Instability of the HLA-E peptidome of HIV presents a major barrier to therapeutic targeting.

Naturally occurring T cells that recognize microbial peptides via HLA-E, a nonpolymorphic HLA class Ib molecule, could provide the foundation for new universal immunotherapeutics. However, confidence in the biological relevance of putative ligands is crucial, given that the mechanisms by which pathogen-derived peptides can access the HLA-E presentation pathway are poorly understood. We systematically interrogated the HIV proteome using immunopeptidomic and bioinformatic approaches, coupled with biochemical and cellular assays. No HIV HLA-E peptides were identified by tandem mass spectrometry analysis of HIV-infected cells. In addition, all bioinformatically predicted HIV peptide ligands (>80) were characterized by poor complex stability. Furthermore, infected cell elimination assays using an affinity-enhanced T cell receptor bispecific targeted to a previously reported HIV Gag HLA-E epitope demonstrated inconsistent presentation of the peptide, despite normal HLA-E expression on HIV-infected cells. This work highlights the instability of the HIV HLA-E peptidome as a major challenge for drug development.

Sleep and Depression in Older Adults: A Narrative Review.

PURPOSE OF REVIEW: The sleep-depression association has been recognized for decades. Efforts to clarify this association continue at an increasing pace. This review summarizes recent research on the sleep-depression association in older adults. RECENT FINDINGS: Research over the past 4 years has utilized cross-sectional, longitudinal, cohort, and intervention designs to examine these associations. Short (< 7 h) and long (> 8-9 h) sleep durations and insomnia symptoms are risk factors for depression in older adults. Similarly, short sleep, long sleep, insomnia symptoms, and depression are all risk factors for poorer health in late life, including increased risk of cognitive decline, falls, and poorer quality-of-life. Intervention studies have produced mixed findings, with some studies suggesting that sleep interventions may be potentially effective in improving both insomnia and mood symptoms. Intervention studies incorporating both behavioral and physiological measures of sleep, and larger and diverse samples may enhance the field's understanding of the complex interplay between sleep and mood in older adults.

A First Glimpse at the Latent Structure of Sleep Valuation Using a Sleep Valuation Item Bank.

Introduction: Sleep valuation is the relative worth individuals place on sleep. Our prior study using a Sleep Valuation Item Bank (SVIB) showed that sleep valuation relates to age, gender, and health status. In this study, the psychometric properties of the SVIB and its latent factor structure were explored. We also investigated how sleep valuation factors relate to demographic, psychological, and sleep features. Methods: Participants (N = 854) were recruited through TurkPRIME and completed a survey consisting of demographic, psychological, and sleep-related questions. The distributional properties of the SVIB items were quantified. Cronbach's alpha and correlation analyses were used to assess the internal consistency and test-retest reliability of SVIB items. Iterated principal factoring with a Promax rotation was used on the SVIB to explore its latent factor structure. Multiple regression analyses were used to investigate the variables associated with each factor. Results: The factor analysis identified 29 items with factor loadings ≥0.4 on four major factors, tentatively called (1) sleep wanting, (2) sleep prioritizing, (3) sleep onset preference, and (4) sleep devaluation. While women had higher sleep wanting and lower sleep devaluation scores than men, they had lower sleep prioritizing. Older individuals tended to value sleep less but also devalued it less than younger participants. Finally, although both individuals with insomnia and depression devalued sleep, depressed individuals prioritized it more than those who were less depressed, while individuals with insomnia symptoms wanted sleep and preferred sleep onset more than those with less insomnia symptoms. Discussion: The current SVIB captures broad dimensions of sleep valuation (wanting, prioritizing, preferring) and sleep devaluation. These broad dimensions had distinct patterns across person-level factors. Recognition of individual differences in sleep valuation may help target sleep health advocacy efforts and individualized treatment approaches, including for those with depression or insomnia.

Neural activation changes in response to pain following cognitive behavioral therapy for patients with comorbid fibromyalgia and insomnia: a pilot study.

