Patent Application
20220240834
The present disclosure relates generally to an electroencephalogram (“EEG”), and more specifically, to exemplary embodiments of exemplary system, method, and computer-accessible medium for visualization and analysis of electroencephalogram oscillations in the alpha band.
Intraoperative neuromonitoring can assist anesthesia providers to avoid administering unnecessarily high doses of anesthetics. Failure to properly titrate anesthetic medications presents a risk factor for the occurrence of perioperative neurocognitive disorders (“PNDs”). (See, e.g., References 1 and 2). PND is an umbrella term for cognitive impairment or deterioration identified in the perioperative period, and can include acute events, for example, PACU delirium, as well as delayed neurocognitive recovery after surgery. (See, e.g., Reference 3).
Previous studies have demonstrated that not only the anesthetic dose, but also the presence or absence of certain EEG patterns are correlated with PNDs. (See, e.g., References 4). In particular, pronounced alpha oscillations in the frontal EEG, especially during the emergence from anesthesia appear to be predictors of favorable neurocognitive outcomes. (See, e.g., Reference 5). The EEG alpha rhythm was originally been defined by the International Federation of Societies for Electroencephalography and Clinical Neurophysiology (“IFSECN”) as a rhythm at 8-13 Hz. (See, e.g., Reference 6). However, the classical range is often extended to group oscillations thought to be related by a common mechanism, for example, 7-17 Hz. (See, e.g., References 7-10). Although alpha oscillations over the frontal cortex in anesthesia are thought to be related to distributed, reciprocally connected, populations of cortical and thalamic neurons (see, e.g., references 11-13), the mechanisms are not fully understood. Since frontal alpha oscillations can be seen during propofol as well as volatile anesthesia it has been suggested to be a marker of a state of stable unconsciousness. (See, e.g., References 7, 8, and 14). In addition, frontal alpha power is reduced by noxious stimulation, for example, surgical incision, but can be restored by administering analgesics. (See, e.g., References 10 and 15-17). Thus, the presence of alpha oscillatory activity in the EEG can represent a state of adequate anesthesia. (See, e.g., Reference 18).
Use of the density spectral array (“DSA”) for maximization of alpha band power through adjustment of the anesthesia regimen has been suggested as an intraoperative strategy. (See, e.g., References 19 and 20). Unfortunately, elderly patients show a general decrease in EEG power under general anesthesia. (See, e.g., References 21 and 22). Furthermore, previous studies demonstrated a decrease of the peak alpha frequency with increasing age and anesthetic concentration possibly resulting in a peak frequency beyond the classic alpha range. (See, e.g., Reference 7). Visual inspection of the frontal alpha band might therefore prove challenging in certain populations or intraoperative situations. (See, e.g., References 9 and 23).
Thus, it may be beneficial to provide an exemplary system, method, and computer-accessible medium for visualization and analysis of electroencephalogram oscillations in the alpha band which can overcome at least some of the deficiencies described herein above.
An exemplary system, method and computer-accessible medium for providing an indication(s) to administer an anesthesia medication(s) to a patient(s) can include, for example, receiving electroencephalogram (“EEG”) information for the patient(s), determining a power spectra(s) of an alpha band of the patient(s) from the EEG information, and providing the indication(s) to administer the anesthesia medication(s) to the patient(s) based on a predetermined drop in the power spectra(s). The predetermined drop can be about 20%. The predetermined drop can also be about 10%, about 15%, or about 25%. An amount to assign for the predetermined drop can be received.
In certain exemplary embodiments of the present disclosure, a baseline power spectra for the patient(s) can be determined. The baseline power spectra can be determined over a predetermined time series, which can be an approximate time of a medical procedure to be performed on the patient(s). The predetermined drop can be determined based on the baseline power spectra. The predetermined drop can be determined based on a rate of a drop in the power spectra(s) over time. The predetermined drop can be determined using a machine learning procedure(s), which can be a convolutional neural network.
In further exemplary embodiments of the present disclosure, a first derivative power spectra can be determined based on the alpha band, and the indication(s) to administer the anesthesia medication(s) to the patient(s) can be provided based on a further predetermined drop in the first derivative power spectra. A signal strength of the power spectra(s) can be determined, and the first derivative power spectra can be determined if the signal strength is below a threshold value. The threshold value can be received from a user(s). A finite difference approximation of the first derivative power spectra can be determined. A peak(s) in the power spectra(s) can be automatically determined. The peak(s) can be automatically determined using a linear regression procedure. A spectral property(ies) in EEG segments in the EEG information can be determined.
