Rigorous benchmarking of T-cell receptor repertoire profiling methods for cancer RNA sequencing.

The ability to identify and track T-cell receptor (TCR) sequences from patient samples is becoming central to the field of cancer research and immunotherapy. Tracking genetically engineered T cells expressing TCRs that target specific tumor antigens is important to determine the persistence of these cells and quantify tumor responses. The available high-throughput method to profile TCR repertoires is generally referred to as TCR sequencing (TCR-Seq). However, the available TCR-Seq data are limited compared with RNA sequencing (RNA-Seq). In this paper, we have benchmarked the ability of RNA-Seq-based methods to profile TCR repertoires by examining 19 bulk RNA-Seq samples across 4 cancer cohorts including both T-cell-rich and T-cell-poor tissue types. We have performed a comprehensive evaluation of the existing RNA-Seq-based repertoire profiling methods using targeted TCR-Seq as the gold standard. We also highlighted scenarios under which the RNA-Seq approach is suitable and can provide comparable accuracy to the TCR-Seq approach. Our results show that RNA-Seq-based methods are able to effectively capture the clonotypes and estimate the diversity of TCR repertoires, as well as provide relative frequencies of clonotypes in T-cell-rich tissues and low-diversity repertoires. However, RNA-Seq-based TCR profiling methods have limited power in T-cell-poor tissues, especially in highly diverse repertoires of T-cell-poor tissues. The results of our benchmarking provide an additional appealing argument to incorporate RNA-Seq into the immune repertoire screening of cancer patients as it offers broader knowledge into the transcriptomic changes that exceed the limited information provided by TCR-Seq.

Sleep insufficiency, circadian rhythms, and metabolomics: the connection between metabolic and sleep disorders.

PURPOSE: US adults who report experiencing insufficient sleep are more likely to suffer from metabolic disorders such as hyperlipidemia, diabetes, and obesity than those with sufficient sleep. Less is understood about the underlying molecular mechanisms connecting these phenomena. A systematic, qualitative review of metabolomics studies exploring metabolic changes in response to sleep insufficiency, sleep deprivation, or circadian disruption was conducted in accordance with PRISMA guidelines. METHODS: An electronic literature review in the PubMed database was performed considering publications through May 2021 and screening and eligibility criteria were applied to articles retrieved. The following keywords were used: "metabolomics" and "sleep disorders" or "sleep deprivation" or "sleep disturbance" or "circadian rhythm." After screening and addition of studies included from reference lists of retrieved studies, 16 records were identified for review. RESULTS: Consistent changes in metabolites were observed across studies between individuals experiencing sleep deprivation compared to non-sleep deprived controls. Significant increases in phosphatidylcholines, acylcarnitines, sphingolipids, and other lipids were consistent across studies. Increased levels of amino acids such as tryptophan and phenylalanine were also noted. However, studies were limited to small samples of young, healthy, mostly male participants conducted in short inpatient sessions, limiting generalizability. CONCLUSION: Changes in lipid and amino acid metabolites accompanying sleep deprivation and/or circadian rhythms may indicate cellular membrane and protein breakdown underlying the connection between sleep disturbance, hyperlipidemia, and other metabolic disorders. Larger epidemiological studies examining changes in the human metabolome in response to chronic insufficient sleep would help elucidate this relationship.

Obesity does not modify the effect of continuous positive airway pressure on insulin resistance in adults with obstructive sleep apnoea.

This study found no evidence that obesity significantly modifies the effect of 4 months of CPAP treatment on HOMA-IR. Longer duration of CPAP treatment may be needed in order to reduce insulin resistance and determine whether obesity modifies the effect. https://bit.ly/3CtX7jZ.

The effects of time-restricted eating on sleep, cognitive decline, and Alzheimer's disease.

