Professor Debra J. Skene

Professor of Neuroendocrinology; Section Lead Chronobiology
B Pharm, MSc, PhD
+44 (0)1483 689706
16 AY 02


Areas of specialism

Chronometabolomics; Circadian rhythms; Human chronobiology; Light; Older people; Pineal melatonin; Shift work; Sleep; Chrono-nutrition

University roles and responsibilities

  • Section Leader of Chronobiology
  • Academic Lead of Metabolomics Core Facility

    Business, industry and community links

    Chronobiology International
    Editorial Board, 2007 -
    Journal of Sleep Research
    Associate Editor, 2008 -
    Sleep and Biological Rhythms
    Advisory Board, 2012 -


    Research interests

    Indicators of esteem

    • Royal Society Wolfson Research Merit Award, Linking light, circadian rhythms, sleep and metabolism in health and disease2011 - 2016

    • Chair, Gordon Research Conference on Pineal Cell Biology: Links to clocks, sleep and metabolism, Hotel Galvez, Galveston, Texas, USA, 29th January -3rd February, 2012.

      Research funding


      Postgraduate research supervision

      Postgraduate research supervision


      Jason E. McDermot, Jon M. Jacobs, Nathaniel J. Merrill, Hugh Mitchell, Osama A Arshad, Ryan McClure, Justin Teeguarden, Rajendra P Gajula, Kenneth I Porter, Brieann C Satterfield, Kirsie R. Lundholm, Debra J. Skene, Shobhan Gaddameedhi, Hans P A Van Dongen (2024)Molecular-Level Dysregulation of Insulin Pathways and Inflammatory Processes in Peripheral Blood Mononuclear Cells by Circadian Misalignment, In: Journal of proteome research American Chemical Society

      Circadian misalignment due to night work has been associated with elevated risk for chronic diseases. We investigated the effects of circadian misalignment using shotgun protein profiling of peripheral blood mononuclear cells taken from healthy humans during a constant routine protocol, which was conducted immediately after participants had been subjected to a 3-day simulated night shift schedule or a 3-day simulated day shift schedule. By comparing proteomic profiles between the simulated shift conditions, we identified proteins and pathways that are associated with the effects of circadian misalignment, and observed that insulin regulation pathways and inflammation-related proteins displayed markedly different temporal patterns after simulated night shift. Further, by integrating the proteomic profiles with previously assessed metabolomic profiles in a network-based approach, we found key associations between circadian dysregulation of protein-level pathways and metabolites of interest in the context of chronic metabolic diseases. Endogenous circadian rhythms in circulating glucose and insulin differed between the simulated shift conditions. Overall, our results suggest that circadian misalignment is associated with a tug of war between central clock mechanisms controlling insulin secretion and peripheral clock mechanisms regulating insulin sensitivity, which may lead to adverse long-term outcomes such as diabetes and obesity. Our study provides a molecular-level mechanism linking circadian misalignment and adverse long-term health consequences of night work.

      Anthony Onoja, Johanna Von Gerichten, Holly-May Lewis, Melanie Jane Bailey, Debra Jean Skene, Nophar Geifman, Matt Spick (2023)Meta-Analysis of COVID-19 Metabolomics Identifies Variations in Robustness of Biomarkers, In: International journal of molecular sciences24(18)14371 Mdpi

      The global COVID-19 pandemic resulted in widespread harms but also rapid advances in vaccine development, diagnostic testing, and treatment. As the disease moves to endemic status, the need to identify characteristic biomarkers of the disease for diagnostics or therapeutics has lessened, but lessons can still be learned to inform biomarker research in dealing with future pathogens. In this work, we test five sets of research-derived biomarkers against an independent targeted and quantitative Liquid Chromatography-Mass Spectrometry metabolomics dataset to evaluate how robustly these proposed panels would distinguish between COVID-19-positive and negative patients in a hospital setting. We further evaluate a crowdsourced panel comprising the COVID-19 metabolomics biomarkers most commonly mentioned in the literature between 2020 and 2023. The best-performing panel in the independent dataset-measured by F1 score (0.76) and AUROC (0.77)-included nine biomarkers: lactic acid, glutamate, aspartate, phenylalanine, & beta;-alanine, ornithine, arachidonic acid, choline, and hypoxanthine. Panels comprising fewer metabolites performed less well, showing weaker statistical significance in the independent cohort than originally reported in their respective discovery studies. Whilst the studies reviewed here were small and may be subject to confounders, it is desirable that biomarker panels be resilient across cohorts if they are to find use in the clinic, highlighting the importance of assessing the robustness and reproducibility of metabolomics analyses in independent populations.

      Debra Jean Skene, Gregory Hammad, Katharina Wulff, Mirjam Münch, Manuel Spitschan (2024)Open-Source Python Module for the Analysis of Personalized Light Exposure Data from Wearable Light Loggers and Dosimeters, In: Leukos

      Light exposure fundamentally influences human physiology and behavior, with light being the most important zeitgeber of the circadian system. Throughout the day, people are exposed to various scenes differing in light level, spectral composition and spatio-temporal properties. Personalized light exposure can be measured through wearable light loggers and dosimeters, including wrist-worn actimeters containing light sensors, yielding time series of an individual’s light exposure. There is growing interest in relating light exposure patterns to health outcomes, requiring analytic techniques to summarize light exposure properties. Building on the previously published Python-based pyActigraphy module, here we introduce the module pyLight. This module allows users to extract light exposure data recordings from a wide range of devices. It also includes software tools to clean and filter the data, and to compute common metrics for quantifying and visualizing light exposure data. For this tutorial, we demonstrate the use of pyLight in one example dataset with the following processing steps: (1) loading, accessing and visual inspection of a publicly available dataset, (2) truncation, masking, filtering and binarization of the dataset, (3) calculation of summary metrics, including time above threshold (TAT) and mean light timing above threshold (MLiT). The pyLight module paves the way for open-source, large-scale automated analyses of light-exposure data.

      Sara Montagnese, Lisa Zarantonello, Chiara Formentin, Gianluca Giusti, Chiara Mangini, Cheryl M Isherwood, Paolo Ferrari, Antonio Paoli, Daniela Mapelli, Rosario Rizzuto, Stefano Toppo, Debra J Skene, Roberto Vettor, Rodolfo Costa (2022)A Circadian Hygiene Education Initiative Covering the Pre-pandemic and Pandemic Period Resulted in Earlier Get-Up Times in Italian University Students: An Ecological Study, In: Frontiers in neuroscience16848602

      The aims of the present study were to obtain sleep quality and sleep timing information in a group of university students and to evaluate the effects of a circadian hygiene education initiative. All students of the University of Padova (approximately 64,000) were contacted by e-mail (major campaigns in October 2019 and October 2020) and directed to an ad hoc website for collection of demographics and sleep quality/timing information. Participants (= 5,740) received one of two sets of circadian hygiene advice ("A regular life" or "Bright days and dark nights"). Every month, they were then asked how easy it had been to comply and provided with the advice again. At any even month from joining, they completed the sleep quality/timing questionnaires again. Information on academic performance was obtained, together with representative samples of lecture (= 5,972) and examination (= 1,800) timings, plus lecture attendances (= 25,302). Fifty-two percent of students had poor sleep quality, and 82% showed signs of social jetlag. Those who joined in October 2020, after several months of lockdown and distance learning, had better sleep quality, less social jetlag, and later sleep habits. Over approximately a year, the "Bright days and dark nights" advice resulted in significantly earlier get-up times compared with the "A regular life" advice. Similarly, it also resulted in a trend toward earlier midsleep (i.e., the midpoint, expressed as clock time, between sleep onset and sleep offset) and toward a decrease in the latency between wake-up and get-up time, with no impact on sleep duration. Significant changes in most sleep quality and sleep timing variables (i.e., fewer night awakenings, less social jetlag, and delayed sleep timing during lock-down) were observed in both advice groups over approximately a year, mostly in association with pandemic-related events characterizing 2020. Early chronotype students had better academic performances compared with their later chronotype counterparts. In a multivariate model, sleep quality, chronotype and study subject (science and technology, health and medical, or social and humanities) were independent predictors of academic performance. Taken together, these results underlie the importance of designing circadian-friendly university timetables.

      Cecile F. Frampas, Katie Longman, Matt Spick, Holly-May Lewis, Catia D. S. Costa, Alex Stewart, Deborah Dunn-Walters, Danni Greener, George Evetts, Debra J. Skene, Drupad Trivedi, Andy Pitt, Katherine Hollywood, Perdita Barran, Melanie J. Bailey (2022)Untargeted saliva metabolomics by liquid chromatography-Mass spectrometry reveals markers of COVID-19 severity, In: PloS one17(9)e0274967 Public Library Science

      Background The COVID-19 pandemic is likely to represent an ongoing global health issue given the potential for new variants, vaccine escape and the low likelihood of eliminating all reservoirs of the disease. Whilst diagnostic testing has progressed at a fast pace, the metabolic drivers of outcomes-and whether markers can be found in different biofluids-are not well understood. Recent research has shown that serum metabolomics has potential for prognosis of disease progression. In a hospital setting, collection of saliva samples is more convenient for both staff and patients, and therefore offers an alternative sampling matrix to serum. Methods Saliva samples were collected from hospitalised patients with clinical suspicion of COVID-19, alongside clinical metadata. COVID-19 diagnosis was confirmed using RT-PCR testing, and COVID-19 severity was classified using clinical descriptors (respiratory rate, peripheral oxygen saturation score and C-reactive protein levels). Metabolites were extracted and analysed using high resolution liquid chromatography-mass spectrometry, and the resulting peak area matrix was analysed using multivariate techniques. Results Positive percent agreement of 1.00 between a partial least squares-discriminant analysis metabolomics model employing a panel of 6 features (5 of which were amino acids, one that could be identified by formula only) and the clinical diagnosis of COVID-19 severity was achieved. The negative percent agreement with the clinical severity diagnosis was also 1.00, leading to an area under receiver operating characteristics curve of 1.00 for the panel of features identified. Conclusions In this exploratory work, we found that saliva metabolomics and in particular amino acids can be capable of separating high severity COVID-19 patients from low severity COVID-19 patients. This expands the atlas of COVID-19 metabolic dysregulation and could in future offer the basis of a quick and non-invasive means of sampling patients, intended to supplement existing clinical tests, with the goal of offering timely treatment to patients with potentially poor outcomes.

      Debra J. Skene, Elena Skornyakov, Namrata R. Chowdhury, Rajendra P. Gajula, Benita Middleton, Brieann C. Satterfield, Kenneth I. Porter, Hans P. A. Van Dongen, Shobhan Gaddameedhi (2021)Separation of circadian- and behavior-driven metabolite rhythms in humans provides a window on peripheral oscillators and metabolism (vol 115, pg 7825, 2018), In: Proceedings of the National Academy of Sciences - PNAS118(36)2113275118 Natl Acad Sciences
      Matt Spick, Thomas P.M. Hancox, Namrata R. Chowdhury, Benita Middleton, Debra J. Skene, Debra Jean Skene, A. Jennifer Morton (2023)Metabolomic Analysis of Plasma in Huntington’s Disease Transgenic Sheep (Ovis aries) Reveals Progressive Circadian Rhythm Dysregulation, In: Journal of Huntington's disease12(1)pp. 31-42 IOS Press

      Background: Metabolic abnormalities have long been predicted in Huntington’s disease (HD) but remain poorly characterized. Chronobiological dysregulation has been described in HD and may include abnormalities in circadian-driven metabolism. Objective: Here we investigated metabolite profiles in the transgenic sheep model of HD (OVT73) at presymptomatic ages. Our goal was to understand changes to the metabolome as well as potential metabolite rhythm changes associated with HD. Methods: We used targeted liquid chromatography mass spectrometry (LC-MS) metabolomics to analyze metabolites in plasma samples taken from female HD transgenic and normal (control) sheep aged 5 and 7 years. Samples were taken hourly across a 27-h period. The resulting dataset was investigated by machine learning and chronobiological analysis. Results: The metabolic profiles of HD and control sheep were separable by machine learning at both ages. We found both absolute and rhythmic differences in metabolites in HD compared to control sheep at 5 years of age. An increase in both the number of disturbed metabolites and the magnitude of change of acrophase (the time at which the rhythms peak) was seen in samples from 7-year-old HD compared to control sheep. There were striking similarities between the dysregulated metabolites identified in HD sheep and human patients (notably of phosphatidylcholines, amino acids, urea, and threonine). Conclusion: This work provides the first integrated analysis of changes in metabolism and circadian rhythmicity of metabolites in a large animal model of presymptomatic HD.

      Cibele A. Crispim, Ana E. M. Rinaldi, Catarina M. Azeredo, Debra Jean Skene, Claudia R. C. Moreno (2023)Is time of eating associated with BMI and obesity? A population-based study, In: European Journal of Nutrition Springer

      Purpose Time-related eating patterns have been associated with metabolic and nutritional diseases such as obesity. However, there is a lack of representative studies on this subject. This study's aim was to assess the association between the timing of eating and obesity in a large and representative sample of the Brazilian adult population (POF 2008–2009 survey). Methods Two days of adults’ food diary (n = 21,020) were used to estimate tertiles of first and last meal intake times, eating midpoint, caloric midpoint time, and calories consumed from 18:00 h onwards. BMI was estimated and its values, as well as excess weight (BMI ≥ 25 kg/m2) and obesity (BMI ≥ 30 kg/m2) were used as outcomes. Multiple linear and logistic regressions were performed. Results The first (β = 0.65, 95% CI 0.37–0.93) and last food intake time (β = 0.40, 95% CI 0.14–0.66), eating midpoint (β = 0.61, 95% CI 0.34–0.88) and calories consumed after 21:00 h (β = 0.74, 95% CI 0.32–1.16) and 22:00 h (β = 0.75, 95% CI 0.18–1.32) were positively associated with BMI. The likelihood of having excess weight or obesity was significantly higher in the third tertile of the first food intake time (OR = 1.28, 95% CI 1.13–1.45 and OR = 1.34, 95% CI 1.13–1.58, respectively), last food intake time (OR = 1.16, 95% CI 1.03–1.32; and OR = 1.18, 95% CI 1.00–1.41, respectively), eating midpoint (OR = 1.28, 95% CI 1.13–1.45; and OR = 1.35, 95% CI 1.14–1.59, respectively) and energy consumption after 21:00 h (OR = 1.33, 95% CI 1.10–1.59). Conclusion Chrononutrition meal patterns indicative of late meal intake were significantly associated with high BMI, excess weight and obesity in the Brazilian population.

      Juliane Hannemann, Anika Laing, Karin Glismann, Debra Skene, BENITA ANNE MIDDLETON, B Staels, Nikolaus Marx, Peter J Grant, MO Federici, Josef Niebauer, Raina Boger (2020)Timed physical exercise does not influence circadian rhythms and glucose tolerance in rotating night shift workers: The EuRhythDia study, In: Diabetes and Vascular Disease Research17(5)pp. 1479164120950616-1479164120950616 SAGE Publications
      Yves Dauvilliers, Lucie Barateau, Benita Middleton, Daan R. van der Veen, Debra Skene (2021)Metabolomics Signature of Patients with Narcolepsy, In: Neurology98(5) Lippincott, Williams & Wilkin

      Background and Objectives Narcolepsy type 1 (NT1) is an orphan brain disorder caused by the irreversible destruction of orexin neurons. Metabolic disturbances are common in patients with NT1 who have a body mass index (BMI) 10% to 20% higher than the general population, with one-third being obese (BMI >30 kg/m2). Besides the destruction of orexin neurons in NT1, the metabolic alterations in obese and nonobese patients with NT1 remain unknown. The aim of this study was to identify possible differences in plasma metabolic profiles between patients with NT1 and controls as a function of their BMI status. Methods We used a targeted liquid chromatography–mass spectrometry metabolomics approach to measure 141 circulating, low-molecular-weight metabolites in drug-free fasted plasma samples from 117 patients with NT1 (including 41 obese individuals) compared with 116 BMI-matched controls (including 57 obese individuals). Results Common metabolites driving the difference between patients with NT1 and controls, regardless of BMI, were identified, namely sarcosine, glutamate, nonaylcarnitine (C9), 5 long-chain lysophosphatidylcholine acyls, 1 sphingolipid, 12 phosphatidylcholine diacyls, and 11 phosphatidylcholine acyl-akyls, all showing increased concentrations in NT1. Metabolite concentrations significantly affected by NT1 (n = 42) and BMI category (n = 40) showed little overlap (n = 5). Quantitative enrichment analysis revealed common metabolic pathways that were implicated in the NT1/control differences in both normal BMI and obese comparisons, namely glycine and serine, arachidonic acid, and tryptophan metabolism. The metabolites driving these differences were glutamate, sarcosine, and ornithine (glycine and serine metabolism); glutamate and PC aa C34:4 (arachidonic acid metabolism); and glutamate, serotonin, and tryptophan (tryptophan metabolism). Linear metabolite-endophenotype regression analyses highlight that as part of the NT1 metabolic phenotype, most of the relationships between the sleep parameters (i.e., slow-wave sleep duration, sleep latency, and periodic leg movement) and metabolite concentrations seen in the controls were lost. Discussion These results represent the most comprehensive metabolic profiling of patients with NT1 as a function of BMI and propose some metabolic diagnostic biomarkers for NT1, namely glutamate, sarcosine, serotonin, tryptophan, nonaylcarnitine, and some phosphatidylcholines. The metabolic pathways identified offer, if confirmed, possible targets for treatment of obesity in NT1. Classification of Evidence This study provides Class II evidence that a distinct metabolic profile can differentiate patients with NT1 from patients without the disorder.

      Juliane Hannemann, Debra Jean Skene, Benita Middleton, Edzard Schwedhelm, Anika Laing, Rainer Böger (2023)Diurnal Variation of L-Arginine and the Cardiovascular Risk Markers Asymmetric and Symmetric Dimethylarginine and Homoarginine in Rotating Night Shift Workers and Controls, In: Biomolecules13(9)1282 MDPI

      Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) interfere with nitric oxide (NO) formation from L-arginine via different mechanisms. ADMA is a biomarker of cardiovascular disease and mortality, whilst SDMA is a biomarker of mortality after ischemic stroke. Homoarginine, another L-arginine-derived amino acid, is associated with stroke and congestive heart failure. Acute ischemic events like myocardial infarction show a time-of-day variation in the timing of their onset, as do NO-mediated vascular function and blood pressure. We studied whether the plasma concentrations of L-arginine-related amino acid metabolites show diurnal variation in a clinical study comparing 12 non-night shift workers with 60 rotating night shift workers. The plasma concentrations of L-arginine-related biomarkers, melatonin, and cortisol were measured every 3 h during a 24-h period. In addition, 24-h blood pressure recordings were performed. In non-night shift workers, L-arginine and homoarginine plasma concentrations showed diurnal variation with a 12-h period, which were both attenuated in night shift workers. ADMA and SDMA showed a 24-h rhythmicity with no significant differences in phase between night shift and non-night shift workers. The plasma profiles of melatonin and cortisol were not significantly different between both groups, suggesting that the rotating night shift work does not have a major influence on central suprachiasmatic nuclei clock timing. In addition, systolic and diastolic blood pressure patterns were similar between both groups. Our data show diurnal variation of dimethylarginines with the timing of their acrophases corresponding to the published timing of the peak incidence of cardiac ischemic events.

      Edward Hayter, Sophie Wehrens, Hans P A Van Dongen, Alessandra Stangherlin, Shobhan Gaddameedhi, Elena Crooks, Nichola Barron, Luigi Venetucci, John S. O’Neill, Timothy M Brown, DEBRA JEAN SKENE, Andrew Trafford, David Bechtold (2021)Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia, In: Nature communications Nature Research

      Electrical activity in the heart exhibits 24-hour rhythmicity, and potentially fatal arrhythmias are more likely to occur at specific times of day. Here, we demonstrate that circadian clocks within the brain and heart set daily rhythms in sinoatrial (SA) and atrioventricular (AV) node activity, and impose a time-of–day dependent susceptibility to ventricular arrhythmia. Critically, the balance of circadian inputs from the autonomic nervous system and cardiomyocyte clock to the SA and AV nodes differ, and this renders the cardiac conduction system sensitive to decoupling during abrupt shifts in behavioural routine and sleep-wake timing. Our findings reveal a functional segregation of circadian control across the heart’s conduction system and inherent susceptibility to arrhythmia.

      B.N Harding, G Castano-Vinyals, A. Palomar-Cros, K Papantoniou, A Espinosa, DEBRA JEAN SKENE, B Middleton, A Gomez-Gomez, J.M. Navarrete, P.S. Faro, A Torrejón, M Kogevinas, OJ Pozo (2021)Changes in melatonin and sex steroid hormone production among men as a result of rotating night shift work – the HORMONIT study, In: Scandinavian journal of work, environment & health.

      Objective Data from real world settings on circadian disruption and subsequent hormone-related changes may explain the higher risk of hormone-dependent cancers among night shift workers.The present study examines the melatonin and sex steroid hormone levels among night shift workers. Methods We included 44 male, rotating shift workers from a car factory in Spain, sampled both at the end of a 3-week night shift (22:00–06:00 hrs) and a 3-week early morning shift (06:00–14:00 hrs). Participants collected all urine voids over 24-hours during each shift. Urinary concentrations of sex steroid hormones (estrogens, androgens and progestogens) and 6-sulfatoxymelatonin (aMT6s, major melatonin metabolite) were determined. Individual cosinor analysis was used to derive the acrophase (peak time) and area under the curve (total production). Linear mixed models examined intraindividual associations between night shift work and log-transformed 24-hour peak time and total production of hormones compared to early morning shift work. Results The acrophase was delayed during the night shift for aMT6s [geometric mean difference (GMD) 7.53 hrs, 95% confidence interval (CI) 4.46–10.60], androgens (eg, testosterone: GMD 6.83 hrs, 95% CI 0.34–13.32) and progestogens (eg, 17-hydroxyprogesterone: GMD 4.54 hrs, 95% CI 2.92–6.16) compared to the early morning shift. We found a higher production of adrenal androgen 11-oxoandrosterone/11-oxoetiocholanolone [geometric mean ratio (GMR) 1.43, 95% CI 1.12–1.81], and a lower production of adrenal progestogen 16-cysteinylprogesterone (GMR 0.79, 95% CI 0.67–0.93) during the night shift compared to the early morning shift levels. Conclusions Night shift work was associated with melatonin and sex hormone-related changes in timing and total production, providing insight into the mechanistic path for its association with hormone-dependent cancer.

      Elise R Facer-Childs, Brunno M de Campos, Benita Middleton, Debra J Skene, Andrew P Bagshaw (2021)Temporal organisation of the brain's intrinsic motor network: The relationship with circadian phenotype and motor performance, In: NeuroImage (Orlando, Fla.)232117840 Elsevier Inc

      Functional connectivity (FC) of the motor network (MN) is often used to investigate how intrinsic properties of the brain are associated with motor abilities and performance. In addition, the MN is a key feature in clinical work to map the recovery after stroke and aid the understanding of neurodegenerative disorders. Time of day variation and individual differences in circadian timing, however, have not yet been considered collectively when looking at FC. A total of 33 healthy, right handed individuals (13 male, 23.1 ± 4.2 years) took part in the study. Actigraphy, sleep diaries and circadian phase markers (dim light melatonin onset and cortisol awakening response) were used to determine early (ECP, n =13) and late (LCP, n = 20) circadian phenotype groups. Resting state functional MRI testing sessions were conducted at 14:00 h, 20:00 h and 08:00 h and preceded by a maximum voluntary contraction test for isometric grip strength to measure motor performance. Significant differences in FC of the MN between ECPs and LCPs were found, as well as significant variations between different times of day. A higher amplitude in diurnal variation of FC and performance was observed in LCPs compared to ECPs, with the morning being most significantly affected. Overall, lower FC was significantly associated with poorer motor performance. Our findings uncover intrinsic differences between times of day and circadian phenotype groups. This suggests that central mechanisms contribute to diurnal variation in motor performance and the functional integrity of the MN at rest influences the ability to perform in a motor task.

      Dawn Querstret, Katie O'Brien, Debra J. Skene, Jill Maben (2020)Improving fatigue risk management in healthcare: A systematic scoping review of sleep-related/fatigue-management interventions for nurses and midwives, In: International Journal of Nursing Studies106103513 Elsevier

      Background Nurses and midwives make up almost 50% of the global healthcare shift working workforce. Shift work interferes with sleep and causes fatigue with adverse effects for nurses’ and midwives’ health, as well as on patient safety and care. Where other safety-critical sectors have developed Fatigue Risk Management Systems, healthcare is behind the curve; with published literature only focussing on the evaluation of discreet sleep-related/fatigue-management interventions. Little is known, however, about which interventions have been evaluated for nurses and midwives. Our review is a critical first step to building the evidence-base for healthcare organisations seeking to address this important operational issue. Objectives We address two questions: (1) what sleep-related/fatigue-management interventions have been assessed in nurses and midwives and what is their evidence-base? and (2) what measures are used by researchers to assess intervention effectiveness? Design and data sources The following databases were searched in November, 2018 with no limit on publication dates: MEDLINE, PsychINFO and CINAHL. Review methods We included: (1) studies conducted in adult samples of nurses and/or midwives that had evaluated a sleep-related/fatigue-management intervention; and (2) studies that reported intervention effects on fatigue, sleep, or performance at work, and on measures of attention or cognitive performance (as they relate to the impact of shift working on patient safety/care). Results The search identified 798 potentially relevant articles, out of which 32 met our inclusion criteria. There were 8619 participants across the included studies and all were nurses (88.6% female). We did not find any studies conducted in midwives nor any studies conducted in the UK, with most studies conducted in the US, Italy and Taiwan. There was heterogeneity both in terms of the interventions evaluated and the measures used to assess effectiveness. Napping could be beneficial but there was wide variation regarding nap duration and timing, and we need to understand more about barriers to implementation. Longer shifts, shift patterns including nights, and inadequate recovery time between shifts (quick returns) were associated with poorer sleep, increased sleepiness and increased levels of fatigue. Light exposure and/or light attenuation interventions showed promise but the literature was dominated by small, potentially unrepresentative samples. Conclusions The literature related to sleep-related/fatigue-management interventions for nurses and midwives is fragmented and lacks cohesion. Further empirical work is warranted with a view to developing comprehensive Fatigue Risk Management Systems to protect against fatigue in nurses, midwives, and other shift working healthcare staff.

      Cheryl Isherwood, M. Denise Robertson, Debra Jean Skene, Jonathan D. Johnston (2023)Daily rhythms of diabetogenic factors in men: role of type 2 diabetes and body weight, In: Endocrine Connections12(11)e230064 BioScientifica

      Obesity is a major cause of type 2 diabetes. Transition from obesity to type 2 diabetes manifests in the dysregulation of hormones controlling glucose homeostasis and inflammation. As metabolism is a dynamic process that changes across 24 h, we assessed diurnal rhythmicity in a panel of 10 diabetes-related hormones. Plasma hormones were analysed every 2 h over 24 h in a controlled laboratory study with hourly isocaloric drinks during wake. To separate effects of body mass from type 2 diabetes, we recruited three groups of middle-aged men: an overweight (OW) group with type 2 diabetes and two control groups (lean and OW). Average daily concentrations of glucose, triacylglycerol and all the hormones except visfatin were significantly higher in the OW group compared to the lean group (P < 0.001). In type 2 diabetes, glucose, insulin, C-peptide, glucose-dependent insulinotropic peptide and glucagon-like peptide-1 increased further (P < 0.05), whereas triacylglycerol, ghrelin and plasminogen activator inhibitor-1 concentrations were significantly lower compared to the OW group (P < 0.001). Insulin, C-peptide, glucose-dependent insulinotropic peptide and leptin exhibited significant diurnal rhythms in all study groups (P < 0.05). Other hormones were only rhythmic in 1 or 2 groups. In every group, hormones associated with glucose regulation (insulin, C-peptide, glucose-dependent insulinotropic peptide, ghrelin and plasminogen activator inhibitor-1), triacylglycerol and glucose peaked in the afternoon, whereas glucagon and hormones associated with appetite and inflammation peaked at night. Thus being OW with or without type 2 diabetes significantly affected hormone concentrations but did not affect the timing of the hormonal rhythms.

      Anna Wirz-Justice, Debra J Skene, Mirjam Münch (2020)The relevance of daylight for humans, In: Biochemical pharmacology114304 Elsevier Inc

      Daylight is ubiquitous and is crucial for mammalian vision as well as for non-visual input to the brain via the intrinsically photosensitive retinal ganglion cells (ipRGCs) that express the photopigment melanopsin. The ipRGCs project to the circadian clock in the suprachiasmatic nuclei and thereby ensure entrainment to the 24-hour day-night cycle, and changes in daylength trigger the appropriate seasonal behaviours. The ipRGCs also project to the perihabenular nucleus and surrounding brain regions that modulate mood, stress and learning in animals and humans. Given that light has strong direct effects on mood, cognition, alertness, performance, and sleep, light can be considered a “drug” to treat many clinical conditions. Light therapy is already well established for winter and other depressions and circadian sleep disorders. Beyond visual and non-visual effects via the retina, daylight contributes to prevent myopia in the young by its impact on eye development, and is important for Vitamin D synthesis and bone health via the skin. The sun is the most powerful light source and, dependent on dose, its ultraviolet radiance is toxic for living organisms and can be used as a disinfectant. Most research involves laboratory-based electric light, without the dynamic and spectral changes that daylight undergoes moment by moment. There is a gap between the importance of daylight for human beings and the amount of research being done on this subject. Daylight is taken for granted as an environmental factor, to be enjoyed or avoided, according to conditions. More daylight awareness in architecture and urban design beyond aesthetic values and visual comfort may lead to higher quality work and living environments. Although we do not yet have a factual basis for the assumption that natural daylight is overall “better” than electric light, the environmental debate mandates serious consideration of sunlight not just for solar power but also as biologically necessary for sustainable and healthy living.

