Methods and devices for detecting a corpus luteum

Abstract

A method of determining the presence or absence of a corpus luteum in a uterus of an animal The method comprises obtaining sensed temperature data indicative of temperature from at least one target region in the uterus. The sensed temperature data is provided at a processor, and processed to determine the presence or absence of a corpus luteum in the animal. Also disclosed is a device for accessing the reproductive tract of an animal to determine the presence of a corpus luteum.

Description

[0001] "Methods and devices for detecting a corpus luteum"

[0002] Technical Field

[0003] The present disclosure relates to animal reproductive technologies and particularly to methods and devices for identifying the presence and / or location of a corpus luteum (CL) within an animal.

[0004] Background

[0005] Artificial reproductive technologies (ART), such as artificial insemination (Al) and embryo transfer (ET), are frequently used within animal breeding programs in the livestock industry to improve herd productivity, product quality and herd genetics. However, the success of reproductive technologies relies heavily on the reproductive status of animals and the ability to optimise the timing and delivery of reproductive material (e.g. semen or embryo) to those animals. In many instances, accurately determining the presence and functional status of the corpus luteum (CL) can be used to predict an animal's readiness for pregnancy, since the CL (which is a transient endocrine gland formed in the ovary after ovulation) produces progesterone which is crucial for maintaining early gestation. Conversely, failure to correctly determine the presence or absence of a CL can lead to inefficiencies in reproductive programs.

[0006] Furthermore, in species with a bifurcated uterus, such as cattle, swine, and certain small ruminants, it is often important to identify the location of the corpus luteum (CL) i.e., which ovary the CL is located on, prior to deploying the reproductive material. This is because pregnancy in these species is typically maintained in the uterine horn located on the same side as the ovary containing the functional corpus luteum, due to the localised effects of progesterone. Misidentifying the location of the CL can therefore result in delivery of reproductive material, e.g., embryo transfer, to the incorrect uterine horn, significantly reducing the chances of successful implantation and pregnancy.

[0007] Current methods for detecting the presence and / or location of the CL include manual palpation per rectum, ultrasonography, and hormonal assays. Manual palpation, though widely used, is subjective and requires significant expertise to ensure accurate detection.

[0008] Ultrasonography, while more precise, requires specialised equipment and trained personnel, making it less accessible for routine use. Hormonal assays, such as progesterone testing via blood or milk samples, provide indirect measurements of CL activity but do not reveal its precise location, limiting their utility.

[0009] In view of these shortcomings and the benefit of being able to accurately detect the presence and / or location of the CL when performing artificial reproductive technologies, there is a need for improved devices and methods for detecting the presence and / or location of the CL toenable deployment of reproductive material to the receptive animals and in the desired location within the uterus.

[0010] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each of the appended claims.

[0011] Summary

[0012] The present disclosure relates generally to a method and device for identifying the presence or absence and / or the location of a CL in an animal, particularly prior to the deployment of reproductive materials to the uterus of the animal. In this regard, the inventors have shown for the first time that data pertaining to thermal characteristics and profile within the bovine uterus (including, but not limited to, maximum temperature within the uterus, temperature differential between uterine horns, fluctuations in temperature within the uterus over time and differences in fluctuations between uterine horns, differences between uterine temperature and resting body temperature, heat flux within the uterus, and differences in heat flux between the uterine horns based on relative perfusion, for example) can be used to predict the presence or absence of a CL within animals. The inventors then developed a statistical model trained on animal data for covariates relating to thermal characteristics and profile within bovine uteruses and tested the ability of the model to predict the presence or absence of a CL (CL BINARY), as well as CL location / side of the uterus (CL LEFT RIGHT). In doing so, the inventors were able to show that, inter alia, temperature profiles within the uterus can be used to determine the presence and location (left vs. right) of the CL. Based on these findings, the present inventors have developed methods and devices which may be particularly suited for detecting the presence / absence and / or location of CL in livestock species e.g., cattle, based on data relating to uterine temperature, uterine temperature flux, relative differences in temperature between uterine horns, and / or relative differences in temperature flux between uterine horns, for example.

[0013] In addition to processing uterine temperature data to make predictions regarding the presence / absence and / or location of the CL, it is contemplated that the devices of the disclosure may be suitably configured to sense temperature data within the uterus. Accordingly, devices may be configured to access the reproductive tract of an animal via the animal’s vagina and measure temperature at desired locations within the uterus via temperature sensing probes with minimal trauma to the animal. This could be undertaken immediately prior to delivering reproductive material to an animal’s uterus and may therefore be conveniently integrated into a device which is also configured to deliver the reproductive material.According to one aspect of the present disclosure, there is provided a method of determining the presence or absence of a corpus luteum in a uterus of an animal, the method comprising:

[0014] (a) obtaining sensed temperature data indicative of temperature at a target region in the uterus;

[0015] (b) providing the sensed temperature data at a processor; and

[0016] (c) processing the sensed temperature data at the processor to determine the presence or absence of a corpus luteum in the animal.

[0017] According to another aspect of the present disclosure, there is provided a method of determining the presence or absence of a corpus luteum in a uterus of an animal, the method comprising:

[0018] (a) receiving, at a processor, sensed temperature data indicative of temperature at a target region in the uterus; and

[0019] (b) processing the sensed temperature data at the processor to determine the presence or absence of a corpus luteum in the animal.

[0020] According to another aspect of the present disclosure, there is provided a non-transitory computer-readable medium configured to perform the method according to one or more examples of the present disclosure.

[0021] In any aspect disclosed herein, the method may comprise one or more of the following features.

[0022] In some examples, the method of the disclosure may comprise determining a basal body temperature of the animal. Processing the sensed data may comprise comparing the sensed temperature data to the basal body temperature.

[0023] In some examples, the method may comprise inserting a probe into the uterus of the animal via the vagina, wherein the probe includes a sensor capable of sensing temperature within the uterus, thereby obtaining the sensed temperature data indicative of temperature at a target region in the uterus. The sensed data may be obtained from within at least one uterine horn. Accordingly, the target region may be located within a uterine horn.

[0024] In some examples, the method may comprise obtaining sensed temperature data indicative of temperature at first target region within a first uterine horn of the animal. The method may comprise obtaining sensed temperature data indicative of temperature at a second target region within a second uterine horn of the animal.

[0025] In some examples, the method comprises determining the location of the corpus luteum based on the sensed temperature data. For example, the method may comprise determiningwhether the CL is located at an ovary associated with a first uterine horn or an ovary associated with a second uterine horn.

[0026] Processing the sensed temperature data may comprise comparing the sensed temperature data from the first target region in the first uterine horn to the sensed data from the second target region in the second uterine horn. Processing the sensed temperature data may comprise determining a temperature differential between the first uterine horn and the second uterine horn.

[0027] In some examples, the method may comprise inserting a probe into at least a first uterine horn of the animal to reach a first target region in the first uterine horn, wherein the probe includes a sensor, and obtaining the sensed temperature data indicative of temperature at the first target region from the sensor. In some examples, the method may comprise inserting the probe into a second uterine horn of the animal to reach a second target region in the second uterine horn, and obtaining the sensed temperature data indicative of temperature at the second target region from the sensor.

[0028] In some examples, the method may comprise inserting first and second probes into respective first and second uterine horns of the animal to reach respective first and second target regions of the uterine horns, wherein the first and second elongate probes include respective first and second sensors, and obtaining sensed temperature data indicative of temperature at the first and second target regions from the first and second sensors, respectively.

[0029] In some examples, the method may comprise applying thermal energy to tissue of the first uterine horn and / or the second uterine horn, adjacent the first and / or second probes at the first and / or second target regions. Thermal energy may be applied to influence a temperature of the tissue of the first uterine horn and / or the second uterine horn, adjacent the first and / or second probes at the first and / or second target regions. In some examples, the applying of the thermal energy may be configured to cause a rise in temperature of the tissue. In some examples, the applying of the thermal energy may be configured to maintain a substantially constant temperature in the tissue. The sensed temperature data may be obtained prior to, during, and / or subsequent to the applying of the thermal energy.

