Executive Summary

The U.S. military’s concerns about the individual combat service member’s ability to avoid performance degradation, in conjunction with the need to maintain both mental and physical capabilities in highly stressful situations, have led to an interest in developing methods by which commanders can monitor the status of combat service members in the field. This includes monitoring the physical and mental status of the combat service member, as well as monitoring the service member’s environment (e.g., ambient temperature, geolocation, chemical exposure). Equally important are the development of methods for and the training of individual combat service members and unit commanders on self-monitoring (or monitoring of peers) of designated parameters predictive of performance. This ability would allow commanders to determine when individuals need to rest, eat, or consume fluids, or if their condition has deteriorated to the point that they need to be replaced rather than risk combat injury. Training service members in physiology and psychology then becomes an important aspect of their education.

Similarly, in the civilian sector, it is necessary to have the ability to monitor the physiological and cognitive status of individuals involved in situations such as sustained fire-fighting operations and chemical and other hazardous materials clean-ups, and for emergency medical personnel working extended shifts. Metabolic monitoring techniques would also be valuable in the practice of telemedicine and would enable healthcare workers to predict when an individual might need special attention or transport to a medical facility.

CHARGE TO COMMITTEE

This report examines appropriate biological markers, monitoring technologies currently available and in need of development, and appropriate algorithms to interpret the data obtained in order to provide information for command decisions relative to the physiological and psychological “readiness” of each combat service member. More specifically, this report also provides responses to ques-



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Monitoring Metabolic Status: Predicting Decrements in Physiological and Cognitive Performance Executive Summary The U.S. military’s concerns about the individual combat service member’s ability to avoid performance degradation, in conjunction with the need to maintain both mental and physical capabilities in highly stressful situations, have led to an interest in developing methods by which commanders can monitor the status of combat service members in the field. This includes monitoring the physical and mental status of the combat service member, as well as monitoring the service member’s environment (e.g., ambient temperature, geolocation, chemical exposure). Equally important are the development of methods for and the training of individual combat service members and unit commanders on self-monitoring (or monitoring of peers) of designated parameters predictive of performance. This ability would allow commanders to determine when individuals need to rest, eat, or consume fluids, or if their condition has deteriorated to the point that they need to be replaced rather than risk combat injury. Training service members in physiology and psychology then becomes an important aspect of their education. Similarly, in the civilian sector, it is necessary to have the ability to monitor the physiological and cognitive status of individuals involved in situations such as sustained fire-fighting operations and chemical and other hazardous materials clean-ups, and for emergency medical personnel working extended shifts. Metabolic monitoring techniques would also be valuable in the practice of telemedicine and would enable healthcare workers to predict when an individual might need special attention or transport to a medical facility. CHARGE TO COMMITTEE This report examines appropriate biological markers, monitoring technologies currently available and in need of development, and appropriate algorithms to interpret the data obtained in order to provide information for command decisions relative to the physiological and psychological “readiness” of each combat service member. More specifically, this report also provides responses to ques-

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Monitoring Metabolic Status: Predicting Decrements in Physiological and Cognitive Performance tions posed by the military relative to monitoring the metabolic status of military personnel in training and operational situations, focusing on metabolic regulation during prolonged, exhaustive efforts (such as combat training or field operations), where nutrition/hydration and repair mechanisms may be mismatched to intakes and rest, or where specific metabolic derangements are present (e.g., following toxic chemical exposures or psychological threats). The committee was also asked to make a “blue sky” forecast for useful metabolic monitoring approaches and current research investments that may lead to revolutionary advances. FINDINGS OF THE COMMITTEE The Importance of Individual Differences Biobehavioral research is among the most challenging of scientific endeavors as biological organisms display wide-ranging individual differences in physiology. A thorough exploration of biobehavioral responses requires the extensive study of individuals over time. In addition, the study of interactions between living systems and their environments has tested the limits of research methodologies and theoretical models. It is a truism in the biobehavioral sciences that no single measure or aspect of responding can adequately represent a complex latent construct; rather such constructs must be represented by an entire pattern of manifestations. In view of the prevalence and importance of rhythmicity in biological regulatory mechanisms, the inclusion of time-varying or temporal aspects of responding is crucial to accurately portray such activity. All recorded activity might be considered as relevant; functional relationships among ongoing physiological processes could then be extracted across observations. In response to these various concerns, an alternative framework for research on monitoring the metabolic status of combat service members is suggested: a multivariate, systems perspective that emphasizes the study of individuals (combat service members). The three most important sources of variance (persons, occasions, and variables [or tests]) are present in nearly all experimental designs. Their relationship should be explicitly investigated, and the systematic variance associated with each should be accounted for before valid inferences can be drawn. The fact that such individualized, multivariate relationships have not been fully illuminated has seriously hampered the development of reliable monitoring strategies. Biomarkers of Overall Physical Status The overall physical status of service members in the field can be evaluated by analyzing either objective physiological measurements (e.g., energy expenditure, vital signs) or subjective measurements of self-assessments (or assessments by peers).