STUDY OBJECTIVES: To examine whether cognitive behavioral treatments for insomnia (CBT-I) and pain (CBT-P) lead to neural activation changes in response to pain in fibromyalgia. METHODS: Thirty-two patients with fibromyalgia (mean age = 55.9, standard deviation = 12.2) underwent an experimental pain protocol during functional magnetic resonance imaging and completed 14-day diaries assessing total wake time, total sleep time, and pain intensity before and after CBT-I, CBT-P, or waitlist control. Random effects analysis of covariance identified regions with significant group (CBT-I, CBT-P, waitlist control) by time (baseline, post-treatment) interactions in blood oxygen level-dependent response to pain. Linear regressions using residualized change scores examined how changes in total wake time, total sleep time, and pain intensity were related to activation (blood oxygen level-dependent) changes. RESULTS: Twelve regions exhibited small to moderate effects with significant interactions Ps < .00; right hemisphere: inferior frontal, middle occipital, and superior temporal gyri, insula, lentiform nucleus; left hemisphere: angular, superior temporal, midfrontal, inferior occipital, midtemporal, and inferior frontal gyri. Blood oxygen level-dependent response to pain decreased in 8 regions following CBT-I, and in 3 regions following CBT-P (CBT-I effects > CBT-P). Blood oxygen level-dependent response also increased in 3 regions following CBT-P and in 6 regions following waitlist control. Improved total wake time and/or total sleep time, not pain intensity, predicted decreased blood oxygen level-dependence in 7 regions (Ps < .05), accounting for 18%-47% of the variance. CONCLUSIONS: CBT-I prompted greater decreases in neural activation in response to pain across more regions associated with pain and sleep processing than CBT-P. Reported sleep improvements may underlie those decreases. Future research examining the longer-term impact of CBT-I and improved sleep on central pain and sleep mechanisms is warranted. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: Sleep and Pain Interventions in Fibromyalgia (SPIN); Identifier: NCT02001077; URL: https://clinicaltrials.gov/ct2/show/NCT02001077. CITATION: McCrae CS, Craggs JG, Curtis AF, et al. Neural activation changes in response to pain following cognitive behavioral therapy for patients with comorbid fibromyalgia and insomnia: a pilot study. J Clin Sleep Med. 2022;18(1):203-215.

Fidelity of Information Processing on a Psychomotor Vigilance Task Predicts Changes in Self-Reported Sleepiness Ratings.

INTRODUCTION: Daytime sleepiness is a common problem. Although sleepiness is primarily assessed at the self-report unit of analysis, factors that contribute to an individual's experience and report of sleepiness remain poorly understood. While sleepiness is known to impact vigilance performance, the impact of vigilance performance on sleepiness reports is less well understood. We aimed to explore how performance on a psychomotor vigilance task (PVT) relates to changes in self-reported sleepiness in a rested condition. METHODS: Participants were 66 adults (Mdn=23, range 18-49 years old), 47% female, 88% white, with a wide range of insomnia symptoms. Participants rated their sleepiness on a scale from 1 (not sleepy) to 10 (extremely sleepy) at the start (pre) and the end (post) of a 10-minute computerized PVT. Ordinal regression determined whether mean reciprocal reaction time, a measure of overall performance, or the log-transformed signal-to-noise ratio (LSNR), a measure of fidelity of information processing, predicted post-sleepiness, adjusting for pre-sleepiness, insomnia, and potential confounds. RESULTS: Lower LSNR predicted greater change in sleepiness (pre-to-post PVT) and higher post-sleepiness even after adjusting for pre-sleepiness, mean reciprocal reaction time, insomnia, and other potential confounds (p<0.05). DISCUSSION: When adjusting for insomnia symptoms and potential confounds, participants with lower fidelity of information processing reported higher sleepiness than they had reported at the start of the PVT. Possible mechanisms and explanations are discussed in relation to a 3-factor model of sleep-wake states. This line of research may contribute to innovative approaches to assessing and treating sleepiness.

Sleep Valuation Is Associated with Components of Sleep Health and Daytime Functioning in a College Sample: A Survey Study.