According to the United Nations, by 2050, one in six individuals will be over age 65 globally, and one in four people would be aged 65 and older in western countries. The unprecedented growth of the aging population is associated with increased age-related disorders like Alzheimer's disease (AD) and Mild cognitive impairment (MCI). To date, no cure is known for AD, thus lifestyle interventions including calorie restriction (CR) and time-restricted eating (TRE) are proposed as potential approach to delay the onset and progression of the disease. Sleep disturbances are common in people with MCI and AD. Moreover, accumulating data indicates that pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), IL-6, IL-8 and IL-10 increase in individuals with AD and MCI versus healthy subjects. Thus, the purpose of the present review is to describe the potential effects of TRE on sleep, cognition decline, and neuroinflammatory markers in humans. Preliminary evidence suggests that TRE may produce neuroprotective effects on cognition and reduce neuroinflammatory markers related to AD in humans. To date, no studies investigated the effects of TRE on sleep disturbances and patients with AD. Thereby, the impact of TRE on cognition in individuals with cognitive decline and AD needs to be investigated further in randomized controlled trials (RCTs).

Examining the role of micronutrients on improving long COVID sleep-related symptoms.

AIMS AND OBJECTIVES: Long COVID is defined as the continuation of symptoms for four or more weeks after initial contraction of the virus. This review article examines the role of four select micronutrients (zinc, vitamins C, D and polyphenols) for their anti-inflammatory and therapeutic potential to improve sleep-related symptoms in persons with long COVID. BACKGROUND: Evidence suggests a link between long COVID and increased inflammation. There are currently no therapeutic interventions for common sleep-related symptoms associated with long COVID. Micronutrients, due to their antioxidant and anti-inflammatory properties, may have a role in the treatment of sleep-related symptoms in the context of long COVID. DESIGN: A narrative literature review was conducted and guided by the PRISMA checklist. METHODS: All articles were screened from PubMed, ScienceDirect, NCBI or Google Scholar and were limited to human studies. The following keywords were used: 'COVID-19', 'sleep symptoms', 'zinc', 'vitamin C', 'vitamin D', 'polyphenols' and 'micronutrients'. RESULTS: There are currently no studies that examine the usage of micronutrients and its impacts on long-term, sleep-related symptoms post-COVID-19 infection. We focussed our review on prior studies that examined micronutrients in the context of sleep symptoms and inflammation, while exploring the potential for micronutrients to help improve sleep-related symptoms associated with long COVID. CONCLUSIONS: There is evidence to suggest that sleep-related symptoms associated with long COVID, such as fatigue and poor sleep quality, are associated with inflammation. Zinc, vitamins C, D and polyphenols all have the potential to improve both inflammation and sleep quality to alleviate symptoms. Future research should further examine these micronutrients in the context of long COVID to improve sleep and quality of life. RELEVANCE TO CLINICAL PRACTICE: This article provides implications for clinicians to be at the forefront of research on the usage of micronutrients to improve sleep-related symptoms in persons with long COVID.

Sleep duration and biomarkers of inflammation in African American and white participants with a parental history of Alzheimer's disease.

Introduction: African Americans (AA)s have worse inflammation, worse sleep, and a greater incidence of Alzheimer's disease (AD) compared to whites; however, no studies have examined associations between biomarkers, sleep, and cognition, and differences by race. Methods: Seventy-six cognitively normal, middle aged (45-65 years) adults with a parental history of AD were included in this study. Associations between biomarkers (tumor necrosis factor-α [TNF-α], interleukin-10 [IL-10], intercellular adhesion molecule-1 [ICAM-1],, and C-reactive protein [CRP]) and self-reported sleep or cognition measures, were assessed. Results: Average sleep duration was significantly lower for AA versus whites (average[SD]) in hours: 6.02(1.18) versus 7.23(0.91), P = .000004). We found a statistically significant association between plasma IL-10 and sleep duration (Spearman's ρ = 0.26, P = .04) and CSF ICAM-1 and sleep quality (Spearman's ρ = 0.30, P = .03). Discussion: Longer sleep duration is positively associated with plasma IL-10 levels irrespective of race. Sleep quality was positively associated with CSF ICAM-1 only in African Americans.

Sphinganine is associated with 24-h MAP in the non-sleepy with OSA.

