Patent Application
20230337625
Embodiments disclosed herein relate to systems and methods for monitoring of animals in laboratory environments where the animals are housed in homecages.
Experimental research with animals is usually conducted in laboratories where the animals are housed for observation. Examples of applied research conducted on animals include testing disease treatments, disease reactions, breeding, defense research and toxicology. As part of the research it is necessary to evaluate the reaction or health of the animal to the test being performed. Thus, ongoing animal monitoring/observation is performed as part of the animal-based research.
Animals are usually housed for observation in “homecages” under defined conditions related to the research that the animals are part of. These cages may or may not be separated from the surrounding environment for providing a home to the animals. A typical homecage and cage rack arrangement is illustrated in
As shown in
In some embodiments, homecage 22 includes cage slides 36 mounted on the sides of homecage 22 for removably placing homecage 22 into a cage rack 20. As shown in
Cage rack 20 includes multiple rows and columns for accommodating multiple cages 22. In the exemplary embodiment of
It should therefore be appreciated that research institutions may be required to monitor multiple animals in multiple cages in multiple cage racks in multiple zones of the facility, totaling hundreds or thousands of animals under simultaneous observation.
One current approach to animal monitoring is manual evaluation of the animals. The animals are weighed and placed in the homecages and allowed to acclimatize to the homecage for a short period of time, typically 2-4 days. Following this period, the research is started by, for example, injecting the experimental group of animals with a pharmacological agent. The research period typically lasts for a period of days to months. During this period the animals in both control and experimental groups are repeatedly removed from their homecages and each weighed or otherwise examined to determine the effects of the applied pharmacological agents. It should be appreciated that the manual observation process is very time consuming and causes significant disturbance to the animals that are constantly removed from the homecages for observation, sometimes even at the expense of the animal recovery process. Finally, the manually measured observation points such as weight need to be entered, recorded and analyzed—an equally time-consuming process. It should also be appreciated that animal monitoring is also required by various kinds of research centers for animals that are housed and bred and are not part of any particular experiment, in order to track animal welfare and prevent any kind of discomfort or an outbreak of diseases.
Other approaches for animal observation have been proposed. Russel proposes monitoring of only a single animal per cage using an infrared photobeam with the beam source and physically separated opposite photocell receiver set in the long sides of the cage, but ultimately concludes that sniffing by the animal activates photobeam breaks more than ambulating “as might be expected” (Russell, P. A. “Sex differences in rats' stationary-cage activity measured by observation and automatic recording.” Animal Learning & Behavior 1.4 (1973): 278-282). Svensson discusses use of photobeams but concludes that more than one is required for monitoring more than a single animal as “with a single photocell one animal may block the registration of his companions' movements” (Svensson, T. H., and G. Thieme. “An investigation of a new instrument to measure motor activity of small animals.” Psychopharmacologia 14.2 (1969): 157-163).
Other monitoring products using multiple photobeams or photobeam matrixes include: a proprietary cage with 32 photobeams for measuring the movement of only a single animal sold by Omnitech Electronics; The Afasci® Smartcage is a proprietary cage that includes multiple sensors including a floor-vibration sensor, an infrared matrix and flexible modular devices for monitoring only a single animal; The PAS-Open Field from Bilaney® is a further proprietary cage that includes a 16×16 photobeam matrix for monitoring of only a single animal; U.S. Pat. No. 4,267,443 to Caroll et al discloses monitoring only a single animal using multiple photobeams which are broken in the X and Y directions in all three planes; and U.S. Pat. No. 3,304,911 to Hiroshi et al discloses use of multiple photobeams and moving cameras for monitoring of only a single animal.
Further more complex technological approaches include use of RFID tracking devices implanted into each animal that are tracked by a sensor plate added to every single cage such as the Activity Monitor of Phenosys®; The Supermex of Muromachi® includes a pyroelectric sensor for thermal analysis of only a single animal in a cage; The Digital Ventilated Cage of Tecniplast® is a proprietary cage that features a sensor base plate performing electrical capacitance sensing of movement in the cage; Genewsky discloses a proprietary cage monitored by a microwave detector (Genewsky, Andreas, et al. “A simplified microwave-based motion detector for home cage activity monitoring in mice.” Journal of biological engineering 11.1 (2017): 36); and US20100111359 to Bai et al discloses animal monitoring using at least two video cameras.
