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Ethics approval and consent to participate | All study-related measures were performed in accordance with the ethical principles formulated by the Declaration of Helsinki in its current version. In conformity, the study protocol was reviewed and ethical approval was provided by both the institutional review boards of both University Medical Center Groningen (METc2015/483) and Hannover Medical School (no. 2874–2015). Written informed consent was obtained from all subjects included in the study. | PMC10294515 | ||
Consent for publication | Not applicable. | PMC10294515 | ||
Competing interests | The authors declare no competing interests. | PMC10294515 | ||
References | PMC10294515 | |||
Introduction | JETLAG, ARTERIAL STIFFNESS | The discrepancy in sleep–wake timing between workdays and free (non-work) days due to modern work schedules possibly causes mild circadian misalignment between endogenous circadian rhythm and the sleep schedule imposed by social obligations. This jetlag-like phenomenon is called “social jetlag (SJL),” [In humans, blood pressure (BP) shows circadian variations; it decreases during sleep and increases in the morning [Thus, the purpose of the present study was to investigate the acute effects of SJL on morning BP surge. As an unhealthy lifestyle on free days, such as excess intake of energy as well as reduced physical activity levels, may confound the effects of SJL, we designed a randomized crossover trial to eliminate these potential confounding effects. We hypothesized that even acute SJL augments morning BP surge. Furthermore, the present study evaluated the effects of acute SJL on other cardiovascular variables and the autonomic nervous system, such as central arterial stiffness and sympathetic nerve activity in a vessel, to elucidate the underlying physiological mechanisms of the morning BP surge due to acute SJL. | PMC10477072 | |
Materials and methods | PMC10477072 | |||
Participants | hypertension, DBP] ≤, cardiovascular disease, diabetes | HYPERTENSION, CARDIOVASCULAR DISEASE, DIABETES | Twenty healthy men were recruited to participate in this study. All participants did not have a history of hypertension (systolic BP [SBP] ≤ 140 and diastolic BP [DBP] ≤ 90 mmHg), were nonsmokers, and were free of overt cardiovascular disease or diabetes, as assessed by medical history. All participants provided written informed consent to participate before the start of this study. The purpose, procedures, and risks involved in this study were reviewed and approved by the Human Research Committee of Waseda University (approval No. 2021-214). This study was conducted according to the guidelines of the 1975 Declaration of Helsinki. | PMC10477072 |
Experimental design | The present study was an open-label, randomized crossover trial consisting of the SJL and control (CON) trials (Figure SAfter written informed consent was obtained, wearable devices (Fitbit Charge 5, Fitbit, CA, USA) were distributed to the participants to monitor sleep variables and energy balance throughout this study. The device automatically measures bedtime, awake time, sleep duration (percentage of time in rapid eye movement [REM], light and deep sleep), and daily total energy expenditure. The validity of Fitbit Charge series for measuring the sleep variables has been confirmed by comparison with polysomnography and actigraphy [ | PMC10477072 | ||
Week one | We started with a screening term to confirm sleep variables (bedtime, awake time, and mid-sleep time [median time between bedtime and awake time]) under free-living conditions for each participant from Wednesday in week one to Tuesday in week two. We confirmed that day-to-day intraindividual variation in mid-sleep time on weekdays was within 2 h. | PMC10477072 | ||
Week two | ARTERIAL STIFFNESS | Resting hemodynamics, autonomic nervous system, cardiovagal baroreflex sensitivity (cvBRS), and central arterial stiffness were measured on Friday morning as pre-intervention measurement one. The participants were required to perform the SJL or CON trial from Friday night to Sunday morning. | PMC10477072 | |
Week three | Post-intervention measurement one was conducted on Monday morning, as with pre-intervention measurement one. Afterward, the participants were required to live according to everyday routine until Thursday as a washout term. Pre-intervention measurement two was conducted on Friday morning. The participants were then crossed over to the opposite trial and were instructed to have the same meal and to perform physical activity as per the last weekend to avoid the confounding effect of energy expenditure and intake. | PMC10477072 | ||
Week four | Post-intervention measurement two was performed on Monday morning. After that, the participants were required to live according to routine life until Thursday as a follow-up. | PMC10477072 | ||
Social jetlag and control trials | In the SJL trial, the participants were required to delay their bedtime by 3 h on Friday and Saturday nights in week two or three (Figure S | PMC10477072 | ||
Pre- and post-intervention measurements | Pre- and post-intervention measurements were performed on Friday and Monday mornings; the participants were tested at the same time of day throughout the study period to avoid potential diurnal variations. Before these measurements, the participants were instructed to avoid food and caffeine and alcohol intake for at least 12 and 24 h, respectively. Pre- and post-intervention measurements were conducted under comfortable laboratory conditions between 09:00 AM and 11:00 AM. | PMC10477072 | ||
Body composition | The percentage of body fat and lean body mass was measured using bioelectrical impedance analysis (InBody 720, InBody, Tokyo, Japan) with the participants in the upright position. The validity of the device for measuring body composition has been confirmed by comparison with dual-energy x-ray absorptiometry, which is the gold standard for measuring body composition [ | PMC10477072 | ||
Central arterial stiffness | ARTERIAL STIFFNESS | The participants were studied under quiet resting conditions for 10 min in the supine position. Carotid-femoral pulse wave velocity (cfPWV), which is the gold standard for measuring central arterial stiffness [The coefficient of variation for the cfPWV was 4.9 ± 4.1% within the same participant. | PMC10477072 | |
