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      Keeping an eye on circadian time in clinical research and medicine

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          Abstract

          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.

          Abstract

          Understanding the contribution of the endogenous circadian system to observed time‐of‐day rhythms can yield insights that further health‐related research and optimize clinical treatments and increase life expectancy. This manuscript provides guidance on best practices in measuring and distinguishing endogenous circadian rhythms from time‐of‐day rhythms in a variety of settings.

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          Most cited references105

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          The Pittsburgh sleep quality index: A new instrument for psychiatric practice and research

          Despite the prevalence of sleep complaints among psychiatric patients, few questionnaires have been specifically designed to measure sleep quality in clinical populations. The Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep quality and disturbances over a 1-month time interval. Nineteen individual items generate seven "component" scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of scores for these seven components yields one global score. Clinical and clinimetric properties of the PSQI were assessed over an 18-month period with "good" sleepers (healthy subjects, n = 52) and "poor" sleepers (depressed patients, n = 54; sleep-disorder patients, n = 62). Acceptable measures of internal homogeneity, consistency (test-retest reliability), and validity were obtained. A global PSQI score greater than 5 yielded a diagnostic sensitivity of 89.6% and specificity of 86.5% (kappa = 0.75, p less than 0.001) in distinguishing good and poor sleepers. The clinimetric and clinical properties of the PSQI suggest its utility both in psychiatric clinical practice and research activities.
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            A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms.

            An English language self-assessment Morningness-Eveningness questionnaire is presented and evaluated against individual differences in the circadian vatiation of oral temperature. 48 subjects falling into Morning, Evening and Intermediate type categories regularly took their temperature. Circadian peak time were identified from the smoothed temperature curves of each subject. Results showed that Morning types and a significantly earlier peak time than Evening types and tended to have a higher daytime temperature and lower post peak temperature. The Intermediate type had temperatures between those of the other groups. Although no significant differences in sleep lengths were found between the three types, Morning types retired and arose significantly earlier than Evening types. Whilst these time significatly correlated with peak time, the questionnaire showed a higher peak time correlation. Although sleep habits are an important déterminant of peak time there are other contibutory factors, and these appear to be partly covered by the questionnaire. Although the questionnaire appears to be valid, further evaluation using a wider subject population is required.
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              Adverse metabolic and cardiovascular consequences of circadian misalignment.

              There is considerable epidemiological evidence that shift work is associated with increased risk for obesity, diabetes, and cardiovascular disease, perhaps the result of physiologic maladaptation to chronically sleeping and eating at abnormal circadian times. To begin to understand underlying mechanisms, we determined the effects of such misalignment between behavioral cycles (fasting/feeding and sleep/wake cycles) and endogenous circadian cycles on metabolic, autonomic, and endocrine predictors of obesity, diabetes, and cardiovascular risk. Ten adults (5 female) underwent a 10-day laboratory protocol, wherein subjects ate and slept at all phases of the circadian cycle-achieved by scheduling a recurring 28-h "day." Subjects ate 4 isocaloric meals each 28-h "day." For 8 days, plasma leptin, insulin, glucose, and cortisol were measured hourly, urinary catecholamines 2 hourly (totaling approximately 1,000 assays/subject), and blood pressure, heart rate, cardiac vagal modulation, oxygen consumption, respiratory exchange ratio, and polysomnographic sleep daily. Core body temperature was recorded continuously for 10 days to assess circadian phase. Circadian misalignment, when subjects ate and slept approximately 12 h out of phase from their habitual times, systematically decreased leptin (-17%, P < 0.001), increased glucose (+6%, P < 0.001) despite increased insulin (+22%, P = 0.006), completely reversed the daily cortisol rhythm (P < 0.001), increased mean arterial pressure (+3%, P = 0.001), and reduced sleep efficiency (-20%, P < 0.002). Notably, circadian misalignment caused 3 of 8 subjects (with sufficient available data) to exhibit postprandial glucose responses in the range typical of a prediabetic state. These findings demonstrate the adverse cardiometabolic implications of circadian misalignment, as occurs acutely with jet lag and chronically with shift work.
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                Author and article information

