Corrigendum: The impact of circadian rhythm on Bacillus Calmette-Guérin vaccination effects on SARS-CoV-2 infections.

[This corrects the article DOI: 10.3389/fimmu.2023.980711.].

Impacts of Coronavirus Disease 2019 Pandemic on Sleep Pattern

The ongoing coronavirus disease 2019 (COVID-19) pandemic is the third global crisis after two epidemics of severe acute respiratory syndromes. It has affected general public besides health care systems and governments. Confinements and lock downs have changed waking up time and going to bed time, ultimately affecting circadian clocks that can disturb sleep quality which can lead to anxiety, stress, and depression. This puts the most susceptible group -young adults and females at risk of psychological disorders and even inflammatory events. Several kinds of sleep disorders due to COVID-19 including insomnia, sleep apnea, sleepiness during daytime, post-traumatic-like sleep dysfunction, abnormal dreams, and restless legs syndrome have been reported. As sleep deprivation can alter circadian clock and weaken immunity which makes human more susceptible to pulmonary inflammatory process of COVID-19 and even enhance its manifestations, it should be considered as an urgent complication that needs to be treated. Furthermore, longstanding effects of sleep disturbances during COVID-19 pandemic need to be elucidated © 2023 The Korean Society of Sleep Medicine

The impact of circadian rhythm on Bacillus Calmette-Guérin vaccination effects on SARS-CoV-2 infections.

Background and objective: A recent study has suggested that circadian rhythm has an important impact on the immunological effects induced by Bacillus Calmette-Guérin (BCG) vaccination. The objective of this study was to evaluate whether the timing of BCG vaccination (morning or afternoon) affects its impact on severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infections and clinically relevant respiratory tract infections (RTIs). Methods: This is a post-hoc analysis of the BCG-CORONA-ELDERLY (NCT04417335) multicenter, placebo-controlled trial, in which participants aged 60 years and older were randomly assigned to vaccination with BCG or placebo, and followed for 12 months. The primary endpoint was the cumulative incidence of SARS-CoV-2 infection. To assess the impact of circadian rhythm on the BCG effects, participants were divided into four groups: vaccinated with either BCG or placebo in the morning (between 9:00h and 11:30h) or in the afternoon (between 14:30h and 18:00h). Results: The subdistribution hazard ratio of SARS-CoV-2 infection in the first six months after vaccination was 2.394 (95% confidence interval [CI], 0.856-6.696) for the morning BCG group and 0.284 (95% CI, 0.055-1.480) for the afternoon BCG group. When comparing those two groups, the interaction hazard ratio was 8.966 (95% CI, 1.366-58.836). In the period from six months until 12 months after vaccination cumulative incidences of SARS-CoV-2 infection were comparable, as well as cumulative incidences of clinically relevant RTI in both periods. Conclusion: Vaccination with BCG in the afternoon offered better protection against SARS-CoV-2 infections than BCG vaccination in the morning in the first six months after vaccination.

The relationship of light exposure to sleep outcomes among office workers. Part 1: Working in the office versus at home before and during the COVID-pandemic

The relationship between everyday light exposure and sleep was studied for office workers. The study was conducted during the upswing of the COVID-19 pandemic, enabling a comparison between Office and Home Workdays. Fifteen full-time office employees were monitored for a period of 4-6 weeks. They wore a light-tracking device on their clothes and had a sleep tracker at home. Compared to an Office Workday, light exposure was lower in the afternoon and total sleep time was almost 5 minutes longer on a Home Workday. Sleep efficiency was the same on both workday types. A higher median illuminance level in the afternoon was significantly related to later sleep onset on an Office Workday. Higher median illuminance levels in the morning were related to earlier awakening. Counter to expectations, higher light levels in the evening were also related to earlier awakening. Everyday light exposure matters for sleep quality but may affect circadian functioning differently than the often more extreme light interventions employed in laboratory experiments. Moreover, differences in outcomes between Office and Home Workdays signal the need for further investigation to provide supportive light levels during workhours.

