Abstract
BACKGROUND:
In office environments, thermal comfort is one of the most significant factor affecting employees’ performance.
OBJECTIVE:
This study aimed to determine the effects of exposure to low air temperatures on human cognitive performance, physiological responses, and thermal perceptions during mental work.
METHODS:
Twenty-four volunteers with an age range of 18–30 years participated in this study. The subjects were exposed to four different air temperatures (10, 14, 18, and 22°C) in a climate chamber based on a within-subject design. The n-back, CPT, and PVT tests were employed to evaluate some basic aspects of cognitive performance. Body physiological responses and the subjective thermal comfort were also measured.
RESULTS:
When the thermal condition deviated from relatively neutral temperature, the subjects’ cognitive responses significantly disturbed (P < 0.05), such that the response accuracy was more affected by reduction of air temperature. The blood pressures and heart rate, galvanic skin response, and respiration rate increased as the air temperature decreased (P < 0.05), such that the galvanic skin response as a stress indicator was more affected. In the test configurations, as a result of decrease in air temperature of 1°C, the finger and body skin temperatures reduced to 0.74°C and 0.25°C, respectively.
CONCLUSIONS:
The findings confirmed that low thermal condition can considerably affect cognitive performance and physiological responses during some office work tasks. The subjects’ thermal comfort votes proposed that air temperature lower than 14 °C can be intolerable for employees during routine mental work. It is suggested that personalized conditioning systems should be used to provide individual thermal comfort in moderate cold air conditions.
Introduction
According to the ASHRAE standard, thermal comfort is defined as a mental condition that expresses satisfaction with the thermal environment [1]. Thermal comfort is important in work environments because it affects comfort, productivity, and health. Indoor thermal condition is important because it can change the state of health by causing a lack of concentration, fatigue, reduced mental performance, discomfort, and dissatisfaction [2]. In open-plan offices, second to noise, thermal comfort is the most important factor which the employees complained about [3]. Continuous interaction between human and the environment causes the body to have physiological and psychological responses, affecting the occupants’ comfort, efficiency, and productivity [4]. Exposure to cold air temperatures can affect cognitive performance and lead to unpleasant effects and health-related consequences [2]. In other words, performance and safety might be negatively affected when cognitive tasks are impaired at work in low thermal conditions [5]. Some studies have investigated the effects of low thermal conditions on cognitive functions. Cold air exposure causes an interim arousal response from stress so that limits cognitive function aspects [6]. Another study showed that cold air induced adrenergic stress in command and control functions [7].
A meta-analysis by Pilcher indicated that heat and cold exposure had a negative effect on performance in a wide range of cognitive tasks. Cold air exposure (below 18.3 °C) had a significant negative effect on performances of reasoning, learning, and memory tasks. The attentional and perceptual tasks were more negatively affected by warm exposure (26.6 ° C and above) compared with cold air exposure. Pilcher reported that exposure to cold air for less than one hour had a larger negative effect on cognitive functions than exposure for more than one hour [8]. The effects of cold air on mental functions have also been studied using different cognitive tests. In general, simple tasks, as compared with complex ones, are more negatively affected by exposure to cold air [9].
Most of the effects reported to be related to low air temperatures have indicated changes in response times and an increase in the number of errors in cognitive performance tests [10]. Some researchers showed that skin cooling had a negative effect on attention by acting as a distractor [11]. Some studies have observed significantly impaired reasoning [12, 13], whereas others found no significant reductions in body temperature [14]. Several investigations showed that response times during cognitive functions are slow when participants are exposed to cold air [15, 16]. Other studies found little or no impact on reaction time under cold air exposure [17]. In many studies, it has been hypothesized that cold air is associated with a decrease in cognitive performance [2, 7]. However, some studies have also reported evidence of improved performance in some cognitive tasks under moderate cold air temperatures [18]. Other reviews have shown that cold stress has the largest effects on psychomotor performance and perceptual tasks [19].
It should be noted that low air temperature in indoor environments can lead to some negative changes in physical and mental performance such as increased human errors and reduced productivity in the workforce. Few studies have investigated the effects of low thermal conditions on different aspects of human cognitive functions. The present study aimed to investigate the effects of low air temperatures on cognitive functions, thermal perceptions and physiological responses in a simulated office environment. It seems that the findings of this study may make it possible to estimate the effect size of low thermal conditions on various aspects of the employee’s body responses in office work tasks.
