Systems and methods for improving growth faltering in newborns and infants

Abstract

Provided herein is a method of reducing weight loss, increasing weight, increasing rate of weight gain, and / or treating failure to thrive in a patient, including administering to the patient vibrotactile stimulation for a duration and frequency sufficient to reduce weight loss, increase weight, increase rate of weight gain, and / or treat failure to thrive in the patient.

Description

SYSTEMS AND METHODS FOR IMPROVING GROWTH FALTERING IN NEWBORNS AND INFANTS CROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims priority to U.S. Provisional Patent Application No. 63 / 710,344, filed October 22, 2024, the disclosure of which is hereby incorporated by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under DA042074 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTIONField of the Invention

[0003] Provided herein are systems and methods for treating patients, in some embodiments systems and methods for administering vibrotactile stimulation for treating growth faltering in infants.Description of Related Art

[0004] Prenatal opioid exposure (POE) impairs fetal growth and brain development that often results in newborns with POE having comparatively lower birth weight and smaller head circumference than non-opioid exposed newborns. Newborns with POE commonly have sleep problems, hyperirritability, excessive crying, poor feeding, and gastrointestinal issues (diarrhea, vomiting) that may contribute to neonatal weight loss and impede early weight gain trajectories. Such early infancy weight faltering (a.k.a. failure to thrive) has implications for long-term adverse health issues and neurodevelopmental outcomes, including cognitive, emotional, and motor impairment. Currently, there are no effective treatments for weight faltering that do not rely on nutritional intake, thus there is a need in the art for advancements.SUMMARY OF THE INVENTION

[0005] Provided herein is a method of reducing weight loss, increasing weight, increasing rate of weight gain, and / or treating failure to thrive in a patient, including administering to the patient vibrotactile stimulation for a duration and frequencysufficient to reduce weight loss, increase weight, increase rate of weight gain, and / or treat failure to thrive in the patient.

[0006] Also provided here is a system for administering vibrotactile stimulation to a patient, including an actuator, at least one processor in communication with the actuator, wherein the at least one processor is configured to control the actuator to deliver vibrotactile stimulation to the patient, and optionally, at least one sensor configured to detect proximity of the actuator to the patient, the sensor in communication with the at least one processor.

[0007] Also provided herein is use of a system as described herein for reducing weight loss, increasing weight, increasing rate of weight gain, and / or treating failure to thrive in a patient.

[0008] Further non-limiting embodiments are set forth in the following numbered clauses:

[0009] 1. A method of reducing weight loss, increasing weight, increasing rate of weight gain, and / or treating failure to thrive in a patient, comprising:

[0010] administering to the patient vibrotactile stimulation for a duration and frequency sufficient to reduce weight loss, increase weight, increase rate of weight gain, and / or treat failure to thrive in the patient.

[0011] 2. The method of clause 1 , wherein the patient is an infant.

[0012] 3. The method of clause 1 or clause 2, where in the patient is a human.

[0013] 4. The method of any of clauses 1-3, wherein the stimulation is administered using a device arranged in the patient’s bed, crib, seat, isolette, and / or incubator.

[0014] 5. The method of any of clauses 1-4, wherein the stimulation is administered using a device arranged in and / or on a substrate on which the patient sits, lays, and / or sleeps.

[0015] 6. The method of any of clauses 1-5, wherein the device is included in the mattress.

[0016] 7. The method of any of clauses 1-6, wherein the mattress includes an active region and a passive region, and the stimulation is only applied in the active region.

[0017] 8. The method of any of clauses 1-7, wherein the stimulation is administered using a device arranged in a garment configured to be worn by the patient.

[0018] 9. The method of any of clauses 1-8, wherein the garment includes an active region and a passive region, and the stimulation is only applied in the active region.

[0019] 10. The method of any of clauses 1-9, wherein the stimulation is stochastic.

[0020] 11. The method of any of clauses 1-10, wherein the stimulation is delivered at a frequency of about 1 Hz to about 1000 Hz.

[0021] 12. The method of any of clauses 1-11, wherein the stimulation has an RMS amplitude or displacement of about 10 pm to about 25 pm.

[0022] 13. The method of any of clauses 1-12, wherein the stimulation is delivered intermittently or continuously.

[0023] 14. The method of any of clauses 1-13, wherein the stimulation is delivered for a first period of time and is not delivered for a second period of time.

[0024] 15. The method of any of causes 1 -14, wherein the first period of time has a duration of from about 1 minute to about 24 hours.

[0025] 16. The method of any of clauses 1-15, wherein the second period of time has a duration of from about 1 minute to about 6 hours.

[0026] 17. The method of any of clauses 1-16, wherein the stimulation is delivered from immediately following the patient’s birth until the patient is 1 month of age.

[0027] 18. A method of treating weight faltering, weight loss, a reduction in weight gain, a failure to thrive, a physical impairment, and / or a cognitive and / or emotional impairment in an infant, comprising administering to the patient vibrotactile stimulation for at least 3 hours a day, at a frequency of about 30 to about 60 Hz, with an RMS amplitude or displacement of about 12 pm, for four months, thereby treating weight faltering, weight loss, a reduction in weight gain, a failure to thrive, a physical impairment, and / or a cognitive and / or emotional impairment in the infant.

[0028] 19. A system for administering vibrotactile stimulation to a patient, comprising: an actuator; at least one processor in communication with the actuator, wherein the at least one processor is configured to control the actuator to deliver vibrotactile stimulation to the patient; and optionally, at least one sensor configured to detect proximity of the actuator to the patient, the sensor in communication with the at least one processor.

[0029] 20. The system of clause 19, wherein the actuator is arranged in a mattress.

[0030] 21. The system of clause 19 or clause 20, wherein the mattress includes an active region and a passive region, and the actuator is arranged in the active region.

[0031] 22. The system of any of clauses 19-21 , wherein the actuator is arranged in a garment configured to be worn by the patient.

[0032] 23. The system of any of clauses 19-22, wherein the garment includes an active region and a passive region, and the actuator is arranged in the active region.

[0033] 24. The system of any of clauses 19-23, wherein the at least one processor is configured to control the actuator to provide stochastic vibrotactile stimulation.

[0034] 25. The system of any of clauses 19-24, wherein the at least one processor is configured to control the actuator to deliver vibrotactile stimulation at a frequency of about 1 Hz to about 1000 Hz.

[0035] 26. The system of any of clauses 19-25, wherein the at least one processor is configured to control the actuator to deliver vibrotactile stimulation having an RMS amplitude or displacement of about 10 pm to about 25 pm.

[0036] 27. The system of any of clauses 19-26, wherein the at least one processor is configured to control the actuator to deliver vibrotactile stimulation intermittently.

[0037] 28. The system of any of clauses 19-27, wherein the at least one processor is configured to control the actuator to deliver vibrotactile stimulation for a first period of time, and to not deliver vibrotactile stimulation for a second period of time.

[0038] 29. The system of any of clauses 19-28, wherein the first period of time has a duration of about 1 minute to about 24 hours.

[0039] 30. The system of any of clauses 19-29, wherein the second period of time has a duration of from about 1 minute to about 6 hours.

[0040] 31. The system of any of clauses 19-30, wherein the at least one processor is configured to receive data from the at least one sensor and determine, based on the data, a length of time that stimulation has been delivered to the patient.

[0041] 32. The system of any of clauses 19-31 , wherein the at least one processor is configured to control the actuator based on the determination of the length of time that stimulation has been delivered to the patient.

[0042] 33. A system for administering vibrotactile stimulation to a patient, comprising: a mechanical actuator; at least one processor in communication with the actuator, wherein the at least one processor is configured to control the actuator to deliver vibrotactile stimulation to the patient; and at least one sensor configured to detect proximity of the actuator to the patient, the sensor in communication with the at least one processor, wherein the at least one processor is configured to control the mechanical actuator to deliver stimulation at a frequency of about 30 to about 60 Hzand with an RMS amplitude or displacement of about 12 pm, and wherein the at least one processor is configured to: receive, from the at least one sensor, proximity data relating to a proximity of the patient to the mechanical actuator; determine, based at least in part on the proximity data, whether the patient is receiving the vibrotactile stimulation; and based on the determination, stop the vibrotactile stimulation when the patient has received about four hours of stimulation in a 24-hour period.

[0043] 34. Use of the system of any of clauses 19-33 for treating weight faltering, weight loss, a reduction in weight gain, a failure to thrive, a physical impairment, and / or a cognitive and / or emotional impairment in an infant.BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Additional advantages and details of the methods and devices are explained in greater detail below with reference to the exemplary embodiments and aspects, and the following figures in which:

[0045] FIGS. 1A-1C show schematics of non-liming embodiments of devices useful in the systems and methods described herein;

[0046] FIG. 2 is a schematic diagram of example components of one or more devices of FIGS. 1A-1C, according to non-limiting embodiments described herein;

[0047] FIGS. 3A-3B show weekly weight change for study infants with POE compared to published nomograms for infants without POE in a study relating to nonlimiting embodiments of systems and methods as disclosed herein;

[0048] FIG. 4 shows unadjusted comparisons of outcomes in a study relating to non-limiting embodiments of systems and methods as disclosed herein, where pharmacotherapy, Treated cohort=Subset of analyzed cohort who received morphine treatment and either SVS=stochastic vibrotactile stimulation or TAU=Treatment as usual; Nadir=Days to lowest weight following birth weight; MaxLoss=Maximal percent weight loss from birth weight; RtB=Days to return to birthweight; WlChange-W4Change=Percent weight change from birth to week 1 through week 4, respectively. Note, weight gain was not assessed in the untreated cohort as these infants were discharged within the first week of life; and

[0049] FIG. 5 shows score on the Pediatric Quality of Life Physical Functioning test at 12 months in groups receiving stimulation as described herein as infants versus those receiving treatment as usual.DESCRIPTION OF THE INVENTION

[0050] The use of numerical values in the various ranges specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges are both preceded by the word "about". In this manner, slight variations above and below the stated ranges can be used to achieve substantially the same results as values within the ranges. Also, unless indicated otherwise, the disclosure of these ranges is intended as a continuous range including every value between the minimum and maximum values. For definitions provided herein, those definitions refer to word forms, cognates and grammatical variants of those words or phrases.

