BACKGROUND

Field

Disclosed are sensor devices, systems, and methods for monitoring oxygen-related physiology of the human body. Specifically, sensor systems of the disclosure provide for real-time and near real-time, non-invasive monitoring of need for oxygen vs. supply of oxygen at the cellular level. The systems, devices and methods monitor the full range of oxygen-based physiology, from ‘not enough cellular oxygen’ (cellular hypoxia), through ‘just right’ (aerobic metabolism), to ‘too much cellular oxygen’ (cellular hyperoxia).

Background

Current clinical methods of monitoring oxygen intake during sleep, for example, are limited to indirectly measuring the oxygen saturation of blood hemoglobin by pulse oximetry (SpO2), which indicates the supply of oxygen in the blood, with the assumption that if the blood level of oxygen is within the ‘normal range,’ vital organ tissue will be safely and effectively supplied with oxygen to meet the cellular need for oxygen. However, through experiments and a proof of concept (POC) clinical study, it is determined that the physiologic stress and pathology associated with sleep-disordered breathing (SDB) occurs at the cellular level; not in the blood. The long-held assumption about adequate cellular oxygen supply with ‘normal’ oxygen saturation blood has not been verified due to lack of a sensor able to discern if the cellular need for oxygen is being adequately met or exceeded.

Blood oxygen level measures how much oxygen a person's red blood cells are carrying. Under normal conditions the body closely regulates the blood oxygen level to maintain a consistent range of oxygen-saturated blood. People with abnormal lung function may need to monitor blood oxygen levels to determine if treatments are working or need adjustment. One way of testing blood oxygen level is with an arterial blood gas test. This test requires that blood be drawn from an artery (typically the wrist). The blood is then sent to a lab for testing. Another option is the use of a pulse oximeter device. The pulse oximeter provides an estimate of a percentage of blood oxygen saturation with a 2% error rate.

While blood oxygen saturation is clinically important information, the adequacy of cellular oxygen supply, vs. cellular need for oxygen, is key to sustaining vital functions and avoiding cellular injury. Several instruments, called ‘tissue oximeters,’ claim to measure tissue oxygen supply status by timed sampling of light absorption through skin, or deeper, tissue; attributing these signal changes to be coming only from blood. Where the ‘peak’ and ‘trough’ signal sampling used in pulse oximeters effectively excludes variations in signal due to capillary and venous blood, and to cellular chemistry, the timed sampling in ‘tissue oximeters’ cannot exclude these major confounding contributions. ‘Tissue oximeters’ process their detected signals with Log10ratio computation as is used in pulse oximeters and, per the assumption that the signal variations are due to blood, calibrate with hemoglobin to produce a percent (0% to 100%) ‘tissue oxygen saturation’ (StO2). Under minimal stress conditions, the StO2data responds generally like pulse oximetry. However, when blood flow to the monitored tissue is stopped, then restarted, the interpretation of StO2signal responses having originated only from blood becomes deeply flawed. The recorded magnitude of detected signal variation upon reperfusion (up to 20% full scale at 685 nm) is far too large to be due to oxygen saturation change in capillary blood, which occupies less than 1% of the sensor light path in the skin. The timing and direction of spectral absorption responses upon reperfusion are also inconsistent with blood volume or with oxygen transfer from the blood. Collectively, these experimental results cast doubt on the assumptions and methods currently applied in ‘tissue oximeters.’

Sleep disordered breathing (SDB) is an increasingly recognized major health problem in people of all ages, from premature newborn infants to the elderly. The rising societal cost of SDB, and of associated obesity, includes increased transportation accidents, lost worker productivity, and increased incidence of major co-morbidity health problems, including hypertension, heart attack, atrial fibrillation, and stroke. The most typical SDB events are airway obstruction, due to relaxation of tongue, soft palate, and throat muscles during sleep (Obstructive Sleep Apnea (OSA)), and decreased central nervous system breathing drive, (Central Sleep Apnea (CSA)). Once diagnosed with sleep apnea, patients are typically prescribed an airway therapy device. Airway therapy devices include positive airway pressure devices such as a continuous positive airway pressure (CPAP) machine, which delivers one steady airway pressure and is used with the assumption that patients have the same continuous issues over time. Alternatively, an automatically-regulating positive airway pressure (APAP) machine, that adjusts pressure in a feedback controlled manner, is most commonly used with OSA patients who have changes in the patency of their airway during sleep. Patients with CSA have difficulty with timing and with sufficient effort of breathing during sleep, and are often treated with bilevel positive airway pressure (BiPAP) machines that provide increased pressure assistance with individual breaths. Variable positive airway pressure machines (VPAP) are used when decreased airflow resistance during exhalation is needed. Oral appliance therapy may be appropriate for treatment of mild SDB, but its effectiveness needs to be validated with individual users.

Several major areas of human disease are clinically recognized as having strong statistical association, if not direct cause-effect relationship, with the occurrence of SDB, including ischemic stroke, atrial fibrillation, and heart attack. It has also long been clinically assumed that there is a cause-effect physiologic relationship between snoring and risk of high blood pressure, or hypertension. However, polysomnography (PSG) sleep studies, which include continuous monitoring of arterial blood oxygen saturation by pulse oximetry (SpO2), either do not detect, or do not show consistent occurrence of lowered blood oxygen, or hypoxemia, during snoring. Snoring during sleep, without a drop in SpO2, is currently not ‘scored’ as a pathologic event in PSG sleep studies because there is no association with lowered blood oxygen. As a result of snoring not being scored as an SDB event, airway pressure devices (such as CPAP and APAP devices) are not covered by most medical health insurance policies or Medicare for snoring that does not result in lowered blood oxygen. Hypoxic stress at the cellular level is, apparently, occurring during snoring, but this cannot be detected by the PSG pulse oximeter.

Many other pathologic processes are statistically known to be aggravated by coincident SDB and could possibly be made less severe if the person's SDB was effectively treated. It is currently estimated that about 80% of the about 54 million adults in the United States (US) who suffer from SDB and/or SDB-related co-morbidities, are currently either not diagnosed or are not being effectively treated. Published research has also included sudden infant death syndrome (SIDS) as very likely due to an infant variant of SDB pathology, with peak incidence associated with nervous system development at about 2 months and extending to about one year of age.

The technical complexity of the PSG sensor system is especially limiting in the case of newborn infants afflicted with SDB. Effective screening of all newborn infants to assure stable breathing drive and functional airway during sleep may be needed to identify the infants who are at increased risk of SIDS. Currently, about 3,500 US infants die annually of SIDS, despite extensive efforts to educate parents about infant sleeping position, bedding, etc. Once identified, the at-risk infant needs to be provided a safe sleeping environment and be continuously and effectively monitored during all sleep periods, including daytime naps.