The approaches described above suffer from several limitations including:
The problem to be solved is therefore implementation of an animal monitoring system that is scalable to large numbers, that can be retrofitted to existing homecages and cage racks, that is cost effective, that can monitor varying numbers of animals per cage, that can be deployed for different animal types and that provides long term reliability, all while still providing accurate monitoring data.
Exemplary embodiments disclosed herein relate to a system and method for monitoring animals in homecages. The homecage monitoring system (HCMS) as disclosed herein may include a detector assembly including a mounting assembly and detector configured for attachment to existing cage racks by use of an adjustable mounting assembly, a controller for interfacing with the detector, and an analyzer for collecting monitoring data from the controller. In some embodiments, environmental sensors (e.g. light, temperature, humidity) may also provide data to the controller. The detector may include a single retroreflective sensor that only needs to be mounted on one side of a monitored cage. The adjustable mounting assembly may enable positioning of the retroreflective sensor such that the retroreflective sensor can detect animal movement of multiple animals in a single homecage.
The known art disclosed above describes use in currently available systems of multiple photobeams per cage for monitoring of single animals. The industry acceptance of multiple photobeam monitoring is based on the conclusions of prior research that a single photobeam for measuring animal movement is insufficient for monitoring of a single animal in a cage and also ineffective for monitoring of multiple animals in a single cage. The use of a retroreflective-sensor-based single beam system as disclosed herein is therefore inventive based on research conducted by the inventors presented herein and as described in Vagima, Yaron, et al. “Group activity of mice in communal home cage used as an indicator of disease progression and rate of recovery: effects of LPS and influenza virus.” Life Sciences 258 (2020): 118214. The experiments below and in Vagima, et al. (2020), show a single-beam system monitoring multiple animals in a single cage providing animal movement data that correlates accurately to the animal health and thereby confirming the effectiveness of the single beam approach.
The systems and methods disclosed herein may provide multiple benefits not provided by current systems including:
The limited number of components may increase the reliability of the system such that it is suitable for large scale deployments.
In some embodiments, a homecage monitoring system includes: a detection assembly including: a single detector; a mounting assembly configured for mounting of the single detector thereto and configured for attachment of the mounting assembly adjacent to a homecage to be monitored.
In some embodiments, the system further includes a controller in data communication with the single detector and adapted for collecting the output data from the single detector. In some embodiments, the system further includes an analyzer in data communication with the controller, wherein the analyzer is a computing device. In some embodiments, the single detector includes a retroreflective sensor. In some embodiments, the system further includes sensors in communication with the controller. In some embodiments, the sensors are for one or more of: temperature, light, humidity, homecage pH, food level, water level, and animal play devices.
In some embodiments, the system further includes one or more pause buttons in communication with the controller, wherein the pause button is adapted for indicating the start and end of a period of interruption in animal monitoring to the controller. In some embodiments, the mounting assembly is configured for retrofitting to an existing cage rack. In some embodiments, the mounting assembly includes column clamps, a detector mount, and a backplane, wherein the single detector is mounted on the detector mount. In some embodiments, the detector mount is slidably attached to the backplane such that the position of the detector mount can be adjusted.
In some embodiments, the detector is mounted on the detector mount such that the detector position can be adjusted. In some embodiments, the column clamps are configured for adjusting to fit a horizontal distance between rack columns according to the cage rack dimensions. In some embodiments, multiple detection assemblies are in communication with the controller. In some embodiments, multiple controllers are in communication with the analyzer. In some embodiments, the single detector provides an output signal indicating obstruction of a light beam emitted by the detector. In some embodiments, the analyzer is adapted for collecting numbers of beam obstructions detected by the detectors. In some embodiments, the numbers of beam obstructions are displayed on a user interface of the analyzer.
In some embodiments, a method for monitoring animals in a homecage comprises: providing the homecage monitoring system positioned opposite a homecage including the animals for monitoring; and monitoring the detected beam breaks of the single detector to determine animal activity. In some embodiments, pressing of the pause button results in a pause in monitoring or an indication of the time period of an interruption. In some embodiments, data from the sensors is used for analysis of animal activity as detected.