[0030] In some examples, processing the sensed temperature data may comprise determining a rate of temperature change at the first and / or second target regions during and / or following the applying of the thermal energy, such as determining a rate of temperature rise during the application of thermal energy to the tissue and / or determining a rate of temperature drop following cessation of the applying of the thermal energy to the tissue. Processing the data may include determining a temperature rise at the first and / or second target regions over a predetermined period of time. Processing the data may include determining a temperature rise in response to applying of a predetermined amount of thermal energy.In some examples, processing the data may comprise comparing the rate of temperature change at the first target region to the rate of temperature change at the second target region. Processing the data may comprise determining, based on the comparison, a presence or absence of a corpus luteum in the animal. Processing the data may comprise determining, based on the comparison, a location of a corpus luteum as associated with the first uterine horn or second uterine horn.

[0031] In some examples, the method may comprise maintaining a substantially constant temperature at the first and / or second target regions by applying thermal energy via the first and / or second probes. The method may comprise determining a differential in energy input required to maintain the substantially constant temperature at the first target region compared to the second target region. The differential in energy input may be indicative of a difference in perfusion between the first and second uterine horns, which may be used to determine the presence or absence and / or location of a corpus luteum.

[0032] In some examples, processing the sensed temperature data may comprise maintaining a substantially constant temperature at the first and / or second target regions. The method may comprise determining an amount of thermal energy applied to maintain the substantially constant temperature at the first target region and an amount of thermal energy applied to maintain the substantially constant temperature at the second target region. Processing the data may comprise comparing the amount of thermal energy applied at the first target region to the amount of thermal energy applied at the second target region. A higher energy input required to maintain the substantially constant temperature may indicate relatively higher perfusion of the tissue, which may serve as an indicator of the presence of a corpus luteum.

[0033] In each of the foregoing examples describing a method of determining the presence or absence and / or location of a corpus luteum in an animal, the method may further comprise transferring an indication of the presence or absence of a corpus luteum, and / or the location of the corpus luteum, to a user via a display.

[0034] According to one aspect of the present disclosure, there is provided a device for accessing the reproductive tract of an animal to determine the presence of a corpus luteum, the device comprising:

[0035] at least one elongate probe, the elongate probe including at least one sensor; wherein the elongate probe is extendable into the uterus of the animal to reach a target region of the uterus.

[0036] The at least one sensor may be provided at a distal region of the elongate probe. The at least one sensor may be configured to obtain sensed data from the uterus. The sensed data may comprise temperature data indicative of temperature at the target region.

[0037] The elongate probe may comprise a heating element.The device may comprise an introducer having a distal region configured for insertion into a uterine cervix of the animal. The introducer may comprise a longitudinal shaft extending from a proximal end to a distal end. The at least one elongate probe may be slidably receivable by the introducer. The at least one elongate probe may be flexible. The at least one elongate probe may be configured to be extendable from the distal region of the introducer into a uterine horn of the animal.

[0038] According to another aspect of the present disclosure, there is provided a device for accessing the reproductive tract of an animal to determine the presence of a corpus luteum, the device comprising:

[0039] a first flexible elongate probe; and

[0040] a second flexible elongate probe,

[0041] wherein the first and second elongate probes are configured to be extendable into respective first and second uterine horns of the animal to reach respective first and second target regions of the uterine horns, wherein the first and second elongate probes each comprise at least one sensor.

[0042] The first and second elongate probes may be simultaneously extendable. The first and second elongate probes may be individually extendable.

[0043] The first elongate probe may comprise one or more first sensors at a distal region of the first elongate probe. The second elongate probe may comprise one or more second sensors at a distal region of the second elongate probe. The first and second sensors may be configured to obtain sensed data from the first and second uterine horns. The sensed data may comprise temperature data indicative of temperature at the first and second target regions.

[0044] The first and second elongate probe may each comprise a respective heating element. The introducer shaft may define first and second elongate channels configured to receive the first and second elongate probes. The first and second elongate channels may extend through the introducer shaft. The first and second elongate channels may extend from the proximal end of the shaft to the distal region of the introducer.

[0045] The introducer shaft may include a central divider separating the first and second channels. The central divider may include opposed first and second side walls defining respective medial walls of the first and second channels. The central divider may include a flared portion in the distal region of the introducer shaft. At the flared portion, the first and second walls may curve relative to a longitudinal axis of the introducer shaft. For example, the first and second walls may curve such that, during deployment of the probes, the first and second walls deflect the elongate probes away from the longitudinal axis of the introducer. The first and second walls may curve relative to the longitudinal axis in two planes.The device may comprise (and / or may be configured to be communicatively coupled with) a processor. The processor may be configured to receive and process the sensed data to determine the presence or absence of a corpus luteum in one or both uterine horns of the animal. The processor may be configured to receive and process the sensed data to determine a location of the corpus luteum as associated with one or both uterine horns of the animal.

[0046] The device may be configured to determine a basal body temperature of the animal. The basal body temperature may be determined via one or more of the elongate probes, for example by obtaining a temperature measurement from the probe prior to applying thermal energy.

[0047] Additionally, or alternatively, the device may comprise a separate basal temperature sensor configured to measure basal body temperature. The basal temperature sensor may be provided on the introducer, for example at a proximal region of the introducer shaft. Additionally, or alternatively, the basal temperature sensor may be provided as a separate component. The basal temperature sensor may be configured for placement at a rectal location, a vaginal location, or another suitable location on or within the animal. In some examples, the basal body temperature may be determined from a temperature measurement obtained from the elongate probes within the reproductive tract of the animal, for example from within the vagina or cervix, prior to insertion of the elongate probes into the uterine horns. According to another aspect of the present disclosure, there is provided a method for accessing the reproductive tract of an animal to determine the presence or absence of a corpus luteum, the method including:

[0048] inserting a distal region of an introducer into a uterine cervix of the animal, the introducer comprising a longitudinal shaft extending from a proximal end to a distal end; and deploying an elongate probe from the distal region of the introducer to reach a target region of the uterine horns;

[0049] obtaining sensed temperature data indicative of temperature at a target region in the uterus;

[0050] providing the sensed temperature data at a processor; and

[0051] processing the sensed temperature data at the processor to determine the presence or absence of a corpus luteum in the animal.

[0052] In some examples, the method may comprise deploying first and second elongate probes from the distal region of the introducer into respective first and second uterine horns of the animal to reach respective first and second target regions of the uterine horns. The method may comprise obtaining sensed temperature data indicative of temperature at first target region within a first uterine horn of the animal and obtaining sensed temperature data indicative of temperature at a second target region within a second uterine horn of the animal.

[0053] Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.Brief Description of the Drawings

[0054] Embodiments will now be described by way of example only with reference to the drawings in which:

[0055] Figure l is a partial perspective view of an introducer and probes of a device for accessing the reproductive tract of an animal to determine the presence of a corpus luteum according to one embodiment of the present disclosure, including probes shown in a partially extended position;

[0056] Figure 2 is a partial perspective view of the introducer and probes of the device of Figure 1, with the probes shown in a partially retracted position;

[0057] Figure 3 is a partial front view of the introducer and probes of the device of Figure 1, with the probes shown in a partially extended position;

[0058] Figure 4 is a partial front view of the introducer and probes of the device of Figure 1, with the probes shown in a partially retracted position;

[0059] Figure 5 is a partial perspective view of a probe of the device of Figure 1;

[0060] Figure 6 is a partial cut-away side view of the probe of Figure 5;

[0061] Figure 7 is a partial cut-away perspective view of the probe of Figure 5;

[0062] Figure 8 is a cross-section of an elongate probe of according to one embodiment of the present disclosure;

[0063] Figure 9 is a cross-section of an elongate probe of according to another embodiment of the present disclosure;

[0064] Figure 10 illustrates the device of Figure 1 in use, with the probes being deployed into respective uterine horns of the animal;

[0065] Figure 11 shows temperature data recorded in response to a delivered bolus of thermal energy by two elongate probes according to the disclosure deployed in respective uterine horns of a cow; and

[0066] Figure 12 illustrates the use of a random forest model to determine the most significant covariates for predicting the presence / absence of a CL and location within the uterus (left vs right horn).Detailed Description

[0067] The present disclosure is directed generally to methods for detecting a corpus luteum in an animal. Several approaches are described herein for determining whether a corpus luteum is present or absent, and determining the location of the corpus luteum.