[0051] The figures accompanying this application are representative in nature and should not be construed as implying any particular scale or directionality unless otherwise indicated. For purposes of the description hereinafter, the terms “upper”, “lower”, “right”, “left”, “vertical”, “horizontal”, “top”, “bottom”, “lateral”, “longitudinal” and derivatives thereof shall relate to the invention as it is oriented in the drawing figures. However, it is to be understood that the invention may assume various alternative variations and step sequences, except where expressly specified to the contrary. Hence, specific dimensions and other physical characteristics related to the embodiments disclosed herein are not to be considered as limiting.

[0052] As used herein, the term “comprising” and like terms are open-ended. The term “consisting essentially of’ limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention. The term “consisting of’ excludes any element, step, or ingredient not specified in the claim.

[0053] As used herein, the terms “a” and “an” refer to one or more.

[0054] As used herein, the term “patient” is any mammal, including humans, and a “human patient” is any human. The terms “infant” and “newborn” are used interchangeably herein.

[0055] As used herein, the term "computing device" may refer to one or more electronic devices configured to process data. A computing device may, in some examples, include the necessary components to receive, process, and output data, such as a processor, a display, a memory, an input device, a network interface, and / or the like. A computing device may be a mobile device. As an example, a mobile device may include a cellular phone (e.g., a smartphone or standard cellular phone), aportable computer, awearable device (e.g., watches, glasses, lenses, clothing, and / or the like), a personal digital assistant (PDA), and / or other like devices. A computing device may also be a desktop computer or other form of non-mobile computer.

[0056] As used herein, the terms “communication” and “communicate” refer to the receipt, transmission, or transfer of one or more signals, messages, commands, or other type of data. For one unit or device to be in communication with another unit or device means that the one unit or device is able to receive data from and / or transmit data to the other unit or device. A communication can use a direct or indirect connection and can be wired and / or wireless in nature. Additionally, two units or devices can be in communication with each other even though the data transmitted can be modified, processed, routed, etc., between the first and second unit or device. For example, a first unit can be in communication with a second unit even though the first unit passively receives data and does not actively transmit data to the second unit. As another example, a first unit can be in communication with a second unit if an intermediary unit processes data from one unit and transmits processed data to the second unit. It will be appreciated that numerous other arrangements are possible. Any known electronic communication protocols and / or algorithms can be used such as, for example, TCP / IP (including HTTP and other protocols), WLAN (including 802.11 a / b / g / n and other radio frequency-based protocols and methods), analog transmissions, Global System for Mobile Communications (GSM), 3G / 4G / LTE, BLUETOOTH, ZigBee, EnOcean, TransferJet, Wireless USB, and the like known to those of skill in the art.

[0057] As used herein, “electrical communication,” for example in the context of transmitting electrical pulses from a pulse generator to an actuator refers to sending an electrical pulse produced by a pulse generator to an actuator for providing vibrotactile stimulation as described herein, typically through an electrically conductive lead, such as a wire. The mechanical stimulation may be delivered on the body surface via a device-tap or via air puff or applied within the body via lab-on-a-chip, on or near a generalized or focused areas of the patient.

[0058] Provided herein are systems and methods for aiding patients, in non-limiting embodiments newborns and infants, in gaining weight, increasing the rate at which weight can be gained, reducing weight loss, and / or treating failure to thrive (e.g., growth faltering). The terms “growth faltering,” “weight faltering,” and “failure to thrive” are used interchangeably herein. The systems and methods described herein provide technological advances in the field of treatment of conditions relating to and / orincluding as a symptom weight loss, slow weight gain, failure to thrive, and / or growth faltering in any patient without the need for or complementary to pharmacological interventions. Such devices, systems, and methods include administration of vibrotactile stimulation to patients.

[0059] Turning to FIGS. 1 A-1C, shown are schematics of non-limiting embodiments of devices, useful in systems and methods for delivering vibrotactile stimulation as described herein. FIG. 1A shows a mattress 100 with a device 110 (therein, thereon, or external thereto) that may include one or more actuator(s) 120 for delivering vibrotactile stimulation arranged therein or thereon. FIG. 1B shows a garment, for example a vest 100, with a device 110, which may contain actuator(s) 120, for delivering vibrotactile stimulation arranged therein or thereon. FIG. 1C shows a wrap or swaddle 100, with a device 110, which may contain one or more actuator 120. While FIGS. 1A-1C show general arrangements of device 110 relative to mattress, garment, or swaddle 100, those of skill in the art will appreciate that any arrangement (e.g., location) falls within the scope of this disclosure.

[0060] While a mattress (FIG. 1A), a vest (FIG. 1B), and a wrap / swaddle (FIG. 1C) are illustrated, those of skill in the art will appreciate that suitable actuators may be configured to be included in and / or on various substrates, such as a mattress insert, mattress pad, pillow, pillow case, sheet, and / or other garments such as, without limitation, a onesie, a shirt, pants, shorts, a hat, a vest, a bib, a sock, a beanie, a swaddle, a blanket, a kangaroo-care garment, a stuffed animal, and / or like item that can be maintained in close proximity to a patient and thereby deliver vibrotactile stimulation to the patient. In non-limiting embodiments, device 110 may be included in a crib, swing, bassinet, chair, seat, isolette, and / or incubator. Those of skill in the art will appreciate that the substrates and / or garments may be formed of suitable materials to permit the generated stimulation to be transmitted to the patient and / or to isolate the stimulation to one or more discrete areas of the substrate and / or garment. That is, a substrate including a device 110 for delivering vibrotactile stimulation may be configured such that there is an active region (e.g., where stimulation is delivered and / or may be sensed) and a passive region (e.g., where stimulation is not delivered and / or may not be sensed).

[0061] Device 110 as described herein may include one or more actuator(s) 120, for example a mechanical actuator, for example a device that converts electrical signals received from a pulse generator to vibrotactile pulses, for example a hapticactuator. Suitable actuators 120 are known to those of skill in the art and may include mass actuators, for example rotating mass actuators, which may be powered by an electrical current delivered by a power source, for example alternating current (AC) and / or a battery, such as a rechargeable battery, such as a wirelessly-rechargeable battery. In non-limiting embodiments the actuator may be powered by compressed air and / or a pressurized fluid. The vibration pattern of actuator(s) 120 may be static, random, and / or adjustable and may vary as a function of type of actuator, e.g., eccentric rotating mass, linear resonant, piezo, and arrays. Suitable actuators are also described, for example, in U.S. Patent Application Publication No. 2020 / 0237615, U.S. Patent Nos. 10,251,552 and 10,358,531 and Luan et al., “Programmable stimulation and actuation in flexible and stretchable electronics,” Adv. Intel. Sys. 2021 , 3: 200028, each of which are incorporated herein by reference in their entirety. Suitable devices 110 may include actuator(s) 120, for example haptic actuators, and control circuitry 130. In non-limiting embodiments, a device 110, including an actuator 120, with or without control circuitry 130, may be in the form of a chip. Control circuitry 130 may be included within device 110 and / or may be physically separated from device 110 and may communicate with device 110 wirelessly (e.g., as shown in FIG. 1B) and / or through a wired (e.g., as shown in FIG. 1A) and / or wireless connection. Devices 110 including actuators 120 and / or control circuitry 130 as described herein may include power sources as described above.

[0062] With continuing reference to FIGS. 1A-1C, and with reference to FIG. 2, as noted above, any component of device 110, such as actuator 120 and / or control circuity 130 may have one or more elements of device 200 shown in FIG. 2. With regard to FIG. 2, shown is a diagram of example components of a device 200 according to non-limiting embodiments. Device 200 may correspond to any element of FIGS. 1A-1C, including, as an example, control circuity 130. In some non-limiting embodiments, such systems or devices may include at least one device 200 and / or at least one component of device 200. The number and arrangement of components shown are provided as an example. In some non-limiting embodiments, device 200 may include additional components, fewer components, different components, or differently arranged components than those shown. Additionally, or alternatively, a set of components (e.g., one or more components) of device 200 may perform one or more functions described as being performed by another set of components of device 200.

[0063] As shown in FIG. 2, device 200 may include a bus 202, a processor 204, memory 206, a storage component 208, an input component 210, an output component 212, and a communication interface 214. Bus 202 may include a component that permits communication among the components of device 200. In some non-limiting embodiments, processor 204 may be implemented in hardware, firmware, or a combination of hardware and software. For example, processor 204 may include a processor (e.g., a central processing unit (CPU), a graphics processing unit (GPU), an accelerated processing unit (APU), etc.), a microprocessor, a digital signal processor (DSP), and / or any processing component (e.g., a field-programmable gate array (FPGA), an application-specific integrated circuit (ASIC), etc.) that can be programmed to perform a function. Memory 206 may include random access memory (RAM), read only memory (ROM), and / or another type of dynamic or static storage device (e.g., flash memory, magnetic memory, optical memory, etc.) that stores information and / or instructions for use by processor 204.

