USE OF DIAPHRAGMATIC ULTRASOUND TO DETERMINE PATIENT-SPECIFIC VENTILATOR SETTINGS AND OPTIMIZE PATIENT-VENTILATOR ASYNCHRONY DETECTION ALGORITHMS
20230181851 · 2023-06-15
Inventors
- Jaap Roger Haartsen (Eindhoven, NL)
- Roberto Buizza (Eindhoven, NL)
- Joerg Sabczynski (Hamburg, DE)
- Rafael Wiemker (Hamburg, DE)
- Thomas Koehler (Hamburg, DE)
- Cornelis Petrus Hendriks (Eindhoven, NL)
- Michael Polkey (London, GB)
- Rita Priori (Eindhoven, NL)
- Nataly Wieberneit (Hamburg, DE)
- Stefan Winter (Aachen, DE)
Cpc classification
A61M16/024
HUMAN NECESSITIES
G16H20/40
PHYSICS
International classification
A61M16/00
HUMAN NECESSITIES
G16H20/40
PHYSICS
Abstract
A medical device for treating an associated patient includes an electronic processing device configured to receive ventilation waveform data during mechanical ventilation of the associated patient and to perform a patient-ventilator asynchrony monitoring method including detecting initial patient-ventilator asynchrony events during a training period of the mechanical ventilation by analysis of measurements of the associated patient acquired during the training period; training a machine learning (ML) component to analyze ventilation waveform data to detect patient-ventilator asynchrony events using the ventilation waveform data received during the training period with labels indicating the initial patient-ventilator asynchrony events; applying the patient-specific ML component to the ventilation waveform data received after the training period to detect patient-ventilator asynchrony events occurring after the training period; and a display device configured to display an indication of patient-ventilator asynchrony events detected by the applying of the patient-specific ML component.
Claims
1. A medical device for treating an associated patient, comprising: an electronic processing device configured to receive ventilation waveform data during mechanical ventilation of the associated patient and to perform a patient-ventilator asynchrony monitoring method including: detecting initial patient-ventilator asynchrony events during a training period of the mechanical ventilation by analysis of measurements of the associated patient acquired during the training period; training a machine learning (ML) component to analyze ventilation waveform data to detect patient-ventilator asynchrony events using the ventilation waveform data received during the training period with labels indicating the initial patient-ventilator asynchrony events, the trained ML component forming a patient-specific ML component that is specific to the associated patient; applying the patient-specific ML component to the ventilation waveform data received after the training period to detect patient-ventilator asynchrony events occurring after the training period; and a display device configured to display an indication of patient-ventilator asynchrony events detected by the applying of the patient-specific ML component.
2. The device of claim 1, wherein the measurements comprise diaphragmatic or lung sliding ultrasound measurements or parasternal electromyography (EMG) measurements or central venous pressure (CVP) measurements.
3. The device of claim 1, wherein the measurements comprise noninvasive measurements.
4. The device of claim 1, wherein the training period is in a range of 1 minute to 20 minutes inclusive.
5. The device of claim 1, wherein the patient-ventilator asynchrony monitoring method further includes: determining a proposed adjustment to the mechanical ventilation to reduce or eliminate the patient-ventilator asynchrony events detected by the applying of the patient-specific ML component; wherein the display device is further configured to display the proposed adjustment.
6. The device of claim 1, further comprising: a posture sensor configured to detect a posture of the associated patient as a function of time during the mechanical ventilation; wherein the training further uses posture measurements received from the posture sensor to train the patient-specific ML component to detect patient-ventilator asynchrony events by analyzing ventilation waveform data and posture measurements.
7. The device of claim 1, wherein the ML component is further trained using imaging data of the associated patient.
8. The device of claim 7, further comprising: an imaging device configured to acquire the imaging data.
9. The device of claim 1, wherein the indication of patient-ventilator asynchrony events comprises an asynchrony index; and wherein the asynchrony index is displayed on the display device.
10. The device of claim 9, wherein the patient-ventilator asynchrony monitoring method further includes: calculate the asynchrony index as a ratio of a number of asynchronous breaths of the patient in labelled waveforms over a predetermined time period and a total breath count of the patient over the predetermined time period.