Sleep valuation, the worth individuals place on sleep, is an understudied construct in the field of sleep medicine. This study introduced a Sleep Valuation Item Bank and explored how sleep valuation is related to sleep health and daytime functioning within a sample of college students. The participants in this study were 247 (85% white, 83% female) undergraduate students who completed an online survey that included questions from a Sleep Valuation Item Bank and questions about sleep and daytime functioning. Correlation and regression analyses were conducted to determine associations between sleep valuation, aspects of sleep health and daytime functioning. Mediation analyses were conducted to determine whether the sleep health variables explained the associations between sleep valuation and daytime functioning. In correlation analyses, sleep valuation was negatively associated with sleepiness and sleep quality. It was also associated with daytime functioning, including general mental and physical health, depression, and anxiety. In the regression analyses, daytime impairments including poorer physical and mental health, anxiety, and depression were associated with higher sleep valuation. Poorer sleep health, including greater sleepiness and lower sleep quality, explained these associations and were associated with higher sleep valuation. Thus, while daytime impairments, such as anxiety and depression, are related to sleep valuation, this relationship may be due in part to the sleep disturbance that often co-occurs with these impairments.

The Effect of Beat Frequency Vibration on Sleep Latency and Neural Complexity: A Pilot Study.

Insomnia affects millions of people worldwide, and non-pharmacological treatment options are limited. A bed excited with multiple vibration sources was used to explore beat frequency vibration (BFV) as a non-pharmacological treatment for insomnia. A repeated measures design pilot study of 14 participants with mild-moderate insomnia symptom severity (self-reported on the Insomnia Severity Index) was conducted to determine the effects of BFV, and traditional standing wave vibration (SWV) on sleep latency and sleep electrocortical activity. Participants were monitored using high-density electroencephalography (HD-EEG). Sleep latency was compared between treatment conditions. A trend of decreasing sleep latency due to BFV was found for unequivocal sleep latency (p ≤ 0.068). Neural complexity during wake, N1, and N2 stages were compared using Multi-Scale Sample Entropy (MSE), which demonstrated significantly lower MSE between wake and N2 stages (p ≤ 0.002). During N2 sleep, BFV showed lower MSE than the control session in the left frontoparietal region. As a measure of information integration, reduced entropy may indicate that BFV decreases conscious awareness during deeper stages of sleep. SWV caused reduced alpha activity and increased delta activity during wake. BFV caused increased delta activity during N2 sleep. These preliminary results suggest that BFV may help decrease sleep latency, reduce conscious awareness, and increase sleep drive expression during deeper stages of sleep. SWV may be beneficial for decreasing expression of arousal and increasing expression of sleep drive during wake, implying that beat frequency vibration may be beneficial to sleep.

Parental genetic contributions to neonatal temperament in a nonhuman primate (Macaca mulatta) model.

Temperament is an individual's nature and is widely believed to have a heritable foundation. Few studies, however, have evaluated paternal and maternal contributions to the triadic dimensions of temperament. Rhesus monkeys are widely utilized to model genetic contributions to human development due to their close genetic-relatedness and common temperament structure, providing a powerful translational model for investigating paternal and maternal genetic influences on temperament. The temperament of rhesus monkey infants born to 19 different sires and 50 different dams was assessed during the first month of life by comparing the temperament of paternal or maternal half-siblings reared with their mothers in species-normative conditions or reared in a neonatal nursery. Factor scores from three dimensions of temperament were obtained (Orienting/Regulation, Negative Affectivity, and Surgency/Extraversion) and ANOVAs were used to assess genetic effects. For paternal half-siblings, results showed a statistically significant paternal contribution to Orienting/Regulation, Negative Affectivity, and Surgency/Extraversion factor scores. For maternal half-siblings, results showed a statistically significant contribution to Orienting/Regulation factor scores. When parsed by early rearing condition, results showed a paternal contribution Orienting/Regulation, Negative Affectivity, and Surgency/Extraversion scores for paternal half-siblings reared in the neonatal nursery, while there was only a paternal contribution to Surgency/Extraversion for paternal half-siblings reared by their mothers. There was only a maternal contribution to Orienting/Regulation for maternal half-siblings reared by their mothers. These results show that paternal and maternal contributions to temperament vary by environmental context, and that mothers may environmentally buffer their infants from paternal contributions to their temperament.