[0064] With continued reference to FIG. 2, storage component 208 may store information and / or software related to the operation and use of device 200. For example, storage component 208 may include a hard disk (e.g., a magnetic disk, an optical disk, a magneto-optic disk, a solid-state disk, etc.) and / or another type of computer-readable medium. Input component 210 may include a component that permits device 200 to receive information, such as via user input (e.g., a touch screen display, a keyboard, a keypad, a mouse, a button, a switch, a microphone, etc.). Additionally, or alternatively, input component 210 may include a sensor for sensing information (e.g., a global positioning system (GPS) component, an accelerometer, a gyroscope, an actuator, etc.). Sensors useful here may include biochemical sensors, proximity sensors, sensors configured to detect weight, and / or the like. Output component 212 may include a component that provides output information from device 200 (e.g., a display, a speaker, one or more light-emitting diodes (LEDs), etc.). Communication interface 214 may include a transceiver-like component (e.g., a transceiver, a separate receiver and transmitter, etc.) that enables device 200 to communicate with other devices, such as via a wired connection, a wireless connection, or a combination of wired and wireless connections. Communication interface 214 may permit device 200 to receive information from another device and / or provide information to another device. For example, communication interface 214 may include an Ethernet interface, an optical interface, a coaxial interface, an infraredinterface, a radio frequency (RF) interface, a universal serial bus (USB) interface, a Wi-Fi® interface, a cellular network interface, and / or the like.

[0065] Device 200 may perform one or more processes described herein. Device 200 may perform these processes based on processor 204 executing software instructions stored by a computer-readable medium, such as memory 206 and / or storage component 208. A computer-readable medium may include any non-transitory memory device. A memory device includes memory space located inside of a single physical storage device or memory space spread across multiple physical storage devices. Software instructions may be read into memory 206 and / or storage component 208 from another computer-readable medium or from another device via communication interface 214. When executed, software instructions stored in memory 206 and / or storage component 208 may cause processor 204 to perform one or more processes described herein. Additionally, or alternatively, hardwired circuitry may be used in place of or in combination with software instructions to perform one or more processes described herein. Thus, embodiments described herein are not limited to any specific combination of hardware circuitry and software. The term “configured to,” as used herein, may refer to an arrangement of software, device(s), and / or hardware for performing and / or enabling one or more functions (e.g., actions, processes, steps of a process, and / or the like). For example, “a processor configured to” may refer to a processor that executes software instructions (e.g., program code) that cause the processor to perform one or more functions.

[0066] One or more elements of control circuity 130 of an actuator-containing device 110 may be received within a housing with, for example, actuator 120. In nonlimiting embodiments, an actuator-containing device 110 may include an actuator 120, control circuity 130, and / or pulse generator(s) (and / or other source of power and / or force for actuator 120, such as a source of compressed air and / or pressurized liquid) 140, and one or more components of control circuity 130 may be received within device 110. In non-limiting embodiments, device 110 may include actuator 120 and pulse generator(s) 140, and one or more components of control circuity 130 may be arranged externally of device 110. Control circuitry may include both internal (e.g., within device 110) and external (e.g., outside of device 110) components, and may allow for, for example, remote control of device 110, for example by a computing device as described herein.

[0067] Control circuitry 130 may be programmed and / or configured to cause pulse generator(s) 140 and / or actuator(s) 120 to deliver vibrotactile stimulation with any stimulation parameters of interest. In non-limiting embodiments, control circuitry 130 is a closed system, e.g., control circuitry 130 cannot be programmed to change the stimulation parameters. In non-limiting embodiments, control circuitry 130 is an open system, in that a healthcare provider, for example, may change the stimulation parameters. In non-limiting embodiments, control circuitry 130 may be programmed and / or configured to receive data from at least one sensor 150 (e.g., a proximity sensor) and determine, based on the data, a length of time that stimulation has been delivered to the patient. Proximity sensors are known to those of skill in the art and may include inductive sensors, capacitive sensors, photoelectric sensors, and / or magnetic sensors. In non-limiting embodiments, control circuitry 130 may be programmed and / or configured to control actuator 120 based on the determination of the length of time that stimulation has been delivered to the patient. For example, in non-limiting embodiments, control circuitry 130 may be programmed and / or configured to turn stimulation on or off depending on the length of time that is determined. In nonlimiting embodiments, for example where a system as described herein may include a proximity sensor, control circuitry may receive, from the sensor, proximity data relating to a proximity of the patient to the actuator(s) 120. Control circuity 130 may, thereafter, determine, based at least in part on the proximity data, whether the patient is receiving the vibrotactile stimulation (e.g., whether the patient is close enough to the actuator(s) 120 so as to be stimulated). In non-limiting embodiments, based at least in part on the determination, control circuity 130 stop the vibrotactile stimulation when the patient has received a set (e.g., preset) amount of stimulation within a given period, for example within a 24-hour period, a 1-week period, a 1 -month period, a 4-month period, a 12-month period, and / or any value or subrange therebetween. The set amount of stimulation may be programmed and may be any amount as described herein. However, in non-limiting embodiments, control circuitry 130 may be programmed to cease stimulation once the patient has received about four hours of stimulation in a 24-hour period.

[0068] Stimulation as described herein may be delivered (e.g, control circuitry 130 may be programmed to cause actuator 120 to deliver stimulation) at various frequencies, for various durations, intermittently and / or constantly, with various amplitudes. In non-limiting embodiments, the stimulation is stochastic. In non-limitingembodiments, vibrotactile stimulation may be delivered at a frequency of about 1 Hz to about 1000 Hz, optionally about 1 Hz to about 100 Hz, optionally about 10 Hz to about 90 Hz, optionally about 20 Hz to about 80 Hz, optionally about 30 Hz to about 70 Hz, optionally about 40 Hz to about 60 Hz, optionally about 30 Hz to about 60 Hz, optionally about 80 to about 110 Hz, all values and subranges therebetween inclusive. In non-limiting embodiments, vibrotactile stimulation may be delivered with a root mean square (RMS) amplitude, or displacement, of about 10 pm to about 25 pm, optionally about 12 pm, all values plus / minus 10%, and all values and subranges therebetween inclusive. The use of the terms “amplitude” and “displacement” herein with reference to the RMS may be considered to be equivalent to an intensity of the vibrotactile stimulation. In non-limiting embodiments, vibrotactile stimulation may be delivered intermittently, for example for first period(s) where stimulation is delivered, with second period(s) in which stimulation of different parameters (including, for example, no stimulation) is delivered. In non-limiting embodiments the first period and / or the second period has a duration of from about 1 minute to about 24 hours, optionally about 1 minute to about 12 hours, optionally about 1 minute to about 6 hours, optionally about 3 hours, all values and subranges therebetween inclusive. In non-limiting embodiments, the amount of stimulation is monitored, and, optionally, controlled based on how much exposure a patient receives. Vibrotactile stimulation as described herein may also be ramped on and off (e.g., stimulation may begin with lower frequencies and / or amplitudes, one or both of which may be increased, and stimulation may similarly be reduced from a given frequency and / or amplitude to lower values of one or both). Those of skill will appreciate that stimulation parameters may change across a patient’s lifespan, and may vary depending on patient’s weight, biological sex, disease state, and / or species.

[0069] As discussed herein, devices, systems, and methods of the present disclosure may be useful for treating conditions such as failure to thrive and weight loss in newborns and infants, and / or also in increasing weight and / or increasing a rate of weight gain. Accordingly, in non-limiting embodiments, the patient is a human patient, for example a newborn and / or an infant. In non-limiting embodiments the patient is a newborn and / or infant who has been exposed to an opioid, for example in utero. In non-limiting embodiments, the patient has not been exposed to an opioid, including in utero. In non-limiting embodiments, the patient is a newborn and / or infant who, for whatever underlying reason and based on any etiology, is experiencingweight faltering, weight loss, a reduction in weight gain, a failure to thrive, a physical impairment, and / or a cognitive and / or emotional impairment. In non-limiting embodiments, the patient is any human (e.g., newborn / infant, toddler, child, teen, adult, and / or senior) exposed pre- or post-partum to opioids, selective serotonin reuptake inhibitors, nicotine / tobacco, alcohol, caffeine, and / or other medication / drug (central nervous system stimulants, depressants, hallucinogens), whether prescribed or illicit. For example and without limitation, stimulation as described herein may be delivered to treat infant apnea of prematurity, necrotizing enterocolitis, neonatal opioid withdrawal, intrauterine growth restriction, iatrogenic opioid withdrawal, withdrawal syndromes (e.g., antidepressant discontinuation syndrome, antipsychotic withdrawal syndrome), weight faltering due to malabsorption diseases (e.g., celiac and cystic fibrosis), digestive disorders (e.g., inflammatory bowel disease), increased metabolic demand hormonal disorders (hyperthyroidism, Addisons, chronic kidney disease, diabetes, heart failure), chronic illnesses (HIV / AIDs, cancer), genetic (Downs Syndrome), diseases that increased energy needs (infections, heart failure and lung disease, COPD), food allergies, and / or eating disorders.

[0070] In non-limiting embodiments, methods provided herein may, based at least on one or more maternal characteristics, determine whether stimulation as described herein may benefit a patient (e.g., in terms of a therapeutic effect as described herein, including at least an improvement (such as a statistically significant improvement) in weight gain compared to patients not receiving the stimulation, such as a newborn and / or infant). In non-limiting embodiments, the one or more maternal characteristics include drug use, for example opioid use (e.g., buprenorphine, methadone, heroin), SSRI use, caffeine use, nicotine / tobacco and / or other substance use, maternal weight at delivery, a diagnosis of gestational diabetes and / or other prenatal complications. In non-limiting embodiments the determination may further include one or more additional neonatal parameters, for example, birth sex, gestational age, birth weight and / or current weight, delivery mode (cesarean or vaginal), feed type (e.g., breast milk or formula (including type / caloric content of formula)), and weight trajectory, for example during the first week of life.