      Juliane Hannemann, Anika Laing, Benita Middleton, Edzard Schwedhelm, Nikolaus Marx, Massimo Federici, Mariola Kastner, Debra J Skene, Rainer Böger (2024)Effect of oral melatonin treatment on insulin resistance and diurnal blood pressure variability in night shift workers. A double-blind, randomized, placebo-controlled study, In: Pharmacological research199

      BACKGROUNDNight shift work is associated with sleep disturbances, obesity, and cardiometabolic diseases. Disruption of the circadian clock system has been suggested to be an independent cause of type 2 diabetes and cardiovascular disease in shift workers. We aimed to improve alignment of circadian timing with social and environmental factors with administration of melatonin.METHODSIn a randomized, placebo-controlled, prospective study, we analysed the effects of 2mg of sustained-release melatonin versus placebo on glucose tolerance, insulin resistance indices, sleep quality, circadian profiles of plasma melatonin and cortisol, and diurnal blood pressure profiles in 24 rotating night shift workers during 12 weeks of treatment, followed by 12 weeks of wash-out. In a novel design, the time of melatonin administration (at night or in the morning) depended upon the shift schedule. We also compared the baseline profiles of the night shift (NS) workers with 12 healthy non-night shift (NNS)-working controls.RESULTSWe found significantly impaired indices of insulin resistance at baseline in NS versus NNS (p < 0.05), but no differences in oral glucose tolerance tests nor in the diurnal profiles of melatonin, cortisol, or blood pressure. Twelve weeks of melatonin treatment did not significantly improve insulin resistance, nor did it significantly affect diurnal blood pressure or melatonin and cortisol profiles. Melatonin administration, however, caused a significant improvement in sleep quality which was significantly impaired in NS versus NNS at baseline (p < 0.001).CONCLUSIONSRotating night shift work causes mild-to-moderate impairment of sleep quality and insulin resistance. Melatonin treatment at bedtime improves sleep quality, but does not significantly affect insulin resistance in rotating night shift workers after 12 weeks of administration.

      Kimberley F Prior, Benita Middleton, Alíz T.Y Owolabi, Mary L Westwood, Jacob Holland, Aidan J O'Donnell, Michael J Blackman, Debra J Skene, Sarah E Reece (2021)Synchrony between daily rhythms of malaria parasites and hosts is driven by an essential amino acid, In: Wellcome Open Research6186

      Background: Rapid asexual replication of blood stage malaria parasites is responsible for the severity of disease symptoms and fuels the production of transmission forms. Here, we demonstrate that a Plasmodium chabaudi’s schedule for asexual replication can be orchestrated by isoleucine, a metabolite provided to the parasite in a periodic manner due to the host’s rhythmic intake of food. Methods: We infect female C57BL/6 and Per1/2-null mice which have a disrupted canonical (transcription translation feedback loop, TTFL) clock with 1×105 red blood cells containing P. chabaudi (DK genotype). We perturb the timing of rhythms in asexual replication and host feeding-fasting cycles to identify nutrients with rhythms that match all combinations of host and parasite rhythms. We then test whether perturbing the availability of the best candidate nutrient in vitro changes the schedule for asexual development. Results: Our large-scale metabolomics experiment and follow up experiments reveal that only one metabolite - the amino acid isoleucine – fits criteria for a time-of-day cue used by parasites to set the schedule for replication. The response to isoleucine is a parasite strategy rather than solely the consequences of a constraint imposed by host rhythms, because unlike when parasites are deprived of other essential nutrients, they suffer no apparent costs from isoleucine withdrawal. Conclusions: Overall, our data suggest parasites can use the daily rhythmicity of blood-isoleucine concentration to synchronise asexual development with the availability of isoleucine, and potentially other resources, that arrive in the blood in a periodic manner due to the host’s daily feeding-fasting cycle. Identifying both how and why parasites keep time opens avenues for interventions; interfering with the parasite’s time-keeping mechanism may stall replication, increasing the efficacy of drugs and immune responses, and could also prevent parasites from entering dormancy to tolerate drugs.

      Steven W. Lockley, Josephine Arendt, Debra J. Skene (2017)Visual Impairment and Circadian Rhythm Sleep Disorders, In: Reference Module in Neuroscience and Biobehavioral Psychologypp. 428-437 Elsevier Inc

      Many aspects of human physiology, metabolism, and behavior are dominated by 24-h circadian rhythms including the sleep–wake cycle, alertness and performance patterns, and some hormones. These rhythms are spontaneously generated by an internal circadian clock in the brain and daily light exposure to the eyes synchronizes the clock with the external environment. Most blind people with no perception of light, however, experience continual circadian desynchrony through a failure of light information to reach the circadian pacemaker, resulting in non-24-h sleep–wake disorder. Daily melatonin administration, which provides a replacement synchronizing daily “time cue,” is a promising therapeutic strategy to treat this disorder.

      S.W. Lockley, D.J. Skene (2013)Visual impairment and circadian rhythm sleep disorders, In: Encyclopedia of Sleep and Circadian Rhythmspp. 450-459 Elsevier
      Roberta Bonomo, Annalisa Canta, Alessia Chiorazzi, Valentina Alda Carozzi, Cristina Meregalli, Eleonora Pozzi, Paola Alberti, Cecile F Frampas, Daan R Van der Veen, Paola Marmiroli, Debra J Skene, Guido Cavaletti (2023)Effect of age on metabolomic changes in a model of paclitaxel-induced peripheral neurotoxicity, In: Journal of the peripheral nervous system

      Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most common dose-limiting side-effects of paclitaxel (PTX) treatment. Many age-related changes have been hypothesized to underlie susceptibility to damage or impaired regeneration/repair after nerve injury. The results of these studies, however, are inconclusive and other potential biomarkers of nerve impairment need to be investigated. Twenty-four young (2 months) and 24 adult (9 months) Wistar male rats were randomized to either PTX treatment (10 mg/kg i.v. once/week for 4 weeks) or vehicle administration. Neurophysiological and behavioral tests were performed at baseline, after 4 weeks of treatment and 2-week follow-up. Skin biopsies and nerve specimens collected from sacrificed animals were examined for intraepidermal nerve fiber (IENF) density assessment and nerve morphology/morphometry. Blood and liver samples were collected for targeted metabolomics analysis. At the end of treatment, the neurophysiological studies revealed a reduction in sensory nerve action potential amplitude (p 

      Michael E. Hughes, Katherine C. Abruzzi, Ravi Allada, Ron Anafi, Alaaddin Bulak Arpat, Gad Asher, Pierre Baldi, Charissa de Bekker, Deborah Bell-Pedersen, Justin Blau, Steve Brown, M. Fernanda Ceriani, Zheng Chen, Joanna C. Chiu, Juergen Cox, Alexander M. Crowell, Jason P. DeBruyne, Derk-Jan Dijk, Luciano DiTacchio, Francis J. Doyle, Giles E. Duffield, Jay C. Dunlap, Kristin Eckel-Mahan, Karyn A. Esser, Garret A. FitzGerald, Daniel B. Forger, Lauren J. Francey, Ying-Hui Fu, Frédéric Gachon, David Gatfield, Paul de Goede, Susan S. Golden, Carla Green, John Harer, Stacey Harmer, Jeff Haspel, Michael H. Hastings, Hanspeter Herzel, Erik D. Herzog, Christy Hoffmann, Christian Hong, Jacob J. Hughey, Jennifer M. Hurley, Horacio O. de la Iglesia, Carl Johnson, Steve A. Kay, Nobuya Koike, Karl Kornacker, Achim Kramer, Katja Lamia, Tanya Leise, Scott A. Lewis, Jiajia Li, Xiaodong Li, Andrew C. Liu, Jennifer J. Loros, Tami A. Martino, Jerome S. Menet, Martha Merrow, Andrew J. Millar, Todd Mockler, Felix Naef, Emi Nagoshi, Michael N. Nitabach, Maria Olmedo, Dmitri A. Nusinow, Louis J. Ptáček, David Rand, Akhilesh B. Reddy, Maria S. Robles, Till Roenneberg, Michael Rosbash, Marc D. Ruben, Samuel S.C. Rund, Aziz Sancar, Paolo Sassone-Corsi, Amita Sehgal, Scott Sherrill-Mix, Debra Skene, Kai-Florian Storch, Joseph S. Takahashi, Hiroki R. Ueda, Han Wang, Charles Weitz, Pål O. Westermark, Herman Wijnen, Ying Xu, Gang Wu, Seung-Hee Yoo, Michael Young, Eric Erquan Zhang, Tomasz Zielinski, John B. Hogenesch (2017)Guidelines for Genome-Scale Analysis of Biological Rhythms, In: Journal of Biological Rhythms32(5)pp. 380-393 SAGE Publications

      Genome biology approaches have made enormous contributions to our understanding of biological rhythms, particularly in identifying outputs of the clock, including RNAs, proteins, and metabolites, whose abundance oscillates throughout the day. These methods hold significant promise for future discovery, particularly when combined with computational modeling. However, genome-scale experiments are costly and laborious, yielding “big data” that are conceptually and statistically difficult to analyze. There is no obvious consensus regarding design or analysis. Here we discuss the relevant technical considerations to generate reproducible, statistically sound, and broadly useful genome-scale data. Rather than suggest a set of rigid rules, we aim to codify principles by which investigators, reviewers, and readers of the primary literature can evaluate the suitability of different experimental designs for measuring different aspects of biological rhythms. We introduce CircaInSilico, a web-based application for generating synthetic genome biology data to benchmark statistical methods for studying biological rhythms. Finally, we discuss several unmet analytical needs, including applications to clinical medicine, and suggest productive avenues to address them.

      Edward A. Hayter, Sophie M. T. Wehrens, Hans P. A. Van Dongen, Alessandra Stangherlin, Shobhan Gaddameedhi, Elena Crooks, Nichola J. Barron, Luigi A. Venetucci, John S. O’Neill, Timothy M. Brown, Debra J. Skene, Andrew W. Trafford, David A. Bechtold (2021)Author Correction: Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia, In: Nature communications12(1)7284pp. 7284-7284 Nature Publishing Group UK
      Elise R Facer-Childs, Benita Middleton, Andrew P Bagshaw, Debra J Skene (2020)Human Circadian Phenotyping and Diurnal Performance Testing in the Real World, In: Journal of visualized experiments2020(158)e60448

      In our continuously developing 'around the clock' society, there is a need to increase our understanding of how changes in biology, physiology and psychology influence our health and performance. Embedded within this challenge, is the increasing need to account for individual differences in sleep and circadian rhythms, as well as to explore the impact of time of day on performance in the real world. There are a number of ways to measure sleep and circadian rhythms from subjective questionnaire-based methods to objective sleep/wake monitoring, actigraphy and analysis of biological samples. This paper proposes a protocol that combines multiple techniques to categorize individuals into Early, Intermediate or Late circadian phenotype groups (ECPs/ICPs/LCPs) and recommends how to conduct diurnal performance testing in the field. Representative results show large differences in rest-activity patterns derived from actigraphy, circadian phase (dim light melatonin onset and peak time of cortisol awakening response) between circadian phenotypes. In addition, significant differences in diurnal performance rhythms between ECPs and LCPs emphasizes the need to account for circadian phenotype. In summary, despite the difficulties in controlling influencing factors, this protocol allows a real-world assessment of the impact of circadian phenotype on performance. This paper presents a simple method to assess circadian phenotype in the field and supports the need to consider time of day when designing performance studies.

      Isaiah Joseph Ting, Andreas Psomas, Debra J. Skene, Daan R. van der Veen (2023)Reduced glucose concentration enhances ultradian rhythms in Pdcd5 promoter activity in vitro, In: Frontiers in Physiology Frontiers

      Intrinsically driven ultradian rhythms in the hourly range are often co-expressed with circadian rhythms in various physiological processes including metabolic processes such as feeding behaviour, gene expression and cellular metabolism. Several behavioural observations show that reduced energy intake or increased energy expenditure leads to a re-balancing of ultradian and circadian timing, favouring ultradian feeding and activity patterns when energy availability is limited. This suggests a close link between ultradian rhythmicity and metabolic homeostasis, but we currently lack models to test this hypothesis at a cellular level. We therefore transduced 3T3-L1 pre-adipocyte cells with a reporter construct that drives a destabilised luciferase via the Pdcd5 promotor, a gene we previously showed to exhibit robust ultradian rhythms in vitro. Ultradian rhythmicity in Pdcd5 promotor driven bioluminescence was observed in > 80% of all cultures that were synchronised with dexamethasone, whereas significantly lower numbers exhibited ultradian rhythmicity in non-synchronised cultures (~11%). Cosine fits to ultradian bioluminescence rhythms in cells cultured and measured in low glucose concentrations (2 mM and 5 mM), exhibited significantly higher amplitudes than all other cultures, and a shorter period (6.9 h vs. 8.2 h, N = 12). Our findings show substantial ultradian rhythmicity in Pdcd5 promotor activity in cells in which the circadian clocks have been synchronised in vitro, which is in line with observations of circadian synchronisation of behavioural ultradian rhythms. Critically, we show that the amplitude of ultradian rhythms is enhanced in low glucose conditions, suggesting that low energy availability enhances ultradian rhythmicity at the cellular level in vitro.

      Tom Woelders, Victoria Louise Revell, Benita Middleton, Katrin Ackermann, Manfred Kayser, Florence I. Raynaud, Debra Jean Skene, Roelof A. Hut (2023)Machine learning estimation of human body time using metabolomic profiling, In: Proceedings of the National Academy of Sciences of the United States of America120(18)e2212685120 National Academy of Sciences

      Circadian rhythms influence physiology, metabolism, and molecular processes in the human body. Estimation of individual body time (circadian phase) is therefore highly relevant for individual optimization of behavior (sleep, meals, sports), diagnostic sampling, medical treatment, and for treatment of circadian rhythm disorders. Here, we provide a partial least squares regression (PLSR) machine learning approach that uses plasma-derived metabolomics data in one or more samples to estimate dim light melatonin onset (DLMO) as a proxy for circadian phase of the human body. For this purpose, our protocol was aimed to stay close to real-life conditions. We found that a metabolomics approach optimized for either women or men under entrained conditions performed equally well or better than existing approaches using more labor-intensive RNA sequencing-based methods. Although estimation of circadian body time using blood-targeted metabolomics requires further validation in shift work and other real-world conditions, it currently may offer a robust, feasible technique with relatively high accuracy to aid personalized optimization of behavior and clinical treatment after appropriate validation in patient populations.

      JF Walters, SM Hampton, GAA Ferns, DJ Skene (2005)Effect of menopause on melatonin and alertness rhythms investigated in constant routine conditions, In: CHRONOBIOLOGY INTERNATIONAL22(5)pp. 859-872 TAYLOR & FRANCIS INC
      Claudia R.C Moreno, Kenneth P. Wright, DEBRA JEAN SKENE, Fernando Mazzilli Louzada (2020)Phenotypic plasticity of circadian entrainment under a range of light conditions, In: Neurobiology of Sleep and Circadian Rhythms Elsevier

      The response to a zeitgeber, particularly the light/dark cycle, may vary phenotypically. Phenotypic plasticity can be defined as the ability of one genome to express different phenotypes in response to environmental variation. In this opinion paper, we present some evidence that one of the most prominent effects of the introduction of electric light to the everyday life of humans is a significant increase in phenotypic plasticity and differences in interindividual phases of entrainment. We propose that the healthy limits of phenotypic plasticity have been surpassed in contemporary society.

      Skevoulla Christou, Sophie M T Wehrens, Cheryl Isherwood, Carla S Moller-Levet, Huihai Wu, Victoria L Revell, Giselda Bucca, Debra J Skene, Emma E Laing, Simon N Archer, Jonathan D Johnston (2019)Circadian regulation in human white adipose tissue revealed by transcriptome and metabolic network analysis, In: Scientific Reports Nature Research

      Studying circadian rhythms in most human tissues is hampered by difficulty in collecting serial samples. Here we reveal circadian rhythms in the transcriptome and metabolic pathways of human white adipose tissue. Subcutaneous adipose tissue was taken from seven healthy males under highly controlled ‘constant routine’ conditions. Five biopsies per participant were taken at six-hourly intervals for microarray analysis and in silico integrative metabolic modelling. We identified 837 transcripts exhibiting circadian expression profiles (2% of 41619 transcript targeting probes on the array), with clear separation of transcripts peaking in the morning (258 probes) and evening (579 probes). There was only partial overlap of our rhythmic transcripts with published animal adipose and human blood transcriptome data. Morning-peaking transcripts associated with regulation of gene expression, nitrogen compound metabolism, and nucleic acid biology; evening-peaking transcripts associated with organic acid metabolism, cofactor metabolism and redox activity. In silico pathway analysis further indicated circadian regulation of lipid and nucleic acid metabolism; it also predicted circadian variation in key metabolic pathways such as the citric acid cycle and branched chain amino acid degradation. In summary, in vivo circadian rhythms exist in multiple adipose metabolic pathways, including those involved in lipid metabolism, and core aspects of cellular biochemistry.

      P.A. Nehme, F.G. Amaral, B. Middleton, A. Lowden, E. Marqueze, I. França-Junior, J.L.F. Antunes, J. Cipolla-Neto, D.J Skene, C.R.C. Moreno (2019)Melatonin profiles during the third trimester of pregnancy and health status in the offspring among day and night workers: A case series, In: Neurobiology of Sleep and Circadian Rhythms6pp. 70-76 Elsevier Inc.

      Successful pregnancy requires adaptation in maternal physiology. During intrauterine life the mother's circadian timing system supports successful birth and postnatal development. Maternal melatonin is important to transmit circadian timing and day length to the fetus. This study aims to describe the third trimester of pregnancy among day (n = 5) and night (n = 3) workers by assessing their melatonin levels in a natural environment. Additionally, we describe the worker's metabolic profiles and compare the health status of the newborns between groups of day and night working mothers. Our results indicate an occurrence of assisted delivery (caesarean and forceps) among night workers. Moreover, the newborns of night workers showed lower Apgar index and breastfeeding difficulty indicating a worse condition to deal with the immediate outside the womb environment.Additionally, there was lower night-time melatonin production among pregnant night workers compared to day workers. These findings may be related to light-induced suppression of melatonin that occurs during night work. We conclude that night work and consequent exposure to light at unconventional times might compromise the success of pregnancy and the health of the newborn. Further studies need to be carried out to monitor pregnancy and newborn health in pregnant night workers.

      Dawn Querstret, Katie O'Brien, Debra Skene, Jill Maben (2020)Improving fatigue risk management in healthcare: A systematic scoping review of sleep-related/fatigue-management interventions for nurses and midwives, In: International Journal of Nursing Studies

      Nurses and midwives make up almost 50% of the global healthcare shift working workforce. Shift work interferes with sleep and causes fatigue with adverse effects for nurses’ and midwives’ health, as well as on patient safety and care. Where other safety-critical sectors have developed Fatigue Risk Management Systems, healthcare is behind the curve; with published literature only focussing on the evaluation of discreet sleep-related/fatigue-management interventions. Little is known, however, about which interventions have been evaluated for nurses and midwives. Our review is a critical first step to building the evidence-base for healthcare organisations seeking to address this important operational issue.

      Elise Facer-Childs, Benita Middleton, Andrew P. Bagshaw, Debra J. Skene (2019)Methods for Human Circadian Phenotyping and Diurnal Performance Testing in the Real World, In: Journal of Visualized Experiments Journal of Visualized Experiments (JoVE)

      In our continuously developing 'around the clock' society, there is a need to increase our understanding of how changes in biology, physiology and psychology influence our health and performance. Embedded within this challenge, is the increasing need to account for individual differences in sleep and circadian rhythms, as well as to explore the impact of time of day on performance in the real world. There are a number of ways to measure sleep and circadian rhythms from subjective questionnaire-based methods to objective sleep/wake monitoring, actigraphy and analysis of biological samples. This paper proposes a protocol that combines multiple techniques to categorize individuals into Early, Intermediate or Late circadian phenotype groups (ECPs/ICPs/LCPs) and recommends how to conduct diurnal performance testing in the field. Representative results show large differences in rest-activity patterns derived from actigraphy, circadian phase (dim light melatonin onset and peak time of cortisol awakening response) between circadian phenotypes. In addition, significant differences in diurnal performance rhythms between ECPs and LCPs emphasizes the need to account for circadian phenotype. In summary, despite the difficulties in controlling influencing factors, this protocol allows a real-world assessment of the impact of circadian phenotype on performance. This paper presents a simple method to assess circadian phenotype in the field and supports the need to consider time of day when designing performance studies.

      Jefferson Souza Santos, Debra Jean Skene, Cibele Aparecida Crispim, Claudia Roberta de Castro Moreno (2023)Seasonal and Regional Differences in Eating Times in a Representative Sample of the Brazilian Population, In: Nutrients MDPI

      Human food intake and its timing are a complex behavior that can be influenced by a variety of factors, some of which may vary from season to season or from region to region. In this study, our aim was to investigate the seasonal variation in food intake times, with a particular focus on how these may vary across different regions of a country. We conducted an analysis of data from 20,622 adults from the National Household Budget Survey (POF-IBGE), encompassing complete food diaries collected from individuals residing in Brazil, and thereby ensuring representation across different latitudes. Each participant’s daily food intake was reported for two non-consecutive days at different times in the same week using food diaries. An ANOVA revealed a later food intake time in the evening in high-latitude regions compared to low-latitude regions. The Sidak post-hoc test showed a significant interaction effect between region and season, demonstrating a pattern of early First Intake Time and Eating Midpoint in the Northeast region during spring/summer. Additionally, we observed an independent effect of the region, as early food intake times were found in low-latitude regions. These findings offer a basis for discussing food intake times among individuals living in different regions located on distinct latitudes.

      VL Warman, DJ Dijk, GR Warman, J Arendt, DJ Skene (2003)Phase advancing human circadian rhythms with short wavelength light, In: NEUROSCIENCE LETTERS342(1-2)pp. 37-40 ELSEVIER SCI IRELAND LTD
      JB Zawilska, B Vivien-Roels, DJ Skene, P Pevet, JZ Nowak (2000)Phase-shifting effects of light on the circadian rhythms of 5-methoxytryptophol and melatonin in the chick pineal gland, In: JOURNAL OF PINEAL RESEARCH29(1)pp. 1-7 MUNKSGAARD INT PUBL LTD
      R Lucas, T Brown, SN Peirson, DM Berson, H Cooper, CA Czeisler, SW Lockley, MG Figueiro, PD Gamlin, JB O'Hagan, LLA Price, I Provencio, Debra Skene, GC Brainard (2013)Measuring and using light in the melanopsin age, In: Trends in Neurosciences37(1)pp. 1-9 Elsevier

      Light is a potent stimulus for regulating circadian, hormonal, and behavioral systems. In addition, light therapy is effective for certain affective disorders, sleep problems, and circadian rhythm disruption. These biological and behavioral effects of light are influenced by a distinct photoreceptor in the eye, melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), in addition to conventional rods and cones. We summarize the neurophysiology of this newly described sensory pathway and consider implications for the measurement, production, and application of light. A new light-measurement strategy taking account of the complex photoreceptive inputs to these non-visual responses is proposed for use by researchers, and simple suggestions for artificial/architectural lighting are provided for regulatory authorities, lighting manufacturers, designers, and engineers. © 2013 Elsevier Ltd.

      Circadian rhythms, near-24 h oscillations that reflect homeostatic control by an internal timing system rather than the influence of external factors, are an important and sometimes underappreciated aspect of human physiology and biochemistry. Over the past few decades, the pineal gland hormone melatonin has been established both as a robust marker of circadian phase in plasma or saliva, and as a chronobiotic drug administered to reset the timing of the circadian oscillator. Recent work by our own and other laboratories has sought to systematically investigate whole categories of molecular components in blood samples in a hypothesis-free fashion by employing metabolomic methodologies to study low-molecular-weight compounds and transcriptomic methodologies to study gene expression in white blood cells, respectively. A number of components have been pinpointed that show a rhythmic circadian variation or are affected by imposed factors such as sleep deprivation. Although melatonin, a robust and reliable circadian phase marker, will be a hard act to follow, these lines of research suggest numerous potential leads for useful new markers of biological timing.

      SW Lockley, D-J Dijk, O Kosti, DJ Skene, J Arendt (2008)Alertness, mood and performance rhythm disturbances associated with circadian sleep disorders in the blind, In: JOURNAL OF SLEEP RESEARCH17(2)pp. 207-216 WILEY-BLACKWELL
      Samantha Hopkins, Peter Lloyd Morgan, Luc J.M. Schlangen, Peter Williams, Debra Skene, Benita Middleton (2017)Blue-enriched Lighting for Older People Living in Care Homes: Effect on Activity, Actigraphic Sleep, Mood and Alertness, In: Current Alzheimer Research14(10)pp. 1053-1062 Bentham Science Publishers

      Objective: Environmental (little outdoor light; low indoor lighting) and age-related physiological factors (reduced light transmission through the ocular lens, reduced mobility) contribute to a light-deprived environment for older people living in care homes. Methods: This study investigates the effect of increasing indoor light levels with blue-enriched white lighting on objective (rest-activity rhythms, performance) and self-reported (mood, sleep, alertness) measures in older people. Eighty residents (69 female), aged 86 ± 8 yrs (mean ± SD), participated (MMSE 19 ± 6). Overhead fluorescent lighting was installed in communal rooms (n=20) of seven care homes. Four weeks of blue-enriched white lighting (17000 K ≅ 900 lux) were compared with four weeks of control white lighting (4000 K ≅ 200 lux), separated by three weeks wash-out. Participants completed validated mood and sleep questionnaires, psychomotor vigilance task (PVT) and wore activity and light monitors (AWL). Rest-activity rhythms were assessed by cosinor, non-parametric circadian rhythm (NPCRA) and actigraphic sleep analysis. Blue-enriched (17000 K) light increased wake time and activity during sleep decreasing actual sleep time, sleep percentage and sleep efficiency (p < 0.05) (actigraphic sleep). Compared to 4000 K lighting, blue-enriched 17000 K lighting significantly (p < 0.05) advanced the timing of participants’ rest-activity rhythm (cosinor), increased daytime and night-time activity (NPCRA), reduced subjective anxiety (HADA) and sleep quality (PSQI). There was no difference between the two light conditions in daytime alertness and performance (PVT). Conclusion: Blue-enriched lighting produced some positive (increased daytime activity, reduced anxiety) and negative (increased night-time activity, reduced sleep efficiency and quality) effects in older people.