[0068] The term “animal” as used herein may refer to a female mammal. The animal may be a livestock animal. For example, the animal may be a ruminant livestock animal. Although the examples described herein are configured particularly for use with bovine animals, this is not intended to be limiting on the scope of the disclosure. The disclosed method and device may be configured for use with animal species including but not limited to bovine, caprine, ovine or porcine. For example, a skilled person would appreciate that the method and device may be well suitable for detecting the location of a CL in an animal having a bifurcated uterus.

[0069] In one example, the method of the disclosure includes the following general method steps:

[0070] (a) obtaining sensed temperature data indicative of temperature from at least one target region in the uterus;

[0071] (b) providing the sensed temperature data at a processor; and

[0072] (c) processing the sensed temperature data at the processor to determine the presence or absence of a corpus luteum in the animal.

[0073] In some examples, the method may comprise determining a basal body temperature of the animal. Processing the sensed data may comprise comparing the sensed temperature data to the basal body temperature. In some examples, the basal body temperature may be determined based on a measured temperature of the animal. The measured temperature may comprise a measured rectal temperature. In other examples, the basal body temperature may be based on a temperature measured at different location in the animal. In some examples, the basal body temperature may be determined using a separate device, such as a thermometer, for example a rectal thermometer.

[0074] The sensed data may be obtained from within at least one uterine horn. The target region may be located within the uterine horn. In some examples, the method may comprise obtaining sensed temperature data indicative of temperature at first target region within a first uterine horn of the animal and a second target region within a second uterine horn of the animal. In such examples, the method may comprise determining the location of the corpus luteum based on the sensed temperature data. For example, the method may comprise determining whether the CL is located at an ovary associated with a first uterine horn or an ovary associated with a second uterine horn.

[0075] Processing the sensed temperature data may comprise comparing the sensed temperature data from the first target region in the first uterine horn to the sensed data from the second targetregion in the second uterine horn and / or determining a temperature differential between the first uterine horn and the second uterine horn.

[0076] In some examples, the method may comprise applying thermal energy to tissue of the first uterine horn and / or the second uterine horn. The sensed temperature data may be obtained prior to, during, and / or subsequent to the applying of the thermal energy. Processing the data may comprise determining a rate or a degree of temperature change.

[0077] In some examples, processing the data may comprise comparing the rate of temperature change at the first target region to the rate of temperature change at the second target region. Processing the data may comprise determining, based on the comparison, a presence or absence of a corpus luteum in the animal. Processing the data may comprise determining, based on the comparison, a location of a corpus luteum as associated with the first uterine horn or second uterine horn.

[0078] The disclosed methods may be performed using a device for accessing the reproductive tract of an animal. In the drawings, reference numeral 10 generally designates a device according to the present disclosure. The device 10 may be configured to obtain sensed data to determine the presence of a corpus luteum. It will be appreciated that the disclosure is not limited to the illustrated device and that the disclosed methods may be performed with other devices suitable for obtaining sensed data from the uterus of the animal.

[0079] The term “proximal end” as used herein refers to the end of the device (or component) that is closes to the user in use. The term “distal end” as used herein refers to the end of the device (or component) that is furthest from the user in use.

[0080] Referring initially to Figure 1, the device 10 comprises an introducer 100. A partial view of an example introducer 100 is shown in Figure 1. The introducer 100 comprises an introducer shaft 110, which may extend longitudinally from a proximal end to a distal end 112. A distal region 115 of the introducer 100 is configured for insertion into and / or through a uterine cervix of the animal.

[0081] The introducer shaft 110 may have a length configured for insertion through a cervix of the animal. The length of the introducer shaft 110 may be configured for use with a desired type of animal, for example a particular species and / or breed. A length of the shaft 110 may be configured based on an expected maximum cervical length of the animals with which the device 10 is to be used, to facilitate insertion of the introducer shaft 110 through the cervix. For example, the introducer shaft 110 may have a length of between about 10 cm and about 20 cm, between about 12 cm and about 18 cm, between about 14 cm and about 16 cm or about 15 cm.

[0082] The introducer 100 may be formed from a metal, for example, stainless steel. The introducer 100 may be formed by 3D printing. Additionally, or alternatively, the introducer 100may be formed from plastics. For example, one or more portions of the introducer 100 may be injection moulded or over-moulded.

[0083] In illustrated examples, the introducer 100 is configured to receive first and second elongate probes 200a, 200b. In other examples, the device 10 may have only a single elongate probe. The first and second elongate probes 200a, 200b are each slidably receivable by the introducer 100 and extendable from the distal region 215 of the introducer 100. The first and second elongate probes 200a, 200b may be configured to extend from the introducer 100 into respective first and second uterine horns of the animal, to reach respective first and second target regions of the uterine horns. The first and second elongate probes 200a, 200b may be individually and / or simultaneously extendible from the introducer 100. In other examples, the device 10 may comprise at least one elongate probe 200, configured to be slidably receivable by the introducer 100 and extendable from the distal region 115 of the introducer 100 into a single uterine horn of the animal to reach a target region of the uterine horn.

[0084] The target region(s) may be identified as a desired location for obtaining of the sensed data (e.g. temperature data) within uterus. For example, in the case of embryo transfer, it may be desirable to obtain the sensed temperature data in proximity to an oviduct in the uterine horn.

[0085] The first and second elongate probes 200a, 200b may be configured to be received within the introducer 100. The introducer shaft 110 defines first and second channels 120a, 120b configured to receive the first and second elongate probes 200a, 200b, respectively. The first and second channels 120a, 120b may extend along the introducer shaft 110 from the proximal end to the distal region 115. The channels 120a, 120b each define a distal opening 121a, 121b through which the first and second elongate 200a, 200b may extend. The first and second elongate probes 200a, 200b may be slidable in the distal direction to advance the probes distally relative to the introducer such that respective distal tips 202a, 202b of the first and second elongate probes 200a, 200b extend beyond the distal end 112 of the introducer shaft 100.

[0086] As shown in Figure 4, the introducer shaft 100 includes a central divider 130 separating the first and second channels 120a, 120b. The central divider 130 includes opposed first and second side walls 131a, 131b defining respective medial walls of the first and second channels 120a, 120b. The channels 120a, 120b may define a path along which the probes travel during sliding movement through the introducer shaft 110. The channels 120a, 120b extend generally parallel with a longitudinal axis X of the introducer shaft 110.

[0087] The introducer shaft 110 may include one or more structures configured to deflect the probes as they extend from the distal region 115 of the introducer 100. The probes may be deflected in one or more planes.

[0088] For example, the central divider 130 of the introducer shaft 110 may include a flared portion in the distal region of the introducer shaft. The central divider 130 may increase in widthtoward the distal end 112 of the introducer shaft 110. At the flared portion 132, the first and second side walls 131a, 131b may extend in a direction away from a longitudinal axis of the introducer shaft 110. For example, the walls 131a, 131b may curve away from the longitudinal axis X in a transverse plane. The walls 131a, 13 lb at the flared portion may define a curved path of the channels 120a, 120b. The curved path may follow an arc having a radius of about 40 mm, for example. The distal portion of the walls 131a, 13 lb in the flared portion therefore acts as a wedge, deflecting the first and second elongate probes 200a, 200b laterally away from each other, and away from the distal end 112, as they extend from the introducer 100.

[0089] In some examples, the first and second side walls 131a, 131b may extend in a direction away from the longitudinal axis in two planes. In the illustrated examples, the first and second side walls 131a, 131b curve away from the longitudinal axis X in a second plane. In the illustrated example, the side walls 131a, 131b curve downward (based on a reference orientation of the device as shown in Figures 1-4) relative to the longitudinal axis. As such, the probes 200a / b are deflected downward, away from the longitudinal axis as they extend from the introducer shaft 110, as shown in Figure 3. In this example, the channels 120a, 120b are configured to deflect the probes downwards at an angle of approximately 45 degrees relative to the horizontal plane in the reference orientation.

