Abstract: One aspect of the present disclosure relates to a system for treating obstructive sleep apnea in a subject. The system can include a power source and a neuromuscular stimulator in electrical communications with the power source. The neuromuscular stimulator can include a controller and at least one electrode. The controller can be configured to receive certain power and stimulation parameters associated with a therapy signal from the power source. The at least one electrode can be configured to deliver the therapy signal to a target tissue associated with control of a posterior base of the tongue of the subject.

Abstract: Herein are provided systems, devices, and methods for the treatment of oral and pharyngeal disorders via the stimulation of pharyngeal muscles. Contraction of the pharyngeal muscle cells (9) is induced by activation of at least one ion channel (1) formed in at least one of a muscle cell and a neural cell. The ion channel opens (4) when it is activated by a stimulus (3). This allows ions to flow into (5) and out of (6) the cell, causing muscle contraction. This muscle contraction can be targeted towards specific muscles depending upon the condition to be treated.

Abstract: Described herein are devices and methods of treating obstructive breathing disorders in a patient. A method may include: attaching an anchor to a dorsal region of a tongue body; applying an external force to the tongue body; and adjusting a magnitude of the external force. In some embodiments, the magnitude of the external force is adjustable across multiple levels based on one or more of: patient comfort, desired therapeutic effect, or patient wake or sleep state. In some embodiments, at least a portion of the external force is directed along an anterior direction. In some embodiments, the external force causes at least one of the following actions: anterior displacement of a portion of the posterior tongue during sleep or reducing posterior displacement of a portion of the tongue during sleep.

Abstract: Systems and methods of evaluating a patient comprise the steps of obtaining temporal data of the patient after an event, monitoring a plurality of patient parameters, compiling patient data based on the temporal data and patient parameters, determining a state or change in state of the patient based on the compiled patient data, and alerting medical staff of the state or change in state.

Abstract: An in vitro training method for training genioglossus muscle strength includes adhering an electrode patch of an in vitro training device to a bottom of a chin of a user during a non-sleep period. The electrode patch receives an electrical stimulation signal from an electrical stimulation module of the in vitro training device to stimulate the genioglossus muscle of the user through transdermal electrical stimulation. The electrode patch includes a body surface adhering face and an assembling face opposite to the body surface adhering face. The body surface adhering face is adhered to the bottom of the chin of the user to align with the genioglossus muscle. The electrical stimulation module is disposed on the assembling face and in electrical connection with the electrode patch. The electrical stimulation module sends an electrical stimulation signal to stimulate the genioglossus muscle through transdermal electrical stimulation.

Abstract: A method of detecting sleep apnea includes generating a cardiac signal indicating activity of a heart of a patient. The method further includes determining a short-term average heart rate and a long-term average heart rate. The method further includes determining a start and end of a heart rate cycle based on the short-term average heart rate and the long-term average heart rate. The method further includes determining physiological parameter values occurring during the heart rate cycle. The method further includes determining whether patient has or has not experienced a sleep apnea event based on whether one or more conditions are satisfied by one or more parameter values for one or more heart rate cycles and responsively generating an indication that patient has or has not experienced a sleep apnea event.

Abstract: One aspect of the present disclosure relates to a system for treating obstructive sleep apnea in a subject. The system can include a power source and a neuromuscular stimulator in electrical communications with the power source. The neuromuscular stimulator can include a controller and at least one electrode. The controller can be configured to receive certain power and stimulation parameters associated with a therapy signal from the power source. The at least one electrode can be configured to deliver the therapy signal to a target tissue associated with control of a posterior base of the tongue of the subject.

Abstract: Implantable devices and/or sensors can be wirelessly powered by controlling and propagating electromagnetic waves in a patient's tissue. Such implantable devices/sensors can be implanted at target locations in a patient, to stimulate areas such as the heart, brain, spinal cord, or muscle tissue, and/or to sense biological, physiological, chemical attributes of the blood, tissue, and other patient parameters. The propagating electromagnetic waves can be generated with sub-wavelength structures configured to manipulate evanescent fields outside of tissue to generate the propagating waves inside the tissue. Methods of use are also described.