11. The device of claim 1, wherein the patient-ventilator asynchrony monitoring method further includes: determining one or more optimized settings of the mechanical ventilator based on the detected patient-ventilator asynchrony events; and displaying the one or more optimized settings of the mechanical ventilator on the display device.
12. The device of claim 1, wherein the patient-ventilator asynchrony monitoring method further includes: determining one or more optimized settings of the mechanical ventilator based on received imaging data; and displaying the one or more optimized settings of the mechanical ventilator on the display device.
13. The device of claim 11, wherein the patient-ventilator asynchrony monitoring method further includes: controlling the mechanical ventilator by adjusting settings of the mechanical ventilator with the determined one or more optimized settings.
14. The device of claim 13, wherein the patient-ventilator asynchrony monitoring method further includes: tracking a progression of a patient-ventilator interaction; and predicting a future patient-ventilator asynchrony event based on the tracking.
15. A mechanical ventilation method comprising: receiving ventilation waveform data during mechanical ventilation of an associated patient; detecting initial patient-ventilator asynchrony events during a training period of the mechanical ventilation by analysis of measurements of the associated patient acquired during the training period; training a machine learning (ML) component to analyze ventilation waveform data to detect patient-ventilator asynchrony events using the ventilation waveform data received during the training period with labels indicating the initial patient-ventilator asynchrony events, the trained ML component forming a patient-specific ML component that is specific to the associated patient; applying the patient-specific ML component to the ventilation waveform data received after the training period to detect patient-ventilator asynchrony events occurring after the training period; and displaying an indication of patient-ventilator asynchrony events detected by the applying of the patient-specific ML component.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] The disclosure may take form in various components and arrangements of components, and in various steps and arrangements of steps. The drawings are only for purposes of illustrating the preferred embodiments and are not to be construed as limiting the disclosure.
[0029]
[0030]
DETAILED DESCRIPTION
[0031] As used herein, the singular form of “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. As used herein, statements that two or more parts or components are “coupled,” “connected,” or “engaged” shall mean that the parts are joined, operate, or co-act together either directly or indirectly, i.e., through one or more intermediate parts or components, so long as a link occurs. Directional phrases used herein, such as, for example and without limitation, top, bottom, left, right, upper, lower, front, back, and derivatives thereof, relate to the orientation of the elements shown in the drawings and are not limiting upon the scope of the claimed invention unless expressly recited therein. The word “comprising” or “including” does not exclude the presence of elements or steps other than those described herein and/or listed in a claim. In a device comprised of several means, several of these means may be embodied by one and the same item of hardware.
[0032] In various embodiments disclosed herein, improved patient-ventilator asynchrony monitoring is disclosed, which is noninvasive and provides continuous monitoring. In some illustrative embodiments, initial patient-ventilator asynchrony events are detected during a training period of the mechanical ventilation. This is done by analysis of second modality measurements of the patient acquired during the training period using a second modality, such as ultrasound. A machine learning (ML) component is then trained to analyze ventilation waveform data to detect patient-ventilator asynchrony events. The training uses ventilation waveform data received during the training period and labeled with the initial patient-ventilator asynchrony events from the second modality measurement analysis. The trained ML component thus forms a patient-specific NIL component that is specific to the specific patient undergoing mechanical ventilation. The patient-specific ML component is applied to the ventilation waveform data received after the training period to detect patient-ventilator asynchrony events occurring after the training period.
[0033] The training period typically corresponds to an initial period of the mechanical ventilation, for example with the ultrasound or other second modality monitoring being applied immediately after the patient is placed onto or otherwise connected to the mechanical ventilator. This is convenient as the patient is already likely to be being closely monitored during this initial period. The training period can be relatively brief, for example in a range of 1 minute to 20 minutes inclusive in some non-limiting embodiments. Additionally or alternatively, the training period can be continued until some minimum number of initial patient-ventilator asynchrony events are detected, so as to provide a sufficient number of events for training the ML component.
[0034] Since the ultrasound or other second modality patient measurements are noninvasive, the training period can advantageously be repeated if conditions of the mechanical ventilation change, in order to provide further data for update-training the ML component. For example, if the patient's physician changes the ventilation mode, or the patient's condition improves or deteriorates, then the training period can be repeated to adjust the ML component to account for those changed conditions. In another contemplated variant, a training period can be used for each of two or more different patient postures (e.g., lying down or sitting in a wheelchair) and different versions of the ML component can be trained for the different patient postures. This can be beneficial since patient-ventilator asynchrony can be patient posture-dependent.