Methods
Participants
Twenty-four healthy university students (12 males and 12 females) aged between 18 and 30 years old participated in the experiment. Their mean (±SD) age, height, weight, and body mass index were respectively 22.25±2.38 years, 169.87±8.29 cm, 65.70±8.64 kg, and 22.68±1.76 kg/m2. To increase the accuracy of the study, the participants were screened using a self-reported questionnaire in terms of their state of mental and physical health. Before initiation of the tests, the study was approved by the Ethics Committee of Hamadan University of Medical Sciences (ethics code: IR.UMSHA.REC.1396.773), and a written informed consent form was signed by the subjects participating in this research. A day before the test, the subjects were informed and requested to have enough sleep and rest, maintain a regular diet, and avoid taking medicines, coffee, and caffeine.
Experimental setup
All the experiments were done in a climate chamber located in Hamadan University of Medical Sciences. The dimension of the climate chamber was L×W×H = 3.70×2.40×2.70 m, and it had a workstation consisting of a desk, a chair, and a computer. It was possible to set and fix the chamber’s thermal conditions using an air-conditioning system located outside the chamber, which was able to adjust the temperature from –10°C to 50°C. The thermometer sensors installed on the room’s wall which continuously monitored the thermal conditions including air temperature and relative humidity inside the room during the experiment. When the thermal conditions of the room were being controlled, the room air temperature and relative humidity feedback were regularly obtained from the thermometer sensors. Thermal conditions were relatively homogenous in the whole chamber so as to prevent the subjects’ local thermal discomfort. The chamber was equipped with two LED light sources so that the lighting level in the chamber was fixed about 300 lux in order to provide relatively visual comfort. The wall of the chamber was made of pre-made panels of injected polyurethane. Figure 1 shows the experimental setup in the climate chamber.

The experimental setup in the climate chamber.
In this study, four scenarios including the exposure to air temperatures of 10, 14, 18, and 22°C were designed. It should be noted that, the literature reviews confirmed that the selected air temperatures ranges from 10 to 22°C can often occur in office indoor environments in cold season [2, 7]. The experiments were performed using a within-subject design, such that all of the subjects were tested in four experimental conditions, thus acting as their own controls. The background noise level of the room was 55 dBA and had a low frequency nature due to the air-conditioning fans. It should be noted that, all participants were tested based on same condition in all experimental scenarios, therefore, the possible errors due to some other environmental factors were very low when comparing different thermal condition scenario results.
Based on the ASHRAE recommendations published in 1992, which presents the optimum thermal comfort conditions in winter and summer [20], the subject thermal adjusting was set at 24°C for twenty minute the subjects before the considered experiments were begun. The volunteers were exposed to different air temperatures in the chamber for four sessions each of which lasted 55 minutes. All of the cognitive tests were taught to each person three times, and training exams were given to ensure that they understood the procedures well. Each participant started the test at a pre-scheduled time of the day, and there was only one participant in the room each session. The possible carryover effects were partially controlled by random exposure to different scenarios. All the cognitive tests were performed using a personal computer. The relative humidity of the chamber was controlled and set at a fixed level of 50%, and air velocity was set at a level less than 0.2 m/s. Prior to each test, the air temperature condition was set. In this study, the subjects remained seated and performed light work. In keeping with ISO 8996 standard, the fixed metabolic rate for office work (light, sitting like typing) is 70 w/m2, equivalent to 1.2 met [21]. In all of the scenarios, consistent with ISO 9920 standard, the fixed clothing insulation was set at 0.75 clo [22]. Before each exposure scenario, physiological parameters such as heart rate, blood pressure, skin body temperature, finger skin temperature, galvanic skin response, and respiration rate were measured for ten minutes and recorded as baseline parameters. Then the subjects were exposed to different air temperatures for twenty minutes so as to make sure about the body’s thermal balance with their surrounding environment. It should be noted that, in the training sessions, the different thermal adaptation times were also tested. It was observed that, twenty minute is relatively acceptable and more practical for reducing the whole time of each session in order to encourage subjects to perform the experiments correctly. During this period, books and magazines were at their disposal, after that they began to take the tests. The first cognitive test was the n-back test (n = 2) which lasted for five minutes. After that, the subjects had a rest for five minutes to prevent mental fatigue, and then they did the continuous performance test for five minutes. At the end of the test, they rested for five minutes again and performed the psychomotor vigilance task for five minutes. Simultaneous with the PVT test, respiration rate was measured for five minutes. After that, thermal sensation and comfort were assessed with the questionnaires for five minutes. Finally, the body physiological parameters were re-measured. Figure 2 shows the experimental protocol.