[0090] Deflection of the probes in at least the transverse plane may assist accurate deployment of the first and second elongate probes 200a, 200b into the respective uterine horns of the animal. For example, deflection of the first and second elongate probes 200a, 200b during extension from the introducer 100 may promote the distal tips 202a, 202b of the first and second elongate probes 200a, 200b moving away from each other laterally as they are extended, inhibiting the first and second elongate probes 200a, 200b from entering the same uterine horn. That is, when the probes are extended in vivo, lateral deflection of the first and second elongate probes 200a, 200b may promote the first and second elongate probes 200a, 200b extending on opposite sides of the internal bifurcation, or the point at which the uterine horns begin to fork.

[0091] The channels 120a, 120b may be at least partially open. For example, the channels 120a, 120b may be open along at least part of a length of the channel. In the example introducer 100 of Figures 1-4, the walls 131a, 131b partially enclose the channels 120a, 120b, such that the channels 120a, 120b are open on one side. Open channels may enhance ease of cleaning after use of the device 10, for example by increasing access to an inner region of the channels and visibility of any residual mucus or other material accumulated in the channels 120a, 120b after use.

[0092] The walls 131a, 131b may be curved to define a C-shaped cross-section of the channels 120a, 120b. The walls 131a, 131b may be configured to enclose the channels 120a, 120b to a sufficient extent to retain the first and second elongate probes 200a, 200b within the channels120a, 120b as the probes slide through the channels 120a, 120b. In some examples, the channels 120a, 120b may be at least partially, or substantially, enclosed.

[0093] Probes

[0094] The first and second elongate probes 200a, 200b may each comprise a tubular body 205a, 205b. The tubular body 205a, 205b may extend between a proximal end of the probes and the distal tips 202a, 202b. The tubular body 205a, 205b may define one or more internal lumens. In some examples, the first and second elongate probes 200a, 200b may define a plurality of lumens. For example, the first and second elongate probes 200a, 200b may include one or more lumens configured to receive one or more sensors and / or electrical connecting members, such as a cable or lead.

[0095] An example first elongate probe 200a is shown Figures 5 - 9 and discussed further below. Unless specified otherwise, second elongate probe 200b should be understood to include equivalent features as described in relation to the first elongate probe 200a.

[0096] The first elongate probe 200a may be configured to have a desired level of rigidity. The rigidity may be configured to be high enough to inhibit kinking or buckling of the first elongate probe 200a during insertion through the channel 120a of the body 300 and introducer 100, while maintaining a degree of flexibility sufficient to allow the first elongate probe 200a to conform to the shape of the uterine horn during deployment through the horn. The tubular body 205a of the first elongate probe 200a may be configured to confer a desired level of rigidity to the first elongate probe 200a. The tubular body 205a may include a stiffening member, such as a wire or one or more ridge elements. Additionally, or alternatively, the tubular body 205a may include a braided structure.

[0097] In some examples, a portion of the first elongate probe 200a (e.g. at least a distal region of tubular body 205a) may be configured to be resiliently flexible. For example, the first elongate probe 200a may be formed with a curved shape in the longitudinal direction (for example, by thermoforming the tubular body 205a). The first elongate probe 200a may be configured to straighten during insertion through the channel 120a and to return to the curved shape as the first elongate probe 200a exits the distal end of the channel. This may enhance conforming of the first elongate probe 200a to the natural shape of the uterine horn during insertion and / or minimise forces applied between the probe first elongate 200a and the horn.

[0098] In some examples, the first and second elongate probes 200a, 200b may be configured for transfer of material to the target region of the uterine horns. The material may include a reproductive material (such as semen and / or an embryo) and / or a therapeutic substance. The first and second elongate probes 200a, 200b may be configured to receive the material, such as the reproductive and / or therapeutic substance for transfer through the probes to the target region of the uterine horn. For example, the tubular bodies 205a, 205b may comprise a first lumenconfigured for receiving the material (such as reproductive material) and facilitating transfer of the material from the proximal end to the distal tip 202a, 202b of the first and second elongate probes 200a, 200b.

[0099] Probe sensors

[0100] The first and second elongate probes 200a, 200b may comprise one or more sensors, such as a temperature sensor. In some examples, the first elongate probe 200a comprises one or more first sensors and the second elongate probe 200b comprises one or more second sensors. The sensors may be configured to be positioned at or adjacent to a distal region of the first and second elongate probes 200a, 200b. The sensors may be configured to obtain sensed data from one or both of the first and second uterine horns when one or both of the first and second elongate probes 200a, 200b are extended into the uterine horns.

[0101] The elongate probes 200a / b may comprise one or more sensors, such as a temperature sensor. The elongate probes 200a / b may comprise a heating element.

[0102] The first elongate probe 200a may be configured to receive the one or more sensors within the first elongate probe 200a, for example within a lumen thereof, such as within tubular body 205a.

[0103] In some examples, the elongate probes 200a / b includes a sensor lumen 225a, as shown in Figures 5-7. The sensor lumen may be configured to receive a sensor 250a and one or more associated sensor leads 251a. When inserted, the sensor 250a may be positioned at or adjacent to the distal tip 202a of the first elongate probe 200a. The sensor 250a and lead 251a may be slidably insertable to the sensor lumen 225a. The sensor lumen 225a may include a stop member configured to inhibit movement of sensor 250a in a distal direction beyond the stop member. For example, the sensor 250a may be configured to abut the stop member when in an assembled position. In some examples, such as shown in Figures 6 and 7, the sensor lumen 225a may comprise a blind distal end. The sensor 250a may be configured to abut the blind distal end when inserted.

[0104] The sensor 250a may be configured to obtain data from the target region of the uterine horn when the distal tip 202a of the probe is positioned at or adjacent to the target region. The probe 200b may be similarly configured to receive a discrete sensor, which may be substantially as described for sensor 250a. The lead 251a may be configured to provide power to the sensor 250a and / or transfer signals to and / or from the sensor 250a. In some examples, the device 10 may be configured to determine a basal body temperature of the animal. The basal body temperature may be used as a reference temperature for processing the sensed temperature data from the uterine horns.

[0105] In some examples, the basal body temperature may be determined via one or more of the elongate probes 200a, 200b. For example, a basal temperature measurement may be obtainedfrom one or both of the probes 200a, 200b prior to applying thermal energy, such as when the probe is positioned within a portion of the reproductive tract, for example before full deployment to the target regions.

[0106] In some examples, the device 10 may comprise, or be configured for use with, a separate basal temperature sensor. The basal temperature sensor may be configured to obtain a basal body temperature of the animal.

[0107] The basal temperature sensor may be configured for placement at a rectal location of the animal. Additionally, or alternatively, the basal temperature sensor may be configured for placement at a vaginal location, a cervical location, or another suitable location on or within the animal. The basal temperature sensor may be provided as a discrete component, such as a rectal thermometer. In some examples, the basal temperature sensor may be integrated with the device 10, for example provided on the introducer 100. The basal temperature sensor may be provided at a proximal region of the introducer shaft 110, such that the basal temperature sensor is positioned within the vagina when the distal region 115 of the introducer is inserted through the cervix.

[0108] The device 10 may include, or be configured for use with, a controller. The controller may be configured to receive and process the sensed data to determine the presence or absence and / or location of a corpus luteum in a uterine horn.

[0109] In some examples, processing the data may comprise determining a temperature differential between the first uterine horn and the second uterine horn. The presence of a corpus luteum may be determined based on the determined temperature differential. For example, a higher temperature may indicate the presence of a corpus luteum.

[0110] Additionally, or alternatively, the presence of a corpus luteum may be determined based on a difference in heat flux between the first and second uterine horn. The device 10 may be configured to apply thermal energy to tissues adjacent to the first and second probes 200a, 200b. For example, the first and second elongate probes 200a, 200b may each include a heating element (such as a resistive heating element). The heating elements may be actuatable to increase a temperature of the heating element, thereby to apply thermal energy to the surrounding tissue. The thermal energy may be applied for a predetermined period of time. The device may be configured to sense temperature data during and / or after applying of the thermal energy.