According to at least some embodiments, a homecage monitoring system includes: a detection assembly including: a single detector; a mounting assembly configured for mounting of the single detector thereto and for attachment of the mounting assembly to a cage rack adjacent to a homecage to be monitored; and a controller in data communication with the single detector and adapted for collecting the output data from the single detector. In some embodiments, the system further includes an analyzer in data communication with the controller, wherein the analyzer is a computing device.
In some embodiments, the single detector includes a retroreflective sensor. In some embodiments, the system further includes sensors in communication with the controller. In some embodiments, the sensors are selected from the group consisting of: sensors for temperature, light, humidity, homecage pH, food level, water level, and animal play devices. In some embodiments, the system further includes one or more pause buttons in communication with the controller, wherein the pause button is adapted for indicating the start and end of a period of interruption in animal monitoring.
In some embodiments, the mounting assembly is adapted for retrofitting to an existing standard and/or non-standard cage rack. In some embodiments, the mounting assembly includes a detector mount and a backplane, wherein the single detector is mounted on the detector mount. In some embodiments, the detector mount is slidably attached to the backplane such that the position of the detector mount can be adjusted. In some embodiments, the detector is mounted on the detector mount such that the detector position can be adjusted. In some embodiments, multiple detection assemblies are in communication with the controller. In some embodiments, multiple controllers are in communication with the analyzer.
In some embodiments, the single detector provides an output signal indicating breaking of a light beam emitted by the detector. In some embodiments, the analyzer is adapted for collecting numbers of beam breaks detected by the detectors. In some embodiments, the numbers of beam breaks are displayed on a user interface of the analyzer.
In some embodiments, a method for monitoring animals in a homecage includes: providing the system as described above attached to a homecage including the animals for monitoring; and monitoring the detected beam breaks of the single detector to determine animal activity. In some embodiments, pressing of the pause button results in a pause in monitoring. In some embodiments, data from the sensors is used for analysis of animal activity as detected.
The term “animal” as used herein may refer to any type of animal typically used in laboratory experimentation including but not limited to mice, rats, guinea pigs, hamsters, rabbits, fish, primates, amphibians, reptiles and so forth. The term “homecage” as used herein refers to any laboratory enclosure for housing animals and includes cages, terrariums, and aquariums.
As used herein the term “existing” as it relates to homecages and/or cage racks refers to homecages and/or cage racks that do not have automated processor-based monitoring built into the homecage or cage rack and therefore require some form of retrofitting of a monitoring system (such as disclosed herein) in order to provide automated processor-based monitoring of animals in the homecage or cage rack. Advantageously, the HCMS as disclosed herein may be retrofitted to existing cage racks for providing automated processor-based monitoring of animals in the homecages therein. Existing homecages and/or cage racks may have already been acquired and/or are in use by an institution or refer to homecages and/or cage racks of a type routinely acquired by an institution. Existing homecages and/or cage racks may be of varying dimensions.
As used herein the term “standard” as it relates to homecages and/or cage racks may refer to homecages and/or cage racks manufactured in large quantities (thousands per year) by recognized homecage manufacturers known in the art with no modification made to the homecages and/or cage racks for automated processor-based monitoring purposes. A non-limiting example of a standard homecage used for small rodents is the Tecniplast® 1500U having dimensions of 513×381×256 mm (L×W×H) and a non-limiting example of a standard cage rack is the associated 2U20 rack having a capacity of 20 1500U cages. Existing cages may be standard or non-standard.
Although the experiments included herein relate to mice and hamsters, it should be appreciated that the system disclosed herein may be adapted for monitoring of any type of animal.
Various embodiments are described herein with reference to a system, method, device, or computer readable medium. It is intended that the disclosure of one is a disclosure for all. For example, it is to be understood that disclosure of a computer readable medium described herein also constitutes a disclosure of methods implemented by the computer readable medium, and systems and devices for implementing those methods, via for example. at least one processor. It is to be understood that this form of disclosure is for each of discussion only, and one or more aspects of one-embodiment herein may be combined with one or more aspects of other embodiments herein, within the intended scope of this disclosure.
The details of one or more implementations are set forth in the accompanying drawings and the description below. Other features will be apparent from the description and drawings.
Aspects, embodiments, and features disclosed herein will become apparent from the following detailed description when considered in conjunction with the accompanying drawings. Like elements may be marked with like numerals in different figures, where:
The present disclosure describes technological improvements in devices, systems, methods, and computer readable media for animal monitoring platforms that may allow monitoring of large numbers of animals in homecages.