[0035] In further variant embodiments, the system can propose ventilator setting adjustment(s) based on detected patient-ventilator asynchrony events. In further variant embodiments, the system can be operatively connected to automatically execute such ventilator setting adjustment(s).
[0036] With reference to
[0037]
[0038]
[0039] Alternatively, instead of imaging data acquired by the imaging device 15, the sensor 9 can measure measurements sensitive to patient-ventilator asynchrony (e.g., via a catheter (not shown) to measure central venous pressure (CVP), or the sensor 9 can comprise an electromyography (EMG) sensor to measure parasternal activity of abdominal muscles, an esophageal sensor, a sensor to measure EAdi, and so forth) which may be used to provide a signal indicative of the respiratory muscle activities.
[0040] With continuing reference to
[0041] The electronic controller 20 is operatively connected with one or more non-transitory storage media 26. The non-transitory storage media 26 may, by way of nonlimiting illustrative example, include one or more of a magnetic disk, RAID, or other magnetic storage medium; a solid state drive, flash drive, electronically erasable read-only memory (EEROM) or other electronic memory; an optical disk or other optical storage; various combinations thereof, or so forth; and may be for example a network storage, an internal hard drive of the ventilation assistance device 18, various combinations thereof, or so forth. It is to be understood that any reference to a non-transitory medium or media 26 herein is to be broadly construed as encompassing a single medium or multiple media of the same or different types. Likewise, the electronic controller 20 may be embodied as a single electronic processor or as two or more electronic processors. The non-transitory storage media 26 stores instructions executable by the at least one electronic controller 20. The instructions include instructions to generate a graphical user interface (GUI) 28 for display on the display device 24.
[0042] In some embodiments, a cloud server computer 30 (shown in
[0043] As described herein, the patient-ventilator asynchrony monitoring method 100 can be performed by the electronic processing device 18, or can be performed by the electronic controller 13 of the mechanical ventilator 2.
[0044] With reference to
[0045] At an operation 104, second modality measurements of the associated patient are acquired during a training period using a second modality. In the illustrative example, the second modality is ultrasound and the operation 104 acquires ultrasound imaging data (e.g., B-mode, or M-mode, and so forth) of the patient is acquired using the US image acquisition device 15. The ultrasound imaging data can comprise imaging of the diaphragm of the patient P, accessory inspiratory muscles (i.e. abdominal, intercostal, etc.) of the patient P, or lung sliding of the patient P undergoing mechanical ventilation. In other embodiments, another non-invasive second modality that is sensitive to patient-ventilator asynchrony may be used, such as measurements of parasternal electromyography (EMG) activity of abdominal muscles. The imaging data can be transmitted to the cloud server 30.
[0046] At an operation 106, initial patient-ventilator asynchrony events are detected during a training period of the mechanical ventilation by analysis of the second modality measurements of the patient P, for example by analysis of diaphragm thickening or lung sliding in the case of US measurements, or analysis of EMG activity of abdominal muscles. The second modality measurements are acquired during the training period in the second modality measurement operation 104. The training period is in a range of 1 minute to 20 minutes. The patient-ventilator asynchrony event detection operation 106 is performed by the cloud server 30 or by the electronic processing device 18.
[0047] At an operation 108, a machine learning (ML) component 32 (implemented in the cloud server 30 or the mechanical ventilator 2) is trained (i.e., using a large data set of asynchrony events) to detect patient-ventilator asynchrony events using the ventilation waveform data from the ventilation waveform data acquisition operation 102 labeled with patient-ventilator asynchrony events identified in the operation 106 from the imaging data acquired during the image acquisition operation 104. For example, in some embodiments the ML component 32 is an existing algorithm for automatic detection of patient-ventilator asynchrony events with one or more thresholds or other parameters of the algorithm optimized for the patient P by the training. The ML component 32 forms a patient-specific ML component that is specific to the patient P. The training operation 108 trains the ML component 32 to analyze the ventilation waveform data that are labeled with the initial patient-ventilator asynchrony events from the initial patient-ventilator asynchrony events detection operation 106.