INTRODUCTION: Excessive daytime sleepiness is a debilitating symptom of obstructive sleep apnea (OSA) linked to cardiovascular disease, and metabolomic mechanisms underlying this relationship remain unknown. We examine whether metabolites from inflammatory and oxidative stress-related pathways that were identified in our prior work could be involved in connecting the two phenomena. METHODS: This study included 57 sleepy (Epworth Sleepiness Scale (ESS) ≥ 10) and 37 non-sleepy (ESS < 10) participants newly diagnosed and untreated for OSA that completed an overnight in-lab or at home sleep study who were recruited from the Emory Mechanisms of Sleepiness Symptoms Study (EMOSS). Differences in fasting blood samples of metabolites were explored in participants with sleepiness versus those without and multiple linear regression models were utilized to examine the association between metabolites and mean arterial pressure (MAP). RESULTS: The 24-h MAP was higher in sleepy 92.8 mmHg (8.4) as compared to non-sleepy 88.8 mmHg (8.1) individuals (P = 0.03). Although targeted metabolites were not significantly associated with MAP, when we stratified by sleepiness group, we found that sphinganine is significantly associated with MAP (Estimate = 8.7, SE = 3.7, P = 0.045) in non-sleepy patients when controlling for age, BMI, smoking status, and apnea-hypopnea index (AHI). CONCLUSION: This is the first study to evaluate the relationship of inflammation and oxidative stress related metabolites in sleepy versus non-sleepy participants with newly diagnosed OSA and their association with 24-h MAP. Our study suggests that Sphinganine is associated with 24 hour MAP in the non-sleepy participants with OSA.

Changes in sleepiness and 24-h blood pressure following 4 months of CPAP treatment are not mediated by ICAM-1.

OBJECTIVE: Continuous positive airway pressure (CPAP) therapy reduces circulating intercellular adhesion molecule 1 (ICAM-1) in adults with obstructive sleep apnea (OSA). ICAM-1 levels may affect the daytime sleepiness and elevated blood pressure associated with OSA. We evaluated the association of changes from baseline in ICAM-1 with changes of objective and subjective measures of sleepiness, as well as 24-h ambulatory blood pressure monitoring (ABPM) measures, following 4 months of CPAP treatment. METHODS: The study sample included adults with newly diagnosed OSA. Plasma ICAM-1, 24-h ABPM, Epworth Sleepiness Scale (ESS), and psychomotor vigilance task (PVT) were obtained at baseline and following adequate CPAP treatment. The associations between changes in natural log ICAM-1 and changes in the number of lapses on PVT, ESS score, and 24-h mean arterial blood pressure (MAP) were assessed using multivariate regression models, controlling for a priori baseline covariates of age, sex, BMI, race, site, smoking status, physical activity, anti-hypertensive medications, AHI, and daily hours of CPAP use. RESULTS: Among 140 adults (83% men), mean (± SD) body mass index (BMI) was 31.5 ± 4.2 kg/m2, and apnea-hyopnea index (AHI) was 36.8 ± 15.3 events/h. Sleepiness measures, although not ICAM-1 or ABPM measures, improved significantly following CPAP treatment. We observed no statistically significant associations between the change in ICAM-1 and changes in sleepiness, MAP, or other ABPM measures. CONCLUSION: Changes in ICAM-1 levels were not related to changes in sleepiness or ABPM following CPAP treatment of adults with OSA. Future work should explore whether or not other biomarkers may have a role in mediating these treatment outcomes in adults with OSA.

Daytime sleepiness predicts inflammation and ambulatory blood pressure in sleep apnoea.

INTRODUCTION: Sleepiness in obstructive sleep apnoea is associated with cardiovascular risk; however, the biological mechanisms are not known. This study explored whether those with subjective sleepiness have increased plasma tumour necrosis factor-related protein 1 (C1qTNF1), a novel adipose-derived hormone (adipokine), and 24-h ambulatory blood pressure (ABP) compared to those without sleepiness in newly diagnosed, treatment-naïve participants with obstructive sleep apnoea. METHODS: Overall, 94 participants were included in the analysis. Participants completed the Epworth Sleepiness Scale (ESS), 24-h ABP was monitored, and plasma C1qTNF1 was measured. Sleepy participants were defined as ESS≥10 and nonsleepy as ESS<10. Multiple linear regression was used to explore differences in C1qTNF1, and 24-h mean arterial pressure (MAP) between sleepy and nonsleepy participants, adjusting for age, sex, body mass index, apnoea-hypopnoea index, and smoking status. RESULTS: C1qTNF1 was significantly higher in sleepy participants (n=57) compared to nonsleepy participants (n=37) (ß=0.41 NPX, 95% CI 0.02, 0.80; p=0.04). The 24-h MAP was significantly higher in sleepy participants compared to nonsleepy participants (ß=4.06 mmHg, 95% CI 0.36, 7.77; p=0.03). CONCLUSIONS: Our findings show that sleepiness is associated with inflammation and higher 24-h MAP in sleep apnoea.