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Monitoring Metabolic Status: Predicting Decrements in Physiological and Cognitive Performance Monitoring core body temperature, skin temperature, and sweat losses would be invaluable in predicting if a service member was in danger of hypothermia, hyperthermia, heat stroke, or other environmentally induced overall physiological imbalance. Some technologies and algorithms currently exist that also consider environmental temperature, humidity, and wind speed. There is evidence for the efficacy of using self-ratings of perceived and preferred levels of exertion to accurately predict physical performance in trained athletes. These methodologies need to be validated in military environments. Biomarkers of Physiological Status The specific metabolic systems of particular concern to the military are: bone and muscle metabolism, kidney function and hydration, and stress and immune function. Maintaining a healthy bone is essential to minimize the incidence of fracture, which is predicted by measuring bone mineral density. However, the low level of precision of this method limits its use; therefore, for short-term changes, intermediate biological markers of bone remodeling may provide a better indication of potential fractures. Bone remodeling or the balance between resorption and formation dictates the risk of fracture. Because bone remodeling is a relatively slow process, it is more appropriate to monitor these changes during training rather than in actual combat situations. There are a variety of compounds that can be used as markers of bone resorption; however, for an accurate evaluation, biomarkers of bone formation also need to be monitored but, up to this time, their value is not clear. In addition to bone remodeling, stress is related to changes in bone health. Although cortisol appears to be a promising indicator of bone health, validation in the field is still needed. Heavy physical exertion, inadequate energy intake, and psychological stress can all influence muscle metabolism, causing muscle damage and muscle protein breakdown. Single blood and urinary markers of these processes are difficult to interpret for a variety of reasons. For example, levels of cortisol as a measure of stress show diurnal patterns of variation. The urinary level of 3-methylhistidine, an ideal biomarker of protein catabolism because of its abundance in muscle, also may be misleading depending on the dietary consumption of muscle meats. More advanced technology for minimally invasive sampling of muscle tissue is needed before these methodologies are field-ready. Muscle soreness and ratings of self-assessment (or peer assessments) also can be good predictors of performance and indicate the need for rest. Monitoring renal function is important because of the role of the kidneys in maintaining proper hydration, fluid homeostasis, and electrolyte balance, all of them critical to sustain both physical and cognitive functions; in addition, excretion of products of protein metabolism may also be an indicator of protein status. In the field, monitoring urinary output, color, odor, and specific gravity would all provide important information relative to hydration, electrolyte balance,