The procedure of the experiment.
The some basic cognitive performance parameters included working memory, sustained attention, and simple reaction time were employed in this research. In this study, some cognitive abilities for performing office work tasks were measured. The detailed descriptions of the cognitive performance tests were as follows.
N-back working memory task
To evaluate the performance of the working memory, the visual n-back cognitive task, which is a software-based task, was used. The n-back task is an executive function measurement task that is commonly used in nerve imaging studies to stimulate the brain function of subjects. This task was first introduced by Kirchner in 1958. The overall trend of this task is to provide a sequence of stimuli (visual or auditory) to the subject step by step, and the subject should check whether the current stimulus matches the stimulus presented in the preceding step. This test is performed using different values of n and with increasing n, the difficulty of the task increases as well. Thus, in the 1-back cognitive task, the last presented stimulus is compared with the previous stimulus and in the 2-back and 3-back, the last stimulus is compared with two and three previous stimuli, respectively [23]. Previous studies have shown that its various types are well suited for experimental studies of the working memory. For example, Kane and others have reported that the validity of this test was very acceptable to measure the performance of the active memory [24]. In this study, only the 2-back task was used. It should be noted that, the 1-back task is a simple task so that it is not affected considerably by changes. Because of the complexity and difficulty of the 3-back task, very different responses may be occur by changes. The percentage of correct answers (accuracy) and the average response time (ms) were recorded as dependent variables.
CPT Cognitive task (continuous performance test)
The continuous performance test (CPT) is used to assess sustained attention. The CPT is now cited as the most frequently used measure of attention in both practice and research. The purpose of this test is to measure the sustainability of attention and care. In all forms of the CPT test, the subject must pay attention to a relatively simple visual stimulus set for a while, and when he viewed the target stimulus, he should respond with the push of a key. In this test, 150 stimuli (visual type) are presented from which 20 %are the target stimuli on the computer screen. In this study, the target stimulus was number 4 [25]. The number of correct answers, commission and omission errors, and the average response time (ms) were recorded as dependent variables.
PVT Cognitive task (psychomotor vigilance task)
The psychomotor vigilance test (PVT) as a simple reaction time test is currently known as valid and useful for cognitive performance assessment. In this study, PVT task was used to measure the response speed. This task was developed during the Second World War to simulate radar surveillance operations. In this task, a red dot emerges in the middle of a computer screen, and subjects should respond to the stimuli quickly [26]. In our study, this test consisted of red circles which appeared on the screen randomly with a certain time interval, and the participants were asked to press the specified key as soon as the target stimulus was presented. The software recorded the simple reaction time in milliseconds. PVT test is validated for measuring cognitive function, sleepiness, and fatigue [27].
Subjective measurement
Based on the ISO 10551 standard, thermal sensation votes were cast on a 7-point thermal sensation scale (values ranging from –3 to +3), and thermal comfort votes were cast on a 4-point thermal comfort scale (values ranging from 0 to 3) [28]. Figure 3 shows the thermal sensation and thermal comfort scales adopted in this study.

Subjective scales for thermal sensation and comfort.
Body physiological parameters including systolic and diastolic blood pressures, heart rate, skin body temperature, finger skin temperature, respiration rate, and galvanic skin response were measured before and after each exposure scenario. A digital pressure gauge (Omron M6 Comfort model) was used to measure blood pressure and heart rate. Body skin temperature was measured from forehead using the FLIR TG165 imaging IR thermometer with temperature range of –25 to 380°C. Finger skin temperature, galvanic skin response, and respiration rate were measured using the Nexus-4 device (manufactured by Mind Media, the Netherlands). The Nexus-4 device is capable of measuring a wide variety of signals such as muscle tension, brainwaves, heart rate, relative blood flow, skin conductance, respiration, and temperature. The Nexus-4 communicates wirelessly with a computer using Bluetooth technology. The Nexus-4 comes with the extremely flexible Bio Trace+software. In this study, three sensors including finger skin temperature, galvanic skin response, and respiration sensors were used (Fig. 4).

