Abstract: A method of implanting a prosthetic heart valve includes advancing a prosthetic heart valve to an implantation location within a patient's body, positioning the prosthetic heart valve within a native heart valve annulus, expanding a frame of the prosthetic heart valve from a first contracted configuration to a first expanded configuration, and then contracting the frame to a second contracted configuration. The prosthetic heart valve may be repositioned and then re-expanded from the second contracted configuration to a second expanded configuration. The prosthetic heart valve is preferably released from the delivery apparatus while in the second expanded configuration. Releasing the prosthetic heart valve from the delivery apparatus may result in radial expansion of a flange portion of the prosthetic heart valve.

Abstract: An artificial cardiac valve is disclosed, which includes an outer stent; an inner stent nested within and connected to the outer stent; leaflets disposed inside the inner stent; and membranes attached to walls of the outer and inner stents. The inner stent is a cylindrical mesh tube, and the outer stent includes a first stent segment, a second stent segment and a third stent segment which are connected sequentially. The first stent segment is a mesh tube. The second stent is a mesh tube having a substantially D-shaped cross-section, and the third stent segment is a flared mesh tube. The first stent segment has a maximum diameter that is equal to a diameter of the second stent segment and to a minimum diameter of the third stent segment. In this stent design, the inner stent can withstand traction forces from the leaflets, and the outer stent is adapted to match the anatomy of the native valve.

Abstract: Embodiments of a radially collapsible and expandable prosthetic heart valve are disclosed. A valve frame can have a tapered profile when mounted on a delivery shaft, with an inflow end portion having a smaller diameter than an outflow end portion. The valve can comprise generally V-shaped leaflets, reducing material within the inflow end of the frame. An outer skirt can be secured to the outside of the inflow end portion of the frame, the outer skirt having longitudinal slack when the valve is expanded and lying flat against the frame when the valve is collapsed. A diagonally woven inner skirt can elongate axially with the frame. Side tabs of adjacent leaflets can extend through and be secured to window frame portions of the frame to form commissures. The window frame portions can be depressed radially inward relative to surrounding frame portions when the valve is crimped onto a delivery shaft.

Abstract: An exemplary two-stage prosthetic heart valve system has a radially expandable base stent implanted within a native valve annulus. The base stent desirably has three position markers projecting in the axial direction from the outflow end of the base stent to assist in aligning the stent with respect to the commissures of the native valve. The two-stage heart valve system also has a valve component that is delivered to and mounted within the base stent in a separate or sequential operation after the base stent has been anchored within the annulus. The valve component in certain embodiments comprises a hybrid valve component that includes a conventional, non-expandable surgical valve that is modified to include an expandable coupling stent that can be expanded to engage the inner surface of the base stent, thereby anchoring the valve component to the base stent.

Abstract: A delivery device for a prosthetic mitral valve includes five sheaths and a handle. The first sheath is coupled to a first handle portion and is rotatable and bendable. The second sheath is coupled to a second handle portion and extends through the first sheath. The second sheath is bendable, rotatable and translatable relative to the first sheath. The third sheath is coupled to a third handle portion and extends through the first and second sheaths. The third sheath is translatable relative to the second sheath. The second handle portion is coupled to the first and third handle portions. The fourth sheath extends through the third sheath and forms part of a compartment to store the prosthetic valve. The fifth sheath extends through the fourth sheath to a tip and is coupled to a retaining sheath that closes the compartment to retain the valve in a collapsed condition.

Abstract: An annuloplasty implant comprises a plurality of individual wires, each extending in a longitudinal direction of the implant between first and second opposite ends of the implant. A locking unit arranged at at least one of the ends comprises a locking structure connected to the plurality of individual wires, thereby collecting said plurality of individual wires together at at least one of the ends. The locking structure is configured to allow a relative movement between at least two of the plurality of individual wires inside the locking structure.

Abstract: A device structured to suppress mitral regurgitation by restricting prolapse of a mitral valve leaflet and including a base correspondingly dimensioned to the mitral valve and including a central portion, structured to allow blood flow there through and a peripheral portion or ring connected to the central portion in substantially surrounding relation thereto. An operative position of the base includes the central portion disposed in overlying, movement restricting relation to at least one of the valve leaflets and the ring concurrently anchored adjacent or directly to the native annulus of the mitral valve. The physical characteristics of the base facilitate its movement with and conformance to the mitral valve during diastole and systole cycles of the heart.

