Effects of cognitive behavioural therapy and bright light therapy for insomnia in youths with eveningness: study protocol for a randomised controlled trial.

BACKGROUND: Insomnia and eveningness are common and often comorbid conditions in youths. While cognitive behavioural therapy for insomnia (CBT-I) has been suggested as a promising intervention, it remains unclear whether it is sufficient to also address circadian issues in youths. In addition, despite that light has been shown to be effective in phase-shifting one's circadian rhythm, there has been limited data on the effects of bright light therapy and its combination with CBT-I on sleep and circadian outcomes in youths. The current protocol outlines a randomised controlled trial that examines the efficacy of CBT-I and CBT-I plus bright light therapy (BLT) in reducing insomnia severity, improving mood symptoms and daytime functioning (e.g. sleepiness, fatigue, cognitive function), and improving subjective and objective sleep and circadian measures compared to a waitlist control group. METHODS: We will carry out a randomised controlled trial (RCT) with 150 youths aged 12-24 who meet the criteria of insomnia and eveningness. Participants will be randomised into one of three groups: CBT-I with bright light therapy, CBT-I with placebo light, and waitlist control. Six sessions of CBT-I will be delivered in a group format, while participants will be currently asked to use a portable light device for 30 min daily immediately after awakening throughout the intervention period for bright light therapy. The CBT-I with light therapy group will receive bright constant green light (506 lx) while the CBT-I with placebo light group will receive the modified light device with the LEDs emitting less than 10 lx. All participants will be assessed at baseline and post-treatment, while the two active treatment groups will be additionally followed up at 1 month and 6 months post-intervention. The primary outcome will be insomnia severity, as measured by the Insomnia Severity Index. Secondary outcomes include self-reported mood, circadian, daytime functioning, and quality of life measures, as well as sleep parameters derived from actigraphy and sleep diary and neurocognitive assessments. Objective measures of the circadian phase using dim-light melatonin onset assessment and sleep parameters using polysomnography will also be included as the secondary outcomes. DISCUSSION: This study will be the first RCT to directly compare the effects of CBT-I and BLT in youths with insomnia and eveningness. Findings from the study will provide evidence to inform the clinical management of insomnia problems and eveningness in youths. TRIAL REGISTRATION: ClinicalTrials.gov NCT04256915. Registered on 5 February 2020.

Objective and subjective sleep in patients with non-seasonal major depressive disorder and eveningness - Results from a randomized controlled trial of bright light therapy.

STUDY OBJECTIVES: This study examines the (dis)agreement between objective and subjective sleep and their prospective changes in a randomized controlled trial of bright light therapy (BLT) in patients with major depressive disorder (MDD) and eveningness. METHODS: A total of 93 adults were randomized to receive either 30-min daily of 10,000 lux BLT or 50lux placebo dim red light therapy (DRL group) for a total of 5 weeks. Actigraphic data were collected at the baseline and during the last week of treatment. (Dis)Concordance of diary and actigraphic sleep parameters were assessed by partial correlations and Bland-Altman plots, and the associations between these discrepancies to depression severity was assessed by linear regression models. Changes of sleep parameters were assessed by linear mixed models. RESULTS: Significant correlations were found between subjective sleep timings and chronotype to actigraphic parameters. Discrepancies between diary- and actigraphic-measures were observed, and patients with more severe depressive symptoms were associated with a greater under-estimation of total sleep time (TST). A greater advance in the diary-based time to fall sleep and rise time were achieved in the BLT group as compared to the DRL group, while diary-based wake after sleep onset (WASO), TST and sleep efficiency (SE) comparably improved with time in both groups. There was no significant difference between the two groups in the actigraphic parameters after treatment. CONCLUSIONS: In this study, we found that depression severity influenced subjective report of sleep. BLT led to a greater advance in subjective sleep timings when compared to the placebo group.

Prediction of Dropout in a Randomized Controlled Trial of Adjunctive Light Treatment in Patients with Non-Seasonal Depression and Evening Chronotype.