Additionally, exemplary system, method and computer-accessible medium for providing an indication(s) to titrate a sedation medication(s) for a patient(s) can include, for example, receiving electroencephalogram (“EEG”) information for the patient(s), determining a power spectra(s) of an alpha band of the patient(s) from the EEG information, and providing the indication(s) to titrate the sedation medication(s) for the patient(s) based on a predetermined drop in the power spectra(s). The predetermined drop can be about 20%. The predetermined drop can also be about 10%, about 15%, or about 25%. Other drop indications are possible according to various exemplary embodiments of the present disclosure. An amount to assign for the predetermined drop can be received.
In additional exemplary embodiments of the present disclosure, a baseline power spectra for the patient(s) can be determined. The baseline power spectra can be determined over a predetermined time series, which can be an approximate time of a medical procedure to be performed on the patient(s). The predetermined drop can be determined based on the baseline power spectra. The predetermined drop can be determined based on a rate of a drop in the power spectra(s) over time. The predetermined drop can be determined using a machine learning procedure(s), which can be a convolutional neural network.
In further exemplary embodiments of the present disclosure, a first derivative power spectra can be determined based on the alpha band, and the indication(s) to titrate the sedation medication(s) for the patient(s) can be provided based on a further predetermined drop in the first derivative power spectra. A signal strength of the power spectra(s) can be determined, and the first derivative power spectra can be determined if the signal strength is below a threshold value. The threshold value can be received from a user(s). A finite difference approximation of the first derivative power spectra can be determined. A peak(s) in the power spectra(s) can be automatically determined. The peak(s) can be automatically determined using a linear regression procedure. A spectral property(ies) in EEG segments in the EEG information can be determined.
These and other objects, features and advantages of the exemplary embodiments of the present disclosure will become apparent upon reading the following detailed description of the exemplary embodiments of the present disclosure, when taken in conjunction with the appended claims.
Further objects, features and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying Figures showing illustrative embodiments of the present disclosure, in which:
Throughout the drawings, the same reference numerals and characters, unless otherwise stated, are used to denote like features, elements, components or portions of the illustrated embodiments. Moreover, while the present disclosure will now be described in detail with reference to the figures, it is done so in connection with the illustrative embodiments and is not limited by the particular embodiments illustrated in the figures and the appended claims.
The exemplary system, method and computer-accessible medium, according to an exemplary embodiment of the present disclosure, was used to analyze EEG records from 180 patients undergoing non-cardiac, non-neurologic surgery under general anesthesia. For EEG recording, either a Bispectral Index (“BIS” with a sampling rate of 128/s) or Entropy (GE Healthcare, Helsinki, Finland, with a sampling rate: 100/s) anesthetic depth monitor was used. To ensure comparability, raw EEG from the BIS was resampled to about 100 Hz (plus or minus about 10%). For the exemplary analysis, ten seconds of artefact-free, non-burst-suppression EEG, were used. To exclude the influence of surgical stimulation, EEG data recorded two to five minutes prior to surgical incision was selected.
The power spectrum of the EEG in a double-logarithmic presentation can coarsely follow a 1/fk distribution. The k-coefficient can lie around k=1 at wakeful eyes open or eyes closed conditions, and can decrease to around k=2 during unconscious conditions with propofol or xenon. (See, e.g., Reference 24). The EEG power spectrum can include a 1/f background component and additional oscillatory activity on top thereof. (See, e.g., References 24 and 25).
Differentiation can function as a ‘whitening’ filter on signals with a 1/f spectral distribution. The exemplary discrete-time differentiation approach can compensate for the 1/fk low pass characteristic of the EEG. (See, e.g.,
For the exemplary analyses, the finite difference sequence (“diffEEG”) of each of the 10 s EEG episodes was obtained by using the MATLAB R2017a (The MathWorks Inc., Natick, Mass.) diff function. For a given time series X=[x(t1), x(t2), . . . , x(tn)] of n samples, its finite difference sequence X′=[x(t2)−x(t1), . . . , x(tn)−x(tn−1)] can include n−1 samples.
The power spectral density (“PSD”) was determined using Welch's power spectral density estimate for the 10 s EEG episodes as well as for the diffEEG of these episodes (“diffPSD”). MATLAB R2017a (The MathWorks Inc., Natick, Mass.) pwelch function (e.g., default settings and NFFT=128) was utilized. A finite difference sequence is a discrete-time approximation of the first derivative dx(t)/dt of a signal x(t).