      DJ Skene, J Arendt (2007)Circadian rhythm sleep disorders in the blind and their treatment with melatonin, In: SLEEP MEDICINE8(6)pp. 651-655 ELSEVIER SCIENCE BV
      A Dzaja, S Arber, J Hislop, M Kerkhofs, C Kopp, T Pollmacher, P Polo-Kantola, DJ Skene, P Stenuit, I Tobler, T Porkka-Heiskanen (2005)Women's sleep in health and disease, In: JOURNAL OF PSYCHIATRIC RESEARCH39(1)pp. 55-76 PERGAMON-ELSEVIER SCIENCE LTD
      VL Revell, DJ Skene (2007)Light-induced melatonin suppression in humans with polychromatic and monochromatic light, In: CHRONOBIOLOGY INTERNATIONAL24(6)pp. 1125-1137 TAYLOR & FRANCIS INC
      RE Mistlberger, DJ Skene (2004)Social influences on mammalian circadian rhythms: animal and human studies, In: BIOLOGICAL REVIEWS79(3)pp. 533-556 CAMBRIDGE UNIV PRESS
      Cheryl Isherwood, Daan R. van der Veen, Jonathan Johnston, Debra Skene (2017)Twenty-four-hour rhythmicity of circulatingmetabolites: effect of body mass and type 2 diabetes, In: FASEB journal31(12)pp. 5557-5567 Federation of American Society of Experimental Biology

      Metabolic profiling of individuals with type 2 diabetes mellitus (T2DM) has previously been limited to single-time-point samples, ignoring time-of-day variation. Here, we tested our hypothesis that body mass and T2DM affect daily rhythmicity and concentrations of circulating metabolites across a 24-h day in 3 age-matched, male groups—lean, overweight/obese (OW/OB), and OW/OB with T2DM—in controlled laboratory conditions, which were not confounded by large meals. By using targeted liquid chromatography/mass spectrometry metabolomics, we quantified 130 plasma metabolites every 2 h over 24 h, and we show that average metabolite concentrations were significantly altered by increased body mass (90 of 130) and T2DM (56 of 130). Thirty-eight percent of metabolites exhibited daily rhythms in at least 1 study group, and where a metabolite was rhythmic in >1 group, its peak time was comparable. The optimal time of day was assessed to provide discriminating biomarkers. This differed between metabolite classes and study groups—for example, phospholipids showed maximal difference at 5:00 AM (lean vs. OW/OB) and at 5:00 PM (OW/OB vs. T2DM). Metabolites that were identified with both robust 24-h rhythms and significant concentration differences between study groups emphasize the importance of controlling the time of day for diagnosis and biomarker discovery, offering a significant improvement over current single sampling.—Isherwood, C. M., Van der Veen, D. R., Johnston, J. D., Skene, D. J. Twenty-four-hour rhythmicity of circulating metabolites: effect of body mass and type 2 diabetes. It is widely accepted that obesity is the main risk factor for type 2 diabetes mellitus (T2DM) (1). The progression from obesity to T2DM is largely a result of comorbidities, such as systemic inflammation and insulin resistance. Metabolic profiling by using targeted metabolomics, which enables the quantification of more than 100 low-MW intermediates of metabolism, is increasingly used to characterize (pre)diabetic phenotypes and has identified differences in metabolite profiles between those individuals who are obese and those with T2DM (2–5). Recent work by our group and others has shown a 24-h variation in the human metabolome in healthy individuals, analyzed by using a range of analytical platforms (6–12), which has demonstrated that an estimated 15–20% of the metabolome is rhythmic in blood (6, 7). Transgenic mice that carry targeted genetic manipulation of circadian clock genes also exhibit a phenotype that involves defective metabolism, and associations between the circadian timing system and metabolic responses have been reported in humans (13). Reviews of these studies, including the higher incidence of obesity, T2DM, and related disorders in shift workers, have recently been published (14, 15). Existing metabolomics studies in T2DM have been restricted to the analysis of single-time-point, mostly fasting, samples, which cannot characterize the effect of increased body mass and T2DM on rhythmic metabolites. Characterizing 24-h metabolite rhythms in T2DM compared with age- and body mass–matched controls may therefore provide novel insights into the etiology and progression of T2DM. Identification of the optimal time of day for blood sampling—when metabolite levels show the biggest difference between T2DM and controls—would also provide more discriminating diagnostic biomarkers, rather than taking a single morning fasting sample. We thus assessed the effect of increased body mass [overweight/obese (OW/OB)] and T2DM on 24-h rhythms of circulating metabolites in men by using a quantitative targeted liquid chromatography/mass spectrometry (LC/MS) metabolomics approach. As T2DM is often accompanied by obesity, we set out to distinguish the effects of T2DM from those of increased body mass by incorporating both a lean and an OW/OB control group into the current study design.

      LM Hack, SW Lockley, J Arendt, DJ Skene (2003)The effects of low-dose 0.5-mg melatonin on the free-running circadian rhythms of blind subjects, In: JOURNAL OF BIOLOGICAL RHYTHMS18(5)pp. 420-429 SAGE PUBLICATIONS LTD
      T Kantermann, F Duboutay, D Haubruge, M Kerkhofs, A Schmidt-Trucksäss, DJ Skene (2013)Atherosclerotic risk and social jetlag in rotating shift-workers: First evidence from a pilot study., In: Work IOS Press

      OBJECTIVE: The aim of this study was to identify atherosclerotic risk using pulse wave velocity (PWV) in steel workers employed in different shift-work rotations, and to elucidate its relationship to social jetlag and shift schedule details. PARTICIPANTS: Male workers in a steel factory (n=77, 32 fast clockwise (CW), 30 slow counterclockwise (CC), 15 day workers (DW); mean age 42 ± SD 7.6 yrs) with at least 5 years of experience in their current work schedule participated. METHODS: All workers completed questionnaires on demographics, health, psychotropic agents, sleep, social and work life, social jetlag (difference between mid-sleep time on workdays and days off used as a marker of circadian disruption) and chronotype (mid-sleep time on free days corrected for sleep deficit on workdays). In 63 workers we measured PWV, blood pressure (BP), heart rate (HR) between 08:00 and 12:30 h in controlled posture conditions (no caffeine/smoking/exercise). RESULTS: There was no significant difference in PWV (covariates: age, BP) between the different shift-rotations (CW, CC and DW). In all workers combined, HR and social jetlag were significantly positively correlated. Demographic variables did not differ between shift-workers and day workers; shift-workers (CW, CC) reported significantly more stomach upsets, digestion problems, weight fluctuations, and social jetlag. The CW and CC workers did not differ in ratings of how shift-work affected sleep, social and work life. CONCLUSIONS: PWV was not different between the two shift-rotations. This pilot study shows first evidence that HR is related to social jetlag, and therefore warrants more studies in different shift schedules.

      S Montagnese, B Middleton, DJ Skene, MY Morgan (2009)Sleep-wake patterns in patients with cirrhosis: All you need to know on a single sheet A simple sleep questionnaire for clinical use, In: JOURNAL OF HEPATOLOGY51(4)pp. 690-695 ELSEVIER SCIENCE BV
      Philipp S. Ritter, Bettina Soltmann, Cathrin Sauer, Abdulbaki Yakac, Lynn Boekstaegers, Mirjam Reichard, Konstanze Günther, Michael Bauer, Henry Güldner, Stefanie Neumann, Falk Wieland, DEBRA JEAN SKENE (2021)Supersensitivity of patients with Bipolar-I-Disorder to light-induced phase delay by Narrow Bandwidth Blue Light, In: Biological Psychiatry Global Open Science Elsevier
      FL Ruberg, DJ Skene, JP Hanifin, MD Rollag, J English, J Arendt, GC Brainard (1996)Melatonin regulation in humans with color vision deficiencies, In: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM81(8)pp. 2980-2985 ENDOCRINE SOC
      S Montagnese, B Middleton, AR Mani, DJ Skene, MY Morgan (2010)Melatonin Rhythms in Patients With Cirrhosis, In: AMERICAN JOURNAL OF GASTROENTEROLOGY105(1)pp. 220-222 NATURE PUBLISHING GROUP
      Elise R Facer-Childs, Brunno M Campos, Benita Middleton, Debra J Skene, Andrew P Bagshaw (2019)Circadian phenotype impacts the brain’s resting state functional connectivity, attentional performance and sleepiness, In: Sleep42(5)zsz033 Oxford University Press (OUP)

      INTRODUCTION Functional connectivity (FC) of the human brain’s intrinsically connected networks underpins cognitive functioning and disruptions of FC are associated with sleep and neurological disorders. However, there is limited research on the impact of circadian phenotype and time of day on FC. STUDY OBJECTIVES The aim of this study was to investigate resting state FC of the default mode network (DMN) in Early and Late circadian phenotypes over a socially constrained day. METHODS 38 healthy individuals (14 male, 22.7 ± 4.2 years) categorised as Early (n =16) or Late (n = 22) using the Munich ChronoType Questionnaire took part. Following a two week baseline of actigraphy coupled with saliva samples for melatonin and cortisol rhythms, participants underwent testing at 14.00 h, 20.00 h and 08.00 h the following morning. Testing consisted of resting state functional MRI, a structural T1 scan, attentional cognitive performance tasks and self-reported daytime sleepiness. Seed based FC analysis from the medial prefrontal and posterior cingulate cortices of the DMN was performed, compared between groups and linked with behavioural data. RESULTS Fundamental differences in the DMN were observed between Early and Late circadian phenotypes. Resting state FC of the DMN predicted individual differences in attention and subjective ratings of sleepiness. CONCLUSION Differences in FC of the DMN may underlie the compromised attentional performance and increased sleepiness commonly associated with Late types when they conform to a societally constrained day that does not match their intrinsic circadian phenotype.

      S Montagnese, B Middleton, DJ Skene, MY Morgan (2009)Night-time sleep disturbance does not correlate with neuropsychiatric impairment in patients with cirrhosis, In: LIVER INTERNATIONAL29(9)pp. 1372-1382 WILEY-BLACKWELL PUBLISHING, INC
      I Gogenur, B Kucukakin, T Bisgaard, V Kristiansen, N-C Hjorto, DJ Skene, J Rosenberg (2009)The Effect of Melatonin on Sleep Quality After Laparoscopic Cholecystectomy: A Randomized, Placebo-Controlled Trial, In: ANESTHESIA AND ANALGESIA108(4)pp. 1152-1156 LIPPINCOTT WILLIAMS & WILKINS
      J Dawson, J Boyle, N Stanley, S Johnsen, I Hindrnarch, DJ Skene (2008)Benzodiazepine-induced reduction in activity mirrors decrements in cognitive and psychomotor performance, In: HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL23(7)pp. 605-613 JOHN WILEY & SONS LTD
      E Lowson, Benita Middleton, Sara Arber, Debra Skene (2013)Effects of night work on sleep, cortisol and mood of female nurses, their husbands and children, In: Sleep and Biological Rhythms11(1)pp. 7-13 Wiley-Blackwell

      Negative impacts of night work on employees are well documented, but little is known about immediate consequences for family members. This study examines how night work within a rotating shift pattern affects the sleep, mood and cortisol levels of female nurses, their husbands and children. Participants included twenty nurses (42.7 ± 6.5 years), their husbands and children (n=34, 8-18 years) who completed sleep diaries, rated their sleep quality, alertness and mood daily, and collected saliva samples each morning and evening for 14 days. Comparisons were made between night work and other shifts (Wilcoxon Signed Ranks test); and between periods preceding, during and following night shifts (repeated measures ANOVA with Tukey posthoc tests). Nurses’ sleep after the final night shift was significantly shorter (3h 58 mins ± 46 mins) and ended significantly earlier (13:28 ± 0:48h) than after the first night shift (sleep duration 5h 17 mins ± 1h 36 mins; wake time 14:58 ± 1:41h) (p

      JB Zawilska, M Berezinska, J Rosiak, DJ Skene, B Vivien-Roels, JZ Nowak (2004)Suppression of melatonin biosynthesis in the chicken pineal gland by retinally perceived light - involvement of D1-dopamine receptors, In: JOURNAL OF PINEAL RESEARCH36(2)pp. 80-86 BLACKWELL MUNKSGAARD
      JB Zawilska, M Berezinska, J Rosiak, B Vivien-Roels, DJ Skene, P Pevet, JZ Nowak (2003)Daily variation in the concentration of melatonin and 5-methoxytryptophol in the goose pineal gland, retina, and plasma, In: GENERAL AND COMPARATIVE ENDOCRINOLOGY134(3)pp. 296-302 ACADEMIC PRESS INC ELSEVIER SCIENCE
      Till Roenneberg, Anna Wirz-Justice, Debra J. Skene, Sonia Ancoli-Israel, Kenneth P. Wright, Derk-Jan Dijk, Phyllis Zee, Michael R. Gorman, Eva C. Winnebeck, Elizabeth B. Klerman (2019)Why Should We Abolish Daylight Saving Time?, In: Journal of Biological Rhythms34(3)pp. 227-230 Sage Publications

      Local and national governments around the world are currently considering the elimination of the annual switch to and from Daylight Saving Time (DST). As an international organization of scientists dedicated to studying circadian and other biological rhythms, the Society for Research on Biological Rhythms (SRBR) engaged experts in the field to write a Position Paper on the consequences of choosing to live on DST or Standard Time (ST). The authors take the position that, based on comparisons of large populations living in DST or ST or on western versus eastern edges of time zones, the advantages of permanent ST outweigh switching to DST annually or permanently. Four peer reviewers provided expert critiques of the initial submission, and the SRBR Executive Board approved the revised manuscript as a Position Paper to help educate the public in their evaluation of current legislative actions to end DST.

      K Papantoniou, OJ Pozo, A Espinosa, J Marcos, G Castano-Vinyals, X Basagana, FC Ribas, J Mirabent, J Martin, G Carenys, CR Martin, B Middleton, DJ Skene, M Kogevinas (2014)Circadian Variation of Melatonin, Light Exposure, and Diurnal Preference in Day and Night Shift Workers of Both Sexes, In: CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION23(7)pp. 1176-1186 AMER ASSOC CANCER RESEARCH
      AU Viola, SN Archer, LM James, JA Groeger, JCY Lo, DJ Skene, M von Schantz, D-J Dijk (2007)PER3 polymorphism predicts sleep structure and waking performance, In: CURRENT BIOLOGY17(7)pp. 613-618 CELL PRESS
      DJ Skene, J Arendt (2006)Human circadian rhythms: physiological and therapeutic relevance of light and melatonin, In: ANNALS OF CLINICAL BIOCHEMISTRY43pp. 344-353 ROYAL SOC MEDICINE PRESS LTD
      JB Zawilska, DJ Skene, JZ Nowak (1998)5-Methoxytryptophol rhythms in the chick pineal gland: effect of environmental lighting conditions, In: NEUROSCIENCE LETTERS251(1)pp. 33-36 ELSEVIER SCI IRELAND LTD
      J Arendt, DJ Skene, B Middleton, SW Lockley, S Deacon (1997)Efficacy of melatonin treatment in jet lag, shift work, and blindness., In: Journal of Biological Rhythms12(6)pp. 604-617 Sage

      Melatonin has chronobiotic properties in humans. It is able to phase shift strongly endogenous rhythms, such as core temperature and its own endogenous rhythm, together with the sleep-wake cycle. Its ability to synchronize free-running rhythms has not been fully investigated in humans. There is evidence for synchronization of the sleep-wake cycle, but the available data suggest that it is less effective with regard to endogenous melatonin and core temperature rhythms. When suitably timed, most studies indicate that fast release preparations are able to hasten adaptation to phase shift in both field and simulation studies of jet lag and shift work. Both subjective and objective measures support this statement. However, not all studies have been successful. Careful evaluation of the effects on work-related performance is required. When used to alleviate the non-24-h sleep-wake disorder in blind subjects, again most studies report a successful outcome using behavioral measures, albeit in a small number of individuals. The pres suggest, however, that although leep-wake can be stabilized to 24 h, entrainment of other rhythms is exceptionally rare.

      JB Zawilska, M Berezinska, A Lorenc, DJ Skene, JZ Nowak (2004)Retinal illumination phase shifts the circadian rhythm of serotonin N-acetyltransferase activity in the chicken pineal gland, In: NEUROSCIENCE LETTERS360(3)pp. 153-156 ELSEVIER SCI IRELAND LTD
      A. Jennifer Morton, Benita Middleton, Skye Rudiger, C. Simon Bawden, Timothy R. Kuchel, Debra Skene (2020)Increased plasma melatonin in presymptomatic Huntington disease sheep ( Ovis aries ): Compensatory neuroprotection in a neurodegenerative disease?, In: Journal of Pineal Research68(2)e12624 Wiley

      Melatonin is a pleiotrophic hormone, synthesised primarily by the pineal gland under the control of the suprachiasmatic nuclei (SCN). It not only provides a hormonal signal of darkness but also has neuroprotective properties. Huntington's disease (HD) is a progressive neurodegenerative disorder characterised by abnormal motor, cognitive and psychiatric symptoms. There is growing evidence, particularly from animal models, that circadian rhythms may also be disturbed in HD. We measured two circadian‐regulated hormones, melatonin and cortisol, in plasma samples collected around‐the‐clock from normal and presymptomatic transgenic HD sheep (Ovis aries) at 5 and 7 years of age, to assess SCN‐driven rhythms and the effect of genotype, sex and age. Melatonin‐related precursors and metabolites (tryptophan, serotonin, kynurenine) were also measured by liquid chromatography (LC)‐mass spectrometry (MS). At 5 years of age in both rams and ewes, plasma melatonin levels were significantly elevated in HD sheep. In ewes measured 2 years later, there was still a significant elevation of nocturnal melatonin. Furthermore, the daytime baseline levels of melatonin were significantly higher in HD sheep. Since increased melatonin could have global beneficial effects on brain function, we suggest that the increased melatonin measured in presymptomatic HD sheep is part of an autoprotective response to mutant huntingtin toxicity that may account, at least in part, for the late onset of disease that characterises HD.

      DJ Skene, E Papagiannidou, E Hashemi, J Snelling, DFV Lewis, M Fernandez, C Ioannides (2001)Contribution of CYP1A2 in the hepatic metabolism of melatonin: studies with isolated microsomal preparations and liver slices, In: JOURNAL OF PINEAL RESEARCH31(4)pp. 333-342 MUNKSGAARD INT PUBL LTD
      SW Lockley, DJ Skene, H Tabandeh, AC Bird, R Defrance, J Arendt (1997)Relationship between napping and melatonin in the blind, In: JOURNAL OF BIOLOGICAL RHYTHMS12(1)pp. 16-25 SAGE PUBLICATIONS INC
      Sophie Wehrens, Skevoulla Christou, Cheryl Isherwood, Benita Middleton, Michelle Gibbs, Simon Archer, Debra Skene, Jonathan Johnston (2017)Meal Timing Regulates the Human Circadian System, In: Current Biology27(12)pp. 1768-1775e3 Elsevier (Cell Press)

      Circadian rhythms, metabolism and nutrition are intimately linked [1, 2], although effects of meal timing on the human circadian system are poorly understood. We investigated the effect of a 5-hour delay in meals on markers of the human master clock and multiple peripheral circadian rhythms. Ten healthy young men undertook a 13-day laboratory protocol. Three meals (breakfast, lunch, dinner) were given at 5-hour intervals, beginning either 0.5 (early) or 5.5 (late) hours after wake. Participants were acclimated to early meals and then switched to late meals for 6 days. After each meal schedule, participants' circadian rhythms were measured in a 37-hour constant routine that removes sleep and environmental rhythms while replacing meals with hourly isocaloric snacks. Meal timing did not alter actigraphic sleep parameters before circadian rhythm measurement. In constant routines, meal timing did not affect rhythms of subjective hunger and sleepiness, master clock markers (plasma melatonin and cortisol), plasma triglycerides, or clock gene expression in whole blood. Following late meals, however, plasma glucose rhythms were delayed by 5.69 ± 1.29 hours (p < 0.001) and average glucose concentration decreased by 0.27 ± 0.05 mM (p < 0.001). In adipose tissue, PER2 mRNA rhythms were delayed by 0.97 ± 0.29 hours (p < 0.01), indicating that human molecular clocks may be regulated by feeding time and could underpin plasma glucose changes. Timed meals therefore play a role in synchronising peripheral circadian rhythms in humans, and may have particular relevance for patients with circadian rhythm disorders, shift workers, and transmeridian travellers.

      JD Carpen, M von Schantz, M Smits, DJ Skene, SN Archer (2006)A silent polymorphism in the PER1 gene associates with extreme diurnal preference in humans, In: JOURNAL OF HUMAN GENETICS51(12)pp. 1122-1125 SPRINGER TOKYO
      Juliane Fagotti, Adriano D. S. Targa, Lais S. Rodrigues, Ana Carolina D. Noseda, Flávia W. C. Dorieux, Franciele F. Scarante, Jessica L. Ilkiw, Fernando M. Louzada, Namrata Chowdhury, Daan R. van der Veen, Benita Middleton, Jeroen L. A. Pennings, Jonathan R. Swann, Debra Skene, Marcelo M. S. Lima (2018)Chronic sleep restriction in the rotenone Parkinson’s disease model in rats reveals peripheral early-phase biomarkers, In: Scientific Reports9(1)1898 Springer Nature Publishing

      Parkinson’s disease (PD) is a chronic disorder that presents a range of premotor signs, such as sleep disturbances and cognitive decline, which are key non-motor features of the disease. Increasing evidence of a possible association between sleep disruption and the neurodegenerative process suggests that sleep impairment could produce a detectable metabolic signature on the disease. In order to integrate neurocognitive and metabolic parameters, we performed untargeted and targeted metabolic profiling of the rotenone PD model in a chronic sleep restriction (SR) (6 h/day for 21 days) condition. We found that SR combined with PD altered several behavioural (reversal of locomotor activity impairment; cognitive impairment; delay of rest-activity rhythm) and metabolic parameters (branched-chain amino acids, tryptophan pathway, phenylalanine, and lipoproteins, pointing to mitochondrial impairment). If combined, our results bring a plethora of parameters that represents reliable early-phase PD biomarkers which can easily be measured and could be translated to human studies.

      Erlend Sunde, Torhild Pedersen, Jelena Mrdalj, Eirunn Thun, Janne Grønli, Anette Harris, Bjørn Bjorvatn, Siri Waage, Debra Skene, Ståle Pallesen (2020)Blue-Enriched White Light Improves Performance but Not Subjective Alertness and Circadian Adaptation During Three Consecutive Simulated Night Shifts, In: Frontiers in Psychology112172 Frontiers Media

      Use of blue-enriched light has received increasing interest regarding its activating and performance sustaining effects. However, studies assessing effects of such light during night work are few, and novel strategies for lighting using light emitting diode (LED) technology need to be researched. In a counterbalanced crossover design, we investigated the effects of a standard polychromatic blue-enriched white light (7000 K; 200 lx) compared to a warm white light (2500 K), of similar photon density (1.6 1014 photons/cm2/s), during three consecutive simulated night shifts. A total of 30 healthy participants [10 males, mean age 23.3 (SD = 2.9) years] were included in the study. Dependent variables comprised subjective alertness using the Karolinska Sleepiness Scale, a psychomotor vigilance task (PVT) and a digit symbol substitution test (DSST), all administered at five time points throughout each night shift. We also assessed dim-light melatonin onset (DLMO) before and after the night shifts, as well as participants’ opinion of the light conditions. Subjective alertness and performance on the PVT and DSST deteriorated during the night shifts, but 7000 K light was more beneficial for performance, mainly in terms of fewer errors on the PVT, at the end of the first- and second- night shift, compared to 2500 K light. Blue-enriched light only had a minor impact on PVT response times (RTs), as only the fastest 10% of the RTs were significantly improved in 7000 K compared to 2500 K light. In both 7000 and 2500 K light, the DLMO was delayed in those participants with valid assessment of this parameter [n = 20 (69.0%) in 7000 K light, n = 22 (78.6%) in 2500 K light], with a mean of 2:34 (SE = 0:14) and 2:12 (SE = 0:14) hours, respectively, which was not significantly different between the light conditions. Both light conditions were positively rated, although participants found 7000 K to be more suitable for work yet evaluated 2500 K light as more pleasant. The data indicate minor, but beneficial, effects of 7000 K light compared to 2500 K light on performance during night work. Circadian adaptation did not differ significantly between light conditions, though caution should be taken when interpreting these findings due to missing data. Field studies are needed to investigate similar light interventions in real-life settings, to develop recommendations regarding illumination for night workers.

      DJ Skene, DF Swaab (2003)Melatonin rhythmicity: effect of age and Alzheimer's disease, In: EXPERIMENTAL GERONTOLOGY38(1-2)PII S0531-pp. 199-206 PERGAMON-ELSEVIER SCIENCE LTD
      H Tabandeh, SW Lockley, R Buttery, DJ Skene, R Defrance, J Arendt, AC Bird (1998)Disturbance of sleep in blindness, In: AMERICAN JOURNAL OF OPHTHALMOLOGY126(5)pp. 707-712 ELSEVIER SCIENCE INC
      JE Ang, V Revell, A Mann, S Mäntele, DT Otway, JD Johnston, AE Thumser, DJ Skene, F Raynaud (2012)Identification of Human Plasma Metabolites Exhibiting Time-of-Day Variation Using an Untargeted Liquid Chromatography-Mass Spectrometry Metabolomic Approach., In: Chronobiol Int29(7)pp. 868-881 Informa Healthcare

      Although daily rhythms regulate multiple aspects of human physiology, rhythmic control of the metabolome remains poorly understood. The primary objective of this proof-of-concept study was identification of metabolites in human plasma that exhibit significant 24-h variation. This was assessed via an untargeted metabolomic approach using liquid chromatography-mass spectrometry (LC-MS). Eight lean, healthy, and unmedicated men, mean age 53.6 (SD ± 6.0) yrs, maintained a fixed sleep/wake schedule and dietary regime for 1 wk at home prior to an adaptation night and followed by a 25-h experimental session in the laboratory where the light/dark cycle, sleep/wake, posture, and calorific intake were strictly controlled. Plasma samples from each individual at selected time points were prepared using liquid-phase extraction followed by reverse-phase LC coupled to quadrupole time-of-flight MS analysis in positive ionization mode. Time-of-day variation in the metabolites was screened for using orthogonal partial least square discrimination between selected time points of 10:00 vs. 22:00 h, 16:00 vs. 04:00 h, and 07:00 (d 1) vs. 16:00 h, as well as repeated-measures analysis of variance with time as an independent variable. Subsequently, cosinor analysis was performed on all the sampled time points across the 24-h day to assess for significant daily variation. In this study, analytical variability, assessed using known internal standards, was low with coefficients of variation

      T Kantermann, SM Wehrens, MA Ulhôa, C Moreno, DJ Skene (2012)Noisy and individual, but doable: shift-work research in humans., In: Prog Brain Res199pp. 399-411 Elsevier

      Working around the clock is common for many occupations, as diverse as nurses, truck drivers, physicians, steel workers, and pilots. Each shift-work profession is individual in more aspects than just work hours and individual work scenarios, each posing a different impact on the health of workers. Related health problems in shift workers, therefore, are also diverse and encompass sleep problems, metabolic and cardiovascular system disturbances, as well as cancer. Little is known about how all these individual factors influence a shift worker's health status, partly because many shift-work studies show inconsistent results. In addition, these individual factors create many methodological difficulties for researchers who investigate such work scenarios. This chapter presents examples from our laboratory and field studies of shift workers, which emphasize the importance of taking individual circumstances into account. Both study approaches, laboratory and field based, are needed to fully account for the difficulties that shift-work studies pose on both workers and researchers. Finally, understanding the mechanisms that underpin interindividual differences in response to shift work will advance our understanding of how to design better and healthier shift-work schedules in the future.

      S Marini, O Santangeli, P Saarelainen, Benita Middleton, Namrata Roy Chowdhury, Debra Skene, R Costa, T Porkka-Heiskanen, S Montagnese (2017)Abnormalities in the Polysomnographic, Adenosine and Metabolic Response to Sleep Deprivation in an Animal Model of Hyperammonemia, In: Frontiers in Physiology8636 Frontiers Media

      Patients with liver cirrhosis can develop hyperammonemia and hepatic encephalopathy (HE), accompanied by pronounced daytime sleepiness. Previous studies with healthy volunteers show that experimental increase in blood ammonium levels increases sleepiness and slows the waking EEG. As ammonium increases adenosine levels in vitro, and adenosine is a known regulator of sleep/wake homeostasis, we hypothesized that the sleepiness-inducing effect of ammonium is mediated by adenosine. Eight adult male Wistar rats were fed with an ammonium-enriched diet for 4 weeks; eight rats on standard diet served as controls. Each animal was implanted with electroencephalography/electromyography (EEG/EMG) electrodes and a microdialysis probe. Sleep EEG recording and cerebral microdialysis were carried out at baseline and after 6 hours of sleep deprivation. Adenosine and metabolite levels were measured by HPLC and targeted LC/MS metabolomics, respectively. Baseline adenosine and metabolite levels (12 of 16 amino acids, taurine, t4-hydroxy-proline and acetylcarnitine) were lower in hyperammonemic animals, while putrescine was higher. After sleep deprivation, hyperammonemic animals exhibited a larger increase in adenosine levels, and a number of metabolites showed a different time-course in the two groups. In both groups the recovery period was characterized by a significant decrease in wakefulness/increase in NREM and REM sleep. However, while control animals exhibited a gradual compensatory effect, hyperammonemic animals showed a significantly shorter recovery phase. In conclusion, the adenosine/metabolite/EEG response to sleep deprivation was modulated by hyperammonemia, suggesting that ammonia affects homeostatic sleep regulation and its metabolic correlates.

      DJ Skene, SW Lockley, K Thapan, J Arendt (1999)Effects of light on human circadian rhythms, In: REPRODUCTION NUTRITION DEVELOPMENT39(3)pp. 295-304 EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
      EE Flynn-Evans, H Tabandeh, DJ Skene, SW Lockley (2014)Circadian Rhythm Disorders and Melatonin Production in 127 Blind Women with and without Light Perception, In: JOURNAL OF BIOLOGICAL RHYTHMS29(3)pp. 215-224 SAGE PUBLICATIONS INC
      FM Fischer, S Puttonen, DJ Skene (2014)21st International Symposium on Shiftwork and Working Time: The 24/7 Society - From chronobiology to practical life INTRODUCTION, In: CHRONOBIOLOGY INTERNATIONAL31(10)pp. 1093-1099 INFORMA HEALTHCARE
      Andressa J. Martins, Cheryl M. Isherwood, Suleima P. Vasconcelos, Arne Lowden, DEBRA JEAN SKENE, Claudia R.C. Moreno (2020)The effect of urbanization on sleep, sleep/wake routine, and metabolic health of residents in the Amazon region of Brazil, In: Chronobiology Internationalpp. 1-9 International Society for Chronobiology

      Studying communities with different levels of urbanization may further the understanding of risk factors underlying metabolic diseases. The present study is unique by comprising detailed assessment of sleep and activity, biological rhythms, and metabolic factors of men from the same geographical location and place of birth that reside in different, rural vs. town, stages of urbanization. Sleep patterns, activity, and metabolic indicators in two groups (rural, n = 22 and town/urban, n = 20) of men residing in an Amazonian community (Xapuri, Acre, Brazil) were compared. Sociodemographic, anthropometric, and metabolic variables – fasting glucose, insulin resistance, triglycerides, total HDL cholesterol, LDL cholesterol, and VLDL cholesterol – were assessed. Sleep patterns, light exposure, and physical activity levels were additionally assessed by actigraphy, plus daily activities were recorded in diaries for 10 days. Town/urban dwellers were found to have significantly higher body weight, fasting glucose, insulin levels, and insulin resistance than rural dwellers, whereas triglycerides levels were similar. Town/Urban dwellers had shorter sleep duration (p < .01) and later sleep onset and offset times (p = .01). Our findings show an association between stage of urbanization and presence of risk factors for metabolic disorders, such as overweight, insulin resistance, increased glucose levels, short sleep duration, and less natural light exposure during work times.

