Different heart rate variability profile during sleep in mid-later life adults with remitted early-onset versus late-onset depression.

BACKGROUND: In mid-later life adults, early-onset and late-onset (i.e., onset ≥50 years) depression appear to be underpinned by different pathophysiology yet have not been examined in relation to autonomic function. Sleep provides an opportunity to examine the autonomic nervous system as the physiology changes across the night. Hence, we aimed to explore if autonomic profile is altered in mid-later life adults with remitted early-onset, late-onset and no history of lifetime depression. METHODS: Participants aged 50-90 years (n = 188) from a specialised clinic underwent a comprehensive clinical assessment and completed an overnight polysomnography study. General Linear Models were used to examine the heart rate variability differences among the three groups for four distinct sleep stages and the wake after sleep onset. All analyses controlled for potential confounders - age, sex, current depressive symptoms and antidepressant usage. RESULTS: For the wake after sleep onset, mid-later life adults with remitted early-onset depression had reduced standard deviation of Normal to Normal intervals (SDNN; p = .014, d = -0.64) and Shannon Entropy (p = .004, d = -0.46,) than those with no history of lifetime depression. Further, the late-onset group showed a reduction in high-frequency heart rate variability (HFn.u.) during non-rapid eye movement sleep stage 2 (N2; p = .005, d = -0.53) and non-rapid eye movement sleep stage 3 (N3; p = .009, d = -0.55) when compared to those with no lifetime history. LIMITATIONS: Causality between heart rate variability and depression cannot be derived in this cross-sectional study. Longitudinal studies are needed to examine the effects remitted depressive episodes on autonomic function. CONCLUSION: The findings suggest differential autonomic profile for remitted early-onset and late-onset mid-later life adults during sleep stages and wake periods. The differences could potentially serve as peripheral biomarkers in conjunction with more disease-specific markers of depression to improve diagnosis and prognosis.

Cannabinol (CBN; 30 and 300 mg) effects on sleep and next-day function in insomnia disorder ('CUPID' study): protocol for a randomised, double-blind, placebo-controlled, cross-over, three-arm, proof-of-concept trial.

OBJECTIVE: Insomnia is the most prevalent sleep disorder, with few effective pharmacotherapies. Anecdotal reports and recent preclinical research suggest that cannabinol (CBN), a constituent of Cannabis sativa derived from delta-9-tetrahydrocannabinol, could be an effective treatment. Despite this, the isolated effects of CBN on sleep have yet to be systematically studied in humans. METHODS: The present protocol paper describes a randomised, double-blind, placebo-controlled, single-dose, three-arm, cross-over, proof-of-concept study which investigates the effects of CBN on sleep and next-day function in 20 participants with clinician-diagnosed insomnia disorder and an Insomnia Severity Index Score ≥15. Participants receive a single fixed oral liquid dose of 30 mg CBN, 300 mg CBN and matched placebo, in random order on three treatment nights; each separated by a 2-week wash-out period. Participants undergo overnight sleep assessment using in-laboratory polysomnography and next-day neurobehavioural function tests. The primary outcome is wake after sleep onset minutes. Secondary outcomes include changes to traditional sleep staging, sleep-onset latency and absolute spectral power during non-rapid eye movement (NREM) sleep. Tertiary outcomes include changes to sleep spindles during NREM sleep, arousal indices, absolute spectral power during REM sleep and subjective sleep quality. Safety-related and exploratory outcomes include changes to next-day simulated driving performance, subjective mood and drug effects, postural sway, alertness and reaction time, overnight memory consolidation, pre and post-sleep subjective and objective sleepiness; and plasma, urinary, and salivary cannabinoid concentrations. The study will provide novel preliminary data on CBN efficacy and safety in insomnia disorder, which will inform larger clinical trials. ETHICS AND DISSEMINATION: Human Research Ethics Committee approval has been granted by Bellberry (2021-08-907). Study findings will be disseminated in a peer-reviewed journal and at academic conferences. TRIAL REGISTRATION NUMBER: NCT05344170.

Does daily energy and macronutrient intake differ between work and non-workdays in shift workers? A mixed methods study.