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Monitoring Metabolic Status: Predicting Decrements in Physiological and Cognitive Performance muscle breakdown, and protein and energy status, as well as to the presence of infection. Changes in body weight, when coupled with knowledge of serum osmolality and/or serum sodium, would assist greatly in defining the presence and severity of disturbances in body volume status. Stress can be defined as a constellation of events that begins with a stimulus called the stressor, which precipitates a reaction in the brain (stress perception) and subsequently activates physiological systems in the body, called the stress response. The stress response results in the release of neurotransmitters and hormones that serve as the brain’s messengers for regulation of the immune and other systems and can be damaging when chronic. The rate of change of stress hormones in response to stressful stimuli is a critical variable in adaptive physiological responses. An important aspect of monitoring should include measurements (at baseline, during the stress exposure, and in the period of recovery) of indicators of stress and immune responses currently in use and in development, such as cortisol levels and heart rate variability. Self-report inventories could be adapted to offer valuable information about individual stress levels. Biomarkers of Cognitive Status Optimal performance in today’s military is also increasingly dependent on a high level of cognitive fitness. The widespread use of computerized surveillance and reconnaissance systems, complex communications and targeting devices, highly interactive weapons systems, and even the technologically advanced diagnostic systems used in the maintenance of military equipment demands the highest level of cognitive readiness. The efficiency of combatants in sustained operations can be significantly compromised by inadequate sleep, which can cause increased reaction time, mood declines, perceptual disturbances, motivational decrements, impaired attention, short-term memory loss, carelessness, reduced physical endurance, degraded verbal communication skills, and impaired judgment. In all probability most technologies in development will be useful only in laboratory environments or in fixed-based operational facilities (such as posts in which radar and sonar equipment are monitored or stations from which remote-controlled vehicles are piloted) where complex equipment can be housed, lengthy recording procedures can be conducted, and rigid controls can be maintained. Only a small subset of the strategies is likely to be suitable for operational settings. The most promising techniques for accomplishing real-time, continuous assessments of foot-soldier cognitive readiness in military field settings are: (1) actigraphy-based, or (2) electroencephalographic- (EEG) based, although neither technique is currently ready for widespread application. The most promising techniques for accomplishing real-time, continuous evaluations of the operators of military vehicles and monitoring equipment and those whose jobs consist of interfacing with computers and communications devices, are those suitable for

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Monitoring Metabolic Status: Predicting Decrements in Physiological and Cognitive Performance stationary situations such as EEG based, or eye-movement based. Eye-movement parameters (i.e., PERCLOS) have already proven feasible for the detection of changes in truck-driver alertness, and efforts are underway to establish an automated PERCLOS that could be used in aviation settings. Before implementing these methods, their feasibility in specific environments should be evaluated and a cost-benefit analysis should be performed. For example, the pilot of a B-2 bomber or other highly complex modern aircraft may be among the first to benefit from newly developed approaches because there are relatively few of these aircraft, and the cost of losing even one would be significant by any standard. On top of these considerations is the fact that aircrew fatigue is known to be an operational hazard in B-2s. Therefore, the costs associated with instrumentation of such a platform are easily justifiable. A great deal of progress has been made toward helping the armed forces address fatigue-related cognitive decrements once they have been identified. However, highly reliable, efficient, and cost-effective technological means of initially detecting and predicting those decrements remain to be developed. REPONSES TO THE MILITARY’S QUESTIONS QUESTION 1 What are the most promising biomarkers for the prediction of: (a) excessive rates of bone loss and muscle turnover, (b) reduced glucose and energy metabolism (e.g., bioelectrical indicators of muscle and mental fatigue), (c) dehydration, and (d) decrements in cognitive function? The committee recommends that, initially, simple protocol data of normal/abnormal ranges based on group averages may be used. However, these ranges may be sufficiently imprecise to make individual-based predictions dubious. Irrespective of the biological or cognitive markers selected, there is a need for baseline measurements of individual combat service members so that it can be determined, on an individual basis, if a marker is significantly altered under stress. Biomarkers for Bone and Muscle Metabolism Bone Bone remodeling is a relatively slow biological process and thus not amenable to monitoring in field situations. Prediction of bone changes that increase fracture risk may be of greater importance in initial entry training, when individuals are transitioning to a greater state of fitness, than in combat. There are no groups of intermediate markers of bone health that can provide a one-time identification of risk of fractures, including stress fracture. Markers should include bone density (as measured by dual-energy X-ray absorptiometry), sensation of bone pain, menstrual status, and mental state as related to cor-