[0048] In some embodiments, multiple versions of the ML component 32 may be trained for different postures of the patient P. To do so, the training phase 101 is repeated with the patient in different postures (e.g., sitting, laying down) to generate labeled training data for each posture, which is used to train patient-specific and posture-specific ML components 32 for the different postures. Similarly, the training phase 101 can be repeated any time there is a significant change in the patient's situation, such as improvement or deterioration of the patient's condition, a change in the mode of mechanical ventilation therapy, a material change in some other therapy also being administered to the patient (e.g., if the patient is placed on a new drug or taken off a previous drug that may be reasonably expected to affect the patient's respiratory system).
[0049] To train the ML component 32, a machine learning asynchrony detection algorithm implemented in the ML component 32 is trained using the labelled ventilator waveforms. Alternative optimization methods may be used. For example, in the case of an algorithm that detects ineffective efforts through the analysis of flow and airway pressure deflections the optimal trigger threshold level is determined such that the amount of detected ineffective efforts is maximal (which is achieved by lowering the threshold level for higher sensitivity) while the amount of auto-triggers is minimal (avoiding the threshold level being too low). In case no asynchronies occurred in the training period (i.e., 1-10 minutes) predetermined threshold levels could be used that are optimal values for a group of patients. The design of the algorithm may be such that it allows for quantification of patient-ventilator interaction (e.g., to quantify delays between onset of diaphragm strain, thickening or excursion and pressure support). The detection algorithm is not limited to ineffective efforts only but can be broader such as to detect other types of asynchronies as well. The ventilation waveform data and the imaging data may be split into a training, validation, and test set to allow for (intermediate) validation and (final) testing of the optimized model.
[0050] In some embodiments of the training phase 101, the mechanical ventilator 2 could automatically change its settings, or suggest that a medical professional apply new settings to facilitate the appearance of asynchrony events to enrich the data used in the training phase 101. The mechanical ventilator 2 and the US imaging device 15 can share a common clock to ensure accurate synchronization of the acquired data. Alternatively, the cloud server 30 (or edge device or hub) can be programmed to synchronize the signal between the ventilator data and the ultrasound imaging data.
[0051] Furthermore, while a single ML component 32 is described here, more generally multiple classification algorithms (i.e., multiple ML components) may be trained to detect various types of patient-ventilator asynchronies. For example, one ML component may be trained to detect delayed triggering, another to detect flow asynchrony, another to detect early cycling, and/or so forth. This enables each ML component to be optimized for a specific type of patient-ventilator asynchrony. For any ML component where the training data includes no labeled events of that particular type of patient-ventilator asynchrony, a default value or values for the optimizable parameters of that ML component can be used, or alternatively that ML component can be left unused under the assumption the patient is not suffering from that type of patient-ventilator asynchrony. Still further, multiple parameters may be used as input to the classification algorithms (e.g., diaphragm excursion, thickness, auxiliary muscle activities, EMG, ventilation settings of the mechanical ventilator 2, and so forth). Next to classification, the ultrasound time-series data and ventilator waveforms may be used for quantification of patient-ventilator interaction, e.g., to quantify delays between onset of diaphragm strain, thickening or excursion and pressure support. The ventilator waveform data and the imaging data can then be labelled.
[0052] The ultrasound imaging data is processed by the cloud server 30 and/or the ultrasound imaging device 15 to extract time-series data such as diaphragm excursion, diaphragm thickness, diaphragm strain or strain rate, accessory inspiratory muscle activity or lung sliding. The ultrasound imaging data may be pre-processed for noise reduction using known techniques such as autoencoders. Techniques for feature detection such as the diaphragm or pleural line can also be used, such as computer vision (CV) techniques like edge detection or convolutional neural networks (CNNs) trained for detection of the diaphragm or pleural line. Also, techniques for quantification of displacement of regions of interest on the detected features, such as determining the cross-correlation of regions of interest between various frames, can be used. Finally, time-series data may be filtered. The processed ultrasound time-series data and simultaneously acquired ventilator pressure and flow waveforms are uploaded to the cloud server 30 (when processed by the imaging device 15) or locally stored on imaging device 15 and/or the mechanical ventilator 2.