A Validation Study of PROMIS Sleep Disturbance (PROMIS-SD) and Sleep Related Impairment (PROMIS-SRI) Item Banks in Individuals with Idiopathic Parkinson's Disease and Matched Controls.

BACKGROUND: Parkinson's disease (PD) is associated with sleep disturbance (SD) and sleep-related impairment (SRI). Validation of self-report measures of these problems is needed in PD. The Patient-Reported Outcomes Measurement Information System (PROMIS) includes tools that assess these problems (PROMIS-SD and PROMIS-SRI, respectively). OBJECTIVE: This study aimed to further validate these measures in individuals with PD and matched controls. METHODS: Individuals with early-stage PD (n=50) and matched controls (n=48) completed measures of SD including the PROMIS-SD, Pittsburgh Sleep Quality Index (PSQI), and Insomnia Severity Index (ISI). They also completed measures of daytime impairment including the PROMIS-SRI, Epworth Sleepiness Scale, State-Trait Anxiety Inventory, Beck Depression Inventory 2nd edition, and Parkinson's Disease Questionnaire-39. Internal consistency for the PROMIS measures were assessed using Cronbach's α coefficient and item-total correlations in the total sample. Convergent and divergent validity of the PROMIS item banks were assessed using Spearman correlations. RESULTS: The PROMIS item banks had excellent internal consistency (α>0.94). Supporting convergent validity, the PROMIS-SD had strong correlations with other measures of SD (ρ>0.68, for PSQI and ISI) and the PROMIS-SRI had moderate to strong correlations with all measures of daytime impairment (ρ=0.41-0.72). Supporting divergent validity within the PD group, the PROMIS-SD correlated more strongly with SRI than with the Parkinson's Disease Questionnaire total score, a metric of PD related impairment. CONCLUSION: In middle-aged and older adults, with and without early-stage PD, the PROMIS-SD and PROMIS-SRI are reliable and valid measures of SD and SRI, respectively.

Insomnia symptom severity is associated with increased suicidality and death by suicide in a sample of patients with psychiatric disorders.

STUDY OBJECTIVES: Insomnia is a risk factor for suicidal behavior including attempts and death by suicide. We investigated whether insomnia symptom severity was associated with suicidality and death by suicide in patients with psychiatric disorders. METHODS: The sample included 180 deceased patients with psychiatric disorders seen at Weber Human Services between 2008 and 2018 who completed the Outpatient Questionnaire-45.2 (OQ) prior to death. Insomnia symptom severity was assessed using item 41 from the OQ. Manner of death was determined by death records and autopsy reports. History of suicidality was determined through electronic medical records. Cases were grouped into four lifetime categories: non-suicidal (n = 30), suicidal ideation (n = 36), suicide attempt (n = 95), and death by suicide (n = 19). Demographic, medical, and psychiatric features of each group were compared using linear regression. Logistic regression was used to determine whether insomnia symptom severity was associated with lifetime suicidality severity grouping, adjusting for psychiatric disorders commonly linked to suicidality. RESULTS: Lifetime suicidality was associated with sleep problems, fatigue, headaches, and psychiatric disorders (i.e. depressive, personality, and trauma-related disorders). Referenced to the non-suicidal group, greater insomnia symptom severity was significantly associated with suicide attempts and death by suicide, with odds ratios (OR) of OR = 2.67, p = 0.011, and OR = 5.53, p = 0.002, respectively, even after adjusting important psychiatric diagnoses. CONCLUSIONS: Results suggest that insomnia symptom severity endorsed during a clinical visit is associated with heightened suicidality, especially suicidal behavior. The presence of insomnia symptoms in patients with psychiatric disorders may indicate risk for suicide and is a target for suicide prevention.

Multi-group multi-time point confirmatory factor analysis of the triadic structure of temperament: A nonhuman primate model.