The 1994-1998 Collaborative Home Infant Monitor Evaluation (CHIME) study, included 1,079 infants, many of whom were considered to be at higher than baseline risk of SIDS because they were siblings of infants who had died of SIDS. This study provided conclusive evidence that SDB, including OSA and CSA, is a major factor in SIDS. Unfortunately, the mini-PSG monitor system used during the CHIME study was so difficult and time-consuming to apply that some parents were unwilling to fully comply with the study protocol; possibly contributing to the five study infant deaths that occurred while not being monitored.

Following the CHIME study, The American Academy of Pediatrics issued a policy statement that discourages use of currently available technology for home infant monitoring for the purpose of preventing SIDS. The Academy's position was that there is no infant monitoring system capable of recognizing and alarming to SDB events uniquely associated with SIDS in a timely-enough fashion to be useful for preventing death. Newborn intensive care unit (NICU) cardiorespiratory monitoring technology is the only available option, and is typically sent home with graduating premature newborns when the infant still needs to be monitored for ‘apnea/bradycardia spells;’ which is one of the premature infant-associated forms of SDB. Existing NICU monitoring technology was minimally adapted from adult monitors and, as such, is functionally unable to recognize research-identified breathing control, airway, and cellular oxygen supply problems that appear to be unique to infants at risk of SIDS. Additionally, because NICU monitoring technology is designed with the assumption that safe and effective operation requires the operator to be a qualified nurse or physician, its mechanical and operational complexity presents a significant barrier to effective use by parents at home. An unmet need remains for an easy to apply, fully effective SDB monitoring and alarming means that can be used for screening all newborn infants for SDB risk, and that can also be conveniently used by parents at home through their identified infant's period of SIDS risk extending from about 1 month to about 1 year of age.

Additionally, many children and young adults snore during sleep; some also with episodes of total obstruction of their airway during sleep due to enlarged tonsils and adenoids. Effective diagnosis currently requires these children to undergo a PSG study, which can be very frightening for a child. Surgical removal of enlarged tonsils and adenoids (commonly referred to as T&A surgery) to stop snoring during sleep has risks and may not be covered by medical insurance unless there is a formal PSG-based diagnosis of SDB, and/or medical record documentation of a specified number of group-A streptococcal throat infections.

Unfortunately, even those diagnosed as having SDB, and currently using an airway pressure device during sleep, may not be receiving fully-effective therapy. Many factors are involved in this low rate of diagnosis and borderline-effective treatment, including (1) the accessibility, high cost, and discomfort of PSG sleep studies in a sleep lab that are currently required for prescription and management of an airway pressure device at home, (2) the initial discomfort of therapy during sleep, and (3) the significant probability of less than optimal long-term management of therapy, primarily due to incomplete, or lack of, objective information beyond the PSG sleep study and initial titration of the airway pressure device settings.

One of the common threads in the above-mentioned areas of medical care is an unmet need for directly monitoring cellular oxygen supply that cannot be provided by pulse oximetry. This is also a significant challenge in several major health problems, including ischemic heart attack, ischemic stroke, organ transplant, and retinopathy of prematurity. Long-standing theory holds that the cellular injuries occur primarily during the ischemic or hypoxic phase of the condition. Cellular adaptation to insufficient oxygen supply has, apparently, not been considered to be a contributor. However, current research evidence clearly indicates that the beginning of reperfusion is the time when microvascular obstruction begins, followed by death of the surrounding tissue. This correlation indicates that cellular adaptation likely took place during the ischemic period, such that, upon reperfusion with ‘normally’ oxygenated blood, there was microvascular endothelial injury due to relatively excess oxygen supply, leading to white blood cell adhesion and obstruction of the capillaries and venules. Phase I of retinopathy of prematurity (ROP) appears to occur during the rapid increase in blood oxygen from the relatively low fetal range to the ‘normal newborn’ level at birth and during intensive care, apparently indicating cellular adaptation to the previous much lower fetal oxygen supply rate at the time of birth. Current research also indicates that microvascular obstruction and cellular injury occurs during reperfusion of transplant organs, apparently indicating cellular adaptation to the much lower oxygen supply during organ harvest and transport. Therefore, reperfusion of ischemic vital organ tissue may benefit from a more gradual resupply of oxygen; starting reperfusion with recipient venous blood, followed by blending in an increasing fraction of arterial blood until normally oxygenated arterial blood flow is tolerated without inducing injury. Premature newborn infants may benefit from starting initial care with breathing gas that provides ‘placental’ range oxygen availability, followed by gradual increase of oxygen content until breathing air is tolerated without injury. An apparent unmet need in all of these areas is for a means of indicating the upper threshold of cellular oxygen tolerance to help minimize or prevent these adverse therapeutic outcomes.

Pulse oximeters have known limitations during and following surgical anesthesia where surgical blood loss and blood dilution with IV fluids may result in insufficient oxygen delivery to vital organs. Oxygen delivery during surgical anesthesia is often maintained on the high end of normal, or even significantly excessive, in an attempt to provide a safety buffer against episodes of hypoxemia. Pulse oximetry cannot detect excess oxygen delivery and cannot provide a warning of potential, or actively occurring, harm from excess oxygen. Pulse oximetry also has significant limitations for Remote Patient Monitoring for post-hospital care surveillance and for management of chronic conditions. The awkward application site and motion intolerance of pulse oximeter sensors make them impractical for use as high-risk worker safety alarms that are needed by military and commercial pilots, astronauts, divers, firefighters, underground mine workers, and by other industrial workers in potentially toxic atmospheric environments.

SUMMARY

The disclosed devices, systems and methods provide for the detection and characterization of the physiologic components of SDB in comfortable and conveniently wearable formats configurable for all age groups. Application of the sensor can help reduce the societal costs of SDB by: (1) improving access to diagnosis of SDB with people of all ages by enabling optimal diagnostic testing in the sleep lab and at home, (2) optimizing the physiologic criteria defining payer coverage of airway pressure device therapy (and T&A surgery with children), (3) optimizing the effectiveness and comfort of airway pressure device therapy with physiology-based feed-back control, (4) validating the effectiveness of oral appliance therapy, and (5) spot-checking and continuous surveillance of sleep quality in the general population. Other needful application areas where the disclosed devices offer significant benefits include high-risk worker safety alarms for military/commercial pilots, astronauts, divers, firefighters, underground mine workers, and workers in other toxic industrial environments.