      Alan Flanagan, Elizabeth Lowson, Sara Arber, Bruce A. Griffin, Debra J. Skene (2020)Dietary Patterns of Nurses on Rotational Shifts Are Marked by Redistribution of Energy into the Nightshift, In: Nutrients12(4) MDPI

      Nightshift work is associated with adverse health outcomes, which may be related to eating during the biological night, when circadian rhythms and food intake are misaligned. Nurses often undertake nightshift work, and we aimed to investigate patterns of energy distribution and dietary intake across 14 days in 20 UK National Health Service (NHS) nurses working rotational shifts. We hypothesised that the proportion of daily energy consumed during the nightshift would increase over consecutive nights. Primary and secondary outcome measures included intakes of energy and macronutrients. Our results show that nurses consumed the same total daily energy on nightshifts and non-nightshifts, but redistributed energy to the nightshift period in increasing proportions with a significant difference between Night 1 and 2 in the proportion of total daily energy consumed (26.0 ± 15.7% vs. 33.5 ± 20.2%, mean ± SD; p < 0.01). This finding indicates that, rather than increasing total energy intake, nurses redistribute energy consumed during nightshifts as a behavioural response to consecutive nightshifts. This finding informs our understanding of how the intake of energy during the biological night can influence adverse health outcomes of nightshift work.

      JB Zawilska, J Rosiak, B Vivien-Roels, DJ Skene, P Pevet, JZ Nowak (2002)Daily variation in the concentration of 5-methoxytryptophol and melatonin in the duck pineal gland and plasma, In: JOURNAL OF PINEAL RESEARCH32(4)pp. 214-218 BLACKWELL MUNKSGAARD
      GDM Potter, DJ Skene, J Arendt, JE Cade, PJ Grant, LJ Hardie (2016)Circadian Rhythm and Sleep Disruption: Causes Metabolic Consequences and Countermeasures, In: Endocrine Reviews37(6) Endocrine Society

      Circadian (∼24-hour) timing systems pervade all kingdoms of life and temporally optimize behavior and physiology in humans. Relatively recent changes to our environments, such as the introduction of artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behavior and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these, too, are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioral and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important.

      T Penzel, D Pevernagie, Z Dogas, L Grote, S de Lacy, A Rodenbeck, C Bassetti, S Berg, F Cirignotta, MP d'Ortho, D Garcia-Borreguero, P Levy, L Nobili, T Paiva, P Peigneux, T Pollmächer, D Riemann, DJ Skene, M Zucconi, C Espie (2014)Catalogue of knowledge and skills for sleep medicine, In: Journal of Sleep Research23(2)pp. 222-238

      Summmary: Sleep medicine is evolving globally into a medical subspeciality in its own right, and in parallel, behavioural sleep medicine and sleep technology are expanding rapidly. Educational programmes are being implemented at different levels in many European countries. However, these programmes would benefit from a common, interdisciplinary curriculum. This 'catalogue of knowledge and skills' for sleep medicine is proposed, therefore, as a template for developing more standardized curricula across Europe. The Board and The Sleep Medicine Committee of the European Sleep Research Society (ESRS) have compiled the catalogue based on textbooks, standard of practice publications, systematic reviews and professional experience, validated subsequently by an online survey completed by 110 delegates specialized in sleep medicine from different European countries. The catalogue comprises 10 chapters covering physiology, pathology, diagnostic and treatment procedures to societal and organizational aspects of sleep medicine. Required levels of knowledge and skills are defined, as is a proposed workload of 60 points according to the European Credit Transfer System (ECTS). The catalogue is intended to be a basis for sleep medicine education, for sleep medicine courses and for sleep medicine examinations, serving not only physicians with a medical speciality degree, but also PhD and MSc health professionals such as clinical psychologists and scientists, technologists and nurses, all of whom may be involved professionally in sleep medicine. In the future, the catalogue will be revised in accordance with advances in the field of sleep medicine. Copyright © 2014 European Sleep Research Society 232 April 2014 10.1111/jsr.12095 Catalogue for sleep medicine Catalogue for sleep medicine © 2013 European Sleep Research Society.

      Karolina Lech, Fan Liu, Sarah K. Davies, Katrin Ackermann, Joo Ern Ang, Benita Middleton, Victoria L. Revell, Florence I. Raynaud, Igor Hoveijn, Roelof A. Hut, Debra J. Skene, Manfred Kayser (2017)investigation of metabolites for estimating blood deposition time, In: International Journal of Legal Medicine132(1)pp. 25-32 Springer Verlag

      Trace deposition timing reflects a novel concept in forensic molecular biology involving the use of rhythmic biomarkers for estimating the time within a 24-h day/night cycle a human biological sample was left at the crime scene, which in principle allows verifying a sample donor’s alibi. Previously, we introduced two circadian hormones for trace deposition timing and recently demonstrated that messenger RNA (mRNA) biomarkers significantly improve time prediction accuracy. Here, we investigate the suitability of metabolites measured using a targeted metabolomics approach, for trace deposition timing. Analysis of 171 plasma metabolites collected around the clock at 2-h intervals for 36 h from 12 male participants under controlled laboratory conditions identified 56 metabolites showing statistically significant oscillations, with peak times falling into three day/night time categories: morning/noon, afternoon/evening and night/early morning. Time prediction modelling identified 10 independently contributing metabolite biomarkers, which together achieved prediction accuracies expressed as AUC of 0.81, 0.86 and 0.90 for these three time categories respectively. Combining metabolites with previously established hormone and mRNA biomarkers in time prediction modelling resulted in an improved prediction accuracy reaching AUCs of 0.85, 0.89 and 0.96 respectively. The additional impact of metabolite biomarkers, however, was rather minor as the previously established model with melatonin, cortisol and three mRNA biomarkers achieved AUC values of 0.88, 0.88 and 0.95 for the same three time categories respectively. Nevertheless, the selected metabolites could become practically useful in scenarios where RNA marker information is unavailable such as due to RNA degradation. This is the first metabolomics study investigating circulating metabolites for trace deposition timing, and more work is needed to fully establish their usefulness for this forensic purpose.

      Debra Skene, Elena Skornyakov, Namrata Chowdhury, Rajendra P Gajula, Benita Middleton, Brieann C Satterfield, Kenneth I Porter, Hans P A Van Dongen, Shobhan Gaddameedhi (2018)Separation of circadian- and behavior-driven metabolite rhythms in humans provides a window on peripheral oscillators and metabolism, In: PNAS115(30)pp. 7825-7830 National Academy of Sciences

      Misalignment between internal circadian rhythmicity and externally imposed behavioral schedules, such as occurs in shift workers, has been implicated in elevated risk of metabolic disorders. To determine underlying mechanisms, it is esse ntial to assess whether and how peripheral clocks are disturbed during shift work and to what extent this is linked to the central suprachiasmatic nuclei (SCN) pacemaker and/or misaligned behavioral time cues. Investigating rhythms in circulating metabolites as biomarkers of peripheral clock distur- bances may offer new insight s. We evaluated the impact of misaligned sleep/wake and feeding/fasting cycles on circulating metabolites using a targeted metabolomics approach. Sequential plasma samples obtained during a 24-h constant routine that followed a 3-d simulated night-s hift schedule, compared with a simulated day-shift schedule, we re analyzed for 132 circulating metabolites. Nearly half of these metabolites showed a 24-h rhyth- micity under constant routine following either or both simulated shift schedules. However, while tradition al markers of the circadian clock in the SCN — melatonin, cortisol, and PER3 expression — maintained a stable phase alignment after both schedules, only a few metabo- lites did the same. Many showed reversed rhythms, lost their rhythms, or showed rhythmicity only under constant routine fol- lowing the night-shift schedule. Here, 95% of the metabolites with a 24-h rhythmicity showed rhythms that were driven by behavior- al time cues externally imposed during the preceding simulated shift schedule rather than being driven by the central SCN circa- dian clock. Characterization of these metabolite rhythms will pro- vide insight into the underlying mechanisms linking shift work and metabolic disorders

      Philipp Ritter, Falk Wieland, Debra J. Skene, Andrea Pfennig, Maria Weiss, Michael Bauer, Emanuel Severus, Henry Güldner, Cathrin Sauer, Bettina Soltmann, Stefanie Neumann (2019)Melatonin suppression by melanopsin-weighted light in patients with bipolar I disorder compared to healthy controls, In: Journal of Psychiatry and Neurosciencepp. 1-8 Canadian Medical Association

      Background: Multiple lines of evidence suggest that the onset and course of bipolar disorder is influenced by environmental light conditions. Increased suppression of melatonin by light (supersensitivity) in patients with bipolar disorder has been postulated as an endophenotype by several studies. However, due to methodological shortcomings, the results of these studies remain inconclusive. This study investigated melatonin suppression in euthymic patients with bipolar I disorder using evening blue light specifically targeting the melanopsin system. Methods: Melatonin suppression was assessed in euthymic patients with bipolar I disorder and healthy controls by exposure to monochromatic blue light (λmax = 475 nm; photon density = 1.6 × 10¹³ photons/cm²/s) for 30 minutes at 2300 h, administered via a ganzfeld dome for highly uniform light exposure. Serum melatonin concentrations were determined from serial blood sampling via radioimmunoassay. All participants received mydriatic eye drops and were genotyped for the PER3 VNTR polymorphism to avoid or adjust for potential confounding. As secondary outcomes, serum melatonin concentrations during dark conditions and after monochromatic red light exposure (λmax = 624 nm; photon density = 1.6 × 10¹³ photons/cm²/s) were also investigated. Changes in subjective alertness were investigated for all 3 lighting conditions. Results: A total of 90 participants (57 controls, 33 bipolar I disorder) completed the study. Melatonin suppression by monochromatic blue light did not differ between groups (F1,80 = 0.56; p = 0.46). Moreover, there were no differences in melatonin suppression by monochromatic red light (F1,82 = 1.80; p = 0.18) or differences in melatonin concentrations during dark conditions (F1,74 = 1.16; p = 0.29). Healthy controls displayed a stronger increase in subjective alertness during exposure to blue light than patients with bipolar I disorder (t85 = 2.28; p = 0.027). Limitations: Large interindividual differences in melatonin kinetics may have masked a true difference. Conclusion: Despite using a large cohort and highly controlled laboratory conditions, we found no differences in melatonin suppression between euthymic patients with bipolar I disorder and healthy controls. These findings do not support the notion that supersensitivity is a valid endophenotype in bipolar I disorder.

      Elise R. Facer-Childs, Benita Middleton, Debra J. Skene, Andrew P. Bagshaw (2019)Resetting the late timing of ‘night owls’ has a positive impact on mental health and performance, In: Sleep Medicine60pp. 236-247 Elsevier

      Background There is conflict between living according to our endogenous biological rhythms and our external environment, with disruptions resulting in negative consequences to health and performance. This is often documented in shift work and jet lag, but ‘societal norms’ (eg, typical working hours) can create profound issues for ‘night owls’, people whose internal biological timing predisposes them to follow an unusually late sleep-wake cycle. Night owls have also been associated with health issues, mood disturbances, poorer performance and increased mortality rates. Methods This study used a randomized control trial design aimed to shift the late timing of night owls to an earlier time (phase advance), using non-pharmacological, practical interventions in a real-world setting. These interventions targeted light exposure (through earlier wake up/sleep times), fixed meals times, caffeine intake and exercise. Results Overall, participants demonstrated a significant advance of ~2 h in sleep/wake timings as measured by actigraphy and circadian phase markers (dim light melatonin onset and peak time of the cortisol awakening response), whilst having no adverse effect on sleep duration. Notably, the phase advance was accompanied by significant improvements to self-reported depression and stress, as well as improved cognitive (reaction time) and physical (grip strength) performance measures during the typical 'suboptimal morning hours. Conclusions Our findings propose a novel strategy for shifting clock timing towards a pattern that is more aligned to societal demands that could significantly improve elements of performance, mental health and sleep timing in the real world.

      HC Thorne, Shelagh Hampton, Linda Morgan, Debra Skene, Josephine Arendt (2010)Returning from night shift to day life: Beneficial effects of light on sleep, In: SLEEP AND BIOLOGICAL RHYTHMS8(3)pp. 212-221 WILEY-BLACKWELL

      Subjects working a 12h night shift offshore for 2 weeks normally adapt to the night shift and are out of synchrony when they return home to day life, with consequent problems of poor sleep. The aim of the study was to investigate the effectiveness of timed light treatment to hasten circadian adaptation and improve sleep after the night shift. Ten male shift workers worked 19.00-07.00h (n=4) or 18.00-06.00h (n=6) offshore shift schedules. They were assessed for the last 7 days of a 14 or 21 day night shift offshore and for the following 14 days at home. Either timed light treatment/sunglasses or no light treatment/no sunglasses were scheduled in a crossover design during days 1-5 after the night shift, theoretically timed to advance the circadian system. Subjects wore an Actiwatch-L throughout the study to monitor light and activity and completed daily sleep diaries. Actigraphic sleep efficiency after the light/sunglasses treatment was significantly improved (days 1-5) 86.7 ± 5.8% (light treatment) compared to the no light treatment leg 79.4 ± 10.3% (mean ± SD) P < 0.05. Subjective and objective sleep duration (days 6-14) was significantly improved in the light treatment leg; actigraphic sleep duration was longer after light treatment (6.75 ± 0.50h) compared to 5.76 ± 0.73h, P < 0.05, whilst subjective sleep duration was 8.05 h ± 0.72h compared to 7.32 ± 0.55h, respectively, P < 0.05. If appropriately timed, light and darkness has beneficial effects on sleep efficiency and sleep duration following a night shift.

      S Mäntele, DT Otway, Benita Middleton, S Bretschneider, John Wright, Margaret Robertson, Debra Skene, Jonathan Johnston (2012)Daily Rhythms of Plasma Melatonin, but Not Plasma Leptin or Leptin mRNA, Vary between Lean, Obese and Type 2 Diabetic Men., In: PLoS One7(5)pp. e37123-? Public Library of Science

      Melatonin and leptin exhibit daily rhythms that may contribute towards changes in metabolic physiology. It remains unclear, however, whether this rhythmicity is altered in obesity or type 2 diabetes (T2DM). We tested the hypothesis that 24-hour profiles of melatonin, leptin and leptin mRNA are altered by metabolic status in laboratory conditions. Men between 45-65 years old were recruited into lean, obese-non-diabetic or obese-T2DM groups. Volunteers followed strict sleep-wake and dietary regimes for 1 week before the laboratory study. They were then maintained in controlled light-dark conditions, semi-recumbent posture and fed hourly iso-energetic drinks during wake periods. Hourly blood samples were collected for hormone analysis. Subcutaneous adipose biopsies were collected 6-hourly for gene expression analysis. Although there was no effect of subject group on the timing of dim light melatonin onset (DLMO), nocturnal plasma melatonin concentration was significantly higher in obese-non-diabetic subjects compared to weight-matched T2DM subjects (p

      Andrea Darling, Kath Hart, MA Gibbs, Susan Lanham-New, F Gossiel, R Eastell, T Kantermann, K Horton, Sigurd Johnsen, JL Berry, DJ Skene, R Vieth (2014)Greater seasonal cycling of 25-hydroxyvitamin D is associated with increased parathyroid hormone and bone resorption, In: Osteoporosis International25(3)pp. 933-941

      This analysis assessed whether seasonal change in 25-hydroxyvitamin D concentration was associated with bone resorption, as evidenced by serum parathyroid hormone and C-terminal telopeptide concentrations. The main finding was that increased seasonal fluctuation in 25-hydroxyvitamin D was associated with increased levels of parathyroid hormone and C-terminal telopeptide. Introduction: It is established that adequate 25-hydroxyvitamin D (25(OH)D, vitamin D) concentration is required for healthy bone mineralisation. It is unknown whether seasonal fluctuations in 25(OH)D also impact on bone health. If large seasonal fluctuations in 25(OH)D were associated with increased bone resorption, this would suggest a detriment to bone health. Therefore, this analysis assessed whether there is an association between seasonal variation in 25(OH)D and bone resorption. Methods: The participants were (n = 279) Caucasian and (n = 88) South Asian women (mean (±SD); age 48.2 years (14.4)) who participated in the longitudinal Diet, Food Intake, Nutrition and Exposure to the Sun in Southern England study (2006-2007). The main outcomes were serum 25(OH)D, serum parathyroid hormone (sPTH) and serum C-terminal telopeptide of collagen (sCTX), sampled once per season for each participant. Results: Non-linear mixed modelling showed the (amplitude/mesor) ratio for seasonal change in log 25(OH)D to be predictive of log sPTH (estimate = 0.057, 95 % CI (0.051, 0.063), p < 0.0001). Therefore, individuals with a higher seasonal change in log 25(OH)D, adjusted for overall log 25(OH)D concentration, showed increased levels of log sPTH. There was a corresponding significant ability to predict the range of seasonal change in log 25(OH)D through the level of sCTX. Here, the corresponding parameter statistics were estimate = 0.528, 95 % CI (0.418, 0.638) and p ≤ 0.0001. Conclusions: These findings suggest a possible detriment to bone health via increased levels of sPTH and sCTX in individuals with a larger seasonal change in 25(OH)D concentration. Further larger cohort studies are required to further investigate these preliminary findings. © 2013 International Osteoporosis Foundation and National Osteoporosis Foundation.

      Natalia M. Tiuganji, Patricia Nehme, Elaine C. Marqueze, Cheryl M. Isherwood, Andressa J. Martins, Suleima Vasconcelos, José Cipolla-Neto, Arne Lowden, Debra J. Skene, Claudia R. C. Moreno (2020)Eating Behavior (Duration, Content, and Timing) Among Workers Living under Different Levels of Urbanization, In: Nutrients12(2)375 MDPI

      Urbanization has contributed to extended wakefulness, which may in turn be associated with eating over a longer period. Here, we present a field study conducted in four groups with different work hours and places of living in order to investigate eating behavior (duration, content, and timing). Anthropometric measures were taken from the participants (rural (n = 22); town (n = 19); city-day workers (n = 11); city-night workers (n = 14)). In addition, a sociodemographic questionnaire was self-answered and 24-h food recalls were applied for three days. The 24-h food recalls revealed that fat intake varied according to the groups, with the highest consumption by the city-day workers. By contrast, city-day workers had the lowest intake of carbohydrate, whereas the rural group had the highest. In general, all groups had some degree of inadequacy in food consumption. Eating duration was negatively correlated with total energy intake, fat, and protein consumption in the rural and town groups. There was a positive correlation between body mass index and eating duration in both city groups. The rural group had the earliest start time of eating, and this was associated with a lower body mass index. This study suggested that food content and timing, as well as eating duration, differed according to place of living, which in turn may be linked to lifestyle.

      T Kantermann, F Duboutay, D Haubruge, S Hampton, AL Darling, JL Berry, M Kerkhofs, KZ Boudjeltia, DJ Skene (2014)The direction of shift-work rotation impacts metabolic risk independent of chronotype and social jetlag - An exploratory pilot study., In: F Portaluppi (eds.), Chronobiology International: the journal of biological and medical rhythm researchpp. 1-7 Informa Healthcare

      The aim of this pilot study was to explore the risk of metabolic abnormalities in steel workers employed in different shift-work rotations. Male workers in a steel factory [16 employed in a fast clockwise rotation (CW), 18 in slow counterclockwise rotation (CC), 9 day workers (DW); mean age 43.3 ± SD 6.8 years] with at least 5 years experience in their current work schedule participated. All workers provided fasting blood samples between 06:00 and 08:00 h for plasma glucose, insulin, apo-lipoproteins A and B (ApoA, ApoB), high- and low-density lipoproteins (HDL and LDL), total cholesterol (tCH), triglycerides (TG), minimally oxidized (mox) LDL, C-reactive protein (CRP), interleukin-8 (IL-8) and serum 25-hydroxyvitamin D (25(OH)D). HOMA index (homeostatic model assessment) was calculated to evaluate insulin resistance, beta cell function and risk of diabetes. Information on demographics, health, stimulants, sleep, social and work life, chronotype (phase of entrainment) and social jetlag (difference between mid-sleep on workdays and free days) as a surrogate for circadian disruption was collected by questionnaire. Neither chronotype nor social jetlag was associated with any of the metabolic risk blood markers. There were no significant differences in 25(OH)D, ApoA, ApoB, CRP, HDL, IL-8, insulin, LDL, mox-LDL, mox-LDL/ApoB ratio, tCH and TG levels between the three work groups. Although we did observe absolute differences in some of these markers, the small sample size of our study population might prevent these differences being statistically significant. Fasting glucose and HOMA index were significantly lower in CW compared to DW and CC, indicating lower metabolic risk. Reasons for the lower fasting glucose and HOMA index in CW workers remains to be clarified. Future studies of workers in different shift rotations are warranted to understand better the differential effects of shift-work on individual workers and their health indices.

      HO de la Iglesia, C Moreno, A Lowden, F Louzada, E Marqueze, R Levandovski, LK Pilz, C Valeggia, E Fernandez-Duque, DA Golombek, CA Czeisler, Debra Skene, JF Duffy, T Roenneberg (2016)Ancestral sleep., In: Current Biology26(7)pp. R271-R272 Elsevier

      While we do not yet understand all the functions of sleep, its critical role for normal physiology and behaviour is evident. Its amount and temporal pattern depend on species and condition. Humans sleep about a third of the day with the longest, consolidated episode during the night. The change in lifestyle from hunter-gatherers via agricultural communities to densely populated industrialized centres has certainly affected sleep, and a major concern in the medical community is the impact of insufficient sleep on health [1,2]. One of the causal mechanisms leading to insufficient sleep is altered exposure to the natural light-dark cycle. This includes the wide availability of electric light, attenuated exposure to daylight within buildings, and evening use of light-emitting devices, all of which decrease the strength of natural light-dark signals that entrain circadian systems [3].

      I Gogenur, B Middleton, VB Kristiansen, DJ Skene, J Rosenberg (2007)Disturbances in melatonin and core body temperature circadian rhythms after minimal invasive surgery, In: ACTA ANAESTHESIOLOGICA SCANDINAVICA51(8)pp. 1099-1106 BLACKWELL PUBLISHING
      VL Revell, DJ Skene (2010)Impact of age on human non-visual responses to light, In: SLEEP AND BIOLOGICAL RHYTHMS8(2)pp. 84-94 WILEY-BLACKWELL

      Ageing is associated with increased disturbances in the timing, duration, and quality of sleep. These disruptions may reflect changes in the circadian timing system and/or the sleep homeostat which are both necessary to produce consolidated sleep at an appropriate time. In addition, it is possible that age-related alterations in the detection and transmission of the photic signal responsible for synchronizing the circadian clock may play a role. Ageing is accompanied by many changes within the eye including alterations in pupil size, lens transmission, and number of photoreceptors. The observed increase in ocular lens density with age will diminish the transmission of short wavelength blue light to which the circadian system has been shown to be most sensitive, and may contribute, in part, to the observed increase in sleep disturbances in older people. We were the first group to test the hypothesis that non-visual responses to blue light would be impaired in older individuals. Our research has demonstrated that whilst acute non-visual effects of blue light are impaired with age, the light resetting effect appears unaltered. Future research should work towards optimizing the light environment for older people to promote good quality sleep and daytime functioning.

      SW Lockley, DJ Skene, J Arendt, H Tabandeh, AC Bird, R Defrance (1997)Relationship between melatonin rhythms and visual loss in the blind, In: J CLIN ENDOCR METAB82(11)pp. 3763-3770 ENDOCRINE SOC

      Melatonin rhythms were assessed in 49 registered blind individuals by measurement of the urinary metabolite of melatonin, 6-sulfatoxymelatonin (aMT6s). Subjects had different causes of visual loss and were classified as having light perception or better (LP; n 5 19) or having no perception of light (NPL; n 5 30). Subjects collected four-hourly urine samples (eight-hourly overnight) for 48 h at weekly intervals for 3–5 weeks. The majority of LP subjects (14 of 19) had normally entrained aMT6s rhythms (mean acrophase range, 2.4–6.2 h), 4 were abnormally entrained to 24 h (mean acrophase range, 8.9–1.0 h), and 1 was unclassified. Conversely, mostNPLsubjects had abnormal rhythms (23 of 30), the incidence of which was greater in uni- and bilaterally enucleated subjects. The majority of NPL subjects (17 of 30) had free-running aMT6s rhythms (period range, 24.13– 24.79 h), 5 were abnormally entrained to 24 h (acrophase range, 7.2–20.6 h), and 1 was unclassified. Output (micrograms of aMT6s per 24 h) and amplitude (micrograms per h) of aMT6s production did not vary between LP and NPL subjects (mean 24-h output 6 SD, 12.7 6 7.5 and 9.4 6 6.4 mg aMT6s/24 h, respectively; mean amplitude 6 SD, 0.660.4 and 0.560.3 mg/h, respectively). These results indicate that a higher proportion of NPL subjects have abnormal melatonin rhythms compared to those with LP. (J Clin Endocrinol Metab 82: 3763–3770, 1997)

      AJ Martins, SP Vasconcelos, Debra Skene, A Lowden, CR de Castro Moreno (2016)Effects of physical activity at work and life-style on sleep in workers from an Amazonian Extractivist Reserve, In: Sleep Science9pp. 289-294 Elsevier

      Physical activity has been recommended as a strategy for improving sleep. Nevertheless, physical effort at work might not be not the ideal type of activity to promote sleep quality. The aim of this study was to evaluate the effects of type of job (low vs. high physical effort) and life-style on sleep of workers from an Amazonian Extractivist Reserve, Brazil. A cross-sectional study of 148 low physical activity (factory workers) and 340 high physical activity (rubber tappers) was conducted between September and November 2011. The workers filled out questionnaires collecting data on demographics (sex, age, occupation, marital status and children), health (reported morbidities, sleep disturbances, musculoskeletal pain and body mass index) and life-style (smoking, alcohol use and practice of leisure-time physical activity). Logistic regression models were applied with the presence of sleep disturbances as the primary outcome variable. The prevalence of sleep disturbances among factory workers and rubber tappers was 15.5% and 27.9%, respectively. The following independent variables of the analysis were selected based on a univariate model (p40 years), and having musculoskeletal pain (≥5 symptoms). Rubber tapper work, owing to greater physical effort, pain and musculoskeletal fatigue, was associated with sleep disturbances. Being female and older than 40 years were also predictors of poor sleep. In short, these findings suggest that demanding physical exertion at work may not improve sleep quality.

      K Lech, F Liu, K Ackermann, Victoria Revell, O Lao, Debra Skene, M Kayser (2016)Evaluation of mRNA markers for estimating blood deposition time: Towards alibi testing from human forensic stains with rhythmic biomarkers, In: FORENSIC SCIENCE INTERNATIONAL-GENETICS21pp. 119-125 ELSEVIER IRELAND LTD

      Determining the time a biological trace was left at a scene of crime reflects a crucial aspect of forensic investigations as – if possible – it would permit testing the sample donor’s alibi directly from the trace evidence, helping to link (or not) the DNA-identified sample donor with the crime event. However, reliable and robust methodology is lacking thus far. In this study, we assessed the suitability of mRNA for the purpose of estimating blood deposition time, and its added value relative to melatonin and cortisol, two circadian hormones we previously introduced for this purpose. By analysing 21 candidate mRNA markers in blood samples from 12 individuals collected around the clock at 2 h intervals for 36 h under real-life, controlled conditions, we identified 11 mRNAs with statistically significant expression rhythms. We then used these 11 significantly rhythmic mRNA markers, with and without melatonin and cortisol also analysed in these samples, to establish statistical models for predicting day/night time categories. We found that although in general mRNA-based estimation of time categories was less accurate than hormone-based estimation, the use of three mRNA markers HSPA1B, MKNK2 and PER3 together with melatonin and cortisol generally enhanced the time prediction accuracy relative to the use of the two hormones alone. Our data best support a model that by using these five molecular biomarkers estimates three time categories, i.e. night/early morning, morning/noon, and afternoon/evening with prediction accuracies expressed as AUC values of 0.88, 0.88, and 0.95, respectively. For the first time, we demonstrate the value of mRNA for blood deposition timing and introduce a statistical model for estimating day/night time categories based on molecular biomarkers, which shall be further validated with additional samples in the future. Moreover, our work provides new leads for molecular approaches on time of death estimation using the significantly rhythmic mRNA markers established here.