Ambulatory blood pressure and heart rate | The ambulatory BP monitoring (ABPM) device (TM-2441, A&D Medical, Tokyo, Japan) automatically measured ambulatory BP and heart rate (HR) using the oscillometric method every 30–60 min during the sleep and awake period until measurement was completed for 2 h after wake-up. The ambulatory BP monitoring device has been confirmed to be accurate and fulfilled all ISO 81060-2:2013 standard requirements for ABPM determination in adults [Sleep BP was defined as the average BP readings during sleep. The lowest BP was defined as the average of three BP readings (1.5 h) during sleep. Preawakening BP was defined as the average BP readings during the 2 h just before awake time (four BP readings). Morning BP was defined as the average BP readings during the first 2 h after the awake time (four BP readings) (Figure S
The coefficients of variation for the morning SBP and the lowest nocturnal SBP were 7.1 ± 6.6% and 7.0 ± 7.3% within the same participant, respectively [ | PMC10477072 | ||
Cardiovagal baroreflex sensitivity | Spontaneous cardiovagal baroreflex sensitivity (cvBRS) was determined from beat-to-beat changes in R–R interval (RRI) and SBP using an analysis software (Beatscope, version 1.1, Finapres Medical Systems, Amsterdam, The Netherlands). Three or more beats of progressive SBP changes and corresponding changes of RRI were identified as baroreflex sequences. Both were recorded in the present study. The minimum criteria for accepting a sequence were set at 1 mmHg for SBP and 4 ms for RRI. The slope of the linear correlation between RRI and SBP was assessed for up–up (progressive increases of SBP followed by a lengthening of the RRI) and down–down (progressive decreases of SBP with a subsequent shortening of the RRI) cvBRSs, which was determined if the r-value was > 0.8. Both cvBRSs were averaged for each participant for the last 5 min of 10-min rest [ | PMC10477072 | ||
HR and BP variabilities | HR variability (HRV) was measured as a reliable quantitative marker to assess the activity of the sympathetic and parasympathetic branches of the autonomic nervous system using HRV analysis module (MLS 310, AD Instruments, New South Wales, Australia). In the time domain, the root mean square of the squared differences of successive RRI (RMSSD) estimates short-term variation of HR caused by parasympathetic activity [BP variability was assessed as a marker of efferent sympathetic vascular modulation [ | PMC10477072 | ||
Hemodynamics in rest | HR and beat-to-beat BP waveform were monitored using a three-lead electrocardiogram (BSM-2401, Nihon Kohden, Tokyo, Japan) and finger photoplethysmography (Finometer MIDI, Finapres Medical Systems, Amsterdam, The Netherlands), respectively. The latter instrument was attached to the middle finger of the left hand. The BP value obtained from the finger was automatically reconstructed as the brachial BP value (Beatscope, version 1.1, Finapres Medical Systems, Amsterdam, The Netherlands) [ | PMC10477072 | ||
Statistical analyses | ARTERIAL STIFFNESS | A priori statistical power analysis was performed to determine the sample size needed for the present study using G*Power 3.1.9.6 [All data are expressed as mean ± standard deviation (SD). Statistical analyses were performed using IBM SPSS Statistics for Mac version 27.0 (IBM Corp., Armonk, N.Y., USA). The effects of time and trials were examined by the two-way repeated-measures ANOVA (trial × time) for participants’ characteristics, ambulatory BP and HR, hemodynamics, baroreflex sensitivity, autonomic nervous system, central arterial stiffness, and morning BP surge. The difference in the time course of ambulatory SBP and physical activity between the trials was also analyzed by the two-way repeated-measures ANOVA. In the case of significant Moreover, we calculated the absolute change (Δ) from Friday to Monday in each trial in cfPWV, morning BP surge, and LF-SBP. Then, Pearson’s correlation coefficients were used to assess the relationships between the ΔcfPWV and Δmorning BP surge or ΔLF-SBP, Δmorning BP surge, and ΔLF-SBP. The level of significance for all comparisons was set at | PMC10477072 | |
Results | PMC10477072 | |||
Data exclusion | Six participants were excluded from this study because four showed SJL of < 2 h in the SJL trial, and the ambulatory BP monitoring device did not work for two participants. Therefore, results were based on the remaining 14 participants who completed all measurements (Figure S | PMC10477072 | ||
Ambulatory blood pressure, heart rate, and physical activity | JETLAG | Table SFigure Time course of ambulatory systolic blood pressure (line chart) and physical activity (vertical bar chart) for 2 h before and after the awake time (n = 14). A vertical bar line means the awakening point as zero. Line charts show the time course of ambulatory systolic blood pressure as follows: open triangle (△): CON trial on Friday, open circle (○): CON trial on Monday, closed triangle (▲): SJL trial on Friday, closed circle (●): SJL trial on Monday. Vertical bar charts show as follows: white bar: CON trial on Friday, white bar with a black dot: CON trial on Monday, black bar: SJL trial on Friday, black bar with a white dot: SJL trial on Monday. CON, control trial; SBP, systolic blood pressure; SJL, social jetlag trial. Values are presented as mean ± standard deviation. | PMC10477072 | |
Central arterial stiffness and morning BP | arterial stiffness | ARTERIAL STIFFNESS | Figure Central arterial stiffness ( | PMC10477072 |
Association between changes in central arterial stiffness, morning BP surge and sympathetic nerve activity in vessels | ARTERIAL STIFFNESS | Figure Association between changes in central arterial stiffness and morning blood pressure surge ( | PMC10477072 | |
Discussion | The significant finding of the present study was that acute SJL on weekends (181 ± 24 min) increased cfPWV and morning BP surge on Monday (Figs. | PMC10477072 | ||
Alteration of morning BP surge by acute social jetlag | SJL trial significantly augmented morning BP surge (Fig. As baroreceptors, located in the carotid artery and aortic arch, are stretch receptors, the deformation of the barosensory arterial wall is required to initiate neural firing [ | PMC10477072 | ||
