Abstract.  

Humans possess complex thermoregulation that maintains thermal homeostasis in any environment. Sensory neurons detect when the body is to too warm, which triggers the hypothalamus to send signals to dissipate excess heat.  Blood flow increases to the body’s periphery and blood vessels in the skin dilate to allow increased blood flows. Sweat glands increase the production of sweat onto the skin.  As the sweat evaporates, it extracts heat from the skin and cools the body. Concentrated cooling on the skin efficiently extracts heat from the body to augment thermoregulation to help maintain thermal homeostasis. The underside (flexor side) of the wrist is an ideal spot for concentrated cooling.  The glabrous (non-hairy) skin has a unique role in thermoregulation.  It is innervated solely by vasoconstrictor nerve fibers and has a number of specialized meshes of blood vessels where arteries meet venules and veins (arteriovenous anastomoses) that not only dissipate heat from the body, but also return cooled blood to core through the venous systems. The venous blood returning from the blood vessels in the hands, wrists, and feet can significantly lower core body temperature, especially the temperature of organs and muscles that are receiving highest amounts of blood flow.  Concentrated cooling at the hand, wrist and feet is optimal to alter thermoregulation, rapidly lower core body temperature, and quickly restore temperature homeostasis.  The wrist is the most practical location.  

​

A Brief Overview of Thermoregulation

Thermoregulation is the process by which mammals, including humans, keep body temperature within a certain range. Unlike “cold blooded” animals or ectotherms that require the environment to provide warmth and sustain body temperature, endotherms, including humans, can maintain their own core body temperature relatively independent from their surroundings. Animals that can thermoregulate have a very powerful advantage in that they can survive in various climates and latitudes. Without thermoregulation, the human body would come to equilibrium as (the same temperature with) its surrounding environment. Fortunately, we have a number of mechanisms in place to maintain body temperature homeostasis. The principles of human thermoregulation are: sense temperature, signal the body’s heating or cooling systems and stabilize the body’s temperature.

​

Thermoregulation is a Form of Homeostasis

Humans, like other mammals, thermoregulate through a process called homeostasis. Homeostasis describes a process by which an organism maintains a physical state despite what is happening in the organism’s environment. Humans are capable of many forms of homeostasis—thermoregulation is just one of them. Homeostasis is accomplished through feedback systems. If a value moves a little too high or a little too low, the body senses it and exerts an opposite effect to counterbalance it. For homeostasis, the body needs three things: (1) a biological sensor that can sense the level of something important for health and survival (e.g., pH, oxygen, temperature), (2) the biological sensor must be able to send signals to body systems to change the internal environment when the level becomes too high or too low, (3) the body must be able to change the internal environment in the opposite direction.

 

Human Body Temperature Sensors

The body senses temperature in many ways. Two types of sensory neurons detect innocuous warmth and innocuous cold, that is, warm or cold that will not harm tissues. The sensory endings are found in the skin and the viscera and detect heat or cold. Their cell bodies are located in dorsal root ganglion (primary sensory ganglia or trigeminal ganglia), and a second axon extends to the dorsal horn of the spinal cord (or the nucleus of the trigeminal nerve).2 This sensory information then ascends through the spinal cord into the brain, first to the lateral parabrachial nuclei and then the preoptic area, which is part of the hypothalamus. The nerves that sense warmth or coolness are usually separate, but a small percentage can sense both, and send different signals for the two different kinds of temperature information.3 Other tissues participate in temperature sensation, too. The four major temperature sensing organs are skin, spinal cord, viscera and brain.4,5 The brain and spinal cord sense core body temperature and the skin senses ambient temperature, i.e., the temperature of the environment. Each of these sensors sends a bit of information to higher levels in the brain; ultimately it is the job of the hypothalamus to make a decision about body temperature and what to do about it.

​

The Hypothalamus Controls Thermoregulation

These sites provide different sorts of information that must be processed to come to a verdict about the actual temperature of the entire body. The verdict is not a simple addition, it is the complex calculation that considers information from all of the temperature sensors in the body. While we only know a little about how the calculation is made, we know where the calculation is made: the hypothalamus. When researchers stimulated the preoptic area or the dorsomedial hypothalamus in various ways, they could change how the body directly managed its own core temperature.6 Indeed, various lines of research have shown that the hypothalamus is the major arbiter of body temperature assessment and the center that then controls the body’s reaction to changes in temperature. In other words, the hypothalamus could be considered the body’s thermostat.