Abstract: An exemplary valve repair device for repairing a native valve of a patient has a paddle frame, an inner paddle, and an outer paddle. The outer paddle is connected to the inner paddle. The inner and outer paddles are connected to the paddle frame at a connection between the inner paddle and the outer paddle. A portion of the inner paddle is moveable away from a portion of the outer paddle to open the inner and outer paddles.

Abstract: Devices for assisting with the functioning of a tricuspid valve of a heart include a shaft, a flow optimizer, and an anchoring mechanism. A tilting mechanism can be configured to tilt the shaft relative to a central axis of the anchoring mechanism. Leaflets (e.g., multi-layer leaflets) of the flow optimizer can include a membrane and a rim, and the rim can have a higher stiffness than the membrane.

Abstract: An active annuloplasty ring holder having a template that can be folded or pivoted to the side allowing the template to align longitudinally with the handle and enter the patient's chest through a small incision. The holder may include a mechanism to remotely detach sutures fastening the ring to the holder, thereby detaching the ring while avoiding the risk associated with introducing a scalpel into the operating field. A detachment mechanism may include a movable pin actuated by a pull wire that releases a plurality of holding sutures, or a hot wire, knives, or pull wire that severs the sutures. The holder may have a built-in light source for better visualization of the ring inside the heart. The holder may also have an optical means of visualizing the inside of the heart from the proximal end of the handle.

Abstract: Systems, devices, and methods for reducing regurgitation through an atrioventricular heart valve: i.e., the mitral valve and the tricuspid valve. The device includes a flexible anchor rail anchored in the tissue of the ventricle and an offset coaptation element on a catheter that rides over the anchor rail and is positionable between the valve leaflets. The proximal end of the coaptation catheter is fixed subcutaneously adjacent the subclavian vein. The coaptation element includes an inert covering over a foam interior, and is radially offset on the catheter so that the foam body projects away from the septal side of the valve to reduce or minimize deformation from contact with the septal wall of the ventricle. Markers on the coaptation element facilitate positioning in the desired rotational orientation during delivery and implant.

Abstract: Systems and methods for de-airing a cardiac chamber during cardiac surgery are provided. A catheter-based inflatable device is inserted adjacent a target area of the heart, and the frequency of inflation and deflation of the inflatable device is controlled via a remote controller to change the shape of the cardiac chamber to dislodge air bubbles from their deposition site in the cardiac chamber.

Abstract: A tibial implant may include a plurality of implant subunits. The implant subunits may be configured for individual insertion within a wedge-shaped-void of the tibia. The implant subunits may further be configured for assembly in order to provide an implant substantially covering an exposed portion of cortical bone formed when performing a surgical osteotomy. Methods and kits for insertion and assembly of implants are further described.

Abstract: A spinal interbody cage implant includes a cage, an endplate, and flexible barbs. The endplate is separately attached to the cage and is configured to receive, hold and direct a flexible barb into an upper vertebral surface and a flexible barb into a lower adjacent vertebral surface. Each proximal leg of the cage is configured to receive the endplate, and has a lateral bore that receives a pin which retains the endplate. The endplate directs a first flexible barb upwardly toward an upper vertebral surface, and directs a second flexible barb downwardly toward a lower vertebral surface. Each flexible barb has a proximal head, a shaft extending from the head with a bore extending from the head to its distal end. Teeth are provided along the exterior surface of the shaft with two flats disposed on opposite sides thereof with a slit extending from the distal end towards the head.

Abstract: An implant comprising a porous microstructure is disclosed which has an external surface, where at least a region of the external surface is formed of the porous microstructure. The microstructure is defined by at least one lattice of cells. Each cell has a predetermined cell topology and a plurality of edges. One or more of the edges of each cell connect to an adjacent cell along a corresponding edge thereof. Collectively, the cells have a periodic or aperiodic arrangement within the at least one lattice.

Abstract: A temporo-mandibular prosthesis including a glenoid part and a condylar part intended to be articulated relative to the glenoid part. The glenoid part including a glenoid support made in a metallic material; and a glenoid insert made in a non-metal lie material, and defining a seat for a head of said condylar part to define said articulation, wherein the glenoid support defines a housing having an opening through which said glenoid insert is insertable into said housing, said opening opening on an external side (E) of said glenoid support, the glenoid support comprising a tab configurable in a passive position and in an active position in which said tab allows and forbids, respectively, the insertion and the extraction, respectively, of said glenoid insert into and out of said housing, respectively.