[0111] In some examples, processing the data may comprise determining a rate of temperature increase of the tissue during applying of the thermal energy and / or determining a rate of temperature decrease following cessation of applying of the thermal energy. A slower rise in temperature during applying of the thermal energy and / or a faster decrease in temperature following cessation of application of the thermal energy may indicate relatively higher perfusion of the tissue, which may serve as an indicator of the presence of a corpus luteum.In some examples, the presence of a corpus luteum may be determined based on a differential in energy input required to maintain a substantially constant temperature at the first and second target regions. The device 10 may be configured to apply thermal energy to tissues adjacent to the first and second probes 200a, 200b to maintain a target temperature at the first and second target regions. For example, the heating elements of the first and second elongate probes 200a, 200b may be controlled to maintain a substantially constant temperature at the distal regions of the probes. The device 10 may be configured to monitor and / or record the amount of energy (e.g., electrical power) supplied to each heating element to maintain the target temperature.

[0112] Processing the data may comprise determining a differential between the energy input at the first target region and the energy input at the second target region. A higher energy input required to maintain the target temperature may indicate relatively higher perfusion of the tissue, as increased blood flow may dissipate heat more rapidly from the probe and surrounding tissue. Accordingly, a higher energy input at one of the target regions relative to the other may serve as an indicator of the presence of a corpus luteum associated with that uterine horn.

[0113] Examples of an elongate probe 200a including a heating element (e.g. resistor) 203a and a temperature sensor (e.g. thermistor) 204a are shown in cross section in Figures 8 and 9. In the illustrated examples, the heating element 203a and temperature sensor 204a are located within tubular body 205a. In some examples, the heating element 203a and temperature sensor 204a may be provided as a surface mount on an exterior surface of the probe 200a. In the example probe 200a of Figure 8, the heating element 203 a and temperature sensor 204a are located within tubular body 205a, surrounded by a pocket of air. By contrast, in the example probe 200a of Figure 9, the heating element 203a and temperature sensor 204a are encased with a layer of plastic material 206a within the tubular body 205a. The plastic material 206a may be an epoxy resin or other suitable material, such as other plastic material. Encasing the heating element 203a and temperature sensor 204a may increase the thermal diffusivity of the probe 200a, improving heat conductivity out of the probe 200a to the surrounding tissues.

[0114] In some examples, the temperature sensor may comprise a printed resistance temperature detector (RTD). In some examples, the temperature sensor 204a and / or the heating element 203a may be provided as part of a flexible circuit. The temperature sensor 204a and / or the heating element 203a may be provided on a substrate. The substrate may be printed directly onto the respective probe 200a, or may be printed on a flexible substrate and attached (e.g. laminated, or applied via adhesive) to the probe 200a.

[0115] In some examples, device 10 may include a control mechanism for controlling the applying of thermal energy. For example, the device 10 may include a button, switch or other user input device on a body of the device, for activating and / or deactivating the heating element to start / stop applying of the thermal energy. In some examples, the applying of thermal energymay be automated or semi-automated. For example, the device 10 may be configured to allow a user to trigger commencing of applying thermal energy, after which the device 10 runs an automated heating and cooling cycle, based on a one or more of a predetermined heating time, and a predetermined temperature rise.

[0116] The device 10 may be configured to facilitate selective deployment of reproductive material from one of the first and second elongate probes 200a, 200b, based on the determined presence of a corpus luteum (CL). For example, the device may be configured to activate deployment of reproductive material from only one of the extended probes 200a, 200b into the horn in which a corpus luteum is detected. In other examples, the device 10 may be configured to provide an indication to a user to indicate the presence of the corpus luteum and the horn (e.g. left or right) in which the corpus luteum was detected. The user may then manually deploy the material (e.g. an embryo) into the horn indicated as associated with the corpus luteum.

[0117] In some examples, the elongate probes 200a and 200b are configured to detect the presence of a CL and deploy reproductive material. In some examples, the elongate probes 200a and 200b are configured to detect the presence of a CL and deploy the reproductive material. In other examples, these functions may be performed by separate sets of probes 200a / 200b having different characteristics. For example, a first pair of elongate probes 200a and 200b including sensors may be used for detecting the presence of a CL, while a second probe (or probes) 200a and / or 200b including a tubular body 205a / 205b may be used for deploying the reproductive material.

[0118] Use

[0119] The device 10 as described in examples above may be used to access the reproductive tract of an animal to determine the presence or absence of a corpus luteum. Figure 10 illustrates a user accessing the reproductive tract of an animal using a device 10 according to the present disclosure.

[0120] Prior to insertion, the user may perform preliminary steps of assembling one or more components of the device 10. For example, the user may assemble the probes 200a, 200b by inserting the sensor 250a with connected sensor lead 251a into the sensor lumen 225a to position the sensor 250a at or adjacent to the distal tip 202a of the first elongate probe 200a. In other examples, the first and second elongate probes 200a, 200b may have the sensors 250a, 250b and leads 251a, 251b pre-assembled therein.

[0121] Once prepared, the first and second elongate probes 200a, 200b may be inserted into the channels 120a, 120b of the device 10, for example by inserting the distal tips of the first and second elongate probes 200a, 200b into a proximal end of the channels 120a, 120b and applying force to the probes (e.g. via a user’s fingers) to slide the first and second elongate probes 200a, 200b through the channels 120a, 120b in the distal direction. The first and second elongateprobes 200a, 200b may be positioned with their distal tips at or adjacent to respective distal ends of the channels 120a, 120b. The user may plug connectors of the probes 200a, 200b into sensor connector ports on the body 300 of the device 10.

[0122] The user may insert the distal end of the device into the vagina of the animal as shown in Figure 10.

[0123] The user may then advance the distal end 112 of the introducer into the cervical opening. The user may then push to advance introducer 100 through the cervix, for example until the distal end 112 of the introducer 100 reaches a transition between the cervix and the uterus, or enters the uterus.

[0124] The user may then deploy one, or both, of the first and second elongate probes 200a, 200b into the uterine horns. For example, the user may feed a slack length of the first and second elongate probes 200a, 200b at the proximal end thereof through the channels 120a, 120b such that the distal ends of the probes 200a, 200b are pushed forward to extend beyond the distal end 112 of the introducer shaft 110. Figure 10 shows both probes 200a, 200b extending simultaneously into the respective uterine horns.

[0125] As discussed previously, the shaft 110 of the introducer 100 is configured to cause the first and second elongate probes 200a, 200b to diverge away from each other and to curve downwards as they extend from the introducer 100. Further, the probes 200a, 200b may be configured to curve as they extend from the introducer 100 to conform to the anatomical shape of the uterine horns. This may allow the first and second elongate probes 200a, 200b to enter respective first and second uterine horns and to extend through the horns to reach the target transfer region.

[0126] Once the distal tips of the first and second elongate probes 200a, 200b are positioned at the target transfer regions within the respective horns, the device may obtain sensed data (e.g. temperature data) via the sensors of the first and second elongate probes 200a, 200b. In some examples, the device 10 may deliver a bolus of thermal energy to the tissue in the target region via heating elements in the first and second elongate probes 200a, 200b. In some examples, sensed data (e.g. temperature data) may be obtained from each of the uterine horns sequentially via the sensor of a single probe 200a. The device 10 may obtain sensed data temperature data during delivery of the thermal energy and / or following cessation of delivery of the thermal energy.

[0127] The sensed data may be provided to a processor in the controller and processed to determine the presence of a corpus luteum in one of the horns, for example, based on a temperature differential between the horns and / or based on a difference in a rate of heat dissipation in the horns. The controller may provide an indication as to the side on which the corpus luteum was detected.The user may then affect deployment of the reproductive material (e.g. embryo) into the horn in which the corpus luteum was detected.

[0128] After use, the device 10 may be withdrawn from the animal. One or more components of the device 10 may be configured to be cleanable for re-use. In general, the device 10 may be hermetically sealed and configured to be cleaned, for example by wiping of external surfaces of the device 10. Additionally, or alternatively, one or more component of the device 10 may be disposable and / or replaceable.