Abstract: An intra-oral appliance to power and/or communicate with a neurostimulator is provided. The intra-oral appliance can include a teeth covering configured to fit over mandibular incisor, canine and/or premolar teeth of a human being and a remote controller in the form of a housing extending posteriorly from and operably connected to the teeth covering. The housing can include a power source, a coupling coil configured to transmit power to the neurostimulator and configured to receive power from an external charger, and electrical circuitry operably connected to the coupling coil and the power source.

Abstract: Methods and systems for proving spinal cord stimulation (SCS) for treating pain in a patient are described. Embodiments of the described methods and systems can provide sub-perception SCS that has a fast wash-in time by using stimulation parameters that activate surround inhibition in the patient. Measuring retrograde potentials evoked by the stimulation can be performed to facilitate choosing the best stimulation parameters, in particular, the best stimulating electrode contact configurations for activating surround inhibition. For example, peripheral electrodes may be placed at the center of the patient's pain (within a local receptive field (LRF), with respect to the patient's pain center) and within an area surrounding the patient's pain center (within a surrounding receptive field (SRF), with respect to the patient's pain center). Retrograde evoked potentials measured and the SRF and/or the LRF can be used to guide the selection of the stimulation parameters.

Abstract: A catheter includes an expandable frame for insertion into an organ of a patient, one or more first electrodes, and a second electrode. The one or more first electrodes are disposed on the expandable frame at one or more first positions for placing in contact with a target tissue of the organ, and are configured to perform one or both of: (i) sensing one or more electrical signals from the target tissue, and (ii) applying one or more ablation pulses to the target tissue. The second electrode is disposed within an internal volume of the expandable frame, at a second position that is not in contact with the target tissue while the one or more first electrodes contact the target tissue, and is configured to serve as a return or common electrode for the electrical signals.

Abstract: Disclosed herein is a method for electrical nerve (510) stimulation, the method comprising: generating an electrical stimulation pattern (100) comprising a plurality of successive pulse trains (110), wherein each pulse train (110) has a pulse train amplitude (111); delivering the electrical stimulation pattern (100) to a subject's hypoglossal nerve (510) with a stimulator (300) having at least one electrode (310); modulating the electrical stimulation pattern (100), wherein modulation of the electrical stimulation pattern (100) comprises gradually increasing the pulse train amplitude (111) from one pulse train (110) to a successive pulse train (110) at stimulation onset (101) until a determined target stimulation amplitude (130) is reached; characterized in that modulation of the electrical stimulation pattern (100) further comprises decreasing the target stimulation amplitude (130) to a defined step-down amplitude (140) within each pulse train (110) after the target stimulation amplitude (130) was reached.

Abstract: In methods for treating a patient, a time varying magnetic field is applied to a patient's body and causes a muscle contraction. The time-varying magnetic field may be monophasic, biphasic, polyphasic and/or static. The method may reduce adipose tissue, improve metabolism, blood and/or lymph circulation. The method may use combinations of treatments to enhance the visual appearance of the patient.

Abstract: A method includes applying a stimulation profile having a plurality of stimulation signals to at least one muscle of a recipient and/or to at least one neuron configured to control the at least one muscle. The method further includes monitoring muscle fatigue of the at least one muscle during said applying the stimulation profile. The method further includes automatically modifying the stimulation profile in response to said muscle fatigue.

Abstract: Methods, systems and non-transitory computer readable storage media of electric field treatment planning of a target tissue. A method of electric field treatment planning of a target tissue site includes: (a) obtaining an image of the target tissue site, (b) determining volume and one or more electric properties of the target tissue site, (c) using the volume and the one or more electric properties to: (i) determine a number of electrodes to treat the target tissue site with electric fields, each electrode having one or more contacts, (ii) determine a placement of the number of electrodes within the target tissue site, and (iii) relative to one of the contacts in one of the number of electrodes at the placement determined in (ii), determine an electric field that results in a prescribed electric field coverage of the target tissue site.

Abstract: Examples are described herein for determining aggregate psychological states of multiple individuals. In various examples, sensor data indicative of affects of multiple individuals may be analyzed. Based on the analyzing, the multiple individuals may be partitioned into multiple distinct clusters of individuals. An aggregate psychological state of the individuals of a given cluster of the multiple distinct clusters of individuals may be determined. Data indicative of the aggregate psychological state may be transmitted to cause a computing device to render output that conveys the aggregate psychological state of the individuals of the cluster.