      K Lech, K Ackermann, Victoria Revell, O Lao, Debra Skene, M Kayser (2016)Dissecting Daily and Circadian Expression Rhythms of Clock-Controlled Genes in Human Blood, In: JOURNAL OF BIOLOGICAL RHYTHMS31(1)pp. 68-81 SAGE PUBLICATIONS INC

      The identification and investigation of novel clock-controlled genes (CCGs) has been conducted thus far mainly in model organisms such as nocturnal rodents, with limited information in humans. Here, we aimed to characterize daily and circadian expression rhythms of CCGs in human peripheral blood during a sleep/sleep deprivation (S/SD) study and a constant routine (CR) study. Blood expression levels of 9 candidate CCGs (SREBF1, TRIB1, USF1, THRA1, SIRT1, STAT3, CAPRIN1, MKNK2, and ROCK2), were measured across 48 h in 12 participants in the S/SD study and across 33 h in 12 participants in the CR study. Statistically significant rhythms in expression were observed for STAT3, SREBF1, TRIB1, and THRA1 in samples from both the S/SD and the CR studies, indicating that their rhythmicity is driven by the endogenous clock. The MKNK2 gene was significantly rhythmic in the S/SD but not the CR study, which implies its exogenously driven rhythmic expression. In addition, we confirmed the circadian expression of PER1, PER3, and REV-ERBα in the CR study samples, while BMAL1 and HSPA1B were not significantly rhythmic in the CR samples; all 5 genes previously showed significant expression in the S/SD study samples. Overall, our results demonstrate that rhythmic expression patterns of clock and selected clock-controlled genes in human blood cells are in part determined by exogenous factors (sleep and fasting state) and in part by the endogenous circadian timing system. Knowledge of the exogenous and endogenous regulation of gene expression rhythms is needed prior to the selection of potential candidate marker genes for future applications in medical and forensic settings.

      DT Otway, S Mäntele, S Bretschneider, J Wright, P Trayhurn, DJ Skene, MD Robertson, JD Johnston (2011)Rhythmic Diurnal Gene Expression in Human Adipose Tissue From Individuals Who Are Lean, Overweight, and Have Type 2 Diabetes., In: Diabetes American Diabetes Association

      OBJECTIVE Previous animal studies suggest a functional relationship between metabolism, type 2 diabetes, and the amplitude of daily rhythms in white adipose tissue (WAT). However, data interpretation is confounded by differences in genetic background and diet or limited sampling points. We have taken the novel approach of analyzing serial human WAT biopsies across a 24-h cycle in controlled laboratory conditions.RESEARCH DESIGN AND METHODS Lean (n = 8), overweight/obese (n = 11), or overweight/obese type 2 diabetic (n = 8) volunteers followed a strict sleep-wake and dietary regimen for 1 week prior to the laboratory study. They were then maintained in controlled light-dark conditions in a semirecumbent posture and fed hourly during wake periods. Subcutaneous WAT biopsies were collected every 6 h over 24 h, and gene expression was measured by quantitative PCR.RESULTS Lean individuals exhibited significant (P < 0.05) temporal changes of core clock (PERI, PER2, PER3, CRY2, BMAL1, and DBP) and metabolic (REVERB alpha,RIP140, and PGC1 alpha) genes. The BMAL1 rhythm was in approximate antiphase with the other clock genes. It is noteworthy that there was no significant effect (P > 0.05) of increased body weight or type 2 diabetes on rhythmic gene expression.CONCLUSIONS The robust nature of these rhythms and their relative phasing indicate that WAT now can be considered as a peripheral tissue suitable for the study of in vivo human rhythms. Comparison of data between subject groups clearly indicates that obesity and type 2 diabetes are not related to the amplitude of rhythmic WAT gene expression in humans maintained under controlled conditions. Diabetes 60:1577-1581, 2011

      SW Lockley, DJ Skene, J Arendt (1999)Comparison between subjective and actigraphic measurement of sleep and sleep rhythms, In: JOURNAL OF SLEEP RESEARCH8(3)pp. 175-183 BLACKWELL SCIENCE LTD
      M De Rui, Benita Middleton, A Sticca, A Gatta, P Amodio, Debra Skene, S Montagnese (2015)Sleep and Circadian Rhythms in Hospitalized Patients with Decompensated Cirrhosis: Effect of Light Therapy, In: NEUROCHEMICAL RESEARCH40(2)pp. 284-292 SPRINGER/PLENUM PUBLISHERS
      S Montagnese, B Middleton, AR Mani, DJ Skene, MY Morgan (2010)On the origin and the consequences of circadian abnormalities in patients with cirrhosis., In: Am J Gastroenterol105(8)pp. 1773-1781

      OBJECTIVES: Plasma melatonin profile abnormalities have been described in patients with cirrhosis and generally attributed to impaired hepatic melatonin metabolism. The possibility that they might reflect circadian clock dysfunction has not been explored. In addition, the relationship between plasma melatonin profiles and the sleep disturbances observed in these patients remains unclear. The aims of this study were: (i) to evaluate circadian clock function and hepatic melatonin metabolism in cirrhotic patients, and (ii) to study the relationship between plasma melatonin profiles and sleep-wake behavior. METHODS: The study population comprised 20 patients with cirrhosis (mean (range) age, 59 (39-77) years) and 9 healthy volunteers (60 (38-84) years). Plasma melatonin/cortisol concentrations were measured hourly, for 24 h, in light/posture-controlled conditions. Urinary 6-sulfatoxymelatonin, the main melatonin metabolite, was measured simultaneously to determine clearance. The ability of light to suppress nocturnal melatonin synthesis was assessed. Habitual sleep quality/timing was evaluated using a questionnaire, actigraphy, and sleep diaries. RESULTS: There was evidence of central circadian disruption in patients compared with healthy controls: peak plasma melatonin/cortisol times were delayed (04:48+/-02:36 vs. 02:48+/-00:54, P=0.01; 10:18+/-02:54 vs. 08:54+/-01:24, P=0.06) and the plasma melatonin response to light was reduced (12%+/-19% vs. 24%+/-15%, P=0.09). However, the mean 24 h plasma melatonin clearance did not differ significantly between patients and healthy volunteers (0.22+/-0.10 vs. 0.28+/-0.17 l/kg per h, P=0.36). Finally, although patients showed a degree of misalignment between sleep and circadian timings, there was no association between circadian abnormalities and impaired sleep quality. CONCLUSIONS: Plasma melatonin profile abnormalities, predominantly central in origin, are observed in patients with mild to moderately decompensated cirrhosis. However, they are substantially unrelated to the sleep disturbances prevalent in this population.

      MA Bonmati-Carrion, K Hild, C Isherwood, SJ Sweeney, VL Revell, DJ Skene, MA Rol, JA Madrid (2016)Relationship between Human Pupillary Light Reflex and Circadian System Status, In: PLoS One11(9)e0162476 Public Library of Science (PLoS)

      Intrinsically photosensitive retinal ganglion cells (ipRGCs), whose photopigment melanopsin has a peak of sensitivity in the short wavelength range of the spectrum, constitute a common light input pathway to the olivary pretectal nucleus (OPN), the pupillary light reflex (PLR) regulatory centre, and to the suprachiasmatic nuclei (SCN), the major pacemaker of the circadian system. Thus, evaluating PLR under short wavelength light (λmax 500 nm) and creating an integrated PLR parameter, as a possible tool to indirectly assess the status of the circadian system, becomes of interest. Nine monochromatic, photon-matched light stimuli (300 s), in 10 nm increments from λmax 420 to 500 nm were administered to 15 healthy young participants (8 females), analyzing: i) the PLR; ii) wrist temperature (WT) and motor activity rhythms (WA), iii) light exposure (L) pattern and iv) diurnal preference (Horne- Östberg), sleep quality (Pittsburgh) and daytime sleepiness (Epworth). Linear correlations between the different PLR parameters and circadian status index obtained from WT, WA and L recordings and scores from questionnaires were calculated. In summary, we found markers of robust circadian rhythms, namely high stability, reduced fragmentation, high amplitude, phase advance and low internal desynchronization, were correlated with a reduced PLR to 460–490 nm wavelengths. Integrated circadian (CSI) and PLR (cp-PLR) parameters are proposed, that also showed an inverse correlation. These results demonstrate, for the first time, the existence of a close relationship between the circadian system robustness and the pupillary reflex response, two non-visual functions primarily under melanopsin-ipRGC input.

      S Montagnese, M De Rui, M Corrias, M Turco, C Merkel, P Amodio, A Gatta, C De Pittà, R Costa, Debra Skene (2014)Sleep-wake abnormalities in patients with cirrhosis, In: Hepatology59(2)pp. 705-712

      A considerable proportion of patients with cirrhosis exhibit insomnia, delayed sleep habits, and excessive daytime sleepiness. These have been variously attributed to hepatic encephalopathy and impaired hepatic melatonin metabolism, but the understanding of their pathophysiology remains limited and their treatment problematic. Sleep is regulated by the interaction of a homeostatic and a circadian process. The homeostatic process determines sleep propensity in relation to sleep-wake history, thus the need to sleep increases with the duration of the waking period. The circadian process, which is marked by the 24-hour rhythm of the hormone melatonin, is responsible for the alternation of high/low sleep propensity in relation to dark/light cues. Circadian sleep regulation has been studied in some depth in patients with cirrhosis, who show delays in the 24-hour melatonin rhythm, most likely in relation to reduced sensitivity to light cues. However, while melatonin abnormalities are associated with delayed sleep habits, they do not seem to offer a comprehensive explanation to the insomnia exhibited by these patients. Fewer data are available on homeostatic sleep control: it has been recently hypothesized that patients with cirrhosis and hepatic encephalopathy might be unable, due to excessive daytime sleepiness, to accumulate the need/ability to produce restorative sleep. This review will describe in some detail the features of sleep-wake disturbances in patients with cirrhosis, their mutual relationships, and those, if any, with hepatic failure/hepatic encephalopathy. A separate section will cover the available information on their pathophysiology. Finally, etiological treatment will be briefly discussed. © 2013 by the American Association for the Study of Liver Diseases.

      María Ángeles Bonmati-Carrion, Konstanze Hild, Cheryl Isherwood, Stephen J Sweeney, Victoria Revell, Juan Antonio Madrid, María Ángeles Rol, Debra Skene (2018)Effect of single and combined monochromatic light on the human pupillary light response, In: Frontiers in Neurology91019 Frontiers Media

      The pupillary light reflex (PLR) is a neurological reflex driven by rods, cones, and melanopsin-containing retinal ganglion cells. Our aim was to achieve a more precise picture of the effects of 5-min duration monochromatic light stimuli, alone or in combination, on the human PLR, to determine its spectral sensitivity and to assess the importance of photon flux. Using pupillometry, the PLR was assessed in 13 participants (6 women) aged 27.2 ± 5.41 years (mean ± SD) during 5-min light stimuli of purple (437 nm), blue (479 nm), red (627 nm), and combinations of red+purple or red+blue light. In addition, nine 5-min, photon-matched light stimuli, ranging in 10 nm increments peaking between 420 and 500 nm were tested in 15 participants (8 women) aged 25.7 ± 8.90 years. Maximum pupil constriction, time to achieve this, constriction velocity, area under the curve (AUC) at short (0–60 s), and longer duration (240–300 s) light exposures, and 6-s post-illumination pupillary response (6-s PIPR) were assessed. Photoreceptor activation was estimated by mathematical modeling. The velocity of constriction was significantly faster with blue monochromatic light than with red or purple light. Within the blue light spectrum (between 420 and 500 nm), the velocity of constriction was significantly faster with the 480 nm light stimulus, while the slowest pupil constriction was observed with 430 nm light. Maximum pupil constriction was achieved with 470 nm light, and the greatest AUC0−60 and AUC240−300 was observed with 490 and 460 nm light, respectively. The 6-s PIPR was maximum after 490 nm light stimulus. Both the transient (AUC0−60) and sustained (AUC240−300) response was significantly correlated with melanopic activation. Higher photon fluxes for both purple and blue light produced greater amplitude sustained pupillary constriction. The findings confirm human PLR dependence on wavelength, monochromatic or bichromatic light and photon flux under 5-min duration light stimuli. Since the most rapid and high amplitude PLR occurred within the 460–490 nm light range (alone or combined), our results suggest that color discrimination should be studied under total or partial substitution of this blue light range (460–490 nm) by shorter wavelengths (~440 nm). Thus for nocturnal lighting, replacement of blue light with purple light might be a plausible solution to preserve color discrimination while minimizing melanopic activation.

      K Ackermann, R Plomp, O Lao, B Middleton, VL Revell, DJ Skene, M Kayser (2013)Effect of sleep deprivation on rhythms of clock gene expression and melatonin in humans., In: Chronobiol Int30(7)pp. 901-909 Informa Healthcare

      This study investigated the impact of sleep deprivation on the human circadian system. Plasma melatonin and cortisol levels and leukocyte expression levels of 12 genes were examined over 48 h (sleep vs. no-sleep nights) in 12 young males (mean ± SD: 23 ± 5 yrs). During one night of total sleep deprivation, BMAL1 expression was suppressed, the heat shock gene HSPA1B expression was induced, and the amplitude of the melatonin rhythm increased, whereas other high-amplitude clock gene rhythms (e.g., PER1-3, REV-ERBα) remained unaffected. These data suggest that the core clock mechanism in peripheral oscillators is compromised during acute sleep deprivation.

      SW Lockley, DJ Skene, K Thapan, J English, D Ribeiro, I Haimov, S Hampton, B Middleton, M von Schantz, J Arendt (1998)Extraocular light exposure does not suppress plasma melatonin in humans, In: J CLIN ENDOCR METAB83(9)pp. 3369-3372 ENDOCRINE SOC

      Light affects the circadian axis in at least two ways. It can cause the acute suppression of pineal melatonin synthesis, and/or a phase-shift of the circadian oscillator. As recent evidence has suggested that extraocular light exposure may cause phase-shifts of the circadian clock, we have investigated whether suppression of melatonin can be induced by the same type of light exposure. In the first study subjects’ eyes were exposed to white light (2250 lux for 30 min) via a fibre optic cable. As expected, suppression of nighttime plasma melatonin levels (61 ± 6%) was observed. In the second study, light of the same quality but higher intensity (14,000 or 67,500 lux for 180 mins) was delivered in the same manner to the popliteal region behind the subjects’ knees, whilst shielding their eyes. No suppression of plasma melatonin levels (4 ± 7%) was detected in any of the subjects. Thus, extraocular photoreception, if it exists in mammals, does not affect the suprachiasmatic nuclei-pineal pathway.

      JB Zawilska, J Rosiak, B Vivien-Roels, DJ Skene, P Pevet, JZ Nowak (2000)Effects of cycloheximide and aminophylline on 5-methoxytryptophol and melatonin contents in the chick pineal gland, In: GENERAL AND COMPARATIVE ENDOCRINOLOGY120(2)pp. 212-219 ACADEMIC PRESS INC
      H Thorne, S Hampton, L Morgan, DJ Skene, J Arendt (2008)Differences in sleep, light, and circadian phase in offshore 18.00-06.00 h and 19.00-07.00 h shift workers, In: CHRONOBIOLOGY INTERNATIONAL25(2-3)pp. 225-235 INFORMA HEALTHCARE
      C Schmoll, G Lascaratos, B Dhillon, D Skene, RL Riha (2011)The role of retinal regulation of sleep in health and disease, In: SLEEP MEDICINE REVIEWS15(2)pp. 107-113 W B SAUNDERS CO LTD
      K Ackermann, VL Revell, O Lao, EJ Rombouts, DJ Skene, M Kayser (2012)Diurnal rhythms in blood cell populations and the effect of acute sleep deprivation in healthy young men., In: Sleep35(7)pp. 933-940

      The sleep/wake cycle is accompanied by changes in circulating numbers of immune cells. The goal of this study was to provide an in-depth characterization of diurnal rhythms in different blood cell populations and to investigate the effect of acute sleep deprivation on the immune system, as an indicator of the body's acute stress response.

      I Gogenur, U Ocak, O Altunpinar, B Middleton, DJ Skene, J Rosenberg (2007)Disturbances in melatonin, cortisol and core body temperature rhythms after major surgery, In: WORLD JOURNAL OF SURGERY31(2)pp. 290-298 SPRINGER
      JE Ang, A Pal, YJ Asad, AT Henley, M Valenti, G Box, A de haven Brandon, Victoria Revell, Debra Skene, M Venturi, R Rueger, V Meresse, SA Eccles, JS de Bono, SB Kaye, P Workman, U Banerji, FI Raynaud (2017)Modulation of plasma metabolite biomarkers of MAPK pathway with the MEK inhibitor RO4987655: pharmacodynamic and predictive potential in metastatic melanoma., In: Molecular Cancer Therapeutics American Association for Cancer Research

      MAPK pathway activation is frequently observed in human malignancies, including melanoma, and is associated with sensitivity to MEK inhibition and changes in cellular metabolism. Using quantitative mass spectrometry-based metabolomics, we identified in preclinical models 21 plasma metabolites including amino acids, propionylcarnitine, phosphatidylcholines and sphingomyelins that were significantly altered in two B-RAF mutant melanoma xenografts and that were reversed following a single dose of the potent and selective MEK inhibitor RO4987655. Treatment of non-tumour bearing animals and mice bearing the PTEN null U87MG human glioblastoma xenograft elicited plasma changes only in amino acids and propionylcarnitine. In patients with advanced melanoma treated with RO4987655, on-treatment changes of amino acids were observed in patients with disease progression and not in responders. In contrast, changes in phosphatidylcholines and sphingomyelins were observed in responders. Furthermore, pre-treatment levels of 7 lipids identified in the preclinical screen were statistically significantly able to predict objective responses to RO4987655. The RO4987655 treatment-related changes were greater than baseline physiological variability in non-treated individuals. This study provides evidence of a translational exo-metabolomic plasma readout predictive of clinical efficacy together with pharmacodynamic utility following treatment with a signal transduction inhibitor.

      S Daugaard, AH Garde, JPE Bonde, J Christoffersen, AM Hansen, J Markvart, V Schlünssen, Debra Skene, HT Vistisen, HA Kolstad (2017)Night work, light exposure and melatonin on work days and days off, In: Chronobiology International34(7)pp. 942-955 Taylor & Francis

      We aimed to examine the effects of night work on salivary melatonin concentration during and subsequent to night work and the mediating role of light. We included 254 day workers and 87 night workers who were followed during 322 work days and 301 days off work. Each day was defined as the 24 hour period starting from the beginning of a night shift or from waking in the mornings with day work and days off. Light levels were recorded and synchronized with diary information (start and end of sleep and work). On average, participants provided four saliva samples per day, and these were analyzed for melatonin concentration by liquid chromatography tandem mass spectrometry (LC-MS/MS). Differences between day and night workers on work days and days off were assessed with multilevel regression models with melatonin concentration as the primary outcome. All models were stratified or adjusted by time of day. For light exposure, we estimated the total, direct and indirect effects of night work on melatonin concentrations obtaining 95% confidence intervals through bootstrapping. On work days, night workers showed 15% lower salivary melatonin concentrations compared with day workers (−15.0%; 95% CI: −31.4%; 5.2%). During the night, light exposure mediated a melatonin suppression of approximately 6% (−5.9%, 95% CI: −10.2%; −1.5%). No mediating effect of light was seen during the day time. On days off, we observed no difference in melatonin concentrations between day and night workers. These findings are in accordance with a transient and partly light-mediated effect of night work on melatonin production.

      EC Marqueze, S Vasconcelos, J Garefelt, DJ Skene, CR Moreno, A Lowden (2015)Natural Light Exposure, Sleep and Depression among Day Workers and Shiftworkers at Arctic and Equatorial Latitudes, In: PLOS ONE10(4)UNSP epp. ?-? Public Library of Science

      OBJECTIVES: This study aimed to investigate the relationship between individual natural light exposure, sleep need, and depression at two latitudes, one extreme with a few hours of light per day during winter, and the other with equal hours of light and darkness throughout the year. METHODS: This cross-sectional study included a sample of Brazilian workers (Equatorial, n = 488 workers) and a Swedish sample (Arctic, n = 1,273). RESULTS: The reported mean total natural light exposure per 4-week cycle differed significantly between the Equatorial and Arctic regions. However, shiftworkers from both sites reported similar hours of natural light exposure. Short light exposure was a predictor for insufficient sleep. CONCLUSION: Reduced exposure to natural light appears to increase the perception of obtaining insufficient sleep. Arctic workers were more prone to develop depression than Equatorial workers.

      J Fischer, Z Dogas, CL Bassetti, S Berg, L Grote, P Jennum, P Levy, S Mihaicuta, L Nobili, D Riemann, FJ Puertas Cuesta, DJ Skene, N Stanley, D Pevernagie, F Raschke (2012)Standard procedures for adults in accredited sleep medicine centres in Europe, In: Journal of Sleep Research21(4)pp. 357-368

      Summary: The present paper describes standardized procedures within clinical sleep medicine. As such, it is a continuation of the previously published European guidelines for the accreditation of sleep medicine centres and European guidelines for the certification of professionals in sleep medicine, aimed at creating standards of practice in European sleep medicine. It is also part of a broader action plan of the European Sleep Research Society, including the process of accreditation of sleep medicine centres and certification of sleep medicine experts, as well as publishing the Catalogue of Knowledge and Skills for sleep medicine experts (physicians, non-medical health care providers, nurses and technologists), which will be a basis for the development of relevant educational curricula. In the current paper, the standard operational procedures sleep medicine centres regarding the diagnostic and therapeutic management of patients evaluated at sleep medicine centres, accredited according to the European Guidelines, are based primarily on prevailing evidence-based medicine principles. In addition, parts of the standard operational procedures are based on a formalized consensus procedure applied by a group of Sleep Medicine Experts from the European National Sleep Societies. The final recommendations for standard operational procedures are categorized either as 'standard practice', 'procedure that could be useful', 'procedure that is not useful' or 'procedure with insufficient information available'. Standard operational procedures described here include both subjective and objective testing, as well as recommendations for follow-up visits and for ensuring patients' safety in sleep medicine. The overall goal of the actual standard operational procedures is to further develop excellence in the practice and quality assurance of sleep medicine in Europe. © 2011 European Sleep Research Society.

      Matteo Turco, Nora Cazzagon, Irene Franceschet, Chiara Formentin, Giovanni Frighetto, Francesca Giordani, Nicola Cellini, Gabriella Mazzotta, Rodolfo Costa, Benita Middleton, Debra Skene, Annarosa Floreani, Sara Montagnese (2018)Morning Bright Light Treatment for Sleep-Wake Disturbances in Primary Biliary Cholangitis: A Pilot Study, In: Frontiers in Physiology91530 Frontiers Media

      Patients with Primary Biliary Cholangitis (PBC) exhibit delayed sleep-wake habits, disturbed night sleep and daytime sleepiness/fatigue. Such combination of symptoms is reminiscent of delayed sleep-wake phase disorder (DSPD), which benefits from morning light treatment. The aim of the present pilot study was to test the effect of morning light treatment in a group of 13 well-characterized patients with PBC [all females; (mean ± SD) 53 ± 10 years]. Six healthy individuals (4 females, 57 ± 14 years) and 7 patients with cirrhosis (1 female, 57 ± 12 years) served as controls and diseased controls, respectively. At baseline, all participants underwent an assessment of quality of life, diurnal preference, sleep quality/timing (subjective plus actigraphy), daytime sleepiness, and urinary 6-sulphatoxymelatonin (aMT6s) rhythmicity. Then they underwent a 15-day course of morning bright light treatment, immediately after getting up (light box, 10,000 lux, 45 min) whilst monitoring sleep-wake patterns and aMT6s rhythmicity. At baseline, both patients with PBC and patients with cirrhosis had significantly worse subjective sleep quality compared to controls. In patients with PBC, light treatment resulted in an improvement in subjective sleep quality and a reduction in daytime sleepiness. In addition, both their sleep onset and get-up time were significantly advanced. Finally, the robustness of aMT6s rhythmicity (i.e., strength of the cosinor fit) increased after light administration but post-hoc comparisons were not significant in any of the groups. In conclusion, a brief course of morning bright light treatment had positive effects on subjective sleep quality, daytime sleepiness, and sleep timing in patients with PBC. This unobtrusive, side-effect free, non-pharmacological treatment is worthy of further study.

      SW Lockley, DJ Skene, K James, K Thapan, J Wright, J Arendt (2000)Melatonin administration can entrain the free-running circadian system of blind subjects, In: JOURNAL OF ENDOCRINOLOGY164(1)pp. R1-R6 SOC ENDOCRINOLOGY
      L Pagani, EA Semenova, E Moriggi, VL Revell, LM Hack, SW Lockley, J Arendt, DJ Skene, F Meier, J Izakovic (2010)The physiological period length of the human circadian clock in vivo is directly proportional to period in human fibroblasts., In: PLoS One5(10)pp. e13376-? Public Library of Science

      Diurnal behavior in humans is governed by the period length of a circadian clock in the suprachiasmatic nuclei of the brain hypothalamus. Nevertheless, the cell-intrinsic mechanism of this clock is present in most cells of the body. We have shown previously that for individuals of extreme chronotype ("larks" and "owls"), clock properties measured in human fibroblasts correlated with extreme diurnal behavior.

      I Gogenur, B Middleton, S Burgdorf, LS Rasmussen, DJ Skene, J Rosenberg (2007)Impact of sleep and circadian disturbances in urinary 6-sulphatoxymelatonin levels, on cognitive function after major surgery, In: JOURNAL OF PINEAL RESEARCH43(2)pp. 179-184 BLACKWELL PUBLISHING
      P Gringras, B Middleton, DJ Skene, VL Revell (2015)Bigger, Brighter, Bluer-Better? Current Light-Emitting Devices - Adverse Sleep Properties and Preventative Strategies., In: Frontiers in public health3 Frontiers Media

      OBJECTIVE: In an effort to enhance the efficiency, brightness, and contrast of light-emitting (LE) devices during the day, displays often generate substantial short-wavelength (blue-enriched) light emissions that can adversely affect sleep. We set out to verify the extent of such short-wavelength emissions, produced by a tablet (iPad Air), e-reader (Kindle Paperwhite 1st generation), and smartphone (iPhone 5s) and to determine the impact of strategies designed to reduce these light emissions. SETTING: University of Surrey dedicated chronobiology facility. METHODS: First, the spectral power of all the LE devices was assessed when displaying identical text. Second, we compared the text output with that of "Angry Birds" - a popular top 100 "App Store" game. Finally, we measured the impact of two strategies that attempt to reduce the output of short-wavelength light emissions. The first strategy employed an inexpensive commercially available pair of orange-tinted "blue-blocking" glasses. The second strategy tested an app designed to be "sleep-aware" whose designers deliberately attempted to reduce short-wavelength light emissions. RESULTS: All the LE devices shared very similar enhanced short-wavelength peaks when displaying text. This included the output from the backlit Kindle Paperwhite device. The spectra when comparing text to the Angry Birds game were also very similar, although the text emissions were higher intensity. Both the orange-tinted glasses and the "sleep-aware" app significantly reduced short-wavelength emissions. CONCLUSION: The LE devices tested were all bright and characterized by short-wavelength enriched emissions. Since this type of light is likely to cause the most disruption to sleep as it most effectively suppresses melatonin and increases alertness, there needs to be the recognition that at night-time "brighter and bluer" is not synonymous with "better." Ideally future software design could be better optimized when night-time use is anticipated, and hardware should allow an automatic "bedtime mode" that shifts blue and green light emissions to yellow and red as well as reduce backlight/light intensity.

      Debra Skene, Benita Middleton, CK Fraser, JLA Pennings, TR Kuchel, SR Rudiger, CS Bawden, AJ Morton (2017)Metabolic profiling of presymptomatic Huntington’s disease sheep reveals novel biomarkers, In: Scientific Reports743030 Nature Publishing Group

      The pronounced cachexia (unexplained wasting) seen in Huntington’s disease (HD) patients suggests that metabolic dysregulation plays a role in HD pathogenesis, although evidence of metabolic abnormalities in HD patients is inconsistent. We performed metabolic profiling of plasma from presymptomatic HD transgenic and control sheep. Metabolites were quantified in sequential plasma samples taken over a 25h period using a targeted LC/MS metabolomics approach. Significant changes with respect to genotype were observed in 89/130 identified metabolites, including sphingolipids, biogenic amines, amino acids and urea. Citrulline and arginine increased significantly in HD compared to control sheep. Ten other amino acids decreased in presymptomatic HD sheep, including branched chain amino acids (isoleucine, leucine and valine) that have been identified previously as potential biomarkers of HD. Significant increases in urea, arginine, citrulline, asymmetric and symmetric dimethylarginine, alongside decreases in sphingolipids, indicate that both the urea cycle and nitric oxide pathways are dysregulated at early stages in HD. Logistic prediction modelling identified a set of 8 biomarkers that can identify 80% of the presymptomatic HD sheep as transgenic, with 90% confidence. This level of sensitivity, using minimally invasive methods, offers novel opportunities for monitoring disease progression in HD patients.