[0071] In non-limiting embodiments, methods provided herein may determine a treatment protocol (e.g., a frequency, amplitude, duration of active stimulation (e.g., per day), and / or length of time that stimulation is delivered to the patient), with stimulation as described herein, that provides the greatest benefit (e.g., in terms of atherapeutic effect as described herein, including at least an improvement (such as a statistically significant improvement) in weight gain compared to patients not receiving the stimulation, for example weight gain over a specific time period as described herein, for example over the first four weeks of life. In non-limiting embodiments, this determination may be based on at least one or more maternal characteristics and / or characteristics of the patient. In non-limiting embodiments, the one or more maternal characteristics include drug use, for example opioid use (e.g., buprenorphine, methadone, heroin), SSRI use, caffeine use, nicotine / tobacco and / or other substance use, maternal weight at delivery, a diagnosis of gestational diabetes and / or other prenatal complications. In non-limiting embodiments the determination may further include one or more additional neonatal parameters, for example, birth sex, gestational age, birth weight and / or current weight, delivery mode (cesarean or vaginal) feed type (e.g., breast milk or formula (including type / caloric content of formula)), and weight trajectory, for example during the first week of life.

[0072] Newborns with prenatal exposure to substances (including, without limitation, opioids and anti-seizure medications (ASMs) may benefit from the methods and systems disclosed herein. Newborns with prenatal opioid exposure (e.g., methadone, buprenorphine, heroin) and / or other drug exposure / s may benefit from whole-body SVS using a device as described herein arranged in a crib mattress, garment, and / or swaddle (or any other item as described herein above) that delivers SVS (e.g., 30-60 Hz, ~12 pm RMS) on an automated 3-hour on-off cycle initiated within 48 hours of birth and continues throughout the infant’s hospitalization until 12-24 hours before anticipated discharge or upon completion of morphine treatment for infants who receive pharmacotherapy. Infants with low birth weight, pharmacologically managed for neonatal opioid withdrawal, born prematurely, treated for apnea of prematurity, and infants with iatrogenic opioid withdrawal, sleep disturbance and / or feeding / gastrointestinal issues with prolonged hospitalization (e.g, >1 week) may benefit from daily doses of SVS administered complementary to standard care. Infants who fall below normal weight-growth curves despite standard or increased caloric intake may benefit from complementary use of SVS at shorter cycles (e.g., 30 min on-off) or longer cycles (e.g., 6 hr on-off), indicated by daily and weekly growth trajectories plotted on respective nomograms for boys vs girls, c-section vs vaginal delivery, formula vs breastmilk intake. While particular stimulation parameters are described in this section, those of skill will appreciate that any stimulation parameters disclosedherein may be useful and may be administered to a patient to treat any of the conditions listed herein.

[0073] In non-limiting embodiments, vibrotactile stimulation as described herein may be delivered, with any device and / or any stimulation parameters as described herein, from immediately following the patient’s birth until the patient is 1 month, 2 months, 3 moths, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months 10 months, 11 months of age, and / or 12 months of age, all values and subranges therebetween inclusive. In non-limiting embodiments, stimulation may be delivered to any patient (e.g., any age or any species) experiencing weight faltering, weight loss, a reduction in weight gain, a failure to thrive, a physical impairment, and / or a cognitive and / or emotional impairment, and stimulation parameters as described herein may be altered based on patient age. In non-limiting embodiments, stimulation may be delivered for as long as a therapeutic effect is detected. In non-limiting embodiments, the stimulation is delivered for 1 month (e.g., four weeks), and a therapeutic effect, such as a significant therapeutic effect (e.g., a significant improvement in one or more of the outcomes described herein) is seen at that time as compared to patients not receiving the stimulation. In non-limiting embodiments, the therapeutic effect is seen at 6 months and / or 12 months following treatment.

[0074] By “therapeutic effect” it is meant an increase in weight, increase in a rate of weight gain, a decrease in weight loss, improvement in organ growth and function, improvement in physiologic regulation (e.g., reduced tachycardia, tachypnea, apnea), reduced need for pharmacologic intervention(s), optimized energy expenditure (e.g., reduced crying and excessive movement activity, improved sleep activity), improved nutrition absorption (e.g., reduced diarrhea and vomiting), reduced long-term adverse health issues (e.g., cardiovascular disease and obesity), improved neurodevelopmental outcomes, and / or reduced care-costs. In non-limiting embodiments, the therapeutic effect is an improvement in neurodevelopment, including neurocognition and physical health. In non-limiting embodiments neurodevelopment may be assessed with an instrument, such as, for example, the GOS-E Peds, Pediatric Quality of Life (PedsQL), the Bayley Scales of Infant and Toddler, Bayley Social and Emotion Scale (Bayley S&E), Pediatric Evaluation of Disability Inventory (PEDI), and / or Brief Infant Sleep Questionnaire (BISQ). While the foregoing may be directed to or configured for use in a particular patient population (e.g., newborns and / or infants), those of skill in the art will appreciate that appropriatechild, adolescent, and / or adult measurements of developmental outcome or neurocognition (in adults) include surveys and validated, performance-based neuropsychological instruments that probe similar metrics and / or cognitive domains, and thus that improvements in other patient populations can be assessed. In nonlimiting embodiments, the improvement may be in one or more of physical function, physical symptoms, emotional function, social function, cognitive function, visual preference, attention, memory, sensorimotor performance, exploration, manipulation, concept formation, fine and / or gross motor skills, sleep behavior, and / or the like.Example 1Materials and MethodsStudy Design

[0075] This prospective, dual-site, randomized, controlled, parallel group, modified (analyzed for condition received) intention-to-treat, clinical trial (NCT02801331) assessed weight trajectories in newborns with POE. Reporting and analyses followed the Consolidated Standards of Reporting Trials (https: / / www.equator-network.org / reporting-guidelines / consort / ).Study Population

[0076] Term newborns (>37 weeks’ gestation) with POE (confirmed meconium and / or urine toxicology report and / or documented in-utero opioid exposure such as methadone, buprenorphine, oxycodone, and heroin) were enrolled at UMass Memorial Healthcare (UMass) and at UPMC Magee-Women’s Hospital (UPitt). Inclusion / exclusion details have been previously described (Bloch-Salisbury et al., 2021, 2023)). The University of Massachusetts Medical School Institutional Board approved the study through a reliance agreement with the University of Pittsburgh. Written informed consent was obtained from the biological mother of each infant either prenatally or within 48 h after delivery.Protocol

[0077] Study infants were randomly assigned via a computer-generated force-block design to receive treatment as usual (TAU) or whole-body SVS using a uniquely-constructed crib mattress (30-60 Hz, ~12 pm RMS; Wyss Institute, Harvard University; Cofab Design, LLC) that delivered SVS on an automated 3-h on-off cycle. SVS was initiated within 48 hours of birth and continued throughout the infant’s hospitalization until 12-24 hours before anticipated discharge or upon completion of morphine treatment for infants who received pharmacotherapy. All infants received standard ofcare, including non-pharmacologic strategies, clinical assessments of opioid withdrawal and morphine as first-line pharmacologic management for infants meeting clinical criteria to treat. Start / stop times of feeding, holding, and use of hospital-issued motorized seats (mamaRoo; 4moms) were recorded in a bedside computerized study log to provide a 24 h record of routine cares. Infant and maternal demographics and medical history were obtained from electronic medical records and maternal questionnaires. Infant daily clinical nursing assessments, including daily weight, feeds, and pharmacologic treatment, were also retrieved from electronic medical records. Race and ethnicity reported by the biological mother from a questionnaire with predefined categories were documented per National Institutes of Health reporting requirements and used to assess association with outcomes. Data were entered by research staff into the study database.Outcome Measures

[0078] The a priori primary outcome analyzed in this paper was velocity of weight gain. Because weight loss is common in newborns in the first week of life and precedes weight gain, we first examined the trajectory of weight loss. The endpoints for weight loss were days to weight nadir (Nadir; defined as the lowest weight following birthweight) and the maximal percent weight loss from birthweight [MaxLoss; defined as (nadir weight-birthweight) / birthweight*100)]. The endpoints for weight gain were days to return to birthweight (RtB; defined as the first weight to reach or surpass birthweight) and percent weight change from birth, calculated weekly for the first month of life (W1 Change, W2Change, W3Change, W4Change). We examined the influence of variables identified a priori (e.g., demographic data, prenatal drug exposure, and postnatal feed type) as well as dose-response duration (minutes per day) effects of SVS on, SVS off, caregiver hold, and hospital-issued motorized baby swing (mamaRoo®; 4moms) on these endpoints. Given the novelty of the SVS-mattress device, we also provided post-hoc comparisons of weight trajectories between study infants and published nomograms for non-opioid exposed newborns.Statistical Analysis

[0079] Demographics and other baseline mother and infant characteristics were described by condition (TAU or SVS). Unadjusted effects of condition on each outcome measure were compared using two-sided hypothesis tests; 2-sample t-tests were used for continuous variables and Fisher exact tests for categorical variables. Adjusted effects of condition were assessed using multivariate regression-basedmodels for the population of infants who completed hospitalization. The models adjusted for a priori variables of biological sex (male v female), birthweight (g), delivery method (cesarean vs vaginal), site (UMass vs UPitt), prenatal opioid exposure (buprenorphine, methadone, other), feed type (formula only vs breast milk with and / or without formula). Association of duration (hours per day) of the dose-response variables (SVS on, SVS off, caregiver hold, mamaRoo® motorized swing) were also analyzed for each of the outcomes. In instances where daily weight was missing in the electronic medical records, the average weight for the two days prior and two days after the missing daily weight was used. For infants discharged prior to achieving any weight gain, the discharge weight defined Nadir and MaxLoss. Days to RtB and weekly weight gain (%) from birth through the first month of life (W1 Change, W2Change, W3Change and W4Change) were analyzed only in the treated cohort who were transferred to the neonatal intensive care unit (NICU) for pharmacotherapy. The prolonged hospitalization in the treated cohort provided adequate time to regain birth weight, whereas untreated infants were discharged within the first week of life when newborns predominantly lose weight. Accordingly, for the full cohort who completed hospitalization at their respective study site, weight loss trajectories Nadir and MaxLoss) were compared between TAU and SVS from birth to Nadir, RtB, and weekly changes within the first month of life were compared between infants assigned TAU and SVS adjusting for dose-response activities in the newborn unit. For infants who received morphine treatment, weight loss as well as weight gain trajectories (RtB and weekly changes within the first month of life) were compared between TAU and SVS adjusting separately for dose-response variables in the newborn unit and in the NICU. Percentile curves for treated infants were compared to published nomograms for nonopioid exposed newborns (www.newbornweight.org; Paul et al., 2016). Analyses were performed according to condition received, noting that one infant assigned to TAU received SVS due to staff allocation error. All statistical analyses were performed using R programming, version 1.4.1717 (R Foundation for Statistical Computing). Statistical significance was determined with a threshold level of a = .05. All adjusted analyses are presented with 95% Cis.Results

