At the crossroads of chemistry, electronics, mechanical engineering, polymer science, biology, tissue engineering, computer science, and materials science, electrical devices are currently being engineered that blend directly within organs and tissues. These sophisticated devices are mediators, recorders, and stimulators of electricity with the capacity to monitor important electrophysiological events, replace disabled body parts, or even stimulate tissues to overcome their current limitations. They are therefore capable of leading humanity forward into the age of cyborgs, a time in which human biology can be hacked at will to yield beings with abilities beyond their natural capabilities. The resulting advances have been made possible by the emergence of conformal and soft electronic materials that can readily integrate with the curvilinear, dynamic, delicate, and flexible human body. This article discusses the recent rapid pace of development in the field of cybernetics with special emphasis on the important role that flexible and electrically active materials have played therein. A great variety of cybernetic concepts are currently under development, some have already hit the healthcare market, while others are being carefully evaluated in laboratories all over the world.The manufacturing of the abovementioned cybernetics relies on a number of challenges that have only recently begun to be addressed in depth. First, one of the key requirements of any device intended to interface with the human body is a proper integration between the device and the body to assure long‐term performance. To this end, a number of challenges related to the mechanical mismatch between conventional rigid electronic materials and the dynamic, soft, and curvilinear human body need to be solved as the elastic moduli of silicon and metal‐based electronics range from 1–170 GPa,Overall, the gateway into the field of flexible bioelectronics is currently heavily related to the development of new multifunctional materials, which are flexible, resilient, and electrically active at the same time. In this review, we will highlight the recent advances of such electronic and flexible materials with a special focus on how these formidable materials currently are being used by scientist all over the world to reshape the field of cybernetics into a readily implementable technology. To this end, we will exclusively focus on healthcare monitoring devices, cybernetic prosthetics, brain–machine interfaces, and the exciting emergence of cyborganics. The review will begin with a brief overview of flexible and conductive polymers, since these materials are instrumental in the engineering of flexible bioelectronics. We will then proceed to discuss the incorporation of liquid metals and 2D nanoelectronic materials into such polymers, as the research and development of such composite systems in our opinion will soon lead to a number of scientific breakthroughs in the field of cybernetics. We will initially focus on the application of these materials in wearable and implantable healthcare monitors before highlighting their use in cybernetic prosthetics. As a new standpoint, we have also reviewed the recent progress in the development of cyborganics and the possible new directions that this emerging field might spearhead in the future. Finally, some of the current material‐based limitations in the field of cybernetics and how they can be successfully addressed will be discussed.2FigureFlexible bioelectronics enable a great variety of biomedical applications that would otherwise be impossible to achieve using conventional rigid electronics, as these devices need to conform well to the human body in order to yield high‐quality recordings of physiological events.2.1Electronic devices are mainly fabricated at high temperatures; this may lead to expansion or shrinkage due to internal stresses in the underlying polymeric material and therefore dimensional instability of the device.Another key requirement is a high barrier property because moisture and gas permeation may lead to dimensional instability of the polymer material. Still, there are many applications for flexible bioelectronics where the materials need not to be fully impermeable—but semi‐permeable—to allow biosensors to operate, such as in smart bandages.Surface roughness is another important parameter in the fabrication of flexible electronics, since the current transport in such devices is limited by surface defects and cracks.2.2Tg) and melting temperature (Tm). In this respect, the amorphous polymers have no clear melting point and their glass transition temperatures are approximately between −125 and 350 °C. On the other hand, semi‐crystalline polymers have a distinct Tm, while their Tg in general is higher than amorphous polymers and typically in the range 75–260 °C.Tm and do not have any Tg associated to them. Crystalline polymers can especially have extraordinary properties such as high stability, strength, and good resistance toward the surrounding environment.−1, 89–92%, and 50–80 g m−2 d−1, respectively.Polymers are essentially made from long chains of repeating monomer units held together by strong intermolecular interactions.Tg ≈ −125 °C) PDMS is a highly flexible and stretchable (≈1000%) material with a relatively low shear modulus ranging between 100 kPa and 3 MPa and flexural modulus ≈54 MPa.−1) as compared to other amorphous polymers.Polydimethylsiloxane (PDMS) is another interesting amorphous polymer that has found wide usage in bioelectronics due to its biocompatibility, nontoxicity, excellent optical transparency, and reasonable chemical resistance.−1).Polyimides (PIs) are an interesting class of amorphous polymers that offer most of the advantages of semi‐crystalline polymers along with a high glass transition temperature (350 °C) and low CTE , and good moisture barrier properties (0.1–0.5%).Tg point (80–100 °C), low CTE (35 ppm °C−1),Various semi‐crystalline polymers can be used for bioelectronics including PET, polyethylene naphthalate (PEN), and polyetheretherketone (PEEK).Due to a growing technological demand, a significant amount of electronics are discarded and trashed every year.−1 have been reported,−1).Extensive research has been done on flexible and degradable electronics made from cellulose (paper) and silk‐based biopolymers. The degradation pathway of cellulose is typically driven through hydrolysis mediated by the family of cellulose enzymes, whereas silk—in its low‐crystalline state—is a highly water‐soluble protein, which disperses in physiological relevant solutions. Out of these materials, paper is particularly recognized for being a good material candidate in flexible electronics due to its high availability, flexibility, light weight, and sustainability.3Many important biological processes such as neuronal activity,3.1Electrically active polymers have emerged as a new class of mechanically robust and biocompatible materials for flexible bioelectronics.3.1.1−1.PPY is considered to be one of the pioneering polymeric conductors in bioelectronics due to its ease of functionalization and unique electrochemical properties (high conductivity and stability in oxidized states).3.1.2−1; a parameter that can be fine‐tuned through molecular weight,PANI was discovered as early as 1862,3.1.3−1.−1 under 100% strains, because of their enhanced crystallinity and more interconnected polymeric networks.PEDOT is perhaps the most‐investigated electroactive polymer to date,3.1.4P3HT is another interesting semi‐conducting polymer, which has been widely used in various types of electronics—in particular organic solar cells—since its discovery in 1980.3.2Replacing inorganic semiconductors with their organic counterparts involves a number of trade‐offs. The advantages include decreased manufacturing expenses, higher flexibility, and light‐weight.Over the years, several modification strategies aimed at strengthening intermolecular polymer bonds have been used to increase the stability of organic semiconductors. Especially, PEDOT:PSS has garnered significant attention, as it can be easily functionalized and is susceptible to electrical dopants.Figure2O2) by glucose oxidase. The formation of hydrogen peroxide was quite essential, as it significantly alters the gate potential resulting in a huge current drop across the transistor channel.In simple terms, a bipolar junction transistor consists of three semiconductors: a collector, base, and an emitter.In summary, organic semiconductors hold great promise in flexible bioelectronics due to their reasonable sensitivity, high flexibility, biodegradability, and low cost. They have already successfully been used in a wide range of biological and medical applications, and further applications are expected once their response time and conductivity are made to match their inorganic counterparts.4One avenue to bridge the current gap between conductive polymers and their inorganic counterparts is to reinforce them with inorganic fillers. The prime components of most of today's inorganically reinforced polymers are 2D and 1D nanomaterials.Another area that avenues to improve the electrical properties of flexible polymers is the incorporation of liquid metals into them, as liquid metals are conductive, self‐healing, and reconfigurable. It has therefore been foreseen that their incorporation into polymers can lead to sophisticated electronic circuits that can spontaneously repair upon damage.Even though the research and development of the abovementioned inorganic fillers is still in its infancy, the achievements obtained to date are truly remarkable and have already surpassed those reported by conventional organic‐based polymers. We are therefore confident that these fillers will be a game‐changer in flexible bioelectronics. One concern, however, is their cytotoxicity and biocompatibility in vivo, which still has not been carefully evaluated. This is beyond doubt one of the major challenges that needs to be addressed before their potential can be translated into devices that can integrate seamlessly with the human body.4.15 cm2 V−1 s−1),−1 K−1),−6 K−1).2 g−1),In brief, graphene consists of a monolayer of carbon atoms that are packed densely into a 2D hexagonal honeycomb lattice with a carbon–carbon bond length of 1.42 ÅFigureTypically, graphene is synthesized by either top‐down or bottom‐up strategies.Given these unique features of graphene, it has attracted tremendous attention as an electroactive and mechanical nanoreinforcer with the capacity to turn nonconductive polymer‐based materials into amazing conductors of electricity with impressive mechanical properties.As an example, graphene incorporation within PEDOT has resulted in significant improvement of mechanical and electrical properties, features that were used to enhance the performance of neural and microelectrode interfaces.3+.−1) at only 3 wt% graphene loading. Although this approach is effective for homogeneous dispersion of graphene sheets in the polymer matrix, it is limited, as the rate of polymerization is decreased at high graphene content. By contrast, the solution blending method is the most straightforward approach to use for developing polymer films at high graphene concentrations. To this end, Seol et al. recently developed a stretchable and transparent conducting electrode based on mixing PEDOT:PSS with rGO.−1), as compared to rGO–PEDOT:PSS and pristine PEDOT:PSS.Graphene may also be used to effectively reinforce PEDOT:PSS polymer film for flexible bioelectronics. Toward this endeavor, studies have shown that the graphene–PEDOT:PSS composites can be formed by either in situ polymerization or various blending processes.