      M Herljevic, Benita Middleton, K Thapan, Debra Skene (2005)Light-induced melatonin suppression: age-related reduction in response to short wavelength light, In: Experimental Gerontology40(3)pp. 237-242 Elsevier

      One of the possible causes of disturbed circadian rhythms and sleep in the elderly may be impaired photic input to the circadian clock. Age-related changes in lens density are known to reduce the transmission of short wavelength light, which has been shown to be most effective in suppressing nocturnal melatonin. The aim of the study therefore was to investigate age-related changes in melatonin suppression in response to short and medium wavelength light. Young premenopausal (n=13) and postmenopausal (n=21) women were exposed to 30 min of monochromatic light at two different wavelengths and irradiances (λmax 456 nm: 3.8 and 9.8 μW/cm2; λmax 548 nm: 28 and 62 μW/cm2). Melatonin suppression was compared across light treatments and between age groups. Significantly reduced melatonin suppression was noted in the elderly subjects following exposure to short wavelength (456 nm) light compared to the young subjects. These results are likely to reflect age-related changes in lens density.

      MA Ulhôa, EC Marqueze, T Kantermann, D Skene, C Moreno (2011)When does stress end? Evidence of a prolonged stress reaction in shiftworking truck drivers., In: Chronobiology International28(9)pp. 810-818 Informa Healthcare

      This study aimed to analyze individual cortisol levels in relation to work conditions, sleep, and health parameters among truck drivers working day shifts (n?=?21) compared to those working irregular shifts (n?=?21). A total of 42 male truck drivers (39.8???6.2 yrs) completed questionnaires about sociodemographics, job content, work environment, health, and lifestyle. Rest-activity profiles were measured using actigraphy, and cardiovascular blood parameters were collected. Salivary cortisol samples were obtained: (i) at waking time, (ii) 30?min after waking, and (iii) at bedtime, during both one workday and one day off from work. Irregular-shift workers, compared to day-shift workers, showed significantly higher waist-hip ratio, very-low-density lipoprotein (VLDL) cholesterol, tiredness after work, years working as a driver, truck vibration, and less job demand (p?

      J Arendt, DJ Skene (2005)Melatonin as a chronobiotic, In: SLEEP MEDICINE REVIEWS9(1)pp. 25-39 W B SAUNDERS CO LTD
      K Ackermann, TL Sletten, VL Revell, SN Archer, DJ Skene (2009)Blue-Light Phase Shifts PER3 Gene Expression in Human Leukocytes, In: CHRONOBIOLOGY INTERNATIONAL26(4)PII 911212pp. 769-779 TAYLOR & FRANCIS INC
      P.A. Nehme, F. Amaral, A. Lowden, D.J. Skene, J. Cipolla-Neto, C.R.C. Moreno (2019)Reduced melatonin synthesis in pregnant night workers: Metabolic implications for offspring, In: Medical Hypotheses132109353pp. 1-5 Elsevier

      Several novel animal studies have shown that intrauterine metabolic programming can be modified in the event of reduced melatonin synthesis during pregnancy, leading to glucose intolerance and insulin resistance in the offspring. It is therefore postulated that female night workers when pregnant may expose the offspring to unwanted health threats. This may be explained by the fact that melatonin is essential for regulating energy metabolism and can influence reproductive activity. Moreover, the circadian misalignment caused by shift work affects fertility and the fetus, increasing the risk of miscarriage, premature birth and low birth weight, phenomena observed in night workers. Thus, we hypothesize that light-induced melatonin suppression as a result of night work may alter intrauterine metabolic programming in pregnant women, potentially leading to metabolic disorders in their offspring.

      GF Giskeodegard, SK Davies, VL Revell, H Keun, DJ Skene (2015)Diurnal rhythms in the human urine metabolome during sleep and total sleep deprivation, In: SCIENTIFIC REPORTS5ARTN 1 NATURE PUBLISHING GROUP

      Understanding how metabolite levels change over the 24 hour day is of crucial importance for clinical and epidemiological studies. Additionally, the association between sleep deprivation and metabolic disorders such as diabetes and obesity requires investigation into the links between sleep and metabolism. Here, we characterise time-of-day variation and the effects of sleep deprivation on urinary metabolite profiles. Healthy male participants (n = 15) completed an in-laboratory study comprising one 24 h sleep/wake cycle prior to 24 h of continual wakefulness under highly controlled environmental conditions. Urine samples were collected over set 2-8 h intervals and analysed by (1)H NMR spectroscopy. Significant changes were observed with respect to both time of day and sleep deprivation. Of 32 identified metabolites, 7 (22%) exhibited cosine rhythmicity over at least one 24 h period; 5 exhibiting a cosine rhythm on both days. Eight metabolites significantly increased during sleep deprivation compared with sleep (taurine, formate, citrate, 3-indoxyl sulfate, carnitine, 3-hydroxyisobutyrate, TMAO and acetate) and 8 significantly decreased (dimethylamine, 4-DTA, creatinine, ascorbate, 2-hydroxyisobutyrate, allantoin, 4-DEA, 4-hydroxyphenylacetate). These data indicate that sampling time, the presence or absence of sleep and the response to sleep deprivation are highly relevant when identifying biomarkers in urinary metabolic profiling studies.

      CR Moreno, S Vasconcelos, EC Marqueze, A Lowden, B Middleton, FM Fischer, FM Louzada, DJ Skene (2015)Sleep patterns in Amazon rubber tappers with and without electric light at home., In: SCIENTIFIC REPORTS5 NATURE PUBLISHING GROUP

      Today's modern society is exposed to artificial electric lighting in addition to the natural light-dark cycle. Studies assessing the impact of electric light exposure on sleep and its relation to work hours are rare due to the ubiquitous presence of electricity. Here we report a unique study conducted in two phases in a homogenous group of rubber tappers living and working in a remote area of the Amazon forest, comparing those living without electric light (n = 243 in first phase; n = 25 in second phase) to those with electric light at home (n = 97 in first phase; n = 17 in second phase). Questionnaire data (Phase 1) revealed that rubber tappers with availability of electric light had significantly shorter sleep on work days (30 min/day less) than those without electric light. Analysis of the data from the Phase 2 sample showed a significant delay in the timing of melatonin onset in workers with electric light compared to those without electric light (p 

      RE Mistlberger, DJ Skene (2005)Nonphotic entrainment in humans?, In: JOURNAL OF BIOLOGICAL RHYTHMS20(4)pp. 339-352 SAGE PUBLICATIONS LTD
      JB Zawilska, M Berezinska, O Stasikowska, A Lorenc, DJ Skene, JZ Nowak (2005)Posthatching developmental changes in noradrenaline content in the chicken pineal gland, In: JOURNAL OF PINEAL RESEARCH38(2)pp. 123-129 BLACKWELL MUNKSGAARD
      Sophie Wehrens, Shelagh Hampton, RE Finn, Debra Skene (2010)Effect of total sleep deprivation on postprandial metabolic and insulin responses in shift workers and non-shift workers, In: Journal of Endocrinology206(2)pp. 205-215

      Epidemiological studies have shown that shift workers are at a greater risk of developing cardiovascular disease which may, in part, be related to metabolic and hormonal changes. Partial sleep deprivation, a common consequence of rotating shift work, has been shown to affect glucose tolerance and insulin sensitivity. The current study investigated the effects of one night of total sleep deprivation, as a proxy for the first night shift, on postprandial glucose, insulin and lipid (triacylglycerols (TAGs) and non-esterified fatty acids (NEFAs)) responses under controlled laboratory conditions in shift workers and non-shift workers. Eleven experienced shift workers (35.7±7.2 years, mean±s.d.) who had worked in shifts for 8.7±5.25 years were matched with 13 non-shift workers who had worked for 32.8±6.4 years. After an adaptation night and a baseline sleep night, volunteers were kept awake for 30.5 h, followed by a nap (4 h) and recovery sleep. Blood samples were taken prior to and after a standard breakfast following baseline sleep, total sleep deprivation and recovery sleep. Basal TAG levels prior to the standard breakfast were significantly lower after sleep deprivation, indicating higher energy expenditure. Basal NEFA levels were significantly lower after recovery sleep. Postprandial insulin and TAG responses were significantly increased, and the NEFA response was decreased after recovery sleep, suggestive of insulin insensitivity. Although there were no overall significant differences between non-shift workers and shift workers, non-shift workers showed significantly higher basal insulin levels, lower basal NEFA levels, and an increased postprandial insulin and a decreased NEFA response after recovery sleep. In future, the reasons for these inter-group differences are to be investigated.

      DL Robilliard, SN Archer, J Arendt, SW Lockley, LM Hack, J English, D Leger, MG Smits, A Williams, DJ Skene, M von Schantz (2002)The 3111 Clock gene polymorphism is not associated with sleep and circadian rhythmicity in phenotypically characterized human subjects, In: JOURNAL OF SLEEP RESEARCH11(4)pp. 305-312 BLACKWELL PUBLISHING LTD
      DJ Skene, SE Timbers, B Middleton, J English, C Kopp, I Tobler, C Ioannides (2006)Mice convert melatonin to 6-sulphatoxymelatonin, In: GENERAL AND COMPARATIVE ENDOCRINOLOGY147(3)pp. 371-376 ACADEMIC PRESS INC ELSEVIER SCIENCE
      C Papamichael, DJ Skene, VL Revell (2012)Human non-visual responses to simultaneous presentation of blue and red monochromatic light., In: Journal of Biological Rhythms27(1)pp. 70-78 Sage

      Blue light sensitivity of melatonin suppression and subjective mood and alertness responses in humans is recognised as being melanopsin based. Observations that long wavelength (red) light can potentiate responses to subsequent short wavelength (blue) light have been attributed to the bistable nature of melanopsin whereby it forms stable associations with both 11-cis and alltrans isoforms of retinaldehyde and uses light to transition between these states. The current study examined the effect of concurrent administration of blue and red monochromatic light, as would occur in real-world white light, on acute melatonin suppression and subjective mood and alertness responses in humans. Young healthy males (18-35 years; n = 21) were studied in highly controlled laboratory sessions that included an individually timed 30 min light stimulus of blue (λmax 479 nm) or red (λmax 627 nm) monochromatic light at varying intensities (1013 - 1014 photons/cm2/s) presented, either alone or in combination, in a within-subject randomised design. Plasma melatonin levels and subjective mood and alertness were assessed at regular intervals relative to the light stimulus. Subjective alertness levels were elevated after light onset irrespective of light wavelength or irradiance. For melatonin suppression, a significant irradiance response was observed with blue light. Co-administration of red light, at any of the irradiances tested, did not significantly alter the response to blue light alone. Under the current experimental conditions the primary determinant of the melatonin suppression response was the irradiance of blue 479 nm light and this was unaffected by simultaneous red light administration.

      M De Rui, S Gaiani, B Middleton, DJ Skene, S Schiff, A Gatta, C Merkel, P Amodio, S Montagnese (2011)Bright times for patients with cirrhosis and delayed sleep habits: a case report on the beneficial effect of light therapy., In: Am J Gastroenterol106(11)pp. 2048-2049
      TL Sletten, VL Revell, B Middleton, KA Lederle, DJ Skene (2009)Age-Related Changes in Acute and Phase-Advancing Responses to Monochromatic Light, In: JOURNAL OF BIOLOGICAL RHYTHMS24(1)pp. 73-84 SAGE PUBLICATIONS INC
      JB Zawilska, A Lorenc, M Berezinska, B Vivien-Roels, P Pevet, DJ Skene (2006)Diurnal and circadian rhythms in melatonin synthesis in the turkey pineal gland and retina, In: GENERAL AND COMPARATIVE ENDOCRINOLOGY145(2)pp. 162-168 ACADEMIC PRESS INC ELSEVIER SCIENCE
      JD Carpen, SN Archer, DJ Skene, M Smits, M von Schantz (2005)A single-nucleotide polymorphism in the 5 '-untranslated region of the hPER2 gene is associated with diurnal preference, In: JOURNAL OF SLEEP RESEARCH14(3)pp. 293-297 BLACKWELL PUBLISHING
      VL Revell, J Arendt, M Terman, DJ Skene (2005)Short-wavelength sensitivity of the human circadian system to phase-advancing light, In: JOURNAL OF BIOLOGICAL RHYTHMS20(3)pp. 270-272 SAGE PUBLICATIONS LTD
      S Montagnese, B Middleton, M Corrias, AR Mani, DJ Skene, MY Morgan (2015)Assessment of 6-sulfatoxymelatonin rhythms and melatonin response to light in disease states: Lessons from cirrhosis, In: CHRONOBIOLOGY INTERNATIONAL32(2)pp. 187-194 INFORMA HEALTHCARE

      Circadian rhythmicity and non-visual sensitivity to light can be assessed, in healthy subjects, by measuring the rhythm of the urinary melatonin metabolite 6-sulphatoxymelatonin (aMT6s) and by determining the response of plasma melatonin to nocturnal retinal light exposure, respectively. However, the validity of these techniques has not been assessed in disease states in which disruption of the circadian rhythm is known or suspected to occur. Thus, the aims of this study were as follows: (i) to assess the reliability of circadian aMT6s profile estimates derived from 36 h versus 56 h urine collections and (ii) to test different models for calculating melatonin suppression in response to light in healthy volunteers and patients with cirrhosis. Twenty patients with biopsy-proven cirrhosis and 10 matched healthy volunteers undertook: (i) separate 36 - and 56-h urine collections, under controlled conditions, for cosinor analysis of the urinary aMT6s profile; (ii) a melatonin suppression test, comprising of a baseline night, during which subjects were woken and asked to sit in front of a switched off light sphere, and an experimental night, identically executed, except that the light sphere was switched on and the subjects were exposed to white light (4.1 × 10(14) photons/cm(2)/s) for 30 min. Alternative approaches to the calculation of melatonin suppression were taken, with/without inclusion of the baseline night. Eighteen patients and eight healthy volunteers had matched analysable 36 - and 56-h urinary samples. Cosinor analysis showed a significant fit in 88% of the remaining 56 h collections, and 48% of the remaining 36-h collections. Thus, eight patients and five healthy volunteers had matched analysable samples for cosinor analysis. In the healthy volunteers, aMT6s profile indices obtained using the 36 - and the 56-h collections did not differ significantly. In contrast, considerably more variability was observed in patients [i.e. the difference in the aMT6s peak time was 0.5 ± 1.7 h (limits of agreement: -3.9; +2.9 h)]. No difficulties were encountered in obtaining suppression estimates by use of the experimental night only. In contrast, suppression estimates obtained by use of both nights were considered inaccurate in one (11%) healthy volunteer and in 5 (28%) patients, primarily because: (i) melatonin concentrations at the beginning of light administration were significantly different on baseline and experimental night; (ii) the rise in melatonin was inconsistent on baseline night; and (iii) the shape of the rising phase of melatonin was different on baseline and experimental night. In conclusion, shorter urine collections lead to a higher number of profiles with no significant cosinor fit, and differences in cosinor indices obtained from the 36 - and 56-h collections were considerable, especially in patients. Thus, 56-h collections are probably advisable. Use of both baseline and experimental nights to calculate melatonin suppression often resulted in increased variation and confounding, due to point oscillations in melatonin concentration and lack of repeatability of the melatonin profiles on the two nights. Thus, use of the experimental night only is probably advisable.

      Mirjam Munch, Anna Wirz-Justice, Steven Brown, Thomas Kantermann, Klaus Martiny, Oliver Stefani, Celine Vetter, Kenneth P. Wright Jr., Katharina Wulff, Debra Skene (2020)The role of daylight for humans: Gaps in current knowledge, In: Clocks and Sleep2(1)pp. 61-85 MDPI

      Daylight stems solely from direct, scattered and reflected sunlight, and undergoes dynamic changes in irradiance and spectral power composition due to latitude, time of day, time of year and the nature of the physical environment (reflections, buildings and vegetation). Humans and their ancestors evolved under these natural day/night cycles over millions of years. Electric light, a relatively recent invention, interacts and competes with the natural light–dark cycle to impact human biology. What are the consequences of living in industrialised urban areas with much less daylight and more use of electric light, throughout the day (and at night), on general health and quality of life? In this workshop report, we have classified key gaps of knowledge in daylight research into three main groups: (I) uncertainty as to daylight quantity and quality needed for “optimal” physiological and psychological functioning, (II) lack of consensus on practical measurement and assessment methods and tools for monitoring real (day) light exposure across multiple time scales, and (III) insufficient integration and exchange of daylight knowledge bases from different disciplines. Crucial short and long-term objectives to fill these gaps are proposed.

      E Papagiannidou, DJ Skene, C Ioannides (2014)Potential drug interactions with melatonin, In: PHYSIOLOGY & BEHAVIOR131pp. 17-24 PERGAMON-ELSEVIER SCIENCE LTD
      F Auld, EL Maschauer, I Morrison, Debra Skene, RL Riha (2016)Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders, In: Sleep Medicine Reviews34pp. 10-22 Elsevier

      Melatonin is a physiological hormone involved in sleep timing and is currently used exogenously in the treatment of primary and secondary sleep disorders with empirical evidence of efficacy, but very little evidence from randomised, controlled studies. The aim of this meta-analysis was to assess the evidence base for the therapeutic effects of exogenous melatonin in treating primary sleep disorders. An electronic literature review search of MEDLINE (1950-present) EMBASE (1980- present), PsycINFO (1987- present), and SCOPUS (1990- present), along with a hand-searching of key journals was performed in July 2013 and then again in May 2015. This identified all studies that compared the effect of exogenous melatonin and placebo in patients with primary insomnia, delayed sleep phase syndrome, Non 24- hour sleep wake syndrome in people who are blind, and REM-Behaviour Disorder. Meta-analyses were performed to determine the effect of magnitude in studies of melatonin in improving sleep. A total of 5030 studies were identified; of these citations, 13 were included for review based on the inclusion criteria of being: double or single-blind, randomised and controlled. Results from the meta-analyses showed the most convincing evidence for exogenous melatonin use was in reducing sleep onset latency in primary insomnia (p=0.002), delayed sleep phase syndrome (p

      T Kantermann, DJ Skene, D Haubruge (2013)The Shift-Work Accident Rate is More Related to the Shift Type than to Shift Rotation, In: Human and Ecological Risk Assessment19(6)pp. 1586-1594 Taylor and Francis

      The current study investigated the accident rates across morning, late, and night shifts in rotating shift-workers employed in two different shift rotations at the same steel work factory. A retrospective analysis has been performed of accident data (N = 578) over a 5-year period (2003 through 2007) of 730 male shift-workers employed in either a clockwise (mean age of the workers 38.1 ± SD 9.8 years) or counterclockwise rotation (mean age 38.0 ± SD 10.1 years) with comparable work conditions. The overall accident rate across the 24-h day was not significantly different between clockwise and counterclockwise shift rotation. In both shift-work rotations, morning shifts as opposed to night shifts exhibited a significantly higher accident rate. There was no significant difference between late shifts and morning or night shifts in either shift rotation. The increased accident rate in the morning shift at this steel factory could be related to the early starting time of the shift and to this shift being more labor intensive in both shift rotations. These findings suggest that work-related factors must be considered in addition to shift-work schedules when investigating accident rates in rotating shift-workers. © 2013 Copyright Taylor and Francis Group, LLC.

      Roberta Bonomo, Guido Cavaletti, Debra Skene (2020)Metabolomics markers in Neurology: current knowledge and future perspectives for therapeutic targeting., In: Expert Review of Neurotherapeutics Taylor and Francis

      Introduction: Metabolomics is an emerging approach providing new insights into the 7 metabolic changes and underlying mechanisms involved in the pathogenesis of 8 neurological disorders. 9 Areas covered: Here, we present an overview of the current knowledge of metabolic 10 profiling (metabolomics) to provide critical insight on the role of biochemical markers and metabolic alterations in neurological diseases. Expert opinion: Elucidation of characteristic metabolic alterations in neurological disorders is crucial for a better understanding of their pathogenesis, and for identifying potential biomarkers and drug targets. Nevertheless, discrepancies in diagnostic criteria, sample handling protocols, and analytical methods still affect the generalizability of current study results.

      Shanaz Diessler, Maxime Jan, Yann Emmenegger, Nicolas Guex, Benita Middleton, Debra J. Skene, Mark Ibberson, Frederic Burdet, Lou Götz, Marco Pagni, Martial Sankar, Robin Liechti, Charlotte N. Hor, Ioannis Xenarios, Paul Franken (2018)A systems genetics resource and analysis of sleep regulation in the mouse, In: PLOS Biology16(8)e2005750pp. 1-39 Public Library of Science

      Sleep is essential for optimal brain functioning and health, but the biological substrates through which sleep delivers these beneficial effects remain largely unknown. We used a systems genetics approach in the BXD genetic reference population (GRP) of mice and assembled a comprehensive experimental knowledge base comprising a deep "sleep-wake" phenome, central and peripheral transcriptomes, and plasma metabolome data, collected under undisturbed baseline conditions and after sleep deprivation (SD). We present analytical tools to interactively interrogate the database, visualize the molecular networks altered by sleep loss, and prioritize candidate genes. We found that a one-time, short disruption of sleep already extensively reshaped the systems genetics landscape by altering 60%–78% of the transcriptomes and the metabolome, with numerous genetic loci affecting the magnitude and direction of change. Systems genetics integrative analyses drawing on all levels of organization imply α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking and fatty acid turnover as substrates of the negative effects of insufficient sleep. Our analyses demonstrate that genetic heterogeneity and the effects of insufficient sleep itself on the transcriptome and metabolome are far more widespread than previously reported.

      JF Walters, SM Hampton, GA Ferns, DJ Skene (2005)Effect of menopause on melatonin and alertness rhythms investigated in constant routine conditions., In: Chronobiol Int22(5)pp. 859-872

      Although studies have reported the effects of the menstrual cycle on melatonin rhythmicity, none has investigated the effects of menopause on the melatonin rhythm. The circadian rhythm in melatonin and its relationship to subjective alertness was investigated in pre- and postmenopausal women under constant routine conditions (controlled posture, dim lighting, calorie intake, temperature, and prolonged wakefulness). Eleven healthy pre-menopausal (42+/-4 yr) and 10 postmenopausal women (55+/-2 yr) participated in the study. Salivary melatonin samples and subjective measures of alertness and sleepiness were assessed hourly during the 22 h constant routine protocol. Postmenopausal women had a significantly earlier melatonin acrophase (1.1+/-0.5 h clock time in decimal h; mean+/-SEM, p

      PJ Gunn, Benita Middleton, SK Davies, Victoria Revell, Debra Skene (2016)Sex differences in the circadian profiles of melatonin and cortisol in plasma and urine matrices under constant routine conditions, In: CHRONOBIOLOGY INTERNATIONAL33(1)pp. 39-50 TAYLOR & FRANCIS INC

      Conflicting evidence exists as to whether there are differences between males and females in circadian timing. The aim of the current study was to assess whether sex differences are present in the circadian regulation of melatonin and cortisol in plasma and urine matrices during a constant routine protocol. Thirty-two healthy individuals (16 females taking the oral contraceptive pill (OCP)), aged 23.8 ± 3.7 (mean ± SD) years, participated. Blood (hourly) and urine (4-hourly) samples were collected for measurement of plasma melatonin and cortisol, and urinary 6-sulfatoxymelatonin (aMT6s) and cortisol, respectively. Data from 28 individuals (14 females) showed no significant differences in the timing of plasma and urinary circadian phase markers between sexes. Females, however, exhibited significantly greater levels of plasma melatonin and cortisol than males (AUC melatonin: 937 ± 104 (mean ± SEM) vs. 642 ± 47 pg/ml.h; AUC cortisol: 13581 ± 1313 vs. 7340 ± 368 mmol/L.h). Females also exhibited a significantly higher amplitude rhythm in both hormones (melatonin: 43.8 ± 5.8 vs. 29.9 ± 2.3 pg/ml; cortisol: 241.7 ± 23.1 vs. 161.8 ± 15.9 mmol/L). Males excreted significantly more urinary cortisol than females during the CR (519.5 ± 63.8 vs. 349.2 ± 39.3 mol) but aMT6s levels did not differ between sexes. It was not possible to distinguish whether the elevated plasma melatonin and cortisol levels observed in females resulted from innate sex differences or the OCP affecting the synthetic and metabolic pathways of these hormones. The fact that the sex differences observed in total plasma concentrations for melatonin and cortisol were not reproduced in the urinary markers challenges their use as a proxy for plasma levels in circadian research, especially in OCP users.

      SK Davies, JE Ang, VL Revell, B Holmes, A Mann, FP Robertson, N Cui, B Middleton, K Ackermann, M Kayser, AE Thumser, FI Raynaud, DJ Skene (2014)Effect of sleep deprivation on the human metabolome, In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA111(29)pp. 10761-10766 NATL ACAD SCIENCES
      MA Bonmati-Carrion, B Middleton, VL Revell, DJ Skene, MA Rol, JA Madrid (2015)Validation of an innovative method, based on tilt sensing, for the assessment of activity and body position, In: CHRONOBIOLOGY INTERNATIONAL32(5)pp. 701-710 INFORMA HEALTHCARE
      Maria-Angeles Bonmati-Carrion, Victoria Revell, Tom J. Cook, Thomas R.E Welch, Maria-Angeles Rol, DEBRA JEAN SKENE, Juan Antonio Madrid (2020)Living Without Temporal Cues: A Case Study, In: Frontiers in Physiology11 Frontiers Media

      Isolation from external time cues allows endogenous circadian rhythmicity to be demonstrated. In this study, also filmed as a television documentary, we assessed rhythmic changes in a healthy man time isolated in a bunker for 9 days/nights. During this period the lighting conditions were varied between: (1) self-selected light/dark cycle, (2) constant dim light, and (3) light/dark cycle with early wake up. A range of variables was assessed and related to the sleep-wake cycle, psychomotor and physical performance and clock-time estimation. This case study using modern non-invasive monitoring techniques emphasizes how different physiological circadian rhythms persist in temporal isolation under constant dim light conditions with different waveforms, free-running with a period (t) between 24 and 25 h. In addition, a significant correlation between time estimation and mid-sleep time, a proxy for circadian phase, was demonstrated.

      Aya Honma, Victoria L. Revell, Pippa J. Gunn, Sarah K. Davies, Benita Middleton, Florence I. Raynaud, Debra J. Skene (2019)Effect of Acute Total Sleep Deprivation on Plasma Melatonin, Cortisol and Metabolite Rhythms in Females, In: European Journal of Neuroscience Wiley

      Disruption to sleep and circadian rhythms can impact on metabolism. The study aimed to investigate the effect of acute sleep deprivation on plasma melatonin, cortisol and metabolites, to increase understanding of the metabolic pathways involved in sleep/wake regulation processes. Twelve healthy young female subjects remained in controlled laboratory conditions for ~92 h with respect to posture, meals and environment light (18:00‐23:00 h and 07:00‐09:00 h

      VL Revell, J Arendt, FF Louis, DJ Skene (2006)Alerting effects of light are sensitive to very short wavelengths, In: NEUROSCIENCE LETTERS399(1-2)pp. 96-100 ELSEVIER IRELAND LTD
      A.L. Darling, K.H. Hart, S. Arber, J.L. Berry, P.L. Morgan, B.A. Middleton, S. Lanham-New, D.J. Skene (2019)25-Hydroxyvitamin D status, light exposure and sleep quality in UK dwelling South Asian and Caucasian postmenopausal women, In: The Journal of Steroid Biochemistry and Molecular Biology189pp. pp 265-273 Elsevier

      There is a lack of research into 25-hydroxyvitamin D (25(OH)D) status, light exposure and sleep patterns in South Asian populations. In addition, results of research studies are conflicting as to whether there is an association between 25(OH)D status and sleep quality. We investigated 25(OH)D status, self-reported and actigraphic sleep quality in n = 35 UK dwelling postmenopausal women (n = 13 South Asians, n = 22 Caucasians), who kept daily sleep diaries and wore wrist-worn actiwatch (AWL-L) devices for 14 days. A subset of n = 27 women (n = 11 South Asian and n = 16 Caucasian) also wore a neck-worn AWL-L device to measure their light exposure. For 25(OH)D concentration, South Asians had a median ± IQR of 43.8 ± 28.2 nmol/L, which was significantly lower than Caucasians (68.7 ± 37.4 nmol/L)(P = 0.001). Similarly, there was a higher sleep fragmentation in the South Asians (mean ± SD 36.9 ± 8.9) compared with the Caucasians (24.7 ± 7.1)(P = 0.002). Non-parametric circadian rhythm analysis of rest/activity patterns showed a higher night-time activity (L5) (22.6 ± 14.0 vs. 10.5 ± 4.4; P = 0.0008) and lower relative amplitude (0.85 ± 0.07 vs. 0.94 ± 0.02; P ˂ 0.0001) in the South Asian compared with the Caucasian women. More South Asians (50%) met the criteria for sleep disorders (PSQI score ˃5) than did Caucasians (27%) (P = 0.001, Fishers Exact Test). However, there was no association between 25(OH)D concentration and any sleep parameter measured (P ˃ 0.05) in either ethnic group. South Asians spent significantly less time in illuminance levels over 200 lx (P = 0.009) than did Caucasians. Overall, our results show that postmenopausal South Asian women have lower 25(OH)D concentration than Caucasian women. They also have higher sleep fragmentation, as well as a lower light exposure across the day. This may have detrimental implications for their general health and further research into sleep quality and light exposure in the South Asian ethnic group is warranted.