The current study examined the possible predictors of dropout during a five-week light treatment (LT) with a gradual advance protocol in 93 patients with unipolar non-seasonal depression and evening chronotypes by comparing their clinical characteristics and performing a logistic regression analysis. Nineteen out of ninety-three (20%) subjects (80% female, 46.5 ± 11.7 years old) dropped out during the 5-week light treatment. Treatment non-adherence (i.e., receiving LT for less than 80% of the prescribed duration) over the first treatment week predicted a five-fold increase in risk of dropout during light therapy (OR: 5.85, CI: 1.41-24.21) after controlling for potential confounders, including age, gender, treatment group, rise time at the baseline, patient expectation, and treatment-emergent adverse events. There is a need to incorporate strategies to enhance treatment adherence and retention in both research and clinical settings. Chinese clinical trial registry (ChiCTR-IOR-15006937).

Change in circadian preference predicts sustained treatment outcomes in patients with unipolar depression and evening preference.

STUDY OBJECTIVES: Eveningness is associated with worse outcomes in depression. It remained unclear if eveningness could be altered with chronobiological therapy and whether such a change would predict long-term outcomes of depression. METHODS: Data from a randomized controlled trial of 5-week adjunctive bright light therapy with a gradual advance protocol conducted in 91 adult patients with nonseasonal unipolar depression and eveningness (Morningness-Eveningness Questionnaire, score ≤ 41) was examined. "Change of eveningness" was defined by Morningness-Eveningness Questionnaire score over 41 at posttreatment week 5 and "persistent change of eveningness" was defined as maintenance of Morningness-Eveningness Questionnaire score > 41 throughout the follow-up period from week 5 to posttreatment 5 months. RESULTS: Thirty-three participants (36%) had change of eveningness at week 5. Generalized estimating equations models showed that a change of eveningness at week 5 predicted a 2-fold increase in remission of depression over the 5-month follow up (odds ratio = 2.61 95% confidence interval 1.20-5.71, P = .016). Twenty-five participants (75.7%) had a persistent change and were more likely to achieve a remission of depression over the 5-month follow up (odds ratio = 3.18, 95% confidence interval: 1.35-7.50, P = .008). CONCLUSIONS: One-third of the patients with depression changed their evening-preference after 5-week of chronotherapeutic treatment, and such change predicted a higher likelihood of depression remission over 5 months of follow-up. CLINICAL TRIAL REGISTRATION: Registry: Chinese Clinical Trial Registry; Name: Adjunctive light treatment in major depressive disorder patients with evening chronotype-A randomized controlled trial; URL: https://www.chictr.org.cn/showprojen.aspx?proj=11672; Identifier: ChiCTR-IOR-15006937. CITATION: Chan JWY, Chan NY, Li SX, et al. Change in circadian preference predicts sustained treatment outcomes in patients with unipolar depression and evening preference. J Clin Sleep Med. 2022;18(2):523-531.

The efficacy of mind-body (Baduanjin) exercise on self-reported sleep quality and quality of life in elderly subjects with sleep disturbances: a randomized controlled trial.

OBJECTIVES: To examine the efficacy of a 24-week Baduanjin exercise program on self-reported sleep quality and quality of life in community-dwelling elderly subjects with sleep disturbances. METHODS: Community-dwelling elderly men and women meeting criteria for sleep disturbances (i.e., Pittsburgh Sleep Quality of Index (PSQI) score ≥ 5) were recruited and randomized to a Baduanjin exercise intervention group or a control group. Participants in the intervention group completed five 45-min exercise sessions per week for 24 weeks, while those in control group were instructed to maintain their usual lifestyle behaviors. RESULTS: A total of 139 participants were enrolled and randomized. Sixty-two of 67 participants in the intervention group (response rate of 92.5%) and 57 of 72 participants (response rate of 79.6%) in the control group completed intervention and follow-up. The intervention group reported significant improvements in overall sleep quality after 24 weeks compared with those randomized to control (PSQI endpoint-to-baseline change = - 2.6 ± 4.0 vs. - 0.5 ± 4.2, time × group interaction p = 0.007). Intervention group participants had higher response rates at both week 12 (23.9% vs. 9.7%, p = 0.025) and week 24 (40.3% vs. 15.3%, p = 0.001) when compared with the control group. There was a trend that the intervention group had increased quality of life (The Short Form Health Survey [SF-36] endpoint=tobaseline change 6.3 ± 10.9 vs. 2.2 ± 10.9, time × group interaction p = 0.06) when compared with the control group. CONCLUSIONS: Baduanjin exercise is an effective and feasible approach to improve self-reported sleep quality but less likely the quality of life in community-dwelling elderly men and women with sleep disturbances. TRIAL REGISTRATION: Effect of Baduanjin Exercise on the Elderly's Sleep; http://www.chictr.org.cn/listbycreater.aspx; ChiCTR1800014706, registered 1 January 2018.