As will be appreciated by those skilled in the art, light can be described as having a wavelength and an intensity. The wavelength of light is, in the visible portion of the spectrum, commonly perceived by the eyes as the color of the light. In the visible portion of the spectrum, the intensity of light is seen by the eyes as the brightness of the light and, in a light-based sensor instrument, as the amount of photocurrent produced by a detector. The disclosed light-based sensor can use 685 nm+/−10 nm as a first center wavelength for detection of insufficient cellular oxygen supply. The sensor can use 850 nm+/−10 nm as a second center wavelength as a blank against which the 685 nm+/−10 nm signal is compared during less than and normal cellular oxygen supply. The sensor can also use 850 nm+/−10 nm as a second center wavelength for detection, by prolonged, decreased detected light intensity, of excess cellular oxygen supply. The sensor can detect an intensity value of light at 850 nm+/−10 nm after the light has passed through skin and then subtract that value from the detected intensity value at 685 nm+/−10 nm after that light has passed through the skin at each data acquisition cycle to produce an ECi data output value. Hereinafter, the use of 685 nm (red), or the use of 850 nm (infrared), indicate that these center wavelengths include center wavelengths within the respective range of +/−10 nm of these numeric values.

The disclosed sensor is an Energy Conversion Monitor (ECM). The ECi value scale it produces centers at zero when a person being tested is acclimated to the atmospheric oxygen supply and is awake, breathing normally, and at rest. Once multiple (e.g., two or more) ECi values are obtained while at rest, a negative-going trend line (less than zero) indicates less than the optimum cellular supply of oxygen is being received by the skin. Multiple ECi entries that produce a flat or near flat trend line centering around zero indicates a stable and normal status relative to cellular supply of oxygen in the skin. A positive-going trend (above zero) indicates that the skin may be receiving more cellular oxygen supply than is needed. Sensor detection of tandem variation in detected light signal that typically occurs with breathing and changes in body position can also be used to detect a photonic analog of breathing effort and body orientation during sleep.

The disclosed sensor systems are configurable to also include, for example, one or more of an electronic accelerometer sensor for detecting (a) mechanical vibration, (b) sensor/body orientation vs. earth gravity, and (c) body motion. Additional components of a sensor system include, but are not limited to, a skin surface temperature sensor and a vibrator motor for generating haptic (tactile) sensory stimulation, such as an attempt to abort a sensor system-recognized apnea event. The disclosed sensor is configurable to receive instructions and send data via, for example, BluetoothLE® RF communication to a device, such as a smartphone, running a custom software application (“app”) as part of a disclosed sensor system.

Light-based sensors are disclosed that use oversampling and mathematical integration to compensate during initialization of the 685 nm light power level for the absorption of 685 nm light by skin pigment; thereby, enabling measurement through the full range of skin pigment level. With lightly to moderately pigmented skin the power level of the 685 nm light can be incrementally increased in, for example, 12-bit microcontroller D/A control voltage steps, until the averaged sample equals, or just exceeds 85% full scale, whereupon the successful control voltage level value is stored in sensor memory. Recording with the ECM under a wide variety of conditions and use cases shows a need for a minimum of 10% light intensity detection overhead, plus a 5% buffer to minimize saturating the A/D converter; thus, the 85% target. The disclosed averaged sample procedure could, for example, include obtaining a nominal number, such as 16, of burst samples of light intensity during illumination of the light, summing the 16 detected intensity values, then dividing the sum by the nominal number, 16, to help reduce the noise level in the signal. However, the 685 nm LED has an upper limit of sustainable power input that has been found by experiment to result in insufficient light output for optimum use with deeply pigmented skin. When the upper limit of sustainable LED power input is reached, but the averaged sample is still less than 85% full scale, and a further procedure involving an extended illumination period, oversampling, and mathematical integration will be used to achieve 85% full scale detected intensity. The oversampling and mathematical integration procedure is configurable so the sum of the total number of burst samples obtained will, when divided by the nominal burst sample number (e.g. 16), equal or just exceed 85% full scale. For example, initialization of the sensor on a person's darkly pigmented skin may require extending the illumination period of the 685 nm LED so that, for example, 25 burst sample values may be obtained, the sum of which when divided by 16, just exceeds 85% full scale. In this exemplary case, the design-specified full sustainable 685 nm LED power control value (e.g. 4095) and the total burst number of samples, 25, are stored in sensor memory to be used for operating the sensor during the current recording session. Using more than the nominal number of burst samples, by the above disclosed method, produces the desired level of signal resolution and signal overhead range, but will slightly decrease the output signal/noise ratio, which may be mitigated with a low noise, high gain, and adequate bandwidth analog transimpedance amplifier for the detector signal.

The disclosed sensors are configurable to be applied to the mid-upper arm and used for monitoring during sleep. However, as will be appreciated by those skilled in the art, other application sites may include, for example, the wrist, torso, or legs. Based on experimental evidence to date, the mid-upper arm is an optimum location for positioning the ECM. However, other locations on the body can be used without departing from the scope of the disclosure. There are known differences between body locations in the detected sensitivity, data value range, and response timing of spectral optical density changes that occur. For instance, the same cellular hypoxia challenge induces a slightly delayed, but larger amplitude, sensor light intensity variation on the wrist, thigh, and lower leg, vs. the upper arm; requiring less amplification prior to digitization. Conversely, when applied on the mid-upper back, such as, for example, with aging adults suffering from dementia who are often intolerant of unfamiliar devices attached to their bodies, the ECM provides a lower amplitude signal variation compared with the upper arm location; requiring slightly more signal amplification to achieve the desired resolution.

The disclosed light-based sensors identify each subject's individual oxygen supply, vs. oxygen need center zone, or Energy Conversion Index (ECi) Zero. When a person is healthy, at rest or asleep, and breathing normally, the intake of oxygen by breathing can be considered to be a normal minimum amount for that person, and can also be described as a natural balance of minimum oxygen intake, vs. minimum oxygen need. This condition is further described herein as an ECi Zero condition; with not enough oxygen intake to meet the needs of the body, or cellular hypoxia condition, producing a negative ECi numeric trend less than zero, and more than enough oxygen intake, or cellular hyperoxia, producing a positive ECi numeric trend greater than zero.