Attempts to describe the latent structure of human infant temperament have led some to suggest the existence of three major dimensions. An earlier exploratory factor analysis (EFA) supported a triadic structure of temperament in week-old rhesus monkey infants, paralleling the structure in human infants. This study sought to confirm the latent triadic structure of temperament across the first month of life in a larger sample of rhesus monkey infants (N = 668), reared by their mothers or in a neonatal nursery. A weekly behavioral assessment was obtained during the first month of life using a subset of items from the widely utilized Infant Behavioral Assessment Scale (IBAS), an instrument designed to measure temperament in infant monkeys. Using the latent constructs proposed by the earlier EFA (Orienting/Regulation, Negative Affectivity, Surgency/Extraversion), multi-group, multi-time point confirmatory factor analyses were conducted to confirm the latent temperament structure across rearing groups at each time point (weeks 1-4). Results confirm and extend those of the earlier EFA: latent Orienting/Regulation,  Negative Affectivity, and Surgency/Extraversion constructs were present across the rearing groups at each time point, with the IBAS items consistently loading onto the latent factors to a similar degree across rearing groups at each time point. These findings suggest foundational evolutionary roots for the triadic structure of human infant temperament, but that its behavioral manifestations vary across maturation and rearing condition. Similarities in latent temperament structure in humans and a representative nonhuman primate highlights the potential for utilizing translational nonhuman primate models to increase understanding of human temperament.

Insomnia Is Associated With Frequency of Suicidal Ideation Independent of Depression: A Replication and Extension of Findings From the National Health and Nutrition Examination Survey.

OBJECTIVE: Insomnia is associated with suicidality, although the mechanisms of this association are unclear. This study sought to replicate previous findings showing that insomnia symptoms but not sleep duration are associated with frequency of suicidal ideation in adults. We further investigated whether depression or sleep duration moderates the association between insomnia symptoms and frequency of suicidal ideation. MATERIALS AND METHODS: We used the 2005-2006 cycle of the National Health and Nutrition Examination Survey to replicate previously reported findings from the 2007-2008 cycle. We used ordered logistic regression to determine whether insomnia symptoms were associated with frequency of suicidal ideation independently of depression and other potential confounds. To extend these findings, we tested whether depression or sleep duration moderated the association between insomnia symptoms and frequency of suicidal ideation. We further replicated these findings in parallel analyses using the combined data from the 2005-2006 and 2007-2008 cycles. RESULTS: This study replicated previous results showing that insomnia symptoms are associated with frequency of suicidal ideation in the NHANES 2005-2006 cycle (OR = 1.09, p < 0.05), even after adjusting for potentially confounding variables, including depression. Neither depression nor sleep duration moderated this association. Difficulty with sleep maintenance insomnia symptoms were most robustly associated with frequency of suicidal ideation (OR ≥ 1.97, p < 0.05). Sleep duration was not robustly associated with suicidal ideation. CONCLUSIONS: In this study, we found that insomnia symptoms were uniquely associated with frequency of suicidal ideation. This association cannot be explained by the shared association with depression or sleep duration.

Sleep Inconsistency and Markers of Inflammation.

Objective: Poor sleep is associated with higher levels of inflammatory biomarkers. Conventionally, higher average time awake, lower average time asleep, and lower sleep efficiency define poor sleep. Recent research suggests that, in addition to average sleep, sleep inconsistency is an important indicator of sleep dysfunction. The current study sought to extend our knowledge of the relationship between sleep and inflammation through an examination of sleep inconsistency and inflammatory biomarkers. Methods: Secondary analyses of the Survey of Midlife in the United States (MIDUS) sleep study were conducted. Five hundred thirty-three individuals completed nightly sleep diaries, actigraphy, and underwent a blood draw for the inflammatory biomarkers C-reactive protein, interleukin-6, and fibrinogen. Sleep inconsistency was derived from 7 consecutive nights of assessment and was operationalized as nightly fluctuations in the following variables: terminal wakefulness, number of awakenings, time in bed, sleep onset latency, and wake after sleep onset. Structural equation modeling was used to examine the influence of a latent average sleep and a latent sleep inconsistency variable on a latent inflammation variable. Models were subsequently adjusted for age, sex, BMI, health, and medication. Stratified models by sex were also analyzed. Results: The average sleep model would not converge. The sleep inconsistency model fit the data well. A significant positive association between the latent factors sleep inconsistency and inflammation was observed (ß = 10.18, SE = 4.40, p = 0.021), suggesting inconsistent sleep is associated with higher levels of inflammatory biomarkers. When stratified by sex, the association between the latent sleep inconsistency factor and inflammation was significant for women (ß = 1.93, SE = 0.82, p = 0.018), but not men (ß = 0.20, SE = 0.35, p = 0.566). The association between sleep inconsistency and inflammation weakened following multivariate adjustment (ß = 6.23, SE = 3.71, p = 0.093). Conclusions: Inconsistent sleep may be an associated feature of inflammatory dysfunction, especially in women. Future studies should build upon this preliminary work and examine these associations longitudinally and through treatment trials.