Abstract: Maxillary devices and mandibular devices each have a first housing connectable to a tooth of a user or connectable or integral with a teeth covering, wherein the housing encloses an on-board circuit board and a power source. The first housing of the maxillary devices has a tooth connecting portion, a palate housing portion and/or a buccal housing portion. The first housing of the mandibular devices has a tooth connecting portion and a sublingual portion. Each of the palate housing portion and the buccal housing portion enclose a stimulator having an electrode electrically connected to the on-board circuit board and the power source, and can enclose a sensor and/or a medicament dispenser. Methods of treatment using the same are disclosed also.

Abstract: A method includes delivering, via a first stimulation element and during a treatment period, stimulation to an upper airway patency-related nerve to cause contraction of upper airway patency-related muscles. The method also may include delivering upon detecting central sleep apnea behavior, via a second stimulation element and during a treatment period, stimulation to a central sleep apnea-related nerve. The method also may include delivering the stimulation to the upper airway patency-related nerve independently of a decisional process and trigger to deliver stimulation to the different central sleep apnea-related nerve.

Abstract: Obstructive sleep apnea from blockage of the upper airway can result in significant daytime drowsiness, with many long-term co-morbidities associated with this disorder such as such as hypertension. A common cause of obstructive sleep apnea is the complete concentric collapse of the soft pallet or retrusion of the genioglossus muscle into the upper airway obstructing breathing. The latter can be due to exhaustion of the muscle due to heightened activation during wake periods, or a greater number of type II muscle fibers can contribute to muscle fatigue. It could also be neurological, whereby the hypoglossal nerve which controls most the upper airway muscles fails to innervate the genioglossus sufficiently to prevent backward movement and pharyngeal block.

Abstract: Neuromodulation of cranial nerves can be used to treat sleep or breathing disorders, among other diseases and disorders. A neuromodulation system can include a housing configured for implantation in an anterior cervical region of a patient, such as at or under a mandible of the patient, such as at least partially in one or more of a submental triangle, a submandibular triangle, and a carotid triangle. The system can include an electrode lead coupled to the housing, and the electrode lead can include an electrode configured to be disposed at or near a cranial nerve target in the patient. The system can be configured to generate electrical neuromodulation signals for delivery to the cranial nerve target using the electrode.

Abstract: The present technology is generally directed to methods for addressing a patient's sleep apnea. At least some of the methods can include one or more of percutaneously inserting an implantable signal delivery device at an insertion point on the patient's neck, moving the signal delivery device in a medial-to-lateral direction toward an ansa cervicalis nerve of the patient, and implanting the signal delivery device at a target location at least proximate to the ansa cervicalis nerve. The signal delivery device can include at least one electrode positioned to deliver a modulation signal to tissue at least proximate to the target location, such as a portion of the ansa cervicalis nerve. In some embodiments, delivery of the modulation signal can induce caudal traction in the patient and thereby address the patient's sleep apnea.

Abstract: The disclosure provides a respirator, which includes a ventilation device, configured for providing ventilation airflow to a patient. The respirator further includes a first monitor, configured for monitoring a pressure or a flow velocity with which the ventilation device ventilates the patient, and a second monitor, configured for measuring a pressure change that reflects a self-respiratory effort of the patient. The respirator also includes a processor, configured for identifying an inspiratory trigger moment or an expiratory trigger moment of the patient according to the pressure change that reflects the self-respiratory effort of the patient.

Abstract: Devices and/or methods for treating sleep disordered breathing may include stimulation of a single nerve, multiple nerves, as well as other tissues relating to upper airway patency.

Abstract: One example of an implantable medical device includes an output signal driver, a first electrode, a second electrode, and a controller. The output signal driver is configured to generate stimulation pulses to stimulate a nerve within a patient. The first electrode is coupled to the output signal driver. The second electrode is coupled to the output signal driver. The controller is configured to control the output signal driver to selectively apply between the first electrode and the second electrode a first pulse train and a second pulse train interleaved with the first pulse train.

Abstract: A method of reducing bronchial constriction in a subject includes delivering energy to create one or more lesions on a main bronchus so as to transect pulmonary nerves sufficiently to reduce bronchial constriction in a lung of the patient distal to the main bronchus.