To get a sense of the challenge that the hypothalamus faces in making this calculation, consider a person sitting in a hot tub on a cold winter day. The core body temperature may actually rise higher than normal from the hot water, such that homeostatic cooling mechanisms must take place. However, once the person gets out of the hot tub and is exposed to cold air, there is a mismatch between ambient temperature, now very low, and core body temperature, still quite high. The result is that the cold air feels bracingly cold, but does not provoke shivering until later, once the core body temperature drops. In fact, the initial overall sensation may be one of relief, not discomfort. This processing is complex and takes place at various points along the temperature sensing pathways. The process is not so complex that we cannot use it to our advantage, that is, by using concentrated cooling to lower core body temperature.

​

Cooling Systems in the Body

Once the hypothalamus senses the body is too warm, it sends signals to the body to try to dissipate excess heat. Blood vessels in the skin dilate to allow increased blood flow to the body’s periphery. Increased blood flow through wider vessels allows some of the heat contained within the blood to dissipate through the skin and away from the body. Sweat glands increase the production of sweat. Chloride is released from sweat glands and water follows. As the sweat evaporates, it extracts heat from the skin and cools the body. After copious amounts of sweat have been produced, the body tends to need water and electrolytes. Drinking cold beverages can further reduce core body temperature. In fact, people tend to feel uncomfortable when they are in an environment that is too hot. They seek out shade or a cool area to bring their body back to normal. The mechanism for this is more complex than blood vessel dilation or sweating, but it achieves the same effect—reducing body temperature. Using a fan, bathing or showering in cool water, really any behavioral action taken to reduce temperature and stop the uncomfortable sensation of feeling too hot is part of a complex homeostatic process.2 Even though it requires higher order thought processes and complex behavior, seeking a cool environment when it feels too warm is a homeostatic mechanism. The body senses a form of discomfort and takes steps to ease that discomfort. Once the body cools down, the person subjectively feels better (and the body has maintained its internal temperature state).

The autonomic nervous system plays a major role in the control of blood flow to the skin.8 Unlike the central nervous system that mostly executes conscious actions like thinking and movement, the autonomic nervous system operates behind the scenes on an unconscious level to regulate breathing, heart rate, pupil dilation, sweating and many other activities. This nervous system drives many of the bodily functions we take for granted so they can operate without thinking about them. The two sides of the autonomic nervous stem are the sympathetic and parasympathetic systems. Simply put, they work in opposite directions. The sympathetic nervous system raises heart rate and the parasympathetic nervous system lowers it, for example. One system causes the body to sweat, the other stops it from sweating, and so forth.

​

The Unique Role of Non-Hairy (Glabrous) Skin in Thermoregulation

While the hypothalamus receives temperature information from various sensors in the body and makes a global assessment, not all information is weighted in the same way. By far the biggest difference in skin temperature sensation is between hairy and non-hairy (glabrous) skin. Despite being relatively hairless compared to other primates, humans have much more hairy skin than glabrous skin (the hair may be fine, but the skin is still hairy skin). When it comes to temperature regulation, the difference between glabrous and non-glabrous skin is important. Hair-bearing skin (non-glabrous skin) is innervated by both by blood vessel constriction (vasoconstrictors) and blood vessel widening (vasodilators) nerves of the autonomic nervous system.9 Non-hairy skin (glabrous skin), present on the palms, wrists, ankles, soles and lips, is innervated solely by vasoconstrictor nerve fibers. Glabrous skin also has a number of specialized meshes of blood vessels where arteries meet venules and veins (arteriovenous anastomoses). When opened, these specialized blood vessels can release a considerable amount of heat and, in turn, cool the body.9 Moreover, if the heat lost through the through glabrous skin doesn’t sufficiently cool the body, then blood flow to non-glabrous (hairy) skin can further increase and magnify the heat lost through the skin.10