Maternal neglect and the serotonin system are associated with daytime sleep in infant rhesus monkeys.

Environmental and biological factors contribute to sleep development during infancy. Parenting plays a particularly important role in modulating infant sleep, potentially via the serotonin system, which is itself involved in regulating infant sleep. We hypothesized that maternal neglect and serotonin system dysregulation would be associated with daytime sleep in infant rhesus monkeys. Subjects were nursery-reared infant rhesus macaques (n = 287). During the first month of life, daytime sleep-wake states were rated bihourly (0800-2100). Infants were considered neglected (n = 16) if before nursery-rearing, their mother repeatedly failed to retrieve them. Serotonin transporter genotype and concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) were used as markers of central serotonin system functioning. t tests showed that neglected infants were observed sleeping less frequently, weighed less, and had higher 5-HIAA than non-neglected nursery-reared infants. Regression revealed that serotonin transporter genotype moderated the relationship between 5-HIAA and daytime sleep: in subjects possessing the Ls genotype, there was a positive correlation between 5-HIAA and daytime sleep, whereas in subjects possessing the LL genotype there was no association. These results highlight the pivotal roles that parents and the serotonin system play in sleep development. Daytime sleep alterations observed in neglected infants may partially derive from serotonin system dysregulation.

Cognitive Impairments and Self-Reported Sleep in Early-Stage Parkinson's Disease with Versus without Probable REM Sleep Behavior Disorder.

Parkinson's disease (PD) is associated with cognitive and sleep impairments. The presence of rapid eye movement (REM) sleep behavior disorder (RBD) symptoms may represent a worse disease prognosis for PD individuals. We investigated cognitive functioning and self-reported sleep in early-stage PD individuals with (n = 19) or without (n = 31) probable RBD. Probable RBD was defined as >5 on the REM Sleep Behavior Disorder Screening Questionnaire. Inhibition, visuospatial cognitive abilities, working memory, sustained visual attention, verbal fluency, and episodic memory were assessed. Sleep impairments were assessed using the Pittsburgh Sleep Quality Index, Insomnia Severity Index, Epworth Sleepiness Scale, and Patient-Reported Outcomes Measurement Information System questionnaires. Chi-squared, Mann-Whitney U, and independent sample t-tests were employed to assess group differences. Participants with PD and probable RBD performed significantly worse on word reading and switching verbal fluency tasks than PD participants without probable RBD (p < 0.05). No significant differences were found in mood, PD severity, or sleep measures between PD individuals with or without probable RBD. Cognitive tasks that involve verbal or switching components may be most impaired in PD individuals with probable RBD. Larger samples are needed to determine whether other cognitive domains and sleep features are significantly associated with RBD in PD.

Impact of acute sleep restriction on cerebral glucose metabolism during recovery non-rapid eye movement sleep among individuals with primary insomnia and good sleeper controls.