Abstract: A method of right atrial pacing of a heart of a patient includes the steps of: stimulating right atrial tissue of the heart using a right atrial lead of a dual chamber cardiac pacemaker to pace the heart with a stimulus architecture protocol; and stimulating local sympathetic and/or parasympathetic tissues with the stimulus architecture protocol proximate to the paced right atrial tissue causing nervous system activity that inhibits the autonomous nervous system to reduce blood pressure. A closed loop system operating according to this method and a cardiac pacing lead for implementing this method also are included within the scope of the illustrated embodiments.

Abstract: An electro-magnetic induction device for activating a target tissue in a body via its muscular or neural system includes an electro-magnetic field generator with a coil design configured to generate an electro-magnetic field, a mounting arrangement holding the coil design at the body, a sensor member configured to detect an activation of a target tissue, an electro-magnetic field adjustment mechanism configured to automatically adjust the position and a field strength of the electro-magnetic field, and a calibration unit in communication with the sensor member and the electro-magnetic field adjustment mechanism.

Abstract: A peripheral nerve interface including a microclip having a substantial U-shape and including an upper entry portion for entry of a nerve into the microclip and a lower seating portion for seating the nerve in the lower seating portion of the microclip; a stretchable microelectrode array including a plurality of electrodes, wherein the stretchable microelectrode array has a proximal end portion fixed to the microclip and a portion that is moveable and dragged into the upper entry portion and then the lower entry portion of the microclip in response to the microclip be positioned on the nerve; and an interface connected to a distal end of the stretchable microelectrode array and configured to interface with an external device for applying electrical stimulation to the nerve seated in the lower seating portion and for recording electrical characteristic of the nerve seated in the lower seating portion via the plurality of electrodes in the stretchable microelectrode array.

Abstract: A medical device for indicating a chest compression depth, including a first electrode assembly structured to be disposed on a chest of a patient, a second electrode assembly structured to be disposed on a back of the patient, and a processor configured to determine a chest compression depth as a proportion of chest height based on a first impedance measurement between the first electrode assembly and the second electrode assembly when the chest is not compressed and a second impedance measurement between the first electrode assembly and the second electrode assembly when the chest is compressed.

Abstract: A computer system for intra-ear sensing and stimulating receives, health data, from an earbud sensor. The system repeatedly calculates an exponential moving average (EMA) of a moving window for the received health data. The system compares each calculated exponential moving average with a lower threshold value and an upper threshold value. The upper threshold value and the lower threshold value are determined based, at least in part, upon a saturation level associated within an amplifier performing the adaptive gain control. When the calculated exponential moving average is larger than the upper threshold, the system decreases a gain associated with the amplifier. When the calculated exponential moving average is smaller than the lower threshold, the system increases a gain associated with the amplifier.

Abstract: A method of treating obstructive sleep apnea according to this disclosure may include: providing an implant comprising a substantially planar central body portion having a top side and a bottom side; at least two adjustable wing portions; and at least two connecting members, each one of the at least two connecting members extending from opposite sides of the central body portion, the each one of the at least two connecting members being configured for flexibly connecting each one of the at least two wing portions at opposite sides to said central body portion; forming a surgical opening to expose a genioglossus muscle; exposing a branch of a hypoglossal nerve for stimulation by the implant at least on one side of the geniouglossus; forming at least one pocket on at least one side of the geniouglossus; such that the pocket dimensions are configured to fit the at least one of the at least two wing portions of the device; inserting an implant device through the surgical opening such that the central body extends

Abstract: Methods for treating a patient using therapeutic renal neuromodulation and associated devices, system, and methods are disclosed herein. One aspect of the present technology is directed to neuromodulating nerve tissue in selected anatomical regions. In one embodiment, the method can include intravascularly advancing an elongate shaft of a catheter to renal vasculature of a human patient and locating a first neuromodulation element of the catheter within a distalmost portion of a main renal artery. The method includes locating a second neuromodulation element of the catheter within a branch vessel of the renal artery distal to a bifurcation at a distal end of the main renal artery. Neuromodulation of the nerve tissue surrounding the selected anatomical treatment locations can inhibit sympathetic neural activity in nerves proximate a portion of a renal artery and/or a renal branch artery proximate a renal parenchyma.

