Towards Outcome-Driven Patient Subgroups: A Machine Learning Analysis Across Six Depression Treatment Studies.

BACKGROUND: Major depressive disorder (MDD) is a heterogeneous condition; multiple underlying neurobiological and behavioral substrates are associated with treatment response variability. Understanding the sources of this variability and predicting outcomes has been elusive. Machine learning (ML) shows promise in predicting treatment response in MDD, but its application is limited by challenges to the clinical interpretability of ML models, and clinicians often lack confidence in model results. In order to improve the interpretability of ML models in clinical practice, our goal was to demonstrate the derivation of treatment-relevant patient profiles comprised of clinical and demographic information using a novel ML approach. METHODS: We analyzed data from six clinical trials of pharmacological treatment for depression (total n = 5438) using the Differential Prototypes Neural Network (DPNN), a ML model that derives patient prototypes which can be used to derive treatment-relevant patient clusters while learning to generate probabilities for differential treatment response. A model classifying remission and outputting individual remission probabilities for five first-line monotherapies and three combination treatments was trained using clinical and demographic data. Prototypes were evaluated for interpretability by assessing differences in feature distributions (e.g. age, sex, symptom severity) and treatment-specific outcomes. RESULTS: A 3-prototype model achieved an area under the receiver operating curve of 0.66 and an expected absolute improvement in remission rate for those receiving the best predicted treatment of 6.5% (relative improvement of 15.6%) compared to the population remission rate. We identified three treatment-relevant patient clusters. Cluster A patients tended to be younger, to have increased levels of fatigue, and more severe symptoms. Cluster B patients tended to be older, female, have less severe symptoms, and the highest remission rates. Cluster C patients had more severe symptoms, lower remission rates, more psychomotor agitation, more intense suicidal ideation, and more somatic genital symptoms. CONCLUSION: It is possible to produce novel treatment-relevant patient profiles using ML models; doing so may improve interpretability of ML models and the quality of precision medicine treatments for MDD.

Developing a novel mobile application for cognitive behavioral therapy for insomnia for people with schizophrenia: integration of wearable and environmental sleep sensors.

BACKGROUND: People with serious mental illnesses (SMIs) have three-fold higher rates of comorbid insomnia than the general population, which has downstream effects on cognitive, mental, and physical health. Cognitive Behavioral Therapy for Insomnia (CBT-i) is a safe and effective first-line treatment for insomnia, though the therapy's effectiveness relies on completing nightly sleep diaries which can be challenging for some people with SMI and comorbid cognitive deficits. Supportive technologies such as mobile applications and sleep sensors may aid with completing sleep diaries. However, commercially available CBT-i apps are not designed for individuals with cognitive deficits. To aid with this challenge, we have developed an integrated mobile application, named "Sleep Catcher," that will automatically incorporate data from a wearable fitness tracker and a bed sensor to track nightly sleep duration, overnight awakenings, bed-times, and wake-times to generate nightly sleep diaries for CBT-i. METHODS: The application development process will be described-writing algorithms to generating useful data, creating a clinician web portal to oversee patients and the mobile application, and integrating sleep data from device platforms and user input. RESULTS: The mobile and web applications were developed using Flutter, IBM Code Engine, and IBM Cloudant database. The mobile application was developed with a user-centered approach and incremental changes informed by a series of beta tests. Special user-interface features were considered to address the challenges of developing a simple and effective mobile application targeting people with SMI. CONCLUSION: There is strong potential for synergy between engineering and mental health expertise to develop technologies for specific clinical populations. Digital health technologies allow for the development of multi-disciplinary solutions to existing health disparities in vulnerable populations, particularly in people with SMI.

The Role of Cannabis and The Endocannabinoid System in Sleep Regulation and Cognition: A Review of Human and Animal Studies.