−1.Graphene has also in recent years been used in wearable sensor systems due to its ability to improve the accuracy in position, acceleration, and velocity detection of its wearer at high strains and strain rates.Other properties of graphene such as electrical and mechanical stability can be further coupled with control over the specific interactions between graphene and polymers to generate a self‐healing and conductive composite system.4.29 A cm−2),−1 K−1 at room temperature),FigureCNTs belong to the fullerene family of nanomaterial's and consist of graphene sheets that are rolled‐up into high‐aspect ratio tubes (>1000).The outstanding properties of CNTs have turned them into widely used nanofillers in polymer matrixes for the construction of flexible, stretchable, and deformable electronics.5 MPa−1 at 0.9 MPa pressure.Notably, CNTs typically form a percolation network within the matrix, which in turn significantly enhances the electrical conductivity within the polymer. For instance, several studies have shown that CNTs networks can be formed within polymers to yield highly conductive and stretchable strain sensors.One avenue to improve the CNT percolation network is based on generating a PDMS foam consisting of 3D‐interconnected networks and then dip the entire polymeric foam into a CNT solution.As previously mentioned, the integration of self‐healing properties into polymers has speared a major paradigm shift toward the development of flexible and stretchable electronic devices with higher durability during successive loadings. Toward this endeavor, a self‐healing piezoresistive strain sensor device, which is able to detect the dynamic movement of the human body was recently developed by incorporating SWCNTs into a self‐healing PVA polymer matrix Figure .196 The 4.3Existing bioelectronic devices primarily use metal electrodes such as Au, Pt, and Ag because of their suitable electrical properties, biocompatibility and corrosion resistance.−1 in the pressure range of 0–5 kPa. Due to its excellent sensing, flexibility, and robustness, this device was used for real‐time monitoring of blood pressure and various acoustic vibrations. Although, AuNWs‐based devices are quite promising for the field of flexible electronics their conductivity could be improved even more. A possible approach for improving the conductivity of such devices is by combining them with conductive polymers. For example, PANI microparticles have been doped into AuNWs films to yield a tenfold improvement in conductivity and eightfold enhancement in electrical sensitivity in comparison to pristine AuNW‐based strain sensors.For instance, Au nanostructures in the form of nanowires have gained great interests in flexible and stretchable bioelectronics, owing to their remarkable aspect ratio (≈10 000), mechanical and electrical properties.Silver nanowires (AgNWs) are another interesting class of metallic nanowires, which has been widely used in various types of wearable and flexible bioelectronics.−1. This composite system could endure up to 600 cycles of bending, stretching, and twisting tests without breaking.Although, AgNWs and AuNWs have demonstrated promising results in the field of flexible electronics, they are relatively expensive compared to their organic counterparts Hence, copper nanowires (CuNWs) have become an appealing alternative, since they are cheaper, but yet, display an electrical conductivity similar to that of silver (Ag) and Au.4.41D silicon nanowires (SiNWs) are also steadily gaining a foothold in bioelectronics—albeit to a lesser degree compared to graphene and CNTs—due to their unique electrical, mechanical, and optical properties.Various techniques based on both top‐down and bottom‐up manufacturing have over the years been developed to generate silicon nanowires.Due to their amazing electronic properties, silicon nanowire devices display impressive sensitivity when it comes down to measuring bioelectrical signals in the body.4.5Figure2O3).6 S cm−1),−1 K−1 at ≈37 °C),Another class of inorganic materials for flexible electronics is liquid metals, as these materials are liquid near room temperature and therefore flow readily in response to stress Figure7.258 Tb‐(ethylene‐co‐butylene)‐b‐styrene] fibers have lead to stretchable and electrically conductive circuits that could stretch up to 800% before mechanical failure, without losing their electrical continuity.Due to their unique material properties and below room temperature melting point , gallium alloys have recently been used as conductive fillers in place of rigid filler particles to improve the electrical and mechanical properties of elastomeric polymers.Liquid alloys composed of gallium are also ideal candidates for creating conductive circuits within elastomeric substrates, which spontaneously can self‐heal electrical and mechanical defects imposed on them during wear and tear.The incorporation of liquid metals within polymers and then the deposition of the entire system onto a conductive metal trace is another avenue for achieving a self‐healing circuit, as this ingenuity enables liquid metals to readily reconnect distal parts emerged during tear caused by either wear or mechanical failure.67In20.5Sn12.5 alloy encased in a biodegradable gelatin hydrogel to achieve a minimally invasive integration between electrode and tissue. Although gelatin is widely recognized as a biocompatible and degradable polymer, it however is not conductive and stretchable. To this end, we anticipate that it is possible to use other types of polymers such as conductive PEDOT‐based polymers to improve electrical and mechanical properties of the system.Indeed, the aforementioned multifunctional properties of gallium and its alloys have also made them attractive candidates for bioelectronics. For instance, it has been reported that the EGaIn electrodes can be used to both record and stimulate electrical activity in individual neurons.Another interesting feature of the liquid metals is their ability to change shape via a variety of mechanisms such as mechanical and electrical stimuli, because this unique trait could be useful for a number of applications such as reconfigurable electronics and bioactuators. Furthermore, recent studies have also shown that the combination of fluidity, deformation reversibility, and conductivity in liquid metals can yield artificial microrobots that can move through blood vessels or intestines to fulfill numerous biomedical purposes.5FigureCurrently, there are a growing number of breakthroughs in bioelectronics driven by the emergence of better and smarter materials that can readily integrate with the dynamic human body. These technological breakthroughs are aiming to empower the patient through technical health aids that enable real‐time monitoring of medical risk factors.5.15.1.1FigureThe human skin can reveal important information about the overall health status of the patient as the mechanical metrics of skin are intimately linked to the circulatory function of the bodyRecently, more sophisticated circuits have been built to expand the sensing capabilities of e‐skin to encompass changes in temperature,Overall, the abovementioned advancements have led to the development of multifunctional and mechanically robust e‐skin platforms with formidable sensory capabilities for wireless diagnostics.5.1.2Chronic wounds represent a global healthcare challenge that is expected to grow at a tremendous speed in the coming years as the population ages.Over the years, a comprehensive list of potential biomarkers for wound healing has been established, which include markers such as pH value, temperature, proteins, inflammatory mediators, cytokines, enzymes, hormones, and nutritional factors.In addition to monitoring the infection and inflammation status of a wound, other approaches can be explored to promote the healing process by administrating drugs and growth factors to the site. In a recent study by Bagherifard et al.,Bandages with textile‐like materials have also been extensively used for covering wounds, since they are porous, biocompatible, and capable of delivering oxygen and removing exudates from the wound site.Despite the recent advancements in the development of new smart wound management systems, the available sensors for wearable diagnostic dressings are currently directed toward few physiological markers and thus cannot be specific about the intricate mechanisms occurring in the wound environment. Moreover, the suggested platforms are rarely commercialized and are still in early preclinical stages, choosing the right combination of incorporated sensors and the management of the huge amount of output data is another challenge that needs to be addressed in the future to provide even better wound management systems.5.1.3Tattoo‐based electrochemical sensors hold significant potential for low‐cost healthcare monitoring applications, thanks to their ability to perform real‐time and noninvasive electrochemical analysis of important biomarkers present in body fluids.Recently, a range of landmark studies by Bandodkar and Wang has led to the development of a variety of noninvasive tattoo‐based sensors that can effectively monitor several electrolytes and metabolites including sodium,Tattoo‐based wearable sensors have also been developed to monitor electromyography (EMG) signals from the skin surface. The monitoring and subsequent control of such electrical signals have over the years been used for many clinical purposes, such as identifying neuromuscular disorders,Although, such flexible EMG devices are well suited for electrophysiological recordings at various locations on the body, they still face significant challenges related to their stretchability and electrical response time. One noteworthy attempt to remedy this bottleneck was based on using graphene‐based electronic tattoos, wherein graphene was incorporated into a flexible thin (≈463 nm) poly (methyl methacrylate) substrate.Like‐wise, tattoo‐based e‐skin has been developed for controlling human prosthetics by stimulating the muscles in the vicinity of the implant electrically.Further advancements in 3D printing of electronic materials into highly complex circuits are expected to lead to miniaturized and electronically integrated tattoo‐based skin devices with higher mechanical and chemical potency that can cover a broader range of biomedical applications. Moreover, development of tattoo‐based energy harvesting devices5.1.4The human brain has always been one of the biggest mysteries in biology and is still in many ways an uncharted territory. Hence, different types of recording systems have been invented to collect information that can elucidate what really lies hidden beneath the skull and deep within the human brain. EEG is one of the gold standards for this endeavor because of its cost‐effectiveness, inexpensiveness, noninvasiveness, and high temporal resolution. In brief, EEG devices record the spontaneous electrical activity along the human scalp to detect neural oscillations from the brain—the so‐called “brain waves”—as abnormal brain wave activity typically coincides with most brain disorders.One avenue for remedying the current situation is through the development of new and better materials that can yield conformable EEG electrodes capable of adhering onto the human skin without creating any discomfort for the patient. An achievement like this will undoubtedly initiate a more widespread use of EEG devices for many patient empowering applications, including at‐home management of brain‐related disorders, sleep monitoring, and cognitive control. Several