(a) Finger skin temperature and galvanic skin response sensor. (b) Respiration sensor.
The Nexus temperature sensor has been provided for determination of very small temperature changes in the peripheral extremities. A stressful event, arousal or in other words, sympathetic nervous system activity, can lead to vasoconstriction in the peripheral extremities, causing a reduction in temperature. Temperature was reported in degree Celsius. The temperature Nexus sensor uses a thermistor, a small tip that is usually placed on the palmar surface of one of the fingers, often the non-dominant hand. The Nexus skin conductance sensor provides information about sweat gland activity on the hand. Sweat gland activity is closely correlated with sympathetic nervous system activity, arousal, and stress. This variable is called GSR (Galvanic Skin Response). GSR shows a change in the electrical resistance of the skin caused by stimuli such as noise, air temperature, etc. Skin conductance is expressed in micro-Siemens and increases when the arousal level increases. During relaxation, the skin conductance level normally reduces. The Nexus GSR sensor needs Ag-AgCL electrodes (which are included) that snap into the two connectors. The electrodes are usually attached to two fingers or two sites on the palm.
The respiration Nexus sensor is employed to monitor abdominal breathing. Respiration rate is an indicator of changes in the autonomic nervous system in response to environmental stressors. The respiration Nexus sensor is usually attached in the abdominal area, with the central part of the sensor just above the navel. The respiration Nexus sensor includes a belt set [29].
The collected data were analyzed using SPSS 22 software. The normality of the data was tested using the Kolmogorov-Smirnov test. When data were normally distributed or when distributions were similarly skewed, they were analyzed using repeated-measures ANOVA. The Greenhouse-Geisser correction was applied when Mauchly’s test indicated the violation of sphericity, and the corresponding P-values were reported. Friedman test was used when data were not normally distributed and were not similarly skewed. The significance level for all the tests was set to be 0.05.
Results
Results of cognitive performance responses
The results of cognitive performance tests are presented in Table 1. The results showed that there is a significant difference among the simple reaction times in different air temperature conditions (P < 0.05), such that the thermal condition deviated from relatively neutral temperature, the simple reaction time increased. According to Table 1, there is a significant difference among the correct responses (accuracy) and response times in the n-back test at different air temperatures (P < 0.05), such that the thermal environment deviated from 22°C, the accuracy decreased and the response time increased. In CPT test, there were also significant differences among the mean number of correct responses, commission and omission errors, and response times at different air temperatures (P < 0.05). The highest mean number of correct responses was at 22 ° C, and the number of correct responses decreased with a decrease in air temperature. Moreover, the lowest mean number of commission and omission errors were observed at 22 ° C. The shortest response time was at 22 ° C, and the response time got worse as air temperature decreased.
Means±SD of cognitive performance parameters under different air temperatures
Means±SD of cognitive performance parameters under different air temperatures
Note: SD: standard deviation, ES: effect size.
As shown in Table 1, the effect size of decreased air temperature on response accuracy was higher than that on the other cognitive performance parameters. In other words, accuracy was more affected by reduced air temperature.
The changes in body physiological responses are presented in Table 2. There was a significant difference among the systolic blood pressure changes at different air temperatures (P < 0.05). Decreased air temperature led to an increase in mean changes in systolic blood pressure. However, there was no significant difference among the mean diastolic blood pressure changes in various conditions (P > 0.05). Decreased air temperature caused an increase in mean changes in heart rates (P < 0.05). Statistical analysis showed that with a decrease in air temperature from the relatively neutral state (22°C), the mean changes in galvanic skin response and respiration rate increased (P < 0.05). The results also showed that with a decrease in air temperature, finger and body skin temperatures dropped (P < 0.05).
Means±SD of changes in physiological responses under different air temperatures
Means±SD of changes in physiological responses under different air temperatures
Note: SD: standard deviation, ES: effect size.
According to Table 2, the effect size of decreased air temperature on mean changes in body skin temperature and galvanic skin response was higher than that on the other physiological parameters. In other words, galvanic skin response as arousal indicator was more affected by reduced air temperature compared with the other physiological responses.