OBJECTIVES: Both sleep and cognition are partially modulated by the endocannabinoid (ECB) system. Cannabis has been reported to have effects on sleep and cognition. This review aims to summarize the recent literature on the ECB system, the role of cannabis and the ECB system on sleep regulation and cognition. Further, this review will identify existing gaps in knowledge and suggest potential targets for future research. METHODS: We performed this review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Reports were identified by searching PubMed/MEDLINE, Embase, CINAHL, Web of Science, and PsycINFO for articles published through September 2021 for studies with data available on aspects of cognition, cannabis, or the ECB system, and sleep or circadian rhythms (CRs). RESULTS: We identified 6 human and 6 animal studies to be eligible for inclusion in this review. Several human studies found that cannabis use is not associated with changes in sleep quality or cognitive function. However, individual cannabinoids appeared to have independent effects on cognition and sleep; THC alone decreased cognitive performance and increased daytime sleepiness, whereas CBD alone had no effect on sleep or cognition. Animal studies demonstrated that manipulation of the ECB system altered activity and cognitive function, some of which appeared to be dependent on the light/dark cycle. CONCLUSION: The sleep-wake cycle and CRs are both likely modulated by the ECB system, potentially resulting in effects on cognition, however this area is critically understudied.

Reductions in sleep quality and circadian activity rhythmicity predict longitudinal changes in objective and subjective cognitive functioning in women treated for breast cancer.

PURPOSE: To examine long-term cognitive effects of chemotherapy and identify predictors among women with breast cancer (WBC). PATIENTS AND METHODS: Sixty-nine WBC scheduled to receive chemotherapy, and 64 matched-controls with no cancer, participated. Objective and subjective cognition, total sleep time, nap time, circadian activity rhythms (CAR), sleep quality, fatigue, and depression were measured pre-chemotherapy (Baseline), end of cycle 4 (Cycle-4), and one-year post-chemotherapy (1-Year). RESULTS: WBC showed no change in objective cognitive measures from Baseline to Cycle-4 but significantly improved from both time points to 1-Year. Matched-controls showed an increase in test performance at all time points. WBC had significantly higher self-reported cognitive dysfunction at Cycle-4 and 1-Year compared to baseline and compared to matched-controls. Worse neuropsychological functioning was predicted by less robust CARs (i.e., inconsistent 24 h pattern), worse sleep quality, longer naps, and worse cognitive complaints. Worse subjective cognition was predicted by lower sleep quality and higher fatigue and depressed mood. CONCLUSION: Objective testing showed increases in performance scores from pre- and post-chemotherapy to one year later in WBC, but matched-controls showed an increase in test performance from baseline to Cycle-4 and from Cycle-4 to 1-Year, likely due to a practice effect. The fact that WBC showed no practice effects may reflect a form of learning deficit. Compared with the matched-controls, WBC reported significant worsened cognitive function. In WBC, worse objective and subjective cognitive functioning were predicted by worse sleep and sleep-related behaviors (naps and CAR). Interventions that target sleep, circadian rhythms, and fatigue may benefit cognitive function in WBC.

Time of day, time of sleep, and time on task effects on sleepiness and cognitive performance of bus drivers.

PURPOSE: Optimal cognitive performance might prevent vehicle accidents. Identifying time-related circadian and homeostatic parameters having an impact on cognitive performance of drivers may be crucial to optimize drivers' performance. METHODS: In this prospective study conducted on bus drivers, two drivers alternated driving during a 24-h round trip and were accompanied by an interviewer. Each driver was tested using Karolinska Sleepiness Scale (KSS) and the reversed digit span Wechsler Working Memory test before the start of his shift and then every 6 h during a "work/driving" day. Psychomotor Vigilance Task (PVT) was assessed before and after the journey. Linear mixed model was used to explore the factors affecting cognitive performance and sleepiness in univariate and multivariate analysis. RESULTS: Among 35 bus drivers, the effect of time of day on working memories was statistically significant (p = 0.001), with the lowest working memory scores at 04:00 am (± 1). The highest score of subjective sleepiness was also at 04:00 am (± 1). The time on task parameter affected sleepiness significantly (p = 0.024) and sleepiness was significantly associated with decreased working memory. Psychomotor Vigilance Task reaction time mean and the number of minor lapses were significantly increased after the journey, which suggested decreased vigilance. In multivariable analysis, a longer interval between the beginning of working hours and testing time (B (95% CI) = 15.25 (0.49 to 30), p = 0.043) was associated with higher (i.e., slower) PVT reaction time mean. CONCLUSIONS: These results suggest that optimizing bus drivers' working schedules may improve drivers' sleepiness and cognitive performance and thus increase road safety.

Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep.

Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.

Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans.

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits [the apnea hypopnea index (AHI), overnight average oxyhemoglobin saturation (SaO2) and percentage time SaO2 < 90%] and a secondary trait (respiratory event duration) in a Hispanic/Latino American population study of 11 575 individuals with significant variation in ancestral background. Linear mixed models were performed using previously inferred African, European and Amerindian local genetic ancestry markers. Global African ancestry was associated with a lower AHI, higher SaO2 and shorter event duration. Admixture mapping analysis of the primary OSA traits identified local African ancestry at the chromosomal region 2q37 as genome-wide significantly associated with AHI (P < 5.7 × 10-5), and European and Amerindian ancestries at 18q21 suggestively associated with both AHI and percentage time SaO2 < 90% (P < 10-3). Follow-up joint ancestry-SNP association analyses identified novel variants in ferrochelatase (FECH), significantly associated with AHI and percentage time SaO2 < 90% after adjusting for multiple tests (P < 8 × 10-6). These signals contributed to the admixture mapping associations and were replicated in independent cohorts. In this first admixture mapping study of OSA, novel associations with variants in the iron/heme metabolism pathway suggest a role for iron in influencing respiratory traits underlying OSA.

Relationship between circadian activity rhythms and fatigue in hospitalized children with CNS cancers receiving high-dose chemotherapy.

PURPOSE: Robust circadian rhythms are increasingly recognized as essential to good health. Adult cancer patients with dysregulated circadian activity rhythms (CAR) experience greater fatigue, lower responsiveness to chemotherapy, and shorter time to relapse. There is scant research describing circadian rhythms and associated outcomes in children with cancer. As part of a larger study examining whether a cognitive-behavioral intervention could preserve sleep in children and adolescents with central nervous system cancers hospitalized for high-dose chemotherapy (HDCT), this study aimed to compare CAR of these children to published values and to investigate the relationship between CAR and fatigue. METHODS: Participants aged 4-19 years wore an actigraph throughout their hospitalization (5 days). From activity counts recorded by actigraphy, six CAR variables were calculated: amplitude, 24-h autocorrelation (r24), dichotomy index (I < O), interdaily stability (IS), intradaily variability (IV), and acrophase. Parent-reported child fatigue and child/adolescent self-reported fatigue measures were collected daily. RESULTS: Thirty-three participants were included. Three CAR variables (amplitude, r24, and I < O) showed dysregulation compared to published values. Older age was significantly associated with later acrophase and greater dysregulation of all other CAR variables. Controlling for age, more dysregulated amplitude (p = 0.001), r24 (p = 0.003), IS (p = 0.017), and IV (p = 0.001) were associated with higher parent-reported fatigue; more dysregulated IV (p = 0.003) was associated with higher child-reported fatigue. CONCLUSIONS: Participants demonstrated dysregulated CAR during hospitalization for HDCT. Greater dysregulation was associated with greater fatigue. Research on circadian dysregulation and its relationship to health-related outcomes in children with cancer, and interventions to support circadian rhythmicity, is urgently needed.

Sleep disturbance and cancer-related fatigue symptom cluster in breast cancer patients undergoing chemotherapy.

PURPOSE: Sleep disturbance and cancer-related fatigue (CRF) are among the most commonly reported symptoms associated with breast cancer and its treatment. This study identified symptom cluster groups of breast cancer patients based on multidimensional assessment of sleep disturbance and CRF prior to and during chemotherapy. METHODS: Participants were 152 women with stage I-IIIA breast cancer. Data were collected before chemotherapy (T1) and during the final week of the fourth chemotherapy cycle (T2). Latent profile analysis was used to derive groups of patients at each timepoint who scored similarly on percent of the day/night asleep per actigraphy, the Pittsburgh Sleep Quality Index global score, and the five subscales of the Multidimensional Fatigue Symptom Inventory-Short Form. Bivariate logistic regression evaluated if sociodemographic/medical characteristics at T1 were associated with group membership at each timepoint. RESULTS: Three groups (Fatigued with sleep complaints, Average, Minimal symptoms) were identified at T1, and five groups (Severely fatigued with poor sleep, Emotionally fatigued with average sleep, Physically fatigued with average sleep, Average, Minimal symptoms) at T2. The majority of individuals in a group characterized by more severe symptoms at T1 were also in a more severe symptom group at T2. Sociodemographic/medical variables at T1 were significantly associated with group membership at T1 and T2. CONCLUSIONS: This study identified groups of breast cancer patients with differentially severe sleep disturbance and CRF symptom profiles prior to and during chemotherapy. Identifying groups with different symptom management needs and distinguishing groups by baseline sociodemographic/medical variables can identify patients at risk for greater symptom burden.