noteworthy solutions have already been suggested to initiate this landmark change with the major focus being directed toward the inclusion of soft, conformable, and adhesive electronics into the existing EEG concept.FigureTo this end, a conductive polymer‐based EEG electrode was recently developed that enables a much better conformal contact with the skin and higher quality recordings compared to gel‐based EEG systems.Conformable, durable and user‐friendly EEG electrodes based on flexible, conductive and biocompatible materials are something that the health‐oriented consumer is currently craving, as EEG electrodes are already being used to improve the level of concentration5.25.2.1−1).2 and with a center‐to‐center distance of 60 µm. This high‐density configuration enabled unprecedented recordings of the electrical activity in rat brains along with good biocompatibility and flexibility. The developed ECoG electrode was also able to record signals that bear resemblance to epileptic spikes in a high‐fidelity manner. Building on these results, an even more dense and flexible electrode that could record action potentials in the brain was developed.Even though wearable EEG electrodes have provided neuroscientists with a wealth of information over the years, electrodes that are in direct contact with brain neurons enable much higher fidelity recordings in terms of spatial resolution (≈1 cm).5.2.2Cardiac‐related diseases remain one of the major health issues in the world and are currently the number one cause of mortality in the developed countries.Conventional ECG electrodes are typically assembled on rigid substrates with sharp edges and therefore cannot integrate properly with the curvilinear and soft heart tissue to enable the needed electrical coupling between tissue and device for high‐fidelity recordings.Although the abovementioned flexible ECG devices are well suited for recording electricity from the curved heart surface, they are incapable of penetrating the many ripples and grooves of its surface, instead they are only able to establish conformal contact with localized regions underneath the heart surface. This current lack of methodology limits the recording and stimulation capabilities of ECG devices, and therefore even more cardiac‐friendly systems are called upon. One of the most obvious attempts to address this challenge is to replace the nonadhesive and biologically stable PI substrate used in most flexible ECG devices with a more conformable, adhesive, and bioresorbable material.An alternative system to the silk‐based material strategies was recently developed to further improve recording/stimulation of the cardiac tissue by using ultrathin elastic membranes that matched the complex heart tissue architecture while simultaneously providing excellent electrical contact with important physiological areas on the heart tissue.In summary, the abovementioned flexible and bioresorbable materials have enabled ECG systems for real‐time monitoring of cardiac activity with the grand goal of treating cardiac‐related disorders, as these materials have improved the devices so they can record electrical signals from previously unattainable electrical points within the ripples and grooves of the beating heart while, at the same time, enabling localized cardiac tissue stimulation to mend potentially life‐threatening chronic heart conditions. However, the stability of such electronic devices within biological fluids remains unclear, since biocorrosion at the electrode/tissue interface and the associated lowering of the device functionalities present a significant bottleneck within the field.5.2.32) in atmospheric air, which degrades into Mg2+ and OH− in the body.An impaired blood circulatory system is among the major causes of mortality in the world, as it can disconnect vital tissues and organs in the body from receiving nutrients and oxygen.In a recent study, these concepts have been united into a sophisticated bioresorbable stent that is capable of giving real‐time feedback on postsurgery inflammation and blood flow through the targeted vessel.FigureIn addition to the use of stents in treating circulatory related diseases they are also capable of recording and stimulating brain activity from within the narrow capillaries of the brain.In summary, the progress made in the field of electronic stents is truly remarkable and will undoubtedly address one of the biggest killers in our times: cardiac‐related diseases. Notably, endovascular stent‐electrode arrays for deep brain stimulation will undoubtedly facilitate breakthroughs in the field of brain–machine interfaces, as they in the authors opinion, will enable seizure prediction in patients with epilepsy and become viable treatment options for those suffering from Parkinson's disease.6FigureDriven by the unification of prosthetics and flexible bioelectronics, the applications of cybernetic prosthetics are numerous and rapidly expanding. Examples include: spinal cord implants that enable the paralysed to move again; brain–machine interfaces that enable the immobilized to mobilize their thoughts to control man‐made limbs; retinal implants that bridge the gap between the brain and the blinded eye to restore vision in the patient; ear implants that make the hearing disabled hear again; and last but not least scientists are following a daring goal of uniting inanimate electronics with living tissues to create cyborganic transplants with unheard of properties Figure12. It 6.1Traumatic injuries to the spinal cord significantly deteriorate the quality of life of those affected, and the affected ones typically suffer from chronic paralysis.FigureThe research and development of soft and conformable materials for neural implants is still in its infancy and therefore presents an uncharted territory ripe for fruitful investigations. In a recent cutting‐edge study by a group of scientists from École Polytechnique Fédérale de Lausanne (EPFL), this daunting challenge was addressed by embedding flexible Pt electrodes and interconnects within a soft and biocompatible silicone‐based substrate, which they coined electronic dura matter or simply “e‐Dura” Figure13.15 T6.2FigureWhile spinal cord electrodes aim to restore mobility in paralysed patients by reconnecting the lost motor area with the brain cortex, brain–machine interfaces achieve this by rerouting motor‐related signals to manipulate prosthetic limps.However, unfortunately, many of the above‐referenced brain–machine interfaces do not meld well with the human brain due to a mechanical and biological mismatch.FigureAlthough flexible brain–machine interfaces hold great promise as a less invasive treatment than their rigid counterparts, they still rely on invasive and costly surgical procedures. To address this challenge, a method is required that is completely noninvasive to enable a seamless merger between flexible electronics and the brain. To address this grand challenge, a methodology was recently introduced by Lieber and co‐workers,6.3Tg compared to PI, as described in Section Age‐related and disease‐related degeneration of the human eye affects millions of people worldwide and is expected to grow rapidly in the coming years due to the ageing global population.One noteworthy example of PI‐based retinal devices is the Argus II, which consists of 60 Pt microelectrodes embedded on a flexible PI‐substrate.6.4Whereas the aforementioned applications of flexible electronics were primarily directed toward establishing conformal electrical contacts with tissues in vivo to restore and/or enhance the functions of the human body, even more impressive cybernetic systems are currently under development to create cyborg organic constructs (cyborganics). In its essence, “cyborganics” represents an emerging concept at the crossroads of tissue engineering, materials science, electronics, and chemistry with the daring aim to create a new class of hybrid organs and hydrogel carriers made from a combination of inanimate and biological matter.FigureThe concept of “cyborganics” was also recently applied to create cochlea‐shaped electrodes consisting of cartilage tissue interweaved with inductive coil antennas Figure16.428 77.1Flexible and conductive polymers will unequivocally reshape the field of bioelectronics and herald a new age in modern electronics. However, there are many challenges that need to be addressed, since the thermal stability, solvent resistance, CTE coefficients, and conductivity of polymer materials still differ a lot from their inorganic counterparts.−1 at 0% and 140% strains, respectively.In one paramount study, carbon nanotubes functionalized with Ag nanoparticles were incorporated into a matrix of polyvinylidenefluoride and solvent cast into an ultrathin sheet (<140 µm). The hybrid film displayed unusual electromechanical properties with a conductivity at 5710 and 20 S cmMoreover, properties such as high‐field‐effect carrier mobility and long‐term stability under mechanical, electrical, and environmental stress have made inorganic semiconductors and nanomaterials suitable for various flexible electronic applications.Despite these encouraging results, multifunctional polymers with all of the abovementioned properties are yet to hit the consumer market for flexible electronics. However, the era of nanoreinforced polymers is still in its infancy; we therefore anticipate that further research in this direction will yield polymer composites with even more extraordinary properties than those previously reported.7.2The unsystematic healthcare monitoring of the populace is one of the primary driving forces behind many chronic diseases. Examples include the stealthy plaque buildup in blood vessels caused by unhealthy eating habits, the well‐documented correlation between diabetics 2 and high blood glucose levels and the intimate link between a number of debilitating neurodegenerative diseases and unnoticed cases of neuroinflammation. A number of smart technical health‐aids have already been developed with the ability to gather such vital health data from the patients from home without the need of costly and time‐consuming in‐clinic visits. Indeed, Rogers and co‐workers are currently working hard to spearhead some of these technologies into the consumer market through a newly funded company, namely MC10. MC10 specializes in wearable physiological monitors that are made from materials that enable them to effortlessly adhere and integrate onto the skin; they recently launched the “BioStamp,” which is a conformable e‐skin device that can link physiological data recorded from the body to portable devices for efficient readout and analysis of those data. In a similar vein, Google is currently working on a new wrist‐worn device that will enable ECG, skin temperature, and pulse monitoring. In addition to recordings associated with circulatory health and skin wellness it would be interesting to expand the operational capacity of the commercially available healthcare monitors to also include EEG measurements from the brain, similar to the study from Rogers and co‐workers that we reviewed in Section Stretchable and elastomeric bioelectronics has also been gradually realized in other more specialized sensorial and therapeutic applications. For instance in recent study by Mannoor et al. a flexible material interfaces that can be used to monitor bacterial contaminants on tooth enamel was developed.In another recent study, a multifunctional and transparent endoscope capable of temperature/pH sensing, drug delivery, and performing real‐time optical imaging was developed.In summary, there is currently a push in the field of bioelectronics driven by the