For the automated peak detection, a linear regression procedure was used for the PSD, and a mean and standard deviation approach was used for the diffPSD. The first procedure was to calculate the PSD and diffPSD for the 10 s EEG episode of each patient.
For peak detection in the PSD, the linear fit of the PSD was calculated in a logarithmic scale using the MATLAB polyfit function. The range for calculation of the fit was limited to frequencies below about 30 Hz (plus or minus about 10%). The classical alpha range from 8-12 Hz, or the extended alpha range from 7-17 Hz, was ignored for fitting, because peaks in this range can influence the fit. (See. e.g., References 7 and 10. The influence of the choice of the alpha range on the peak detection was evaluated by a stepwise increase on the alpha range to be excluded. In order to evaluate the influence of the power in the delta range on the fit, and consequently on the peak detection, the frequencies from about 4 Hz downwards (plus or minus about 10%) were excluded in a stepwise manner.
The polyfit function can also return, for example, a 95% prediction interval, and the occurrence of a peak was defined as at least one value in the classical or extended alpha range of the PSD being above the limits of the prediction interval.
For the diffPSD, the mean power and standard deviation of the frequencies were calculated up to about 30 Hz (e.g., plus or minus up to about 10%), with the power values in the classical or extended alpha range excluded. The power in the delta range was excluded in a stepwise fashion and evaluated the influence of a stepwise increasing alpha range as well. Similar to the prediction interval for the PSD, a peak of the diff PSD if the power in the alpha range was above the calculated mean plus two times the standard deviation was defined.
In order to supplement the information regarding a peak, a parameter was added that can reflect the spectral properties of the EEG segments. The EEG was filtered to about the 0.5 to 30 Hz range (e.g., plus or minus about 10%) using the MATLAB filtfilt function and a 5th order Butterworth filter. The centroid frequency of the filtered EEG was estimated for each of the 180 cases. In order to approximate the centroid frequency the zero-crossing-rate was evaluated. (See. e.g., Reference 28. These exemplary calculations were performed with MATLAB. Using this exemplary procedure, a qualitative component was added to the ‘peak detected’ or ‘peak not detected’ decision.
The oscillatory alpha power, defined as the difference between the maximal power in the defined alpha range and the (i) upper bound of the prediction interval of the linear regression PSD or (ii) the mean and 2-fold standard deviation diffPSD, was calculated.
The number of alpha peaks detected by PSD and diffPSD including the delta range was calculated, and the calculation was repeated excluding the delta range. Additionally, cases in which the gradual exclusion of the delta range influenced the peak detection were identified. These cases were classified as ‘mixed’. To evaluate the influence of the alpha range on peak detection, the alpha range was dynamically extended from about 12 Hz (e.g., plus or minus up to about 10%) to 17 Hz (e.g., plus or minus up to about 10%).
The centroid frequencies in the groups ‘no peak’, ‘mixed’, and ‘peak’ for automated detection using the Mann-Whitney U test were compared, and the area under the curve (“AUC”) with 95% confidence intervals were derived from 10 k-fold bootstrapping as effect size. A MATLAB-based MES toolbox was utilized. (See, e.g., Reference 30). The AUC can be used to evaluate the strength of an effect and helps to balance out unclear results derived using the p-value alone. (See, e.g., Reference 31).
Three exemplary cases that highlight the capability of the exemplary system, method, and computer-accessible medium to highlight the alpha peak oscillations on a monitor screen without running into the scaling issues. (See, e.g., Reference 20). The data of three cases that were recorded from patients included in a study previously published. (See, e.g., Reference 5). The EEG was originally recorded with 250 Hz using a SEDLine Legacy device. Prior to processing, band-pass filters were applied to the EEG to a range from 0.5 to 47 Hz (e.g., 5th order Butterworth, MATLAB filtfilt), followed by a downsampling to 125 Hz. The density spectral array (“DSA”) was constructed by calculating the PSD (e.g., Welch's method, MATLAB pwelch) for 10 s of EEG with a one second shift and a frequency resolution of 0.244 Hz.
