle. Protocol 1 consisted of 10 identical consecutive 5-hour 20-minute sleep/wake cycles, and protocol 2 consisted of 5 identical consecutive 18-hour sleep/wake cycles. Salivary melatonin was used as the circadian phase marker (0° = dim light melatonin onset). During each sleep/wake cycle, salivary cortisol was measured upon scheduled awakening and 50-minutes later, with the change in cortisol defined as the CAR. Cosinor analyses were used to detect any significant circadian rhythmicity in the CAR. In secondary analyses, we adjusted the models for time awake before lights on, total sleep time, percent of rapid eye movement (REM) sleep, and percent of non-rapid eye movement (NREM) sleep. Results: Both protocols revealed a similar circadian rhythm in the CAR, with peaks occurring at a circadian phase corresponding to 3:40-3:45 a.m., with no detectable CAR during the circadian phases corresponding to the afternoon. In addition to the sinusoidal component of the circadian rhythm, total sleep time was also associated with the CAR for protocol 1. The percent of sleep spent in REM or NREM sleep were not associated with the CAR in either protocol. Conclusion: Our results show that the CAR exhibits a robust circadian rhythm that persists even after adjusting for prior sleep. Presuming that the CAR optimizes physiological responses to the anticipated stressors related to awakening, these findings may have implications for shift workers who wake up at unusual circadian phases. A blunted CAR in shift workers upon awakening in the evening may result in diminished responses to stressors. [ABSTRACT FROM AUTHOR]

Umbilical cord mesenchymal stem cell-derived extracellular vesicles (UC-MSC-EVs) have become an emerging strategy for treating various autoimmune and metabolic disorders, particularly diabetes. Delivery of UC-MSC-EVs is essential to ensure optimal efficacy of UC-MSC-EVs. To develop safe and superior EVs-based delivery strategies, we explored nuclear techniques including positron emission tomography (PET) to evaluate the delivery of UC-MSC-EVs in vivo. In this study, human UC-MSC-EVs were first successfully tagged with I-124 to permit PET determination. Intravenous (I.V.) and intra-arterial (I.A.) administration routes of [124I]I-UC-MSC-EVs were compared and evaluated by in vivo PET-CT imaging and ex vivo biodistribution in a non-diabetic Lewis (LEW) rat model. For I.A. administration, [124I]I-UC-MSC-EVs were directly infused into the pancreatic parenchyma via the celiac artery. PET imaging revealed that the predominant uptake occurred in the liver for both injection routes, and further imaging characterized clearance patterns of [124I]I-UC-MSC-EVs. For biodistribution, the uptake (%ID/gram) in the spleen was significantly higher for I.V. administration compared to I.A. administration (1.95 ± 0.03 and 0.43 ± 0.07, respectively). Importantly, the pancreas displayed similar uptake levels between the two modalities (0.20 ± 0.06 for I.V. and 0.24 ± 0.03 for I.A.). Therefore, our initial data revealed that both routes had similar delivery efficiency for [124I]I-UC-MSC-EVs except in the spleen and liver, considering that higher spleen uptake could enhance immunomodulatory application of UC-MSC-EVs. These findings could guide the development of safe and efficacious delivery strategies for UC-MSC-EVs in diabetes therapies, in which a minimally invasive I.V. approach would serve as a better delivery strategy. Further confirmation studies are ongoing. [ABSTRACT FROM AUTHOR]

Objective: Endocannabinoids have been implicated in the pathophysiology of Major Depressive Disorder (MDD) and might represent potential targets for therapeutic intervention. Objectives of the study were: (1) to measure plasma levels of endocannabinoids in a group of antidepressant‐free depressed outpatients; (2) to explore their relationship with the severity of depressive symptoms as subjectively perceived by the patients; and (3) to investigate the effect of the selective serotonin reuptake inhibitor escitalopram on endocannabinoid levels. Methods: We measured plasma levels of the two major endocannabinoids, 2‐arachidonoylglycerol (2‐AG) and N‐arachidonoylethanolamine (anadamide), in 12 drug‐free outpatients diagnosed with MDD and in 12 matched healthy controls. In the patient group, endocannabinoids plasma levels were assessed at baseline and after 2 months of treatment with escitalopram. Results: Baseline plasma levels of the two endocannabinoids did not differ between depressed patients and healthy controls. However, there was a significant inverse correlation between 2‐arachidonoylglycerol levels and the severity of subjectively perceived depressive symptoms. Treatment with escitalopram did not change endocannabinoid levels in depressed patients, although it caused the expected improvement of depressive symptoms. Conclusions: Our results suggest that 2‐arachidonylglycerol, the most abundant endocannabinoid in the central nervous system, might act to mitigate depressive symptoms, and raise the interesting possibility that 2‐arachidonylglycerol and anandamide are differentially regulated in patients affected by MDD. Also, our data suggest but do not prove that the endocannabinoid system is not regulated by serotonergic transmission, at least in depressed patients. [ABSTRACT FROM AUTHOR]