emergence of a new class of flexible electronic materials, and in the authors' opinion, it seems like its worldwide applicability is closer to becoming a reality than ever before. As this trend continues, we envision a truly remarkable healthcare revolution in the form of personalized health monitoring devices with impeccable accuracy.7.3Extensive work on animals has paved the way for implementing a wide range of the aforementioned cybernetic extensions in human subjects. However, a large amount of work is still needed in this direction to develop even better material interfaces to reach the grand goal of realizing human cyborgs with supernatural abilities and powers. Especially, the engineering of electrode materials that can bridge between the brain and human consciousness as well as more sophisticated cyborganics are called upon to bring cyborgs out from the realm of science fiction and into real‐world applications.Among the most noteworthy applications of brain–machine interfaces is to treat and possibly cure neurological and physiological disorders. Malfunctions in the neural circuitry of the brain and neurotransmitter imbalance are key factors behind these kinds of brain disorders. One avenue for restoring order in the disordered brain is, as briefly mentioned in Section So far, the prime‐usage of cyborganics has been in various diagnostic and proof‐of‐concept applications. However, the union of electronic materials and living tissues can pave the path for impressive devices that can replace dysfunctional organs and enhance bodily functions beyond normality. We anticipate that 3D printing of living cells along with 2D nanomaterials such as graphene or CNTs can yield even stronger tissue constructs that are part animate and part inanimate. Moreover, the deposition of electronics and cells into architectures similar to those found in native tissues through various microprinting techniques is a feature that definitely will spark unprecedented progress in the field of cybernetics.Given the fact that muscle tissue consists of highly aligned and organized muscle bundles, the combination of 3D printed carbon‐made fibers and muscle cells into anisotropic tissue‐like architectures can lead to alternative treatments for those suffering from scleroses and muscular dystrophy. These cyborg muscles are also anticipated to give the wearer formidable strength, similar to the supernatural abilities of the cyborgs, that have been presented to us through science fiction movies.Ultimately, the engineering of flexible electronics that can blend right in with the human body has driven the field of cybernetics to reach the capacity to deliver truly outstanding human–machine interfaces, that in the authors opinion will yield more advanced and versatile beings in the foreseeable future.8The widespread usage of sophisticated prosthetics such as cochlea, retina, brain–machine, and neural implants along with the projected importance of technical health aids in our daily‐life‐activities clearly indicates that we are slowly entering a cybernetic era. These advances are a direct consequence of flexible and electronic materials that can meld seamlessly with the soft and curved tissues of the body. The development of brain–machine interfaces that enable thought‐controlled movement of objects has especially stirred a lot of frenzy in the field and we anticipate that these cybernetic extensions could potentially expand human cognition to a new level.Another emerging topic  can change the way synthetic material parts and tissue transplants are viewed and ultimately herald a new era in tissue engineering, wherein more durable, better, and stronger tissues are custom‐made in the laboratory to hack the biology of humans beyond our current imagination. In the authors' opinion, further advances in this direction are intimately linked with 3D printing of hybrid neural circuits and nanoreinforced designer materials that can impose exceptional abilities on the user. The advantages that the 3D printing technology bring to the field of cybernetics are first localized printing of cells, materials, and nanoelectronics onto flexible substrates, and second the ability to custom‐make cyborg organs with native‐like tissue architectures. Other areas of research ripe for investigations are cybernetic devices that can harvest energy from the moving body without the need of any interventions or revision surgeries to replace old batteries.In summary, the ongoing progression of research in the field of cybernetics has been made possible from the beautiful trinity between biology, materials science, flexible electronics, and tissue engineering. However, we should be wary of the fact that the implementation of some of the suggested cybernetic inventions need to be carefully and critically evaluated to make sure they follow existing ethical guidelines.The authors declare no conflict of interest.


The Consolidated Framework for Implementation Research (CFIR) is a commonly used implementation science framework to facilitate design, evaluation, and implementation of evidence‐based interventions. Its comprehensiveness is an asset for considering facilitators and barriers to implementation and also makes the framework cumbersome to use. We describe adaptations we made to CFIR to simplify its pragmatic application, for use in a learning health system context, in the evaluation of a complex patient‐centered care transformation.We conducted a qualitative study and structured our evaluation questions, data collection methods, analysis, and reporting around CFIR. We collected qualitative data via semi‐structured interviews and observations with key stakeholders throughout. We identified and documented adaptations to CFIR throughout the evaluation process.We analyzed semi‐structured interviews with key stakeholders (n = 23) from clinical observations (n = 5). We made three key adaptations to CFIR: (a) promoted “patient needs and resources,” a subconstruct of the outer setting, to its own domain within CFIR during data analysis; (b) divided the “inner setting” domain into three layers that account for the hierarchy of health care systems ; and (c) tailored several construct definitions to fit a patient‐centered, primary care setting. Analysis yielded qualitative findings concentrated in the CFIR domains “intervention characteristics” and “outer setting,” with a robust number of findings in the new domain “patient needs and resources.”To make CFIR more accessible and relevant for wider use in the context of patient‐centered care transformations within a learning health system, a few adaptations are key. Specifically, we found success by teasing apart interactions across the inner layers of a health system, tailoring construct definitions, and placing additional focus on patient needs. Some implementers and evaluators have reported struggling to translate the complex and sometimes repetitive construct definitions to fit their initiatives, along with the resulting outcomes derived from our approach.Here, we report adaptations we made to the CFIR in the evaluation of a multicomponent, patient‐centered care transformation, designed to address the Quadruple Aim.2Is the Consolidated Framework for Implementation Research (CFIR) a useful, accessible tool to use when evaluating a complex intervention within a learning health system?Which adaptations are needed to make CFIR better suited to evaluating complex care transformations within a learning health system context?How might our experience of and lessons learned from using CFIR to evaluate a complex primary care transformation within a learning health system inform future evaluations of similar interventions?33.1Primary Care 2.0 is a patient‐centered care model developed by Stanford Primary Care leaders, with input from numerous stakeholders, including patients and families.After extensive staff and provider training and planning, Stanford launched Primary Care 2.0 in June 2016 as a pilot in a new academic primary care clinic located in a community setting. The patient panel was initially about 1700 with a 3‐year goal of 10 000. The clinic serves a patient population that is diverse both ethnically and socioeconomically, with 72% non‐White patients and 14% publicly insured.3.2We divided the evaluation of Primary Care 2.0 into three stages: evaluation design, qualitative data collection and analysis, and assessment of spread. Here, we report on our utilization of CFIR in the first two stages, as stage 3 data collection and analysis of spread are currently in process. At each stage, CFIR served as a skeleton around which we structured our evaluation questions, methods, and reporting.3.2.1In the first stage of our evaluation, we designed a plan appropriate for assessing key implementation outcomes in the context of a rapidly changing health system. We chose to frame our evaluation plan around CFIR as we expected it to be sensitive to most aspects of the complex implementation process. We used CFIR's five broad domains  to focus our evaluation measures by pairing them with the following implementation science outcomes: acceptability, adoption, appropriateness, feasibility, and adaptation. We used this combination of CFIR domains and implementation outcomes for each of the six modules of Primary Care 2.0 to drive our data collection, analysis, and reporting.3.2.2For the second stage of our application of CFIR, we collected and coded qualitative data. Table Table Two qualitatively trained researchers (C.B.J. and N.S.) conducted five site visits over 2 years, utilizing rapid ethnography principles to embed into the pilot site clinic and observe implementation. Rapid ethnography draws upon multiple related data collection methods  in a short time frame while retaining a patient‐centered focus.Both of our field researchers completed field notes within 1 day of each site visit. Field researchers also conducted a 30‐ to 60‐minute debrief with each other at the end of each site visit day to cross‐reference implementation themes, insights, and lessons learned. We used CFIR as an informal checklist to organize findings during these qualitative data rapid synthesis debriefs. The debriefs also surfaced necessary changes and iterations needed in the data collection process.We downloaded qualitative data, including 23 interview transcripts, into NVivo 11.4.2 for analysis. Transcripts included interviews from Stanford Health Care leadership (n = 2), pilot clinic leadership (n = 2), and on‐the‐ground staff and providers (n = 19). Two of the authors (C.B.J. and N.S.) collected, coded, analyzed, and synthesized all qualitative data. Using the 39 CFIR constructs as baseline codes, we developed a codebook to guide the coding process. We tailored definitions for each construct to fit the Primary Care 2.0 model. Coders C.B.J., a PhD qualitative expert, and N.S., an MPH‐trained qualitative researcher, developed and agreed upon adapted definitions. We also added additional codes for each module of the Primary Care 2.0 model and adapted operational definitions for each from the Primary Care 2.0 durable record.Coders analyzed each data source for fit within each Primary Care 2.0 module and CFIR construct; a single data point could be, and often was, categorized to multiple constructs and modules. At periodic intervals, the researchers coded a transcript together to ensure inter‐coder agreement and reliability.We coded transcripts using all 39 of CFIR's constructs and chose to explore each construct using deductive content analysis, an approach that utilizes a framework for analysis based on previous knowledge, 4We made three key adaptations to CFIR at