Novel Method for the Purification of House Dust Mite Allergen Der p 1 and Its Use in Structure-Based Chemical Design of Novel Inhibitors.

House dust mites are globally significant triggers of allergic disease. Notable among their extensive repertoire of allergens are the Group 1 cysteine peptidase allergens which function as digestive enzymes in house dust mites. Compelling evidence suggests that the proteolytic activity of these molecules plays a key role in the development and maintenance of allergic diseases through the activation of innate immune mechanisms which exploit genetic predispositions to allergy. Growing interest in this area creates a requirement for high-quality purified protein, whether natural or recombinantly expressed. It has also identified these allergens as therapeutic targets for a novel approach to allergy treatment through modulation of innate immune responses. The purpose of this chapter is to describe a new method for the purification of Der p 1 and use of the protein produced in a screening assay designed for the discovery of novel inhibitors of Group 1 house dust mite allergens.

Disruption of sleep, sleep-wake activity rhythm, and nocturnal melatonin production in breast cancer patients undergoing adjuvant chemotherapy: prospective cohort study.

OBJECTIVE: This prospective cohort study captured the patterns of sleep, sleep-wake activity rhythm, and first-morning urinary melatonin in breast cancer patients undergoing adjuvant chemotherapy. METHODS: Breast cancer patients undergoing adjuvant chemotherapy wore wrist actigraph for 168 h and collected first-morning void urine samples before treatment, during the first, and at the last cycle of chemotherapy. We converted actigraphy data into sleep duration, sleep efficiency, nighttime total wake time, percent rhythm, F-statistic, amplitude, mesor, and acrophase. We then assessed urinary 6-sulfatoxymelatonin (aMT6s) levels. RESULTS: This cohort contained 180 participants. Compared with the baseline, sleep efficiency during the first and last cycle decreased by 10.16% [95% confidence interval (95% CI): 5.85%, 14.47%] and 5.01% (95% CI: 0.50%, 9.53%), respectively. Similarly, percent rhythm decreased by 27.20% (95% CI: 19.95%, 34.45%) during the first cycle and 21.20% (95% CI: 13.52, 28.89) during the last cycle. Taking the baseline as the reference, aMT6s levels during the first and last cycle decreased by 11.27% (95% CI: 0.37%, 22.16%) and 14.74% (95% CI: 2.34, 27.11), respectively. CONCLUSION: The first administration of adjuvant chemotherapy is associated with sleep disturbance and sleep-wake activity rhythm disruption among breast cancer patients, while the disturbance and disruption during the last cycle are less severe; nevertheless, repeated administration of chemotherapy results in progressive impairment of nocturnal melatonin production.

Study protocol for a randomised controlled trial examining the association between physical activity and sleep quality in children with autism spectrum disorder based on the melatonin-mediated mechanism model.