The disclosed light-based sensors also use algorithmic analysis of the recorded data trend to produce a numeric offset value that, when subtracted from the 850 nm data, fine-tunes the output ECi data trend relative to the true ECi Zero value of the individual person during each session of use. This fine-tuning offset is needed for two reasons: (1) the sensor will most likely be placed on the skin when the person is not actually at the person's ECi Zero, and (2) even with 12-bit resolution on the illumination power levels, it is unlikely that the detected intensities can be brought closer than about 20 digitized intensity level steps to being exactly equal. In the application of sleep testing, the ECi Zero has been most consistently identifiable when the person awakens after having been asleep for at least 3 hours. This enables the fully relaxed and awake person to breathe without airway obstruction or central apnea; thus, likely bringing total body physiology to its optimum resting level. Other applications will likely need to perform ensemble averaging of the ECi trend during periods of apparent minimal activity to scan for a period when the body is most likely to be at ECi Zero status; then define the offset value needed to bring the data recorded during that minimal activity period to center on zero. Once so determined, the offset value is used to offset the entire recording session to center on the most likely current ECi Zero of the person. Experimental experience indicates that ECi Zero is not to be taken as the optimal health status of the person, but rather to establish a convenient and reproduceable ECi value reference point in the person's cellular chemistry continuum. Since light absorption in the skin is due to many thousands of different kinds of molecules within the light path, the sensor cannot be calibrated, in the usual sense, to a single reference molecule, such as hemoglobin is used to calibrate pulse oximeter sensors. Experimental evidence has, however, established that the cellular oxygen supply-related continuum can be usefully sensed and portrayed by referencing the disclosed sensors to a balanced minimum oxygen need, vs. oxygen supply condition, which we call ECi Zero.

An aspect of the disclosure is directed to Energy Conversion Monitor (ECM) sensors. Suitable ECM sensors comprise: a housing; a power source; a first light emitter positioned within an interior of the housing configured to emit a first light at a first wavelength; a second light emitter positioned within the interior of the housing configured to emit a second light at a second wavelength different than the first wavelength; a light detector positioned within the interior of the housing and optically isolated from the first light emitter and the second light emitter wherein the light detector is configured to detect a resulting first tissue-interacted light signal from the first light emitter and a second tissue-interacted light signal from the second light emitter; an illumination power control circuit in communication with the first light emitter and the second light emitter wherein the illumination power control circuit is configured to provide a computer program-defined illumination power to energize the first light emitter and the second light emitter at a respective computer program-defined illumination intensity; a signal amplifier in communication with the light detector; and a microcontroller configured to compute a first output data value from the first tissue-interacted light and a second output data from the second tissue-interacted light. In some configurations the ECM sensor uses a plurality of wavelengths of light selected by in vivo spectrometry. The plurality of wavelengths of light can be selected to maximize a respective variation in detected cellular light absorbance relative to at least one of a known cellular biochemical phenomenon and a known physiologic phenomenon affecting a monitored tissue. The first light emitter can have a first light emitter center wavelength value of from 675 nm to 695 nm inclusive. Additionally, the microcontroller is configurable to compensate during an initialization process for a variation in a skin pigmentation level by step-wise increasing a power delivered to the first light emitter up to a sustainable maximum rated power level for the first light emitter. If a detected intensity at 85% full scale is not detectable when the sustainable maximum rated power level for the first light emitter is reached, the microcontroller is configurable to implement an oversampling and mathematical integration method. Additionally, the microcontroller is configurable to increase a number of burst samples beyond a nominal number, sum all of the burst sample values, and divide the sum of all of the burst samples by the nominal number until a computed intensity value equal or greater than 85% full scale is achieved. The second light emitter can have a second light emitter center wavelength value of from 840 nm to 860 nm inclusive. The light detector can be configured to detect the first tissue-interacted light signal and the second tissue-interacted light signal at one or more timed intervals. Operation of the ECM sensors can be controlled by the user directly (i.e. by interfacing with the sensor) or via a software application on a mobile computing device such as a smart phone or tablet configured to wirelessly control the ECM sensor. In other configurations, the ECM sensors can be operated via a remote computing device which communicates wirelessly with the ECM sensor (e.g. from a clinic or healthcare practitioner facility).

Another aspect of the disclosure is directed to systems in communication with an ECM sensor. Suitable systems comprise: an Energy Conversion Monitor sensor comprising a housing, a power source, a first light emitter positioned within an interior of the housing configured to emit a first light at a first wavelength, a second light emitter positioned within the interior of the housing configured to emit a second light at a second wavelength different than the first intensity, a light detector positioned within the interior of the housing and optically isolated from the first light emitter and the second light emitter wherein the light detector is configured to detect a resulting first tissue-interacted light signal from the first light emitter and a second tissue-interacted light signal from the second light emitter, an illumination power control circuit in communication with the first light emitter and the second light emitter wherein the illumination power control circuit is configured to provide a computer program-defined illumination power to energize the first light emitter and the second light emitter at a respective computer program-defined illumination intensity, a signal amplifier in communication with the light detector, and a microcontroller configured to compute a first output data value from the first tissue-interacted light and a second output data from the second tissue-interacted light; and at least one secondary device. The secondary device can be selected from a second sensor, a sleep disordered breathing (SDB) therapy device, a remote computing device, and a polysomnograph (PSG) system. Additionally the system can be controlled by a software application which is in communication with the ECM sensor and one or more secondary device. Operation of the system can be controlled by the user directly (i.e. by interfacing with the sensor) or via a software application on a mobile computing device such as a smart phone or tablet configured to wirelessly control the system. In other configurations, the system can be operated via a remote computing device which communicates wirelessly with the devices of the system (e.g. from a clinic or healthcare practitioner facility).