Response of central arterial stiffness to acute SJL | OXIDATIVE STRESS, JET LAG | The cfPWV was significantly elevated during the SJL trial compared with pre-intervention (Fig. The mechanisms underlying acute SJL elevation of sympathetic nerve activity remain unclear. We can speculate that the phenomenon is attributed to circadian disruption caused by acute SJL. An animal study has shown that simulated 12-h jet lag caused by air travel led to a pressor response by increasing the activity of the sympathetic nervous system via oxidative stress in the rostral ventrolateral medulla, which plays a role in cardiovascular regulatory nuclei within the brainstem [ | PMC10477072 | |
Response of central arterial stiffness and morning BP surge to acute SJL when including those who did not adhere to the intervention in the SJL trial | Although there were significant interactions in cfPWV, morning BP surge, and time course of ambulatory SBP, the significant interactions disappeared when including participants who did not adhere to the intervention in the SJL trial (SJL < 2 h). The results suggest that acute small SJL ( < 2 h) does not influence cardiovascular system in healthy men. As the present study could not clarify how many hours of SJL influence the cardiovascular system, further study is necessary. | PMC10477072 | ||
Study limitations | This study has some limitations. First, although we randomly assigned participants to two trials, the intervention was not performed in a blinded manner, which might have caused bias in the results. Second, we did not evaluate whether acute SJL altered circadian variables, such as clock gene expression levels and circadian-regulated hormones. Therefore, the present study could not clarify whether the intervention caused circadian disruption. Third, self-reported energy intake might be underestimated because the energy intake was low relative to energy expenditure throughout the intervention. Fourth, because only healthy male participants were recruited for the present study, the generalizability of our findings to other populations is limited. Future studies should be performed to solve these limitations. | PMC10477072 | ||
Perspectives | strokes | EVENTS, ARTERIAL STIFFNESS, STROKES | Our findings may contribute to clarifying pathophysiological mechanisms to prevent the Monday morning-specific increase in cardiovascular events. It has been reported that cardiovascular events and strokes often occur on Mondays [In conclusion, acute SJL augments morning BP surge in the present study. Although this phenomenon may correspond to increase central arterial stiffness, we cannot yet identify the mechanisms that explain the central arterial stiffening with acute SJL. The underlying physiological mechanisms and clinical implications of these findings warrant further study. However, we assert this is the first study revealing the effects of acute SJL on the cardiovascular system. | PMC10477072 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41440-023-01360-5. | PMC10477072 | ||
Acknowledgements | We appreciate the support received from all the participants in this study. Moreover, we would like to thank Editage ( | PMC10477072 | ||
Funding | This work was supported by the JSPS KAKENHI to M Higuchi (Grant-in-Aid for Scientific Research [B], Grant Number: 18H03198). | PMC10477072 | ||
Author contributions | T.K., H.M. and N.N. conceived and designed the study. All authors conducted the experiments. N.N. and T.K. analyzed the data. All authors interpreted the data. N.N. and T.K. wrote the manuscript. | PMC10477072 | ||
Compliance with ethical standards | PMC10477072 | |||
Conflict of interest | The authors declare no competing interests. | PMC10477072 | ||
References | PMC10477072 | |||
Key words: | cardiovascular disease, breast cancer, cancer, cardiometabolic disease, metabolic syndrome, cardiometabolic dysfunction, metabolic abnormalities | CARDIOVASCULAR DISEASE, BREAST CANCER, CANCER, DYSFUNCTION, SECONDARY, METABOLIC SYNDROME | These two authors contributed equally to this workMetabolic dysfunction and excess accumulation of adipose tissue are detrimental side effects from breast cancer treatment. Diet and physical activity are important treatments for metabolic abnormalities, yet patient compliance can be challenging during chemotherapy treatment. Time-restricted eating (TRE) is a feasible dietary pattern where eating is restricted to 8 h/d with water-only fasting for the remaining 16 h. The purpose of this study is to evaluate the effect of a multimodal intervention consisting of TRE, healthy eating, and reduced sedentary time during chemotherapy treatment for early-stage (I–III) breast cancer on accumulation of visceral fat (primary outcome), other fat deposition locations, metabolic syndrome and cardiovascular disease risk (secondary outcomes) compared with usual care. The study will be a two-site, two-arm, parallel-group superiority randomised control trial enrolling 130 women scheduled for chemotherapy for early-stage breast cancer. The intervention will be delivered by telephone, including 30–60-minute calls with a registered dietitian who will provide instructions on TRE, education and counselling on healthy eating, and goal setting for reducing sedentary time. The comparison group will receive usual cancer and supportive care including a single group-based nutrition class and healthy eating and physical activity guidelines. MRI, blood draws and assessment of blood pressure will be performed at baseline, after chemotherapy (primary end point), and 2-year follow-up. If our intervention is successful in attenuating the effect of chemotherapy on visceral fat accumulation and cardiometabolic dysfunction, it has the potential to reduce risk of cardiometabolic disease and related mortality among breast cancer survivors. | PMC10404477 |