[0129] The method and device 10 according to examples of the present disclosure may provide the ability to detect the presence and location of corpus luteum. This may enable selective delivery of reproductive material (for example an embryo), facilitating more accurate and effective embryo transfer (or artificial insemination) practices.

[0130] Example 1 - Corpus Luteum (CL) detection

[0131] A study was conducted to determine the reliability of the device to predict the presence or absence of the Corpus Luteum (CL), as well as the ability of the device to determine location of the CL within the uterus (right or left horn).

[0132] Temperature differential

[0133] Elongate probes 200a, 200b including temperature sensors were inserted into both uterine horns of a cow and fluctuations over time in the temperature of the respective horns were measured. The cow’s resting body temperature was also measured. The difference between the temperature observations and the starting temperature of each horn was also derived for analysis. These variables are expressed as:

[0134] Temp lt: temperature observations at each timestamp;

[0135] Cowbodytemp: resting temperature of the cow:

[0136] Temp diff difference from the starting temperature at each timestamp

[0137] The measurements above were repeated for n=44 animals. A Generalised Additive Model was developed to determine the relationship between the CL and the above variables. This model was used as the relationship between the temperature and CL was observed to be non-linear.

[0138] There is an observable difference in the temperature between the horns when a CL is present. Initial analysis shows a significant relationship between the observed variables and the response variables (p<0.001). The model is moderately robust when predicting the CL side (R2= 0.63). A confusion matrix shows that the model can predict the CL side with >75% accuracy when trained on the dataset. The model was less robust when predicting the CL presence or absence (R2= 0.2). A confusion matrix shows that the model can predict the CL presence or absence with >55% accuracy when trained on the dataset.The model for this example was tested on the same dataset that it was trained on. This can result in ‘overfitting’ which reduces the strength of the model. Additionally, improvements can be made to the accuracy of the model, for example by including further observations. A power analysis was conducted to determine the number of additional observations required for the model to improve to >80% accuracy (n=80).

[0139] Heat flux

[0140] Further testing was conducted to determine the reliability of predicting the presence or absence of the Corpus Luteum (CL), and side of the uterine horn, based on a “heat flux” technique to determine relative perfusion in the uterine horns.

[0141] Elongate probes 200a, 200b each including a temperature sensor (e.g. a thermistor), and heating element (e.g. a resistor) were inserted into both uterine horns of a cow. Heating was applied to each uterine horn via the heating elements and temperature measurements taken during a heating phase, cooling phase and idle state.

[0142] A perfusion calculation was made based on the measured temperature data, after the measured temperature fell below the initial starting temperature, or after 45 seconds had elapsed. In this study, the perfusion algorithm used temperature data obtained from the rising temperature portion of the testing. The presence of a CL was determined based on a difference in temperature rise time between the two elongate probes 200a, 200b. The rise time was calculated using the formula rise time = (cooling start time) - (baseline rise time). The baseline rise time was determined as the time at which the temperature had increased by 1 degree from the initial temperature (i.e. the temperature before commencement of heating). The cooling start time was determined as the time at which the temperature had increased by 3 degrees Celsius from the initial temperature. The system was configured to cease the heating phase and commence the cooling phase once a temperature rise of 3 degrees Celsius or more was detected. This is to prevent excessive heating, which could produce tissue damage and / or an undesirable hormonal response.

[0143] If a difference in rise time between the two horns was detected, the side with the slower temperature rise was selected as likely having the CL. This is because the presence of a CL usually correlates with increased perfusion (i.e. increased blood flow), which would slow the heating of the probe and surrounding tissue. In the present example, a difference in rise time of greater than 0.2 seconds was used to determine the presence and side of the CL.

[0144] One example of data collected using the technique described above is shown in Figure 11. In this example, the white data points represent the temperature data recorded in “horn A” by the first elongate probe 200a and the black data points represent the temperature data recorded in “horn B” by the second elongate probe 200b. In this case, the first elongate probe 200a recorded a steep increase in temperature. Active heating ceased once the temperature rise was over 3degrees. By contrast, the second elongate probe recorded a slower increase in temperature, reaching a steady-state temperature condition in approximately 10 seconds. This indicates that horn A had a greater capacity for heat dissipation than horn B. This may be due to less perfusion in horn A relative to horn B, indicating likely presence of the CL in horn B.

[0145] Preliminary testing using the above-described method was performed on 14 cows. The predicted CL side was compared to data indicating CL side as determined by conventional methods. The heat flux method as described above was able to predict the correct CL side in 11 out of 14 tests (78% success rate).

[0146] Further testing was performed on 3 cows, with a prediction of CL side agreeing with conventional assessment in all 3 cases (100% success rate).

[0147] Further testing was performed on 28 cows, with usable data obtained from 19 tests. The predicted CL side was compared to data indicating CL side as determined by conventional methods. The results indicated 6 tests with no clear high / low heat flux indication, which would indicate no CL. Of these 6 results, 3 correlated with a determination of no CL by conventional methods. The remaining results may have failed to detect a difference due to the probes not being deployed deep enough within the horns, or possibly due to the probes being deployed into the same horn. 13 results showed a clear high / low heat flux differentiation between the left and right sides. Of these 13 results, 7 correlated with the CL side as determined using conventional methods (54% success rate). Individual variation between the probes and / or variation from protocol may have contributed to lower success rate in this trial.

[0148] Testing was performed on a further 8 cows, with a prediction of CL side agreeing with conventional assessment in 6 out of 8 cases (75% success rate).

[0149] Example 2 - Corpus Luteum (CL) detection and localisation

[0150] A further study was conducted to determine the reliability of the device to predict the presence or absence of the Corpus Luteum (CL), as well as the ability of the device to determine location of the CL within the uterus (right or left horn). In the trials described in this example, the elongate probes were deployed as separate components, with successive measurements taken in one uterine horn before moving the probe to the other horn and repeating measurements.

[0151] The presence of a CL within a uterine horn correlates with higher blood perfusion compared to the uterine horn in which the CL is absent. At the time of writing, measurement of blood perfusion is performed by a skilled technician using ultrasound (e.g., Doppler sonography), and this is typically performed during pregnancy to assess blood perfusion and flow to the reproductive tract. However, the use of ultrasound is unlikely to be feasible or practical when performing embryo transfer in many circumstances and requires the presence of a skilled technician to operate the sonography equipment, which may not be available. Based onthe positive evidence in Example 2, the inventors undertook a further study to assess whether the Nbryo device was capable of detecting changes or differences in blood perfusion status with similar effectiveness to ultrasound, albeit using thermal sensing probes inside the uterus deployed using the device. A statistical model was also developed to enable machine prediction of the CL presence or absence (CL BINARY), as well as the side of the uterus (CL LEFT RIGHT).

[0152] This model was developed using data collected from two animal trials. The first trial (n=60) was conducted in December 2024 and preliminary analysis showed a significant relationship (p<0.01) between temperature in the respective uterine horns and the ability to predict in which of the uterine horns the CL is located. In order to improve the model’s accuracy and power, a second trial was conducted in January 2025 (n=81).

[0153] Analysis of the data from both trials has produced a model that can accurately predict (>75%) the presence or absence of a CL and predict to a reasonable degree (>70%) the uterine horn (i.e., left or right) in which the CL is located. In both cases, the prediction is made with 90% power. These models show that there is a statistically significant relationship between the temperature of the cow (p>0.1), the temperature of the uterus (p>0.01) and the difference between those two temperatures (p>0.01). The addition of phenotypic covariates (cow age, number of pregnancies) would improve analysis further.

[0154] Methods

[0155] Animal Trials

[0156] Cows were synchronized 21 days before the trial. The cow’s body temperature was taken using a rectal thermometer. The device probes were entered into the cow on both sides of the uterus and a perfusion detection program was run for 35 seconds. The temperature of the uterus was recorded on both sides each second.