Abstract: Embodiments of a system and method for assessing hip arthroplasty component movement are generally described herein. A method may include receiving data from a sensor embedded in a femoral head component, the femoral head component configured to fit in an acetabular component, determining information about a magnetic field from the data, and outputting an indication of an orientation, coverage, or a force of the femoral head component relative to the acetabular component.

Abstract: A patellar implant includes a body and at least one oblique anchoring pin. The body includes a bone-facing surface that is substantially planar and has a lateral end and a medial end. The body also includes an articulating surface opposite the bone-facing surface. The at least one oblique anchoring pin extends from the bone-facing surface at an acute angle toward the lateral end of the bone-facing surface. The at least one oblique anchoring pin includes a first end attached to the bone-facing surface and a second end spaced from the first end. A longitudinal axis extends from the first end to the second end. The longitudinal axis defines the acute angle with respect to the bone-facing surface. The at least one oblique anchoring pin extends into a surgically-prepared patella when the patellar implant is such that the surgically-prepared patella abuts the bone-facing surface.

Abstract: Implants, device, systems and methods for replacing an articulation surface in a joint, for example, a glenoid implant with an articular surface and an opposing bone contacting surface having a ring and post extending therefrom that respectively mechanically connect with cortical bone and cancellous bone of a glenoid. Methods for implanting the glenoid implant are also disclosed.

Abstract: An implant constituted of: a body exhibiting a longitudinal axis; proximal arms extending from the body, each of the proximal arms extending in a respective direction and exhibiting a respective acute angle with the longitudinal axis, the body positioned between the proximal arms; distal arms extending from the body, each of the distal arms extending in a respective direction and exhibiting a respective acute angle with the longitudinal axis, the respective directions of extension of the distal arms generally opposing the respective directions of extension of the proximal arms, the body positioned between the distal arms; and intermediate arm assemblies extending from the body, each of the intermediate arm assemblies extending in a respective direction rotated about the longitudinal axis from the respective extension directions of the proximal arms and exhibiting a respective acute angle with the longitudinal axis, the body positioned between the intermediate arm assemblies.

Abstract: An implant is insertable in the joint space to separate bones of the joint. The implant has two endplates each configured to engage a separate articulating bone of the joint, and a threaded member positioned between the two endplates and configured to increase the space between the two endplates when the threaded member is rotated. A rotatable gear is engaged with the threaded member, and is engageable with a rotating gear of a connected implantation tool, so that rotation of the gear on the tool causes rotation of the threaded member and expansion of the implant to separate the bones. Connector portions on the tool and the implant may be rotated together to securely engage the implant and the tool so that the gears of the tool and the implant can be rotated using an actuator outside of the body, when the implant is inside the body.

Abstract: An implant (100, 200, 300, 400) includes a base (10), and a sequence of at least two segments including a first segment (12) and a last segment (14). The first segment (12) is pivotally linked to base (10). Adjacent segments are interconnected at pivotal connections (18). A bolt (20) has a threaded shaft (22) and a head (24). The threaded shaft (22) is engaged in a threaded channel (26) of the base (10) so that rotation of the bolt (20) about a central axis of the threaded shaft (22) varies a degree of overlap between the base (10) and the bolt (20). The last segment (14) and the head (24) define therebetween a spherical bearing (28). Rotation of bolt (20) thus varies a distance between spherical bearing (28) and hinge pin (16), thereby causing deflection of the sequence of segments.

Abstract: Systems and methods are described for correcting sagittal imbalance in a spine including instruments for performing the controlled release of the anterior longitudinal ligament through a lateral access corridor and hyper-lordotic lateral implants with detachable fixation tabs.

Abstract: An interbody fusion device includes a top member, a base member, and an expansion member. The top member includes a first bone-engaging side and a threaded opening. The base member is received by the top member and includes a second bone-engaging side and an open cavity aligned with the threaded opening of the top member. The expansion member is disposed within the open cavity for rotation about an axis. The expansion member includes a threaded portion threadably engaged with the threaded opening. Rotation of the expansion member translates the first bone-engaging side away from the second bone-engaging side along the axis.