The analyses of the PSD and diffPSD indicated a more robust behavior of the diffPSD approach for automated peak detection that was not dependent on the range of excluded frequencies in the delta-range. The graphs shown in
No significant difference in the diffPSD analyses were observed. For the classical alpha band excluded, the number of ‘no peaks’ was 13 (e.g., with 0.78-3.91 Hz) vs. 12 without the range (e.g., p=1; Chi-Square=0,
Further, a lower number of patients with a ‘mixed’ result in the diffPSD group was found. For example, whether a peak was detected or not, was independent of the stepwise procedure of excluding the frequencies. This result can indicate that the diffPSD approach may not be influenced by the choice of including or excluding the delta range for alpha peak detection. 11 ‘no peaks’, 26 ‘mixed’, and 143 ‘peaks’ were located when using the classical alpha range and the PSD approach and 12 ‘no peaks’, 1 ‘mixed’ and 167 ‘peaks’ when using diffPSD (e.g., p<0.001; Chi-Square=26.40). For the extended alpha range it was 5/31/144 PSD vs. 5/0/175 diffPSD (e.g., p<0.001; Chi-Square=34.01).
Significantly different centroid frequencies were found for the ‘peak’, ‘mixed’ peak, or ‘no peak’ decisions for both the exemplary PSD approaches (e.g., Kruskal-Wallis: p<0.001; Chi-square: 24.48) and the exemplary diffPSD approach (e.g., p=0.001; Chi-square: 14.41) when excluding the classical alpha range. For the exemplary PSD approach, the median centroid frequencies were 15.3 Hz (e.g., IQR: 2.3 Hz) for ‘no peak’, 13.9 (1.9) Hz for ‘mixed’, and 12.5 (1.8) Hz for ‘peak’. Consequently, post-hoc analysis revealed a significant difference between the ‘peak’ and ‘mixed peak’ (e.g., p<0.001) as well as ‘peak’ and ‘no peak’ (e.g., p=0.001) group. There was no significant difference between the ‘mixed peak’ and ‘no peak’ patients (e.g., p=0.498). For the exemplary diffPSD, the median frequencies (e.g., and IQR) were 15.6 (3.7) Hz for the ‘no peak’, 14.6 Hz for the one ‘mixed’ case and 12.7 (1.8) Hz for the ‘peak’ cases. Because only one case with a ‘mixed peak’ was observed, no post hoc analyses was performed, and the Mann-Whitney U test was presented together with the AUC for the comparison ‘no peak’ vs. ‘peak’. The centroid frequency was significantly higher in the ‘no peak’ cases (e.g., p<0.001) and the AUC indicated a strong effect AUC=0.81 [0.64 0.95].
For the exemplary analyses, the ‘delta range’ and ‘classical alpha’ excluded setting was used. A significant difference was observed between the alpha-oscillatory power in the exemplary PSD approach (e.g., median: 3.93 dB, IQR: 4.22 dB) and the diffPSD approach (e.g., median: 5.98 dB, IQR: 4.22 dB) as depicted by the AUC=0.64 and the 95% confidence interval from 0.58 to 0.70.
The exemplary graphs in
The exemplary diffEEG approach resulted in a more robust automated peak detection because the performance of diffPSD was not dependent on the range of excluded frequencies in the delta-range. Furthermore, the exemplary cases showed an optimized visualization of oscillatory alpha activity in the DSA and demonstrated the ability of the exemplary diffPSD to detect subtler alpha peaks than the exemplary PSD approach. To analyze these exemplary approaches, an interventional clinical trial was initiated, which investigated the influence of intraoperative frontal alpha maximization on patient outcome. (See, e.g., Reference 19). During general anesthesia with common substances like sevoflurane or propofol, EEG patterns with dominant oscillations in the delta and alpha frequency develop that give way to delta-dominant rhythms and ultimately EEG burst suppression. (See, e.g., References 23, 32, and 33). The state with alpha and delta rhythms can present a level of adequate anesthesia with thalamocortical oscillations in an idling state. (See, e.g., References 13, 23, and 32). Identification of strong delta oscillations in the raw EEG and the DSA can be straightforward since the DSA can present the delta oscillations in warmest colors because they can be the dominant frequency in the EEG. Strong oscillatory activity in the alpha range can be more difficult to track, especially when volatiles can be used as a maintenance anesthetic. These volatile anesthetics cause an increase in theta activity as well. (See, e.g., Reference 32). Because the exemplary system, method, and computer-accessible medium can be utilized to identify the highest dominant oscillatory activity, it can be beneficial for monitoring the current composition of brain electrical activity by means of the EEG.