Abstract: The invention relates to an adaptation system (500), comprising a mouthpiece (10), configured to be positioned in a mouth of a person, and an external sensoring device (20). The external sensoring device (20) is configured to be positioned at the person, wherein the external sensoring device (20) comprises at least one sensor (22) configured to sense at least one measurable quantity when the mouthpiece (10) is positioned in the person's mouth and the external sensoring device (20) is positioned at the person. Further, the adaptation system (500) comprises an analysis device (30) configured to determine a compliance of the adaptation system and/or to determine an orientation of an upper jaw (100) and a lower jaw (200) to each other derived from the at least one sensed measurable quantity.

Abstract: A medical system includes a shaft having a proximal end and a distal end, a balloon attached to the distal end of the shaft, the balloon movable between an expanded state and a deflated state where a maximum diameter of the balloon is greater in the expanded state than in the deflated state, and an electrode is attached to the shaft where a portion of the balloon includes a plurality of apertures fluidly connecting an interior of the balloon to an exterior of the balloon.

Abstract: An example medical device includes a plurality of electrodes, therapy delivery circuitry, and processing circuitry configured to control the therapy delivery circuitry to deliver electrical stimulation to an intercostal nerve of a patient via at least two of the plurality of electrodes, wherein the electrical stimulation is delivered with stimulation parameters configured to suppress ventricular tachyarrhythmia of the patient, wherein the stimulation parameters comprise a stimulation frequency less than or equal to 40 hertz (Hz).

Abstract: A system includes a collar that is worn around a neck of the user. A stimulator is coupled to the collar such that the stimulator is positioned adjacent to an airway of the user. The sensor is coupled to the collar and configured to generate data associated with the airway of the user. The memory is coupled to the collar and storing machine-readable instructions. The control system is coupled to the collar and includes one or more processors configured to execute the machine-readable instructions to determine, based at least on an analysis of the generated data, that the user is currently experiencing an apnea event. In response to the determination, the control system causes the stimulator to provide electrical stimulation, at a first intensity level, to one or more muscles of the user that are adjacent to the airway to aid in stopping the apnea event.

Abstract: Methods, devices, and systems are disclosed for controlled delivery of a therapy, such as a stimulant, to a mouth of a subject via an oral device positioned in a secured configuration in the mouth. At least one of a tongue position stimulator (TST) and tongue position sensor (TSE) is provided, according to certain aspects. According to another aspect, a stimulus is delivered to the mouth and/or tongue via a mouthpiece secured to the subject's teeth. In another regard, a stimulus is delivered that generates a natural response to eliminate or reduce sleep disorders, such as for example at least one of snoring and obstructive sleep apnea.

Abstract: At least some embodiments of the present disclosure are directed to systems and methods for managing sleep disordered breathing (e.g., obstructive sleep apnea) for a patient. A first implantable electrode delivers a first stimulation signal proximate to a first nerve of the patient to stimulate the first nerve and activate at least one first muscle for an upper airway dilation of the person. A second implantable electrode delivers a second stimulation signal proximate to a second nerve to stimulate the second nerve and activate at least one second muscle for a caudal tracheal traction for an upper airway of the person. A stimulation signal generator generates the first and second stimulation signals and coordinates the delivery of the first stimulation signal with the delivery of the second stimulation signal.

Abstract: This disclosure describes, among other embodiments, systems and related methods for selecting electrode combinations to be used during nerve pacing procedures. A first set of electrode combinations of a nerve pacing system, such as a phrenic nerve pacing system for diaphragm activation, may be mapped (or tested) to determine the location of the electrode combinations relative to a target nerve. Once the general location of the target nerve is known, a more localized second set of electrode combinations may be tested to determine the most suitable electrode combinations for nerve stimulation. At various stages of the mapping process, electrode combinations that are non-optimal may be discarded as candidates for use in a nerve pacing procedure. The systems and methods described herein may allow for the selection of electrode combinations that are most suitable for stimulation of the left and right phrenic nerves during diaphragm pacing.

Abstract: A neuromodulation system is provided herein. The system can include a cuff electrode, an electronics package, which can be part of a neuromodulation device; an external controller; a sensor; and a computing device. The neuromodulation device can include an antenna including an upper and a lower coil electrically connected to each other in parallel. The computing device can execute a closed-loop algorithm based on physiological sensed data relating to sleep.

Abstract: A method of implanting includes inserting a stimulation element into a head-and-neck region and positioning an electrode array of the stimulation element relative to a target portion of a nerve.