Still another aspect of the disclosure is directed to methods of using an ECM sensor. Suitable methods comprise the steps of: applying an Energy Conversion Monitor sensor to a skin surface of a patient wherein the Energy Conversion Monitor sensor comprises a housing, a power source, a first light emitter positioned within an interior of the housing configured to emit a first light at a first wavelength, a second light emitter positioned within the interior of the housing configured to emit a second light at a second wavelength different than the first wavelength, a light detector positioned within the interior of the housing and optically isolated from the first light emitter and the second light emitter wherein the light detector is configured to detect a resulting first tissue-interacted light signal from the first light emitter and a second tissue-interacted light signal from the second light emitter, an illumination power control circuit in communication with the first light emitter and the second light emitter wherein the illumination power control circuit is configured to provide a computer program-defined illumination power to energize the first light emitter and the second light emitter at a respective computer program-defined illumination intensity, a signal amplifier in communication with the light detector, and a microcontroller configured to compute a first output data value from the first tissue-interacted light and a second output data from the second tissue-interacted light; and powering the Energy Conversion Monitor sensor. In some configurations, the method can also comprise the steps of: delivering a power level to the Energy Conversion Monitor sensor to equalize a first detected intensity of light at a first wavelength between 675 nm and 695 nm inclusive with a second detected intensity of light at a second wavelength between 840 nm and 860 nm inclusive; determining a first detected intensity of light from a first tissue interacted light signal; determining a second detected intensity of light from a second tissue interacted light signal; comparing the first detected intensity of light to a first full scale to determine a first percentage detected intensity of light; comparing the second detected intensity of light to a second full scale to determine a second percentage detected intensity of light; and repeating the delivering, determining, and comparing steps to obtain a detected intensity of light at 85% of full scale for each of the first detected intensity of light and the second detected intensity of light. Additionally, the methods can comprise storing the power level and a total number of burst samples added together and divided by a nominal number of burst samples to achieve a detected, integrated intensity of tissue interacted light from the first emitter of 85% full scale in a memory, and storing the power level to achieve a detected intensity of tissue interacted light from the second emitter of 85% full scale in a memory. In some configurations, the methods can comprise using the stored power level of a first emitter and the number of burst samples of detected tissue interacted light from a first emitter, and the stored power level of a second emitter, as control parameters in data acquisition through a current recording session. In some configurations, the methods can comprise initializing the Energy Conversion Monitor sensor; subtracting a detected intensity from the second light emitter (between 840 nm and 860 nm inclusive), following tissue interaction with a second light, from the detected intensity from the first light emitter (between 675 nm and 695 nm inclusive), following tissue interaction with a first light, to produce an Energy Conversion Index (ECi) output as an at least 12-bit resolution; and generating an integer numeric value analog indication of a status of cellular oxygen supply-related chemistry. Still other configurations can include a method comprising computing one of a cellular oxygen supply-related center and an Energy Conversion Index Zero (ECi Zero) of a user; and applying an offset value to a center the data output of an Energy Conversion Monitor sensor output data. Yet other methods can comprise performing a calculation averaging a period of low activity to define and record an offset numeric value relative to zero; determining a current ECi Zero for a patient; and applying a recorded offset numeric value to center the recorded data on a current ECi Zero of the patient. In some configurations of the method it may be advantageous for the method to also comprise one or more steps of indicating, in response to an ECi data less than zero produced by decreased detected intensity at 685 nm along with simultaneous stable detected intensity at 850 nm, a cellular oxygen supply less than physiologically optimum; indicating, in response to an ECi data greater than zero produced by stable or increased detected first intensity between 675 nm and 695 nm inclusive along with simultaneous stable or decreased second detected intensity between 840 nm and 860 nm inclusive, a cellular oxygen supply more than physiologically optimum; and identifying an indication of changing blood volume beneath the Energy Conversion Monitor sensor resulting from at least one of an Energy Conversion Monitor sensor motion against the skin and a change of body position vs. gravity during sleep causing a tandem variation in a first detected light intensity between 675 nm and 695 nm inclusive and a second detected light intensity between 840 nm and 860 nm inclusive. Some methods also comprise the steps of generating a generated signal between 840 nm and 860 nm inclusive; and detecting the generated signal at a sufficiently frequent timed interval to define an amplitude and a waveform of a breathing-induced, light intensity variation as an indication of one of an increased effort to breathe through a restricted or obstructed airway, and a decreased or absent effort to breathe from a reduced or absent central nervous system breathing drive.

Yet another aspect of the disclosure is directed to methods of using an ECM sensor in specific clinical scenarios. For example, the methods of using the ECM sensor can also comprise: applying the Energy Conversion Monitor sensor on a person identified as possibly suffering from sleep disordered breathing (SDB); monitoring breathing and oxygen supply-related physiology during sleep of the person; and providing recorded data from the monitoring to aid in clinical diagnosis of SDB to help define, validate, and regulate effective therapy. In another clinical method, the method can comprise applying the Energy Conversion Monitor sensor to a person having sleep disordered breathing (SDB) while sleeping at home while using an SDB therapy device; and determining an extent of management of the SDB. Still another method can comprise: applying the Energy Conversion Monitor sensor to a person while sleeping at home while using a sleep disordered breathing (SDB) therapy device to provide ECi and breathing information to the SDB therapy device; controlling the SBD therapy device in response to at least one of the ECi and breathing information from the Energy Conversion Monitor sensor; and providing surveillance during sleep for changes in the person's general health status. Additional methods comprise: applying the Energy Conversion Monitor sensor on a person identified as at risk of developing sepsis; and detecting the possible presence of sepsis as from an ECi value progressively trending less than zero. Another method also comprises applying the Energy Conversion Monitor sensor to an infant; screening the infant for a risk of SIDS by recording a stability and effectiveness of breathing during sleep. Yet another method comprises applying the Energy Conversion Monitor sensor to an infant; monitoring a stability and effectiveness of breathing during sleep; and one or more of delivering a stimulation to arouse the infant from sleep during episodes of detected abnormal breathing during sleep, and delivering an alarm identifying the detected abnormal breathing to a caregiver. Yet another method comprises applying the Energy Conversion Monitor sensor to a newborn infant; and providing feedback to a caregiver for use in regulating an oxygen level in a breathing gas relative to a cellular oxygen need as the infant transitions from fetal life to a higher level of oxygen available from breathing air, or higher levels of oxygen, to help reduce or prevent oxygen supply-related injuries. Another method comprises applying the Energy Conversion Monitor sensor during a resuscitation of a person suffering from at least one of hypoxia and suffocation; and guiding a regulation of oxygen in a breathing gas relative to a cellular oxygen need of the person. Another method comprises applying the Energy Conversion Monitor sensor to a worker in a high-risk atmospheric environment; and monitoring the worker for at least one of hypoxia and adverse effects of toxic gases in their breathing air. Yet another method comprises applying the Energy Conversion Monitor sensor to a forehead of a pilot; and monitoring the pilot for one or more of hypoxia and a g-load-induced loss of blood flow to the head. Still another method comprises applying the Energy Conversion Monitor sensor to an athlete during and following physical exercise; assessing physiologic responses of the athlete; and providing a recommendation for optimum performance. Another method comprises applying the Energy Conversion Monitor sensor having a dual probe to a chest and abdomen of an infant patient in intensive care; monitoring a pre-ductal cellular oxygen supply and a post-ductal cellular oxygen supply; and detecting at least one of an anatomic anomaly of a heart, an anatomic anomaly of a great vessels, and a failure of a ductus arteriosus to close normally. Yet another method comprises applying the Energy Conversion Monitor sensor having a dual probe during at least one of reperfusion of a myocardium during therapy for ischemic heart attack, reperfusion of an affected area of a brain during therapy for a stroke, a reperfusion of a transplant organ, and a guide oxygen resupply to the ischemic tissue relative to cellular oxygen need to help reduce or prevent reperfusion injury.

