The present disclosure relates generally to hemodynamic monitoring, and in particular, to detecting and predicting nociception in a patient using monitored hemodynamic data. Nociception is the process in which nerve endings called nociceptors detect noxious stimuli and send a signal to the central nervous system which is interpreted as pain. Noxious insult initiates a “sharp” signal from the source of the insult. Locally, nociception initiates an inflammation response. The signal then travels through neurons to the spinal column where a muscle reflex is triggered. The signal continues to the brain, where, upon reaching the lower brain, the nociception signal triggers a sympathetic nervous system response. Nociception can cause a sympathetic nervous system response without reaching consciousness or before reaching consciousness; thus, an unconscious patient in surgery or in intensive care can experience pain. To prevent a patient from awaking out of surgery or intensive care in pain, medical workers administer analgesics to the patient before and/or during surgery and at various times in the intensive care. However, knowing the amount of analgesic to administer can be difficult as pain thresholds and tolerances vary from patient to patient, and the patient is unable to verbally communicate or signal feedback while unconscious. Administering too little analgesic to the patient during surgery can result in the patient awaking in pain after the surgery. Administering too much analgesic to the patient during surgery can result in the patient experiencing nausea, drowsiness, impaired thinking skills, and impaired function.
In view of the negative consequences of administering too little analgesic to the patient and the negative consequences of administering too much analgesic to the patient, a solution is needed that will allow medical workers the ability to detect or predict nociception of an unconscious patient during surgery. Accurately detecting or predicting nociception of a patient during surgery can help medical workers know the appropriate amount of analgesic to administer to the patient so that the patient does not awake from surgery with significant pain, without providing too much analgesic to the patient.
In one example, a method for monitoring arterial pressure of a patient and detecting nociception of the patient, includes receiving, by a hemodynamic monitor, sensed hemodynamic data representative of an arterial pressure waveform of the patient from a hemodynamic sensor. The method further includes performing, by a hardware processor of the hemodynamic monitor, waveform analysis of the sensed hemodynamic data to calculate a plurality of signal measures of the sensed hemodynamic data. The hardware processor of the hemodynamic monitor organizes the plurality of signal measures into pairs of signal measures. The hardware processor of the hemodynamic monitor measures a cross-correlational association of each of the pairs of signal measures. A measured cross-correlational association of each of the pairs of signal measures is outputted to a display. The measured cross-correlational association of each of the pairs of signal measures is monitored for an increase above a predetermined threshold in the measured cross-correlational association of at least one of the pairs of signal measures. The hemodynamic monitor sends an alert to medical personnel of a nociception event of the patient when the measured cross-correlational associate of at least one of the pairs of signal measures increases above the predetermined threshold.
In another example, a method for monitoring arterial pressure of a patient and detecting nociception of the patient includes receiving, by a hemodynamic monitor, sensed hemodynamic data representative of an arterial pressure waveform of the patient. A hardware processor of the hemodynamic monitor performs waveform analysis of the sensed hemodynamic data to calculate a plurality of signal measures of the sensed hemodynamic data. The hardware processor of the hemodynamic monitor calculates cross-correlational association between each of the signal measures. The cross-correlational association measurements are outputted to a user interface. The cross-correlational association measurements are monitored for bursts in the cross-correlational association measurements. A nociception event of the patient is detected when a burst in one or more of the cross-correlational association is outputted to the user interface.
In another example, a system for monitoring arterial pressure of a patient and providing a warning to medical personnel of nociception of the patient includes a hemodynamic sensor that produces hemodynamic data representative of an arterial pressure waveform of the patient. The system further includes a system memory that stores nociception detection software code and a user interface that includes a sensory alarm that provides a sensory signal to warn the medical personnel of a nociception event of the patient. A hardware processor is configured to execute the nociception detection software code to perform waveform analysis of the hemodynamic data to determine a plurality of signal measures. The plurality of signal measures is organized into pairs of signal measures and a cross-correlational association of each of the pairs of signal measures is measured. Measurements of cross-correlational association of the pairs of signal measures are outputted to the user interface. The measurements of cross-correlational association of the pairs of signal measures are monitored for bursts in the measurements of cross-correlational association of the pairs of signal measures. A sensory alarm of the user interface is invoked, indicating a nociception event in response to a burst in one or more of the measurements of cross-correlational association of the pairs of signal measures.
