Controllingthe electronicstructure of transition-metalsingle-atomheterogeneous catalysts (SACs) is crucial to unlocking their fullpotential. The ability to do this with increasing precision offersa rational strategy to optimize processes associated with the adsorptionand activation of reactive intermediates, charge transfer dynamics,and light absorption. While several methods have been proposed toalter the electronic characteristics of SACs, such as the oxidationstate, band structure, orbital occupancy, and associated spin, thelack of a systematic approach to their application makes it difficultto control their effects. In this Perspective, we examine how theelectronic configuration of SACs can be engineered for thermochemical,electrochemical, and photochemical applications, exploring the relationshipwith their activity, selectivity, and stability. We discuss syntheticand analytical challenges in controlling and discriminating the electronicstructure of SACs and possible directions toward closing the gap betweencomputational and experimental efforts. By bringing this topic tothe center, we hope to stimulate research to understand, control,and exploit electronic effects in SACs and ultimately spur technologicaldevelopments. Consequently,the properties of support surfaces  are under increasingscrutiny as they now play a much more critical role in defining thecoordination environment and uniformity of metal species.8 The downsizing of metals to single atoms often results in uniqueelectronic structures with multiple discrete and separated states,compared to the continuous bands characteristic of their bulk counterparts.These changes have stimulated great interest in developing approachesfor modulating the electronic structure by controlling the compositionand nanostructure of SACs.10Single-atom heterogeneous catalysts (SACs),relative newcomersin the field of catalysis over supported transition metals, are drivinga revolution, in terms of the application scope, the utilization ofscarce metals, and atomically precise design.d-orbitals in governingcatalytic performance.12 The development of several generalrelationships has helped experimentalists and theoreticians to rationalizethe catalytic behavior of bulk transition metals, arguably the mostsuccessful of which is the well-known d-band model.Nonetheless, as highlighted by several recent works,16 the performance of SACs can significantly differ from that of extendedmetal surfaces, calling for a reanalysis of the suitability of existinggeneral models, e.g., to account for local charges or spin polarization.Beyond heterogeneous catalysts, researchers frequently highlight theresemblance of SACs to organometallic complexes and have exploreddescriptors such as molecular orbitals and oxidation states.18 However, it has also been shown that the coordination of metal atomsto solid supports can differ in nature, compared to ligands,19 and the impacts are not yet fully understood.Understandingthe effect of the electronic structure of SACs ontheir interaction with atoms and molecules is fundamental for elucidatingcatalytic reaction mechanisms and optimizing their design. For transition-metal-basedSACs, theoretical studies have demonstrated the crucial role of chargetransfer and withdrawal from 24 Recently, there has been considerable progress indiscriminating diverse electronic properties of SACs and understandingtheir potential effects in catalysis.25 Nevertheless, these are assessed on a case-by-casebasis, calling for the development of a unified approach to systematicallyinvestigate all electronic features of the active ensembles. ThisPerspective aims to highlight the state-of-the-art in engineeringthe electronic structure of SACs, analyzing the property changes observedcompared to extended metal surfaces, the approaches pursued to modulateand characterize them, and their impact on the mechanisms of thermocatalytic,electrocatalytic, and photocatalytic processes. By highlighting thecurrent opportunities and challenges, we hope to guide research andinspire future contributions in this exciting area.Multiple excellentreviews already provide a comprehensive pictureof approaches to stabilize metal atoms on suitable carriers and applicationswhere they exhibit promising performance.1 This tendency likely derives from the legacyof downsizing supported metal nanoparticles toward improving theirutilization in catalytic applications where the reference was typicallythe bulk metal. However, the distinct properties are not a uniquefeature so much as a direct consequence of the fact that a singleatom exhibits no periodicity and, therefore, no d-band as such if there is no strong interaction with the support.Early studies focused on differences