Another aspect of the disclosure is directed to Energy Conversion Monitor (ECM) sensors. Suitable ECM sensors comprise: a housing means; a power source means; a first light emitter means positioned within an interior of the housing means configured to emit a first light at a first wavelength; a second light emitter means positioned within the interior of the housing means configured to emit a second light at a second wavelength different than the first wavelength; a light detector means positioned within the interior of the housing means and optically isolated from the first light emitter means and the second light emitter means wherein the light detector means is configured to detect a resulting first tissue-interacted light signal from the first light emitter means and a second tissue-interacted light signal from the second light emitter means; an illumination power control circuit means in communication with the first light emitter means and the second light emitter means wherein the illumination power control circuit means is configured to provide a computer program-defined illumination power to energize the first light emitter means and the second light emitter means at a respective computer program-defined illumination intensity; a signal amplifier means in communication with the light detector means; and a microcontroller means configured to compute a first output data value from the first tissue-interacted light and a second output data from the second tissue-interacted light. In some configurations the ECM sensor uses a plurality of wavelengths of light selected by in vivo spectrometry. The plurality of wavelengths of light can be selected to maximize a respective variation in detected cellular light absorbance relative to at least one of a known cellular biochemical phenomenon and a known physiologic phenomenon affecting a monitored tissue. The first light emitter means can have a first light emitter means center wavelength value of from 675 nm to 695 nm inclusive. Additionally, the microcontroller means is configurable to compensate during an initialization process for a variation in a skin pigmentation level by step-wise increasing a power delivered to the first light emitter means up to a sustainable maximum rated power level for the first light emitter means. If a detected intensity at 85% full scale is not detectable when the sustainable maximum rated power level for the first light emitter means is reached, the microcontroller means is configurable to implement an oversampling and mathematical integration method. Additionally, the microcontroller means is configurable to increase a number of burst samples beyond a nominal number, sum all of the burst sample values, and divide the sum of all of the burst samples by the nominal number until a computed intensity value equal or greater than 85% full scale is achieved. The second light emitter means can have a second light emitter means center wavelength value of from 840 nm to 860 nm inclusive. The light detector means can be configured to detect the first tissue-interacted light signal and the second tissue-interacted light signal at one or more timed intervals. Operation of the ECM sensors can be controlled by the user directly (i.e. by interfacing with the sensor) or via a software application on a mobile computing device such as a smart phone or tablet configured to wirelessly control the ECM sensor. In other configurations, the ECM sensors can be operated via a remote computing device which communicates wirelessly with the ECM sensor (e.g. from a clinic or healthcare practitioner facility).

Another aspect of the disclosure is directed to systems in communication with an ECM sensor. Suitable systems comprise: an Energy Conversion Monitor sensor comprising a housing means, a power source means, a first light emitter means positioned within an interior of the housing means configured to emit a first light at a first wavelength, a second light emitter means positioned within the interior of the housing means configured to emit a second light at a second wavelength different than the first intensity, a light detector means positioned within the interior of the housing means and optically isolated from the first light emitter means and the second light emitter means wherein the light detector means is configured to detect a resulting first tissue-interacted light signal from the first light emitter means and a second tissue-interacted light signal from the second light emitter means, an illumination power control circuit means in communication with the first light emitter means and the second light emitter means wherein the illumination power control circuit means is configured to provide a computer program-defined illumination power to energize the first light emitter means and the second light emitter means at a respective computer program-defined illumination intensity, a signal amplifier means in communication with the light detector means, and a microcontroller means configured to compute a first output data value from the first tissue-interacted light and a second output data from the second tissue-interacted light; and at least one secondary device. The secondary device can be selected from a second sensor, a sleep disordered breathing (SDB) therapy device, a remote computing device, and a polysomnograph (PSG) system. Additionally the system can be controlled by a software application which is in communication with the ECM sensor and one or more secondary device. Operation of the system can be controlled by the user directly (i.e. by interfacing with the sensor) or via a software application on a mobile computing device such as a smart phone or tablet configured to wirelessly control the system. In other configurations, the system can be operated via a remote computing device which communicates wirelessly with the devices of the system (e.g. from a clinic or healthcare practitioner facility).