[0053] The ventilator waveforms may be uploaded to the cloud server 30 directly from the mechanical ventilator 2 (or to the edge device or hub), which can advantageously eliminate the need for a connection between the US imaging device 15 and the mechanical ventilator 2. To this end, it is essential that the clocks of the US imaging device 15 and the mechanical ventilator 2 are synchronized and that the processed ultrasound time-series data and ventilator data contain a time stamp to facilitate data synchronization in the cloud server 30. Alternatively, a landmark is created, e.g. by shortly in- or decreasing the applied pressure which is detectable in the ventilator waveforms and processed ultrasound time-series data to facilitate data synchronization.
[0054] Once the ML component 32 is trained, the training phase 101 is complete, the ultrasound, EMG, or other second modality measurement device can be disconnected from the patient P, and the patient-ventilator asynchrony monitoring method 100 proceeds to an application phase 109 in which patient-ventilator asynchrony events are detected using only the ventilation waveform data and/or ventilation settings of the mechanical ventilator 2. At an operation 110, ventilation waveform data of the patient P is acquired by the mechanical ventilator 2 and transferred to the cloud server 30. At an operation 114, the trained patient-specific ML component 32 is applied to the ventilation waveform data acquired during the ventilation waveform data acquisition operation 110 to detect patient-ventilator asynchrony events occurring during mechanical ventilation therapy of the patient P.
[0055] To do so, the ventilation waveform data acquired at the operation 110 are processed by the ML component 32 to detect and classify patient-ventilator asynchronies (e.g., by feeding it into the classification algorithm implemented in the ML component 32 and trained during the training phase 101). If multiple classification algorithms for different types of patient-ventilator asynchronies were trained in the training phase 101, then the operation 114 may apply the various trained classification algorithms to detect the corresponding various types of patient-ventilator asynchronies.
[0056] At an operation 116, an indication 34 of patient-ventilator asynchrony events detected by the patient-specific ML component 32 can be displayed on the display device 14 of the mechanical ventilator 2. In some embodiments, the indication 34 of patient-ventilator asynchrony events comprises an asynchrony index, which is displayed on the display device 14. The asynchrony index can be calculated by the cloud server 30 as a ratio of a number of asynchronous breaths of the patient P in the labelled waveforms and a total breath count of the patient P. The asynchrony index (AI %) is displayed as a number on the display device 14, displaying the ratio of the number of asynchronous breaths of all types of asynchronies and the total breath count, expressed as a percentage. In some examples, the AI % can be shown as an index over a predetermined time period (i.e., an hour or so). In addition, asynchrony specific indices such as ineffective triggering index (ITI %) may be displayed. Also, the asynchrony and asynchrony specific indices may be calculated over a predetermined time interval (e.g., the previous hour or two) and displayed as function of time during the predetermined time interval. Finally, a clustering index or volatility may be calculated and displayed on the display device 14. For example, this could be determined by calculating the standard deviation of the asynchrony index time-series data.
[0057] In other embodiments, the indication 34 can include a message comprising a proposed adjustment to the mechanical ventilation device 2 to reduce or eliminate the patient-ventilator asynchrony events, and the proposed adjustment can be displayed on the display device 14. In other embodiments, the indication 34 can include one or more optimized settings of the mechanical ventilator 2, which can be determined based on the detected patient-ventilator asynchrony events (and optionally also on the received imaging data), and the one or more optimized settings can be displayed on the display device 14. These are merely examples and should not be construed as limiting.
[0058] Optimal ventilation settings can be chosen based on the information provided in Table 2 (below) or other similar compilation of remedial actions. Two main types of asynchronies can include auto-triggering and ineffective triggering, but the optimized algorithm can be able to detect all the asynchronies because the ML component 32 was trained using ground truth data. The ventilator settings optimization may be based on trial and error, (i.e., evaluate the effect of a proposed solution and in case the targeted reduction in AI % is not met, then proceed to the next solution). The ventilation settings optimization algorithm may be self-learning to improve over time. The algorithm to determine the optimal settings may run in the cloud server 30, on the US imaging device 15, the mechanical ventilator 2, or on a separate processing unit (i.e., the electronic processing device 18).