in the oxidation state experimentallydetected by X-ray photoelectron spectroscopy (XPS) and X-ray absorptionspectroscopy (XAS), which were linked to charge transfer between theisolated metal atoms and the support is consistent with density functionaltheory predictions. In contrast to the zerovalent character associatedwith bulk metals, single-atom sites frequently exhibit positive or,less commonly, negative charge states, which depend intimately ontheir coordination environments .26 The possibility to stabilizemetal cations is attractive for several applications, especially thoserequiring oxidation capacity. However, high-valent metals are notsuitable for all applications, and to preserve the benefits of enhancedmetal utilization associated with high dispersion, interest in controllingthe oxidation state of SACs and developing zerovalent systems hasrapidly grown.Researchers often describethe electronic characteristics of single-atomcatalysts as unique relative to extended transition-metal surfaces.28 The strengthof this interaction can range from weak to strong, and can dependon factors such as the type of support, the coordination site of themetal, and the presence of adsorbed species.29 Recent research suggests that controlling EMSI by selecting metalswith higher electronegativity than the surrounding atoms in the supportcan be used to further develop anionic SACs.30Understandinghow metal atoms interact with support materials and other exchangeableligands is crucial for designing and optimizing the electronic structureof SACs. The term electronic metal–support interaction (EMSI)is often used to describe the chemical bonding  and charge transfer between isolated metal atoms and theirsupport.31 Controlling orbital hybridization by varyingthe chemical identity and geometry of the metal center and coordinatingatoms and their associated orbital energies and overlap is increasinglypursued as a strategy to optimize SAC performance, e.g., as illustratedin the design of water electrolysis technologies.35 Orbital hybridization can onlyoccur when the orbitals of the support have similar energies to thoseof the metal center. Because of the prevalent role of p-block elements as coordinating atoms in SAC supports, d-sp orbital hybridization dominates the electronstructure of most reported transition-metal SACs.37 Obviously, the criterion of orbital energy matching may be met toa greater or lesser extent.38 In the designof single-atom alloys (SAAs), weak wave function mixing between minorityand majority elements limits the d–d hybridization, resulting in free-atom-like atomic stateson the minority element.39 SACs with electronicstructures resembling free atoms have also been reported to form underreaction conditions due to weakening of the metal–support interaction,as observed for Pt1/NC in the hydrogen evolution reaction(HER).40Describing EMSIs and their effectson the electronic structure more rigorously requires the considerationof orbital diagrams and potential interactions 1a. Conced-band structure of SACs is increasingly recognizedandpresents numerous opportunities for tuning the interaction with reactantsand intermediates.41 Studies analyzingthe orbitals, closest to the Fermi level of SACs, are growing andindicate that the spatial structures of frontier d-orbitals play a vital role in determining the chemical and catalyticactivities of SACs.38 Besides the coordinatingfirst nearest-neighbor atoms, electron transfer may occur from secondneighbors or beyond.36 Future efforts togain a precise understanding of the effects of the extended structureof SAC sites will help establish the potential for tailoring the performance.The importance of orbital hybridization in regulatingthe d-electrons or empty d-orbitals to adsorb intermediatesduring the catalytic cycle, thereby requiring a comprehensive descriptionof the d-band structure. One of the most widely usedapproaches to link catalytic activity to the electronic structureof transition-metal surfaces is the d-band model,42 which provides an approximate description ofbond formation. In SACs, it is valuable to describe the interactionof the d- and, in some cases, s-or p-states of metal centers with the valence statesof surrounding atoms in the support. The average energy of the d-electronic state of a metal center, described by the d-band center, width, and position of the upper edge relativeto the Fermi level, have all been considered as structural descriptorsfor guiding the design of SACs  and lowest unoccupied molecular orbitals (LUMOs).In terms of SAC stability, the relative position of the Fe3+/Fe2+ reduction potential, compared to the Fermi level,was proposed to be critical to stabilizing active Fe3+ specieson