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Monitoring Metabolic Status: Predicting Decrements in Physiological and Cognitive Performance tisol responsiveness. The role of cortisol in bone health during military exercises, however, may be transient and may not have long-term effects on bone health. Bone mineral density (BMD) is the most predictive measure of risk of fractures; this measure should be used in determining medical suitability for training and combat-related activities. Strategies should be developed to determine the BMD levels that are required to meet medical standards, and approaches should be identified to prevent significant loss of bone mass and fractures prior, during, and after intensive physical training. Muscle There are a number of biomarkers that may be indicative of muscle fatigue or increased catabolism, including protein turnover and 24-hour urinary 3-methylhistidine. However, there is insufficient evidence that can specifically correlate these biomarkers with actual decrements in muscle performance during activities such as weight lifting, timed running trials, and endurance running. In contrast, there is substantial evidence in the sports medicine literature that self-(or peer-) reported measures possess efficacy in predicting physical performance and, in fact, have often been found to be superior to other physiological measures. Biomarkers for Reduced Glucose Metabolism The potential biomarkers for anaerobic glucose metabolism are: Borg’s 6–20 scale of perceived exertion (local, central, and overall); muscle soreness; tissue levels of lactate measured by near-infrared spectroscopy (NIRS); muscle biopsy for glycogen, cytokines, and enzymes; actigraphy; electroencephalography (EEC); heart-rate variability; profile of mood state; and visual analog scale. The use of these biomarkers for this purpose needs to be validated in the field. Biomarkers of Dehydration and Renal Function In the military setting, changes in water and osmotic balance are usually synergistic with increases in water loss. One of the most sensitive indicators of hydration status is short-term changes in body weight since most day-to-day variation in body weight is due to hydration status. The assessment of weight loss or loss of body mass, plasma sodium or plasma osmolality, urinary specific gravity, fluid balance, and the recovery of weight 24 hours after dehydration can be used for the identification of extent and type of dehydration. In the military setting, weight changes over a short period of time reflect fluid changes, and loss of body water coupled with measures of serum sodium or serum osmolality can define the degree of concomitant salt loss. Renal function is also a good indicator of hydration status.

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Monitoring Metabolic Status: Predicting Decrements in Physiological and Cognitive Performance Renal Function There are a number of markers and technologies available that could be adapted for self- (or peer-) monitoring during training or field operations. The military should consider providing and training personnel in the use of simple urine dipstick-type test strips that would provide information on levels of urine protein (a marker for potential kidney damage), ketones and glucose (potential markers for energy metabolism), and leukocyte esterase and nitrates (indicators of urinary tract infections) as indicators of muscle damage and hydration status. These field measures should be taken at mid-day and after the day’s exertion. Biomarkers of Cognitive Function The most promising techniques for accomplishing continuous assessments of ground combat service member cognitive readiness in field settings are actigraphy, EEG, and heart-rate variability. Actigraphy is useful because it offers a field-practical way of monitoring the sleep of combat service members, and insufficient sleep is the primary cause of cognitive degradations in operational environments. EEG is useful because it offers a relatively noninvasive assessment of the brain activity that underlies all types of performance, including vigilance and judgment. Heart-rate variability is a peripheral nervous system measure that also reflects the brain activity that underlies performance attention and mood. In vehicle operators or in radar or other fixed-based system operators, eye-movement monitoring is also promising. Saccadic velocity and percentage-of-eye-closure measures have been shown to reflect the status of the central nervous system. In all probability, most of these measures will be useful only in laboratory environments or in fixed-based operational facilities (such as posts in which radar or sonar equipment is monitored or stations from which remote-controlled vehicles are piloted) where complex equipment can be housed, lengthy recording procedures can be conducted, and rigid controls can be maintained. Only a small subset of these methods will likely be suitable for operational settings. Besides these objective measures, subjective ratings of alertness and fatigue should be considered for use in the field since these have been shown to correlate with performance changes in some situations. However, it should be recognized that self-report data can be influenced by peer pressure (or supervisor pressure); also, there is evidence that self-reports may loose a degree of sensitivity when the stress or fatigue becomes so chronic that the individual has difficulty referencing his or her present feelings to more normal past experiences.