TABLE-US-00002 TABLE 2 Solutions to reduce auto-triggering and ineffective effort type of asynchronies Lab solution Asynchrony Cause Solutions testing Auto 1. High trigger sensitivity 1. Adjust trigger sensitivity 1. Adjust triggering 2. Leaks 2. Reduce noise trigger 3. Random noise in the circuit (e.g., 3. Remove leaks sensitivity cardiac oscillations, 4. Use appropriate non-invasive (priority) condensed water in the ventilator ventilation (NIV) software 2. Cases circuit, copious 5. Remove circuit condensate with and tracheobronchial secretions) without water in tube (not a priority) Ineffective 1. Low trigger sensitivity 1. Adjust trigger sensitivity 1. Adjust efforts 2. Weak respiratory drive or weak 2. Reduce sedation or use drugs trigger effort secondary to with no effect on the respiratory sensitivity heavy sedation, excessive respiratory drive 2. Increase support, or 3. Reduce support PEEP (in diaphragm dysfunction 4. Correct metabolic alkalosis case of 3. Presence of high threshold load 5. Increase PEEP to counter iPEEP) such as intrinsic PEEP (air trapping) intrinsic PEEP 3. Increase 4. Delayed cycling, especially in PSV 6. Shorten inspiratory time Cycling mode or 7. Adjust end-expiratory trigger 4. Decrease obstructive condition (FIG. 2), or criteria in an obstructive PSV during NIV in condition (e.g., COPD) presence of intentional leak in a 8. Use appropriate NIV ventilator unable to software, compensate for them 9. Consider a neural trigger if 5. Inspiratory time too long in a time- the problem persists. cycled breath (related to 4) 10. Check for dyspnea 6. Low level of pCO2 (related to 2) 11. Decrease PSV level (PSV model) Sources: Lucia Mirabella, Gilda Cinnella, Roberta Costa, Andrea Cortegiani, Livio Tullo, Michela Rauseo, Giorgio Conti, Cesare Gregoretti Patient-Ventilator Asynchronies: Clinical Implications and Practical Solutions Respiratory Care Jul 2020, respcare.07284; DOI: 10.4187/respcare.07284; de Haro, C., Ochagavia, A., Lopez-Aguilar, J. et al. Patient-ventilator asynchronies during mechanical ventilation: current knowledge and research priorities. ICMx 7, 43 (2019). https://doi.org/10.1186/s40635-019-0234-5; Subira C, de Haro C, Magrans R, Fernandez R, Blanch L. Minimizing Asynchronies in Mechanical Ventilation: Current and Future Trends. Respir Care. 2018 Apr;63(4):464-478. doi: 10.4187/respcare.05949. Epub 2018 Feb 27. Erratum in: Respir Care. 2019Mar;64(3):e1. PMID: 29487094.; Holanda MA, Vasconcelos RDS, Ferreira JC, Pinheiro BV. Patient-ventilator asynchrony [published correction appears in J Bras Pneumol. 2018 Sep 03;]. J Bras Pneumol. 2018;44(4):321-333. doi:10.1590/S1806-37562017000000185
[0059] At an operation 118, the mechanical ventilator 2 can be controlled by adjusting settings of the mechanical ventilator 2 with the determined one or more optimized settings. In some embodiments, the optimized patient-ventilator detection algorithm (implemented in the ML component 32) can track the progression of the patient-ventilator interaction to predict the possibility of future asynchronies. The output of such prediction can be used directly to optimize further the ventilation settings, or it can be used to alert the medical professionals. The ML component 32 has features that are representative of the patient's physiological state and capture the reasons of the asynchrony. Once the ML component 32 has these interpretable features it can track the progression and predict the appearance of asynchronies. Once the ML component 32 is able to predict asynchronies it can also alarm the caregivers to take preventive actions to avoid the asynchronies or to plan their activities accordingly. The ML component 32 can be optimized using the same patient data, or/and population data.
[0060] In some embodiments, the sensor 9 can include esophageal pressure, Central Venous Pressure (CVP), EAdi or other respiratory effort indicators may be used in addition to, or instead of ultrasound imaging data as ground truth to train the ML component 32.
[0061] In some embodiments, hybrid modelling for faster training of the ML component 32 can be performed with less data (e.g. combination of a biophysical model with machine learning).
[0062] The disclosure has been described with reference to the preferred embodiments. Modifications and alterations may occur to others upon reading and understanding the preceding detailed description. It is intended that the exemplary embodiment be construed as including all such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.