[0157] Covariates

[0158] Several covariates were collected and synthesised for analysis, as summarised in Table 1:

[0159] Table 1 - Covariates for analysis

[0160] DESCRIPTION TYPE

[0161]

[0162] Farm ID of the cow Descriptor

[0163]

[0164] Incremental trial run number Descriptor COWBODYTEMP Body temperature of the cow Predictor STARTINGTEMP Temperature of the uterus before perfusion detection Predictor STARTTEMPD1FF Difference between the cow body temp and starting Predictor temp

[0165] MEANTEMP Mean temperature of the uterus Predictor Difference between cow body temp and mean temp Predictor Maximum temperature of the uterus Predictor Difference between the cow body temp and max temp Predictor Continuous temperature of the uterus Predictor Binary variable noting presence or absence of the CL Outcome Binary variable describing the side of the CL (left=0, Outcome

[0166]

[0167] right 1 )

[0168] Random Forest Importance

[0169] R programming software was used to run a random forest model to determine the most significant covariates for both the presence / absence of the CL and the side.

[0170] The temperature difference (starting and mean) between the uterus and the cow’s body temperature were both found to be the most significant predictors of both the presence or absence of the CL as well as the CL side (Fig. 12).

[0171] Modelling - Presence / Absence

[0172] A training dataset was produced to train generalised linear model (GLM) in determining the CL presence or absence based on the most significant covariates described above in Table 3. The GLM was then assessed against a test dataset and a confusion matrix produced to show the model’s accuracy. The GLM was then tested using an ROC curve to determine the most suitable threshold for classifying the result

[0173] Modelling - Left / Right

[0174] A training dataset was produced for training. A stepwise logistic regression model was used to determine the combination of variables providing the most suitable fit for a GLM. A random forest model was also used as a predictive model. The models were each tested using an ROC curve to determine the most suitable threshold for classifying the result.

[0175] Power Analysis

[0176] A power analysis was undertaken to assess the power of the model’s predictive accuracy.

[0177] Results

[0178] Modelling - Presence / Absence

[0179] The models tested show good accuracy (-75%), suggesting that the method and device correctly detects CL presence in more than 3 out of 4 cows. Two threshold scenarios that produce acceptable results were determined, as shown in Table 2:

[0180] Table 2 - Threshold scenarios

[0181] Threshold - 0.81Sensitivity (model ability to CL if present) 81%

[0182] Specificity (model ability to CL if present ) 57%

[0183] Overall Accuracy - 77.55%

[0184] Threshold - 0.84

[0185] Sensitivity (model ability to CL if present) 73%

[0186] Specificity (model ability to CL if present) 86%

[0187] Overall Accuracy - 75.51%

[0188] Modelling - Left / Right

[0189] Both models showed acceptable accuracy overall (-70%), predicting which of the two uterine horns possessed the CL in more than 3 out of 5 cows. Addition of phenotypic or genetic data is likely to improve these results. The two models used were the Stepwise Model and the Random Forest Model, as shown in Table 3 below.

[0190] Table 3 - Models used for predicting CL side

[0191] Stepwise Model

[0192] Sensitivity (accuracy to predict presence) 77%

[0193] Specificity (accuracy to predict absence) 67%

[0194] Overall Accuracy - 72.73%

[0195] Random Forest

[0196] Sensitivity (accuracy to predict presence) 69%

[0197] Specificity (accuracy to predict absence) 75%

[0198] Overall Accuracy - 70.83%

[0199] Power Analysis

[0200] With a sample size of 140, the models tested range from 70% to 80% accuracy in their ability to predict which side of the uterus contained the CL, with 90% confidence.

[0201] Conclusions

[0202] The additional and larger dataset enabled training of the models on a portion (80%) of the data and the ability to evaluate performance of the models on the remaining data (train and test datasets).

[0203] The evidence from this study demonstrates that temperature profiles within the uterus can be used to determine the presence and location (left vs. right) of the corpus luteum (CL).Furthermore, modelling of the data suggests that the probability of these findings occurring due to random chance (false positives) is relatively low.

[0204] Example 3 - Statistical modelling approaches for CL detection

[0205] A study was conducted to develop and compare statistical modelling approaches for predicting the presence or absence of a corpus luteum (CL) and the location of the CL within the uterus.

[0206] Data Collection

[0207] Data was collected from live cows. Cows were uniquely identified by visual ID. Proof-of-concept analysis was performed using data from 104 recipients, with 76 animals in a training set and 28 animals in a test set. Data was collected using a single probe, with successive measurements taken in one uterine horn before moving the probe to the other horn and repeating measurements. Rectal temperature was separately measured using a commercial thermometer. Ground truth for location of the corpus luteum was determined via rectal ultrasound, with outcomes classified as: No CL, Left Side CL, or Right Side CL.

[0208] Feature Extraction

[0209] The following features were derived from each (i.e. left and right) temperature profile:

[0210] Starting temperature

[0211] Peak temperature

[0212] Time taken to reach peak temperature

[0213] Relative difference between starting temperature and rectal temperature Relative difference between peak temperature and rectal temperature Statistical Modelling Approach #1 - Three-way Model

[0214] A statistical machine learning model (Random Forest) was built to predict: No CL, Left CL, or Right CL. The model uses features derived from each temperature profile as described above.

[0215] Model 1 (with cow body temperature): The three-way Random Forest model achieved an overall accuracy of 53.57% (95% CI: 0.3387, 0.7249). Sensitivity for detecting No CL was 0.60, for Left CL was 0.60, and for Right CL was 0.50. Specificity for No CL was 0.87, for Left CL was 0.74, and for Right CL was 0.60.

[0216] Model 2 (without cow body temperature): Removing cow body temperature reduced sensitivity for No CL (0.60 to 0.20). Specificity was slightly smaller for Left CL (0.74 to 0.69) and remained the same for No CL and Right CL. Overall accuracy was 50% (95% CI: 0.3065, 0.6935).Statistical Modelling Approach #2 - Two-stage Model

[0217] A two-stage modelling approach was developed. Stage 1 (presence-absence) determines whether a CL is present or not, with output being binary: CL present vs. No CL. Stage 2 (left or right) applies to cows predicted to have a CL, where the model makes a second decision as to whether the CL is on the left side or the right side. This step uses a separate model trained only on cows with CLs. The same features as Statistical Modelling Approach #1 were used.

[0218] Model 3 (two-stage with cow body temperature): The two-stage Random Forest model achieved an overall accuracy of 75% (95% CI: 0.5513, 0.8931) and Kappa of 0.5758. Sensitivity for No CL was 0.40, for Left CL was 1.00, and for Right CL was 0.78. Specificity for No CL was 0.83, for Left CL was 0.87, and for Right CL was 1.00. Balanced accuracy for No CL was 0.61, for Left CL was 0.93, and for Right CL was 0.89.

[0219] Model 4 (two-stage without cow body temperature): Overall accuracy was 71.43% (95% CI: 0.5133, 0.8678) and Kappa of 0.5152. Sensitivity for No CL was 0.40, for Left CL was 0.80, and for Right CL was 0.78. Specificity for No CL was 0.78, for Left CL was 0.87, and for Right CL was 1.00. Balanced accuracy for No CL was 0.59, for Left CL was 0.83, and for Right CL was 0.89.

[0220] Conclusions

[0221] The two-stage modelling approach (Models 3 and 4) demonstrated improved performance compared to the three-way model (Models 1 and 2), particularly for detecting the location of the CL (Left vs Right). The two-stage model with cow body temperature (Model 3) achieved the highest overall accuracy of 75%.

[0222] Example 4 - Corpus Luteum (CL) detection using integrated dual-probe device

[0223] A further study was conducted to validate the device’s ability to predict the presence or absence of a CL and the location of the CL within the uterus using a device comprising an integrated dual-probe configuration. In the trials described in Examples 1 and 2, the elongate probes were deployed as separate components. In this Example, the elongate probes were provided as part of an integrated device, with the first and second elongate probes being simultaneously deployable from a common introducer into the respective uterine horns.

[0224] Animal Trials

[0225] Data was collected from N=17 cows. Cows were synchronised prior to the trial. The cow's body temperature was taken using a rectal thermometer. The integrated dual-probe device was inserted into the reproductive tract of the cow, with the distal region of the introducer advanced through the cervix. The first and second elongate probes were then simultaneously deployed from the introducer into the respective first and second uterine horns. Temperature datawas recorded from both uterine horns. Ground truth for location of the corpus luteum was determined via ultrasound, with outcomes classified as: No CL (0), Left (1), Right (2), or Bilateral (B).