Though short sleep has been shown to increase food intake and subsequent weight gain, most excess food intake occurs in after-dinner snacks during the night-time hours (Markwald I et al i . 2013; Spaeth I et al i . 2013). Shift work, sleep loss, and increases in night-time eating and weight gain Work schedules often dictate our sleep-wake cycles. Keywords: cardiometabolic health; circadian misalignment; sleep restriction EN cardiometabolic health circadian misalignment sleep restriction 1603 1605 3 04/04/22 20220401 NES 220401 Due to the arduous demands of the global economy, 15-20% of the workforce in the USA are required to work outside of conventional daytime hours (Woods, 2020). [Extracted from the article]

Background: Firefighters endure large occupational burdens and generally operate under conditions of chronic sleep deficiency and circadian disruption due to long shifts, plus interrupted sleep due to emergency calls during the night. A typical shift for firefighters is 24‐h on/48‐h off, and firefighters are expected to use time‐off to recover from any sleep debt, while balancing social, family, and home responsibilities. This qualitative study sets out to assess family dynamics and how firefighters prioritize sleep and recovery at home based on relationship or family status, as well as a fire department's current shift schedule. Methods: Focus groups were conducted via convenience sampling in Portland, OR, with full‐time firefighters, battalion chiefs, and their spouses. Grounded theory, using NVivo 12 Plus, was used to code transcripts to reveal reoccurring concepts and themes. Results: Major themes centered around the increase of nonemergent calls contributing to compassion fatigue. Spouses can help improve the sleep of firefighters by creating opportunities for recuperative sleep at home. However, spouses also conveyed underlying tones of "resentment" relating to their firefighter being unavailable for emotional and instrumental support. While married firefighters discussed choosing family and home obligations over reducing sleep debt to maintain relationships, single and divorced firefighters spoke of fewer conflicts impeding their ability to prioritize sleep at home. Conclusions: These results improve our understanding of how firefighters prioritize sleep at home based on family dynamics and can inform future decision‐making for fire departments in addressing concerns related to work–family conflict, sleep loss, and compassion fatigue among their members. [ABSTRACT FROM AUTHOR]

Measurements of aldosterone for diagnosis of primary aldosteronism are usually made from blood sampled in the morning when aldosterone typically peaks. We tested the relative contributions and interacting influences of the circadian system, ongoing behaviors, and prior sleep to this morning peak in aldosterone. To determine circadian rhythmicity and separate effects of behaviors on aldosterone, 16 healthy participants completed a 5-day protocol in dim light while all behaviors ranging from sleep to exercise were standardized and scheduled evenly across the 24-h circadian period. In another experiment, to test the separate effects of prior nocturnal sleep or the inactivity that accompanies sleep on aldosterone, 10 healthy participants were studied across 2 nights: 1 with sleep and 1 with maintained wakefulness (randomized order). Plasma aldosterone was measured repeatedly in each experiment. Aldosterone had a significant endogenous rhythm ( P < 0.001), rising across the circadian night and peaking in the morning (~8 AM). Activity, including exercise, increased aldosterone, and different behaviors modulated aldosterone differently across the circadian cycle (circadian phase × behavior interaction; P < 0.001). In the second experiment, prior nocturnal sleep and prior rested wakefulness both increased plasma aldosterone ( P < 0.001) in the morning, to the same extent as the change in circadian phases between evening and morning. The morning increase in aldosterone is due to effects of the circadian system plus increased morning activities and not prior sleep or the inactivity accompanying sleep. These findings have implications for the time of and behaviors preceding measurement of aldosterone, especially under conditions of shift work and jet lag. [ABSTRACT FROM AUTHOR]