INTRODUCTION: Sleep disturbance is commonly observed in children with autism spectrum disorders (ASD). Disturbed sleep may exacerbate the core symptoms of ASD. Behavioural interventions and supplemental melatonin medication are traditionally used to improve sleep quality, but poor sustainability of behavioural intervention effects and use of other medications that metabolise melatonin may degrade the effectiveness of these interventions. However, several studies have suggested that physical activity may provide an effective intervention for treating sleep disturbance in typically developing children. Thus, we designed a study to examine whether such an intervention is also effective in children with ASD. We present a protocol (4 December 2017) for a jogging intervention with a parallel and two-group randomised controlled trial design using objective actigraphic assessment and 6-sulfatoxymelatonin measurement to determine whether a 12-week physical activity intervention elicits changes in sleep quality or melatonin levels. METHODS AND ANALYSIS: All eligible participants will be randomly allocated to either a jogging intervention group or a control group receiving standard care. Changes in sleep quality will be monitored through actigraphic assessment and parental sleep logs. All participants will also be instructed to collect a 24-hour urine sample. 6-sulfatoxymelatonin, a creatinine-adjusted morning urinary melatonin representative of the participant's melatonin levels, will be measured from the sample. All assessments will be carried out before the intervention (T1), immediately after the 12-week intervention or regular treatment (T2), 6 weeks after the intervention (T3) and 12 weeks after the intervention (T4) to examine the sustainability of the intervention effects. The first enrolment began in February 2018. ETHICS AND DISSEMINATION: Ethical approval was obtained through the Human Research Ethics Committee, Education University of Hong Kong. The results of this trial will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03348982.

Help-seeking behaviors for insomnia in Hong Kong Chinese: a community-based study.

OBJECTIVES: To determine the prevalence and correlates of help-seeking behaviors for insomnia in Hong Kong Chinese middle-aged adults and their offspring. METHODS: A total of 2231 middle-aged adults (54.2% females, mean age 45.8 years) and 2186 children and adolescents (51.9% females, mean age 13.4 years) completed a questionnaire on insomnia symptoms, daytime functioning, health condition and treatments sought for insomnia. RESULTS: A total of 40% of adults and 10% of children and adolescents with insomnia reported having sought treatment for insomnia. Conventional Western medicine was the commonly preferred treatment in 33.3% of adults and 13.3% of children and adolescents who sought help for insomnia, while a higher proportion of individuals with insomnia (34.5% of adults and 26.7% of children and adolescents) sought help from complementary and alternative medicine (CAM) therapies. Female gender (odds ratio [OR] [95% confidence interval, CI] = 2.14 [1.01-4.53]), higher family income (≥15,000 HKD/month) (OR [95% CI] = 3.15 [1.27-6.34]), severity of insomnia (Insomnia Severity Index ≥14) (OR [95% CI] = 2.12 [1.10-4.12]), chronic medications (OR [95% CI] = 4.71 [2.27-9.79]), and psychiatric disorders (OR [95% CI] = 2.83 [1.01-7.96]) were associated with help-seeking behaviors in adults. Presence of morning headache was associated with help-seeking behaviors in children and adolescents (OR [95% CI] = 8.66 [1.72-43.70]). CONCLUSIONS: It is uncommon for Hong Kong Chinese to seek help for insomnia, despite the high prevalence of insomnia. The significant unmet need argues for timely intervention to promote sleep-health literacy and to enhance the awareness and accessibility of evidence-based treatment for insomnia.

Reduced spontaneous neuronal activity in the insular cortex and thalamus in healthy adults with insomnia symptoms.

Poor sleep and insomnia have been recognized to be strongly correlated with the development of depression. The exploration of the basic mechanism of sleep disturbance could provide the basis for improved understanding and treatment of insomnia and prevention of depression. In this study, 31 subjects with insomnia symptoms as measured by the Hamilton Rating Scale for Depression (HAMD-17) and 71 age- and gender-matched subjects without insomnia symptoms were recruited to participate in a clinical trial. Using resting-state functional magnetic resonance imaging (rs-fMRI), we examined the alterations in spontaneous brain activity between the two groups. Correlations between the fractional amplitude of low frequency fluctuations (fALFF) and clinical measurements (e.g., insomnia severity and Hamilton Depression Rating Scale [HAMD] scores) were also tested in all subjects. Compared to healthy participants without insomnia symptoms, participants with insomnia symptoms showed a decreased fALFF in the left ventral anterior insula, bilateral posterior insula, left thalamus, and pons but an increased fALFF in the bilateral middle occipital gyrus and right precentral gyrus. More specifically, a significant, negative correlation of fALFF in the left thalamus with early morning awakening scores and HAMD scores in the overall sample was identified. These results suggest that insomnia symptoms are associated with altered spontaneous activity in the brain regions of several important functional networks, including the insular cortex of the salience and the thalamus of the hyperarousal network. The altered fALFF in the left thalamus supports the "hyperarousal theory" of insomnia symptoms, which could serve as a biomarker for insomnia.