Shift workers are at increased risk of obesity and metabolic diseases, but their eating patterns on work and non-workdays are understudied. We aimed to examine whether energy intake and macronutrient intake of day and night shift nurses were different during work and non-workdays. We used a mixed-methods approach to study food intake of shift working nurses from two hospitals during day and night shifts. Participants completed baseline questionnaires about eating behaviour, sleep, chronotype, mood and shift work disorder. Participants then completed a 4-d food diary which included a non-workday prior to the first shift, the first and last shift (either day or night) and the following non-workday. After completion of the food diaries, we used semi-structured interviews to explore the qualitative aspects of eating behaviours. Seventy-nine shift-working nurses participated in the study. Daily energy intake was not significantly different on work and non-workdays in day or night shift workers (p > 0.05). Whilst macronutrient consumption was also not different between day and night shift workers (p > 0.05), sugar intake was higher in day compared to night shift workers (p = 0.02) on the non-workday prior to the first workday. In qualitative interviews, participants reported their eating to be different on day and night shifts as well as work and non-workdays. Eating behaviour in day and night shift workers was highly influenced by food availability, convenience, peers, and family members. Nurses qualitatively report that night and day shifts result in them eating differently despite no statistically discernible difference in energy intake.

Embedding digital sleep health into primary care practice: A triangulation of perspectives from general practitioners, nurses, and pharmacists.

Introduction: While digital health interventions (DHIs) can potentially address the unmet needs for sleep health services, little is known about their implementation in practice. The current study aimed to explore primary care health providers' attitudes and beliefs towards DHIs for sleep and implementation into practice. Methods: A cross-sectional online survey was administered to Australian primary care health professionals: general practitioners (GPs), community nurses, and community pharmacists. Semi-structured interviews were conducted within a sub-sample of participants exploring their experiences with DHIs and perceived barriers/facilitators for embedding DHIs into primary care. Semi-structured interviews were thematically analysed using the framework approach to contextualise survey findings. Results: Ninety-six surveys were returned (GPs = 36, nurses = 30, and pharmacists = 30) and 45 interviews conducted (GPs = 17, nurses = 14, and pharmacists = 14). From the survey, GPs were more likely to endorse familiarity (p = 0.009) and use (p < 0.001) of sleep DHIs in clinical practice than pharmacists and nurses. GPs were more interested in utilising the diagnostic features within a sleep DHI (p = 0.009) compared to other professionals. Thematic analysis of the interviews revealed three major themes, contextualised by profession: (1) Scope for DHIs in Current Practice, (2) Practice Gaps and Training Needs, and (3) Envisioning a Model of Care Using Sleep DHIs. While DHIs can potentially improve care, greater clarity of care pathways and reimbursement structures are needed for integration into practice. Conclusion: Primary care health professionals highlighted the training, care pathway and financial models required to realise the potential for translating findings from efficacy studies for DHIs into primary care to optimise sleep health.

Heart rate variability during slow wave sleep is linked to functional connectivity in the central autonomic network.

Reduced heart rate variability can be an early sign of autonomic dysfunction in neurodegenerative diseases and may be related to brain dysfunction in the central autonomic network. As yet, such autonomic dysfunction has not been examined during sleep-which is an ideal physiological state to study brain-heart interaction as both the central and peripheral nervous systems behave differently compared to during wakefulness. Therefore, the primary aim of the current study was to examine whether heart rate variability during nocturnal sleep, specifically slow wave (deep) sleep, is associated with central autonomic network functional connectivity in older adults 'at-risk' of dementia. Older adults (n = 78; age range = 50-88 years; 64% female) attending a memory clinic for cognitive concerns underwent resting-state functional magnetic resonance imaging and an overnight polysomnography. From these, central autonomic network functional connectivity strength and heart rate variability data during sleep were derived, respectively. High-frequency heart rate variability was extracted to index parasympathetic activity during distinct periods of sleep, including slow wave sleep as well as secondary outcomes of non-rapid eye movement sleep, wake after sleep onset, and rapid eye movement sleep. General linear models were used to examine associations between central autonomic network functional connectivity and high-frequency heart rate variability. Analyses revealed that increased high-frequency heart rate variability during slow wave sleep was associated with stronger functional connectivity (F = 3.98, P = 0.022) in two core brain regions within the central autonomic network, the right anterior insular and posterior midcingulate cortex, as well as stronger functional connectivity (F = 6.21, P = 0.005) between broader central autonomic network brain regions-the right amygdala with three sub-nuclei of the thalamus. There were no significant associations between high-frequency heart rate variability and central autonomic network connectivity during wake after sleep onset or rapid eye movement sleep. These findings show that in older adults 'at-risk' of dementia, parasympathetic regulation during slow wave sleep is uniquely linked to differential functional connectivity within both core and broader central autonomic network brain regions. It is possible that dysfunctional brain-heart interactions manifest primarily during this specific period of sleep known for its role in memory and metabolic clearance. Further studies elucidating the pathophysiology and directionality of this relationship should be conducted to determine if heart rate variability drives neurodegeneration, or if brain degeneration within the central autonomic network promotes aberrant heart rate variability.