As described herein, a hemodynamic monitoring system senses hemodynamic data from a patient and uses the hemodynamic data to detect whether the patient is experiencing a current nociception event. The hemodynamic monitoring system is able to detect a current nociception event from the hemodynamic data of the patient by deriving signal measures from the hemodynamic data, organizing the signal measures into pairs, calculating a cross-correlational association for each of the pairs of signal measures, and monitoring the cross-correlational association for each of the pairs of signal measures. When a burst in value occurs in at least one of the cross-correlational association of the pairs of signal measures, the hemodynamic monitoring system can raise a signal or an alarm to medical workers to alert the medical workers that the patient is experiencing a current nociception event. After receiving the signal, the medical workers can administer an analgesic to the patient to mitigate the nociception event. The hemodynamic monitoring system is described in detail below with reference to
As further described below, hemodynamic monitor 10 includes one or more processors and computer-readable memory that stores nociception detection software code which is executable to produce a score representing a probability of a present (i.e., current) nociception event for a patient. Hemodynamic monitor 10 can receive sensed hemodynamic data representative of an arterial pressure waveform of the patient, such as via one or more hemodynamic sensors connected to hemodynamic monitor 10 via I/O connectors 14. Hemodynamic monitor 10 executes the nociception detection software code to obtain, using the received hemodynamic data, a plurality of signal measures, which can include one or more vital sign parameters characterizing vital sign data of the patient as is further described below.
As illustrated in
As illustrated in
In operation, a column of fluid (e.g., saline solution) is introduced from a fluid source (e.g., a saline bag) through hemodynamic sensor 16 via fluid input port 20 to catheter-side fluid port 22 toward the catheter inserted into the patient. Arterial pressure is communicated through the fluid column to pressure sensors located within housing 16 which sense the pressure of the fluid column. Hemodynamic sensor 16 translates the sensed pressure of the fluid column to an electrical signal via the pressure transducers and outputs the corresponding electrical signal to hemodynamic monitor 10 (
In operation, the pressure controller continually adjusts pressure within the finger cuff to maintain a constant volume of the arteries in the finger (i.e., the unloaded volume of the arteries) as measured via the optical transmitter and optical receiver of inflatable finger cuff 28. The pressure applied by the pressure controller to continuously maintain the unloaded volume is representative of the blood pressure in the finger and is communicated by the pressure controller to hemodynamic monitor 10 shown in
As illustrated in
Hemodynamic monitor 10, as described above with respect to
As illustrated in
Display 12 provides user interface 54, which includes control elements 56 that enable user interaction with hemodynamic monitor 10 and/or other components of hemodynamic monitoring system 32. User interface 54, as illustrated in
Hemodynamic sensor 34 can be attached to patient 36 to sense hemodynamic data representative of the arterial pressure waveform of patient 36. Hemodynamic sensor 34 is operatively connected to hemodynamic monitor 10 (e.g., electrically and/or communicatively connected via wired or wireless connection, or both) to provide the sensed hemodynamic data to hemodynamic monitor 10. In some examples, hemodynamic sensor 34 provides the hemodynamic data representative of the arterial pressure waveform of patient 36 to hemodynamic monitor 10 as an analog signal, which is converted by ADC 44 to digital hemodynamic data representative of the arterial pressure waveform. In other examples, hemodynamic sensor 34 can provide the sensed hemodynamic data to hemodynamic monitor 10 in digital form, in which case hemodynamic monitor 10 may not include or utilize ADC 44. In yet other examples, hemodynamic sensor 34 can provide the hemodynamic data representative of the arterial pressure waveform of patient 36 to hemodynamic monitor 10 as an analog signal, which is analyzed in its analog form by hemodynamic monitor 10.
Hemodynamic sensor 34 can be a non-invasive or minimally invasive sensor attached to patient 36. For instance, hemodynamic sensor 34 can take the form of minimally invasive hemodynamic sensor 16 (
In certain examples, hemodynamic sensor 34 can be configured to sense an arterial pressure of patient 36 in a minimally invasive manner. For instance, hemodynamic sensor 34 can be attached to patient 36 via a radial arterial catheter inserted into an arm of patient 36. In other examples, hemodynamic sensor 34 can be attached to patient 36 via a femoral arterial catheter inserted into a leg of patient 36. Such minimally invasive techniques can similarly enable hemodynamic sensor 34 to provide substantially continuous beat-to-beat monitoring of the arterial pressure of patient 36 over an extended period of time, such as minutes or hours.