Role of Supplemental Nutrition Assistance Program in Improving Diet Quality: Implications for Nurses.

The Supplemental Nutrition Assistance Program (SNAP) provides access to healthy food for low-income individuals and households. Food security, however, does not necessarily achieve higher diet quality for beneficiaries. Diet quality is an important consideration for the development and management of chronic illness, a significant public health concern. In this study, we review incentives and disincentives implemented to improve the diet quality, the evidence on SNAP including benefits, challenges, and the politics of funding. New interventions and policies will be needed in order to improve the overall diet quality of SNAP households. SNAP should align with nutritional science to meet national public health goals. Nurses are trusted advocates for patients and the public and are uniquely positioned to aid in this effort. Informed by evidence, nurses willing to leverage their influence, can lead this needed change.

Sleep Disturbances in MCI and AD: Neuroinflammation as a Possible Mediating Pathway.

Mild cognitive impairment (MCI) and Alzheimer's disease (AD) affect a high proportion of the elderly population with an increasing prevalence. Sleep disturbances are frequent in those with MCI and AD. This review summarizes existing research on sleep disturbances and neuroinflammation in MCI and AD. Although strong evidence supports various pathways linking sleep and AD pathology, the temporal direction of this central relationship is not yet known. Improved understanding of sleep disturbance and neuroinflammation in MCI and AD may aid in the identification of targets for their prevention.

Metabolomics of sleep disorders in HIV: a narrative review.

PURPOSE: Sleep disturbances are prevalent among patients with human immunodeficiency virus (HIV), even those who are being treated on antiretroviral therapy. It is important to understand the metabolomic mechanisms underlying sleep disturbances among people living with HIV (PLWH). METHODS: A review of recent literature was performed to explore the use of metabolomics in understanding sleep among PLWH. RESULTS: We found only two studies that used metabolomics to explore sleep health among PLWH. CONCLUSION: This paper reviews common sleep disorders in HIV, the existing metabolomic studies that may explain the relationship, and implications for future research. The use of metabolomics in exploring sleep disorders among PLWH will help to elucidate mechanistic links to improve patient outcomes.

Metabolomics, sleepiness, and sleep duration in sleep apnea.

PURPOSE: Although the mechanism is unclear, daytime sleepiness, a common sequela of obstructive sleep apnea (OSA), has been found to be correlated with a adverse cardiovascular outcomes. Reviewing metabolomics mechanisms of sleep disturbances and cardiovascular disease may help to explain this correlation. METHODS: This review examines the current literature on the relationships between sleepiness, sleep duration, and metabolites in sleep apnea. RESULTS: Although there is a lack of comprehensive literature in this emerging area, existing studies point to a variety of metabolites in different pathways that are associated with sleepiness and sleep duration. CONCLUSION: Advancing metabolomics research in sleep apnea will guide symptom research and provide alternate and novel opportunities for effective treatment for patients with OSA.

Mechanisms of reduced sleepiness symptoms in heart failure and obstructive sleep apnea.

Patients with both heart failure and obstructive sleep apnea often have poor, repeatedly disrupted sleep, and yet they frequently do not complain of excessive daytime sleepiness. Understanding this lack of perceived sleepiness is crucial for the case identification and treatment of obstructive sleep apnea in the heart failure population at high risk of this disease, especially given the association between untreated obstructive sleep apnea and mortality among patients with heart failure. In this review, we present epidemiologic evidence concerning the lack of sleepiness symptoms in heart failure and obstructive sleep apnea, explore possible mechanistic explanations for this relationship, assess the benefits of treatment in this population, discuss implications for clinical practice and explore directions for future research.

Candidate gene analysis in the São Paulo Epidemiologic Sleep Study (EPISONO) shows an association of variant in PDE4D and sleepiness.