The Relationship between Anxiety, Subjective and Objective Sleep, Chronotype and Circadian Rhythms with Depressive Symptoms in Insomnia Disorder.

Insomnia is a highly prevalent sleep disorder with strong bidirectional associations with depressive symptoms. The circadian preference for eveningness has been shown to be associated with depressive symptoms in insomnia and other mental health conditions. However, there is a lack of studies in insomnia investigating whether objective measures, such as dim light melatonin onset (DLMO) or polysomnographic (PSG) sleep, are associated with depressive symptoms. Therefore, we investigated the associations between subjective measures (questionnaires assessing anxiety, sleep quality and circadian preference, and sleep diary) and depressive symptoms and whether the addition of objective measures (DLMO, PSG parameters) would strengthen the associations with depressive symptoms. In 115 insomnia disorder patients we found that anxiety was strongly associated with depressive symptoms in a model including circadian preference, dysfunctional beliefs of sleep, and self-reported previous depressive symptoms (R2 = 0.496, p < 0.001). The addition of sleep diary measures did not strengthen the model. We also found that the addition of objective measures (DLMO, PSG parameters) did not improve the subjective associations with depressive symptoms. Our data suggest that objective circadian markers are less important in the prediction of depressive symptoms in insomnia compared to subjective measures.

Registered nurses' attitudes towards e-learning and technology in healthcare: A cross-sectional survey.

BACKGROUND: Online learning, also known as e-learning, has increased considerably during the COVID-19 pandemic and is now an important feature of nursing education globally. An understanding of registered nurses' online self-regulated learning, attitudes to e-learning and the relationship of these to attitudes to Information and Communication Technology (ICT) in healthcare facilitates successful educational outcomes. OBJECTIVE: To explore the association between registered nurses' attitudes to e-learning and self-regulated online learning skills on their attitudes towards the use of ICT in healthcare. DESIGN: A quantitative study employing a cross-sectional survey. SETTINGS AND PARTICIPANTS: A convenience sample of registered nurses (n = 120) enrolled in a nursing degree conversion program delivered in Singapore. METHODS: Participants (n = 120) completed an online anonymous survey consisting of three validated instruments (Information Technology Attitude Scale for Health (ITASH), Attitudes towards e-learning and, Online Self-regulated Learning Questionnaire. Descriptive and inferential statistics analyses were conducted. RESULTS: Participant's levels of online self-regulated learning were positively correlated with attitudes to e-learning (r = 0.663, p < 0.001). Attitudes to e-learning (70.4, SD 11.5) were also positively predictive of ITASH (R2 = 0.306, p < 0.001), but online self-regulated learning was not contributory to the prediction of attitudes to ICT in healthcare. CONCLUSIONS: It is recommended that educators involved in online learning focus on strategies aimed at promoting positive attitudes to e-learning and ICT prior to employing those aimed at developing online self-regulation skills. Further research exploring online learning and ICT needs in the workplace are required.

Improving sleep health management in primary care: A potential role for community nurses?