System processor 40 is a hardware processor configured to execute nociception software code 48, which implements first module 50, second module 51, third module 52, and fourth module 53 to produce a nociception score representing a probability of a current nociception event for patient 36. Examples of system processor 40 can include any one or more of a microprocessor, a controller, a digital signal processor (DSP), an application specific integrated circuit (ASIC), a field-programmable gate array (FPGA), or other equivalent discrete or integrated logic circuitry.
System memory 42 can be configured to store information within hemodynamic monitor 10 during operation. System memory 42, in some examples, is described as computer-readable storage media. In some examples, a computer-readable storage medium can include a non-transitory medium. The term “non-transitory” can indicate that the storage medium is not embodied in a carrier wave or a propagated signal. In certain examples, a non-transitory storage medium can store data that can, over time, change (e.g., in RAM or cache). System memory 42 can include volatile and non-volatile computer-readable memories. Examples of volatile memories can include random access memories (RAM), dynamic random access memories (DRAM), static random access memories (SRAM), and other forms of volatile memories. Examples of non-volatile memories can include, e.g., magnetic hard discs, optical discs, flash memories, or forms of electrically programmable memories (EPROM) or electrically erasable and programmable (EEPROM) memories.
Display 12 can be a liquid crystal display (LCD), a light-emitting diode (LED) display, an organic light-emitting diode (OLED) display, or other display device suitable for providing information to users in graphical form. User interface 54 can include graphical and/or physical control elements that enable user input to interact with hemodynamic monitor 10 and/or other components of hemodynamic monitoring system 32. In some examples, user interface 54 can take the form of a graphical user interface (GUI) that presents graphical control elements presented at, e.g., a touch-sensitive and/or presence sensitive display screen of display 12. In such examples, user input can be received in the form of gesture input, such as touch gestures, scroll gestures, zoom gestures, or other gesture input. In certain examples, user interface 54 can take the form of and/or include physical control elements, such as a physical buttons, keys, knobs, or other physical control elements configured to receive user input to interact with components of hemodynamic monitoring system 32. User interface 54 can include a speaker that allows hemodynamic monitor 10 the ability to generate an audible alarm.
In operation, hemodynamic sensor 34 senses hemodynamic data representative of an arterial pressure waveform of patient 36. Hemodynamic sensor 34 provides the hemodynamic data (e.g., as analog sensor data), to hemodynamic monitor 10. ADC 44 converts the analog hemodynamic data to digital hemodynamic data representative of the arterial pressure waveform of patient 36.
System processor 40 executes nociception software code 48 to determine, using the received hemodynamic data, a nociception detection score representing a probability of a current nociception event for patient 36. For instance, system processor 40 can execute first module 50 to perform waveform analysis of the hemodynamic data to determine the plurality of signal measures. System processor 40 executes second module 51 to organize the plurality of signal measures into pairs of signal measures. System processor 40 executes third module 52 to measure or calculate the cross-correlational association of each pair of the signal measures. System processor 40 then executes fourth module 53 to monitor the measured cross-correlational association of each of the pairs of signal measures over time. As fourth module 53 monitors the measured cross-correlational association of each of the pairs of signal measures, fourth module 53 can output a plot of the measured cross-correlational association of each of the pairs of signal measures over time to display 12 to allow medical worker 38 to view the values of the measured cross-correlational association of each of the pairs of signal measures. If fourth module 53 detects a burst (i.e., an increase above a predetermined threshold) in the measured cross-correlational association of at least one of the pairs of signal measures, system processor 40 invokes sensory alarm 58 of user interface 54 to send a sensory signal to alert medical worker 38 that patient 36 is presently experiencing a current nociception event. Medical worker 38 can respond to the warning by administering an analgesic to patient 36, or administering any other form of treatment to patient 36, to mitigate the current nociception event. How first module 50 performs the waveform analysis of the hemodynamic data to determine the plurality of signal measures is discussed below in greater detail with reference to