different stages throughout our evaluation: 1) promoted the “patient needs and resources” construct from the “outer setting” domain to its own sixth domain in the framework; 2) divided the “inner setting” domain into three layers to better reflect the complexity and hierarchy of implementation within a health care system; and 3) tailored CFIR construct definitions to fit the intervention's patient‐centered, team‐based care context and support consistency of data collection and coding.4.1The most significant change to CFIR structure arose in the process of coding of our qualitative data. Following our initial coding, we conducted a matrix analysis juxtaposing the five CFIR domains and each of the Primary Care 2.0 modules, as shown in Table 4.2The CFIR framework draws particular attention to the intervention setting, which it divides into inner and outer settings, in order to capture contextual forces on implementation. The “inner setting” refers to implementation factors as they exist within an “organization,” while the outer setting mostly considers influences external to the organization. Distinct from the original application of CFIR and as part of our data collection planning process, we further divided the inner setting into three distinct subparts, defined in Figure The structural, cultural, and readiness constructs defined within CFIR's inner setting are well‐suited for a simple, evidence‐based intervention within a small organization but do not attend to the complexity, hierarchy, and diverse stakeholders characteristic of a learning health care system. To effectively apply CFIR in the setting of our academic medical center, these stratified layers of inner setting, delineated by stakeholder groups and organization hierarchy, helped us identify the ways in which the different hierarchical components impacted the implementation process. Applying the inner setting constructs independently at these three levels brought our attention to the distinct implementation climates, variation in leadership engagement, patient needs, and cultures in each. Using these levels, we shaped our data collection tools and approach to purposively sample stakeholders across all three. Qualitative data that emerged showed some differences by group. For example, when asked “What does Primary Care 2.0 mean to you?”—a question designed to address the inner setting's “access to knowledge and information” subconstruct—medical assistants implementing the model at the pilot clinic (inner setting level 1) stated, “it's a better way of doing things … an attempt to resolve some of the issues with primary care … ,” whereas implementation leadership within Stanford Health Care administration (inner setting level 3) defined the transformation as “Stanford's version of the advanced medical home … in an effort to try to transform primary care into an activity that meets the quadruple aim.” Stakeholders at peer clinics (inner setting level 2) reported very minimal understanding of the transformation, with some team members stating, “I don't know … it's a little confusing to me and I'm not really sure how it's all gonna work.”4.3The first barrier our team encountered in applying CFIR was agreement for each construct's meaning and application in our specific intervention and clinical context as we developed our data collection materials. We found some constructs repetitive and others too broad in the context of an academic medical center. To address these issues, the primary researchers C.B.J. and N.S. reviewed each construct and codeveloped tailored definitions that were clear to both and a better fit for the context of a patient‐centered care transformation within a learning health system. Table For example, we addressed the overlap between the constructs “goals and feedback” and “reflecting and evaluating” by tailoring each to exist exclusively in different settings. We redefined “goals and feedback,” originally categorized to the “inner setting” domain, as communication and activities around implementation goals and progress that is led by the pilot clinic leadership. We characterized “reflecting and evaluating,” a construct of the “process” domain, as an exercise led by Stanford Health Care leadership with support from evaluation team efforts, as part of a partnered research approach. Although they originally exist within two different domains, the overlap between these constructs in the context of this transformation necessitated a shift of “goals and feedback” to the “process” domain since the new definition articulated a process to support implementation.Much like the process for codebook development in preparation for qualitative data analysis, which emphasizes clear exclusion and inclusion criteria to support inter‐coder reliability,Table 5This study describes the pragmatic adaptations we made to CFIR to make it accessible and relevant for wider use in the context of patient‐centered care transformations. While CFIR has been applied in health care across a wide range of setting and objectives, it has rarely been combined with the complexity of implementing and evaluating a multifaceted restructuring of care. In their systematic review of CFIR application, Kirk et al highlight gaps in depth of use of the framework, variation in selection of CFIR constructs, and a lack of justification of constructs used, limiting comparison of findings across time and contexts.The CFIR modifications we describe enabled us to have a deeper and richer understanding of issues that both facilitated and hindered implementation of each of the modules of Primary Care 2.0, with more robust consideration of patient and local health care system angles, than if we had used the framework in its original form. Primary Care 2.0 is a patient‐centered transformation effort and as such focuses heavily on patient needs, feedback, and satisfaction in each aspect of implementation. CFIR touches on the patient minimally in the construct “patient needs and resources” within the “outer setting” domain but insufficiently for this type of evaluation. Patient perspectives and experience do not feature largely in CFIR nor most studies that rely on it. One indicator of this is a finding by Kirk et al: Among 26 research studies that meaningfully used CFIR, only two of the 26 included patients among their unit of analysis.Our major adaptation of promoting the “patient needs and resources” construct to its own sixth domain in the framework recognizes the fact that health care interventions increasingly put patients and their families front and center, a focus that is given sparse attention in many implementation science frameworks. Focusing on patient needs as an additional dimension to the evaluation provided a richer picture of implementation and surfaced barriers and facilitators otherwise missed through use of the original CFIR with its five domains. The addition of a sixth domain may also ensure that future evaluations prioritize patient needs during evaluation design, data collection, and analysis.Dividing the “inner setting” domain into three layers to better reflect the complexity and hierarchy of our health care system  facilitated our identification of drivers of decisional and operational change. Whereas original use of CFIR would have us consider the inner setting for an organization overall, we harnessed lessons learned from organizational theory to pay attention to differences in implementation factors at various levels throughout. These factors were vital to understanding the evolution of Primary Care 2.0, especially when the health care system leadership changed midway through implementation. Health care administrative leadership changes are a common and ongoing state of health care, and it is wise to plan for them when implementing and evaluating change. Our adaptation of CFIR supports such planning, particularly for complex care transformations that are susceptible to impacts due to leadership changes. Thus, change drivers such as leadership changes became a fascinating part of the evaluation that would otherwise have been missed. Teasing out the layers of the inner setting was valuable to all stakeholders. On‐the‐ground pilot clinic voices were magnified, confidentially, up to those in leadership. Stanford Health Care leadership, in turn, learned of gaps in knowledge and resources at the pilot and peer clinic level that might not have otherwise been surfaced and were attuned to implementation barriers and facilitators through our team's regular rapid‐cycle feedback cycles structured around “lightning reports,” an actionable tool summarizing close‐to‐real time qualitative findings. In a learning health system context, drawing out the nuance of experiences at each level, from front‐line staff to C‐suite executives, supported our evaluation efforts and in turn strengthened our partnered‐research relationship by breaking down communication silos across the inner setting levels. Overall, the ability to describe and evaluate this dynamic system in a way that gave structure to the challenges and facilitators was effectively achieved by teasing out the different inner setting layers of the health care system hierarchy.Lastly, our CFIR adaptation of tailoring and respecifying construct definitions was essential to fit them to our patient‐centered primary care clinical context and to allow consistent data collection and coding. Initially, using CFIR as a framework for data collection and analysis was cumbersome, time‐consuming, and difficult to standardize across researchers. This experience has been reported by other researchers applying the framework to complex evaluations and has been acknowledged by CFIR's creators.There are two limitations to this research. First, we used a subset of qualitative data collected during the evaluation period in this analysis. We used a subset in order to facilitate rapid feedback to Stanford Health Care leadership, but we also were attentive to the need to reach theme saturation, which is a standard approach in rapid qualitative analysis that we achieved in this study.While others have also used CFIR in evaluating care transformations and found the framework valuable in their efforts,6We believe this example of how to tailor CFIR will make CFIR more accessible and relevant for wider use in the context of patient‐centered health care interventions, especially within the context of multi‐part health care systems. Incorporating the adapted CFIR into our evaluation allowed us to assess a complex, dynamic primary care initiative while capturing context and culture‐specific factors that influenced implementation across each level of the organization. We found CFIR to be a powerful longitudinal evaluation tool that facilitated capture of thoughtful nuances and key voices throughout the implementation process. Adaptation of the framework, however, was key for successful pragmatic application.Placing additional emphasis on patient needs and resources; adapting the “inner setting” domain to reflect the complexity of health care organizations; and developing tailored, agreed‐upon definitions for CFIR constructs at the start of the evaluation supported our team in capturing real‐time changes within the implementation process and filled significant gaps in the framework. We believe our adaptations will be helpful to others and encourage wider application of CFIR and these strategies to move forward the science of evaluating patient‐centered health care redesign.CFIRConsolidated Framework for Implementation ResearchAuthor Mahoney is currently a practicing provider in Stanford Health Care's system. We have no other conflicts of interest to report.