AIMS: To explore community nurses sleep health practices and their perspectives on improving sleep health care provision. DESIGN: An exploratory study utilizing the qualitative description methodology. METHODS: Semi-structured interviews were conducted with community nurses from May 2019 - October 2021. Interviews were audio-recorded, transcribed, and subjected to an inductive thematic analysis using a constructivist-interpretive paradigm. RESULTS: Twenty-three Australian community nurses were interviewed. Participants frequently encountered sleep disturbances/disorders in their patients. Data analysis yielded three main themes: (1) Sleep health in the community serviced, (2) sleep health awareness and management, and (3) community nurses' A to Z of improving sleep health. The most common sleep disorder presentations were insomnia and sleep apnea. Although most community sleep apnea cases were appropriately managed, insomnia was often mismanaged. Participants described their sleep health knowledge as deficient, with the majority advocating for increased sleep-related education tailored to their profession. Other important factors needed for improving sleep health provision were standardized patient treatment/referral pathways, increased interprofessional collaboration, and sufficient time for patient consults. CONCLUSION: Community nurses service a patient population that requires increased sleep health care. However, they are currently underequipped to do so, leading to suboptimal treatment provision. Providing community nurses with the appropriate resources, such as increased sleep-related education and standardized treatment frameworks, could enable them to better manage sleep disturbance/disorder presentations, such as insomnia. IMPACT: Little is known about how community nurses care for patients with sleep disturbance/sleep disorders. This study found that contemporary sleep health care was lacking due to knowledge deficits, competing challenges, and a need for standardized care pathways. These findings can inform the development of targeted education/training and standardized guidelines for community nurses providing sleep health care to patients as well as the design of future practice models of care provision. PATIENT OR PUBLIC CONTRIBUTION: Previous research by authors has involved extensive engagement with patients and health professionals, such as community pharmacists, general practitioners, and naturopaths who play a role in sleep health in the primary health care sector. These previous research projects built a significant understanding of the patient and health practitioner experience and have provided the background to the concept and design of this study.

Actigraphic and melatonin alignment in older adults with varying dementia risk.

Circadian rhythms alter with ageing and may be aetiologically linked to neurodegeneration. This study explored the association between clinical markers and 1) dim light melatonin onset (DLMO) time and 2) phase angle derived from sleep midpoint, in older adults with varying dementia risks. Participants completed 14 days of actigraphy followed by in-lab measurement of salivary melatonin, from which DLMO time and phase angle were computed. Eighty participants (age = 65.5, SD = 9.6), 44 males (55%), MMSE (28.6, SD = 1.5) were included in the analysis. Sex (t = 2.15, p = .04), sleep onset (r = 0.49, p < .001) and midpoint (r = 0.44, p < .001) also correlated with DLMO time. Multiple linear regression showed chronotype, average actigraphy-derived light exposure during the DLMO window (window 2 h prior to DLMO to 2 h post), early biological day (6-10 h post DLMO time) and late biological day (10-14 h post DLMO time) were predictive of DLMO time (adjusted R2 = 0.75). Sleep offset, depression severity, average light exposure during the early biological night and early and late biological day were shown to be predictive variables in the estimation of phase angle (adjusted R2 = 0.78). The current study highlights the potential use of clinical variables, such as actigraphy-derived light, as circadian markers in ageing which could be easily implemented into existing clinical practice and could yield potential targets focusing on chronotherapeutic interventions.

How registered nurses are measuring respiratory rates in adult acute care health settings: An integrative review.

AIMS AND OBJECTIVES: This integrative review aimed to draw conclusions from evidence on how registered nurses are measuring respiratory rates for acute care patients. BACKGROUND: Despite the growing research supporting respiratory rate as an early indicator for clinical deterioration, respiratory rate has consistently been the least frequently measured and accurately documented vital sign. DESIGN: An integrative review. METHODS: A systematic literature search was conducted in June 2022 in four databases: CINAHL, PubMed, Medline and Scopus. Quality appraisal was undertaken using the Joanna Briggs Institute's Checklist. PRISMA guidelines were followed to ensure explicit reporting and reported in the PRISMA checklist. RESULTS: Overall, 9915 records were identified, and 19 met the inclusion criteria. Of these 19 articles, seven themes emerged: estimation and digit preference, lack of understanding and knowledge, not valuing the clinical significance of respiratory rate, oxygen saturation substitute, interobserver agreement, subjective concern and count duration. A high prevalence of bias, estimation and incorrect technique was evident. A total of 15 articles reported specifically on how registered nurses are measuring respiratory rates on general medical and surgical wards. CONCLUSIONS: Despite its importance, this integrative review has determined that respiratory rates are not being assessed correctly by nursing staff in the acute care environment. Evidence of using estimation, value bias or quick count and multiply techniques are emerging themes which urgently require further research. No patient or public contribution.

Prenatal ozone exposure programs a sexually dimorphic susceptibility to high-fat diet in adolescent Long Evans rats.