                Contributors
                ebklerman@hms.harvard.edu
                Journal
                Clin Transl Med
                Clin Transl Med
                10.1002/(ISSN)2001-1326
                CTM2
                Clinical and Translational Medicine
                John Wiley and Sons Inc. (Hoboken )
                2001-1326
                25 December 2022
                December 2022
                : 12
                : 12 ( doiID: 10.1002/ctm2.v12.12 )
                : e1131
                Affiliations
                [ 1 ] Department of Neurology Massachusetts General Hospital, Brigham and Women's Hospital Boston Massachusetts USA
                [ 2 ] Division of Sleep Medicine Harvard Medical School Boston Massachusetts USA
                [ 3 ] Plans Analysis, and Futures John F. Kennedy Special Warfare Center and School Fort Bragg North Carolina USA
                [ 4 ] Alpert Medical School of Brown University Department of Psychiatry and Human Behavior EP Bradley Hospital Chronobiology and Sleep Research Providence Rhode Island USA
                [ 5 ] Department of Health and Kinesiology University of Utah Salt Lake City Utah USA
                [ 6 ] Sir Jules Thorn Sleep and Circadian Neuroscience Institute Nuffield Department of Clinical Neurosciences University of Oxford Oxford UK
                [ 7 ] Biological Rhythms Research Laboratory Department of Psychiatry and Behavioral Sciences Rush University Medical Center Chicago Illinois USA
                [ 8 ] Neuroscience Program Smith College Northampton Massachusetts USA
                [ 9 ] Radcliffe Department of Medicine University of Oxford Oxford UK
                [ 10 ] Section of Pulmonary Critical Care, and Sleep Medicine Department of Internal Medicine Yale School of Medicine New Haven Connecticut USA
                [ 11 ] Sleep and Development Laboratory Department of Integrative Physiology University of Colorado Boulder Boulder Colorado USA
                [ 12 ] Boston Children's Hospital and Kirby Neurobiology Center Boston Massachusetts USA
                [ 13 ] Institute of Medical Psychology Faculty of Medicine LMU Munich Germany
                [ 14 ] Department of Medicine University of Padova Padova Italy
                [ 15 ] Clinical Proteomics Research Center and Cardio‐Neurology Division Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA
                [ 16 ] NIHR Oxford Biomedical Research Centre John Radcliffe Hospital Oxford UK
                [ 17 ] Oxford Centre for Diabetes Endocrinology and Metabolism University of Oxford Oxford UK
                [ 18 ] Medical Chronobiology Program Division of Sleep and Circadian Disorders Departments of Medicine and Neurology Brigham and Women's Hospital Boston Massachusetts USA
                [ 19 ] Oregon Institute of Occupational Health Sciences Oregon Health and Science University Portland Oregon USA
                [ 20 ] Chronobiology Faculty of Health and Medical Sciences University of Surrey Guildford UK
                [ 21 ] Department of Anesthesiology and Intensive Care Medicine Charité – Universitaetsmedizin Berlin Berlin Germany
                [ 22 ] Univ Lille Inserm CHU Lille Institut Pasteur de Lille U1011‐EGID Lille France
                [ 23 ] Division of General Medicine and Center of Excellence for Sleep and Circadian Research Department of Medicine Columbia University Irving Medical Center New York New York USA
                [ 24 ] Institute for Stroke and Dementia Research University Hospital LMU Munich Germany
                [ 25 ] Center for Circadian and Sleep Medicine Division of Sleep Medicine Northwestern University Feinberg School of Medicine Chicago Illinois USA
                [ 26 ] Sleep and Circadian Research Laboratory Department of Psychiatry University of Michigan Ann Arbor Michigan USA
                Author notes
                [*] [* ] Correspondence

                Elizabeth B. Klerman, Massachusetts General Hospital, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.

                Email: ebklerman@ 123456hms.harvard.edu

                Author information
                https://orcid.org/0000-0002-7402-3171
                https://orcid.org/0000-0003-0821-8461
                https://orcid.org/0000-0001-7240-0140
                https://orcid.org/0000-0003-2528-5455
                https://orcid.org/0000-0001-6055-2067
                https://orcid.org/0000-0003-2602-1996
                https://orcid.org/0000-0003-2266-6455
                https://orcid.org/0000-0002-1947-4885
                https://orcid.org/0000-0002-7341-850X
                https://orcid.org/0000-0002-7581-5701
                https://orcid.org/0000-0002-9648-0541
                https://orcid.org/0000-0002-8688-2360
                https://orcid.org/0000-0003-2800-9923
                https://orcid.org/0000-0002-4739-6773
                https://orcid.org/0000-0002-2014-7582
                https://orcid.org/0000-0003-1949-0954
                https://orcid.org/0000-0001-8202-6180
                https://orcid.org/0000-0002-1062-0495
                https://orcid.org/0000-0002-3784-1503
                https://orcid.org/0000-0003-1354-1749
                https://orcid.org/0000-0002-8817-8457
                https://orcid.org/0000-0001-6296-6685
                https://orcid.org/0000-0003-3816-8194
                Article
                CTM21131
                10.1002/ctm2.1131
                9790849
                36567263
                35d3f852-a6e8-4860-8a14-6ebf34916593
                © 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 November 2022
                : 09 September 2022
                : 17 November 2022
                Page count
                Figures: 4, Tables: 2, Pages: 21, Words: 12263
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                December 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.3 mode:remove_FC converted:25.12.2022

                Medicine
                chronobiology,chronomedicine,circadian,circadian medicine,daily,diurnal,human,time‐of‐day,translational

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