​

Consider what this means for total body thermoregulation and temperature homeostasis. Despite the fact that the hypothalamus senses temperature from various places in the body to determine whole body temperature, temperature signals in glabrous (non-hairy) skin can directly and powerfully influence thermoregulation. The specialized blood vessels in glabrous skin not only dissipates heat very efficiently, cooled blood returns to the core through the venous system.11 The venous blood returning from these vascular in the hands, wrists, and feet can significantly lower core body temperature, especially the temperature of organs and muscles that are receiving highest amounts of blood flow. In short, cooling the body at the wrist can alter thermoregulation, rapidly lower core body temperature and quickly restore temperature homeostasis.12-15

​

The Advantages of Concentrated Cooling at the Wrist

The body only has a few areas with glabrous (non-hairy) skin. So, if one was to choose a site to cool the body and restore homeostasis, the options are limited. Hands and feet have large patches of glabrous skin, but most daily activities require the use of the hands, the feet, or both. The next best candidates are the wrists and the ankles. Cooling can take place at these sites without disrupting manual or pedal activity. Of the two, the wrist has the more favorable anatomy. The bony prominences on either side of the ankle force any cooling device to be applied above that level. Unfortunately, glabrous skin turns into hairy skin not too far away from the foot. The underside (flexor side) of the wrist is an ideal spot for concentrated cooling. A cooling band can be firmly and comfortably attached to that area without interfering with hand or arm movements. Thus, when choosing a site with glabrous skin to take advantage of concentrated cooling, the underside of the wrist is optimal. Astute readers may wonder why one does not simply cool the body entirely, instead of relying on the wrist or other area of glabrous skin. In short, many athletic trainers and therapists do just that. Many modalities have been tried including cooling garments, cold towels, cold air blow, cold water shower, ice pack and rapid thermal exchanger devices. Athletes routinely use immersion ice baths to restore temperature homeostasis after exertion.16 Others have tried precooling the body prior to activities that we take place in the heat. Drinking crushed ice or ice-cold water is another method that has been tried. For those who are interested, precooling the whole body may improve return to temperature homeostasis (or prevent large-scale heating of the body), while cold water ingestion likely does not.17 While some of these approaches may be effective, they are certainly not terribly practical for most people as they require specialized cooling devices. Arguably, concentrated wrist cooling provides the most practical way to quickly restore thermal homeostasis.

​

Heat Intolerance

Physical Exercise and Performance

Humans, like other mammals and birds, must maintain a rather tight range of body temperatures. As body temperature increases above 101°F, for example, physical performance declines considerably.18 Likewise, as ambient temperature increases, optimal physical performance declines by 10-20%.19 There is increased strain on the heart, because the blood is rerouted to the skin for cooling purposes, which draws blood away from the muscles.20 In an effort to cool the body, thermoregulatory mechanisms increase sweating. As sweat evaporates, it draws water and electrolytes out of the body, leading to a state of relative dehydration. Oral replenishment can restore this balance, but it is a slow and inefficient process. One must interrupt exercise to rehydrate, consuming fluid during exercise often leads to cramps and the time it takes for fluid and electrolytes to be absorbed in the gut takes place more slowly than one would need to restore fluid balance evenly and rapidly. Incidentally, this is why elite endurance athletes receive intravenous fluids after competition—it is a much faster way to replenish fluids in the body. Also consider the amount of energy that the body requires to complete all of these thermoregulatory tasks. Instead of using the body’s limited energy stores for physical performance, a portion must be diverted to thermoregulation to restore homeostasis. Moreover, the behavioral homeostatic drive to cool down the overheated body gets more and more uncomfortable. So, as the body increases in temperature, increasing physical discomfort makes it more and more difficult for the person to perform their desired activity.21 Instead, people want to stop and cool down their bodies. The increasing internal discomfort with increasing core body temperature is a normal, homeostatic process, but it is not particularly helpful in certain situations. In elite athletes, the sensation of being overheated interferes with top athletic performance. A marathon runner running in the heat must overcome the homeostatic drive to cool their body down with an even stronger will to continue running. It is not hard to imagine how cooling the body during exercise could help athletes improve performance—keeping the body cool allows the athlete to focus on physical performance and quiet the drive to cool themselves down. Concentrated cooling also has direct benefits in the physiological aspects of physical exercise and performance. Concentrated cooling keeps the body closer to its homeostatic set point during exercise, even in warm environments. The body, in turn, wastes less energy to regulate body temperature. Cooler body temperatures mean less sweating, which preserves total body water content and electrolytes that would otherwise be excreted and lost during sweating.