DCC-related developmental effects of abused- versus therapeutic-like amphetamine doses in adolescence.

The guidance cue receptor DCC controls mesocortical dopamine development in adolescence. Repeated exposure to an amphetamine regimen of 4 mg/kg during early adolescence induces, in male mice, downregulation of DCC expression in dopamine neurons by recruiting the Dcc microRNA repressor, microRNA-218 (miR-218). This adolescent amphetamine regimen also disrupts mesocortical dopamine connectivity and behavioral control in adulthood. Whether low doses of amphetamine in adolescence induce similar molecular and developmental effects needs to be established. Here, we quantified plasma amphetamine concentrations in early adolescent mice following a 4 or 0.5 mg/kg dose and found peak levels corresponding to those seen in humans following recreational and therapeutic settings, respectively. In contrast to the high doses, the low amphetamine regimen does not alter Dcc mRNA or miR-218 expression; instead, it upregulates DCC protein levels. Furthermore, high, but not low, drug doses downregulate the expression of the DCC receptor ligand, Netrin-1, in the nucleus accumbens and prefrontal cortex. Exposure to the low-dose regimen did not alter the expanse of mesocortical dopamine axons or their number/density of presynaptic sites in adulthood. Strikingly, adolescent exposure to the low-dose drug regimen does not impair behavioral inhibition in adulthood; instead, it induces an overall increase in performance in a go/no-go task. These results show that developmental consequences of exposure to therapeutic- versus abused-like doses of amphetamine in adolescence have dissimilar molecular signatures and opposite behavioral effects. These findings have important clinical relevance since amphetamines are widely used for therapeutic purposes in youth.

Maternal Bonding Predicts Actigraphy-Measured Sleep Parameters in Depressed and Nondepressed Adults.

Associations between subjective maternal bonding recalled from the first 16 years of life and current sleep indices were investigated in a clinical sample of 34 adults with major depressive disorder and 36 normal controls (n = 70) using the self-report parental bonding instrument and wrist actigraphy. Results of multiple linear regression analyses indicated that reports of maternal bonding indices were associated with several sleep indices in adulthood independent of depression status. Higher levels of maternal care were associated with greater time in bed and total sleep time. Higher levels of maternal overprotection were associated with fewer awakenings. Findings indicate that reported maternal bonding characteristics in childhood are related to objectively measured sleep characteristics in adulthood, independent of mood state.

The hypoxic burden of sleep apnoea predicts cardiovascular disease-related mortality: the Osteoporotic Fractures in Men Study and the Sleep Heart Health Study.

AIMS: Apnoea-hypopnoea index (AHI), the universal clinical metric of sleep apnoea severity, poorly predicts the adverse outcomes of sleep apnoea, potentially because the AHI, a frequency measure, does not adequately capture disease burden. Therefore, we sought to evaluate whether quantifying the severity of sleep apnoea by the 'hypoxic burden' would predict mortality among adults aged 40 and older. METHODS AND RESULTS: The samples were derived from two cohort studies: The Outcomes of Sleep Disorders in Older Men (MrOS), which included 2743 men, age 76.3 ± 5.5 years; and the Sleep Heart Health Study (SHHS), which included 5111 middle-aged and older adults (52.8% women), age: 63.7 ± 10.9 years. The outcomes were all-cause and Cardiovascular disease (CVD)-related mortality. The hypoxic burden was determined by measuring the respiratory event-associated area under the desaturation curve from pre-event baseline. Cox models were used to calculate the adjusted hazard ratios for hypoxic burden. Unlike the AHI, the hypoxic burden strongly predicted CVD mortality and all-cause mortality (only in MrOS). Individuals in the MrOS study with hypoxic burden in the highest two quintiles had hazard ratios of 1.81 [95% confidence interval (CI) 1.25-2.62] and 2.73 (95% CI 1.71-4.36), respectively. Similarly, the group in the SHHS with hypoxic burden in the highest quintile had a hazard ratio of 1.96 (95% CI 1.11-3.43). CONCLUSION: The 'hypoxic burden', an easily derived signal from overnight sleep study, predicts CVD mortality across populations. The findings suggest that not only the frequency but the depth and duration of sleep related upper airway obstructions, are important disease characterizing features.