Reference will now be made in detail to non-limiting examples of this disclosure, examples of which are illustrated in the accompanying drawings. The examples are described below by referring to the drawings, wherein like reference numerals refer to like elements. When similar reference numerals are shown, corresponding description(s) are not repeated, and the interested reader is referred to the previously discussed figure(s) for a description of the like element(s).
Aspects of this disclosure may provide a technical solution to the challenging technical problem of animal monitoring and may relate to a system for platforms that may allow monitoring of large numbers of animals in homecages with the system having at least one processor (e.g., processor, processing circuit or other processing structure described herein), including methods, systems, devices, and computer-readable media. For ease of discussion, example methods are described below with the understanding that aspects of the example methods apply equally to systems, devices, and computer-readable media. For example, some aspects of such methods may be implemented by a computing device or software running thereon. The computing device may include at least one processor (e.g., a CPU, GPU, DSP, FPGA, ASIC, or any circuitry for performing logical operations on input data) to perform the example methods. Other aspects of such methods may be implemented over a network (e.g., a wired network, a wireless network, or both).
As another example, some aspects of such methods may be implemented as operations or program codes in a non-transitory computer-readable medium. The operations or program codes may be executed by at least one processor. Non-transitory computer readable media, as described herein, may be implemented as any combination of hardware, firmware, software, or any medium capable of storing data that is readable by any computing device with a processor for performing methods or operations represented by the stored data. In a broadest sense, the example methods are not limited to particular physical or electronic instrumentalities, but rather may be accomplished using many differing instrumentalities.
Referring to the figures,
One detector assembly 110 may be mounted adjacent to each homecage 22 that is to be monitored. In
As shown in
Detector 112 is configured for being fixedly positioned adjacent to a homecage 22 to be monitored. In some embodiments, detector 112 is adapted for retrofitting to an existing homecage or cage rack. In some embodiments, mounting assembly 120 is configured for mounting of the single detector 112 thereto. Mounting assembly 120 is configured for attachment of the mounting assembly 120 to a cage rack 20 adjacent to a homecage 22 to be monitored. In some embodiments, detector assembly 110 is adapted for retrofitting to an existing cage rack by including an adaptable mounting assembly 120. Mounting assembly 120 includes backplane 122, column clamps 124, and detector mount 126. Backplane 122 extends between and is fixedly attached to column clamps 124. Column clamps 124 are spaced one from another in a horizontal plane so as to substantially match the horizontal distance between the rack columns 40 of a cage rack 20 in which mounting assembly 120 is to be mounted. In some embodiments, such as shown in
Detector mount 126 is slidably attached to backplane 122 such that the position of detector mount 126 can be adjusted in a direction shown by arrow “C”. Detector 112 is slidably mounted on detector mount 126 such that the position of detector 112 can be adjusted in a direction shown by arrow “B”. As shown in
Alternative means of configuring detector assembly 110 for mounting to an existing cage rack 20 or homecage 22 may be contemplated including mounting of detector 112 directly to homecage 22 or to another part of cage rack 20 such as to a single rack column 40 or to a rack side mount 42 with an appropriate mounting assembly.
In use, the emitted light beam 118 produced by emitter 114 is reflected back to receiver 116 as reflected light 119 by a reflector. When emitted light beam 118 is obstructed by a reflector the amount of reflected light 119 that arrives at receiver 116 may change. Where no animal obstructs beam 118, the beam 118 is reflected as steady state beam 119 off the opposite wall of homecage 22. When a change in reflected light 119 is detected, the output signal of detector 112 may change state indicating an obstruction of beam 118. As shown in
Each detector 112 may be in wired or wireless data communication with controller 130. Wireless communication between detector 112 and controller 130 may utilize any suitable wireless protocol or standard such as but not limited to WiFi, Bluetooth, Zigbee, and so forth. Controller 130 is a computing device as defined herein and includes at least one processor. In some embodiments, controller 130 may include hardware interface cards (not shown) for monitoring detectors 112. Each beam obstruction transmitted by each detector 112 to controller 130 may be counted by controller 130. In some embodiments, a constant signal from detector 112 indicating a constant obstruction of emitted light beam 118 that exceeds a defined period of time may be identified by controller 130 as an alarm condition. Such a condition might be caused for example by an immobile animal 50 or by movement of nesting material 35 that obstructs emitted light beam 118.