Abstract: The present invention provides an expandable fusion device capable of being installed inside an intervertebral disc space to maintain normal disc spacing and restore spinal stability, thereby facilitating an intervertebral fusion. In one embodiment, the fusion device includes a central ramp, a first endplate, and a second endplate, the central ramp capable of being moved in a first direction to move the first and second endplates outwardly and into an expanded configuration. The fusion device is capable of being deployed down an endoscopic tube.

Abstract: An orthopaedic implant includes an implant body having a first surface, a second surface opposite the first surface, and a cavity formed therein that extends through the first surface and the second surface. The implant body has a third surface with at least one first opening formed therethrough to the cavity. The at least one first opening includes an outer portion having an outer diameter and an inner portion having an inner diameter. The implant includes a load bearing member including a porous material held within the cavity. The outer portion of the at least one first opening is configured to couple to a tool for receiving, from the tool, a material agent, and the inner portion of the at least one first opening is configured to couple to a plug for preventing the material agent from exiting the porous material via the at least one first opening.

Abstract: An implant is provided for performing spinal fusion. The implant includes an implant body having a leading side and a trailing side at opposing ends along a longitudinal axis. Between the leading side and trailing side are an upper surface, a lower surface, an anterior side, and a posterior side. At least one keel structure is provided extending from the implant body for penetration into an adjacent vertebral body. A trial sizer and keel cutter may be utilized to form keel channels within the vertebral body to receive the keel structure.

Abstract: Apparatuses and systems including at least one of mounting and removal of a femoral component on a femur are disclosed. The instrument can include a handle, a plunger, first and second arms and a knob. The handle can define a recess. The recess can extend along a portion of an elongate length of the handle. The plunger can be moveably disposed within the recess and can be configured to extend through an opening in a distal end of the handle to engage a pad to contact the pad against the femoral component. The first and second arms can be pivotally coupled to the handle and can be pivotable relative to one another. The first and second arms can each have at least one coupling feature configured to engage with a corresponding second coupling feature in the femoral component. The knob can be configured to operatively actuate the plunger to move the plunger proximal/distal within the recess to engage the plunger with and disengage the plunger from the pad.

Abstract: An impaction tip can be used in installing an implant. The impaction tip can comprise a body, and a sliding member. The body can have a handle-facing surface and an implant-facing surface. The body can define a grooved portion. The handle-facing surface can define an opening sized to receive a portion of an impaction handle. The sliding member can be located at least partially within the grooved portion. The sliding member can be slideable from an interior position to an exterior position. When the sliding member is in the exterior position a portion of the sliding member can contact the implant.

Abstract: An operating instrument includes a housing, a chassis, a first and second drive shaft, a gear assembly, a switch assembly, and a bearing lock assembly. The first and second drive shafts each has a first portion supported by the chassis in the housing and a second portion extending out of the housing. The gear assembly includes a first gear member fixedly received on the first portion of the first drive shaft and a second gear member slidably received on the first portion of the second drive shaft.

Abstract: A stemless humeral component for replacing the humeral head of a patient's humerus includes a support flange having a number of cantilevered legs extending distally away from a bottom surface thereof. Instruments and methods for surgically installing the stemless humeral component are also disclosed.

Abstract: A prosthetic implant for engagement between first and second vertebrae. The implant includes a first plate configured for attachment to the first vertebrae and defining a first interbody connection member and a second plate configured for attachment to the second vertebrae and defining a second interbody connection member. An interbody component includes a body with a first end defining a first plate connection member configured for connection to the first interbody connection member and a second end defining a second plate connection member configured for connection to the second interbody connection member. A method of inserting the implant is also provided.

Abstract: The disclosure provides apparatus and methods of use pertaining to a bidirectional biomechanical prosthetic finger assembly. One embodiment includes a metacarpophalangeal (MCP) pivot configured for swivelable attachment to a hand of a user, a distal coupler, and an articulation assembly rotatively coupled therebetween. A multiple-finger ring configured to receive a user's residual finger and at least one adjacent finger is disposed upon the articulation assembly, and may be adjusted to a target location based on a length of the residual finger. The articulation assembly is configured to utilize vertical movements of the residual and/or adjacent finger(s) within the multiple-finger ring to articulate the distal coupler within a plane parallel to an x-z plane, and the MCP pivot is configured to utilize lateral movements of the residual finger within the ring to articulate the distal coupler within a plane parallel to an x-y plane. Other embodiments are also disclosed.