Prior presentations N/A INTRODUCTION Coronavirus disease 2019 (COVID-19) magnifies the disproportionate burden of cardiovascular disease, diabetes, and other chronic diseases Black Americans face due to structural racism, psychosocial stress, and socioeconomic status.[1], [2] To monitor the progression of COVID-19 which has increased incidence in Black communities, US regional programs began implementing surveillance and strategies to increase testing and reduce spread among vulnerable populations in April 2020.[1], [3] Yet, Black populations are generally less likely to participate in research, largely due to cultural barriers to recruitment and low representation in educational and healthcare institutions.[4] Community-based methods and partnerships with underrepresented populations can increase trust and study participation; accordingly, we sought to understand potential barriers specific to COVID-19 treatment and prevention in Black Americans using focus groups.[4] METHODS Self-identified Black American residents aged 30-60 years with regular access to primary care (parent study requirement) were recruited nationally using Craigslist and ResearchMatch advertisements. Participants placed the onus largely on individuals to reduce risk factors for disease and slow COVID-19 infection. Structural Racism Considering COVID-19 infection and death rates among Black Americans, many participants questioned how their race, and not pre-existing conditions, could heighten their risk. [Extracted from the article]

Endocannabinoid signaling regulates feeding andmetabolic processes and has been linked to obesity development. Several hormonal signals, such as glucocorticoids and ghrelin, regulate feeding and metabolism by engaging the endocannabinoid system. Similarly, studies have suggested that leptin interacts with the endocannabinoid system, yet the mechanism and functional relevance of this interaction remain elusive. Therefore, we explored the interaction between leptin and endocannabinoid signaling with a focus on fatty acid amide hydrolase (FAAH), the primary degradative enzyme for the endocannabinoid N-arachidonoylethanolamine (anandamide; AEA). Mice deficient in leptin exhibited elevated hypothalamic AEA levels and reductions in FAAH activity while leptin administration to WT mice reduced AEA content and increased FAAH activity. Following high fat diet exposure, mice developed resistance to the effects of leptin administration on hypothalamic AEA content and FAAH activity. At a functional level, pharmacological inhibition of FAAH was sufficient to prevent leptin-mediated effects on body weight and food intake. Using a novel knock-in mouse model recapitulating a common human polymorphism (FAAH C385A; rs324420), which reduces FAAH activity, we investigated whether human genetic variance in FAAH affects leptin sensitivity. While WT (CC) mice were sensitive to leptin-induced reductions in food intake and body weight gain, low-expressing FAAH (AA) mice were unresponsive. These data demonstrate that FAAH activity is required for leptin's hypophagic effects and, at a translational level, suggest that a genetic variant in the FAAH gene contributes to differences in leptin sensitivity in human populations. [ABSTRACT FROM AUTHOR]

To address the authors' claim that shift work and sleep are inextricably linked, we point to work in their argument that either controls for sleep duration while investigating circadian misalignment or demonstrates the metabolic impact of circadian misalignment independent of sleep. In conclusion, although shift work results in insufficient and/or impaired sleep, extensive evidence suggests that the inherent circadian misalignment in conditions of shift work is most responsible for the increased risk of metabolic disease. Keywords: cardiometabolic health; circadian misalignment; sleep restriction EN cardiometabolic health circadian misalignment sleep restriction 1609 1610 2 04/04/22 20220401 NES 220401 In this debate, Drs Ritchie and Broussard argue that insufficient sleep is primarily responsible for the increased risk for metabolic disease in shift workers (Ritchie & Broussard, 2022). [Extracted from the article]

Background Valuable insights on the health and behavior of transit workers can be obtained from qualitative research that considers the social environment, which affects job performance and determines levels of perceived stress. Methods Using a grounded theory approach, semi-structured interviews were conducted with American transit workers (n = 32). Recorded interviews were transcribed and analyzed using a constant comparative method. Results Participants described categories related to entrenched organizational practices, particularly managements' leadership style, which created an atmosphere of distrust. High demanding work schedules, as a result of technological advances, were discussed in relation to diminished breaks, fatigue, and unhealthy diets. Transit workers also attributed increased work demands and irregular working hours to compromised time with family and friends. Conclusions The described barriers to positive health behaviors and social support underscore the need for interventions that ensure adequate breaks and recovery between shifts and increase safety for transit passengers. Am. J. Ind. Med. 60:350-367, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The brain is the central organ involved in perceiving and adapting to social and physical stressors via multiple interacting mediators, from the cell surface to the cytoskeleton to epigenetic regulation and nongenomic mechanisms. A key result of stress is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicates failed resilience. Excitatory amino acids and glucocorticoids have key roles in these processes, along with a growing list of extra- and intracellular mediators that includes endocannabinoids and brain-derived neurotrophic factor (BDNF). The result is a continually changing pattern of gene expression mediated by epigenetic mechanisms involving histone modifications and CpG methylation and hydroxymethylation as well as by the activity of retrotransposons that may alter genomic stability. Elucidation of the underlying mechanisms of plasticity and vulnerability of the brain provides a basis for understanding the efficacy of interventions for anxiety and depressive disorders as well as age-related cognitive decline. [ABSTRACT FROM AUTHOR]