The alpha oscillation can also serve as a marker for adequate analgesia management, because noxious stimulation can lead to a decrease in alpha power and bicoherence. (See, e.g., References 15 and 17). At the same time, age and/or cognitive impairments can change the characteristics of perioperatively detected alpha oscillations. (See, e.g., References 9, 23, and 34). For example, differences in oscillatory characteristics can help to evaluate the functional instead of the chronological age of the patient. (See, e.g., Reference 35). This correlation of frontal alpha oscillations with cognitive performance was not only shown in the perioperative setting, but also in the field of neurodegenerative diseases. (See, e.g., References 36 and 37). Therefore, the application of the exemplary diffPSD approach can be useful to diagnose dementia syndromes and to monitor disease progress. Other exemplary approaches for (alpha-) peak detection exist, for example, the frequently used linear regression. (See, e.g., References 7 and 10). The Fitting Oscillations & One-Over F (“FOOOF”) procedure for instance could help to identify oscillating components (See, e.g., Reference 25), but it needs significant computation. Thus, simpler differentiation procedures can be more usable and implementable to real-time monitoring systems. Furthermore, the centroid frequencies were calculated. These were significantly higher in the PSDs categorized as “no peak detected”. Therefore, the calculation of centroid frequency can be an additional exemplary parameter to assess the EEG and a validation tool for detected alpha peaks.
The exemplary system, method and computer-accessible medium, according to an exemplary embodiment of the present disclosure, can be used to provide an indication to a medical professional (e.g., an anesthesiologist or nurse anesthetist) that a drop in the power spectra of the patient has been detected. The drop can be based on the normal alpha band for the patient, or the first derivative of the alpha band of the patient. For certain patients, for example, the signal from the normal alpha band can be strong enough to determine a power drop, and the indication can be provided based on this drop. However, in certain exemplary cases, the signal from the normal alpha band may not be strong enough. Thus, according to the exemplary embodiment of the present disclosure, the first derivative of the alpha band can be determined, and the exemplary indication can be provided based on the drop in the power spectra of the first derivative.
The exemplary indication provided to the medical professional can include an alarm or any other indication based on a predetermined drop in the power spectra. The exemplary alarm or exemplary indication can be visual, tactile and/or auditory, and can indicate to the medical professional that additional anesthesia medication should be provided to the patient. The predetermined drop can be set by the medical professional for each patient, or it can be fixed regardless of the patient. In some exemplary embodiments of the present disclosure, the predetermined drop can be about a 10% drop, a 15% drop, a 20% drop, a 25% drop, a drop therebetween, and/or any other suitable drop determined to be indicative of requiring additional anesthesia medication for the patient. All exemplary drops can be approximate, can vary, for example, by up to 30% of the value of the predetermined drop.
The exemplary system, method and computer-accessible medium can determine a baseline power spectra for the patient over a predetermined time series, which can be based on the approximate time of the medical procedure being performed on the patient. Once a baseline is determined, the predetermined drop can be based on the determined baseline. The baseline can also be obtained by taken initial measurements immediately before or after the administering of the anesthesia medication, and the drop can be determined based on this baseline. Additional, factors that can determine the exemplary drop can be the rate of the drop over time. For example, in one exemplary embodiment of the present disclosure, an indication may not be provided if there is a sudden drop in the power spectra, as such a sudden drop can be followed by an immediate increase. Thus, in such exemplary embodiment, if a sudden drop is detected, then the exemplary system, method and computer-accessible medium can wait a predetermined amount of time to determine if the power spectra increases before providing the indication. If the spectra does not increase in the predetermined amount of the time, then the indication can be provided. Additionally, if the drop occurs slowly over time, in a further exemplary embodiments of the present disclosure, then the indication can be provided immediately upon the detection of the predetermined amount of the drop.
Further, the exemplary system, method and computer-accessible medium, according to an exemplary embodiment of the present disclosure, can incorporate various machine learning procedures, such as neural networks (e.g., convolutional neural networks (“CNN”)), which can adjust the predetermined drop based on various patient factors. For example, an exemplary CNN can be used to analyze prior patient data and compare it to the date of the current patient. The exemplary system, method and computer-accessible medium, according to an exemplary embodiment of the present disclosure, can then provide a recommendation for the predetermined exemplary drop for the particular patient. Additionally, the exemplary system, method and computer-accessible medium, according to an exemplary embodiment of the present disclosure, can use the exemplary CNN to analyze and recommend potential anesthesia medication treatments plans (e.g., whether to increase or decrease certain types of anesthesia medication). Alternatively or in addition, the exemplary system, method and computer-accessible medium can, e.g., interface with an exemplary system for administering anesthesia, and can automatically increase or decrease the anesthesia medication provided to the patient based on the analysis of the alpha band or the first derivative of the alpha band.