Signal measures are extracted from each of the systolic rise phase, the systolic decay phase, and the diastolic phase from each of the individual cardiac cycles of each of the arterial pressure waveforms of patient 36 sensed by hemodynamic sensor 34. The signal measures can correspond to hemodynamic effects from each of the systolic rise phase, the systolic decay phase, and the diastolic phase from each of the individual cardiac cycles. Those hemodynamic effects can include contractility, aortic compliance, stroke volume, vascular tone, afterload, and full cardiac cycle, all of which can be impacted by the sympathetic nervous response triggered by the nociception event. The signal measures calculated or extracted by the waveform analysis include a mean, a maximum, a minimum, a duration, an area, a standard deviation, derivatives, and/or morphological measures from each of the systolic rise phase, the systolic decay phase, and the diastolic phase from each of the individual cardiac cycles. The signal measures can also include heart rate, respiratory rate, stroke volume, pulse pressure, pulse pressure variation, stroke volume variation, mean arterial pressure (MAP), systolic pressure (SYS), diastolic pressure (DIA), heart rate variability, cardiac output, peripheral resistance, vascular compliance, and/or left-ventricular contractility extracted from each of the individual cardiac cycles of each of the arterial pressure waveforms of patient 36 sensed by hemodynamic sensor 34. As noted above with reference to
where y is heart rate 62, x is systolic blood pressure 60, SD (y) is the standard deviation of heart rate 62, SD (x) is the standard deviation systolic blood pressure 60, and CCAM is the cross-correlational association measure of heart rate 62 and systolic pressure 60. The values for CCAM are then plotted over time as CCAM plots 64. Equation 1 can be applied to all other pairs of the signal measures that are extracted from each of the systolic rise phase, the systolic decay phase, the diastolic phase and the entire waveform from each of the individual cardiac cycles on
The CCAM plots 64 are monitored for bursts 66 by system processor 40 of hemodynamic monitor 10. Bursts 66 occur in CCAM plots 64 when at least one of the plots in the CCAM plots 64 increases above a predetermined threshold. The monitoring/detection of bursts 66 can be performed using a wide variety of mathematical methods, such as detection of amplitude change, change in the area under the curve of each burst 66, and/or changes in the standard deviation of each burst 66. The monitoring/detection of bursts 66 can also be performed with more complex time and frequency domain methods, such as Fast Fourier transform (FFT) based methods and wavelet-based methods. In one example, the predetermined threshold is 50% greater than a moving average of the CCAM plots 64. Thus, in this example, a burst 66 occurs when at least one of the CCAM plots 64 is at least 50% greater than the moving average of the CCAM plots 64 of the pairs of signal measures. If a burst 66 occurs in CCAM for systolic blood pressure 60 and heart rate 62, as shown in the CCAM plots 64 of
While
While the example of
In other examples, hemodynamic monitor 10 can be programmed to calculate a generalized cross correlation (GGC) between a pair of signal measures before calculating the CCAM of the pair of signal measures. Hemodynamic monitor 10 can calculate the GGC between the pair of signal measures by first measuring a ten second window for both a first signal measure (such as systolic blood pressure) and a second signal measure (such as heart rate), represented by the equation below:
where m is a time window measured in seconds, x is the first signal measure (such as systolic blood pressure), y is the second signal measure (such as heart rate), t is a time shift, and GGC is the generalized cross correlation between the first signal measure and the second signal measure. As shown in Equation 2, the first signal measure and the second signal measure are both interpolated and resampled within a ten second window at one second intervals. The ten second window of the first signal measure is cross-correlated with the ten second window of the second signal measure. The time shift t is applied to one of the signal measures with the cross-correlation repeated to achieve a pattern of cross-correlations that include a maximum cross-correlation between the first signal measure and the second signal measure. The maximum cross-correlation (or maximum GGC) indicates the best time delay between the first signal measure and the second signal measure to achieve the highest cross-correlation between the first signal measure and the second signal measure. If the highest cross-correlation is significant at a p-value (the probability that the null hypothesis is true) that is less than 0.05 or any other threshold, Equation 1 can then be applied to the first signal measure and the second signal measure at the best time delay to obtain the CCAM for the first signal measure and the second signal measure. Equation 2 and Equation 1 can be applied to other pairs of signal measures to derive additional plots that are all congregated together as CCAM plots 64. While the example above discloses a time window m of ten seconds, the time window m can be less than ten seconds or greater than ten seconds. Also, while the example above discloses a time shift t of zero to five seconds with a resampling interval of one second, the time shift t can be of set of delays (such as zero to ten seconds in length or negative 10 to positive 10 seconds in length), and the resampling interval can be in any time increment (such as 0.1 second, 0.5 second, 1 second, or 2 seconds). For example, the resampling interval can be any value from 0.1 second to 2 seconds.