Altered fetal growth, which can occur due to environmental stressors during pregnancy, may program a susceptibility to metabolic disease. Gestational exposure to the air pollutant ozone is associated with fetal growth restriction in humans and rodents. However, the impact of this early life ozone exposure on offspring metabolic risk has not yet been investigated. In this study, fetal growth restriction was induced by maternal inhalation of 0.8 ppm ozone on gestation days 5 and 6 (4 hr/day) in Long Evans rats. To uncover any metabolic inflexibility, or an impaired ability to respond to a high-fat diet (HFD), a subset of peri-adolescent male and female offspring from filtered air or ozone exposed dams were fed HFD (45% kcal from fat) for 3 days. By 6 weeks of age, male and female offspring from ozone-exposed dams were heavier than offspring from air controls. Furthermore, offspring from ozone-exposed dams had greater daily caloric consumption and reduced metabolic rate when fed HFD. In addition to energy imbalance, HFD-fed male offspring from ozone-exposed dams had dyslipidemia and increased adiposity, which was not evident in females. HFD consumption in males resulted in the activation of the protective 5'AMP-activated protein kinase (AMPKα) and sirtuin 1 (SIRT1) pathways in the liver, regardless of maternal exposure. Unlike males, ozone-exposed female offspring failed to activate these pathways, retaining hepatic triglycerides following HFD consumption that resulted in increased inflammatory gene expression and reduced insulin signaling genes. Taken together, maternal ozone exposure in early pregnancy programs impaired metabolic flexibility in offspring, which may increase susceptibility to obesity in males and hepatic dysfunction in females.

The short-term effects of opioid and non-opioid pharmacotherapies on sleep in people with chronic low back pain: A systematic review and meta-analysis of randomized controlled trials.

Chronic low back pain (LBP) shares a bidirectional relationship with sleep disturbance. Analgesics are often used for chronic LBP management however, the effects on sleep have not been thoroughly reviewed. This systematic review and meta-analysis assessed the effect of opioid and non-opioid medications on sleep in people with chronic LBP. Electronic databases were searched for randomized controlled trials which resulted in 16 eligible articles (14 studies). Sleep measures were secondary outcomes, with one study assessing sleep objectively and all other studies reporting subjective sleep. Twelve studies assessed opioid therapies whilst two studies examined non-opioid therapies. Eight studies (all opioid) were included in meta-analyses of sleep quality and sleep disturbance comparing opioid therapies with placebo-controls. Opioid therapies significantly improved sleep quality (SMD = 0.27, 95% CI: 0.17-0.36) and reduced sleep disturbance (SMD = 0.32, 95% CI: 0.25-0.40) compared to placebo-control. These findings show a clear improvement in subjective sleep associated with opioid therapies however, future studies should examine objective sleep outcomes which remain largely unexplored in chronic LBP. Addressing both pain and sleep together is important for effective management of comorbid conditions of chronic LBP and sleep disturbance due to their bidirectional relationship.

The Effect of Light Therapy on Electroencephalographic Sleep in Sleep and Circadian Rhythm Disorders: A Scoping Review.

Light therapy is used to treat sleep and circadian rhythm disorders, yet there are limited studies on whether light therapy impacts electroencephalographic (EEG) activity during sleep. Therefore, we aimed to provide an overview of research studies that examined the effects of light therapy on sleep macro- and micro-architecture in populations with sleep and circadian rhythm disorders. We searched for randomized controlled trials that used light therapy and included EEG sleep measures using MEDLINE, PubMed, CINAHL, PsycINFO and Cochrane Central Register of Controlled Trials databases. Five articles met the inclusion criteria of patients with either insomnia or delayed sleep−wake phase disorder (DSWPD). These trials reported sleep macro-architecture outcomes using EEG or polysomnography. Three insomnia trials showed no effect of the timing or intensity of light therapy on total sleep time, wake after sleep onset, sleep efficiency and sleep stage duration compared to controls. Only one insomnia trial reported significantly higher sleep efficiency after evening light therapy (>4000 lx between 21:00−23:00 h) compared with afternoon light therapy (>4000 lx between 15:00−17:00 h). In the only DSWPD trial, six multiple sleep latency tests were conducted across the day (09:00 and 19:00 h) and bright light (2500 lx) significantly lengthened sleep latency in the morning (09:00 and 11:00 h) compared to control light (300 lx). None of the five trials reported any sleep micro-architecture measures. Overall, there was limited research about the effect of light therapy on EEG sleep measures, and studies were confined to patients with insomnia and DSWPD only. More research is needed to better understand whether lighting interventions in clinical populations affect sleep macro- and micro-architecture and objective sleep timing and quality.