Controller 130 may be in wired or wireless data communication with an analyzer 140. Analyzer 140 is a computing device as defined herein including at least one processor. In some embodiments, analyzer 140 is a distributed server or cloud computing environment. Analyzer 140 may include a user interface (UI) 142. In some embodiments, multiple UIs 142 may be supported to enable access to analyzer 140 by multiple users simultaneously. UI 142 may include means for human interaction with analyzer 140 including input means such as a keyboard, mouse and/or touch screen and output means such a screen, audio output or visual indicators.
Analyzer 140 may periodically or continuously receive cumulative or single detector 112 obstruction counts for each deployed detector 112 from controller 130. Analyzer 140 may summarize data received from controller 130 for display on UI 142, or for saving and/or transfer to other analytical systems (not shown).
In some embodiments, UI 142 may also provide action buttons such as but not limited to: reset button 219 for zeroing the activity (obstruction) count such as when a new monitoring period is started, an interrupt button 215 such as describe above, and “show graph” button 220 for displaying a graph of gathered data such as the experimental data described below (
In some embodiments, such as shown in
It should therefore be appreciated that large numbers of homecages 22 in multiple cage racks 20 situated in multiple zones 44 may each be monitored by a separate detector assembly 110 mounted adjacent to each monitored homecage 22 and controlled by controller 130 reporting to an analyzer 140, and the numbers of zones 44, homecages 22, cage racks 20 and detection assemblies 110 shown in the figures should not be considered limiting. HCMS 100 may therefore support simultaneous monitoring of hundreds to thousands of homecages 22 each holding multiple animals 50. Further, as shown, HCMS 100 may include a minimal number of components that may be easily retrofitted to existing cages enabling fast deployment of HCMS 100 to large installed bases of cages.
In some embodiments, environmental sensors 132 may be in wired or wireless data communication with controller 130. As shown in
In some embodiments, a pause button 134 is provided. As shown in
Reference is made to
In step 302, groups of animals (control and experimental) are placed in the homecages and may be allowed to acclimatize to the homecages for a short period of time, typically 2-4 days to monitor (using beam obstruction counts) and record data (including beam obstruction counts) about spontaneous movement of healthy animals and to calibrate the baseline of day/night activity. Following this period, the research is started by, for example, injecting the experimental group of animals with a pharmacological agent. All experimental procedures at the beginning and during the experiment may be documented in the “Note” tab 221 (
In step 304, which may begin before, during or after step 302, monitoring of the animals begins such as by initiating the collection of beam obstruction counts from detectors 112 and also sensor data from sensors 132 by controller 130. In step 306 recording of beam obstruction counts from detectors 112 and also sensor data from sensors 132 by controller 130 may be initiated such as by selecting an “Experiment start” button 222 (
In some embodiments, the animals are not disturbed (physically) during a recorded monitoring period. In some embodiments, animals may be physically disturbed such as where this is deemed to have a negligible effect on monitoring results. During the monitoring period at any time, in step 310, analysis of the results is performed by one or more users (researchers/assistants). In an optional step 308, monitoring/recording is paused by activating pause button 134 by a user such as when cages are cleaned, or animals are physically disturbed, or for removal of dead animals. When the pause button is deactivated in step 314, counting and data recording by the controller and analyzer continues as in step 306. Alternatively, activation/deactivation of the pause button may be recorded in analyzer 140 along with data from the interruption period i.e.: without stopping recording. In step 316, the research is deemed to be completed (as determined by the researchers/users) and a final analysis of the monitoring results may be performed by the users. Continual monitoring does not proceed to step 316 but rather involves repetition of steps 306, 308, and 310 on a continual basis.
The following experiments were performed using HCMS 100 disclosed above to verify that the monitored animal movement data of multiple animals detected using a single beam correlates accurately to the animal health to thereby confirm the effectiveness of the single beam monitoring approach provided by HCMS 100 for multiple cages simultaneously and multiple animals per cage. The experimental data shown below proves the efficacy of the HCMS 100 by showing first the activity differences associate with circadian rhythm and in measured activity between the control and experimental groups as measured by counts of beam obstructions of the single beam.