[0080] There were 208 infants enrolled in the study of whom 105 received SVS and 103 received TAU. We report here on the 181 infants who completed hospitalization at their respective study site (mean birth gestational age 39.0 weeks(SD 1.2); mean birth weight 3076 g (SD 489); 45% male; 76% white)). Among these infants, 94 received SVS (45 UMass, 49 UPitt) and 87 received TAU (41 UMass, 46 UPitt). There were 121 infants who were discharged without medication treatment (untreated cohort) and 60 infants who were transferred to the NICU for pharmacotherapy (treated cohort). Demographics and other characteristics for the biological mother and infant dyads for each of these cohorts are provided in Table 1 , below. There were no differences in characteristics between SVS and TAU for any of these cohorts.Table 1Analyzed Cohort Untreated Cohort Treated Cohort (n=181) (n=121) (n=60) SVS TAU SVS TAU SVS TAUInfant CharacteristicTotal n 94* 87 65 56 29* 31 Male n (%) 41 40 30 27 11 13(43.6) (46.0) (46.2) (48.2) (37.9) (41.9) Race(Black / H PC / Mixed / U n kn ow 3 / 1 / 15 / 5 2 / 0 / 14 / 3 2 / 1 / 10 / 4 1 / 0 / 10 / 0 1 / 0 / 5 / 1 / 1 / 0 / 4 / 3 / n / White) / 70 / 68 / 48 / 45 22 23 Ethnicity (Hispanic / Non- Hispanic / Unknown) 9 / 81 / 4 9 / 74 / 4 6 / 55 / 4 5 / 50 / 1 3 / 26 / 0 4 / 24 / 3Enrolled at UMass, n (%) 45 41 28 24 17 17(47.9) (47.1) (43.1) (42.9) (58.6) (54.8) Enrolled at UPitt, n (%) 49 46 37 32 12 14(52.1) (52.9) (56.9) (57.1) (41.4) (45.2) Gestational Age, Mean wks 38.9 39.1 39.0 39.0 38.9 39.2 (SD) (1.2) (1.2) (1.2) (1.2) (1.1) (1.2) Birth Weight, Mean g (SD) 3066 3086 3078 3081 2993 3092(520) (454) (491) (491) (410) (483) Birth Head Circumference, 33.4 33.6 33.5 33.5 33.3 33.3 Mean cm (SD) (1.7) (1.9) (1.8) (1.8) (1.4) (1.6) Apgar 1 min, Mean (range) 7.9 (1 - 8.0 (4 - 7.9 (1 - 7.9 (5 - 8.2 (5 - 7.7 (4 - 10) 9) 10) 9) 9) 9) Apgar 5 min Mean (range) 8.8 (6 - 8.8 (6 - 8.8 (6 - 8.8 (6 - 8.9 (8 - 8.8 (8 - 10) 9) 10) 9) 10) 9) Delivery Mode Cesarean 20 15 5 5 Section, n (%) 20 (21.3) (23.0) 15 (23.1) (26.8) (17.2) (16.1) Formula Fed Only n (%) 34 (36.2) 31 24 (36.9) 19 10 12(35.6) (33.9) (34.5) (38.7) Max Caloric Intake, Mean 20.7 20.7 20.5 20.6 21.2 20.9 (SD) (1.8) (1.8) (1.6) (1.7) (2.0) (1.9) Discharged on breast milk, 42 29 11 13 n (%) 49 (52.1) (48.3) 38 (58.5)(51.8) (37.9) (41.9) Biological MotherCharacteristicMaternal Age at Infant’s 29.3 30.7 29.8 30.8 28.6 30.9 Birth, Mean yrs (SD) (4.7) (5.3) (3.9) (5.1) (4.0) (4.7) MAT Buprenorphine, n (%) 51 52 41 37 10 15(54.3) (59.8) (63.1) (66.1) (34.5) (48.4)MAT Methadone, n (%) 34 34 19 18 15 16 (36.2) (39.1) (29.2) (32.1) (51.7) (51.6) Non-MAT Opioid, n (%) 9 (9.6) 1 (1.1) 1 (1.8) 45 (7.7) (13.8) 0 (0)Analyzed cohort=Completed hospi talization; Untreated cohort=Subset of analyzed cohort who did not meet clinical criteria for pharmacotherapy; Treated cohort=Subset of analyzed cohort who received morphine treatment; TAU=Treatment as usual; SVS=stochastic vibratory stimulation; Race and Ethnicity as reported by biological mother from questionnaire with predefined categories: Black=Black or African American, HPC=Native Hawaiian or Other Pacific Islander; Hispanic=Hispanic or Latino; MAT=medication assisted therapy, includes one subject assigned to TAU who received SVS.Trajectory of Weight Loss

[0081] Separate unadjusted comparisons between SVS and TAU for Nadir and MaxLoss are provided in FIG. 4. For the cohort of 181 infants who completed hospitalization, Nadir was reached on average 5 days from birth regardless of condition (SVS=4.98 days, TAU=5.05 days, p=0.77). The MaxLoss was also not significantly different between conditions (SVS=8.33%, TAU=8.29%, p=0.92). Unadjusted analyses showed no effects of condition on weight loss outcomes for the untreated cohort (n=121 ) or the treated cohort (n=60; FIG. 4).