      S Montagnese, B Middleton, AR Mani, DJ Skene, MY Morgan (2009)Sleep and circadian abnormalities in patients with cirrhosis: features of delayed sleep phase syndrome?, In: METAB BRAIN DIS24(3)pp. 427-439 SPRINGER/PLENUM PUBLISHERS

      Sleep disturbances are common in patients with cirrhosis but their origins are unknown. The aim of this study was to investigate possible involvement of the circadian system. Sleep was monitored for two weeks, in the home environment, using sleep diaries and actigraphy, in 35 patients with cirrhosis (21 men; mean age [+/- 1SD] 58 +/- 10 yr) and 12 matched healthy controls (eight men; mean age 56 +/- 15 yr); urinary 6-sulphatoxymelatonin (aMT6s), the major metabolite of melatonin, was measured over 56 h, to assess circadian rhythmicity. The patients woke up and got up significantly later than the healthy volunteers and their sleep was significantly more fragmented. Mean 24-hour urinary aMT6s outputs were comparable in the patients and controls (15.5 +/- 13.1 vs. 20.3 +/- 13.8 mu g/24 h) but were significantly lower in the decompensated patients (9.8 +/- 11.3 vs. 17.0 +/- 13.3 mu g/24 h; p=0.03). Significant 24-hour urinary aMT6s rhythms were observed in 26 (79%) of the 33 patients with complete urine collections; 20 patients had a normally timed (midnight-06:00) urinary aMT6s peak, while it was delayed (>= 06:00) in the remainder. Significant correlations were observed between abnormalities in the urinary aMT6s profile (delays and/or lack of a 24-hour rhythm) and indices of sleep timing; parallel delays were observed in sleep habits and urinary aMT6s peaks. The association between delayed circadian rhythms and delayed sleep habits observed in approximately one-third of the patients with cirrhosis is reminiscent of 'delayed sleep phase syndrome'; this condition is managed by attempting to resynchronise the circadian clock by exposure to bright light shortly after morning awakening.

      M Turco, A Biscontin, M Corrias, L Caccin, M Bano, F Chiaromanni, M Salamanca, D Mattei, C Salvoro, G Mazzotta, C De Pittà, Benita Middleton, Debra Skene, S Montagnese, R Costa (2017)Diurnal preference, mood and the response to morning light in relation to polymorphisms in the human clock gene PER3, In: Scientific Reports7(6967)pp. 1-10 Nature Publishing Group

      PER3 gene polymorphisms have been associated with differences in human sleep-wake phenotypes, and sensitivity to light. The aims of this study were to assess: i) the frequency of allelic variants at two PER3 polymorphic sites (rs57875989 length polymorphism: PER34, PER35; rs228697 SNP: PER3C, PER3G) in relation to sleep-wake timing; ii) the effect of morning light on behavioural/circadian variables in PER34/PER34 and PER35/PER35 homozygotes. 786 Caucasian subjects living in Northern Italy donated buccal DNA and completed diurnal preference, sleep quality/timing and sleepiness/ mood questionnaires. 19 PER34/PER34 and 11 PER35/PER35 homozygotes underwent morning light administration, whilst monitoring sleep-wake patterns and the urinary 6-sulphatoxymelatonin (aMT6s) rhythm. No significant relationship was observed between the length polymorphism and diurnal preference. By contrast, a significant association was observed between the PER3G variant and morningness (OR = 2.10), and between the PER3G-PER34 haplotype and morningness (OR = 2.19), for which a mechanistic hypothesis is suggested. No significant differences were observed in sleep timing/ aMT6s rhythms between PER35/PER35 and PER34/PER34 subjects at baseline. After light administration, PER34/PER34 subjects advanced their aMT6s acrophase (p < 0.05), and showed a trend of advanced sleep-wake timing. In conclusion, significant associations were observed between PER3 polymorphic variants/their combinations and both diurnal preference and the response to light.

      Greg Murray, John Gottlieb, Maria Paz Hidalgo, Bruno Etain, Philipp Ritter, Debra Skene, Corrado Garbazza, Ben Bullock, Kathleen Merikangas, Vadim Zipunnikov, Haochang Shou, Robert Gonzalez, Jan Scott, Pierre A. Geoffroy, Benicio N. Frey (2020)Measuring circadian function in bipolar disorders: Empirical and conceptual review of physiological, actigraphic, and self-report approaches, In: Bipolar Disorders22(7)pp. 693-710 John Wiley and Sons

      Background: Interest in biological clock pathways in bipolar disorders (BD) continues to grow, but there has yet to be an audit of circadian measurement tools for use in BD research and practice. Procedure: The International Society for Bipolar Disorders Chronobiology Task Force conducted a critical integrative review of circadian methods that have real-world applicability. Consensus discussion led to the selection of three domains to review – melatonin assessment, actigraphy and self-report. Results: Measurement approaches used to quantify circadian function in BD are described in sufficient detail for researchers and clinicians to make pragmatic decisions about their use. A novel integration of the measurement literature is offered in the form of a provisional taxonomy distinguishing between circadian measures (the instruments and methods used to quantify circadian function, such as dim light melatonin onset) and circadian constructs (the biobehavioural processes to be measured, such as circadian phase). Conclusions: Circadian variables are an important target of measurement in clinical practice and biomarker research. To improve reproducibility and clinical application of circadian constructs, an informed systematic approach to measurement is required. We trust that this review will decrease ambiguity in the literature and support theory-based consideration of measurement options.

      SM Wehrens, SM Hampton, DJ Skene (2012)Heart rate variability and endothelial function after sleep deprivation and recovery sleep among male shift and non-shift workers., In: Scandinavian Journal of Work, Environmental & Health38(12)pp. 171-181 Scandinavian Journal of Work, Environmental & Health

      OBJECTIVES: Endothelial dysfunction and alterations in heart rate variability (HRV) as well as sleep deprivation and shift work have been associated with cardiovascular disease. The aim of this study was to compare HRV and endothelial function among shift and matched non-shift workers in response to total sleep deprivation and recovery sleep under identical laboratory settings. METHODS: Eleven experienced male shift workers (shift work ≥5 years) and 14 non-shift workers were matched for age, body mass index, and cholesterol. HRV parameters [eg, HR variance and low frequency/high frequency (LF/HF) ratio] were derived from 5-minute electrocardiogram bins at 0.25, 4.25, 11.5, 12.5, and 13.5 hours after habitual wake-up time and endothelial function was assessed by flow-mediated dilatation (FMD) using ultrasound at 0.75 and 10.75 hours after habitual wake-up time, following baseline sleep, total sleep deprivation, and recovery sleep (posture- and food-controlled throughout). Circadian phase was assessed before baseline sleep by salivary dim light melatonin onset. RESULTS: There was no difference in circadian phase between shift and non-shift workers. HR variance was highest at 0.25 hours following total sleep deprivation and lowest after recovery sleep. A significantly higher LF/HF ratio, significantly lower HR variance, and a trend for a lower %FMD (P=0.08) were observed among shift compared to non-shift workers. CONCLUSION: Despite similar demographics, circadian phase, posture and food intake, differences in endothelial function and HRV were observed in the two groups, which may reflect higher sympathetic and/or lower parasympathetic activity, contributing to increased cardiovascular risk among the shift workers.

      K Papantoniou, OJ Pozo, A Espinosa, J Marcos, G Castano-Vinyals, X Basagana, E Juanola Pages, J Mirabent, J Martin, P Such Faro, A Gasco Aparici, B Middleton, DJ Skene, M Kogevinas (2015)Increased and Mistimed Sex Hormone Production in Night Shift Workers, In: CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION24(5)pp. 854-863 AMER ASSOC CANCER RESEARCH

      BACKGROUND: Night shift work has been associated with an increased risk for breast and prostate cancer. The effect of circadian disruption on sex steroid production is a possible underlying mechanism, underinvestigated in humans. We have assessed daily rhythms of sex hormones and melatonin in night and day shift workers of both sexes. METHODS: We recruited 75 night and 42 day workers, ages 22 to 64 years, in different working settings. Participants collected urine samples from all voids over 24 hours on a working day. Urinary concentrations of 16 sex steroid hormones and metabolites (estrogens, progestagens, and androgens) and 6-sulfatoxymelatonin were measured in all samples. Mean levels and peak time of total and individual metabolite production were compared between night and day workers. RESULTS: Night workers had higher levels of total progestagens [geometric mean ratio (GMR) 1.65; 95% confidence intervals (CI), 1.17-2.32] and androgens (GMR: 1.44; 95% CI, 1.03-2.00), compared with day workers, after adjusting for potential confounders. The increased sex hormone levels among night shift workers were not related to the observed suppression of 6-sulfatoxymelatonin. Peak time of androgens was significantly later among night workers, compared with day workers (testosterone: 12:14 hours; 10:06-14:48 vs. 08:35 hours; 06:52-10:46). CONCLUSIONS: We found increased levels of progestagens and androgens as well as delayed peak androgen production in night shift workers compared with day workers. IMPACT: The increase and mistiming of sex hormone production may explain part of the increased risk for hormone-related cancers observed in night shift workers.

      K Lech, K Ackermann, A Wollstein, VL Revell, DJ Skene, M Kayser (2014)Assessing the suitability of miRNA-142-5p and miRNA-541 for bloodstain deposition timing, In: FORENSIC SCIENCE INTERNATIONAL-GENETICS12pp. 181-184 ELSEVIER IRELAND LTD

      A recent proof-of-concept pilot study proposed using microRNA (miRNA) markers for time of death determination. The markers – miRNA-142-5p and miRNA-541, were reported to show considerable expression differences in vitreous humor between individuals who died during the day or night. Here, we investigated whether these miRNA markers show the same diurnal expression pattern in blood, which would make them useful for estimating bloodstain deposition time to allow molecular alibi testing for forensic casework. We analyzed venous blood samples collected from 12 healthy individuals every 4 h during the 24 h day/night period under controlled sleep-laboratory conditions. MiRNA-142-5p normalized against miRNA-222 showed no statistically significant expression differences between blood samples collected during daytime and nighttime (one-way ANOVA p = 0.81), and also no statistically significant rhythmicity during the 24 h day/night period (cosine fit for all individuals p > 0.05, averaged data p = 0.932). MicroRNA-541 amplification in blood was above the 34-cycle threshold applied in the study, indicating too low quantities for obtaining reliable data. Overall, we conclude that the two miRNA markers previously suggested for time of death determination in vitreous humor are not suitable for estimating the deposition time of forensic bloodstains. Future studies may find out if miRNA markers with significant diurnal expression patterns can be identified and how useful they would be for forensic trace deposition timing.

      Cheryl Isherwood, Daniel Rutger Van Der Veen, HANA HASSANIN, Debra Jean Skene, Jonathan David Johnston (2023)Human glucose rhythms and subjective hunger anticipate meal timing, In: Current Biology Elsevier

      Circadian rhythms, metabolism, and nutrition are closely linked.1 Timing of a 3-meal daily feeding pattern synchronises some human circadian rhythms.2 Despite animal data showing anticipation of food availability, linked to a Food Entrainable Oscillator3, it is unknown whether human physiology predicts mealtimes and restricted food availability. In a controlled laboratory protocol, we tested the hypothesis that the human circadian system anticipates large meals. Twenty-four male participants undertook an 8-day laboratory study, with strict sleep-wake schedules, light-dark schedules, and food intake. For six days, participants consumed either hourly small meals throughout the waking period, or two large daily meals (7.5 and 14.5-h after wake-up). All participants then undertook a 37-hour constant routine. Interstitial glucose was measured every 15 minutes throughout the protocol. Hunger was assessed hourly during waking periods. Saliva melatonin was measured in the constant routine. During the 6-day feeding pattern, both groups exhibited increasing glucose concentration early each morning. In the small meal group, glucose concentrations continued to increase across the day. However, in the large meal group, glucose concentrations decreased from 2-h after waking until the first meal. Average 24-h glucose concentration did not differ between groups. In the constant routine, there was no difference in melatonin onset between groups, but antiphasic glucose rhythms were observed, with low glucose at the time of previous meals in the large meal group. Moreover, in the large meal group, constant routine hunger scores increased before the predicted meal times. These data support the existence of human food anticipation.

      ALAN FLANAGAN, Elizabeth Lowson, Bruce A. Griffin, DEBRA JEAN SKENE (2021)Effects of Maternal Nightshift Work on Evening Energy Intake, Diet Quality and Meal Timing in the Family: An Observational Study, In: Nursing Reports11(4)pp. 823-831 MDPI
      Matt Spick, Holly-May Lewis, Cecile F. Frampas, Katie Longman, Catia Costa, Alexander Stewart, Deborah Dunn-Walters, Danni Greener, George Evetts, Michael J. Wilde, Eleanor Sinclair, Perdita E. Barran, Debra J. Skene, Melanie J. Bailey (2022)An integrated analysis and comparison of serum, saliva and sebum for COVID-19 metabolomics, In: Scientific reports1211867 Nature Portfolio

      Abstract The majority of metabolomics studies to date have utilised blood serum or plasma, biofluids that do not necessarily address the full range of patient pathologies. Here, correlations between serum metabolites, salivary metabolites and sebum lipids are studied for the first time. 83 COVID-19 positive and negative hospitalised participants provided blood serum alongside saliva and sebum samples for analysis by liquid chromatography mass spectrometry. Widespread alterations to serum-sebum lipid relationships were observed in COVID-19 positive participants versus negative controls. There was also a marked correlation between sebum lipids and the immunostimulatory hormone dehydroepiandrosterone sulphate in the COVID-19 positive cohort. The biofluids analysed herein were also compared in terms of their ability to differentiate COVID-19 positive participants from controls; serum performed best by multivariate analysis (sensitivity and specificity of 0.97), with the dominant changes in triglyceride and bile acid levels, concordant with other studies identifying dyslipidemia as a hallmark of COVID-19 infection. Sebum performed well (sensitivity 0.92; specificity 0.84), with saliva performing worst (sensitivity 0.78; specificity 0.83). These findings show that alterations to skin lipid profiles coincide with dyslipidaemia in serum. The work also signposts the potential for integrated biofluid analyses to provide insight into the whole-body atlas of pathophysiological conditions.

      Erlend Sunde, Torhild Pedersen, Jelena Mrdalj, Eirunn Thun, Janne Grønli, Anette Harris, Bjørn Bjorvatn, Siri Waage, Debra J Skene, Ståle Pallesen (2020)Alerting and Circadian Effects of Short-Wavelength vs. Long-Wavelength Narrow-Bandwidth Light during a Simulated Night Shift, In: Clocks & Sleep2(4)pp. 502-522 MDPI

      Light can be used to facilitate alertness, task performance and circadian adaptation during night work. Novel strategies for illumination of workplaces, using ceiling mounted LED-luminaires, allow the use of a range of different light conditions, altering intensity and spectral composition. This study ( Identifier NCT03203538) investigated the effects of short-wavelength narrow-bandwidth light (λmax = 455 nm) compared to long-wavelength narrow-bandwidth light (λmax = 625 nm), with similar photon density (~2.8 × 1014 photons/cm2/s) across light conditions, during a simulated night shift (23:00–06:45 h) when conducting cognitive performance tasks. Light conditions were administered by ceiling mounted LED-luminaires. Using a within-subjects repeated measurements study design, a total of 34 healthy young adults (27 females and 7 males; mean age = 21.6 years, SD = 2.0 years) participated. The results revealed significantly reduced sleepiness and improved task performance during the night shift with short-wavelength light compared to long-wavelength light. There was also a larger shift of the melatonin rhythm (phase delay) after working a night shift in short-wavelength light compared to long-wavelength light. Participants’ visual comfort was rated as better in the short-wavelength light than the long-wavelength light. Ceiling mounted LED-luminaires may be feasible to use in real workplaces, as these have the potential to provide light conditions that are favorable for alertness and performance among night workers.

      Holly-May Lewis, Yufan Liu, Cecile F. Frampas, Katie Longman, Matt Spick, Alexander Stewart, Emma Sinclair, Nora Kasar, Danni Greener, Anthony D. Whetton, Perdita E. Barran, Tao Chen, Deborah Dunn-Walters, Debra J. Skene, Melanie J. Bailey (2022)Metabolomics Markers of COVID-19 Are Dependent on Collection Wave, In: Metabolites12(8)713 MDPI AG

      The effect of COVID-19 infection on the human metabolome has been widely reported, but to date all such studies have focused on a single wave of infection. COVID-19 has generated numerous waves of disease with different clinical presentations, and therefore it is pertinent to explore whether metabolic disturbance changes accordingly, to gain a better understanding of its impact on host metabolism and enable better treatments. This work used a targeted metabolomics platform (Biocrates Life Sciences) to analyze the serum of 164 hospitalized patients, 123 with confirmed positive COVID-19 RT-PCR tests and 41 providing negative tests, across two waves of infection. Seven COVID-19-positive patients also provided longitudinal samples 2–7 months after infection. Changes to metabolites and lipids between positive and negative patients were found to be dependent on collection wave. A machine learning model identified six metabolites that were robust in diagnosing positive patients across both waves of infection: TG (22:1_32:5), TG (18:0_36:3), glutamic acid (Glu), glycolithocholic acid (GLCA), aspartic acid (Asp) and methionine sulfoxide (Met-SO), with an accuracy of 91%. Although some metabolites (TG (18:0_36:3) and Asp) returned to normal after infection, glutamic acid was still dysregulated in the longitudinal samples. This work demonstrates, for the first time, that metabolic dysregulation has partially changed over the course of the pandemic, reflecting changes in variants, clinical presentation and treatment regimes. It also shows that some metabolic changes are robust across waves, and these can differentiate COVID-19-positive individuals from controls in a hospital setting. This research also supports the hypothesis that some metabolic pathways are disrupted several months after COVID-19 infection.

      Barbara N. Harding, Debra J. Skene, Ana Espinosa, Benita Middleton, Gemma Castaño-Vinyals, Kyriaki Papantoniou, José Maria Navarrete, Patricia Such, Antonio Torrejón, Manolis Kogevinas, Marissa G. Baker (2022)Metabolic profiling of night shift work - The HORMONIT study, In: Chronobiology international Taylor & Francis

      Mechanistic studies are needed to understand how rotating shift work perturbs metabolic processing. We collected plasma samples (n = 196) from 49 males, rotating car factory shift workers at the beginning and end of a night-shift (22:00-06:00 h) and day-shift (06:00 h-14:00 h). Samples underwent targeted LC-MS/MS metabolomics and concentrations of 130 metabolites were log 2 -transformed and pareto-scaled. An elastic net selected the most influential metabolites for linear mixed models examining within-person variation in metabolite levels at night-shift end (06:00 h) compared to day-shift start (06:00 h). Quantitative enrichment analysis explored differentially enriched biological pathways between sample time points. We included 20 metabolites (amino acids, biogenic amines, acylcarnitines, glycerophospholipids) in mixed models. Night-shift was associated with changes in concentrations of arginine (geometric mean ratio [GMR] 2.30, 95%CI 1.25, 4.23), glutamine (GMR 2.22, 95%CI 1.53, 3.24), kynurenine (GMR 3.22, 95%CI 1.05, 9.87), lysoPC18:2 (GMR 1.86, 95%CI 1.11, 3.11), lysoPC20:3 (GMR 2.48, 95%CI 1.05, 5.83), PCaa34:2 (GMR 2.27, 95%CI 1.16, 4.44), and PCae38:5 (GMR 1.66, 95%CI 1.02, 2.68). Tryptophan metabolism, glutathione metabolism, alanine metabolism, glycine and serine metabolism, and urea cycle were pathways differing between shifts. Night shift work was associated with changes in metabolites and the perturbation of metabolic and biochemical pathways related to a variety of health outcomes.

      Elizabeth B Klerman, Allison Brager, Mary A Carskadon, Christopher M Depner, Russell Foster, Namni Goel, Mary Harrington, Paul M Holloway, Melissa P Knauert, Monique K LeBourgeois, Jonathan Lipton, Martha Merrow, Sara Montagnese, Mingming Ning, David Ray, Frank A J L Scheer, Steven A Shea, Debra J Skene, Claudia Spies, Bart Staels, Marie-Pierre St-Onge, Steffen Tiedt, Phyllis C Zee, Helen J Burgess (2022)Keeping an eye on circadian time in clinical research and medicine, In: Clinical and Translational Medicine12(12)e1131 Wiley

      Background Daily rhythms are observed in humans and almost all other organisms. Most of these observed rhythms reflect both underlying endogenous circadian rhythms and evoked responses from behaviours such as sleep/wake, eating/fasting, rest/activity, posture changes and exercise. For many research and clinical purposes, it is important to understand the contribution of the endogenous circadian component to these observed rhythms. Content The goal of this manuscript is to provide guidance on best practices in measuring metrics of endogenous circadian rhythms in humans and promote the inclusion of circadian rhythms assessments in studies of health and disease. Circadian rhythms affect all aspects of physiology. By specifying minimal experimental conditions for studies, we aim to improve the quality, reliability and interpretability of research into circadian and daily (i.e., time-of-day) rhythms and facilitate the interpretation of clinical and translational findings within the context of human circadian rhythms. We describe protocols, variables and analyses commonly used for studying human daily rhythms, including how to assess the relative contributions of the endogenous circadian system and other daily patterns in behaviours or the environment. We conclude with recommendations for protocols, variables, analyses, definitions and examples of circadian terminology. Conclusion Although circadian rhythms and daily effects on health outcomes can be challenging to distinguish in practice, this distinction may be important in many clinical settings. Identifying and targeting the appropriate underlying (patho)physiology is a medical goal. This review provides methods for identifying circadian effects to aid in the interpretation of published work and the inclusion of circadian factors in clinical research and practice.

      DEBRA JEAN SKENE, Dennis Khodasevich, Susan Tsui, Darwin Keung, VICTORIA LOUISE REVELL, Micaela E. Martinez (2021)Characterizing the Modern Light Environment and its Influence on Circadian Rhythms, In: Proceedings of the Royal Society B: Biological Sciences288(1955)20210721 The Royal Society

      Humans have largely supplanted natural light cycles with a variety of artificial light sources and schedules misaligned with day-night cycles. Circadian disruption has been linked to a number of disease processes, but the extent of circadian disruption among the population is unknown. We measured light exposure and wrist temperature among residents of an urban area for a full week during each of the four seasons, as well as light illuminance in nearby outdoor locations. Daily light exposure was significantly lower for individuals, compared to outdoor light sensors, for all four seasons. There was also little seasonal variation in the realized photoperiod experienced by individuals, with the only significant difference between winter and summer. We tested the hypothesis that differential light exposure impacts circadian phase timing, detected via the wrist temperature rhythm. To determine the influence of light exposure on circadian rhythms, we modeled the impact of morning, afternoon, and nighttime light exposure on the timing of the midline-estimating statistic of rhythm (MESOR). We found that morning light exposure and nighttime light exposure had a significant but opposing impact on MESOR timing. Our results demonstrate that nighttime light can shift/alter circadian rhythms to delay the morning transition from nighttime to daytime physiology, while morning light can lead to earlier onset. Our results demonstrate that circadian shifts and disruptions may be a more regular occurrence in the general population than is currently recognized. Significance Statement: Disruption of circadian rhythms has been linked to various diseases, but the prevalence of circadian disruption among the general population is unknown. Light plays a pivotal role in entraining circadian rhythms to the 24-hour day. Humans have largely supplanted natural light cycles with electrical lighting and through time spent indoors. We have shown that individuals experience a disconnect from natural light cycles, with low daytime light exposure, high levels of light-at-night, and minimal seasonal variation in light exposure. We identified measurable changes in the timing of wrist temperature rhythms as a function of differential light exposure during the morning and nighttime hours. Our findings suggest that circadian shifts, and potentially disruption, may be common in the general population.

      Celine Vetter, P. Morgan Pattison, Kevin Houser, Michael Herf, Andrew Phillips, DEBRA JEAN SKENE, Kenneth P. Wright Jr., George C Brainard, Diane Boivin, Gena Glickman (2021)A review of human physiological responses to light: Implications for the development of integrative lighting solutions, In: LEUKOS 18(3) Routledge

      Architectural lighting has potent biological effects but applied lighting practices that capitalize on this potential have been limited. In this review, we endeavor to consolidate and synthesize key references that will be useful for lighting professionals, with the goal of supporting knowledge translation into pragmatic lighting strategies. Specifically, we explain relevant terminology, outline basic concepts, identify key references, provide a balanced overview of the current state of knowledge, and highlight important remaining questions. We summarize the physiological effects of light on human health and well-being, including a description of the processes underlying the photic regulation of circadian, neuroendocrine, and neurobehavioral functions. We review seminal work elucidating the elements mediating the potency of light for these physiological responses, with specific attention to factors critical for interpreting those findings. In parallel, we explain and endorse melanopic Equivalent Daylight Illuminance ( ) as the 𝐸 𝐷65 𝑣, 𝑚𝑒𝑙 preferred measure to quantify the biological potency of light. Ultimately, while future studies are necessary to further facilitate the translation of laboratory knowledge to domestic and workplace settings, the immediate potential for applied lighting to better support human health is clear. Aiming for integrative lighting solutions that have biologically high potency light during the day and low potency during the night is perhaps the most immediate improvement to be made in order to better support applications for humans.

      Elaine C. Marqueze, Luciana F. R. Nogueira, Celine Vetter, DEBRA JEAN SKENE, José Cipolla-Neto, Claudia R. C. Moreno (2021)Exogenous melatonin decreases circadian misalignment and body weight among early types, In: Journal of Pineal Research71(2)e12750 Wiley

      Shift workers experience chronic circadian misalignment, which can manifest itself in reduced melatonin production, and has been associated with metabolic disorders. In addition, chronotype modulates the effect of night shift work, with early types presenting greater circadian misalignment when working night shift as compared to late types. Melatonin supplementation has shown positive results reducing weight gain in animal models, but the effect of exogenous melatonin in humans on body weight in the context of shift work remains inconsistent. The aim of this study was thus to evaluate the effects of exogenous melatonin on circadian misalignment and body weight among overweight night shift workers, according to chronotype, under real life conditions. We conducted a double-blind, randomized, placebo-controlled, crossover trial where melatonin (3 mg) or placebo was administered on non-night shift nights for 12 weeks in 27 female nurses (37.1 yo, ±5.9 yo; BMI 29.9 kg/m2, ±3.3 kg/m2). Melatonin (or placebo) was only taken on nights when the participants did not work night shifts, that is, on nights when they slept (between night shifts and on days-off). Composite Phase Deviations (CPD) of actigraphy-based midsleep timing were calculated to measure circadian misalignment. The analyses were performed for the whole group and by chronotype. We found approximately 20% reduction of circadian misalignment after exogenous melatonin administration considering all chronotypes. Moreover, melatonin supplementation in those who presented high circadian misalignment, as observed in early chronotypes, reduced body weight, BMI, waist circumference, and hip circumference, without any change in the participants’ calorie intake or physical activity levels.

      Thomas P. M. Hancox, DEBRA JEAN SKENE, Robert Dallmann, Warwick B. Dunn (2021)Tick-Tock-Consider the Clock: The Influence of Circadian and External Cycles on Time of Day Variation in the Human Metabolome – A Systematic Review, In: Metabolites11(5)328 MDPI

      This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

      Juliane Hannemann, Anika Laing, Benita Middleton, Jonathan Cridland, Bart Staels, Nikolaus Marx, Peter J Grant, Massimo Federici, Tarja Stenberg, Debra J Skene, Rainer Böger (2021)Light therapy improves diurnal blood pressure control in night shift workers via reduction of catecholamines: the EuRhythDia study, In: Journal of hypertension39(8)pp. 1678-1688

      Objectives: Night shift work is associated with high rates of hypertension and cardiometabolic disease, which are linked to disrupted circadian rhythms. We hypothesized that timed light therapy might improve disrupted circadian rhythms and stabilize diurnal control of blood pressure and glucose in night shift workers. Mthods: We randomized 24 rotating night shift workers (mean age, 36 ± 13 years, 7 men) who had spent a median of 6 years on rotating night shifts (median, six night shifts per month) to 12 weeks of light therapy or no intervention and compared them with 12 daytime workers (37 ± 11 years, 6 men). We measured oral glucose tolerance (OGTT), 24-h blood pressure and arterial stiffness, and the circadian profiles of melatonin, cortisol, metanephrine and nor-metanephrine at baseline, after 12  weeks of intervention, and 12 weeks after the end of intervention. Results: At baseline, fewer night shift workers showed dipper status as compared with daytime workers (29 vs. 58%; P 

      MATTHEW PAUL SPICK, Amy Campbell, Ivona Baricevic-Jones, JOHANNA VON GERICHTEN, HOLLY-MAY LEWIS, CECILE FRANCE FRAMPAS, Katie Longman, ALEXANDER STEWART, DEBORAH DUNN-WALTERS, DEBRA JEAN SKENE, NOPHAR GEIFMAN, Anthony D. Whetton, Melanie J. Bailey (2022)Multi-Omics Reveals Mechanisms of Partial Modulation of COVID-19 Dysregulation by Glucocorticoid Treatment, In: International journal of molecular sciences23(20)12079 MDPI

      Treatments for COVID-19 infections have improved dramatically since the beginning of the pandemic, and glucocorticoids have been a key tool in improving mortality rates. The UK’s National Institute for Health and Care Excellence guidance is for treatment to be targeted only at those requiring oxygen supplementation, however, and the interactions between glucocorticoids and COVID-19 are not completely understood. In this work, a multi-omic analysis of 98 inpatient-recruited participants was performed by quantitative metabolomics (using targeted liquid chromatography-mass spectrometry) and data-independent acquisition proteomics. Both ‘omics datasets were analysed for statistically significant features and pathways differentiating participants whose treatment regimens did or did not include glucocorticoids. Metabolomic differences in glucocorticoid-treated patients included the modulation of cortisol and bile acid concentrations in serum, but no alleviation of serum dyslipidemia or increased amino acid concentrations (including tyrosine and arginine) in the glucocorticoid-treated cohort relative to the untreated cohort. Proteomic pathway analysis indicated neutrophil and platelet degranulation as influenced by glucocorticoid treatment. These results are in keeping with the key role of platelet-associated pathways and neutrophils in COVID-19 pathogenesis and provide opportunity for further understanding of glucocorticoid action. The findings also, however, highlight that glucocorticoids are not fully effective across the wide range of ‘omics dysregulation caused by COVID-19 infections.