Abstract: A prosthetic foot comprising a vacuum system configured to attach to a vacuum attachment apparatus and a residual limb. The prosthetic foot may comprise a resilient bottom member, a resilient top member, and a vacuum system. The resilient bottom member may comprise a front end and a rear end. The resilient top member may comprise a front end and a rear end and the front end of the resilient top member may be connected to the front end of the resilient bottom member. The vacuum system may be coupled to an underside of the rear end of the top member. The vacuum system may comprise a compressible member, a chamber located within the compressible member, a valve system received within the compressible member, a passageway connecting the valve system and the chamber, and an air return coupled to the valve system and the vacuum attachment apparatus.

Abstract: Examples of a stent are provided with interlocking joints removably coupling adjacent axial stent segments. Mating elements forming the interlocking joints maintain engagement when the stent is in the radially compressed configuration, for example, during tracking of the stent to a treatment site of a body vessel, and become disengaged during radial expansion of the stent. When disengaged, the disconnected the axial stent segments remain discrete stent structures separated from one another along the point of treatment.

Abstract: An intraluminal vascular prosthesis assembly, having a hollow cylindrical body with a first end and a second end is provided. The assembly includes, at its first end, a first vascular prosthesis portion, and at its second end, a second vascular prosthesis portion which has only a prosthesis material. The vascular prosthesis assembly has a stent portion which is provided between the first vascular prosthesis portion and the second vascular prosthesis portion, the stent portion being free of prosthesis material to allow fluid flow there through and received within the aortic arch and spanning the brachiocephalic artery, left common carotid artery, and left subclavian artery when placed within the aortic arch of a patient.

Abstract: A stent device includes generally cylindrical rings aligned along a longitudinal axis, and interconnected by interconnecting members. Each interconnecting member includes a first coupling end, a second coupling end, and an elongate portion therebetween. The first coupling end, the elongate portion, and the second coupling end combine in either a first orientation or a second orientation, which are substantially mirror images. For each interconnecting member, the first coupling end can intersect with a midpoint of a transition region of a substantially repeating curved segment on one of the rings, and the second coupling end can intersect with a midpoint of a curved segment of a different and immediately adjacent ring. The interconnecting members can be arranged in rows extending longitudinally along the device. Along each row, consecutive interconnected members alternate between the first orientation and the second orientation. A cover may be provided over the stent device.

Abstract: Disclosed herein is a stent which is compressible to small diameter and usable in neurovascular applications. The device is a braided stent and has a crown geometry which enables compression to small diameter without cracking or tangling. Also disclosed is a method of deploying a stent to a body vessel and its use in a coiling procedure.

Abstract: An endoprosthesis delivery system includes a wire holder on a distal section of an elongated shaft with a plurality of wires extending distally from the wire holder and, in a secured position, terminating in a distal receiver attached to the elongated shaft distal to the wire holder. A single wire attached to the wire holder and extending proximally along the delivery system to a point easily accessible by the operator may be pulled proximally to move the wires out of the distal receiver and release the endoprosthesis.

Abstract: A knee brace assembly comprising a sleeve and a buttress attached to the sleeve and configured to be positioned against a knee of the wearer. The buttress is configured to be positioned proximate a patella of the wearer and configured to provide support to the patella of the wearer. The knee brace includes a wrap having a first end defining an upper tab and lower tab, and a second end defining an upper and lower tab. The wrap is sized to extend around the leg of the wearer. The upper tab of the first end is configured to attach to the upper tab of the second end, and the lower tab of the first end is configured to attach to the lower tab of the second end, such that the wrap is operable to form a compressive fit around the sleeve and buttress.

Abstract: An improved lumbosacral wrap is generally provided. In an example, a lumbosacral wrap can include a lumbosacral panel, first and second bilateral panels, and a posterior pad. In certain examples, the lumbosacral wrap can include a wireless transcutaneous electrical nerve stimulation (TENS) device selectively supported by the lumbosacral panel or the posterior pad. In certain examples, the wireless TENS device is receivable within a cavity of a user engaging surface of the posterior pad in furtherance of supplementing support and compression of a lumbosacral spine with mobile treatment.