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Monitoring Metabolic Status: Predicting Decrements in Physiological and Cognitive Performance QUESTION 2 What monitoring technologies would be required (that may not currently exist) to predict these intermediate targets in critical metabolic pathways? New biomarkers are likely to be identified in the future; still, the greater needs lie in: (1) the development of easier systems to measure and transmit data, and (2) the development of new mathematical models to provide enhanced data integration and analysis by using nonlinear discriminant algorithms. Future monitoring technologies should consist of an integrated system that incorporates noninvasive or minimally invasive sensor technology, communication interface and integration, data analysis tools, and local area networks. This infrastructure should be both redundant and noncentralized. A “black box” or “medical hub” is needed to gather data from multiple sensors or devices, standardize the outputs, and submit these data to a data reduction system or decision-making tool for the creation of both prioritized alarm signals and recommended interventions. Regarding development of models, the major obstacles to be overcome will be the selection of variables and the building of models that truly predict health performance status. QUESTION 3 What tools currently exist for monitoring metabolic status that could be useful in the field? Metabolic status can be defined in part by energy metabolism, intermediary fuels (glucose, fatty acids, and amino acids), acid/base and hydration status, and psychophysiological status. NIRS can examine many different biomarkers of metabolism, such as muscle function and hydration, and shows great promise in the field. Other tools to measure specific biomarkers are described below. Muscle Fatigue One measure that could be useful in the field, after validation in military settings, is self-perception. Predictors of fatigue at an earlier state have also been proposed. The challenge remains to differentiate diagnosis between acute damage from muscle injury, fatigue due to overuse or over conditioning, exercise until exhaustion, hydration, and nutritional status given the interactions of these factors in the subjective feeling of fatigue. Renal Function and Hydration Simple methods that measure renal function and hydration already exist. As mentioned previously, the military should train personnel in the field use of simple urine dipstick-type test strips that would provide information on levels of urine protein, ketones and glucose, and leukocyte esterase and nitrates as indica-

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Monitoring Metabolic Status: Predicting Decrements in Physiological and Cognitive Performance tors of muscle damage and hydration status. Also, a practical method of monitoring weight changes in the field would be of value for monitoring hydration. Energy Expenditure Several field methods have been tested for predicting total daily energy expenditure, including heart-rate monitors, pedometers, and accelerometers. Accelerometer- and pedometer-based monitors provide valid indicators of overall physical activity, but they are less accurate at predicting energy expenditure. In addition, single-axis accelerometers or pedometers and most multidimensional accelerometers are not useful in detecting the increased energy costs of high-intensity exercise, upper-body exercise, carrying a load, or changes in surface or terrain. The combination of doubly labeled water as a measure of total energy expenditure and hand-held indirect calorimetry to measure resting energy expenditure could be used to monitor metabolic status and assess energy metabolism over periods of up to 2 weeks. Self-selected pace, foot-strike devices, and activity monitors that integrate pulse, temperature, and movement could estimate activity and total energy expenditure and may be useful in the field. If predicting total energy expenditure is the goal of monitoring the activity of the combat service member, then more sophisticated multidimensional devices must be developed. Stress and Immune Function The precise combination of measures chosen to monitor stress and immune function depends on the flexibility of the collection of the measures in the field setting. A full evaluation of the effects of activation of stress response systems on immune function requires measures of multiple functional and molecular biomarkers at multiple time points prior to, during, and after the stress exposure. Monitoring biomarkers of the stress response should include molecular and functional measures of the hypothalamic-pituitary-adrenal (HPA) axis, the adrenergic response systems, and the immune system at multiple levels. The HPA axis can be monitored by measuring levels of the corticotropin-releasing hormone, adrenocorticotropin, and cortisol in plasma, cerebrospinal fluid, urine, saliva, and sweat. Measuring heart-rate variability should be considered as an accurate, sensitive, and noninvasive way to measure the relative activity of the sympathetic and parasympathetic nervous systems. Indicators of stress and immune responses that are currently in use and in development include cortisol levels (measured from saliva, sweat, or urine), and heart-rate variability as measured with high-impedance electrocardiogram (ECG) electrodes that are currently available and are being further developed.