Abbreviations: | obesity, non-cancer, malignancy, Breast cancer, cancer, cardiometabolic disease, breast Cancer, cardiotoxicity, metabolic abnormalities, eating and reduced sedentary | OBESITY, CVD, INFLAMMATION, BREAST CANCER, CANCER | Breast cancer is the most commonly diagnosed malignancy in women worldwide, representing 25 % of annual new cancer casesThe direct toxic effects of breast cancer treatment on the heart (cardiotoxicity) are well characterised as a contributor to elevated CVD riskExcess accumulation of fat within ectopic regions (e.g. visceral, intermuscular, or hepatic) triggers adverse metabolic effects and inflammation. In non-cancer populations, ectopic fat is more strongly linked to CVD risk than the total quantity, which is dominated by subcutaneous fatDiet and physical activity interventions play important roles in the treatment of metabolic abnormalities and body composition. Intermittent fasting is a pattern of eating involving voluntary abstinence from food alternated with periods of TRE has positive cardiometabolic health effects, including reduced body fat (whole body, visceral, liver and intermuscularAppropriate nutrition and healthy eating practices can also reduce the burden of chemotherapy symptoms and improve health across the cancer continuum. Dietary intake and physical activity are inextricably linked to cardiometabolic disease risk through reciprocal contributions to energy balance and obesity. Outside of sleep, time spent not being physically active is considered sedentary time, defined as any waking behaviour done while sitting, reclining or lying down that expend ≤ 1·5 metabolic equivalents. Sedentary time has consistently shown to be higher in cancer survivors than controlsThe purpose of the Impact of Metabolic health Patterns And breast Cancer over Time in Women (IMPACT-Women) trial is to evaluate the effect of a multimodal behavioural intervention involving TRE, healthy eating and reduced sedentary time on ectopic AT and cardiometabolic profile | PMC10404477 |
Methods | PMC10404477 | |||
Study design, randomisation and blinding | IMPACT-Women is a two-site, two-arm, parallel-group superiority randomised controlled trial. Participants will be randomised 1:1 to the two groups using permutated blocks with random block sizes of two and four, stratified by study site, chemotherapy type (adjuvant/neoadjuvant), and postmenopausal status (yes/no). Randomisation will occur after completion of baseline assessments using a blinded online electronic randomisation tool, with enrolment and assignment performed by a research coordinator. All outcome assessors will be blinded to group assignment. Blinding participants to a behavioural intervention is not possible but is not expected to bias our physiological outcomes. Participants’ treating oncologists will not be blinded as we expect that group assignment may need to be discussed during care. | PMC10404477 | ||
Ethics approval and registration | Both sites provide independent research ethics approval (HREBA.CC-22–0128; CAPCR.22–5374), which will be amended with protocol modifications. All participants will provide written informed consent. The trial is registered with clinicaltrials.gov (registration #NCT05432856). | PMC10404477 | ||
Participant eligibility | eating disorder, breast cancer | TYPE 1 DIABETES, TYPE 2 DIABETES, BREAST CANCER | We will recruit adult females (≥ 18 years) diagnosed with early-stage (I–III) breast cancer who will receive any type of neoadjuvant (pre-surgical) or adjuvant intravenous chemotherapy. Individuals without access to a cellphone with Bluetooth capability (required for intervention adherence tracking) will be excluded. We will exclude individuals who have type 1 diabetes and type 2 diabetes if hemoglobin A1c > 10 % or are taking insulin or sulfonylureas. For safety reasons, we will also exclude participants with research MRI contraindications (e.g. pacemaker, pregnancy, and magnetic implants), a self-reported history of an eating disorder, BMI < 18·5 kg/m | PMC10404477 |
Participant recruitment | cancer, Cancer | CANCER, CROSS, RECRUITMENT, CANCER | We anticipate that recruitment will start in January 2023 and be completed by December 2024. We will recruit from two Canadian university-affiliated cancer hospitals: the Princess Margaret Cancer Centre and the Cross Cancer Institute. At both sites, recruitment will be facilitated by the breast medical oncology circle of care who will request consent for contact by the research coordinator, who will screen and consent participants. | PMC10404477 |
Intervention | The intervention period will start shortly after randomisation and continue until the participant has completed all post-chemotherapy outcome assessments that occur 2–6 weeks after the last treatment (
Intervention and follow-up diagram. | PMC10404477 | ||
Time-restricted eating | Participants will be asked to follow 16:8 TRE, but with flexibility incorporated to personalise the protocol to adapt to the dynamic nature of treatment symptoms, as well as their lifestyle, or preferences. TRE parameters can vary within the following pre-specified and evidence-based rules shown to improve cardiometabolic health: (1) adjustment of eating window length from 8 h up to 10 h; (2) self-selecting their eating window start time as long as end time is > 3 h before bedtime; (3) follow TRE as many days possible, but if time off is required, aim to limit it to 1–2 d off following at least five successive days each week. | PMC10404477 | ||
Healthy eating | A registered dietitian will provide participants with a copy of Canada’s Food Guide, pre-determined nutritional education based on Canadian dietary guidelines, oncology guidelines for protein intake, individualised counselling and recommendations, and goal setting to promote healthy eating and overall nutritional well-being. | PMC10404477 | ||
Sedentary time reduction | Both environmental and educational strategies will be incorporated to reduce sedentary time. Study staff will provide participants with the Canadian 24-h movement guidelines (which encompass recommendations for sedentary behaviour, physical activity and sleep), as well as education on sedentary time and the associated health impacts, counselling and goal setting on strategies to reduce sedentary time throughout the intervention period. All participants will receive a Fitbit physical activity tracker to enable tracking of daily step counts, reminders to move after periods of sedentary behaviour, and goal setting related to these activities. Goals will be reviewed and progressed throughout the intervention. | PMC10404477 | ||
Intervention delivery | All components of the intervention will be delivered remotely by phone via evidence-based self-regulatory health behaviour support techniques | PMC10404477 | ||
Comparison group | cancer | ADVERSE EVENTS, CANCER | The comparison group will receive the current standard of cancer and supportive care at our institutions including a single group-based ‘nutrition during cancer treatment’ class, a copy of Canada’s Food Guide, the Canadian 24-h movement guidelines and a Fitbit tracker. The control group will be instructed to maintain their usual dietary habits (timing, amount and type) outside of any recommendations given in the nutrition class for the duration of the intervention period. The research coordinator will perform the same number and timing of phone calls for participants in the comparison group as that in the intervention group to control for social support, to track the self-reported eating window to assess contamination and to collect adverse events. | PMC10404477 |