When the clock ticks wrong with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the coronavirus family that causes the novel coronavirus disease first diagnosed in 2019 (COVID-19). Although many studies have been carried out in recent months to determine why the disease clinical presentations and outcomes can vary significantly from asymptomatic to severe or lethal, the underlying mechanisms are not fully understood. It is likely that unique individual characteristics can strongly influence the broad disease variability; thus, tailored diagnostic and therapeutic approaches are needed to improve clinical outcomes. The circadian clock is a critical regulatory mechanism orchestrating major physiological and pathological processes. It is generally accepted that more than half of the cell-specific genes in any given organ are under circadian control. Although it is known that a specific role of the circadian clock is to coordinate the immune system's steady-state function and response to infectious threats, the links between the circadian clock and SARS-CoV-2 infection are only now emerging. How inter-individual variability of the circadian profile and its dysregulation may play a role in the differences noted in the COVID-19-related disease presentations, and outcome remains largely underinvestigated. This review summarizes the current evidence on the potential links between circadian clock dysregulation and SARS-CoV-2 infection susceptibility, disease presentation and progression, and clinical outcomes. Further research in this area may contribute towards novel circadian-centred prognostic, diagnostic and therapeutic approaches for COVID-19 in the era of precision health.

A Preliminary Study on Acute Otitis Media in Spanish Children with Late Dinner Habits.

The timing of caloric intake plays an important role in the long-term process that leads to communicable diseases. The primary objective of this study was to analyse whether children who ate dinner early were at lower risks of acute respiratory infections than children who ate dinner late during the COVID-19 pandemic. METHODS: This cross-sectional study was conducted from July to December 2020 on children attending Majorcan emergency services. Our survey on dinner time habits was carried out by using self-administered questionnaires. RESULTS: A total of 669 children were included in this study. The median dinner time was 8:30 pm. Late dinner eaters accounted for a higher proportion of acute otitis media (7% vs. 3%; p = 0.028) than early dinner eaters. Other infectious diseases were not associated with dinner time habits. CONCLUSIONS: We make a preliminary estimate of the link between late dinner habits and acute otitis media in children. However, no conclusions about causality can be established due to the observational design of the study, and further research is needed in order to confirm the different issues raised by our initial exploration of an emerging research area.

A Study on Chronofatality Trends of COVID-19 Deaths at a Tertiary Care Hospital

The aim of the study is to find out any association between time of death in coronavirus disease (COVID-19) patients and variables like age, sex, and existence of comorbidities including type II diabetes mellitus, hypertension, coronary artery disease, chronic kidney disease, etc. An attempt was also made to elucidate the reasons for relationship between time of death and other aforementioned variables. Mortality data of 1,553 COVID-19 cases from a tertiary care hospital between March 2020 to September 2021 were analyzed. Maximum deaths occurred between 18:01 hours to 06:00 hours of the 24-hour cycle. There is a significant statistical association between time of death and age, time of death and sex, time of death and having a comorbidity of diabetes mellitus in the study sample. The study confirms that the chronofatality of COVID-19 deaths has a nocturnal predilection. The circadian rhythms of glucocorticoids, respiratory physiology of sleep, and circadian hemodynamic variations may have a role in prognosis and fatality of COVID-19. © This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/bync/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © 2021 Korean Academy of Sleep Medicine

Circadian clock modulating small molecules repurposing as inhibitors of SARS-CoV-2 Mpro for pharmacological interventions in COVID-19 pandemic.

The COVID-19 pandemic caused by SARS-CoV-2 is a global health emergency warranting the development of targeted treatment. The main protease Mpro is considered as a key drug target in coronavirus infections because of its vital role in the proteolytic processing of two essential polyproteins required for the replication and transcription of viral RNA. Targeting and inhibiting the Mpro activity represents a valid approach to prevent the SARS-CoV-2 replication and spread. Based on the structure-assisted drug designing, here we report a circadian clock-modulating small molecule "SRT2183" as a potent inhibitor of Mpro to block the replication of SARS-CoV-2. The findings are expected to pave the way for the development of therapeutics for COVID-19.

Metabolic consequences of obesity and type 2 diabetes: Balancing genes and environment for personalized care.

The prevalence of type 2 diabetes and obesity has risen dramatically for decades and is expected to rise further, secondary to the growing aging, sedentary population. The strain on global health care is projected to be colossal. This review explores the latest work and emerging ideas related to genetic and environmental factors influencing metabolism. Translational research and clinical applications, including the impact of the COVID-19 pandemic, are highlighted. Looking forward, strategies to personalize all aspects of prevention, management and care are necessary to improve health outcomes and reduce the impact of these metabolic diseases.

A Timely Call to Arms: COVID-19, the Circadian Clock, and Critical Care.