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Monitoring Metabolic Status: Predicting Decrements in Physiological and Cognitive Performance Sleep Several companies currently offer wrist-worn actigraphs that are capable of estimating the quantity and quality of sleep in a variety of environments and for periods ranging from a few hours to several weeks. Associated software can present sleep/wake histories in a number of user-friendly formats. Significant progress has already been made in developing and validating high-impedance sensors that could soon be mounted in helmets and clothing, a challenge when collecting electrophysiological measures (EEG and ECG) in field settings. The technology for field-portable, individual-worn systems for amplifying, recording, and to some extent analyzing these data already exist. Assessment of eye movements and eye closures will only be possible in limited situations in which monitoring equipment can be mounted and aimed at the combat service member. A subset of oculomotor measures is sensitive to cognitive fatigue, but their utility needs to be validated. Self-assessments, on the other hand, are quite easy to collect and many have been shown to be sensitive to operational stressors, such as mental and physical fatigue. However, readers are cautioned that self-assessments can be significantly confounded by motivational factors or peer pressure or in chronic-demand conditions (e.g., people who are very tired for several days at a time may lose their subjective ability to determine how tired they actually are). QUESTION 4 What algorithms are available that might provide useful predictions from combined sensor signals? What additional measurements would improve specificity of the predictions? Models, such as the Acute Physiologic and Chronic Health Evaluation Scores and Simplified Applied Physiological Score, that use physiological variables to predict health outcomes have worked quite well in the intensive care unit setting where pathological changes in physiological parameters are the rule, but there is little evidence that similar algorithms would be equally effective in the military setting where such parameters vary over a narrower range. The National Aeronautics and Space Administration also has undertaken a major research effort in this area, the design of which may be quite compatible with the military environment. Although it would be reasonable to explore whether new variables made possible by new field technologies would be predictive using simpler algorithms, a parallel initiative to explore presently available physiological measurements with more complex models seems appropriate. The future development of algorithms must include the development of nonlinear models that allow discrimination of more complex decision surfaces (e.g., a graphical representation of a problem in space). More complex models, for example, involving artificial neural networks, are needed. In addition, as described in the response to question 2, the technology must evolve to permit the

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Monitoring Metabolic Status: Predicting Decrements in Physiological and Cognitive Performance integration of data in multiple forms from different devices. Last, it is crucial to develop baseline data for each individual (combat service member) in order to implement effective field strategies for monitoring metabolic status. QUESTION 5 What is the committee’s “blue sky” forecast for useful metabolic monitoring approaches (i.e., 10- to 20-year projection)? What are the current research investments that may lead to revolutionary advances? Evolution of New Cognitive Measurement Approaches The prediction of cognitive responses to stress and fatigue needs to be improved. In addition to performing more research on the utility of traditional approaches using self-reported data, a significant focus should be placed on further developing and implementing new psychophysiological methods for monitoring brain activity, heart-rate variability, eye movements, and metabolites and validating these techniques as predictors of cognitive responses to stress and fatigue. New performance assessment methodologies may soon be available for computerized tasks in which cognitive probes can be unobtrusively introduced during the completion of primary operational demands. In addition, the use of handheld computers to record ecological momentary assessments of cognitive function should be further developed. In addition to developing new psychophysiological methods, more work needs to be undertaken on the mathematical integration of these data and the computer models that will synthesize numerous inputs into a field-useable status assessment. Optimization of Markers to Monitor Stress and Immune Function A limited battery of selected stress response and immune markers should be validated to monitor physiological adaptations to changes in the environment and to evaluate the readiness of individuals for impending deployment. Odors as Biomarkers Studies linking human perception of odors with emotion and cognitive states are currently in their infancy and need to be encouraged in order to ascertain the full range of information that human odors might convey. The military should promote innovative research in chemical signaling that will accelerate these advances. Also, research in the development of sensor technology is likely to yield smaller, more automated devices that reduce analysis time and increase reliability—two factors that are critical for field applications. These advances