Still another aspect of the disclosure is directed to methods of using an ECM sensor. Suitable methods comprise the steps of: applying an Energy Conversion Monitor sensor to a skin surface of a patient wherein the Energy Conversion Monitor sensor comprises a housing means, a power source means, a first light emitter means positioned within an interior of the housing means configured to emit a first light at a first wavelength, a second light emitter means positioned within the interior of the housing means configured to emit a second light at a second wavelength different than the first wavelength, a light detector means positioned within the interior of the housing means and optically isolated from the first light emitter means and the second light emitter means wherein the light detector means is configured to detect a resulting first tissue-interacted light signal from the first light emitter means and a second tissue-interacted light signal from the second light emitter means, an illumination power control circuit means in communication with the first light emitter means and the second light emitter means wherein the illumination power control circuit means is configured to provide a computer program-defined illumination power to energize the first light emitter means and the second light emitter means at a respective computer program-defined illumination intensity, a signal amplifier means in communication with the light detector means, and a microcontroller means configured to compute a first output data value from the first tissue-interacted light and a second output data from the second tissue-interacted light; and powering the Energy Conversion Monitor sensor. In some configurations, the method can also comprise the steps of: delivering a power level to the Energy Conversion Monitor sensor to equalize a first detected intensity of light at a first wavelength between 675 nm and 695 nm inclusive with a second detected intensity of light at a second wavelength between 840 nm and 860 nm inclusive; determining a first detected intensity of light from a first tissue interacted light signal; determining a second detected intensity of light from a second tissue interacted light signal; comparing the first detected intensity of light to a first full scale to determine a first percentage detected intensity of light; comparing the second detected intensity of light to a second full scale to determine a second percentage detected intensity of light; and repeating the delivering, determining, and comparing steps to obtain a detected intensity of light at 85% of full scale for each of the first detected intensity of light and the second detected intensity of light. Additionally, the methods can comprise storing the power level and a total number of burst samples added together and divided by a nominal number of burst samples to achieve a detected, integrated intensity of tissue interacted light from the first emitter of 85% full scale in a memory, and storing the power level to achieve a detected intensity of tissue interacted light from the second emitter of 85% full scale in a memory. In some configurations, the methods can comprise using the stored power level of a first emitter and the number of burst samples of detected tissue interacted light from a first emitter, and the stored power level of a second emitter, as control parameters in data acquisition through a current recording session. In some configurations, the methods can comprise initializing the Energy Conversion Monitor sensor; subtracting a detected intensity from the second light emitter means (between 840 nm and 860 nm inclusive), following tissue interaction with a second light, from the detected intensity from the first light emitter means (between 675 nm and 695 nm inclusive), following tissue interaction with a first light, to produce an Energy Conversion Index (ECi) output as an at least 12-bit resolution; and generating an integer numeric value analog indication of a status of cellular oxygen supply-related chemistry. Still other configurations can include a method comprising computing one of a cellular oxygen supply-related center and an Energy Conversion Index Zero (ECi Zero) of a user; and applying an offset value to a center the data output of an Energy Conversion Monitor sensor output data. Yet other methods can comprise performing a calculation averaging a period of low activity to define and record an offset numeric value relative to zero; determining a current ECi Zero for a patient; and applying a recorded offset numeric value to center the recorded data on a current ECi Zero of the patient. In some configurations of the method it may be advantageous for the method to also comprise one or more steps of indicating, in response to an ECi data less than zero produced by decreased detected intensity at 685 nm along with simultaneous stable detected intensity at 850 nm, a cellular oxygen supply less than physiologically optimum; indicating, in response to an ECi data greater than zero produced by stable or increased detected first intensity between 675 nm and 695 nm inclusive along with simultaneous stable or decreased second detected intensity between 840 nm and 860 nm inclusive, a cellular oxygen supply more than physiologically optimum; and identifying an indication of changing blood volume beneath the Energy Conversion Monitor sensor resulting from at least one of an Energy Conversion Monitor sensor motion against the skin and a change of body position vs. gravity during sleep causing a tandem variation in a first detected light intensity between 675 nm and 695 nm inclusive and a second detected light intensity between 840 nm and 860 nm inclusive. Some methods also comprise the steps of generating a generated signal between 840 nm and 860 nm inclusive; and detecting the generated signal at a sufficiently frequent timed interval to define an amplitude and a waveform of a breathing-induced, light intensity variation as an indication of one of an increased effort to breathe through a restricted or obstructed airway, and a decreased or absent effort to breathe from a reduced or absent central nervous system breathing drive.