Safety of higher doses of melatonin in adults: A systematic review and meta-analysis.

Melatonin is commonly used for sleep and jetlag at low doses. However, there is less documentation on the safety of higher doses, which are being increasingly used for a wide variety of conditions, including more recently COVID-19 prevention and treatment. The aim of this review was to investigate the safety of higher doses of melatonin in adults. Medline, Scopus, Embase and PsycINFO databases from inception until December 2019 with convenience searches until October 2020. Randomised controlled trials investigating high-dose melatonin (≥10 mg) in human adults over 30 years of age were included. Two investigators independently abstracted articles using PRISMA guidelines. Risk of bias was assessed by a committee of three investigators. 79 studies were identified with a total of 3861 participants. Studies included a large range of medical conditions. The meta-analysis was pooled data using a random effects model. The outcomes examined were the number of adverse events (AEs), serious adverse events (SAEs) and withdrawals due to AEs. A total of 29 studies (37%) made no mention of the presence or absence of AEs. Overall, only four studies met the pre-specified low risk of bias criteria for meta-analysis. In that small subset, melatonin did not cause a detectable increase in SAEs (Rate Ratio = 0.88 [0.52, 1.50], p = .64) or withdrawals due to AEs (0.93 [0.24, 3.56], p = .92), but did appear to increase the risk of AEs such as drowsiness, headache and dizziness (1.40 [1.15, 1.69], p < .001). Overall, there has been limited AE reporting from high-dose melatonin studies. Based on this limited evidence, melatonin appears to have a good safety profile. Better safety reporting in future long-term trials is needed to confirm this as our confidence limits were very wide due to the paucity of suitable data.

Insomnia subtypes characterised by objective sleep duration and NREM spectral power and the effect of acute sleep restriction: an exploratory analysis.

Insomnia disorder (ID) is a heterogeneous disorder with proposed subtypes based on objective sleep duration. We speculated that insomnia subtyping with additional power spectral analysis and measurement of response to acute sleep restriction may be informative in overall assessment of ID. To explore alternative classifications of ID subtypes, insomnia patients (n = 99) underwent two consecutive overnight sleep studies: (i) habitual sleep opportunity (polysomnography, PSG) and, (ii) two hours less sleep opportunity (electroencephalography, EEG), with the first night compared to healthy controls (n = 25). ID subtypes were derived from data-driven classification of PSG, EEG spectral power and interhemispheric EEG asymmetry index. Three insomnia subtypes with different sleep duration and NREM spectral power were identified. One subtype (n = 26) had shorter sleep duration and lower NREM delta power than healthy controls (short-sleep delta-deficient; SSDD), the second subtype (n = 51) had normal sleep duration but lower NREM delta power than healthy controls (normal-sleep delta-deficient; NSDD) and a third subtype showed (n = 22) no difference in sleep duration or delta power from healthy controls (normal neurophysiological sleep; NNS). Acute sleep restriction improved multiple objective sleep measures across all insomnia subtypes including increased delta power in SSDD and NSDD, and improvements in subjective sleep quality for SSDD (p = 0.03), with a trend observed for NSDD (p = 0.057). These exploratory results suggest evidence of novel neurophysiological insomnia subtypes that may inform sleep state misperception in ID and with further research, may provide pathways for personalised care.

The efficacy of combined bright light and melatonin therapies on sleep and circadian outcomes: A systematic review.

The aim of this systematic review was to investigate the effects of combined melatonin and bright light therapies on improved sleep and circadian outcomes. We conducted a systematic review that resulted in a total of eight papers meeting criteria. Four papers investigated the effectiveness of combined therapy in inducing a circadian phase shift on healthy participants. Combined therapy outperformed single light and melatonin therapies in phase advancing, but not in delaying, dim light melatonin onset (DLMO). The other four papers investigated the effect of combined therapy on sleep outcomes. Two of them were performed in elderly populations suffering from cognitive decline and two in delayed sleep-wake phase disorder (DSWPD) patients. While combined therapy was more beneficial than single therapy in elderly populations it did not show any benefit in DSWPD patients. The reported adverse effects of melatonin in elderly populations must be carefully considered. Future studies should investigate the separate and combined effect of melatonin and bright light on sleep and circadian outcomes in different target populations.

The association of insomnia disorder characterised by objective short sleep duration with hypertension, diabetes and body mass index: A systematic review and meta-analysis.