The effect of a 1°C decrease in air temperature in the test configurations (from 22°C to 10°C) on physiological indices was statistically analyzed. The results showed that with a decrease in air temperature of 1°C, heart rate increased by 0.57 bpm, galvanic skin response increased 0.26μs, and respiration rate increased by 0.12 bpm. By decreasing 1°C, the finger and body skin temperatures dropped to 0.74°C and 0.25°C, respectively.
The regression analyses were conducted between galvanic skin response as one of the main arousal indicators and cognitive performance responses. As shown in Fig. 5, there was a significant positive correlation between galvanic skin response and simple reaction time in the PVT test (r = 0.562, P < 0.01). In other words, simple reaction time rose with an increase in galvanic skin response.

The scatter plot of galvanic skin response compared to simple reaction time.
There was also a significant inverse correlation between galvanic skin response and accuracy in n-back test (r = –0.721, P < 0.01). Moreover, there was a significant positive correlation between galvanic skin response and response time in n-back test (r = 0.577, P < 0.01). The scatter plots of galvanic skin response compared with accuracy and response time are shown in Figs. 6 7, respectively.

The scatter plot of galvanic skin response compared with the response accuracy.

The scatter plot of galvanic skin response compared to the response time.
According to Fig. 8, the results showed significant differences between thermal sensation and thermal comfort vote of the subjects under different indoor air temperatures (P < 0.05).

Thermal sensation and thermal comfort votes under different air temperatures.
Based on Fig. 8, at air temperatures of 10°C, 14°C, 18°C, and 22°C, predicted mean votes (PMV) of participants were obtained as –3, –2.2, –1.45, and –0.08, respectively. At lower air temperatures, the thermal sensation votes moved to the cool and cold side, and the subjects felt more uncomfortable.
Cognitive performance responses
In this study, cognitive performance responses of working memory, simple reaction time, and sustained attention were more affected by lower thermal conditions than the relatively neutral thermal condition (22°C). These results are consistent with the findings of some studies. Makinen et al. also investigated the effects of exposure to cold air temperatures on cognitive performances (accuracy, efficiency, and response time) and showed that cold exposure had a negative effect on performance in both simple and complex tasks requiring concentration and sustained attention [10]. Muller et al. showed that the working memory, selective reaction time, and executive function decreased when the subjects were exposed to an air temperature of 10°C [5]. Haggblom et al. found that working memory performance was significantly affected by thermal conditions, and the mean errors at an air temperature of 29°C were significantly higher compared to 21 and 25°C [30]. Lian et al. used neurobehavioral tests to measure performance under the three air temperatures of 17, 21, and 28°C and observed that the cognitive performance decreased when the thermal environment deviated from neutral conditions [31]. Pilcher et al. concluded that in cold environments, decrease in air temperatures from 18.28°C to 10°C resulted in a 7.81%reduction in performance and air temperature below 10°C resulted in a 13.91%reduction [8].
Some studies have indicated the effects of thermal stress on different aspects of cognitive performance. Few models have been suggested to best explain the relationship between thermal stress and cognitive performance over the years. The Yerkes-Dodson Inverted-U theory, originally developed by psychologists Yerkes and Dadson in 1908, shows an empirical relationship between arousal and performance. As the theory states the performance increases with physiological or mental arousal, but only up to a point. When levels of arousal become too high and too low, the performance reduces [32]. In the present study, the optimal cognitive performance was observed at the neutral air temperature (22°C), and the performance decreased at lower air temperatures. Exposure to typical extreme cold exposure at an office building (10°C) can activate the nervous system resulted in higher mental arousal and decrease task performance. A reanalysis of 26 studies reported by Seppanen and Fisk showed an inverted-U relationship with the highest performance at an air temperature of 21.6°C [33]. Zhu also found that a range of 22 –26°C air temperature is suitable for optimum cognitive performance [34].
Body physiological responses
The results of this study showed that when thermal environment deviated from the relatively neutral temperature of 22°C, mean changes in the galvanic skin responses and respiration rates increased, and body and finger skin temperatures reduced which indicated an increase in the level of stress. The mean changes in blood pressure and heart rate increased with decreased air temperatures. Makinen et al. reported that the skin temperature and the finger skin temperature decreased significantly during exposure to a temperature of 10°C compared with a reference air temperature of 25°C [10]. In the current study, galvanic skin response was considered as one of the main simple indicators of arousal level. Edmonds et al. reported that with increased human stress which can affect the autonomic nervous system, the individuals’ galvanic skin response increases [29]. Timmons indicated when the subjects suffer from stress, important changes occur in respiration rhythm, such that respiration rate increases [35]. Abbasi et al. found that as the thermal environment deviated from the neutral temperature, the respiration rate increased [36], which is consistent with the results of the present study. Makinen et al. concluded that with a decrease in air temperature, systolic and diastolic blood pressures increased and heart rate decreased [10].