Immune cell differentiation and function depend on metabolic changes for the provision of energy and metabolites. Consequently, cellular metabolism relies on the availability of micronutrients such as vitamins and energy‐rich sources including amino acids and fatty acids. The bone marrow controls the continuous production of blood cells and is thereby reliant on the sophisticated interplay of progenitor and mature immune cells with its stromal microenvironment. The significance of stromal subsets in immunopoiesis is undisputed; however, our current knowledge is limited to their role in the production and secretion of a variety of soluble proteins such as cytokines. In contrast, the role of the haematopoietic niche in controlling and providing nutrients such as fatty acids, amino acids and vitamins, which are required for immune cell differentiation and function, remains largely elusive. In this review, we summarize the current understanding of local nutritional exchange and control between immune and stromal cells in peripheral tissue and, when it is known, in the bone marrow. The parallels found between peripheral tissues and bone marrow stroma raises the question of how local metabolism is capable of influencing haematopoiesis and immunopoiesis. A better understanding of the local exchange of nutrients in the bone marrow can be used to improve immune cell formation during ageing, after haematopoietic stem cell transplantation and during immune challenge. ASCT2alanine, serine, cysteine‐preferring transporter 2ATPadenosine triphosphateBMbone marrowCDcluster of differentiationCXCL12C‐X‐C motif chemokine ligand 12CXCR4C‐X‐C chemokine receptor type 4CYP26cytochrome P450 family 26FAOfatty acid oxidationHSChaematopoietic stem cellILCinnate lymphoid cellILinterleukinMSCmesenchymal stem cellOXPHOSoxidative phosphorylationRAretinoic acidγRARγretinoic acid receptor SLCsolute carrier familySNATsodium‐coupled neutral amino acid transportersTCAtricarboxylic acidThT helperTmemmemory TTregregulatory TVDRvitamin D receptorImmune responses are highly coordinated processes regulated on several levels by immune cells and a variety of non‐haematopoietic cell types. Non‐haematopoietic cells are commonly referred to as ‘stroma’ by haematologists and immunologists. Interactions with stromal cells are essential for immune cells at various stages of immune cell differentiation (immunopoiesis) and immune activation. The deletion of stromal cell types can therefore result in dysfunctional lymphoid organs and thereby hamper immune responses. In 1971, the bone marrow (BM) niche was described as a ‘haematopoietic inductive environment’ that supported the maturation of distinct immune cells.The BM stroma provides a supporting network of cells for the maintenance and survival of immune progenitors through direct cell–cell interactions and the paracrine release of cytokines. This local interaction of the BM stroma with immune cells enables them to respond efficiently to altered environmental cues. For example, during bacterial infections, the BM induces a strong myeloproliferative response through the increased stromal secretion of the pro‐inflammatory cytokine interleukin‐6 (IL‐6).Interestingly, findings in recent years provide evidence for a local metabolite exchange and regulation of nutrients between the stroma and immune cells, which we refer to as ‘local metabolism’. The availability of micronutrients (e.g. vitamins) and energy sources such as amino acids and fatty acids are essential for immune cells. Differentiation and effector functions are metabolically tightly regulated. This link has given rise to a new field in immunology called immunometabolism.The BM is arguably one of the most complex environments in the human body, merging four major biological systems: the skeletal system, the immune system, the endocrine system and the nervous system. This accumulation of biological systems gives the BM a unique capability to react immediately to external stimuli. Besides providing a niche for haematopoietic stem cells (HSC) and other haematopoietic progenitors, it contains the recently identified distinct niches involved in B‐cell lymphopoiesis, myelopoiesis and erythropoiesis. In addition, increasing evidence suggests that the BM hosts mature long‐lived immune cells such as memory T (Tmem) cells and plasma cells.in vivo evidence for the existence of the haematopoietic niche by demonstrating that HSC frequency was controlled through cell‐extrinsic mechanisms.β3‐adrenergic receptors on mesenchymal cells and subsequently controls the egress of haematopoietic progenitors from the BM.The cells that constitute the BM niche have been extensively reviewed in Wei and Frenette.The release of cytokines such as stem cell factor and CXCL12 is crucial for the long‐term survival and function of the haematopoietic system. In this way, distinct BM niche environments control lineage commitment and immune cell egress. This knowledge has led to studies investigating whether co‐transplantation of niche cells improves HSC transplantation, showing that B‐cell recovery and engraftment can be improved in murine models.Cellular metabolism balances energy‐producing processes by the degradation of macromolecules (catabolism) and energy‐consuming synthesis of new macromolecules (anabolism). During catabolic processes, adenosine triphosphate (ATP) is produced through two major pathways: glycolysis and oxidative phosphorylation (OXPHOS). Fast turnover of glucose to acetyl‐Coenzyme A during glycolysis makes ATP quickly available, but produces a lower energetic yield than the full degradation of carbon‐based macromolecules in the tricarboxylic acid (TCA) cycle. The latter process releases electron transporters nicotinamide adenine dinucleotide and flavin adenine dinucleotide, which are oxidized during OXPHOS in the mitochondria resulting in high ATP quantities. Amino acids and fatty acids can be used as alternative energy sources and enter the metabolic pathway in the TCA cycle driving glutaminolysis and fatty acid oxidation (FAO), respectively. Interestingly, many amino acid precursors derive from TCA intermediates and play a role in anabolic processes. Consequently, modulation of the glycolysis–OXPHOS balance can shift cellular bioenergetics and biosynthesis.Immune cells have various metabolic demands based on their differentiation and function. Cells need to utilize different metabolic pathways in a time‐ and space‐dependent manner to produce the energy, metabolites and macromolecules required for their differentiation and function. An increasing body of evidence describes that the fine balance of OXPHOS and glycolysis is crucial for the differentiation of immune cells, including myeloid and T cells.et al. showed that this uptake was significantly increased in ILC2 from mesenteric adipose tissue,Fatty acid oxidation is an important metabolic and bioenergetic pathway for many immune cells. During this catabolic process, cytosolic fatty acids are degraded by the mitochondria, resulting in signalling intermediates and high yields of ATP, which promotes cell differentiation and self‐renewal. For example, in the gut, innate lymphoid type 2 cells (ILC2) are activated during helminth infection. Interestingly, deficiency of retinoic acid (RA) leads to an increase in ILC2 numbers and is primarily dependent on the uptake and catabolism of fatty acid from the environment.de novo fatty acid synthesis and mostly reliant on the import of fatty acids from the environment.γ.Other lymphoid cells such as Treg cells are enriched in peripheral adipose tissues.+ T cells using 2‐deoxyglucose results in an increased generation of Tmem cells, whereas the over‐expression of glycolytic genes prevent their formation.+ Tmem cell populations.+ tissue‐resident Tmem cells in the skin not only rely on FAO but also require exogenous fatty acids for their long‐term survival.Long‐lived immune cells such as Tmem cells and fetally derived B1a B cells seem to preferentially reside in fat tissues such as visceral fat depots and the peritoneum, respectively. These cell subsets depend on fatty acids as an energy source; they are even essential for their differentiation and maintenance.In the past two decades, increasing evidence supports the notion that Tmem cells can be found in distinct niches in the BM.et al. fed mice with a high‐fat diet for several weeks, leading to the preferential differentiation of MSC into adipocytes through the activation of the adipogenic transcription factor peroxisome proliferator‐activated receptor γ2. This resulted in a decreased number of haematopoietic progenitor populations and increased myelopoiesis.Increased marrow adiposity has been associated with increased myelopoiesis in the BM.In conclusion, adipocytes in peripheral tissues are capable of controlling long‐lived memory cell responses by providing essential metabolic support. Similar mechanisms may exist in the BM but have not been addressed in immune homeostasis. Recent examples from the cancer field provide compelling insights into the means of communication at a metabolic level between immune cells and adipocytes Fig. . WhereasIn the last few years, amino acids and their transporters have emerged as key regulators of haematopoiesis and immunopoiesis. A growing number of studies show the importance of nutrient uptake for cell survival, proliferation, differentiation and immunity. While the role of amino acids for cell survival and proliferation is not surprising, their importance for differentiation and immune responses is less obvious.et al. in the mid‐1940s showed that rats fed with a low‐protein diet developed a severe granulocytopenia and anaemia.et al. Pioneering studies from Kornberg SLC38A1, SLC38A2 and SLC1A5 .+ T and Tmem cells compared with wild‐type mice, whereas CD8+ T and Treg cell populations remain unaffected.+ T cells from ASCT2−/− mice express activation markers such as CD69 or CD25 but are unable to raise an appropriate Th1 or Th17 immune response. Interestingly, IL‐2 production is not affected. These results demonstrate that glutamine is required for CD4+ T‐cell homeostasis, differentiation and function.In contrast to valine, glutamine metabolism is well studied and is an essential part of erythropoiesis. The expression of the main glutamine transporter solute carrier family 1A5 (SLC1A5)  as well as glutamine‐driven metabolism for ATP and nucleotide production is crucial to maintain erythropoiesis.l‐ornithine and urea by arginase I and II. These molecules are crucial for the cytotoxic functions of macrophages, cell proliferation and antibacterial response.ζ expression in activated T cells and diminishes their proliferation.et al.'s findings, similar paracrine mechanisms may be present in the BM mediated by platelet‐derived growth factor receptor‐positive cells in a physiological context.Amino acid consumption affects immunity in various, often opposite, ways – like arginine, which is able to enhance macrophage cytotoxicity but blocks Th1 and Th17 responses. Arginine is metabolized in macrophages to produce nitric oxide and citrulline by inducible nitric oxide synthase, and the polyamine precursors Over the past years, our understanding of amino acid catabolism and their various roles in homeostasis and immunity has exponentially increased. Distinct amino acids are crucial for cell survival, proliferation or differentiation Fig. . Howeverin vitro.Some micronutrients such as vitamins are not used for the production of ATP or macromolecules but regulate many metabolic pathways. The term ‘vitamin’ classically refers to organic compounds, which cannot be synthesized in sufficient amounts, but are essential to the health of an organism. Vitamins have pleiotropic effects in humans, some of which are rather unspecific such antioxidants, whereas others have more specific functions as enzymatic co‐factors or hormones. The importance of vitamins in the immune system has been known for a long time.γ (RARγ) leads to decreased HSC number and increased differentiation.γ activation increases the self‐renewing capacity of HSC.γ in the BM stroma induces a myeloproliferative syndrome, which was long believed to be caused by cell‐intrinsic effects only. However, transplantation of wild‐type HSC into an RARγ‐deficient microenvironment was sufficient to initiate myeloproliferative syndrome.Apart from the gut stroma, vitamin A also plays an important role in the BM. Activation of RA signalling preferentially promotes HSC dormancy in the BM and so controls HSC exhaustion. When RA is limited via dietary uptake, HSC are activated to proliferate and differentiate.