Glucocorticoids are known to promote the development of metabolic syndrome through the modulation of both feeding pathways and metabolic processes; however, the precise mechanisms of these effects are not well-understood. Recent evidence shows that glucocorticoids possess the ability to increase endocannabinoid signaling, which is known to regulate appetite, energy balance, and metabolic processes through both central and peripheral pathways. The aim of this study was to determine the role of endocannabinoid signaling in glucocorticoid-mediated obesity and metabolic syndrome. Using a mouse model of excess corticosterone exposure, we found that the ability of glucocorticoids to increase adiposity, weight gain, hormonal dysregulation, hepatic steatosis, and dyslipidemia was reduced or reversed in mice lacking the cannabinoid CB1 receptor as well as mice treated with the global CB1 receptor antagonist AM251. Similarly, a neutral, peripherally restricted CB1 receptor antagonist (AM6545) was able to attenuate the metabolic phenotype caused by chronic corticosterone, suggesting a peripheral mechanism for these effects. Biochemical analyses showed that chronic excess glucocorticoid exposure produced a significant increase in hepatic and circulating levels of the endocannabinoid anandamide, whereas no effect was observed in the hypothalamus. To test the role of the liver, specific and exclusive deletion of hepatic CB1 receptor resulted in a rescue of the dyslipidemic effects of glucocorticoid exposure, while not affecting the obesity phenotype or the elevations in insulin and leptin. Together, these data indicate that glucocorticoids recruit peripheral endocannabinoid signaling to promote metabolic dysregulation, with hepatic endocannabinoid signaling being especially important for changes in lipid metabolism. [ABSTRACT FROM AUTHOR]

Background: Bispecific T-cell engaging antibodies (BiTES), comprising dual anti-CD3 and anti-tumor antigen scFv fragments, are important therapeutic agents for the treatment of cancer. The dual scFv construct for BiTES requires proper protein folding while their small molecular size leads to rapid kidney clearance.Methods: An intact (150 kDa) anti-tumor antigen antibody to CEA was joined in high yield (ca. 30%) to intact (150 kDa) anti-murine and anti-human CD3 antibodies using hinge region specific Click chemistry to form dual-specific, bivalent BiTES (dbBiTES, 300 kDa). dbBiTEs were tested in vitro by EM, flow cytometry and cell cytoxicity and in vivo by PET tumor imaging and redirected T-cell therapy.Results: The interlocked hinge regions are compatible with a structural model that fits the electron micrographs of 300 kDa particles. Compared to intact anti-CEA antibody, dbBiTES exhibit high in vitro cytotoxicity, high in vivo tumor targeting as demonstrated by PET imaging, and redirected dbBiTE coated T-cells (1 microgram/10 million cells) that kill CEA+ target cells in vivo in CEA transgenic mice.Conclusion: dbBiTE redirected T-cell therapy is a promising, efficient approach for targeting and killing cancer cells. [ABSTRACT FROM AUTHOR]

Real-time intraoperative image-guided cancer surgery promises to improve oncologic outcomes. Tumor-specific antibodies conjugated with near-infrared (NIR) fluorophores have demonstrated the potential to enhance visualization of solid tumor margins and metastatic disease; however, multiple challenges remain, including improvement in probe development for clinical utility. We have developed an NIR-IR800 dye on a PEGylated linker (sidewinder) conjugated to the humanized anti-carcinoembryonic antigen (CEA) antibody (M5A) with extended in vivo serum and tumor persistence. The anti-CEA M5A-sidewinder has a high dye-to-antibody ratio (average of 7 per antibody) that allows, in an orthotopic implanted human pancreatic cancer mouse model increased tumor fluorescence, higher tumor-to-background ratio and extends the surgical scheduling window compared to current antibody dye conjugates. These preclinical results demonstrate the potential of this probe for fluorescence-guided surgery of CEA-positive gastrointestinal cancers. [ABSTRACT FROM AUTHOR]