Subjective assessment
The results indicated that under air temperature of 10°C, the subjects felt more uncomfortable compared with other temperatures. At an air temperature of 22°C, the participants were more pleasant and felt a neutral thermal comfort and thermal sensation. Moreover, based on the subjects’ thermal comfort votes, air temperature of lower than 14°C can be intolerable in typical office workroom. Lin et al. showed that most of the subjects felt neutral and were satisfied at 24° C. When the thermal condition deviated from 24° C, the number of participants who were dissatisfied with thermal environment increased. The thermal dissatisfaction votes under cool or cold conditions were more than the warm or hot conditions [37]. Tham et al. investigated the effect of different air temperatures of 20, 23, and 26° C on mental perceptions and showed that air temperature of 23 °C was the most comfortable thermal condition [38].
Fanger (1970) used climate chamber data to develop PMV-PPD model to predict thermal sensation based on thermal condition criteria such as air temperature, humidity, mean radiant temperature, air speed, and some behavioral factors such as metabolic rate and clothing level. Based on Fanger’s model, by assuming an activity level of 1.2 met and clothing with an insulation value of 0.8 Clo, the predicted mean votes of subjects (PMV) should be at –3, –2.3, –1.2, and –0.2 for air temperatures of 10°C, 14°C, 18°C, and 22°C, respectively [39]. In the present study, at air temperatures of 10°C, 14°C, 18°C, and 22°C, the predicted mean votes of the participants were –3, –2.2, –1.45, and –0.08, respectively. The current experimental results confirmed the Fanger’s model predictions of thermal sensation.
One of the limitations of this study is that healthy and young subjects were recruited, thus they are not a representative subpopulation of current office workers. Moreover, impossibility of monitoring the subjects for get enough sleep and maintain a regular diet can be mentioned as another limitation. Generalization of this experimental study is limited and therefore, field studies with similar design are required to investigate employee’s performances in real condition of office work. It is also suggested future research consider the effect of gender as an important variable. It is proposed that future research focus on the effect of air temperatures on other aspects of cognitive functions. In this study, the valid and applicable simple tests were used to prevent missing participants during experiments. It is recommended that they investigate the effects of indoor air temperature on physiological responses using advanced objective methods (e.g. electroencephalography and electrocardiography). This study provide some objective evidence to help experts design and set thermal comfort criteria for office environments to preserve or even improve the performance and productivity of the employees in cold seasons. The costs of maintaining thermal comfort was a challenge for many office building managers, especially in the winter months in an attempt to prevent employees from being exposed to uncomfortable thermal conditions. There is great potential to employ personalized conditioning systems (PCS) in order to save energy and improve individual thermal comfort in offices or even during teleworking at home since COVID-19 during cold weather [40]. It can focus on each individual and his/her critical body parts in moderate unpleasant thermal conditions with air temperatures range approximately from 10°C to 30°C.
Conclusion
Thermal condition in office indoor environments is as one of the main challenges which can affect employee’s comfort and productivity. The result confirmed that during this type of mental work, with a decrease in air temperature from the neutral condition, some aspects of cognitive performance and body physiological responses significantly disturbed. Response accuracy and galvanic skin response are more affected by exposure to low air temperatures. Thermal comfort votes confirmed that such employees should not be exposed to the air temperature lower than 14°C during routine mental work in the winter. In order to reduce the cost of maintaining thermal comfort, it is suggested that personalized conditioning systems (PCS) should be used as a new approach to provide individual thermal comfort without consuming too much energy in moderate cold air condition.
Footnotes
Acknowledgments
This study was financially supported by Research Deputy of Hamadan University of Medical Sciences (Grant No. 9612087893). This research was also approved by the Research Ethics Committee of Hamadan University of Medical Sciences. The authors would like to express their thanks to the participants who volunteered for this study.
Conflict of interest
The authors declare that there are no conflicts of interest.