γ secretion and promoting IL‐4 production, which is crucial for Th2 development.In vitro, adipogenic differentiation of BM‐derived MSC is inhibited in a VDR‐dependent manner suggesting a mechanism to control BM cell composition.Cholecalciferol (or vitamin D3) is predominantly synthesized in the skin from cholesterol through ultraviolet B radiation. As a result of the dependency on sun exposure, vitamin D levels depend on the geographical location of individuals and may require dietary supplementation. Dietary or synthesized vitamin D precursor cholecalciferol is converted in the liver to calcifediol and consequently hydroxylated into its bioactive form 1,25‐dihydroxyvitamin D. Vitamin D controls calcium metabolism, so vitamin D deficiency can lead to osteomalacia, a softening of the bone tissue. Lack of 1,25‐dihydroxyvitamin D3 is implicated in alteration of immune function and can lead to autoimmune diseases such systemic lupus erythematosus and rheumatoid arthritis.Vitamin availability impacts on immune cell function in peripheral tissues and the BM. For vitamin A, we are beginning to understand that niche cells are capable of controlling and providing vitamins in a coordinated manner to immune cells. The resulting impact of vitamins on immune cell metabolism is part of current research efforts. Vitamin D was shown to promote tolerogenic dendritic cell functions by favouring OXPHOS, fuelling it with glycolytic pyruvate.+ T cells are highly migratory and travel between oxygenated blood and hypoxic peripheral tissues. These cells are characterized by an increased spare respiratory capacity to balance their energy levels even under hypoxic conditions compared with naive CD4+ T cells.The field of immunometabolism has provided strong evidence for the close link between cellular metabolism and immune cell differentiation and function. The switch between distinct metabolic pathways maintains energy homeostasis and produces metabolites and intermediates required for the molecular adaptation. Despite the identification of metabolic requirements in a variety of immune cells, it remains unclear how the decision for specific metabolic pathways is established. Nutrients are sequestered by many stromal cells and released upon physiological cues. In particular, well‐controlled immunological niches such as the BM, which contain a distinct stromal composition, may have means to control and provide nutrients to developing and resting immune cell populations and thereby shaping their cellular metabolism. Evidence for the importance of nutrient support by the haematopoietic BM niche is emerging. For example, the availability of vitamins is closely controlled by stromal cell in the BM niche and thereby impacts on lineage commitment and stem cell maintenance. However, despite our knowledge that many vitamins are important co‐factors for metabolic processes, we are only now starting to explore the impact of vitamins in reshaping immune cell metabolism. Other energy‐rich nutrients such as fatty acids and amino acids are released in a controlled manner during times of high energy demand, though the importance of this process in the BM remains largely neglected. Few explorative studies in the cancer field suggest local metabolite exchange in the BM. However, despite these findings, many open questions in the local metabolic interactions of BM stroma and immune cells remain see Box . In addiBox 1Are adipocyte‐derived fatty acids required to support the fatty acid oxidation‐based metabolism in immune cells during maintenance and differentiation in the bone marrow?Can stroma‐derived amino acids support immunopoiesis? If yes, via which mechanisms?Does vitamin availability in the bone marrow direct immunometabolism of differentiating immune cells?Could ‘local metabolism’ be a drug target to improve lineage bias during ageing and haematopoietic stem cell transplantation?in vivo. Using in vitro culture systems, cell interactions can be studied in controlled environments, but these often provide a narrow insight into complex biological systems. Technological advances in BM imaging such as high‐resolution bone microscopy and intravital imaging are providing novel tools to visualize and study distinct niche environments.in vitro and improve ex vivo systems such as ‘BM‐on‐the‐chip’ allowing modelling of the complex marrow environment.A major challenge to address these questions remains the limitations of tools and technologies in order to study local metabolism Addressing the issue of local metabolism in the BM will give us a better understanding of immune cell formation and consequently be useful for fields addressing aberrant immunopoiesis during ageing, metabolic disorders and haematopoietic stem cell transplantation.The authors declare no competing financial interests.


Interventions based on applied behaviour analysis are considered evidence based practice for autism spectrum disorders. Due to the shortage of highly qualified professionals required for their delivery, innovative models should be explored, such as telehealth. Telehealth utilises technology for remote training and supervision. The purpose of our study was to systematically review the literature researching telehealth and ABA. We analysed intervention characteristics, outcomes and research quality in 28 studies and identified gaps. Intervention characteristics were: (1) research design (2) participants (3) technology (4) dependent variables (5) aims. Outcomes were favourable with all studies reporting improvements in at least one variable. Quality ratings were significantly low. Implications for future research and practice are discussed in light of identified methodological downfalls. Autism spectrum disorder (ASD) is a neuro-developmental disorder categorised by impairments in social-communication and restrictions in behaviours or thought patterns   individuals must complete Master’s level training in behaviour analysis, undertake an extensive period of supervised practice and pass an exam BACB . WorkingTelehealth is the use of communication technology to assist in education and treatment of health related conditions. The availability of internet connections has been growing exponentially in recent years. Current estimates suggest that 88% of all people in the UK accessed the internet at some point in the last 3 months  peer review published journal article, (2) study involved telehealth technology in the provision of training, supervision or consultation to interventionists  utilising behavioural principles in the treatment or education of at least one participant with a diagnosis of ASD, Asperger’s or PDD, (3) study was original empirical research with quantitative data and a primary analysis of the effect of an intervention conducted via telehealth and (4) was written in the English language.Studies were excluded from the review if: (1) they did not include original research, (2) telehealth technology did not include a two-way communication system with a professional, (3) participants without a diagnosis of ASD or PDD were included and outcomes for the participants with ASD were not reported in isolation from other diagnoses.Full texts of selected studies were reviewed and information was extracted Table . The folTo ensure internal validity within the review, the first and second authors independently assessed identified studies against inclusion and exclusion criteria. The two resulting lists of eligible studies were subsequently compared. ICA was calculated by dividing the total number of agreed eligible studies by the sum of all studies and multiplying by 100. A total number of two studies were disagreed upon leading to an ICA of 93%. Consensus was reached by discussing disagreements as a team leading to a final ICA of 100% on selected 28 studies. Likewise, ICA was calculated for the descriptive synthesis. The second coder scored 100% of selected studies across all extracted information. ICA was calculated by dividing the total number of agreed variables divided by total number of variables scored and multiplied by 100. There was a 92% agreement on coding. ICA was also calculated on the quality assessment at 96% following discussion on one disagreed study.Intervention outcomes were rated for efficacy on an ordinal scale of ‘Positive’, ‘Mixed’ or ‘Negative’. Visual analysis of graphed data was used for studies employing single subject research designs, while statistical testing was employed to determine outcomes of group designs. Studies were considered ‘positive’ if improvements were made by all participants across all dependent variables. They were considered ‘Mixed’ if positive results were visible but did not apply to all dependent variables and ‘Negative’ if no improvements were made for any dependent variable.Studies included in the review were independently assessed for rigor by the first and second authors using the standards created by Reichow et al. . DisagrePrimary indicators for group research included: participant characteristics, independent variables, comparison conditions, and dependent variable Table . PrimaryA score sheet created by the authors was used to score each of the identified variables against the operational definitions set out in Reichow et al. . Each prAccording to the inclusion criteria, a total of 28 studies were deemed eligible and were incorporated in the descriptive synthesis with key data extracted and coded Table . Each stn = 18) employing a single subject research design and fewer employing a group design . Of the single subject research multiple baseline designs were utilised in 36% of studies (n = 10), as were multielement designs. Reversal designs were rarely used in the research .All but two of the selected studies  were parents, 9% (n = 21) were direct front line staff, including ABA therapists, graduates working in university clinics and other associated professionals working in the field, and 4% (n = 10) were teachers.A total number of 293 interventionists were included in the 28 studies. Of these, 68 were placed in a comparison group and did not undertake any training via telehealth, leaving 225 interventionists in experimental groups across all studies. Of these, 86% (n = 7) of studies reporting both characteristics  of studies reported neither age nor gender  of studies  of studies .In studies where interventionist demographics were reported, a total of 97 females and 14 males took part in the research. The average age of interventionists was 31.7. Few participants had previous experience implementing behavioural analytic procedures  took part in group research, while 42% (n = 96) were included in single subject research designs and 2% (n = 4) were included in studies that did not operate an experimental research design.A total of 307 participants with ASD took part in the 28 studies. Of this, 76 were allocated to a control or comparison group and did not receive telehealth interventions, leaving 231 participants in telehealth experimental groups. Of these 57%, (n = 21) of studies  of studies did not report any information about the age or gender of participants with ASD  of studies in which gender was omitted  of studies investigating these topics  of studies  of studies  of studies  of studies  of studies. Written instructions, websites including interactive modules, a training DVD, manuals or with video-conferenced didactic training were utilised to provide this training. Equipment included laptops, cameras, scanners and commercially available videoconferencing software. A hybrid approach including coaching and technology-based training was undertaken in 75% (n = 21) of studies  of studies measured variables for both interventionists and participants with ASD, 11% (n = 3) of studies measured interventionist behaviour alone. All studies that measured interventionist behaviours included a measure of procedural fidelity via task analysis, a fidelity checklist or video-recorded probes. Knowledge tests were used in 14% (n = 4) of studies and these scores were compared to pre-intervention scores to determine the effect of the intervention  of studies and 68% (n = 19) of studies measured participant with ASD variables alongside interventionist variables. Data collection for child behaviours was conducted via video-recorded probes or questionnaires and standardised tests. Of these, 50% (n = 14) of studies measured individualised problem behaviour as part of an FA to assess function or teach replacement behaviour (e.g. FCT). Examples of the individuals’ challenging behaviour include