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Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The materials, methods, and examples provided herein are illustrative only and not intended to be limiting.
Implementation of the method and system of the present disclosure may involve performing or completing certain selected tasks or steps manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of preferred embodiments of the method and system of the present disclosure, several selected steps may be implemented by hardware (HW) or by software (SW) on any operating system of any firmware, or by a combination thereof. For example, as hardware, selected steps of the disclosure could be implemented as a chip or a circuit. As software or algorithm, selected steps of the disclosure could be implemented as a plurality of software instructions being executed by a computer using any suitable operating system. In any case, selected steps of the method and system of the disclosure could be described as being performed by a data processor, such as a computing device for executing a plurality of instructions.
As used herein, the terms “machine-readable medium” “computer-readable medium” refers to any computer program product, apparatus and/or device (e.g., magnetic discs, optical disks, memory, Programmable Logic Devices (PLDs)) used to provide machine instructions and/or data to a programmable processor, including a machine-readable medium that receives machine instructions as a machine-readable signal. The term “machine-readable signal” refers to any signal used to provide machine instructions and/or data to a programmable processor.
Various implementations of the systems and techniques described here can be realized in digital electronic circuitry, integrated circuitry, specially designed ASICs (application specific integrated circuits), computer hardware, firmware, software, and/or combinations thereof. These various implementations can include implementation in one or more computer programs that are executable and/or interpretable on a programmable system including at least one programmable processor, which may be special or general purpose, coupled to receive data and instructions from, and to transmit data and instructions to, a storage system, at least one input device, and at least one output device.
Although the present disclosure is described with regard to a “computing device”, a “computer”, or “mobile device”, it should be noted that optionally any device featuring a data processor and the ability to execute one or more instructions may be described as a computing device, including but not limited to any type of personal computer (PC), a server, a distributed server, a virtual server, a cloud computing platform, a cellular telephone, an IP telephone, a smartphone, a smart watch or a PDA (personal digital assistant). Any two or more of such devices in communication with each other may optionally comprise a “network” or a “computer network”.
To provide for interaction with a user, the systems and techniques described here can be implemented on a computer having a display device (a LED (light-emitting diode), or OLED (organic LED), or LCD (liquid crystal display) monitor/screen) for displaying information to the user and a keyboard and a pointing device (e.g., a mouse or a trackball) by which the user can provide input to the computer. Other kinds of devices can be used to provide for interaction with a user as well; for example, feedback provided to the user can be any form of sensory feedback (e.g., visual feedback, auditory feedback, or tactile feedback); and input from the user can be received in any form, including acoustic, speech, or tactile input.
The systems and techniques described here can be implemented in a computing system that includes a back end component (e.g., as a data server), or that includes a middleware component (e.g., an application server), or that includes a front end component (e.g., a client computer having a graphical user interface or a Web browser through which a user can interact with an implementation of the systems and techniques described here), or any combination of such back end, middleware, or front end components. The components of the system can be interconnected by any form or medium of digital data communication (e.g., a communication network). Examples of communication networks include a local area network (“LAN”), a wide area network (“WAN”), and the Internet.
The computing system can include clients and servers. A client and server are generally remote from each other and typically interact through a communication network. The relationship of client and server arises by virtue of computer programs running on the respective computers and having a client-server relationship to each other.
It should be appreciated that the above described methods and apparatus may be varied in many ways, including omitting or adding steps, changing the order of steps and the type of devices used. It should be appreciated that different features may be combined in different ways. In particular, not all the features shown above in a particular embodiment or implementation are necessary in every embodiment or implementation of the invention. Further combinations of the above features and implementations are also considered to be within the scope of some embodiments or implementations of the invention.
While certain features of the described implementations have been illustrated as described herein, many modifications, substitutions, changes and equivalents will now occur to those skilled in the art. It should be understood that the embodiments in this disclosure are presented by way of example only, not limitation, and various changes in form and details may be made. Any portion of the apparatus, computer readable media, and/or methods described herein may be combined in any combination, except mutually exclusive combinations. The implementations described herein can include various combinations and/or sub-combinations of the functions, components and/or features of the different implementations described.
It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.
All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present disclosure.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IB2021/051296 | 2/16/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 62977333 | Feb 2020 | US |