[0082] Analyses adjusted for condition and a priori cofactors showed no main effect of stimulus condition (SVS, TAU) on Nadir or MaxLoss for any of the cohorts. Doseresponse analyses showed mean daily duration of bedside activity was not associated with weight loss outcomes for the cohort who did not receive medication (n=121 ). For the pharmacologically treated cohort (n=60), analyses controlling for condition and a priori cofactors showed small, significant effects of site and feed type on Nadir (Table 2, below). Respectively, when controlling for condition, UPitt infants reached Nadir on average 0.6 days earlier than UMass (-1.04 to -0.09, 95% Cl), and infants who received formula only reached Nadir on average 0.5 days later than infants who received some breast milk (0.03 to 0.10, 95% Cl). Similarly, dose-response effects were observed for site on Nadir in the models that controlled for duration infants were in crib with SVS off, held, and in motorized seat while in the nursery (i.e., within the first week of birth prior to transfer to the NICU for medication treatment); UPitt infants reached Nadir earlier than UMass infants. When controlling for the duration infantswere held in the newborn nursery, infants who received formula only took longer to reach Nadir than infants that received some or all breast milk. Dose-response analyses also revealed that when controlling for condition, infants with prenatal methadone exposure had on average 1.2% greater MaxLoss (0.3% to 2.0%, 95% Cl) than infants with prenatal-buprenorphine exposure. Models controlling for duration of SVS off, time held, and time in motorized seats in the newborn nursery identified a similar effect of methadone exposure on MaxLoss. Controlling for SVS on in the NICU revealed UMass infants had a greater MaxLoss than UPitt infants. No other doseresponse effects of bedside activities in the newborn unit or NICU were observed on weight loss outcomes.Table 2ModelDose-Response in Newborn Unit Dose-Response in NICU (95% Cl) (95% Cl) Mean* Meana(95% Cl) Outcome variable3Conditio Time Time Time held Time in Time Time Time held Time in and factor n SVS on SVS off (h / d) motorized SVS on SVS off (h / d) motorized (0=TAU) (h / d) (h / d) seat (h / d) (h / d) (h / d) seat (h / d) Nadir, days (n=60)Main effect (-0.47, (0, 0.06) (-0.01, (0, 0.04) (-0.01, (-0.02, (-0.01, (-0.02, (-0.01, 0)0.45) 0.12) 0.03) 0.00) 0.27) 0.01)Site (0=UMass) (-1.04, (-0.95, (-1.00, (-1.07, (-1.13, (-2.70, (-1.85, (-2.02, (-1.83,-0.09) 0.30) -0.00) -0.12) -0.16) 0.21) 0.06) 0.08) 0.14) -0.57 -0.50 -0.60 -0.65Sex (0=female) (-0.43, (-0.43, (-0.51, (-0.52, (-0.49, (-0.69, (-0.73, (-0.82, (-0.84,0.48) 0.643) 0.43) 0.41) 0.44) 1.68) 1.14) 1.11) 1.09) Birth weight (0,0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) Methadone (-0.44, (-0.59, (-0.36, (-0.37, (-0.48, (-1.30, (-0.71, (-0.89, (-0.82, exposure 0.56) 0.59) 0.67) 0.63) 0.55) 0.99) 1.29) 1.18) 1.17) (O=buprenorphine)Non-MAT (-1.74, (-2.12, (-1.83, (-1.80, (-1.89, (-1.45, (-1.42, (-1.86, (-1.81, exposure 0.35) 0.30) 0.43) 0.42) 0.35) 2.59) 2.51) 2.11) 2.17) (O=buprenorphine)Formula only (0.03, (-2.15, (-0.01, (0.02, (-0.05, (-1.03, (-0.63, (-0.68, (-0.667, (0=no) 1.00) 0.89) 0.99) 1.01) 0.97) 1.19) 1.38) 1.44) 1.45)0.52 0.52Delivery method (-0.83, (-0.95, (-0.90, (-0.71, (-0.96, (-1.67, (-1.26, (-1.39, (-1.38, (0=cesarean) 0.55) 0.50) 0.49) 0.70) 0.45) 2.17) 2.12) 2.18) 2.14)MaxLoss, %Main effect (-0.6, 0) (0, 0) (-0.1, 0) (0, 0) (0, 0) (0, 0) (-0.2, 0.3) (0, 0) (0, 0)Site (O=UMass) (-1.2, (-1.3, 0.9) (-1.2, 0.4) (-1.2, 0.3) (-1.4, 0.2) (-5.0, - (-2.9, 0.1) (-3.2, 0) (-2.9, 0.1) 0.4) 0.2)-2.60Sex (0=female) (-1.0,(-1.1, 0.4) (-1.2, 0.4) (-1.2, 0.4) (-1.8, 2.2) (-1.8, 1.2) (-1.8, 1.2) (-1.9, 1.1) 0.5)Birth weight (0,0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) Methadone (0.3, (-0.2, 1.8) (0.4, (0.4, (0.2, (-1.2, 2.7) (-0.4, 2.7) (-0.4, 2.8) (-0.4, 2.8) exposure 2.0) 2.1) 2.1) 1.9)(O=buprenorphine) 1.15 1.25 1.25 1.05Non-MAT (-2.5,(-1.1, 4.9) exposure 0.9)(O=buprenorphine)Formula only (-0, 0.6)(-0.8, 2.4) (0=no)Delivery method (-2.2, 0)(-3.4, 2.0) (0=cesarean)RtB, days (n=60)Main effect (-4.06, (-0.25, (-0.01, (-0.09, (-0.06, (-0.04, (0.06, (-0.06, (-0.02, 0)1.03) 0.35) 0.59) 0.18) 0.07) 0.03) 0.75) 0.02)0.41Site (0=UMass) (-4.12, (-5.12, (-3.82, (-4.29, (-4.39, (-6.31, (-4.05, (-5.07, (-4.22,1.01) 1.81) 1.34) 1.01) 1.10) 2.15) 0.87) 0.35) 0.94) Sex (0=female) (-2.12, (-1.89, (-2.58, (-2.17, (-2.00, (-1.68, (-1.31, (-1.40, (-1.51,2.94) 5.37) 2.67) 3.20) 3.32) 5.46) 3.38) 3.55) 3.39) Birth weight (0, 0.01) (-0, 0.01) (0, 0.01) (-0, 0.01) (-0, 0.01) (-0, 0.01) (0, 0.01) (0, 0.01)0.01)Methadone (0.84, (-1.78, (1.14, (0.69, (0.51, (-2.12, (0.25, (-0.12 (0.02, exposure 6.25) 4.81) 6.64) 6.35) 6.38) 4.32) 5.53) 5.54) 5.56) (O=buprenorphine) 3.55 3.89 3.51 3.45 2.89 2.79Non-MAT (-6.01, (-17.04, (-12.36, (-14.42, (-14.28, (-4.51, (-2.76, (-4.40, (-3.90, exposure 5.21) -1.65) 1.51) -0.56) -0.39) 10.98) 9.79) 8.76) 9.03) (O=buprenorphine) -9.35 -7.51 -7.34Formula only (-2.096, (-1.95, (-1.54, (-2.13, (-1.77, (-1-44, (-0.11, (-0.27, (-0.04, (Ono) 3.443) 4.39) 3.86) 3.93) 4.18) 4.94) 5.09) 5.48) 5.60) Delivery method (-5.23, (-5.75, (-4.76, (-4.98, (-5.34, (-4.98, (-3.03, (-4.00, (-3.60, (O=cesarean) 4.56) 5.88) 4.56) 4.84) 4.50) 6.49) 5.97) 5.61) 5.86)W1 Change, % (n=60)Main effect (-1.4, (-0.2, 0) (-0.5, 0) (-0.2, (-0.1, 0) (0, 0.1) (-0.5, 0.2) (0, 0.1) (0, 0)2.8) -0.1)0.15Site (0=UMass) (-0.8, (-1.8, 4.0) (-0.8, 3.8) (-0.2, 4.0) (0.3, (1.4, (-0.5, 4.6) (0.8, (-0.6, 4.5)3.5) 4.8) 8.9) 6.0)2.55 5.15 3.40Sex (0=female) (-3.0, (-4.5, 0.6) (-3.1, 1.3) (-2.6, 1.6) (-3.0, 1.3) (-4.3, 1.6) (-3.0, 1.9) (-2.7, 2.0) (-2.8, 2.1)1.1)Birth weight (0, 0) (0, 0) (0, 0)(0, 0) Methadone (-3.4, (3.9, 1.9) (-4.1, 1.1)(-4.6, 1.2) exposure 1.4)(O=buprenorphine)Non-MAT (-11., 0.8) (-11.5, (-8.4, 1.1) (-7.9, 2.1) (-6.0, 3.4) (-7.1, 2.6) exposure1.1(O=buprenorphine)Formula only (-2.0, (-2.2, 2.6) (-2.5, 1.9) (-1.7, 2.6) (-2.1, 2.3) (-3.9, 1.7) (-4.1, 1.3) (-5.1, 0.2) (-4.5, 0.9) (0=no) 2.2)Delivery method (-0.1, (0.1, (-0.2, 6.3) (-1.3, 5.0) (0.4, (-2.2, 6.7) (-2.7, 5.9) (4.2, 4.3) (-3., 5.50) (0=cesarean) 6.3) 7.2) 6.9)3.65 3.65W2Change, % (n=50)Main effect (-4.5, (-0.6, 0.3) (-1.0, 0) (-0.3, 0.2) (-0.2, 0.1) (-0.1, 0.1) (-0.8, 0.4) (0, 0.1) (0, 0) 11.5)Site (O=UMass) (-12.0, (-3.0, 8.8) (-1.8, 6.5) (-0.9, 7.7) (-0.4, 8.4) (-3.4, (-1.0, 7.3) (1.1, (-1.3, 7.1)8.7) 11.3) 9.1)5.1Sex (O=female) (-4.5, (-9.2, 3.6) (-3.3, 0.7) (-4.5, 4.1) (-4.3, 4.) (-9.1, 3.9) (-4.2, 3.7) (-3.6, 3.6) (-4.0, 3.9)3.1)Birth weight (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) Methadone (-6.3, (-7.7, 4.0)(-7.2, 2.3) (-6.7, 2.9) (-6.8, 4.5) (-6.8, 2.4) (-7.3, 1.2) (-7.0, 2.2) exposure 2.3)(O=buprenorphine)Non-MAT n / a n / a n / a n / a n / a (-4.2, (-11.5, (-8.7, (-11.0, exposure 11.7) 9.2) 10.2) 9.3) (O=buprenorphine)Formula only (Ono) Delivery method (-4.2, (-5.2, (-4.9, (-3.8, (-5.6, (-8.6, 7.3) (-5.8, (O=cesarean) 11.4) 11.4) 11.5) 17.1) 11.0) 10.6)W3Change, % (n=36)Main effect (-4.1, (-1.9, 2.0) (-7.8, (-10.5, (-9.7, (-0.1, 0.1) (-5.7, (-12.7, (-6.0,22.6) 22.2) 20.5) 20.8) 21.3) 15.6) 21.8) Site (0=UMass) (-22.0, (-20.2, (-8.0, (-8.5, (-5.4, (-12.7, (-6.9, (-7.0, 7.8) (-11.2,5.5) 23.0) 08.7) 11.6) 12.2) 16.8) 08.5) 7.0) Sex (0=female) (-2.2, (-17.5, (-2.0, (-3.8, (-5.3, 9.4) (-16.2, (-1.8, (-1.4, 9.9) (-1.5,9.3) 14.4) 11.5) 11.3) 12.8) 10.0) 10.9) Birth weight (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) Methadone (-8.4, (-16.3, (-10.6, (-10.8, (-11.1, (-12.3, (-8.4, 5.6) (-11.9, (-9.8, 4.8) exposure 4.7) 12.3) 4.2) 4.9) 4.3) 12.2) 2.4)(O=buprenorphine)Non-MAT n / a n / a n / a n / a n / a (-28.9 (-20.8, (-14.8, (-19.3, exposure 17.3) 06.2) 11.5) 8.3) (O=buprenorphine)Formula only (-1-5, (-18.0, (-1.4, 0.2) (-07, 0.5) (-1.4, 3.9) (-16.7 (-1.7, 0) (0, 0.2) (0, 0.1) (0=no) 10.6) 11.0) 8.4)Delivery method (-8.7, (-11.2, (-13.5, (-17.5, (-19.5, (-6.1, (-9.3, (-19.4, (-11.5, (0=cesarean) 27.6) 41.5) 26.3) 23.6) 21.6) 39.3) 26.6) 17.2) 25.3)W4Change, % (n=19)Main effect (3.3, (-2.6, 57) (-1.8, 0.5) (-07, 1.0) (-1.6, 5.1) (-0.1, 0.1) (-2.8, (-0.2, 0.2) (-0.1, 0)16.8) -0.5)10.05 -1.65Site (0=UMass) (-2.9, (-20.8, (-8.1, (-5.3, (-2.0, (-15.1, (-6.3, (-3.8, (-7.1,13.2) 33.0) 19.6) 27.2) 247) 21.7) 14.9) 24.5) 32.5) Sex (0=female) (-7.5, (89.6, (-9.4, (-12.9, (-10.9, (-19.7, (-9.4, 8.6) (-6.6, (-6.6,7.9) 41.7) 12.3) 14.5) 11.9) 20.5) 15.5) 15.4) Birth weight (0, 0) (-0, 0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) (0, 0) Methadone n / a n / a n / a n / a n / a n / a n / a n / a n / a exposure(O=buprenorphine)Non-MAT n / a n / a n / a n / a n / a n / a n / a n / a n / a exposure(O=buprenorphine)Formula only (-15.6, (-49.2, (-19.7, (-26.9, (-21.6, (-28.0, (-18.5, (-19.1, (-18.1, (0=no) -1.2) 11.0) -1.2) 3.0) -1.6) 4.1) -3.6) 2.4) 1.6)-8.4 -10.45 -11.60 -11.05Delivery method n / a n / a n / a n / a n / a n / a n / a n / a n / a (0=cesarean)Dose-response in newborn unit=Time in newborn unit prior to start of medication treatment; Dose-response in NICU=Timein neonatal intensive care unit upon start of medication treatment; Nadir=Days to lowest weight following birth weight; MaxLoss=Maximal percent weight loss from birth weight; RtB=Days to first weight to reach or surpass birth weight; W1Change-W4Change=Percent weight change from birth to week 1 through week 4, respectively; Time=Duration (mean h / d) infant received bedside activity: SVS On=lnfant in crib with stochastic vibrotactile stimulation on; SVS Off=lnfant in crib with stochastic vibrotactile stimulation off; Time held=lnfant held by caregiver; Time in motorized seat=lnfant in mamaRoo. TAU=Treatment as usual; Non-MAT=ln-utero opioid exposure not prescribed for maternal treatment for opioid-use disorder (e.g., prescribed oxycodin; illicit heroin); n / a = too few subjects to be considered in the model.aMean change (95% Cl) in outcome variable for unit increase of each covariate of the regression models; ‘Mean reported for significant effects at 95% Cl.Trajectory of Weight Gain