The following are non-exclusive descriptions of possible embodiments of the present invention.
A method for monitoring arterial pressure of a patient and detecting nociception of the patient, the method comprising: receiving, by a hemodynamic monitor, sensed hemodynamic data representative of an arterial pressure waveform of the patient from a hemodynamic sensor; performing, by a hardware processor of the hemodynamic monitor, waveform analysis of the sensed hemodynamic data to calculate a plurality of signal measures of the sensed hemodynamic data; organizing, by the hardware processor of the hemodynamic monitor, the plurality of signal measures into pairs of signal measures; measuring, by the hardware processor of the hemodynamic monitor, a cross-correlational association of each of the pairs of signal measures; outputting to a display a measured cross-correlational association of each of the pairs of signal measures; monitoring the measured cross-correlational association of each of the pairs of signal measures for an increase above a predetermined threshold in the measured cross-correlational association of at least one of the pairs of signal measures; and sending, by the hemodynamic monitor, an alert to medical personnel of a nociception event of the patient when the measured cross-correlational association of at least one of the pairs of signal measures increases above the predetermined threshold.
The method of the preceding paragraph can optionally include, additionally and/or alternatively, any one or more of the following features, configurations and/or additional components:
The predetermined threshold is at least 50% greater than a moving average of the measured cross-correlational association of the at least one of the pairs of signal measures.
Normalizing the measured cross-correlational association of each of the pairs of signal measures before outputting the measured cross-correlational association of each of the pairs of signal measures to the display.
The signal measures comprise hemodynamic effects from each of the systolic rise phase, the systolic decay phase, and the diastolic phase from each of the individual cardiac cycles, and wherein the hemodynamic effects comprise contractility, aortic compliance, stroke volume, vascular tone, afterload, and full cardiac cycle.
The signal measures comprise a mean, a maximum, a minimum, a duration, an area, a standard deviation, derivatives, and/or morphological measures from each of the systolic rise phase, the systolic decay phase, and the diastolic phase from each of the individual cardiac cycles.
The signal measures comprise heart rate, respiratory rate, stroke volume, pulse pressure, pulse pressure variation, stroke volume variation, mean arterial pressure (MAP), systolic pressure (SYS), diastolic pressure (DIA), heart rate variability, cardiac output, peripheral resistance, vascular compliance, and/or left-ventricular contractility extracted from each of the individual cardiac cycles.
Measuring the cross-correlational association of each of the pairs of signal measures by the hardware processor comprises: measuring a time window of data for each of the signal measures; interpolating each of the signal measures and resampling each of the signal measures at one second intervals; calculating a cross correlation value between the pair of the signal measures at a set of delays; selecting the delay that provides the highest cross correlation value; measuring a standard deviation of a first signal measure at the delay that provides the highest cross correlation value; measuring a standard deviation of a second signal measure at the delay that provides the highest cross correlation value; and calculating a ratio between the standard deviation of the first signal measure and the standard deviation of the second signal measure if the highest cross correlation value has a p-value less than 0.05.
The time window comprises ten seconds.
The time window is greater than ten seconds.
The time window is less than ten seconds.
The set of delays is from zero to ten seconds with a resampling interval of one second.
The set of delays is from negative ten to positive ten seconds with a resampling interval of 0.1 to 2 seconds.
The set of delays is from zero to five seconds with a resampling interval of 0.1 to 2 seconds.
A method for monitoring arterial pressure of a patient and detecting nociception of the patient, the method comprising: receiving, by a hemodynamic monitor, sensed hemodynamic data representative of an arterial pressure waveform of the patient; performing, by a hardware processor of the hemodynamic monitor, waveform analysis of the sensed hemodynamic data to calculate a plurality of signal measures of the sensed hemodynamic data; calculating, by the hardware processor of the hemodynamic monitor, cross-correlational association measurements between each of the signal measures; outputting to a user interface the cross-correlational association measurements; monitoring the cross-correlational association measurements for bursts in the cross-correlational association measurements; and detecting a nociception event of the patient when a burst in one or more of the cross-correlational association measurements is outputted to the user interface.