The Relationship Between Circulating Interleukin-6 Levels and Future Health Service Use in Dementia Caregivers.

OBJECTIVE: Older adults are among the most frequent users of emergency departments (EDs). Nonspecific symptoms, such as fatigue and widespread pain, are among the most common symptoms in patients admitted at the ED. Interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) are inflammation biomarkers associated with chronic stress (i.e., dementia caregiving) and nonspecific symptoms. This study aimed to determine whether IL-6 and TNF-α were prospectively associated with ED risk in dementia caregivers (CGs). METHODS: Participants were 85 dementia CGs, who reported during three assessments (3, 9, and 15 months after enrollment) if they had visited an ED for any reason. Cox proportional hazards models were used to examine the relations between resting circulating levels of IL-6 and TNF-α obtained at enrollment and subsequent risk for an ED visit, adjusting for age, sex, use of ED 1 month before enrollment, physical and mental health well-being, body mass index, and CG demands. RESULTS: (log) IL-6 significantly predicted ED visits during the 15-month follow-up (B = 1.96, SE = 0.82, p = .017). For every (log) picogram per milliliter increase in IL-6, the risk of visiting an ED was 7.10 times greater. TNF-α was not associated with subsequent ED visits. Exploratory analyses suggested that CGs with levels of IL-6 above the 80th percentile and experiencing high CG demands were at highest risk of an ED visit. CONCLUSIONS: IL-6 levels and CG demands may be useful for predicting vulnerability for future ED visits. Although further studies should be conducted to replicate and extend these findings, interventions that successfully modify inflammation markers, including the underlying pathophysiology related to stress and/or comorbid illnesses, may be useful in preventing costly and detrimental outcomes in this population.

Associations between quantitative sleep EEG and subsequent cognitive decline in older women.

The pathophysiological processes of Alzheimer's dementia predate its clinical manifestation. Sleep disturbances can accelerate the aging process and are common features of dementia. This study examined whether quantitative sleep electroencephalogram changes predate the clinical development of mild cognitive impairment and/or incident dementia. We collected data from a nested case-control sample of women (mean age 83 years) from the Sleep and Cognition Study, an ancillary study to the longitudinal Study of Osteoporotic Fractures, who were characterized as cognitively normal at the time of a baseline polysomnography study (Study of Osteoporotic Fractures visit 8) based on a Mini-Mental Status Exam (MMSE) score >24. Cases (n = 85) were women who developed new mild cognitive impairment or dementia by objective cognitive testing 5 years after polysomnography. Controls were women with no mild cognitive impairment/dementia (n = 85) at baseline or at follow-up. Differences in electroencephalogram absolute and relative power density were observed between the two groups. Specifically, higher electroencephalogram power values were found in the dementia/mild cognitive impairment group, for the alpha (p = .01) and theta bands (p = .04) in non-rapid eye movement sleep, as well as alpha (p = .04) and sigma (p = .04) bands in rapid eye movement sleep. In contrast, there were no group differences in traditional polysomnography measures of sleep architecture and sleep stage distribution, as well as sleep apnea and periodic limb movement indices. Our results provide evidence for quantitative electroencephalogram changes, which precede the clinical onset of cognitive decline and the diagnosis of dementia in elderly women, and support the application of quantitative sleep electroencephalogram analysis as a promising biomarker for imminent cognitive decline.

Sleep Disturbances and Inflammatory Biomarkers in Schizophrenia: Focus on Sex Differences.