Outcomes | metabolic syndrome | METABOLIC SYNDROME, PRESSURE AREA, INSULIN RESISTANCE | All outcomes will be measured at: (1) baseline (prior to first or second chemotherapy treatment), (2) 2–6 weeks post-last chemotherapy (typically lasting 12–18 weeks, depending on prescribed regimen) and (3) 2 years post-baseline. Participants who discontinue or deviate from intervention protocols will be asked to complete all follow-up assessments. The primary outcome is visceral AT volume at the end of chemotherapy. Secondary outcomes include the remaining AT pools (thigh intermuscular and intramuscular, liver, abdominal subcutaneous), metabolic syndrome z-score, 10-year Framingham and Reynolds risk scores, cardiorespiratory fitness, chemotherapy symptoms and quality of life. Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), hemoglobin A1c, lipid profile, waist circumference, fasting glucose and blood pressure are tertiary outcomes as we expect they may only change among those who are metabolically unhealthy at baseline. Exploratory or potential mechanistic/explanatory outcomes will include leptin, adiponectin, IL-6, TNF- | PMC10404477 |
Visceral adipose tissue and regional adipose tissue pools | 3T MRI (Siemens Prisma at both sites) will be used to quantify all AT volumes including the primary outcome of visceral AT. We will use standard chemical shift-encoding MRI and custom PROFIT1 | PMC10404477 | ||
Metabolic syndrome severity | Metabolic syndrome | METABOLIC SYNDROME | Metabolic syndrome will be classified according to the National Cholesterol Education Program Adult Treatment Panel III panel definition, and the severity z-score will be calculated through sex- and ethnic-specific equations | PMC10404477 |
Cardiovascular risk estimate | diabetes | CVD, HEART ATTACK, DIABETES | The Framingham 10-year CVD risk score will be calculated using the Canadian Cardiovascular Society sex-specific scoring system incorporating points for age, total cholesterol, HDL, treated/untreated systolic blood pressure, diabetes, and smoking status. The Reynolds risk score will be calculated using the same variables as well as family history of heart attack (self-report) and C-reactive protein. | PMC10404477 |
Cardiopulmonary exercise test and resting metabolic rate | We will measure cardiorespiratory fitness by the gold standard cardiorespiratory fitness assessment, an incremental-to-maximum exercise test with open-circuit indirect calorimetry. Monitoring before, during and after the test will include heart rate, pulse oximetry, blood pressure and the Borg rating of perceived exertion. Prior to the exercise test, resting metabolic rate will be assessed by using the same metabolic cart during 10–30 min of supine fasted rest. | PMC10404477 | ||
Circulating biomarkers | Participants will be asked to complete an overnight water-only fast prior to venipuncture. Core laboratories at each site will analyse fasting insulin, glucose, lipid profile, hemoglobin A1c and C-reactive protein in fresh blood, while blood will be stored (in each location) at −80°C for later batch analysis of leptin, adiponectin, IL-6, and TNF- | PMC10404477 | ||
Physical activity and sleep | A Fitbit wrist-worn tracker with heart rate monitoring will be used to collect data on average time spent performing physical activity of various intensity levels, sleep duration and quality data, and resting heart rate. | PMC10404477 | ||
Dietary intake | Dietary intake will be assessed by 3-d diet records over two consecutive weekdays and one weekend day. Each of three 24-h records will be collected using the Canadian version of the Automated Self-Administered 24-h Dietary Assessment Tool (ASA24-Canada) | PMC10404477 | ||
Questionnaires | CANCER | Chemotherapy symptom presence and severity will be assessed by the Rotterdam Symptom Checklist, which has been validated in patients with cancer | PMC10404477 | |
Medical outcomes | CVD | CVD, NON-ALCOHOLIC FATTY LIVER DISEASE, HYPERTENSION, TYPE 2 DIABETES, DYSLIPIDEMIA | We will access participant medical records to extract breast cancer diagnostic and treatment information and for chemotherapy outcomes (relative dose intensity, chemotherapy dose reductions and delays). We will also assess incident diagnoses of cardiometabolic conditions (hypertension, dyslipidemia, type 2 diabetes, CVD and non-alcoholic fatty liver disease) at the 2-year follow-up. | PMC10404477 |
Safety outcomes | malnutrition | MALNUTRITION | We will provide all participants with a Fibit body weight smartscale at baseline to take home to measure their weight first thing in the morning at least every 3 weeks. Based on global malnutrition guidelines | PMC10404477 |
Sample size | The proposed sample size of | PMC10404477 | ||
Analyses | SECONDARY | We will evaluate for balance in baseline covariates between groups using Planned secondary analyses include a per-protocol analysis (adherence to all aspects of intervention ≥ 5 of 7 d per week), a model with adjustment for covariates with clinically or statistically significant differences between groups at baseline, and a model with adjustment for covariates hypothesised to affect our outcomes including age and BMI. | PMC10404477 | |
Data management | Data will be de-identified using a studyID and will be securely stored with access limited to study staff and investigators. Electronic data entry or extraction will be double-checked for accuracy. | PMC10404477 | ||