      Timothy M Brown, Kavita Thapan, Josephine Arendt, Victoria L Revell, Debra J Skene (2021)S-cone contribution to the acute melatonin suppression response in humans, In: Journal of pineal research71(1)e12719

      Light influences diverse aspects of human physiology and behaviour including neuroendocrine function, the circadian system and sleep. A role for melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) in driving such effects is well-established. However, rod and/or cone signals routed through ipRGCs could also influence 'non-visual' spectral sensitivity. In humans, this has been most extensively studied for acute, light-dependent, suppression of nocturnal melatonin production. Of the published action spectra for melatonin suppression, one demonstrates a spectral sensitivity consistent with that expected for melanopsin while our own (using briefer 30 min light exposures) displays very high sensitivity to short wavelength light, suggesting a contribution of S-cones. To clarify that possibility, six healthy young male participants were each exposed to 30 min of five irradiances of 415 nm monochromatic light (1 - 40 µW/cm ) across different nights. These data were then combined with the original action spectrum. The aggregated data are incompatible with the involvement of any single opsin and multi-opsin models based on the original action spectrum (including Circadian Stimulus) fail to predict the responses to 415 nm stimuli. Instead, the extended action spectrum can be most simply approximated by an ~2:1 combination of melanopsin and S-cone signals. Such a model also better describes the magnitude of melatonin suppression observed in other studies using an equivalent 30 min mono- or polychromatic light paradigm but not those using longer (90 min) light exposures. In sum, these data provide evidence for an initial S-cone contribution to melatonin suppression that rapidly decays under extended light exposure.

      JF Walters, DJ Skene, SM Hampton, GAA Ferns (2003)Biological rhythms, endothelial health and cardiovascular disease, In: MEDICAL SCIENCE MONITOR9(1)pp. RA1-RA8 INT SCIENTIFIC LITERATURE, INC
      T Kantermann, SMT Wehrens, MA Ulhôa, C Moreno, DJ Skene (2012)Chapter 22 - Noisy and individual, but doable: Shift-work research in humans, In: MM Andries Kalsbeek (eds.), The Neurobiology of Circadian Timingpp. 399-411 Elsevier

      Working around the clock is common for many occupations, as diverse as nurses, truck drivers, physicians, steel workers, and pilots. Each shift-work profession is individual in more aspects than just work hours and individual work scenarios, each posing a different impact on the health of workers. Related health problems in shift workers, therefore, are also diverse and encompass sleep problems, metabolic and cardiovascular system disturbances, as well as cancer. Little is known about how all these individual factors influence a shift worker's health status, partly because many shift-work studies show inconsistent results. In addition, these individual factors create many methodological difficulties for researchers who investigate such work scenarios. This chapter presents examples from our laboratory and field studies of shift workers, which emphasize the importance of taking individual circumstances into account. Both study approaches, laboratory and field based, are needed to fully account for the difficulties that shift-work studies pose on both workers and researchers. Finally, understanding the mechanisms that underpin interindividual differences in response to shift work will advance our understanding of how to design better and healthier shift-work schedules in the future.

      DJ Skene, SW Lockley, K James, J Arendt (1999)Correlation between urinary cortisol and 6-sulphatoxymelatonin rhythms in field studies of blind subjects, In: CLINICAL ENDOCRINOLOGY50(6)pp. 715-719 BLACKWELL SCIENCE LTD
      J Arendt, EJW Van Someren, R Appleton, DJ Skene, T Akerstedt (2008)Clinical update: melatonin and sleep disorders, In: CLINICAL MEDICINE8(4)pp. 381-383 ROY COLL PHYS LONDON EDITORIAL OFFICE

      The hormone melatonin is increasingly used for the treatment of certain sleep disorders, particularly those related to disturbed biological rhythms. This article summarises current knowledge of its mechanism of action and identifies situations where there is good evidence for its efficacy. The authors provide advice, based on their own experience and consistent published data, concerning the dose range of melatonin to be used and the critically important question of the timing of treatment. Anecdotal evidence for the use of melatonin needs to be replaced by data from well-controlled, preferably multi-centre, randomised clinical trials

      JB Zawilska, DJ Skene, J Arendt (2009)Physiology and pharmacology of melatonin in relation to biological rhythms, In: PHARMACOLOGICAL REPORTS61(3)pp. 383-410 POLISH ACAD SCIENCES INST PHARMACOLOGY
      SW Lockley, DJ Skene, LJ Butler, J Arendt (1999)Sleep and activity rhythms are related to circadian phase in the blind, In: SLEEP22(5)pp. 616-623 AMER ACAD SLEEP MEDICINE
      AL Darling, F Gossiel, R Hannon, DJ Skene, JL Berry, R Eastell, SA Lanham-New (2015)ASSOCIATION BETWEEN DEGREE OF SEASONAL FLUCTUATION (‘CYCLING’) OF 25(OH)D, PTH AND BONE RESORPTION IN UK SOUTH ASIAN AND CAUCASIAN WOMEN LIVING AT 51ON (SURREY), In: Abstracts of the Osteoporosis Conference 201021 S3pp. 443-518

      Introduction: It has been hypothesised that the U shaped association between 25(OH)D and some health outcomes may be due to large seasonal fluctuations of 25(OH)D1. It is unknown whether such fluctuation of 25(OH)D (‘cycling’) influences bone health. Methods: In the D-FINES study, n=373 women (South Asian/Caucasian) had repeated measurements in four seasons for serum 25(OH)D and PTH. A random sample (n=66) were measured for serum C-telopeptide (CTX). Seasonal cycling of 25(OH)D was assessed as the absolute difference between winter (nadir) and summer (peak) 25(OH)D and was split into quartiles within ethnicity. Summer to winter change in CTX and PTH were calculated. Results and Discussion: ANCOVA showed no statistically significant association between quartile of cycling of 25(OH)D and CTX or PTH. However, in Asians, there was a trend for increased cycling to be associated with reduced PTH but not CTX, and for an increase in PTH from summer to winter. In Caucasians, there was a trend for increased cycling in all seasons to be associated with reduced CTX. However, increased cycling was associated with increased PTH in summer and spring, but lower PTH in other seasons, as well as a reduction in PTH from summer to winter (p=0.06). Therefore increased cycling in Caucasians was associated with lower bone resorption and was differentially associated with PTH depending on season. Further analysis of banked samples for urine CTX (n=1500) will enable these novel results to be explored further.

      AL Darling, F Gossiel, R Hannon, DJ Skene, JL Berry, R Eastell, SA Lanham-New (2015)Evidence for an Association Between Seasonal Fluctuation of 25(OH)D and Serum C-telopeptide (CTx): Preliminary Evidence from the D-FINES study., In: OSTEOPOROSIS INTERNATIONAL22

      The purpose of this study was to assess whether there is a difference in bone resorption by degree of seasonal change in 25(OH)D and whether this varies by ethnicity. In the recent D-FINES study, (Vitamin D, Food Intake, Nutrition and Exposure to Sunlight in Southern England, 2006-2007), a subset of n=65 from the 293 participants (South Asian (n 30) and Caucasian (n 35)) had blood taken in four seasons for determination of 25(OH)D and serum c-telopeptide (sCTX). sCTX was measured using an electrochemiluminescent immunoassay (Roche cobas e411). Seasonal fluctuation of 25(OH)D was assessed by calculating differences between the winter (nadir) and summer (peak) 25(OH)D. For ease of interpretation these changes were expressed as positive values. This enabled investigation of the absolute change in 25(OH)D but not its direction. This variable was then split into quartiles within ethnicity. The dependent variables were absolute concentration of sCTX in each season as well as summer to winter change in sCTX. ANCOVA was run with absolute summer and winter 25(OH)D status, age, BMI, socioeconomic status, physical activity, and dietary calcium as covariates. In the Asian group there was no clear trend between degree of seasonal fluctuation and absolute sCTX. Indeed, only the autumn data was statistically significant (F=5.93; p= 0.01) and with no consistent pattern among the quartiles. No data were significant for change in summer to winter sCTX in Asians or Caucasians despite a trend in both ethnic groups for lower sCTX in the middle quartiles relative to the highest and lowest. Last, in Caucasians, there was a non-statistically significant (p.0.05) inverse trend between cycling of 25(OH)D and absolute serum C-telopeptide levels. These data suggest lower bone resorption in all seasons in Caucasians with increased cycling, and a reduction in sCTX between summer and winter in both ethnic groups in the middle quartile relative to the other quartiles. As the values were covariate adjusted, these findings are not likely to be due to other variables. However, it must be borne in mind that these results are only trends, which is likely due to the small numbers of subjects. Further research is required to analyse banked urine samples from the D-FINES study (n 293) which would enable us to see if these results are statistically significant with increased statistical power. The D-FINES study was funded by the UK Food Standards Agency. All views are those of the authors alone

      J Arendt, B Middleton, B Stone, D Skene (1999)Complex effects of melatonin: Evidence for photoperiodic responses in humans?, In: SLEEP22(5)pp. 625-635 AMER SLEEP DISORDERS ASSOC
      AL Darling, F Gossiel, R Hannon, DJ Skene, KH Hart, JL Berry, R Eastell, SA Lanham-New (2011)An association between seasonal fluctuation 'cycling' of 25(OH)D and increased bone resorption but not BMD or BMC in UK South Asian and Caucasian women living at 51on, In: BONE48pp. S187-S187

      It has been hypothesised that the U shaped association between 25(OH)D and some health outcomes may be due to large seasonal fluctuations of 25(OH)D1. It is unknown whether such fluctuation of 25(OH)D (‘cycling’) influences bone health. This is an important issue, because if ‘cycling’ is detrimental for bone, then winter only rather than year round vitamin D supplementation may be useful for bone health to ‘blunt’ the rhythm. In the D-FINES study, n = 373 women (South Asian/Caucasian) had repeated measurements in four seasons for serum 25(OH)D and PTH, as well as a DXA scan in autumn and spring. Serum C-telopeptide (sCTX) was also measured in a random subset (n = 66). Cosinor regression analysis was used to identify individuals showing a significant rhythm (p < 0.10) (‘cyclers’) and those not showing a significant seasonal rhythm (‘non-cyclers’). Potential differences in bone indices between the two groups were assessed within ethnicity. Dependent variables analysed were absolute values for autumn femoral neck and lumbar spine BMD, BMC and bone area, and absolute sCTX and sPTH in each season. Also, change in sCTX and sPTH from summer to winter and change in DXA bone indices from autumn to spring were analysed. ANCOVA was run, adjusting for summer and winter 25(OH)D status, age, socioeconomic status, physical activity, and dietary calcium. BMI was also controlled for in the analysis due to its negative correlation with seasonal change in 25(OH)D. There was no statistically significant difference (p>0.05) between ‘cyclers’ and ‘non-cyclers’ for any of the bone indices in either ethnic group. However, there were trends for a higher CTX and PTH in ‘cyclers’ versus ‘non-cyclers’ in both ethnic groups in every season, but no differences for BMD or BMC (Figs. 1–4). This suggests tentatively that ‘cycling’ could be associated with changes in bone metabolism but may not translate into structural changes. In summary, there is no clear evidence here to suggest that ‘cycling’ is detrimental to bone health, although there are trends in PTH and CTX that warrant further investigation with a larger sample.

      JB Zawilska, A Lorenc, M Berezinska, B Vivien-Roels, P Pevet, DJ Skene (2007)Photoperiod-dependent changes in melatonin synthesis in the turkey pineal gland and retina, In: POULTRY SCIENCE86(7)pp. 1397-1405 POULTRY SCIENCE ASSOC INC
      Timothy M. Brown, George C. Brainard, Christian Cajochen, Charles A. Czeisler, John P. Hanifin, Steven W. Lockley, Robert J. Lucas, Mirjam Muench, John B. O'Hagan, Stuart N. Peirson, Luke L. A. Price, Till Roenneberg, Luc J. M. Schlangen, Debra J. Skene, Manuel Spitschan, Celine Vetter, Phyllis C. Zee, Kenneth P. Wright (2022)Recommendations for daytime, evening, and nighttime indoor light exposure to best support physiology, sleep, and wakefulness in healthy adults, In: PLoS biology20(3)e3001571 Public Library Science

      Ocular light exposure has important influences on human health and well-being through modulation of circadian rhythms and sleep, as well as neuroendocrine and cognitive functions. Prevailing patterns of light exposure do not optimally engage these actions for many individuals, but advances in our understanding of the underpinning mechanisms and emerging lighting technologies now present opportunities to adjust lighting to promote optimal physical and mental health and performance. A newly developed, international standard provides a SI-compliant way of quantifying the influence of light on the intrinsically photosensitive, melanopsin-expressing, retinal neurons that mediate these effects. The present report provides recommendations for lighting, based on an expert scientific consensus and expressed in an easily measured quantity (melanopic equivalent daylight illuminance (melaponic EDI)) defined within this standard. The recommendations are supported by detailed analysis of the sensitivity of human circadian, neuroendocrine, and alerting responses to ocular light and provide a straightforward framework to inform lighting design and practice.

      HC Thorne, S Hampton, L Morgan, D Skene, J Arendt (2006)Sleep and circadian adaptation in offshore night shiftworkers, In: JOURNAL OF SLEEP RESEARCH15pp. 95-95
      S Montagnese, B Middleton, AR Mani, DJ Skene, MY Morgan (2006)Evidence of central circadian disruption in patients with cirrhosis, In: JOURNAL OF HEPATOLOGY44pp. S276-S276
      SW Lockley, DJ Skene, K Thapan, J English, D Ribeiro, M von Schantz, J Arendt (1999)Extraocular light exposure does not suppress plasma melatonin in humanspp. 403-406 SPRINGER
      C Isherwood, DT Otway, S Maentele, B Middleton, J Wright, MD Robertson, DJ Skene, M Gibbs, JD Johnston (2015)Daily rhythms in hormonal markers of diabetes and obesity: effect of weight and Type 2 diabetes, In: PROCEEDINGS OF THE NUTRITION SOCIETY74(OCE1)pp. E37-E37
      K Ackermann, O Lao, VL Revell, R Plomp, B Middleton, DJ Skene, M Kayser (2012)Effect of total sleep deprivation on clock gene expression and melatonin rhythms in human peripheral blood cells, In: JOURNAL OF SLEEP RESEARCH21pp. 39-39
      HC Thorne, SM Hampton, LM Morgan, DJ Skene, J Arendt (2008)Use of timed light treatment to hasten circadian adaptation of offshore nightshift workers returning to day life, In: JOURNAL OF SLEEP RESEARCH17pp. 22-23
      I Gogenur, B Middleton, VB Kristiansen, DJ Skene, J Rosenberg (2006)Disturbances in melatonin and core body temperature circadian rhythms after minimal invasive surgery, In: JOURNAL OF SLEEP RESEARCH15pp. 95-95
      DJ Skene, S Deacon, J Arendt (1996)Use of melatonin in circadian rhythm disorders and following phase shifts56pp. 359-362 NENCKI INST EXPERIMENTAL BIOLOGY

      Following abrupt phase shifts (real or simulated time zone changes, night shift work) there is desynchronisation between the internal circadian rhythms (including melatonin) and the external environment with consequent disturbances in sleep, mood and performance. In humans the pineal hormone melatonin has phase-shifting and resynchronising properties with regard to a number of circadian rhythms. Suitably timed melatonin adrninstration hastened adaptation to phase shift and significantly improved self-rated jet lag in large numbers of time zone travellers. Preliminary results in night shift workers showed improved daytime sleep and night-time alertness. In simulated experiments, appropriately timed melatonin improved subjective sleep, alertness and performance and facilitated the readaptation of the melatonin rhythm following a rapid 9 h advance phase shift. Melatonin has also been assessed in circadian rhythm disorders with disturbed sleep (blindness and delayed sleep phase insomnia). Compared with placebo, melatonin significantly improved sleep and synchronised the sleep wake cycle in some blind subjects. Melatonin treatment significantly advanced the sleep onset time in delayed sleep phase insomnia. Taken together these findings suggest that melatonin is of benefit in facilitating adaptation to forced phase shifts and in conditions of circadian rhythm disturbance.

      DJ Skene, SW Lockley, H Tabandeh, R DeFrance, AC Bird, J Arendt (1997)Visual pathology and human circadian rhythmspp. 349-353 P J D PUBLICATIONS LTD
      SW Lockley, J Arendt, DJ Skene (2007)Visual impairment and circadian rhythm disorders., In: Dialogues Clin Neurosci9(3)pp. 301-314

      Many aspects of human physiology and behavior are dominated by 24-hour circadian rhythms that have a major impact on our health and well-being, including the sleep-wake cycle, alertness and performance patterns, and many daily hormone profiles. These rhythms are spontaneously generated by an internal "pacemaker" in the hypothalamus, and daily light exposure to the eyes is required to keep these circadian rhythms synchronized both internally and with the external environment. Sighted individuals take this daily synchronization process for granted, although they experience some of the consequences of circadian desynchrony when "jetlagged" or working night shifts. Most blind people with no perception of light, however, experience continual circadian desynchrony through a failure of light information to reach the hypothalamic circadian clock, resulting in cyclical episodes of poor sleep and daytime dysfunction. Daily melatonin administration, which provides a replacement synchronizing daily "time cue, " is a promising therapeutic strategy, although optimal treatment dose and timing remain to be determined.

      DJ Skene, SW Lockley, J Arendt (1999)Use of melatonin in the treatment of phase shift and sleep disorders467pp. 79-84 KLUWER ACADEMIC/PLENUM PUBL
      PL Morgan, S Hopkins, LJM Schlangen, DJ Skene, B Middleton (2012)Effects of light supplementation on mood, alertness and rest-activity rhythms in older people living in care homes, In: JOURNAL OF SLEEP RESEARCH21pp. 370-371
      K Thapan, J Arendt, DJ Skene (2001)An action spectrum for melatonin suppression: evidence for a novel non-rod, non-cone photoreceptor system in humans, In: J PHYSIOL-LONDON535(1)pp. 261-267 CAMBRIDGE UNIV PRESS

      1. Non-image forming, irradiance-dependent responses mediated by the human eye include synchronisation of the circadian axis and suppression of pineal melatonin production. The retinal photopigment(s) transducing these light responses in humans have not been characterised. 2. Using the ability of light to suppress nocturnal melatonin production, we aimed to investigate its spectral sensitivity and produce an action spectrum. Melatonin suppression was quantified in 22 volunteers in 215 light exposure trials using monochromatic light (30 min pulse administered at circadian time (CT) 16–18) of different wavelengths (gmax 424, 456, 472, 496, 520 and 548 nm) and irradiances (0.7–65.0 μW cm_2). 3. At each wavelength, suppression of plasma melatonin increased with increasing irradiance. Irradiance–response curves (IRCs) were fitted and the generated half-maximal responses (IR50) were corrected for lens filtering and used to construct an action spectrum. 4. The resulting action spectrum showed unique short-wavelength sensitivity very different from the classical scotopic and photopic visual systems. The lack of fit (r2 < 0.1) of our action spectrum with the published rod and cone absorption spectra precluded these photoreceptors from having a major role. Cryptochromes 1 and 2 also had a poor fit to the data. Fitting a series of Dartnall nomograms generated for rhodopsin-based photopigments over the gmax range 420–480 nm showed that rhodopsin templates between gmax 457 and 462 nm fitted the data well (r2 ≥ 0.73). Of these, the best fit was to the rhodopsin template with gmax 459 nm (r2 = 0.74). 5. Our data strongly support a primary role for a novel short-wavelength photopigment in lightinduced melatonin suppression and provide the first direct evidence of a non-rod, non-cone photoreceptive system in humans.

      S Deacon, D Skene, J Arendt (1996)Use of light and/or melatonin in adaptation to phase shiftspp. 398-405 WALTER DE GRUYTER
      JB Zawilska, A Lorenc, M Berezinska, B Vivien-Roels, P Pevet, DJ Skene (2006)Daily oscillation in melatonin synthesis in the turkey pineal gland and retina: Diurnal and circadian rhythms, In: CHRONOBIOLOGY INTERNATIONAL23(1-2)pp. 341-350
      DJ Skene, SW Lockley, J Arendt (1999)Melatonin in circadian sleep disorders in the blind, In: BIOLOGICAL SIGNALS AND RECEPTORS8(1-2)pp. 90-95 KARGER
      S Montagnese, B Middleton, A Mani, D Skene, MY Morgan (2005)Plasma melatonin abnormalities in patients with cirrhosis reflect both hepatic and cerebral dysfunction, In: HEPATOLOGY42(4)pp. 755A-755A
      DJ Skene (1996)The miracle of melatonin: Fact, fancy and future, In: CHEMISTRY & INDUSTRY(17)pp. 637-640 SOC CHEMICAL INDUSTRY
      SW Lockley, DJ Skene, J Arendt (1998)Changes in sleep in relation to circadian phase in the blind1152pp. 247-252 ELSEVIER SCIENCE BV
      AL Darling, KH Hart, DJ Skene, S Arber, SA Lanham-New (2014)Vitamin D status, functional ability and muscle strength in older South Asian and Caucasian women in the UK, In: PROCEEDINGS OF THE NUTRITION SOCIETY73(OCE1)pp. E23-E23
      M Turco, L Caccin, M Corrias, A Biscontin, C De Pitta, B Middleton, DJ Skene, R Costa, S Montagnese (2014)Length polymorphism in the human clock gene Period3 and diurnal preference, subjective sleepiness and the response to morning light, In: JOURNAL OF SLEEP RESEARCH23pp. 55-56
      SN Archer, DL Robilliard, DJ Skene, M Smits, A Williams, J Arendt, M von Schantz (2003)A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference, In: SLEEP26(4)pp. 413-415 AMER ACAD SLEEP MEDICINE
      WM Abi-Saab, DJ Skene, TR Stiger, C McRobie, B Middleton, IV Kaplan, HD Soares, MD Saltarelli (2004)Attenuation of the effects of light on nocturnal melatonin production in humans by the selective NK1 receptor antagonist CP-122,721, In: BIOLOGICAL PSYCHIATRY55pp. 40S-40S
      VL Revell, DJ Skene (2008)Authors' response, In: Chronobiology International25(4)pp. 655-656
      V Vaughan, R Meadows, SN Archer, DJ Skene, S Arber (2006)Diurnal preference in couples: negotiating sleep timing, In: JOURNAL OF SLEEP RESEARCH15pp. 95-95
      TL Sletten, VL Revell, B Middleton, KA Lederle, DJ Skene (2008)Short wavelength light exposure in the elderly: acute and phase shifting effects, In: JOURNAL OF SLEEP RESEARCH17pp. 79-79
      S Montagnese, B Middleton, DJ Skene, MY Morgan (2007)Sleep-wake abnormalities do not correlate with neuropsychiatric performance in patients with cirrhosis, In: HEPATOLOGY46(4)pp. 562A-563A
      SN Archer, JD Carpen, M Gibson, GH Lim, JD Johnston, DJ Skene, M von Schantz (2010)Polymorphism in the PER3 Promoter Associates with Diurnal Preference and Delayed Sleep Phase Disorder, In: SLEEP33(5)pp. 695-701 AMER ACAD SLEEP MEDICINE

      Study Objectives: To screen the PER3 promoter for polymorphisms and investigate the phenotypic associations of these polymorphisms with diurnal preference, delayed sleep phase disorder/syndrome (DSPD/DSPS), and their effects on reporter gene expression. Design: Interspecific comparison was used to define the approximate extent of the PER3 promoter as the region between the transcriptional start site and nucleotide position −874. This region was screened in DNA pools using PCR and direct sequencing, which was also used to screen DNA from individual participants. The different promoter alleles were cloned into a luciferase expression vector and a deletion library created. Promoter activation was measured by chemiluminescence. Setting: N/A Patients or Participants: DNA samples were obtained from volunteers with defined diurnal preference (3 x 80, selected from a pool of 1,590), and DSPD patients (n = 23). Interventions: N/A Measurements and Results: We verified three single nucleotide polymorphisms (G −320T, C −319A, G −294A), and found a novel variable number tandem repeat (VNTR) polymorphism (−318 1/2 VNTR). The −320T and −319A alleles occurred more frequently in DSPD compared to morning (P = 0.042 for each) or evening types (P = 0.006 and 0.033). The allele combination TA2G was more prevalent in DSPD compared to morning (P = 0.033) or evening types (P = 0.002). Luciferase expression driven by the TA2G combination was greater than for the more common GC2A (P < 0.05) and the rarer TA1G (P < 0.001) combinations. Deletion reporter constructs identified two enhancer regions (−703 to −605, and −283 to −80). Conclusions: Polymorphisms in the PER3 promoter could affect its expression, leading to potential differences in the observed functions of PER3.

      JE Ang, R Pandher, Y Asad, DJ Skene, P Workman, S Eccles, J De Bono, S Kaye, U Banerji, S Davies, FI Raynaud (2014)Plasma metabolomic signature of novel signal transduction inhibitors from preclinical identification to clinical validation, In: EUROPEAN JOURNAL OF CANCER50pp. 148-149
      SM Montagnese, M De Rui, M Corrias, M Turco, P Amodio, C De Pitta, R Costa, B Middleton, DJ Skene (2014)Sleep-wake abnormalities in patients with cirrhosis, In: JOURNAL OF SLEEP RESEARCH23pp. 146-146
      W Von Schantz, JD Carpen, M Gibson, G Lim, J Johnston, DJ Skene, SN Archer (2008)Analysis of the PER3 promoter and haplotypes that associate with diurnal preference and delayed sleep phase disorder, In: JOURNAL OF SLEEP RESEARCH17pp. 80-80
      DJ Skene, SK Davies, JE Ang, VL Revell, B Holmes, A Mann, R Robertson, N Cui, B Middleton, K Ackermann, M Kayser, AE Thumser, FI Raynaud (2014)Effect of sleep deprivation on human plasma metabolome rhythms, In: JOURNAL OF SLEEP RESEARCH23pp. 36-37
      S Montagnese, B Middleton, DJ Skene, MY Morgan (2008)Sleep-wake disturbances in patients with cirrhosis: relations to neuropsychiatric performance and health-related quality of life, In: JOURNAL OF SLEEP RESEARCH17pp. 76-76
      T Kantermann, F Duboutay, D Haubruge, D Foy, S Hampton, M Kerkhofs, A Schmidt-Trucksaess, DJ Skene (2012)Atherosclerotic risk factors and social jetlag in rotating shift-workers, In: JOURNAL OF SLEEP RESEARCH21pp. 274-274
      S Montagnese, B Middleton, DJ Skene, MY Morgan (2008)Sleep disturbances are not a feature of hepatic encephalopathy, In: JOURNAL OF HEPATOLOGY48pp. S40-S40
      KH Jones, J Ellis, M Von Schantz, DJ Skene, D Dijk, SN Archer (2006)Age-related change in the association between a variable number tandem repeat polymorphism in the (PER3) gene and preferred timing of sleep and waking activities, In: JOURNAL OF SLEEP RESEARCH15pp. 97-98
      AU Viola, SN Archer, JA Groeger, DJ Skene, M Von Schantz, DJ Dijk (2006)Polymorphism in the clock gene PER3 predicts sleep structure and EEG power spectra, In: JOURNAL OF SLEEP RESEARCH15pp. 53-53
      L Pagani, E Moriggi, VR Revell, LM Hack, J Izakovic, SW Lockley, J Arendt, A Wirz-Justice, C Cajochen, DJ Skene, SA Brown, A Eckert (2009)Human molecular circadian rhythms and ageing, In: PHARMACOPSYCHIATRY42(5)pp. 235-235