[0083] FIG. 4 shows the unadjusted comparisons between SVS and TAU for the weight-gain outcomes for the treated cohort (weight gain was not assessed in the untreated cohort given their early discharge from hospital within the first week of life). There was no significant difference in RtB between SVS (n=29; mean 12.4 days) and TAU (n=31; mean 13.7 days; p=0.22), or between conditions for W1 Change, W2Change, or W3Change (FIG.4). Unadjusted analyses revealed that among treated infants who were still hospitalized at 4 weeks (n=19), there was approximately 12% greater weight gain at 1 -month of age (W4Change) for SVS infants (n=9; mean 29.88%) than TAU infants (n=10; 18.2%, p=0.01). A post-hoc power analysis of this cohort shows that there is a power of 0.99 to detect this observed difference between SVS and TAU groups in a two-sided, two-sample t-test for the cohort at week 4 (n=19).

[0084] Dose-response analyses adjusting for condition and a priori cofactors of the 60 treated infants are provided in Table 2, above. Adjusted analyses revealed Week4Change was the only weight-gain outcome affected by condition. Among infants who remained hospitalized at 4 weeks, Week4Change was on average 10% greater for the SVS infants than TAU infants (3.3% to 16.8%, 95% Cl). Dose-response analyses showed that the duration of SVS off in the NICU was associated with a mean 1.7% per hour / day reduction in W4Change (-2.8% to -0.5%, 95% Cl). This corresponded to a 10% reduction in weight gain at 4 weeks for infants who received 6 hours / day in crib without mattress stimulation (SVS off).

[0085] As shown in Table 2, models controlling for condition and a priori cofactors revealed that RtB was on average 3.6 days later for infants with prenatal methadone exposure than for infants with buprenorphine exposure (0.8 to 6.3 days, 95% Cl). Similar effects of methadone exposure were observed for RtB in models that controlled for duration of SVS off, time held, and time in motorized seats. Dose-response models for W1 Change showed infants delivered via cesarean section had a greater weight gain in the first week of life when adjusting for condition, and duration of SVS on and motorized seat in the newborn nursery. UMass infants had a greater W1 Change than UPitt infants when adjusting for condition, and duration of motorized seat in the newborn nursery and duration of SVS on and caregiver hold in the NICU. Feed type played a significant role in Week4Change; infants who received formula only had on average 8.4% lower weight gain at 4 weeks than infants who received some breastmilk (-15.5 to -8.4%, 95% Cl). Similar dose-response effects of feed type for W4Change were identified in models that controlled for duration of SVS off and in the motorized seat.Post-hoc Analyses for Week-4 Cohort

[0086] Follow-up analyses were performed to further explore differences in weight trajectories for the 19 infants who were pharmacologically treated for > 4 weeks (Week-4 cohort). The only significant difference in infant and maternal variables between conditions was for infant Apgar score at 1 min [SVS mean score 8.4 (SD=0.73), TAU mean score 7.0 (SD 1.58), t=2.7, p=0.03]. Unadjusted analyses for this Week-4 cohort showed that on average, SVS infants returned to birthweight 4.4 days earlier than TAU infants (p=0.01 ; B-H q=0.04) and weekly weight gain from birth (W1 Change-W4Change) were each significantly greater for SVS compared to TAU (p<0.02; B-H q=0.04; FIG. 4).

[0087] Analyses adjusting for condition and a priori cofactors of these 19 infants showed no main effects of condition for Nadir, MaxLoss, or RtB. MaxLoss was significantly affected by prenatal methadone exposure (mean 5.2%, 2.2% to 8.2% Cl), formula only (mean 4.0%, 0.7% to 7.2%) and maximum caloric intake (mean 1.5%, 0.5% to 2.4%). Weekly weight gain remained significantly greater for SVS than TAU when adjusted for cofactors: Weekl Change (mean 4.3%, 0.4 to 8.1 %, 95% Cl); Week2Change (mean 4.2%, 0.3 to 8.1%, 95% Cl); Week3Change (mean 5.4%, 0.1 to 10.6%, 95% Cl); and Week4Change (mean 9.5%, 2.0 to 17.0%, 95% Cl). When controlling for condition, in a majority of models methadone exposed infants had decreased weight gain, UMass infants had increased weight gain, and formula-only infants had decreased weight gain (Table 3, below).Table 3Outcome variableNadir, MaxLoss RtB, W1 W2 W3 W4 days (% / 100) days Change Change Change Change (% / 100) (% / 100) (% / 100) (% / 100)Condition (-3.585, (-0.042, (-7.532, (0.004, (0.003, (0.001, (0.020, (0 = TAU) 1.472) 0.009) 0.956) 0.081) 0.081) 0.106) 0.17) 0.043 0.042 0.054 0.095 Site (-3.619, (-0.038, (-6.787, (-0.02, (0.001, (-0.024, (-0.019, (0=UMass) 1.957) 0.018) 2.572) 0.065) 0.087) 0.091) 0.15)0.044Sex (-3.178, (-0.045, (-4.459, (-0.032, (-0.069, (-0.056, (-0.078, (0=female) 3.096) 0.018) 6.072) 0.063) 0.028) 0.074) 0.112)Birth weight (-0.004, (0, 0) (-0.002, (0, 0) (0, 0) (0, 0) (0, 0) 0.005) 0.013)Methadone (-1.34, (0.022, (-0.14, (-0.116, (-0.099, (-0.137, (-0.175, exposure 4.673) 0.082) 9.953) -0.025) -0.006) -0.013) 0.007) (O=buprenor 0.052 -0.071 -0.053 -0.075phine)Non-MAT (-5.598, (-0.119, (-13.08, (-0.072, (-0.038, (-0.09, (-0.129, exposure 8.53) 0.022) 10.633) 0.142) 0.179) 0.202) 0.298) (O=buprenorphine)Formula (-1.316, (0.007, (-3.594, (-0.043, (-0.095, (-0.134, (-0.21, only (0=no) 4.965) 0.072) 6.95) 0.052) 0.002) -0.004) -0.02) 0.040 -0.069 -0.115 Delivery (-2.662, (-0.041, (-5.122, (-0.095, (-0.06, (-0.101, (-0.123, method 3.91) 0.022) 5.908) 0.005) 0.041) 0.035) 0.076) (0=cesarean)Max (-0.959, (0.005, (-0.507, (-0.035, - (-0.025, (-0.03, (-0.031, calories in 0.975) 0.024) 2.738) 0.006) 0.005) 0.01) 0.028) formula 0.015Adjusted regression analyses for primary weight change outcomes for infants that remained in the hospital at least 4 weeks after birth (Week-4 cohort). Nadir=Days to lowest weight following birth weight; MaxLoss=Maximal proportion weight loss from birth weight; RtB=Days to first weight to reach or surpass birth weight; WlChange-W4Change=Proportion weight change from birth to week 1 through week 4, respectively; TAU=Treatment as usual; Non-MAT=ln-utero opioid exposure not prescribed for maternal treatment for opioid-use disorder (e.g., prescribed oxycodin; illicit heroin). Bold=Mean reported for significant effects at 95% Cl.Comparisons to Nomograms

[0088] FIGS. 3A-3B show weight change trajectories for our SVS and TAU study infants with POE who received pharmacotherapy plotted with published nomograms for newborns without POE (www.newbornweight.org); because delivery mode may affect weight trajectory, we plotted our treated cohort on respective nomograms. Note that at week 4 (28 days), treated infants in our study who received SVS had a weightgain comparable to non-opioid exposed newborns between the 75th’90thpercentile depending on delivery mode, whereas TAU infants had a weight gain around the 30thpercentile regardless of delivery mode.Discussion

[0089] This dual-site this dual-site randomized clinical trial is the first study to examine whether SVS can improve weight trajectories in infants at risk for weight faltering. Newborns with POE typically have lower than average birth weight and tend to fall below average on standard growth curves throughout their first months of life. A recent study indicated that failure to thrive was a top five risk factor for 90-day hospital readmission among infants diagnosed with neonatal opioid withdrawal syndrome (NOWS). There is critical clinical need for interventions to help improve early growth in infants with POE. A key finding of our study was that among pharmacologically managed infants with prolonged hospitalization due to slow resolution of withdrawal symptoms, the SVS cohort returned to birthweight four days earlier and had significantly greater weekly weight gain from birth for the first month of life than the TAU cohort. Greater weekly weight gain was observed for unadjusted analyses and when adjusted for variables known to affect early growth, such as type of prenatal opioid exposure, delivery mode, feed type and caloric intake. These findings support that early tactile stimulation via SVS may improve weight growth in infants with POE at risk for weight faltering.

