**5. Future directions in body temperature and chronotherapy research**

The last two centuries saw a great advancement in our knowledge of the circadian rhythm of living organisms. Yet, much remains to be discovered as relates to both molecular pathways and clinical applications to improve human health. In particular, at the current stage of scientific knowledge, the mechanism that links the circadian rhythm at the cellular level to the circadian rhythm of body temperature on the organismal level remains unknown. Also, there is a significant heterogeneity among human studies, thus making the confirmation of specific associations between disruption in the circadian rhythm and human disease challenging. Further, the clinical interventions currently in use are at best crude and not optimized to reach their full potential. One example is the use of a melatonin pill in the evening to fight insomnia, where research regarding the dose or time of intake remains inconclusive and the effects are modest, as detailed in a metanalysis by Ferracioli-Oda et al. [121]. Another example would be the use of very bright light (7000 to 12,000 lux with the associated possible light damage to the retina) instead of the ordinary 150 lux during night shifts, which was shown to lead to circadian rhythm adaptation to shift work after 4 days of treatment as evidenced by the delay in the body temperature nadir from 3:30 AM to 2:50 PM and improvement in cognitive performance and alertness among healthy volunteers [122]. It should also be pointed out that a big portion of the existing knowledge stems from animal model research and needs validation in humans before wide-spread application in clinical settings could be attempted. What is perhaps most relevant to this book chapter is the fact that the vast majority of circadian rhythm research uses the day-night wake-sleep pattern and measurements of serum biomarkers such as melatonin. Measuring body temperature as the human circadian rhythm marker would be a much less resource-heavy and less invasive approach in research designs. Thanks to the recent advances in electronics, the monitoring of human body temperature can be done at high frequency (collecting several measurements per minute) using relatively inexpensive equipment for data collection with wearable devices that allow for research to be carried out even outside hospitals and research centers. An important requirement for all research involving body temperature would be accurate temperature measurement via careful device calibration and by ensuring the temperature

collection site is not significantly influenced by environmental temperature fluctuations or alternatively devising an algorithm to correct for any external variables.

Many of the experiments that so far involved animal models can be repeated in humans using body temperature as the main circadian rhythm measure. For instance, using the Gibbs et al. encouraging pre-clinical results regarding bacterial infections in mice [108], a human challenge model experimental protocol could be built as follows. One could inflict skin cuts on one arm of healthy volunteers during the day (near the body temperature acrophase) and on the other arm during the night (near the body temperature bathyphase). Then, one would quantify the inflammatory response and the evolution of the infection of each cut, where each person serves as their own internal control. If there is significant difference in the infection severity and healing times akin to the difference observed in mice, then this experiment could inform the timing of surgical procedures based on each patient's specific circadian rhythm. Such an approach would constitute another step toward personalized medicine.

As detailed earlier in this chapter, disruption in the body temperature diurnal cycling pattern can be used as a predictor of events such as early sepsis, it can serve as a predictor of patient outcome among the critically ill, it can monitor the success (or lack thereof) of circadian adaptation in night shift workers, and the list goes on. But if any of these applications are to be used as standard of care tools, we would need well-controlled multi-institutional studies to validate the potential early warning system and clinical prediction models. In order to improve model validity, data from body temperature oscillations will likely have to be combined with other types of information such as the non-temperature vital signs, comorbidities, age, race, environmental specifications such as level of lightning, etc. Similar considerations apply to interventional studies such as light therapy to re-establish the circadian rhythm in night shift workers and people with psychiatric illnesses. Research aiming to identify the most optimal time along the circadian cycle for chemotherapy [123] or antibiotics [124] delivery constitutes yet another promising avenue open for exploration. Given the complexity of the involved models, the field of chronotherapy could prove an opportunity for the application of artificial intelligence to optimize the various model variables.

In conclusion, ours are exciting times for circadian rhythm research and the circadian rhythm of human body temperature provides an easily accessible tool for the development of clinically relevant applications.