Abstract: An orthopedic thumb splint is adapted for stabilizing a carpometacarpal joint of a user. The exemplary thumb splint includes a flexible fabric splint body having a wrist portion and a generally funnel-shaped thumb portion. The thumb portion defines a narrowed opening for receiving a thumb of the user. A thumb-abducting flexible X-strap is secured to the splint body adjacent the narrowed opening of the thumb portion. The X-strap has first and second diverging distal ends having respective inside surfaces. The inside surface of each distal end includes touch fasteners designed to releasably mate with complementary touch fasteners located on an outside surface of the splint body.

Abstract: A penis pump includes a hollow cylinder having an open proximal end sized to allow the insertion of a human penis therein and a distal end. A cushion is inserted into the hollow cylinder between the proximal end and the distal end. A support member has a first end connected to the cushion and a second end attached to the distal end.

Abstract: A device for collection waste from a body includes a collecting pouch and an adhesive wafer connected to the collecting pouch for attaching the collecting pouch to the body. The adhesive wafer includes at least one intermediate layer of adhesive, a skin facing layer of adhesive, a first film layer, and a second film layer. The first film layer is formed of backing layer material, and is positioned between the skin facing layer of adhesive and the intermediate layer of adhesive. The second film layer is formed of backing layer material. The second film layer is positioned adjacent to the intermediate layer of adhesive on an opposite side of the intermediate layer of adhesive from the first film layer. The first film layer is configured to reduce a peel force of the adhesive wafer.

Abstract: A condom assembly includes at least one of a condom, patch or glove made of at least one of natural latex, synthetic latex or the mixture of natural latex and synthetic latex. The natural latex, synthetic latex or the mixture of natural latex and synthetic latex contain prodrugs of nitric oxide and/or other active ingredients.

Abstract: A device and method is provided for treating a person by providing controlled stimulation of a branch of the trigeminal nerve of the person to induce a dive reflex response in the person. A device for providing this treatment includes a stimulus component controllably operable to stimulate a branch of the trigeminal nerve of a person. The stimulus component can be a Peltier device configured to reduce the temperature of the person's face in proximity to a branch of the trigeminal nerve to induce the dive reflex. A controller controls activation of the stimulus component when it is desirable to induce the dive reflex response in the person. The controller can sense physiological and ambient conditions and can activate and deactivate the stimulus component in response to a condition falling within or outside a threshold value.

Abstract: A portable heating/cooling device for clinical hypo/hyperthermia with cuffs especially designed for arterial cooling/heating for raising or lowering the body temperature of a patient is operable by battery power or a wide range of available external power, and is usable in the field or in medical transport where such external power sources are not available. The small size, weight, and robust nature of the device allows it to be transported with the patient without the need for additional conveying devices.

Abstract: The present invention is directed to a self regulating heater including a first layer made of a thin and flexible electrically insulating material. A second electrically conductive layer includes first and second buses spaced from each other. A third resistive layer electrically connects the first and second buses. The third layer has a higher electrical resistance than the second layer. The third layer experiences a positive temperature coefficient (PTC) effect when heated. A fourth interface layer directly connected to at least one of the second electrically conductive layer and the third resistive layer directly engages skin of a patient when the heater is attached to the patient. A combined thickness of the first layer, the second conductive layer, the third resistive layer and the fourth layer may be between 5 mil and 20 mil.

Abstract: Materials and methods for producing localized hypothermia in a patient (e.g., for treatment of acute pancreatitis and pancreatic cancer).

Abstract: A method of treatment is disclosed herein. The method includes administering to a patient in need thereof a polymer implant device containing a biocompatible drug, or a plurality of nanoparticles or microparticles conjugated with the biocompatible drug, the biocompatible drug comprising one or more Rock inhibitors, one or more Wnt inhibitors, one or more integrin inhibitors, and/or one or more glycogen synthase kinase 3 (GSK-3) inhibitors, the patient having a medical condition selected from the group consisting of dry eye, glaucoma, retinal detachment, retinal degeneration, age-related macular degeneration, a cataract, uveitis, a corneal genetic disease, postoperative inflammation, immune-related inflammatory processes, diabetic retinopathy, a side effect occurring after cataract surgery, a side effect occurring after refractive surgery, and combinations thereof.