Insomnia disorder with objective short sleep duration (less than 6 h of objective sleep or sleep efficiency less than 85%) has been considered as a biologically severe subtype of insomnia associated with a higher risk of cardiometabolic disease morbidity. This systematic review and meta-analysis firstly compared insomnia disorder with objective short and normal sleep duration, and subsequently, objective short sleep duration with and without insomnia disorder, and their associations with hypertension, type 2 diabetes and body mass index. A systematic search of five databases yielded 2345 non-duplicated articles, of which 11 individual studies were used for the qualitative review and 10 individual studies for the meta-analysis. The sample size varied from 30 to 4994 participants. A higher risk of hypertension (RR 1.54, 95% CI: [1.30; 1.82] p < 0.0001) and type 2 diabetes (RR 1.63 [1.37; 1.94], p < 0.0001) was associated with insomnia disorder with objective short sleep compared to normal sleep duration, but not for body mass index. Comparisons between insomnia disorder with objective short sleep and objective short sleep without insomnia disorder showed no significant differences. However, the majority of these studies were cross-sectional, and there is a need for more cohort study data.

Feasibility of 3-month melatonin supplementation for brain oxidative stress and sleep in mild cognitive impairment: protocol for a randomised, placebo-controlled study.

INTRODUCTION: Melatonin has multiple proposed therapeutic benefits including antioxidant properties, synchronisation of the circadian system and lowering of blood pressure. In this protocol, we outline a randomised controlled trial to assess the feasibility, acceptability and tolerability of higher dose (25 mg) melatonin to target brain oxidative stress and sleep disturbance in older adults with mild cognitive impairment (MCI). METHODS AND ANALYSIS: The study design is a randomised double-blind, placebo-controlled, parallel group trial. Forty individuals with MCI will be recruited from the Healthy Brain Ageing Clinic, University of Sydney and from the community, and randomised to receive either 25 mg oral melatonin or placebo nightly for 12 weeks. The primary outcomes are feasibility of recruitment, acceptability of intervention and adherence to trial medication at 12 weeks. Secondary outcomes will include the effect of melatonin on brain oxidative stress as measured by magnetic resonance spectroscopy, blood pressure, blood biomarkers, mood, cognition and sleep. Outcomes will be collected at 6 and 12 weeks. The results of this feasibility trial will inform a future conclusive randomised controlled trial to specifically test the efficacy of melatonin on modifiable risk factors of dementia, as well as cognition and brain function. This will be the first trial to investigate the effect of melatonin in the population with MCI in this way, with the future aim of using this approach to reduce progression to dementia. ETHICS AND DISSEMINATION: This protocol has been approved by the Sydney Local Health District Ethics Committee (X18-0077). This randomised controlled trial will be conducted in compliance with the protocol published in the registry, the International Conference for Harmonisation on Good Clinical Practice and all other applicable regulatory requirements. The findings of the trial will be disseminated via conferences, publications and media, as applicable. Participants will be informed of results of the study at the conclusion of the trial. Eligible authors will include investigators who are involved in the conception and design of the study, the conduct of the trial, the analysis of the results, and reporting and presentation of study findings. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ANZCTRN 12619000876190). PROTOCOL VERSION: V.8 15 October 2020.

Pharmacokinetics of exogenous melatonin in relation to formulation, and effects on sleep: A systematic review.

There is conflicting evidence on the clinical efficacy of exogenous melatonin for the treatment of sleep disorders. This may be due to differences in the pharmacokinetic (PK) properties of melatonin formulations used in clinical trials. The aim of this systematic review was to understand the relationship between melatonin formulations and PK parameters and, where possible, the effects on sleep outcomes. To this purpose, we conducted a systematic review and nineteen papers were included. The studies included three melatonin transdermal formulation, thirteen oral formulations, one topical, two buccal, two intravenous and two nasogastric formulations. Seven studies investigated the effect of the melatonin formulation on sleep and six of them found a significant improvement in one or more sleep parameters. The potential for an improved controlled release formulation that delays maximum concentration (Cmax) was identified. The different formulations and doses affect melatonin PK, suggesting that treatment efficacy maybe affected. Based on the current evidence, we are unable to provide recommendations of specific melatonin formulations and PK parameters for specific sleep disorders. Future studies should systematically investigate how different PK parameters of melatonin formulations affect efficacy treatment of sleep as well as circadian disorders.