Abstract: Modulation of neural activity of a ganglion, by applying a signal to a sympathetic nerve adjacent to the ganglion, results in preferential reduction of sympathetic signals to an effector, thereby providing ways of treating and preventing conditions associated with exacerbated sympatho-excitation.

Abstract: A method for treating sleep disordered breathing includes electrically stimulating an upper airway patency-related nerve via implantable stimulation elements.

Abstract: Described herein are methods of treating a tissue using a treatment tip apparatus (e.g., devices, systems, etc.) including one, or more preferably a plurality, of electrodes that are protected by an electrode partition, such as an electrode housing (which may be retractable) until pressed against the tissue for deployment of the electrodes and delivery of a therapeutic treatment. In particular, these methods may include the use of a plurality of treatment electrodes (e.g., needle electrodes) and in some examples may include for the delivery of nanosecond pulsed electric fields.

Abstract: Implementations described and claimed herein provide paddle leads for dorsal root ganglia (DRG) stimulation and methods of implanting the same. In one implementation, the paddle lead has a small profile facilitating deployment into a target space in the neuroforamen dorsal to the DRG and below the vertebral lamina. A paddle body of the paddle lead may include a living hinge and/or a contoured profile to further facilitate implantation in the target space. For suture assisted deployment as well as to resist migration of the paddle lead once deployed, the paddle lead may include a suture loop configuration. The paddle lead further includes an electrode array having electrode contacts arranged in a two dimensional configuration pattern to create an electrical field optimized for stimulation of the DRG.

Abstract: Methods and systems of treating sleep disordered breathing in a patient suffering therefrom by activating one or more infrahyoid strap muscles are provided. Activation of one or more infrahyoid muscles can be accomplished by stimulating an ansa cervicalis, including one or both of the superior root and the inferior root of the ansa cervicalis, alone or in combination with stimulating the hypoglossal nerve.

Abstract: A method for subcutaneously treating pain in a patient includes first providing a neurostimulator with an IPG body and at least a primary, a secondary, and a tertiary integral lead with electrodes disposed thereon. A primary incision is opened to expose the subcutaneous region below the dermis in a selected portion of the body. A pocket is then opened for the IPG through the primary incision and the integral leads are inserted through the primary incision and routed subcutaneously to desired nerve regions along desired paths. The IPG is disposed in the pocket through the primary incision. The primary incision is then closed and the IPG and the electrodes activated to provide localized stimulation to the desired nerve regions and at least three of the nerves associated therewith to achieve a desired pain reduction response from the patient.

Abstract: A method for treatment of a headache disorder in a human subject, including selecting at least one treatment area in the nasal cavity of the human subject, said treatment area being selected from a posterior part of the nasal cavity or an anterior part of the nasal cavity, providing a device including a stimulation member arranged for vibration stimulation of the selected treatment area, and at least one expansion member provided with a channel having a plurality of openings arranged for fluid communication with the stimulation member, introducing the stimulation member into a nasal cavity of the human subject, expanding the stimulation member to a volume such that the stimulation member abuts against the tissue to exert a pressure on tissue of the selected treatment area and bringing the stimulation member to vibrate in the nasal cavity to impart vibrations to the selected treatment area, wherein the vibrations are imparted to a posterior part of the nasal cavity, to an anterior part of the nasal cavity, seq

Abstract: An implantable neurostimulator (INS) and method of use, the INS including an electrical lead having formed thereon at least a pair of bi-polar electrodes, wherein the electrical lead is configured for placement of the pair of bi-polar electrodes proximate protrusor muscles of a patient, a pulse generator electrically connected to the electrical lead and configured to deliver electrical energy to the pair of bi-polar electrodes, the pulse generator having mounted therein a sensor and a control circuit, and the sensor is configured to generate signals representative of an orientation of the pulse generator and communicate the signals to the control circuit and the control circuit is configured to determine the orientation of the pulse generator and deliver electrical energy to the bi-polar electrodes when the determined orientation correlates to a pre-determined orientation.

Abstract: A therapeutic device comprises a sensor positioned proximate to a user and configured to receive a plurality of signals, and a processor coupled to the sensor and configured to determine a biomarker describing a biological characteristic of the user based on the plurality of signals, and determine whether the user is likely to experience an impending sleep disorder episode within a predetermined period of time based on the biomarker.