OBJECTIVES: Persons with schizophrenia, and women in particular, are at high risk for sleep disturbances and inflammatory activation. The sleep-inflammation link has been reported to be stronger in women within the general population. This study sought to examine the sleep-inflammation link in persons with schizophrenia and its relationship with demographic, clinical and cognitive variables. DESIGN: Cross-sectional case-control study. PARTICIPANTS: Community-dwelling outpatients with schizophrenia (N=144, 46% women) and non-psychiatric comparison (NC) participants (N=134, 52% women), age 26-65 years. MEASUREMENTS: Reported sleep disturbances (sleep quality and duration), and mental and physical health were assessed. Cognitive assessments included executive functioning (Delis-Kaplan Executive Function System) and global cognitive functioning (Telephone Interview for Cognitive Status - modified.) Inflammatory biomarkers included pro-inflammatory cytokines [high sensitivity C-Reactive Protein (hs-CRP), Interleukin (IL)-6, Tumor Necrosis Factor-α (TNF-α)] and an anti-inflammatory cytokine (IL-10). RESULTS: The schizophrenia group had longer sleep duration, worse sleep quality, and increased levels of hs-CRP, IL-6, and TNF-α compared to NCs. Women with schizophrenia were less likely to have good sleep quality and had elevated levels of hs-CRP and IL-6 compared to men with schizophrenia. In the schizophrenia group, worse sleep quality and global cognitive functioning were associated with higher hs-CRP and IL-6 levels. Female sex and younger age were also associated with higher hs-CRP levels. CONCLUSIONS: Sleep disturbances and increased inflammation, which were common in schizophrenia, were associated in persons with schizophrenia. Moreover, women with schizophrenia had worse sleep quality and inflammation than men. Further examination of the sleep-inflammation links, their contribution to clinical outcomes, and sex-specific factors is warranted.

A pilot randomized controlled trial to improve sleep and fatigue in children with central nervous system tumors hospitalized for high-dose chemotherapy.

OBJECTIVES: To determine whether a sleep intervention compared with standard of care (SOC) was successful in preserving nighttime sleep in children with central nervous system cancers hospitalized for high-dose chemotherapy (HDCT) and autologous stem cell rescue, and to explore associations between sleep and fatigue during treatment. METHODS: An unblinded, randomized, controlled, multicomponent intervention (NCT00666614) including evidence-based cognitive and behavioral strategies to improve sleep was implemented in 33 children (age 4-12 years) and adolescents (age 13-19 years) during hospitalization. Children wore an actigraph to measure sleep and wake, and reported fatigue scores daily. Parents concurrently kept a sleep diary and reported fatigue scores for their children. RESULTS: The mean age was 9.5 ± 3.9 years, 81.8% were white, and 60.6% were male. Sleep in all children was seriously disturbed throughout the study. Children in the intervention group maintained their longest nighttime sleep across the study, while it declined in children receiving SOC (P = 0.009 for interaction). There were few other differences in sleep between groups. Controlling for age and baseline fatigue, higher nighttime activity score, and lower percent sleep were significantly associated with higher next-day adolescent-reported fatigue (P < 0.05); longest sleep was significantly positively associated with next-day child-reported fatigue (P = 0.018). CONCLUSION: In this sample of children undergoing HDCT, a multicomponent sleep intervention modestly preserved nighttime sleep duration, although overall sleep was poor in both groups. Sleep is an integral component of health, and may influence outcomes of children receiving HDCT. Further investigation into methods of preserving sleep in children undergoing intensive cancer therapy is warranted.

Refining caregiver vulnerability for clinical practice: determinants of self-rated health in spousal dementia caregivers.