​

There are misguided beliefs about body temperature, sweating, fat loss, and exercise. The first myth is that sweating more means that you are getting a better workout. As we have discussed, sweating is one of the body’s ways to maintain temperature homeostasis. Some people think that the more the sweat during a workout, the better the workout is, but this is simply not true. Consider the exact same workout: same distance, same resistance, same everything—except ambient temperature. If you exercise in a room that is at 80 degrees, you will sweat much more than if you were at a room that was 60 degrees, even if the workouts are the same. Or consider relative humidity; if you exercise in a dry environment, sweat will readily evaporate, you will cool more efficiently  and you may not notice you are sweating profusely. Perform that same workout in a humid environment and you will know you are sweating profusely because the sweat is not evaporating. In short, more sweat does not necessarily mean a better workout. The second myth is that sweating more means greater fat loss and long-term weight loss. It is certainly true that more sweating means more water weight is lost; water leaves the body in the form of sweat and evaporates. But sweating simply sheds water weight—it does not affect fat at all. In fact, most people replenish that water weight almost immediately by drinking after exercise. Ironically, if you feel hotter and sweat more, then you are likely to drink even more water (and gain back more water weight) than you lost through sweating. More sweating means greater temporary water weight loss, but it is unrelated to the loss of fat or even average daily body weight. The third myth is the hotter that you are during exercise, the better the workout. This myth is related to the other two; people who think more sweating means more weight loss and a better workout think making body temperature higher will help on both accounts. Wrong and wrong. Consider the behavioral component to thermal regulation. As body temperature increases further beyond the target range, the brain sends out signals of discomfort. As core temperatures rise during exercise, the hypothalamus increases the sensation of thirst, increases the uncomfortable sensations of warmth, and drives the person to rest rather than continue moving. In essence, as the body heats up, the workout gets worse. People take more breaks, stop short of their goal, or become so uncomfortable that they do not return to the gym—exercise just feels so terrible. Moreover, scientific studies have shown that physical performance suffers considerably as body temperature increases and cooling the body improves performance.11,17,19,20,22

​

Menopause

Athletes are not the only ones who suffer from uncomfortable heat sensations. Women who have reached menopause commonly experience hot flashes. Hot flashes are intense feelings of heat that cause sweating, blood flow to the skin, which causes the skin to redden. They can be exquisitely uncomfortable and, unfortunately, there are few effective treatments for hot flashes, if any. Hot flashes are brought on but subtle increases in ambient or body temperature. In fact, most women who suffer from hot flashes have difficulty in places that others would only find warm or even slightly cool. The neurobiology of hot flashes is complex involving a chronic lack of estrogen and other hormones and activation of the brainstem, insula and prefrontal cortex.20 However, at their core, hot flashes are caused by a basic change in a woman’s internal temperature range.21 Simply put, the set point of their thermostat is lower. Consequently, affected women’s bodies perceive that they are too hot and their body takes steps to return them to homeostasis. Specifically, they experience uncomfortable sensations of being hot that the brain hopes will make them seek a cool place and blood is sent to the skin to release what has been determined to be excess heat.

Many postmenopausal women have taken to keeping their surroundings cold to prevent hot flashes—so cold that the surroundings are uncomfortable to others. Moreover, women cannot always control the ambient temperature. Women with moderate or severe hot flashes can no longer tolerate being outside in even modest heat. A rather simple solution is to use the glabrous skin on the wrist to wrest control of the thermoregulatory system back from menopause. By applying concentrated cooling on the non-hairy underside of the wrist, the specialized blood vessels in that area can rapidly reduce core body temperature and signal to the hypothalamus that the body is actually cooler than other sensors in the body are reporting. In that way, concentrated cooling at the wrist has the potential to reduce hot flashes and allow women to live and work in various environments.  