Novel nikkomycin analogues generated by mutasynthesis in Streptomyces ansochromogenes.

BACKGROUND: Nikkomycins are competitive inhibitors of chitin synthase and inhibit the growth of filamentous fungi, insects, acarids and yeasts. The gene cluster responsible for biosynthesis of nikkomycins has been cloned and the biosynthetic pathway was elucidated at the genetic, enzymatic and regulatory levels. RESULTS: Streptomyces ansochromogenes ΔsanL was constructed by homologous recombination and the mutant strain was fed with benzoic acid, 4-hydroxybenzoic acid, nicotinic acid and isonicotinic acid. Two novel nikkomycin analogues were produced when cultures were supplemented with nicotinic acid. These two compounds were identified as nikkomycin Px and Pz by electrospray ionization mass spectrometry (ESI-MS) and nuclear magnetic resonance (NMR). Bioassays against Candida albicans and Alternaria longipes showed that nikkomycin Px and Pz exhibited comparatively strong inhibitory activity as nikkomycin X and Z produced by Streptomyces ansochromogenes 7100 (wild-type strain). Moreover, nikkomycin Px and Pz were found to be more stable than nikkomycin X and Z at different pH and temperature conditions. CONCLUSIONS: Two novel nikkomycin analogues (nikkomycin Px and Pz) were generated by mutasynthesis with the sanL inactivated mutant of Streptomyces ansochromogenes 7100. Although antifungal activities of these two compounds are similar to those of nikkomycin X and Z, their stabilities are much better than nikkomycin X and Z under different pHs and temperatures.

Frequent nightmares in children: familial aggregation and associations with parent-reported behavioral and mood problems.

STUDY OBJECTIVES: To conduct a systematic investigation on the prevalence, correlates, and familial aggregation of frequent nightmares in children, and to scrutinize the associations between frequent nightmares and parent-reported behavioral and mood problems in children. DESIGN: A cross-sectional study was conducted by collecting the data on sociodemographic, sleep, behavioral, and family-related information from a total of 6359 children (age: mean [SD]=9.2 [1.8] years; girls: 49.9%) and their reported biological parents. SETTING: Community. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Prevalence of frequent nightmares with a criterion of at least once per week was 5.2%. Multinomial regression analysis indicated that monthly family income, paternal and maternal nightmares, insomnia symptoms, parasomniac symptoms, and daytime consequences were significantly associated with nightmares in children. Frequent nightmares in children were significantly associated with hyper-activity (odds ratio [OR]=1.68, 95% CI 1.16-2.44), frequent temper outbursts/mood disturbance (OR=1.76, 95%CI 1.27-2.44), and poor academic performance (OR=1.62, 95% CI 1.11-2.36), after controlling for potential confounding factors. Approximately 20% of children with frequent nightmares experienced comorbid frequent insomnia. Comorbid nightmares and insomnia were associated with increased odds of hyperactivity (OR=4.13, 95% CI 2.13-8.00) and frequent temper outbursts/mood disturbance (OR=2.41, 95%CI 1.27-4.60). CONCLUSIONS: Frequent nightmares in children are associated with a constellation of child-, sleep-, and family-related factors, including comorbid sleep problems, such as insomnia and parasomnia, family economic status, and parental predisposition. Frequent nightmares are independently associated with emotional and behavioral problems in children.