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Monitoring Metabolic Status: Predicting Decrements in Physiological and Cognitive Performance will go hand-in-hand with the development of sweat patches that can be uniquely designed to capture the substances of interest. It seems highly plausible that new insights from these diverse areas will converge in 5 to 10 years, making odor biomarkers a viable technology for military field applications. Human Tears as Sources of Biomarkers A number of disparate studies suggest that there may be merit in examining tears as a possible medium for monitoring relevant aspects of metabolic status. For example, it has been reported that tear glucose concentrations are related to blood glucose levels. This is an area where little research has been done, but one that may have significant potential as a noninvasive monitoring technology for a variety of physiological biomarkers. New Algorithms to Integrate Complex Biological Information The use of technology and “smart systems” are required to bridge the cognitive gap created by the lack of skilled clinicians in the field to provide individualized recommendations to support end users. Predictive medical algorithms can be utilized to generate specific recommendations and interventions from complex biological information gathered by metabolic monitoring systems. Further research is needed to develop and validate these models, with a particular emphasis on identifying prognostic factors in asymptomatic subjects. The Impact of Biological and Chemical Hazards on Traditional Biomarkers of Health It is largely unknown how hazards and toxins encountered during deployment will affect the biomarkers used by the military for monitoring. For example, low chronic exposure to a bacterial toxin or a heavy metal may alter serum electrolytes, glucose, or enzymes and confound usual interpretation of these values. In contrast, other biomarkers might serve as critical indicators for biological or chemical toxin exposure; for example, pulse rate alterations may be used as an indication of (sublethal) nerve toxin exposure. Metabolomics/Nutrigenomics The differential expression of genes creates individual differences or phenotypes. It is known, for instance, that single nucleotide polymorphisms can affect the way individuals respond to drugs, their vulnerability to microbiological infections, and their susceptibility to long-term degenerative diseases. Such knowledge is envisioned to enhance a combat service member’s performance and lower the risk of life-threatening injury. Further, it is possible that such de-

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Monitoring Metabolic Status: Predicting Decrements in Physiological and Cognitive Performance terminations would allow for prophylactic vaccinations, prescription of preventative pharmaceuticals, and the possible use of special monitoring sensors. Although it may be a number of years before it becomes possible, it would be ideal to be able to predict how a single combat service member will perform under a variety of different dietary and other environmental conditions based upon his or her phenotype. In this manner, the identification of differences between individuals by the use of genomic and metabolomic information collected on each combat servicemen are the ultimate “blue sky.” RESEARCH RECOMMENDATIONS To develop new algorithms that employ currently measurable biomarkers and nonlinear modeling techniques. In circumstances where average group data may not appropriately correlate with the performance of an individual, prediction models will need to be based on data from repeated measures from individuals. To develop patterns of rates of changes and resiliency. For example, research is needed to elucidate individual patterns of rates of change of stress hormones and to determine the resiliency of these stress responses in returning to baseline after the stressors have been removed. To conduct research to evaluate and validate available technology in the field. For example, technology related to self-assessment of perceived exertion, preferred exertion, and mood states that have been tested extensively in sports settings, but it needs to be evaluated and validated in military settings. Optimal combinations for use with physiological markers need to be determined. To further perform research activities in areas with the greatest long-range benefits, such as genomics/metabolomics, odors as biomarkers, tears as a new media for potential biomarkers, new cognitive measurements approaches, optimization of monitoring stress and immune function markers, the development of new algorithms to integrate complex biological information, and the impact of biological and chemical hazards on traditional biomarkers of health. To continue military activities in bone research. These should include studies of markers of bone loss, especially related to fracture risk and the prevention of lost duty time during initial entry training, advanced training, and combat operations. To continue to study cortisol levels during training and operations to ensure that its elevation is not a contributor to bone loss. To develop non- and minimally invasive technologies, particularly for the determination of muscle metabolism, hydration status, and cognitive function. To develop motion sensors that are inexpensive, but more convenient and reliable than current pedometers and accelerometers.

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Monitoring Metabolic Status: Predicting Decrements in Physiological and Cognitive Performance To conduct research to validate the use of self- (and peer-) assessment tools in the field as indicators of fatigue and cognitive ability. To continue research on the use of NIRS to monitor muscle function and skin hydration status concurrently. This particular technology also has the potential for detecting the occurrence of inflammation. To develop simple field-friendly tests for urine specific gravity as an indicator of hydration status. To develop a practical method of monitoring body-weight change in the field. To conduct research to be able to mount or integrate high impedance EEG and ECG electrodes in helmets or into combat clothing. Although this technology will soon make it possible to continuously record brain activity, heart-rate data, and other electrophysiological parameters, some remaining challenges limit its use in the field.