 

Multiple Sclerosis

About three in every four people with Multiple Sclerosis report that they are intolerant to heat in their environment.22 Not only are MS patients sensitive to heat, increased heat worsens the symptoms of the neurological disease. One of the main ways in which people with MS experience heat is as fatigue.23 As core body temperature increases, fatigue worsens. This phenomenon is one of the main reasons that a large portion of people with MS cannot tolerate physical exercise. However, heat sensitivity strongly correlates with concentration problems and pain, as well.24

​

Multiple sclerosis is above all a disease of demyelination—the insulative covering on nerve axons disintegrates and interferes with the ability of the nerve cell to fire action potentials, i.e., communicated with other nerve cells. Increases in temperature interfere with nerve’s ability to communicate even more.25Unfortunately, very small increases in temperature can degrade nerve signals.23 Heat intolerance in MS appears to be, at least in part, due to changes in the effective operating range of body temperatures. People with MS also have less capacity to sweat and therefore cool themselves. Davis et al. [34] Patients may or may not be aware of their sensitivity to heat, but even when they are not, they tend to avoid warm environments and notice they have fewer MS symptoms when they sleep in a cold room.24 In fact, hypothermia (decreased body temperature) is surprisingly common among people with MS because they place themselves in cold areas. Sure, this decreases MS symptoms, but it is also too cold for other bodily processes. MS lesions in the hypothalamus and the spinal cord may be to blame for this altered temperature regulation.26

​

As with menopause, it is impractical to avoid all physical exertion and all warm environments. A practical solution is to keep the body cool without changing the temperature of the environment. Precooling or cooling the entire body in MS is potentially problematic and impractical. Guides for MS patients on the Web suggest drinking ice cold beverages or taking cold showers to lower core body temperature. While these approaches do lower body temperature, they are also not always possible, depending on circumstances. Concentrated cooling at the wrist offers the same advantages in people with multiple sclerosis as it does in postmenopausal women, namely a rapid and convenient way to return the body to thermal homeostasis. 

​

Conclusions

Humans, like other mammals, thermoregulate through a process called homeostasis, which maintains a physical state despite what is happening in the organism’s environment. Thermoregulation is a complicated process that takes time and energy to maintain; as a result, cooling the body in a hot environment or during exertion is time and energy intensive. Non-hairy skin, known as glabrous skin, is the ideal place on the body to dissipate heat because it has a number of specialized meshes of blood vessels where arteries meet venules and veins (arteriovenous anastomoses). When opened, these specialized blood vessels can release a considerable amount of heat and, in turn, cool the body. Hands, wrist, and feet are the largest patches of glabrous skin, but only the wrist is a practical location to augment the body’s thermoregulation system. Therefore, concentrated cooling at the wrist is optimal to alter thermoregulation, rapidly lower core body temperature and quickly restore temperature homeostasis. 

 

References

1. Atkinson KF, Nauli SM. pH sensors and ion Transporters: Potential therapeutic targets for acid-base disorders. Int J Pharma Res Rev. 2016;5(3):51-58.

2. Tan CL, Knight ZA. Regulation of Body Temperature by the Nervous System. Neuron. 2018;98(1):31-48. 10.1016/j.neuron.2018.02.022

3. Nakamura K, Morrison SF. A thermosensory pathway that controls body temperature. Nat Neurosci. 2008;11(1):62-71. 10.1038/nn2027

4. Jessen C. Thermal afferents in the control of body temperature. Pharmacol Ther. 1985;28(1):107-134. 10.1016/0163-7258(85)90085-3

5. Brock JA, McAllen RM. Spinal cord thermosensitivity: An afferent phenomenon? Temperature (Austin). 2016;3(2):232-239. 10.1080/23328940.2016.1157665

6. Zhao ZD, Yang WZ, Gao C, et al. A hypothalamic circuit that controls body temperature. Proc Natl Acad Sci U S A. 2017;114(8):2042-2047. 10.1073/pnas.1616255114

7. Fenzl A, Kiefer FW. Brown adipose tissue and thermogenesis. Horm Mol Biol Clin Investig. 2014;19(1):25-37. 10.1515/hmbci-2014-0022

8. Charkoudian N. Skin blood flow in adult human thermoregulation: how it works, when it does not, and why. Mayo Clin Proc. 2003;78(5):603-612. 10.4065/78.5.603

9. Tansey EA, Johnson CD. Recent advances in thermoregulation. Adv Physiol Educ. 2015;39(3):139-148. 10.1152/advan.00126.2014

10. Johnson JM, Minson CT, Kellogg DL, Jr. Cutaneous vasodilator and vasoconstrictor mechanisms in temperature regulation. Compr Physiol. 2014;4(1):33-89. 10.1002/cphy.c130015

11. Grahn DA, Murray JV, Heller HC. Cooling via one hand improves physical performance in heat-sensitive individuals with multiple sclerosis: a preliminary study. BMC Neurol. 2008;8:14. 10.1186/1471-2377-8-14

12. Allsopp AJ, Poole KA. The effect of hand immersion on body temperature when wearing impermeable clothing. J R Nav Med Serv. 1991;77(1):41-47.