The method of the preceding paragraph can optionally include, additionally and/or alternatively, any one or more of the following features, configurations and/or additional components:
Performing waveform analysis of the sensed hemodynamic data to calculate the plurality of signal measures of the sensed hemodynamic data comprises: identifying individual cardiac cycles in the arterial pressure waveform; identifying a dicrotic notch in each of the individual cardiac cycles; identifying a systolic rise phase, a systolic decay phase, and a diastolic phase in each of the individual cardiac cycles; and extracting the plurality of signal measures from each of the systolic rise phase, the systolic decay phase, and the diastolic phase from each of the individual cardiac cycles.
The plurality of signal measures comprises hemodynamic effects from each of the systolic rise phase, the systolic decay phase, and the diastolic phase from each of the individual cardiac cycles, wherein the hemodynamic effects comprise contractility, aortic compliance, stroke volume, vascular tone, afterload, and full cardiac cycle.
The plurality of signal measures comprises a mean, a maximum, a minimum, a duration, an area, a standard deviation, derivatives, and/or morphological measures from each of the systolic rise phase, the systolic decay phase, and the diastolic phase from each of the individual cardiac cycles.
The plurality of signal measures comprises heart rate, respiratory rate, stroke volume, pulse pressure, pulse pressure variation, stroke volume variation, mean arterial pressure (MAP), systolic pressure (SYS), diastolic pressure (DIA), heart rate variability, cardiac output, peripheral resistance, vascular compliance, and/or left-ventricular contractility extracted from each of the individual cardiac cycles.
The user interface comprises at least one of a display screen and a speaker.
A system for monitoring arterial pressure of a patient and providing a warning to medical personnel of nociception of the patient, the system comprising: a hemodynamic sensor that produces hemodynamic data representative of an arterial pressure waveform of the patient; a system memory that stores nociception detection software code; a user interface that includes a sensory alarm that provides a sensory signal to warn the medical personnel of a nociception event of the patient; and a hardware processor that is configured to execute the nociception detection software code to: perform waveform analysis of the hemodynamic data to determine a plurality of signal measures; organize the plurality of signal measures into pairs of signal measures; measure a cross-correlational association of each of the pairs of signal measures; output to the user interface measurements of cross-correlational association of the pairs of signal measures; monitor the measurements of cross-correlational association of the pairs of signal measures for bursts in the measurements of cross-correlational association of the pairs of signal measures; and invoke a sensory alarm of the user interface indicating a nociception event in response to a burst in one or more of the measurements of cross-correlational association of the pairs of signal measures.
The system of the preceding paragraph can optionally include, additionally and/or alternatively, any one or more of the following features, configurations and/or additional components:
The hemodynamic sensor is a noninvasive hemodynamic sensor that is attachable to an extremity of the patient.
The hemodynamic sensor is a minimally invasive arterial catheter based hemodynamic sensor.
The hemodynamic sensor produces the hemodynamic data as an analog hemodynamic sensor signal representative of the arterial pressure waveform of the patient.
An analog-to-digital converter that converts the analog hemodynamic sensor signal to digital hemodynamic data representative of the arterial pressure waveform of the patient.
While the invention has been described with reference to an exemplary embodiment(s), it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiments disclosed, but that the invention will include all embodiments falling within the scope of the appended claims.
This application claims the benefit of International Application No. PCT/US2023/012364, filed Feb. 5, 2023, and entitled “HEMODYNAMIC MONITOR WITH NOCICEPTION DETECTION,” the disclosure of which is hereby incorporated by reference in its International Application No. PCT/US2023/012364 claims the benefit of U.S. entirety. Provisional Application No. 63/307,240, filed Feb. 7, 2022, and entitled “HEMODYNAMIC MONITOR WITH NOCICEPTION DETECTION,” the disclosure of which is hereby incorporated by reference in its entirety.
Number | Date | Country | |
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63307240 | Feb 2022 | US |
Number | Date | Country | |
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Parent | PCT/US2023/012364 | Feb 2023 | WO |
Child | 18794938 | US |