BACKGROUND: Caregivers of a family member with a chronic disability or illness such as dementia are at increased risk for chronic disease. There are many factors that contribute to dementia caregiver vulnerability and these factors can be challenging to assess in clinical settings. Self-rated health (SRH) is an independent measure of survival and physical health in the elderly. As an inclusive measure of health, SRH has been proposed as a reliable way to assess a patient's general health in primary care. Therefore, we sought to identify determinants of poor/fair SRH versus categories of at least good SRH in informal caregivers. METHODS: In a cross-sectional study, we examined 134 elderly (≥55 years) providing in-home care for a spouse with dementia who rated their own health with a single-item question: "In general, would you say your health is excellent, very good, good, fair or poor?". In a multivariable model, we compared caregivers with poor/fair SRH to those with good, very good, or excellent SRH on demographics, health characteristics (health behaviors, physical health indicators, psychosocial factors) and caregiving-specific stress (a composite index/total of four caregiving-specific stressors: years of caregiving, dementia severity, care recipient functional impairment and perceived caregiver burden). RESULTS: Compared with caregivers who rated their own health as either good (31.3%), very good (38.8%) or excellent (14.2%), caregivers with poor/fair SRH (15.7%) were more likely to have lower physical function and total greater caregiving-specific stress. More years of caregiving, severe dementia and care recipient functional impairment, but not perceived caregiver burden, were also more likely among caregivers with poor/fair SRH. Additionally, high negative affect and low positive affect were more likely in caregivers with poor/fair vs. good or excellent and very good or excellent SRH, respectively. CONCLUSIONS: Caregivers with poor/fair SRH were characterized by higher levels of medical comorbidity, low physical function, high negative, but low positive affect and longer duration of caregiving, as well as more severe dementia and greater functional impairment of the care recipient. These findings suggest that caregivers need to be more closely evaluated and targeted for preventive interventions in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT02317523 .

Objective napping, cognitive decline, and risk of cognitive impairment in older men.

INTRODUCTION: Little is known about the longitudinal association between napping and cognitive impairment in older adults. METHODS: We used wrist actigraphy to measure naps in 2751 community-dwelling older men. Cognition was assessed repeatedly over 12 years, and clinically significant cognitive impairment was determined by physician diagnosis, Alzheimer's medication use or a significant cognitive decline. RESULTS: After adjustment for all covariates, men with longer napping duration had greater cognitive decline and higher risk of cognitive impairment. Men who napped for ≥120 min/day (vs. <30 min/day) were 66% more likely to develop cognitive impairment (odds ratio = 1.66, 95% CI: 1.09-2.54) in 12 years. Further adjustment for nighttime sleep quality did not appreciably alter the results. The association between napping and cognitive impairment was more pronounced among those with higher sleep efficiency and average sleep duration. DISCUSSION: Napping might be useful as an early marker of cognitive impairment in the elderly, and its cognitive effects may differ by nighttime sleep.

White Matter Structure in Older Adults Moderates the Benefit of Sleep Spindles on Motor Memory Consolidation.

Sleep spindles promote the consolidation of motor skill memory in young adults. Older adults, however, exhibit impoverished sleep-dependent motor memory consolidation. The underlying pathophysiological mechanism(s) explaining why motor memory consolidation in older adults fails to benefit from sleep remains unclear. Here, we demonstrate that male and female older adults show impoverished overnight motor skill memory consolidation relative to young adults, with the extent of impairment being associated with the degree of reduced frontal fast sleep spindle density. The magnitude of the loss of frontal fast sleep spindles in older adults was predicted by the degree of reduced white matter integrity throughout multiple white matter tracts known to connect subcortical and cortical brain regions. We further demonstrate that the structural integrity of selective white matter fiber tracts, specifically within right posterior corona radiata, right tapetum, and bilateral corpus callosum, statistically moderates whether sleep spindles promoted overnight consolidation of motor skill memory. Therefore, white matter integrity within tracts known to connect cortical sensorimotor control regions dictates the functional influence of sleep spindles on motor skill memory consolidation in the elderly. The deterioration of white matter fiber tracts associated with human brain aging thus appears to be one pathophysiological mechanism influencing subcortical-cortical propagation of sleep spindles and their related memory benefits.SIGNIFICANCE STATEMENT Numerous studies have shown that sleep spindle expression is reduced and sleep-dependent motor memory is impaired in older adults. However, the mechanisms underlying these alterations have remained unknown. The present study reveals that age-related degeneration of white matter within select fiber tracts is associated with reduced sleep spindles in older adults. We further demonstrate that, within these same fiber tracts, the degree of degeneration determines whether sleep spindles can promote motor memory consolidation. Therefore, white matter integrity in the human brain, more than age per se, determines the magnitude of decline in sleep spindles in later life and, with it, the success (or lack thereof) of sleep-dependent motor memory consolidation in older adults.

Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men.

Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10-8) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.