nitrogen-doped carbons , intermediate (dxy2 dyz1 dxz1 d2z1), and high (dxy1 dyz1 dxz1 d2z1 d2-y2x1) spin states. Spin state and transitionsoffer exciting opportunities, e.g., to accelerate and impose selectivityon electron transfer.56 More detailed examination ofthe changes in the density of states has also evidenced a redistributionin single atoms compared to bulk metal counterparts, resulting inunoccupied orbitals of a certain directional character near the Fermilevel.57 Several spin-polarized SACs havebeen reported, e.g., Mn1@C2N, and the effecthas been linked to enhanced adsorption and activation of certain molecules.55 Nevertheless, limitations in manipulating spinand its unambiguous assignment still impose challenges for understandingand exploiting the full scope of engineering local spin states, andfurther advances in the range of accessible spin states in SACs areexpected. Future endeavors are encouraged not only to explore anddiscriminate the diversity of SAC electronic properties but also todevelop synthetic strategies enabling control over them. The acquiredknowledge will offer exciting potential to finely tune the metal sitereactivity.Whenconsidering orbital filling, severaldifferent spin states may be energetically accessible and potentiallycoexist, depending on the oxidation state of the metal and the effectsof orbital hybridization 1e, impac13 Nevertheless, despite rapidly growing interest,our ability to exploit these opportunities for designing more effectivecatalysts remains primitive.As with anyother supportedmetal heterogeneous catalyst, the designof SACs begins with choosing suitable metal-host combinations forthe targeted application. As opposed to catalysts featuring extendedmetal surfaces, the electronic and thus catalytic properties of themetal sites in SACs are tunable with atomic-scale rigor by controllingboth the chemical identity and geometry of the coordinating atoms.This includes accounting for the interaction with (i) the anchoringsites in the host, (ii) any exchangeable ligands, and (iii) othermetal atoms or defects that may be present in close proximity. Theengineering of these properties together with attentive modulationof external factors, such as electromagnetic fields or applied voltage,provide immense potential for tailoring the electronic structure ofSACs 2.13 Neve58 While considerable progress has been made intuning the catalytic performance via defect engineering, accurateevaluation of its impact on the metal center orbital configurationis still thwarted by intrinsic limitations of characterization andcomputational techniques (vide infra). Still, this information iscentral to unlocking the full scope of SAC electronic property design.Engineering of the host anchoring sites should enable the effectivestabilization of the metal centers onto the support and adaptativebonding for optimized geometric and electronic properties, dependingon the catalytic cycle in the targeted application.Since the very successful formationof SACs requires stabilizing metal centers on support materials, researchefforts have been extensively focused on host engineering. Defectsites in the host  can trapsingle metal atoms by either covalent or ionic bonding in EMSI.2+ vacancies in a nickel hydroxide support via a solvothermalprocedure enhanced the stabilization of isolated Pt atoms over thesupport, reflecting greater charge transfer from the support to thePt atoms and enhanced performance in diboration reactions  revealed the promotion of electron transfer and, importantly,greater conductivity, boosting the SAC catalytic activity for theHER.Metal-basedsupports, spanning metal oxides, transition metals, metal carbides/nitrides, metal borides (MBenes), and transition-metalchalcogenides , are attractive forSACs. In these systems, vacancy engineering has shown considerablepromise to enhance the properties for various thermocatalytic andelectrocatalytic applications. For example, generation of cationicNieactions 3a.59 Simd–p hybridization and related adsorption propertiesof the metal atoms (vide infra).63 Controlledarrangement of local atomic structures in the host is central to havingsuitable anchoring sites that covalently stabilize the isolated metalatoms on the support and form active sites with desirable electronicand catalytic properties.64 A prominentexample is carbon-supported SACs, as various methods exist to introduceheteroatoms into carbon materials. N-functionalities have been commonlyemployed as anchoring sites, yielding M–NxCy active sites. However, the strongelectronegativity of the coordinating N atoms can result in high reactionGibbs free-energy values for intermediate adsorption on the metalsite, hampering the kinetics of catalytic reactions.67 