[0090] Infants in this study reached Nadir (~5 days), fell within MaxLoss range (~7-10%), and RtB (~13 days) comparable to non-opioid exposed newborns. When the trajectory of our morphine-treated infants was plotted on conventional nomograms for healthy infants (FIGS. 3A-3B), the SVS and TAU infants were at similar weight trajectories in the first two weeks of life, around 25thpercentile of healthy infants. However, whereas TAU infants continued to remain near the 25th-30thpercentile throughout the first month of life, the trajectory of weight growth at four weeks significantly increased for the SVS infants, congruent to 75th’90thpercentile of healthy infants. Together these findings support that following RtB, SVS promotes early weight growth in newborns pharmacologically managed for POE, which has implications for improved outcomes including reduced hospitalizations and associated costs.

[0091] Current methods for the management of newborns and infants with low weight and / or weight faltering focus on improving intake via nutrition / calories (i.e., breastmilk, formula, fortifiers), behavioral interventions (e.g., high hydrostatic pressureand microencapsulation; oral-motor interventions to improve non-nutritive sucking), and educational programs (e.g., dietary and behavioral training). This study employed a novel interventional device and showed that SVS delivered via a crib mattress improved weight gain within the first month of life among a subset of infants with POE. Among infants whose symptoms met criteria for morphine management, those with prolonged hospitalization who received SVS had significantly greater weekly weight gain for the first month of life compared to infants who received TAU. This effect held when adjusted for feed type (formula v. breastmilk with or without formula), high-caloric formula intake (20, 22, 24 kcals / oz), and prenatal methadone exposure - variables known to affect weight growth. It is speculated that improved physiologic function (e.g., reduced tachycardia, tachypnea, irritability) associated with SVS may contribute to organ growth and function, improve nutrition absorption, and minimize energy expenditure to promote weight growth in infants at-risk for weight-faltering.

[0092] Others have found that infants treated with pharmacotherapy for NOWS had growth faltering throughout hospitalization despite increased caloric administration. They concluded that additional pharmacologic and non-pharmacologic interventions were needed to help improve growth in infants with NOWS. This study supports that SVS may serve to provide such non-pharmacologic intervention, particularly among infants who present with disruptive feeding behaviors and / or symptoms that warrant pharmacotherapy. Early weight growth that does not rely on modifying feeds may ensure early healthy development without adverse long-term consequences that have been associated with excessive weight gain due to increased intake (e.g., cardiovascular disease and obesity). SVS may serve to promote weight gain during critical development in infancy independent of feed type and high-caloric intake.

[0093] In conclusion, SVS with a crib mattress increased weight growth among infants with POE in the first month of life. SVS may serve to promote weight gain during critical development in infancy independent of feed type and high-caloric intake. Promoting weight gain trajectories in at-risk infants has implications for organ growth and function, improved developmental, behavioral, and cognitive outcomes, and reduced hospitalizations and associated costs.Example 2Materials and MethodsStudy Design

[0094] Study infants were randomly assigned via a computer-generated force-block design to receive treatment as usual (TAU) or whole-body SVS using a uniquely-constructed crib mattress (30-60 Hz, ~12 pm RMS; Wyss Institute, Harvard University; Cofab Design, LLC) that delivered SVS on an automated 3-h on-off cycle.

[0095] Patients were assessed with a battery of tests, including the GOS-E Peds, Pediatric Quality of Life (PedsQL), the Bayley Scales of Infant and Toddler, 3rdEdition (Bayley III), Bayley Social and Emotion Scale (Bayley S&E), Pediatric Evaluation of Disability Inventory (PEDI), Brief Infant Sleep Questionnaire (BISQ). Developmental assessments were conducted by research outcome specialists masked to infant study condition (TAU or SVS), infant and maternal characteristics, and infant course of treatment, subsequent to hospitalization at ~6mos and ~12mos old.Results

[0096] As shown in FIG. 5, physical health score (as measured with the PedsQL) at 12 months of age was significantly higher in the group receiving SVS as infants as compared to the group receiving TAU. Improved physical health score associated with SVS has implications for reduced need for support services for daily living, healthcare interventions, long-term cares, and for improved quality of life.

[0097] Having described this invention above, it will be understood to those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any embodiment thereof. Any document incorporated herein by reference is only done so to the extent of its technical disclosure and to the extent it is consistent with the present document and the disclosure provided herein.

Claims

THE INVENTION CLAIMED IS:

1. A method of reducing weight loss, increasing weight, increasing rate of weight gain, and / or treating failure to thrive in a patient, comprising:administering to the patient vibrotactile stimulation for a duration and frequency sufficient to reduce weight loss, increase weight, increase rate of weight gain, and / or treat failure to thrive in the patient.

2. The method of claim 1 , wherein the patient is an infant.

3. The method of claim 1 , where in the patient is a human.

4. The method of claim 1, wherein the stimulation is administered using a device arranged in the patient’s bed, crib, seat, isolette, and / or incubator.

5. The method of claim 1, wherein the stimulation is administered using a device arranged in and / or on a substrate on which the patient sits, lays, and / or sleeps.

6. The method of claim 1, wherein the device is included in the mattress.

7. The method of claim 6, wherein the mattress includes an active region and a passive region, and the stimulation is only applied in the active region.

8. The method of claim 1, wherein the stimulation is administered using a device arranged in a garment configured to be worn by the patient.

9. The method of claim 8, wherein the garment includes an active region and a passive region, and the stimulation is only applied in the active region.

10. The method of claim 1 , wherein the stimulation is stochastic.

11. The method of claim 1, wherein the stimulation is delivered at a frequency of about 1 Hz to about 1000 Hz.

12. The method of claim 1, wherein the stimulation has an RMS amplitude or displacement of about 10 pm to about 25 pm.

13. The method of claim 1, wherein the stimulation is delivered intermittently or continuously.

14. The method of claim 1, wherein the stimulation is delivered for a first period of time and is not delivered for a second period of time.

15. The method of claim 14, wherein the first period of time has a duration of from about 1 minute to about 24 hours.

16. The method of claim 14, wherein the second period of time has a duration of from about 1 minute to about 6 hours.

17. The method of claim 1, wherein the stimulation is delivered from immediately following the patient’s birth until the patient is 1 month of age.

18. A method of treating weight faltering, weight loss, a reduction in weight gain, a failure to thrive, a physical impairment, and / or a cognitive and / or emotional impairment in an infant, comprising administering to the patient vibrotactile stimulation for at least 3 hours a day, at a frequency of about 30 to about 60 Hz, with an RMS amplitude or displacement of about 12 pm, for four months, thereby treating weight faltering, weight loss, a reduction in weight gain, a failure to thrive, a physical impairment, and / or a cognitive and / or emotional impairment in the infant.

19. A system for administering vibrotactile stimulation to a patient, comprising:an actuator;at least one processor in communication with the actuator, wherein the at least one processor is configured to control the actuator to deliver vibrotactile stimulation to the patient; andoptionally, at least one sensor configured to detect proximity of the actuator to the patient, the sensor in communication with the at least one processor.

20. The system of claim 19, wherein the actuator is arranged in a mattress.

21. The system of claim 20, wherein the mattress includes an active region and a passive region, and the actuator is arranged in the active region.

22. The system of claim 19, wherein the actuator is arranged in a garment configured to be worn by the patient.

23. The system of claim 22, wherein the garment includes an active region and a passive region, and the actuator is arranged in the active region.

24. The system of claim 19, wherein the at least one processor is configured to control the actuator to provide stochastic vibrotactile stimulation.

25. The system of claim 19, wherein the at least one processor is configured to control the actuator to deliver vibrotactile stimulation at a frequency of about 1 Hz to about 1000 Hz.

26. The system of claim 19, wherein the at least one processor is configured to control the actuator to deliver vibrotactile stimulation having an RMS amplitude or displacement of about 10 pm to about 25 pm.

27. The system of claim 19, wherein the at least one processor is configured to control the actuator to deliver vibrotactile stimulation intermittently.

28. The system of claim 19, wherein the at least one processor is configured to control the actuator to deliver vibrotactile stimulation for a first period of time, and to not deliver vibrotactile stimulation for a second period of time.

29. The system of claim 28, wherein the first period of time has a duration of about 1 minute to about 24 hours.

30. The system of claim 28, wherein the second period of time has a duration of from about 1 minute to about 6 hours.

31. The system of claim 19, wherein the at least one processor is configured to receive data from the at least one sensor and determine, based on the data, a length of time that stimulation has been delivered to the patient.

32. The system of claim 31 , wherein the at least one processor is configured to control the actuator based on the determination of the length of time that stimulation has been delivered to the patient.

33. A system for administering vibrotactile stimulation to a patient, comprising:a mechanical actuator;at least one processor in communication with the actuator, wherein the at least one processor is configured to control the actuator to deliver vibrotactile stimulation to the patient; andat least one sensor configured to detect proximity of the actuator to the patient, the sensor in communication with the at least one processor,wherein the at least one processor is configured to control the mechanical actuator to deliver stimulation at a frequency of about 30 to about 60 Hz and with an RMS amplitude or displacement of about 12 pm, and wherein the at least one processor is configured to:receive, from the at least one sensor, proximity data relating to a proximity of the patient to the mechanical actuator;determine, based at least in part on the proximity data, whether the patient is receiving the vibrotactile stimulation; andbased on the determination, stop the vibrotactile stimulation when the patient has received about four hours of stimulation in a 24-hour period.

34. Use of the system of claim 19 for treating weight faltering, weight loss, a reduction in weight gain, a failure to thrive, a physical impairment, and / or a cognitive and / or emotional impairment in an infant.

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