We currently find ourselves in the midst of a global coronavirus disease 2019 (COVID-19) pandemic, caused by the highly infectious novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we discuss aspects of SARS-CoV-2 biology and pathology and how these might interact with the circadian clock of the host. We further focus on the severe manifestation of the illness, leading to hospitalization in an intensive care unit. The most common severe complications of COVID-19 relate to clock-regulated human physiology. We speculate on how the pandemic might be used to gain insights on the circadian clock but, more importantly, on how knowledge of the circadian clock might be used to mitigate the disease expression and the clinical course of COVID-19.

Melatonin and healthy aging.

Preservation of a robust circadian rhythmicity (particulsarly of the sleep/wake cycle), a proper nutrition and adequate physical exercise are key elements for healthy aging. Aging comes along with circadian alteration, e.g. a disrupted sleep and inflammation, that leads to metabolic disorders. In turn, sleep cycle disturbances cause numerous pathophysiological changes that accelerates the aging process. In the central nervous system, sleep disruption impairs several functions, among them, the clearance of waste molecules. The decrease of plasma melatonin, a molecule of unusual phylogenetic conservation present in all known aerobic organisms, plays a particular role as far as the endocrine sequels of aging. Every day, the late afternoon/nocturnal increase of melatonin synchronizes both the central circadian pacemaker located in the hypothalamic suprachiasmatic nuclei as well as myriads of peripheral cellular circadian clocks. This is called the "chronobiotic effect" of melatonin, the methoxyindole being the prototype of the endogenous family of chronobiotic agents. In addition, melatonin exerts a significant cytoprotective action by buffering free radicals and reversing inflammation via down regulation of proinflammatory cytokines, suppression of low degree inflammation and prevention of insulin resistance. Because of these properties melatonin has been advocated to be a potential therapeutic tool in COVID 19 pandemic. Melatonin administration to aged animals counteracts a significant number of senescence-related changes. In humans, melatonin is effective both as a chronobiotic and a cytoprotective agent to maintain a healthy aging. Circulating melatonin levels are consistently reduced in the metabolic syndrome, ischemic and non-ischemic cardiovascular diseases and neurodegenerative disorders like the Alzheimer's and Parkinson's diseases. The potential therapeutic value of melatonin has been suggested by a limited number of clinical trials generally employing melatonin in the 2-10mg/day range. However, from animal studies the cytoprotective effects of melatonin need higher doses to become apparent (i.e. in the 100mg/day range). Hence, controlled studies employing melatonin doses in this range are urgently needed.

Early dinner or "dinner like a pauper": Evidence, the habitual time of the largest meal of the day - dinner - is predisposing to severe COVID-19 outcome - death.

COVID-19 and metabolic syndrome are devastating pandemics. Effective control of metabolic parameters and their dysfunction may help prevent or minimize the acute and devastating effects of SARS-CoV-2 by reducing the local inflammatory response and blocking the entry of the virus into cells. With such consideration in mind, we gathered data from dietary surveys conducted in nine European countries to explore the relationship between actual clock hour of the large dinner meal and also interval in minutes between it and sunset in the respective countries and death rate above the median rate of per one million people as an index of mortality due to COVID-19 infection. Clock time of the dinner meal varied between 16:00 and 21:00 h across the European counties sampled, and the correlation between dinner mealtime and death rate was strongly correlated, R = 0.7991 (two-tailed p = 0.0098), with R2 explaining 63% of the variation within the data. This strong linear positive correlation indicates that the later the clock time of the dinner meal, the higher is the death rate (and vice versa). The relationship between meal timing in reference to sunset, utilized as a gross surrogate marker of the activity/rest synchronizer of circadian rhythms, and death rate was negative and even slightly stronger, R = -0.8025 (two-tailed p = 0.0092), with R2 explaining 64% of the variation within the data. This strong linear negative correlation indicates that the shorter the interval between the dinner meal and sunset, i.e., the closer the time of the largest meal of the day to bedtime, the greater is the death rate (and vice versa). Our preliminary approach to nighttime eating, in terms of the day's largest caloric intake, as a risk factor for the predisposing conditions of obesity, metabolic syndrome, type 2 diabetes, and other commonly associated comorbidities of being overweight, and death from COVID-19 infection reveals strong correlation with the time of the dinner meal, both in terms of its actual clock and circadian time.