Medium for Sedation A feature common to patients admitted for intensive care can be the large sedation requirements necessary for synchronization with mechanical ventilation. During a pandemic, hospitals face critical shortages of many supplies including medications, innovative attempts to optimize care and manage resources without compromising patient safety are necessary.
Neurologic manifestations, including encephalopathy, can be under-recognized in ICU patients, and may result in an over-use of medications. During the height of the COVID-19 pandemic, it was determined that the most critically ill patients (e.g., 86%) receiving high dose sedation and/or neuromuscular blocking agents for ventilator synchrony during COVID infection exhibited patterns consistent with (i) low alpha power and first-derivative of alpha power, (ii) low total EEG power, and (iii) attenuated and discontinuous EEG patterns consistent with diffuse cerebral dysfunction and/or over-sedation. In the rare patients that did not exhibit discontinuous EEG, a more irregular EEG pattern (e.g., permutation entropy) was observed than might be expected based on the patient's age. When this information was analyzed, a reduction in sedative and analgesic requirements followed in 79% of patients without compromising patient care.
The exemplary system, method, and computer-accessible medium, according to an exemplary embodiment of the present disclosure, as described herein, can be used to determine how the frontal EEG in mechanically ventilated COVID+ patients can be utilized for titration of sedative medications. Exemplary sedative medications can include, but are not limited to, (i) Chloral hydrate, (ii) Midazolam, (iii) Pentobarbital, (iv) Fentanyl, (v) Ketamine, (vi) Precedex, (vii) Propofol, and (viii) Nitrous oxide.
Thirty patients admitted to intensive care units receiving mechanical ventilation for respiratory failure secondary to SARS-CoV-2 infection were included. Adhesive EEG electrodes (e.g., abbreviated montage—F1/2, F7/8, Fz) were placed over the forehead and expert EEG interpretation was provided to aid the ICU team in pharmacologic decision-making. Dose reductions of sedative, analgesic, and/or neuromuscular blocking agents within 24 hours of initiating frontal EEG monitoring were determined.
The majority of the EEG records demonstrated varying degrees of discontinuous, low-voltage activity consistent with high amounts of sedating medication. After sharing this information with the ICU providers, within 24 hours, most patients had significantly reduced sedation regimens.
Neurologic complications while receiving critical care, can delay extubation and can increase ICU stays. Managing ventilation synchrony in severely affected COVID+ patients can include an escalation of sedatives and/or neuromuscular blocking agents. In order to prevent over-use of medications already in critically short supply, an automatic analysis of frontal EEG patterns, using the exemplary system, method, and computer-accessible medium, can provide recommendations for pharmacologic decision-making.
As shown in
Further, the exemplary processing arrangement 1505 can be provided with or include an input/output ports 1535, which can include, for example a wired network, a wireless network, the internet, an intranet, a data collection probe, a sensor, etc. As shown in
The foregoing merely illustrates the principles of the disclosure. Various modifications and alterations to the described embodiments will be apparent to those skilled in the art in view of the teachings herein. It will thus be appreciated that those skilled in the art will be able to devise numerous systems, arrangements, and procedures which, although not explicitly shown or described herein, embody the principles of the disclosure and can be thus within the spirit and scope of the disclosure. Various different exemplary embodiments can be used together with one another, as well as interchangeably therewith, as should be understood by those having ordinary skill in the art. In addition, certain terms used in the present disclosure, including the specification, drawings and claims thereof, can be used synonymously in certain instances, including, but not limited to, for example, data and information. It should be understood that, while these words, and/or other words that can be synonymous to one another, can be used synonymously herein, that there can be instances when such words can be intended to not be used synonymously. Further, to the extent that the prior art knowledge has not been explicitly incorporated by reference herein above, it is explicitly incorporated herein in its entirety. All publications referenced are incorporated herein by reference in their entireties.
The following references are hereby incorporated by reference in their entireties.
This application relates to and claims priority from U.S. Patent Application No. 62/925,650, filed on Oct. 24, 2019, the entire disclosure of which is incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 62925650 | Oct 2019 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US2020/057370 | Oct 2020 | US |
| Child | 17728310 | US |