13. House JR, Holmes C, Allsopp AJ. Prevention of heat strain by immersing the hands and forearms in water. J R Nav Med Serv. 1997;83(1):26-30.

14. Livingstone SD, Nolan RW, Cattroll SW. Heat loss caused by immersing the hands in water. Aviat Space Environ Med. 1989;60(12):1166-1171.

15. Tipton MJ, Allsopp A, Balmi PJ, House JR. Hand immersion as a method of cooling and rewarming: a short review. J R Nav Med Serv. 1993;79(3):125-131. 

16. Bleakley C, McDonough S, Gardner E, Baxter GD, Hopkins JT, Davison GW. Cold-water immersion (cryotherapy) for preventing and treating muscle soreness after exercise. Cochrane Database Syst Rev. 2012(2):CD008262. 10.1002/14651858.CD008262.pub2

17. Jones PR, Barton C, Morrissey D, Maffulli N, Hemmings S. Pre-cooling for endurance exercise performance in the heat: a systematic review. BMC Med. 2012;10:166. 10.1186/1741-7015-10-166

18. Bruck K, Olschewski H. Body temperature related factors diminishing the drive to exercise. Can J Physiol Pharmacol. 1987;65(6):1274-1280. 10.1139/y87-203

19. El Helou N, Tafflet M, Berthelot G, et al. Impact of environmental parameters on marathon running performance. PLoS One. 2012;7(5):e37407. 10.1371/journal.pone.0037407

20. Tyler CJ, Sunderland C, Cheung SS. The effect of cooling prior to and during exercise on exercise performance and capacity in the heat: a meta-analysis. Br J Sports Med. 2015;49(1):7-13. 10.1136/bjsports-2012-091739

21. Dean LG, Breslin A, Ross EZ. Is it hot in here? Thermoregulation and homeostasis through an exercise activity. Adv Physiol Educ. 2014;38(1):99-100. 10.1152/advan.00101.2013

22. Krishnan A, Singh K, Sharma D, Upadhyay V, Singh A. Effect of wrist cooling on aerobic and anaerobic performance in elite sportsmen. Med J Armed Forces India. 2018;74(1):38-43. 10.1016/j.mjafi.2017.04.004

23. Diwadkar VA, Murphy ER, Freedman RR. Temporal sequencing of brain activations during naturally occurring thermoregulatory events. Cereb Cortex. 2014;24(11):3006-3013. 10.1093/cercor/bht155

24. Freedman RR, Krell W. Reduced thermoregulatory null zone in postmenopausal women with hot flashes. Am J Obstet Gynecol. 1999;181(1):66-70. 10.1016/s0002-9378(99)70437-0

25. Syndulko K, Jafari M, Woldanski A, Baumhefner RW, Tourtellotte WW. Effects of temperature in multiple sclerosis: a review of the literature. Journal of Neurologic Rehabilitation. 1996;10(1):23-34.

26. Marino FE. Heat reactions in multiple sclerosis: an overlooked paradigm in the study of comparative fatigue. Int J Hyperthermia. 2009;25(1):34-40. 10.1080/02656730802294020

27. Flensner G, Ek AC, Soderhamn O, Landtblom AM. Sensitivity to heat in MS patients: a factor strongly influencing symptomology--an explorative survey. BMC Neurol. 2011;11:27. 10.1186/1471-2377-11-27

28. Schauf CL, Davis FA. Impulse conduction in multiple sclerosis: a theoretical basis for modification by temperature and pharmacological agents. J Neurol Neurosurg Psychiatry. 1974;37(2):152-161. 10.1136/jnnp.37.2.152

29. Berti F, Arif Z, Constantinescu C, Gran B. Hypothermia in Multiple Sclerosis: Beyond the Hypothalamus? A Case Report and Review of the Literature. Case Rep Neurol Med. 2018;2018:2768493. 10.1155/2018/2768493

30. Shahid MA, Ashraf MA, Sharma S. Physiology, Thyroid Hormone. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020.