Yet another aspect of the disclosure is directed to methods of using an ECM sensor in specific clinical scenarios. For example, the methods of using the ECM sensor can also comprise: applying the Energy Conversion Monitor sensor on a person identified as possibly suffering from sleep disordered breathing (SDB); monitoring breathing and oxygen supply-related physiology during sleep of the person; and providing recorded data from the monitoring to aid in clinical diagnosis of SDB to help define, validate, and regulate effective therapy. In another clinical method, the method can comprise applying the Energy Conversion Monitor sensor to a person having sleep disordered breathing (SDB) while sleeping at home while using an SDB therapy device; and determining an extent of management of the SDB. Still another method can comprise: applying the Energy Conversion Monitor sensor to a person while sleeping at home while using a sleep disordered breathing (SDB) therapy device to provide ECi and breathing information to the SDB therapy device; controlling the SBD therapy device in response to at least one of the ECi and breathing information from the Energy Conversion Monitor sensor; and providing surveillance during sleep for changes in the person's general health status. Additional methods comprise: applying the Energy Conversion Monitor sensor on a person identified as at risk of developing sepsis; and detecting the possible presence of sepsis as from an ECi value progressively trending less than zero. Another method also comprises applying the Energy Conversion Monitor sensor to an infant; screening the infant for a risk of SIDS by recording a stability and effectiveness of breathing during sleep. Yet another method comprises applying the Energy Conversion Monitor sensor to an infant; monitoring a stability and effectiveness of breathing during sleep; and one or more of delivering a stimulation to arouse the infant from sleep during episodes of detected abnormal breathing during sleep, and delivering an alarm identifying the detected abnormal breathing to a caregiver. Yet another method comprises applying the Energy Conversion Monitor sensor to a newborn infant; and providing feedback to a caregiver for use in regulating an oxygen level in a breathing gas relative to a cellular oxygen need as the infant transitions from fetal life to a higher level of oxygen available from breathing air, or higher levels of oxygen, to help reduce or prevent oxygen supply-related injuries. Another method comprises applying the Energy Conversion Monitor sensor during a resuscitation of a person suffering from at least one of hypoxia and suffocation; and guiding a regulation of oxygen in a breathing gas relative to a cellular oxygen need of the person. Another method comprises applying the Energy Conversion Monitor sensor to a worker in a high-risk atmospheric environment; and monitoring the worker for at least one of hypoxia and adverse effects of toxic gases in their breathing air. Yet another method comprises applying the Energy Conversion Monitor sensor to a forehead of a pilot; and monitoring the pilot for one or more of hypoxia and a g-load-induced loss of blood flow to the head. Still another method comprises applying the Energy Conversion Monitor sensor to an athlete during and following physical exercise; assessing physiologic responses of the athlete; and providing a recommendation for optimum performance. Another method comprises applying the Energy Conversion Monitor sensor having a dual probe to a chest and abdomen of an infant patient in intensive care; monitoring a pre-ductal cellular oxygen supply and a post-ductal cellular oxygen supply; and detecting at least one of an anatomic anomaly of a heart, an anatomic anomaly of a great vessels, and a failure of a ductus arteriosus to close normally. Yet another method comprises applying the Energy Conversion Monitor sensor having a dual probe during at least one of reperfusion of a myocardium during therapy for ischemic heart attack, reperfusion of an affected area of a brain during therapy for a stroke, a reperfusion of a transplant organ, and a guide oxygen resupply to the ischemic tissue relative to cellular oxygen need to help reduce or prevent reperfusion injury.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. References include, for example:US 2006/0009685 A1 to Finarov et al. published Jan. 12, 2006 for Device and Method for Non-Invasive Optical Measurements;US 2008/0081966 A1 to Debreczeny published Apr. 3, 2008 for Symmetric LED Array for Pulse Oximetry;US 2008/0208009 A1 to Shklarski published Aug. 28, 2008 for Wearable Device, System and Method for Measuring Vital Parameters;US 2010/0324390 A1 to McLaughlin, published Dec. 23, 2010, for Measurement of Oxygen Saturation of Blood Haemoglobin;US 2011/0054336 A1 to Jornod published Mar. 3, 2011 for Method and Device for Measuring the Pulse by Means of Light Waves with Two Wavelengths;US 2013/0303921 A1 to Chu, published Nov. 14, 2013, for System and Method for Measurement of Physiological Data with Light Modulation;US 2013/0317331 A1 to Bechtel, published Nov. 28, 2013, for Monte Carlo and Iterative Methods for Determination of Tissue Oxygen Saturation;US 2014/0275888 A1 to Wegerich published Sep. 18, 2014 for Wearable Wireless Multisensor Health Monitor with Heat Photoplethysmograph;US 2015/0011854 A1 to Frix, published Jan. 8, 2015, for Continuous Transdermal for “Signal Monitoring System and Method; Including EMI-Shielding Coupler,” CAS Medical Systems, Inc.;US 2015/0057511 A1 to Basu, published Feb. 26, 2015, for Sensor and Method for Continuous Health Monitoring;US 2017/0049336 A1 to Hatch for Physiological Sensors, Systems, Kits and Methods Therefor published Feb. 23, 2017;US 2017/0112422A1 to Hatch for Optical Physiologic Sensors and Methods published Apr. 27, 2017; andU.S. Pat. No. 5,830,137 A to Scharf issued Nov. 3, 1998 for Green Light Pulse Oximeter;U.S. Pat. No. 6,801,799 B2 to Mendelson, issued Oct. 5, 2004, for Pulse Oximeter and Method of Operation;U.S. Pat. No. 7,691,067 B2 to Westbrook, issued Apr. 6, 2010, for Method for Measuring Central Venous Pressure or Respiratory Effort;U.S. Pat. No. 7,738,935 B1 to Turcott, issued Jun. 15, 2010, for Methods and Devices for Reduction of Motion-Induced Noise in Pulse Oximetry;U.S. Pat. No. 8,073,516 B2 to Scharf issued Dec. 6, 2011, for Separating Motion from Cardiac Signals Using Second Order Derivative of the Photo-Plethysmogram and Fast Fourier Transforms;U.S. Pat. No. 8,133,176 B2 to Porges, issued Mar. 13, 2012, for Method and Circuit for Indicating Quality and Accuracy of Physiological Measurements;U.S. Pat. No. 8,346,327 B2 to Campbell, issued Jan. 1, 2013, for Method for Identification of Sensor Site by Local Skin Spectrum Data;U.S. Pat. No. 9,125,563 B2 for “Signal Monitoring System Including EMI-Shielding Coupler,” CAS Medical Systems, Inc., Sep. 8, 2015;U.S. Pat. No. 9,357,954 B2 for “Simultaneous Measurement of Pulse and Regional Blood Oxygen Saturation,” Covidien LP, issued Jun. 7, 2016;U.S. Pat. No. 10,327,710 B2 for “Age Calibration for Tissue Oximetry,” Nonin Medical, Inc., issued Jun. 25, 2019;U.S. Pat. No. 10,335,072 B2 for “Physiologic Monitor,” Masimo Corporation, issued Jul. 2, 2019;U.S. Pat. No. 10,369,310 B2 for “Method and Apparatus for Treatment of Respiratory Disorders” ResMed Limited issued Aug. 6, 2019;U.S. Pat. No. 10,376,670 B2 for “Methods and Systems for Sleep Management” ResMed Sensor Technologies issued Aug. 13, 2019;U.S. Pat. No. 10,383,569 B2 for “Mechanical Ventilation in the Presence of Sleep Disordered Breathing” ResMed Limited, issued Aug. 20, 2019;WO 2015/168235 A1 to Hatch published Nov. 5, 2015, for Physiological Sensors, Systems, Kits and Methods Therefor;Cornet A D, et. al., The potential harm of oxygen therapy in medical emergencies,” Critical Care 2013, 17:313, PMID: 23635028;Hashimoto I, et. al., “The features of thrombus in a microvessel injury model and the antithrombotic efficacy of heparin, urokinase, and prostaglandin E1,” Plastic and Reconstructive Surgery, June 2003, 2307-2314;Hunt C, et. al., “Cardiorespiratory events detected by home memory monitoring and one-year neurodevelopmental outcome,” J Pediatr 2004; 145:465-71, PMID: 15480368;Hyttel-Sorensen S, et. al. “Peripheral tissue oximetry: comparing three commercial near-infrared spectroscopy oximeters on the forearm,” J Clin Monit Computer (2014) 28:149-155, PMID: 23990288;Joosen S A, et. al., “Dynamic loop gain increases upon adopting the supine body position during sleep in patients with obstructive sleep apnea,” Respirology 2017 November; 22(8): 1662-1669, PMID: 28730724;Kalogeris T, et. al., “Ischemia/Reperfusion,” Comprehensive Physiology 7:113-170, 2017, PMID: 28135002;Liegl R, et. al., “Retinopathy of prematurity: the need for prevention,” Eye and Brain 2016:8 91-102, PMID: 28539604;Lopez S, “Pulse Oximeter Fundamentals and Design,” Document Number: AN4327, Rev. 2, 11/20/12, Freescale Semiconductor Application Note;Mayevsky A, et. al., “Mitochondrial function and tissue vitality: bench-to-bedside real-time optical monitoring system,” J Biomedical Optics, 16(6), 067004, June 2017, PMID: 21721825;Miller, et. al., “Antenatal antioxidant treatment with melatonin to decrease newborn neurodevelopmental deficits and brain injury caused by fetal growth restriction,” J Pineal Res 2014 April: 56(3): 283-94, PMID: 24456220;Okuno, et. al., “Rotation and structure of Fo and F1-ATP synthase,” J. Biochem. 2011; 149(6):655-664, PMID: 21524994;Ramanathan R, et. al., “Cardiorespiratory events recorded on home monitors: comparison of healthy infants with those at increased risk for SIDS,” JAMA, May 2, 2001, Vol. 285, No. 17, 2199-2207, PMID: 15480368;Rolfe P, “In vivo near-infrared spectroscopy,” Annu. Rev. Biomed. Eng. 2000 02:715-54, PMID: 11701529; andRozova E V, et. al., “Structural and dynamic changes in mitochondria of rat myocardium under acute hypoxic hypoxia: role of mitochondrial ATP-dependent potassium channel,” Biochemistry (Moscow) 2015, Vol. 89, No. 8, pp. 994-1000, PMID: 26547067.