Discussion | metabolic and/or cardiovascular dysfunction, breast cancer, Metabolic toxicity, metabolic dysfunction, active cancer | SIDE EFFECT, BREAST CANCER, CVD, RECRUITMENT, EVENTS | Metabolic toxicity is an important emerging side effect from chemotherapy treatment resulting in rapid onset of metabolic dysfunction and persistent impairments after treatment completionOur intervention is designed to address potential barriers to adherence common among patients receiving active cancer treatment. For example, we incorporated guidelines that allow participants to deviate from strict TRE in ways that are still supported by evidence for cardiometabolic health effects, including altering the length of TRE, selecting the start time of their eating window and guidance for taking a day off from TRE when required. Accounting for personal preferences in health interventions has been found to enhance recruitment and foster participant autonomy, enjoyment, and intervention adherenceA strength of this study is the use of 3T MRI as a non-invasive, safe (no ionising radiation), and highly reproducible technique to quantify the primary outcome (visceral AT), and other ectopic AT pools in the liver and thigh muscles. Our study will provide novel additions to the emerging evidence that rapid expansion of ectopic AT pools and their associated metabolic and/or cardiovascular dysfunction during breast cancer treatment plays a central role in the increased risk of CVD events among breast cancer survivors.We have taken steps to minimise potential sources of bias. While blinding participants and their care team is not possible due to behavioural nature of the intervention and for patient safety, all outcome assessors will be blinded to the group assignment. In addition, participants in the comparison group will receive the same number and timing of calls to control for social impact and to assess contamination. One limitation is that we are using a parallel study design to implement a multimodal intervention which limits our ability to determine the individual effects of each component of the intervention.In summary, the IMPACT-women study will evaluate the short- and longer-term effects of a multimodal metabolic health intervention during chemotherapy treatment for early-stage breast cancer on markers of metabolic health at the end of chemotherapy. The phone-based intervention consists of | PMC10404477 |
Acknowledgements | Stroke | HEART, STROKE | This trial is supported by the Canadian Institutes of Health Research. The funder will not play a role in study design, collection, management, analysis and interpretation of data. AAK and DIP are supported by the Canadian Institutes of Health Research and/or the Heart and Stroke Foundation of Canada. MJH is supported by the Faculty of Nursing Research Chair in ageing and quality of life at the University of Alberta.R. B. T., A. A. K. and M. J. H. conceived the study and acquired funding. A. A. K. and R. A. G. C. developed and drafted the protocol. M. J. H., M. N., C. M. P., S. D. S., J. N. R., E. P., D. I. P., J. R. M. and R. B. T. developed and edited the protocol. All authors approved the final manuscript. All publications will be prepared by the study team. Authorship will be provided based on the International Committee of Medical Journal Editors guidelines.The authors declare no conflicts of interest. | PMC10404477 |
References | PMC10404477 | |||
1. Introduction | work-related injuries, sleep deficiency | VEHICLE ACCIDENT, BRADLEY, SAID | In this modern society, it is said that a significant proportion of people have problems with sleep, and sleep deprivation or sleep deficiency has become a global concern. For example, according to the Sleep Foundation [A number of previous sleep studies have shown that problems with sleep can cause serious impairments in daytime performance, such as motor vehicle accidents or work-related injuries (Leger et al. [However, since most previous studies described above were based on cross-sectional data, identifying the causality between sleep and productivity is still a challenge. Just as there is an endogeneity problem in identifying the impact of sleep on health, the relationship between sleep and productivity is not clear (see, for example, Anderson and Bradley [ | PMC10553342 |
Causal relationship between sleep and productivity. | presenteeism | In this paper, by introducing the concept of The contributions of this paper are as follows. First, we conducted an RCT in the general workforce to investigate the extent to which sleep health improves and work productivity improves as sleep health improves. As previous studies in sleep health have positioned presenteeism as a measure to capture productivity loss, we also consider presenteeism as productivity and use two measures in a self-response format: a composite indicator using 15 productivity-related questions in our original survey and the Work Limitations Questionnaire (WLQ) developed by Tufts University. Second, although there is a growing body of research demonstrating the impact of sleep health on physical and mental health (for example, Dong et al. [ | PMC10553342 | |
2. Method | PMC10553342 | |||
2–1. Randomized controlled trials | SECONDARY, RECRUITMENT | The randomized controlled trial of the sleep-improvement program analyzed in this paper was conducted among employees of a publicly traded Japanese manufacturing firm with more than 10,000 employees. The program was implemented over a six-month period from November 1, 2020, to the end of April 2021. Using a crossover RCT design, all subjects were randomly assigned to participate in one of the two periods (period 1: November to January, period 2: February to April). Of 215 participants who applied for the program, 157 were assigned to period 1 (treatment group) and 58 to period 2 (control group). The allocation to the two groups was unequal because of the firm’s decision to assign at least two-thirds of participants to the treatment group. Outcomes were assessed for the first period, with those assigned to period 2 serving as the control group.Note that our datasets are proprietary and obtained in a legally restricted manner under confidentiality agreements with the firm and therefore cannot be made publicly available. The research team was provided with the anonymized data after the firm obtained written consent from all participants for the data to be used for academic research purposes. Specifically, this project was an opt-in, rather than mandatory, recruitment process. The firm clearly stated that the data collected would be analyzed within the firm to improve employees’ sleep and that once the internal analysis was completed, the anonymized data would be made available to Waseda University for academic research. Employees were also given the option to refuse to provide their data, but all participants in the project gave their written consent to provide their data. The authors notified the Ethics Review Committee of Waseda University that the program would be implemented by the firm and that the data would be provided for secondary use after the firm conducted an internal evaluation. The committee issued a decision indicating that no ethical review was required.Participants were provided noncontact sensing devices from In addition, two seminars, which aimed to explain the app’s advice in detail and to provide knowledge about sleep hygiene, were held during the three-month program in period 1. However, participation in the seminar was voluntary, and to ensure fairness, the firm allowed not only the treatment group but also the control group to participate in the seminar. Since the data also identify the IDs of individuals who actually participated in the first and second seminars in both groups, the following analysis controls for seminar participation. | PMC10553342 | |