elopement  investigated increases in social-communication responses   of studies were rated as ‘positive’ in which improvements were achieved by all participants across all dependent variables  of studies employed FA + FCT procedures  were also scored as positive  of studies received a ‘mixed’ efficacy rating  of these studies found improvements in interventionist treatment fidelity across all participants but failed to increase scores of social communication or imitation behaviours consistently across participants  received an overall weak quality rating  of studies employing a single subject research design  received an overall adequate quality rating; the remaining 95% (n = 19) received an overall weak quality rating. An overall rating for each study can be found alongside individual indicator ratings in Tables Of the eight studies employing a group research design, all  of studies and with some details emitted in 25% (n = 2). The remaining studies operated a within group design and did not include a comparison group to describe. Statistical analyses were also completed to a high standard in 75% (n = 6) of studies  for studies were rated highly for baseline  were rated as ‘Acceptable’ as more than 50% but less than 100% of baselines in the study met the above criteria  were rated as having unacceptable baseline conditions. Despite conditions being accurately described and for the most part containing three data points, many failed to show stable levels or trends.However, high scores were not evident across all indicators. In single subject research design studies only 10% (n = 3) of the studies were rated highly. This means they reported information on participant age, gender, diagnostic instrument, interventionist characteristics and scores on standardised tests if applicable. An ‘Acceptable’ rating was awarded to 15% (n = 3) of studies, as they provided demographics on all participant’s age and gender, and provided standardised test scores. The remaining 79% (n = 22) of studies all met the ‘Unacceptable’ rating, where age and gender for both the individual with ASD and the interventionists was not reported consistently.For both single subject and group research to be rated ‘High’ for participant characteristics studies needed to report information on participant age, gender, diagnostic instrument, interventionist characteristics and scores on standardised tests if applicable. As many of the studies included measures of both interventionist and participants with ASD behaviour both were considered as participants for the purpose of this review. Overall only 11%  identify and categorise key intervention properties and procedures used in research using telehealth to provide behaviour analytic provisions to individuals with ASD, (b) to assess the overall outcomes of selected studies both in the success of the training procedures and the outcomes for individuals with ASD, and (c) to examine the quality of selected research. It is the aim of the review that it can be used to guide future research and practice by identifying successful procedures and highlighting methodological flaws.n = 28) studies reporting improvements in at least one dependent variable and 61% (n = 17) of studies reporting favourable outcomes across all dependent variables. None of the 28 studies met sufficient quality indicators to be determined as of ‘high’ quality and only one study was determined as being of ‘adequate’ quality. The remaining 96% (n = 27) of studies were rated as ‘weak’. Due to what we consider are minor methodological flaws, an overall rating of ‘not an evidence-based practice’ was assigned to telehealth as a means of providing ABA-based interventions. Although positive outcomes were achieved for involved participants, there is a demand for further high quality research that can adhere to a rigorous methodological structure. Each of the research aims will now be discussed in more detail.Findings from the synthesis of 28 studies suggested that telehealth can be an acceptable platform for behaviour analytic interventions and assessments. A total of 293 interventionists were trained across studies providing intervention to 307 individuals with ASD. Outcomes indicate positive gains across participants with 100% of studies (n = 12) or naturalistic teaching . Research on using telehealth to conduct comprehensive treatment is lacking. Only 7% (n = 2) of selected studies were categorised as ‘comprehensive’  of studies included an initial training period. Initial training has been recognised as a key component in achieving procedural fidelity in behaviour analytic practice  used parent training to support the provision of home-based intervention or assessments. The National Research Council (NRC) dictates that parent involvement is a fundamental component of effective ASD intervention  of studies collected data on at least one measure of interventionist behaviour. All but one collected data on procedural fidelity. Measures of fidelity have been shown to correlate with best outcomes for child participants  of studies. Measures differed based upon the intervention category but as a whole improvement was less consistent than measures of fidelity for interventionists. Measures of challenging behaviour were collected in 50% (n = 14) of studies, social-communication responses were collected in 46% (n = 13) of studies and motor imitation was measured in 17% (n = 5). Overall, there was improvement in target behaviour across studies, although several studies observed little or no improvements in some but not all participant outcomes  were rated as having unacceptable baseline conditions. Despite conditions being accurately described and for the most part containing three data points, many failed to show stable levels or trends. This is perhaps a result of the applied nature of the research in which it is not always practical or even possible to wait for stable trends of baseline responding. Future research should aim to establish a stable baseline level, so that it can provide a stronger demonstration of a functional relation between the intervention and behaviour change and higher levels of internal validity. Pre-planning resources so as to enable extension of baseline if stable levels of behaviour are not achieved in the first three data points should be conducted.In the single subject research design studies, more than half of the studies  of studies being deemed unacceptable. Only two studies were rated highly in this indicator , which would in turn translate to a rating of an ‘Established EBP’. This is a vast difference from the original score. It could be argued that this is a weakness of the quality assessment, which allows relatively small omissions to have such a large effect on ratings; however, as discussed previously, participant information is a vital component in the establishment of external validity therefore collecting and reporting key information is of crucial importance. Interestingly, no group research design studies were rewarded an acceptable rating for the participant indicator, whilst 15% (n = 3) of single subject research design studies scored an acceptable rating. This may allow for conclusions that single subject research design holds a higher standard of research rigor in comparison to group research designs. It is also important to note that only 36% (n = 10) of the reviewed 28 studies included maintenance or follow-up probes. Again, of these studies just 25% (n = 2) of group research designs showed evidence of maintenance probes whilst 50% (n = 10) of single subject research designs reported this variable. This adds to the conclusion that a single subject research design may hold itself above group research design in research quality and the individualised nature and repeated measurements are more suited to the heterogeneity of behaviour analytic interventions. Of all 28 studies, just 30% (n = 3) had promising follow-up data. This should be a prioritised area of focus for future research.Omission of age or gender was quite often the limiting factor restricting quality ratings across studies amongst both single subject research design and group research design. If participant details had been reported even to an adequate standard, three additional group design studies and two additional single subject studies would have gained an overall quality rating of ‘adequate’ (Gibson et al. Current research surrounding telehealth interventions as a means to train interventionists, although still limited, is progressing. The limitations we have identified will aid in the development of methodologically strong studies The use of telehealth is not aimed to replacing face-to-face behavioural interventions but to complement or boost their results. Future reviews are needed to assess the outcomes of a combination of telehealth and face–face models of delivery, which were excluded from this current review. Additionally, all eligible studies were conducted in the United States, therefore future research should focus on the feasibility and cost effectiveness of similar provisions in different countries in which cultural differences might impact on existing models.In sum, this systematic review suggests that training interventionists to implement behaviour analytic provisions for children with ASD via telehealth is feasible and effective. Small improvements in research rigor could lead to this delivery model being deemed an EBP. Future researchers should familiarise themselves with quality indicators to ensure methodologically robust research is conducted.


Pulmonary involvement in endometriosis is well described in the literature but asymptomatic significant hydropneumothorax is considered an unusual presentation. It classically coincides with a menstrual cycle and can be a cause of recurrent disease. We present a young lady who was found to have an incidental asymptomatic right hydropneumothorax on a pre‐employment health screen. She comes from an endemic area of tuberculosis, thus we pursued several diagnostic tests to rule it out. A diagnosis of catamenial hydropneumothorax was reached through a pleural biopsy. This case highlights the importance of adopting a systematic approach in managing uncommon presentations. Pulmonary involvement in endometriosis is well described in the literature but asymptomatic significant hydropneumothorax is considered an unusual presentation A 30‐year‐old African nurse was referred to the Accident & Emergency after an incidental finding of an asymptomatic right hydropneumothorax on a chest X‐ray Fig.  as part Initial investigations showed a mild microcytic hypochromic anaemia. Her C‐reactive protein was normal and had a negative viral screen, normal liver enzymes, and normal urea and electrolytes. A computed tomography thorax was done for further evaluation, described large right hydropneumothorax occupying approximately 20% of right hemithorax with unilocular‐dependent fluid along with multiple pleural tags and 1 cm right pleural nodule Figs. . A chestThe differential diagnosis of an exudative effusion is broad A final diagnosis of catamenial hydropneumothorax was reached based on the histological findings from a pleural biopsy Fig. ; it showShe was kept on the chest drain for a total of 14 days until complete resolution of her hydropneumothorax and was commenced on combined oral contraceptive pill, which contains ethinylestradiol and levonorgestrel, and was discharged with a close follow‐up with the respiratory and gynaecology outpatient service.Endometriosis is characterized by the presence of endometrial‐like tissue outside the uterus and is thought to affect 6%–10% of women of childbearing age This case highlights the importance of a systematic diagnostic approach to establish the correct diagnosis despite unusual presentation. A diagnostic approach of pleural effusion and pneumothorax was made based on transudative versus exudative Adopting a systematic approach in managing uncommon presentations aids in establishing a diagnosis including seeking a tissue biopsy. Pneumothorax coinciding with a menstrual period should alert clinicians to the possibility of catamenial pulmonary disease.The management approach in catamenial hydropneumothorax is to start with definitive treatment by proper drainage through a large bore chest tube followed by secondary prevention as there is high rate of reoccurrence. This is recommended with surgical blebectomy, pleurodesis, or diaphragmatic repair Appropriate written informed consent was obtained for publication of this case report and accompanying images.