INTRODUCTION: Sleepiness and cardiovascular disease share common molecular pathways; thus, genetic risk factors for sleepiness may also predict cardiovascular disease risk. This study explored the associations between subjective sleepiness and single-nucleotide polymorphisms (SNPs) in candidate genes within oxidative stress, inflammatory, and neuronal pathways, which may contribute to sleepiness and downstream cardiovascular disease risk: Cytochrome B-245, Alpha Polypeptide (CYBA), Cytochrome B-245, Beta Polypeptide (CYBB), Neutrophil Cytosolic Factor (NCF2), Tumor Necrosis Factor-Alpha (TNFA), and Phosphodiesterase 4D (PDE4D). METHODS: Adults (N = 918) from the general population who were a part of the São Paulo Epidemiologic Sleep Study (EPISONO) in São Paulo, Brazil, were genotyped using Human Omni Express BeadChip array. The average age was 42 ± 14.5 years, subjects had a mean body mass index (BMI) of 26.9 ± 5.4 kg/m2, and 44% were male. Based on the Epworth Sleepiness Scale (ESS), subjects were classified as having sleepiness (ESS ≥ 10) or no sleepiness (ESS < 10). Logistic regression models were used to examine the associations with SNPs within candidate genes and sleepiness, adjusting for age, gender, BMI, Apnea-Hypopnea Index (AHI), total sleep time, and ancestry informative principal components (PCs). Complementary analyses using linear regression to assess the relationship between SNPs and continuous ESS were performed. RESULTS: We observed a novel association between the C allele of the rs12522161 SNP on PDE4D and a decreased likelihood of sleepiness, controlling for covariates and ancestry [OR (95% CI) = 0.64 (0.50, 0.81); p = 0.0002]. CONCLUSION: We present data for a novel genetic association with sleepiness for an SNP on the PDE4D gene, rs12522161.

Lower plasma choline levels are associated with sleepiness symptoms.

Sleepiness and cardiovascular disease share common molecular pathways; thus, metabolic risk factors for sleepiness may also predict cardiovascular disease risk. Daytime sleepiness predicts mortality and cardiovascular disease, although the mechanism is unidentified. This study explored the associations between subjective sleepiness and metabolite concentrations in human blood plasma within the oxidative and inflammatory pathways, in order to identify mechanisms that may contribute to sleepiness and cardiovascular disease risk. METHODS: An exploratory case-control sample of 36 subjects, categorized based on the Epworth Sleepiness Scale (ESS) questionnaire as sleepy (ESS ≥ 10) or non-sleepy (ESS < 10), was recruited among subjects undergoing an overnight sleep study for suspected sleep apnea at the University of Pennsylvania Sleep Center. The average age was 42.4 ± 10.5 years, the mean body mass index (BMI) was 40.0 ± 9.36 kg/m2, median Apnea Hypopnea Index (AHI) was 8.2 (IQR: 2.5-26.5), and 52% were male. Fasting morning blood plasma samples were collected after an overnight sleep study. Biomarkers were explored in subjects with sleepiness versus those without using the multiple linear regression adjusting for age, BMI, smoking, Apnea Hypopnea Index (sleep apnea severity), study cohort, and hypertension. RESULTS: The level of choline is significantly lower (P = 0.003) in sleepy subjects (N = 18; mean plasma choline concentration of 8.19 ± 2.62 µmol/L) compared with non-sleepy subjects (N = 18; mean plasma choline concentration of 9.14 ± 2.25 µmol/L). Other markers with suggestive differences (P < 0.1) include isovalerylcarnitine, Alpha-Amino apidipic acid, Spingosine 1 Phosphate, Aspartic Acid, Propionylcarnitine, and Ceramides (fatty acids; C14-C16 and C-18). CONCLUSION: This pilot study is the first to show that lower levels of plasma choline metabolites are associated with sleepiness. Further exploration of choline and other noted metabolites and their associations with sleepiness will guide targeted symptom management.

Observation and Interview-based Diurnal Sleepiness Inventory for measurement of sleepiness in older adults.