2–2. Data | For both the treatment and control groups, we used responses to self-administered surveys conducted before the start of the program (the end of October 2020; the baseline survey) and after implementation in period 1 (the end of January 2021; the follow-up survey).To measure the effect of the intervention, only the sample that responded to both the baseline and follow-up surveys was used in the following analysis. Because there were several participants who left the program or did not return the questionnaire, the final sample of participants who completed the follow-up survey included 145 observations in the treatment group and 57 observations in the control group (see | PMC10553342 | ||
Program overview. | PMC10553342 | |||
Composition of the treatment and control groups. | PMC10553342 | |||
2-2-1. Sleep-related behaviors | sleep-related behaviors, ’ behaviors | The baseline and follow-up surveys asked essentially the same nine questions about sleep-related behaviors, which were used in the analysis to examine whether the program resulted in changes in participants’ behaviors that led to improved sleep. The specific questions are indicated in S1 Table in | PMC10553342 | |
2-2-2. Sleep health measures | To test the extent to which RCTs improve sleep health, we used the following six sleep health scale items in accordance with Buysee [ | PMC10553342 | ||
Summary of the six sleep health variables. | PMC10553342 | |||
2-2-3. Productivity | We use two indices of productivity, Respondents were asked to answer each of these questions on a 10-point Likert scale, with higher numbers indicating a greater frequency. Responses to these 15 items are transformed into a composite variable, As the second productivity index, we use presenteeism data based on the As in The number of participants who responded to both baseline and follow-up WLQ surveys was 114 in the treatment group and 39 in the control group. Using these samples, we also conducted tests of the difference in composition as well as | PMC10553342 | ||
Basic statistics. | PMC10553342 | |||
3. Estimation strategy | PMC10553342 | |||
3–2. Two-stage least squares (2SLS) | The treatment effect (γ) of the sleep improvement program calculated in Since the estimation of In addition, note that only 58 people (approximately 40%) in the treatment group had higher posttreatment sleep satisfaction than preintervention, while 8 people (14%) in the control group reported improved sleep satisfaction. Since less than half of the treatment group also experienced improved sleep, it is necessary to determine the extent to which the intervention improved sleep and the extent to which productivity improved through that pathway. Even if the interventions did improve productivity, we do not know if all the improvement was realized through improved sleep health. For example, people may have become more conscious of their health and reviewed their dietary and exercise habits during the program, which in turn might have increased productivity through improved physical condition. It is also possible that the subjects’ assignment to the treatment group increased their loyalty to the company and raised their productivity as a result of working more diligently.If the ATT analysis includes effects through pathways other than sleep improvement, it is not possible to elucidate the extent to which sleep improvement contributed to the improvement in productivity. Therefore, we estimated the causal effect of sleep improvement by 2SLS as follows. Using the sleep health scores In what follows, we estimated the impact of the intervention on sleep health scores | PMC10553342 | ||
4. Estimation results | PMC10553342 | |||
4–1. Changes before and after the program | We first present simple graphs to show the extent to which sleep health improved by comparing the pretreatment and posttreatment sleep health indices of the treatment and control groups. | PMC10553342 | ||
Changes before and after the intervention. | (Notes) The graphs show the mean values of Sleep Health Scores 1 and 2 (SH1 and SH2) of 145 participants in the treatment group and 57 participants in the control group at each time point before and after the program. The larger the value on the vertical axis, the better the sleep health is ensured. The p values shown in the figure indicate the results of significance tests for the two groups before and after the program, indicating that although there was no statistically significant difference between the two groups before the intervention, the sleep improvement in the treatment group was statistically significant at the 1% level after the intervention.In the following, we rigorously examine these results by estimating the three models (ANCOVA and two 2SLS models through diligent participation and sleep improvement) explained in the previous section. | PMC10553342 | ||
Effect of intervention on behavioral change in sleep. | (Notes) 1. Robust standard errors in parentheses.2. ***, **, and * indicate statistical significance at the 1%, 5%, and 10% levels.3. The variables described in section 2.2.4 are used as control variables in the estimation but are omitted from the table. | PMC10553342 | ||
4–3. Treatment effects on sleep improvement | PMC10553342 | |||
4-3-1. Effects on sleep health indices ( | Using | PMC10553342 | ||
Effect of intervention on sleep improvement. | (Notes) 1. Robust standard errors in parentheses.2. ***, **, and * indicate statistical significance at the 1%, 5%, and 10% levels.3. The variables described in section 2.2.4 are used as control variables in the estimation, but only some of them are included in the table. | PMC10553342 | ||