[0226] Data Preparation

[0227] All data was imported and cleaned programmatically. Column names were standardised and units verified. Time-series data was extracted per cow and feature extraction was performed consistently across animals.

[0228] Feature Engineering

[0229] The following primary predictors were computed from the time-series data per cow: startingtemp LEFT (starting temperature of the left uterine horn) startingtemp RIGHT (starting temperature of the right uterine horn) maxtemp LEFT (maximum temperature of the left uterine horn)

[0230] maxtemp RIGHT (maximum temperature of the right uterine horn)

[0231] maxtime LEFT (time to reach maximum temperature in the left uterine horn) maxtime RIGHT (time to reach maximum temperature in the right uterine horn) Additional predictors considered included rectal temperature, left heat percentage, and right heat percentage.

[0232] Modelling Strategy

[0233] Given the small sample size (N=17) and class imbalance (3 cows with no CL, 14 cows with CL), a two-stage modelling strategy was implemented. Stage 1 determined presence vs absence (CL vs No CL). Stage 2 determined lateralisation (Left vs Right), conditional on CL presence. A Random Forest classifier was used in both stages. The two-stage modelling approach was consistent with the approach developed in Example 3, although model thresholds were rebuilt to account for differences in probe configuration and manufacturer.

[0234] Two model specifications were tested:

[0235] Model 1 : 6 thermal predictors only

[0236] Model 2: 6 thermal predictors plus rectal temperature

[0237] Validation Approach

[0238] Due to the smaller sample size compared to Example 3, Leave-One-Recipient-Out Cross-Validation (LOOCV) was used, rather than separate training and test subsets. For each cow, the model was trained on N-l cows and used to predict the held-out cow. This was repeated for all cows. This approach maximises training data usage, provides unbiased out-of-sample evaluation, and avoids optimistic bias from internal re-substitution. All threshold tuning was performed on cross-validated predictions, rather than training data.Results - Phase I: Presence Detection

[0239] Due to an extreme class imbalance in this dataset (3 non-CL vs 14 CL), no stable or generalisable could be developed for presence detection. Models defaulted to predicting CL present. Additional non-CL cases are required for robust presence-detection.

[0240] Results - Phase IP. Left vs Right CL Detection

[0241] Only cows with confirmed CL (n=14) were included in Phase II analysis. Both Model 1 and Model 2 achieved optimal performance with the following results:

[0242] Accuracy: 85.7%

[0243] Balanced Accuracy: 83%

[0244] Sensitivity (Left detection): 67%

[0245] Specificity (Right detection): 100%

[0246] Kappa: 0.70 (indicating substantial agreement beyond chance)

[0247] P-value vs baseline: 0.0248 (model performs significantly better than always predicting the majority class)

[0248] The confusion matrix for Phase II showed: 4 left-sided CL correctly identified as left; 0 right-sided CL incorrectly identified as left; 2 left-sided CL incorrectly identified as right; 8 right-sided CL correctly identified as right.

[0249] All right-sided CL were correctly identified. Two left-sided CL were misclassified out of 6. No right-sided CL were misclassified as left. Performance statistically exceeded the majorityclass baseline.

[0250] Adding rectal temperature did not materially improve performance (Model 2), suggesting the discriminatory signal originates from the probe-derived thermal features.

[0251] Variable Importance

[0252] In Model 1 using thermal predictors only, the dominant predictors were maxtemp RIGHT (mean importance 0.0587) and startingtemp RIGHT (mean importance 0.0528). These two variables contributed substantially more than all others.

[0253] Conclusions

[0254] The results of this study demonstrate that the integrated dual-probe device is capable of detecting the location of a corpus luteum (Left vs Right) with statistically meaningful accuracy (85.7%) under strict leave-one-out cross-validation. The observed performance is consistent with the presence of biologically relevant lateral information within the probe-derived thermal features. The use of an integrated dual-probe device, with first and second elongate probes simultaneously deployable from a common introducer, may provide advantages in terms of easeof use, consistency of probe deployment, and / or simultaneous data collection from both uterine horns.

[0255] It will be appreciated by persons skilled in the art that numerous variations and / or modifications may be made to the above-described embodiments and examples, without departing from the broad general scope of the present disclosure. The present embodiments and examples are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

CLAIMS1. A method of determining the presence or absence of a corpus luteum in a uterus of an animal, the method comprising:(a) obtaining sensed temperature data indicative of temperature from at least one target region in the uterus;(b) providing the sensed temperature data at a processor; and(c) processing the sensed temperature data at the processor to determine the presence or absence of a corpus luteum in the animal.

2. The method of claim 1 comprising determining a basal body temperature of the animal, wherein processing the sensed temperature data comprises comparing the sensed temperature data to the basal body temperature.

3. The method of claim 1 or claim 2, wherein the sensed temperature data is obtained from within at least one uterine horn.

4. The method of any one of the preceding claims, comprising:(a) obtaining sensed temperature data indicative of temperature at first target region within a first uterine horn of the animal; and(b) obtaining sensed temperature data indicative of temperature at a second target region within a second uterine horn of the animal.

5. The method of claim 4, wherein processing the sensed temperature data comprises comparing the sensed temperature data from the first target region in the first uterine horn to the sensed temperature data from the second target region in the second uterine horn.

6. The method of claim 5, wherein processing the sensed temperature data comprises determining a temperature differential between the first uterine horn and the second uterine horn.

7. The method of any one of the preceding claims, comprisinginserting a probe into at least a first uterine horn of the animal to reach a first target region in the first uterine horn, wherein the probe includes a sensor; andobtaining the sensed temperature data indicative of temperature at the first target region from the sensor.

8. The method of claim 7, further comprising:inserting the probe into a second uterine horn of the animal to reach a second target region in the second uterine horn; andobtaining the sensed temperature data indicative of temperature at the second target region from the sensor.

9. The method of any one of the preceding claims, comprising:inserting first and second probes into respective first and second uterine horns of the animal to reach respective first and second target regions of the uterine horns, wherein the first and second elongate probes include respective first and second sensors;obtaining the sensed temperature data indicative of temperature at the first and second target regions from the first and second sensors, respectively.

10. The method of claim 9, comprising applying thermal energy to tissue of the first uterine horn and the second uterine horn adjacent the first and second probes at the first and second target regions.

11. The method of claim 10, wherein processing the sensed temperature data comprises:determining a rate of temperature change at the first and second target regions during and / or following the applying of the thermal energy.

12. The method of claim 11, wherein processing the sensed temperature data further comprises:comparing the rate of temperature change at the first target region to the rate of temperature change at the second target region; anddetermining, based on the comparison, a presence or absence of a corpus luteum in the animal.

13. The method of claim 12, wherein processing the sensed temperature data further comprises:determining, based on the comparison, a location of a corpus luteum as associated with the first uterine horn or second uterine horn.

14. The method of claim 10, comprising:maintaining a substantially constant temperature at the first and second target regions by controlling the applying of the thermal energy to the tissue,wherein processing the sensed temperature data comprises:determining an energy input required to maintain the substantially constant temperature at the first and second target regions,comparing the energy input at the first target region to the energy input at the second target region; anddetermining, based on the comparison, a presence or absence of a corpus luteum in the animal.

15. A device for accessing the reproductive tract of an animal to determine the presence of a corpus luteum, the device comprising:an introducer having a distal region configured for insertion into a uterine cervix of the animal; andat least one elongate probe, the elongate probe including at least one sensor; wherein the elongate probe is extendable from the distal region of the introducer into the uterus of the animal to reach a target region of the uterus.

16. The device of claim 15, comprising:a first flexible elongate probe; anda second flexible elongate probe,wherein the first and second elongate probes are extendable from the distal region of the introducer into respective first and second uterine horns of the animal to reach respective first and second target regions of the uterine horns, wherein the first and second elongate probes each comprise at least one sensor.

17. The device of claim 16, wherein the first and second elongate probes comprise respective heating elements.

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