INTRODUCTION: There is no established reference standard for subjective measures of sleepiness in older adults. METHODS: This study compares the Observation and Interview-based Diurnal Sleepiness Inventory (ODSI) with two existing instruments for measurement of sleepiness and daily functioning, the Epworth Sleepiness Scale (ESS) and Functional Outcomes of Sleep Questionnaire (FOSQ). RESULTS: A total of 125 study participants were included in this study and were administered the ODSI, ESS and FOSQ; subjects had a mean age of 70.9 ± 5.27 years, mean Apnea-Hypopnea Index of 31.9 ± 27.9 events/hour and normal cognitive functioning (Mini-Mental State Examination score > 24). The ODSI showed a significant association with the ESS (Spearman's ρ: 0.67, P < 0.001) and with the FOSQ (Spearman's ρ: -0.52, P < 0.001). The ODSI 1 item (assessing sleepiness in active situations) was borderline significantly correlated with the ESS (ß = 0.14; 95% confidence interval [CI], -0.01 to 0.29; P = 0.069). ODSI 2 item (sleepiness in passive situations) was correlated with the ESS (ß = 1.65; 95% CI, 1.32 to 1.98; P < 0.001). Both ODSI 1 (ß = -0.15; 95% CI, -0.24 to -0.07; P < 0.001) and ODSI 2 (ß = -0.35; 95% CI, -0.55 to 0.16; P < 0.001) were significantly correlated with the FOSQ. CONCLUSION: The ODSI is a suitable measure of sleepiness and is appropriate for usage in clinical care in older adults.

A Three-Item Instrument for Measuring Daytime Sleepiness: The Observation and Interview Based Diurnal Sleepiness Inventory (ODSI).

STUDY OBJECTIVES: We aimed to develop a new three-item assessment tool for daytime sleepiness in older adults, the Observation and interview-based Diurnal Sleepiness Inventory (ODSI) and determine its validity, internal consistency, test-retest reliability, and optimal cutoff score. METHODS: A total of 133 elderly subjects including 73 patients with obstructive sleep apnea (OSA) (mean age, 79 y) and 60 controls (mean age, 80 y) were consecutively enrolled and answered all questionnaires. The ODSI questionnaire was validated using the Epworth Sleepiness Scale considered as a gold standard. Reliability, validity, and cut-points were tested. RESULTS: The ODSI has acceptable validity, internal consistency, and test-retest reliability properties. The ODSI has internal consistency and a reliability coefficient (Pearson rho) of 0.70 for its three items, which suggests strong reliability. The estimated sensitivity and specificity were 0.842 with 95% confidence interval [0.624; 0.945] and 0.851 [0.761; 0.911], respectively. The consistency of summated scale scores during test and retest sessions was high (r = 0.970, 95% bootstrap confidence interval [0.898; 0.991]). Receiver operating characteristic analysis suggests that a cut-point of 6 is effective for identifying older adults with excessive levels of daytime sleepiness. CONCLUSIONS: The ODSI is a brief, valid, easy-to-administer three-item assessment that can screen for excessive daytime sleepiness among elderly patients with OSA.

Determinants of Behavioral Alertness in Adults with Heart Failure.

STUDY OBJECTIVES: The primary objective of this study was to describe characteristics of sleep across the three domains of sleep quality, daytime sleepiness, and behavioral alertness in community-dwelling adults with heart failure. The secondary objective was to identify modifiable factors associated with behavioral alertness. METHODS: A sample of 280 adults with chronic heart failure was enrolled. Widely used, validated, and sensitive measures of sleep quality (Pittsburgh Sleep Quality Index), daytime sleepiness (Epworth Sleepiness Scale, Stanford Sleepiness Scale), and behavioral alertness (Psychomotor Vigilance Test [PVT]) were collected at baseline, 3 and 6 months. Sociodemographic and clinical characteristics, including exercise, were measured at baseline. RESULTS: Participants were primarily male and functionally compromised with a mean left ventricular ejection fraction of 35 percent. The majority of the sample (73%) reported poor sleep quality. The mean (± SD) Epworth Sleepiness Scale score was low (7.0 ± 4.6), indicating they did not perceive daytime sleepiness. In contrast, behavioral alertness was relatively poor as evidenced by a slow PVT mean response time (3.09 ± 0.76). Participants who reported exercising at least one hour in the past week were more alert and had faster response times than those reporting no exercise. CONCLUSIONS: Although sleep quality was poor and behavioral alertness was compromised, these heart failure patients did not feel sleepy. Exercise may help to promote behavioral alertness and reduce daytime sleepiness in adults with heart failure.