4-3-2. Effects on SH2 subscales | ADVERSE EFFECTS, ADVERSE EFFECT | To identify which subitems of SH2 improved through the intervention, we further estimate A statistically significant effect was confirmed for There are some other notable findings in the table. First, from the results in column 7, an increase in the number of days spent working from home may have caused the participants to experience more “trouble sleeping through the night and waking up in the middle of the night.” Telework may have an adverse effect on sleep, such as nocturnal awakening, potentially due to changes in work schedule, such as working until just before going to bed or waking up later. However, no adverse effects other than nocturnal awakening were detected for telework; thus, any adverse effect it has on sleep may be limited. Second, those who had an increase in workload may have experienced a decrease in “falling asleep fast enough to lose consciousness within five minutes” (column 10). Third, for those who were promoted during the RCT implementation period, “feeling sleepy” (column 4) was statistically negative and significant, while “waking up more than an hour early and having trouble going back to sleep” (column 6) was statistically positive and significant. This result can be interpreted as suggesting that immediately after a promotion, workers are more likely to feel nervous and excited by the new tasks they are given and are more likely to have trouble sleeping. No effects were detected for items other than these two, however. | PMC10553342 | |
4–4. Treatment effects on productivity | PMC10553342 | |||
4-4-1. ATT on productivity | We next estimate Column 2 in | PMC10553342 | ||
Effect of intervention on productivity improvement (ANCOVA). | (Notes) 1. Robust standard errors in parentheses.2. ***, **, and * indicate statistical significance at the 1%, 5%, and 10% levels.3. The variables described in section 2.2.4 are used as control variables in the estimation but are omitted from the table.However, as mentioned in the previous section, the causal effects of the intervention presented in | PMC10553342 | ||
4-4-2. Effect of diligent efforts on productivity (2SLS) | In what follows, we use the 2SLS method to determine whether diligent participants in the sleep program improved their productivity. This estimate can be interpreted as the local average treatment effect (LATE) of diligent participation as expressed by the model, Eqs The results are shown in | PMC10553342 | ||
Effect of diligent participation on productivity (LATE). | (Notes) 1. Robust standard errors in parentheses.2. ***, **, and * indicate statistical significance at the 1%, 5%, and 10% levels.3. The variables described in section 2.2.4 are used as control variables in the estimation but are omitted from the table.4. Regarding | PMC10553342 | ||
4-4-3. Effect of sleep improvement on productivity (2SLS) | We next estimated the effect of the intervention on productivity through improvements in the sleep health indices | PMC10553342 | ||
Effect of intervention on productivity through improved sleep (2SLS). | depression, insomnia, depressed | REGRESSION | (Notes) 1. Robust standard errors in parentheses.2. ***, **, and * indicate statistical significance at the 1%, 5%, and 10% levels.3. The variables described in section 2.2.4 are used as control variables in the estimation but are omitted from the table.4. Regarding Note that the purpose of this paper is to examine the relationship between sleep improvement and productivity in the general workforce, rather than in patients with insomnia. Therefore, we did not set any special criteria for recruiting subjects within the company but recruited a wide range of workers who were interested in improving their sleep health. However, we must be aware of the possibility that some of the applicants may have had insomnia or depression, which could substantially affect the effectiveness of the sleep hygiene program. To prevent such cases from affecting our results significantly, we also ran the same regression analysis with a subsample, excluding observations based on several of the criteria (those who had mentioned “sleepless,” “need improvement in physical condition,” or “Feeling depressed almost every day”) as a robustness check. We obtained similar results to those reported in this paper even after excluding those observations. | PMC10553342 |
4–5. Economic return to sleep improvement programs | sleep-related behaviors | In section 4–4, we measured the effects on productivity through three pathways: average effects on the treatment group, local average treatment effects of diligent participants, and indirect effects through sleep improvement. Based on those estimators, we evaluated the economic return to sleep improvement programs using the total WLQ score. Although we should look at the net return on investment, the total cost of the sleep improvement program was not disclosed to us by the firm, so we only evaluated the economic benefit.The following assumptions are made in our calculation.The range of change in the overall WLQ score equals the rate of change in productivity.The average productivity per person per year is 8 million yen (approximately 60,000 US dollars).For the 112 participants in the treatment group who responded to the WLQ, the estimated effect of the intervention continued for one year.The first assumption is based on our understanding that the WLQ was originally designed to measure the value of productivity loss (Lerner et al. [According to Next, the local average treatment effect (LATE) of diligent participation in Finally, the coefficient of sleep improvement (i.e., endogenous variable in 2SLS) in The most uncertain of our assumptions is the third assumption, the duration of the intervention effect. The Hawthorne effect may have exaggerated the short-term effect of the program, and the improved sleep-related behaviors and productivity gains may be reversed in a few months. Conversely, there is also a possibility that participants who realized the importance of sleep may continue to take steps to improve their sleep, and the effects may last for more than a year. | PMC10553342 | |
4–6. Who improved and who did not? | As mentioned in section 4–3, not all participants in the treatment group improved their sleep health through the sleep improvement program. According to previous studies, the effects and dropouts of RCTs vary according to individual characteristics, personality traits and level of education (see, for example, Bagby et al. [We use two dependent variables that specify those whose sleep has improved. The first is a binary variable in which one is assigned to those whose The estimation results are presented in | PMC10553342 |
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