BACKGROUND: Restricting time in bed improves insomnia symptoms, but the neural mechanisms for this effect are unknown. Total and partial acute sleep restriction may be useful paradigms for elucidating these effects. We examined the impact of acute sleep restriction on cerebral glucose metabolism during non-rapid eye movement (NREM) sleep in individuals with primary insomnia (n = 17) and good sleep (n = 19). METHODS: Participants underwent [18F]fluorodeoxyglucose positron emission tomography scans during baseline and recovery NREM sleep following one night of partial or total sleep restriction. We compared group differences in baseline-recovery changes, as well as main effects of group and condition (baseline vs. recovery NREM sleep), for relative regional cerebral metabolic rate for glucose (rCMRglc), whole-brain glucose metabolism, and sleep quality. RESULTS: Relative rCMRglc was significantly lower during recovery NREM sleep compared to baseline in the left frontoparietal cortex, medial frontal cortex, posterior cingulate cortex, and thalamus, with no significant group differences. Good sleepers, but not insomnia patients, had lower whole-brain glucose metabolism during recovery NREM sleep compared to baseline. Acute sleep restriction improved sleep quality in individual with insomnia. Subgroup analyses including only participants who underwent partial sleep restriction yielded the same pattern of findings. CONCLUSION: Individuals with insomnia and good sleepers showed similar relative rCMRglc responses to acute sleep restriction. Brain regions showing the greatest baseline-recovery changes in both groups included regions previously shown to have smaller sleep-wake differences in patients with primary insomnia. Acute sleep restriction, and by extension sleep restriction therapy, may impact regional metabolic alterations that characterize insomnia.

NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses.

Physical stress, including high temperatures, may damage the central metabolic nicotinamide nucleotide cofactors [NAD(P)H], generating toxic derivatives [NAD(P)HX]. The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX. Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death. Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case. Variants were predicted to be potentially deleterious through in silico analysis. Reverse-transcription PCR confirmed altered splicing in one case. Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX. NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD. Subject fibroblasts and muscle biopsies showed impaired mitochondrial function, higher sensitivity to metabolic stress in media containing galactose and azide, but not glucose, and decreased mitochondrial reactive oxygen species production. Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity. This is the first study to identify pathogenic variants in NAXD and to link deficient NADHX repair with mitochondrial dysfunction. The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death.

Sleep disturbances and depression severity in patients with Parkinson's disease.

OBJECTIVES: Parkinson's disease (PD) is a multisystem movement disorder associated with sleep disturbance and depression. Sleep disturbances and depression severity share a bidirectional association. This association may be greater in individuals who are more vulnerable to the deleterious consequences of sleep disturbance and depression severity. We investigated whether the association between sleep disturbances and depression severity is greater in patients with PD than in matched controls (MC). MATERIALS AND METHODS: The study sample (N = 98) included 50 patients with idiopathic PD and 48 age-, race-, sex-, and education-matched controls. Sleep disturbances were assessed using self-reported total sleep time (TST) on the Pittsburgh Sleep Quality Index, the sleep item on the Beck Depression Inventory, 2nd ed. (BDI-II), and the Insomnia Severity Index total score. Depression severity was assessed using the BDI-II total score, excluding the sleep item. Spearman's correlations, chi-squared tests, and multiple regression were used to assess associations between sleep disturbances and depression severity in PD and MC. Fisher's Z transformation was used to test whether the association between sleep disturbances and depression severity was stronger in patients with PD. RESULTS: Shorter TST, sleeping less than usual, and insomnia severity were associated with depression severity in the total sample, rs(94) = -0.35, p = .001; rs(71) = 0.51, p < .001; rs(78) = -0.47, p < .001; rs(98) = 0.46, p < .001, respectively. The association between shorter TST and depression severity was greater in patients with PD than it was in MC, p < .05. CONCLUSION: Short TST may be an important marker, predictor, or consequence of depression severity in patients with Parkinson's disease.

Melatonin Affects Postural Control in Community-Dwelling Older Adults While Dual Tasking: A Randomized Observation Study.

The effects of a single 3-mg dose of melatonin on the postural control and cognitive performance of community-dwelling older adults were documented. The testing involved stepping down while performing a cognitive task (a Stroop test). Thirty-four older adults were recruited. Immediately before and 1 hr after taking a dose of melatonin, they completed a single-leg standing task after stepping down with and without a simultaneous Stroop test, and a double-leg standing task. The findings indicated a statistically significant increase in sway area under the dual-tasking condition after taking melatonin (p = .04) and the double-leg standing task (p = .018). However, cognitive performance per se was not affected by the melatonin. Melatonin impairs postural control in older adults but not cognitive performance.