To overcome this, a second heteroatom can be introduced in the metalcenter coordination environment and redistribute the electron density.This was achieved in Co SACs supported on a N-doped carbon by partiallysubstituting coordinating N atoms with P, as confirmed by extendedX-ray absorption fine structure (EXAFS). In this architecture, thecoordinating P atoms promote charge depletion of the Co active sites,improving the energy barrier and free energies for the HER pathwayson the Co sites.68While the study of EMSI is common practice in heterogeneouscatalysis,the single-site nature of SACs has prompted significant efforts intothe atomic-level engineering of the metal center coordination environmentfor fine-tuning the active site electronic structure. Specifically,control over the type, number, and geometry of coordinating atomsin the host is an important strategy for regulating the 4 to Co–N2 were selectively generated ona zeolitic imidazolate framework (ZIF) carrier. Decreasing N-coordinationled to an upward shift in the d-band center of theCo sites, resulting in stronger *CO2– binding, while simultaneously promoting the desorption of the COintermediate and, thus, superior selectivity toward CO.69 Nevertheless, variation of the coordinationnumber with the support can also affect the active site geometricproperties, which can result in asymmetries in the charge distributionwithin the active ensemble. This aspect was investigated in Fe SACsfor shuttled lithium polysulfides, supported on two different N-richcarbons.70 One of these was derived bypolymerization of pyrrole aiming to selectively yield Fe–N3C2 moieties, asymmetrically connected to threeN and two C atoms, as opposed to a glucose-derived N-doped carbonthat would form Fe–N4 moieties, symmetrically coordinatedwith four N atoms and commonly reported in the literature.73 Consistent with the asymmetric charge redistribution corroboratedby Bader charge analysis, density functional theory (DFT) simulationspredicted the position of the adsorbed S atoms not to be verticalto the Fe ones in the Fe–N3C2 moieties.This outcome suggested the activation of dx2–y2 and dxy orbitals with the formation of additionalπ-bonds, elucidating (i) strengthened d–p orbital hybridization, (ii) facilitated interfacial electrontransfer, and, thus, (iii) catalytically enhanced sulfur redox kineticsin the asymmetric Fe–N3C2 configuration,compared with the symmetric Fe–N4 one. Undoubtedly,these results prompt further studies on geometry-electronic propertyrelations in SACs, whose establishment will require the developmentof characterization techniques able to resolve the differences inthe electronic structure of active ensembles with distinct geometricarchitectures.Similarly, tailoringthe coordination number of Co atoms with thesupport enabled regulation of their electronic features. By simplycontrolling the pyrolysis temperature, species ranging from Co–Nd-orbitalstates of Ag, favors O2 activation by increasing the DOSof its antibonding π*-orbital and/or by depleting the π-and 5 σ-bonding orbitals.28 Althoughnot explicitly stated, this phenomenon appears to be an example ofapplied local strain, dictated by the synthetic procedure. This conceptwas also investigated over ZIF-supported Fe SACs for the oxygen reductionreaction. FeN4 sites with contracted Fe–N bonds,obtained via harsh thermal treatment, exhibited lower activation energyto break the O–O bond. Analysis of the electronic structureby charge density maps shows how shortening of the Fe–N bondsaffects the electronic structure, reflecting in a positive shift ofthe 3d orbitals of the Fe atom and greater chargetransfer from the latter to the adjacent N atoms were obtained simply by employing two distinct synthetic methods:anti-Ostwald ripening or wet impregnation. The stronger EMSI resultingin the former, reflected in upward-shifted  N atoms 3b.7274 In carbon-based supports,this is further complicated by the similar scattering properties ofthe heteroatoms commonly employed as dopants . The developmentof novel techniques and analytical approaches is essential to resolvethe type and abundance of diverse metal species populations and ultimatelyenable comparative studies among different metal–support systems.While all the presented strategies have proven successfulin tailoring the orbital configuration on a case-by-case basis, thelack of systematic studies hinders the derivation of general guidelinesfor SAC electronic structure design via host engineering. To thisend, future endeavors are encouraged to both critically evaluate theaccuracy of the assessment of the engineering strategy impact on themetal center orbital configuration and explore the transferabilityof the proposed approach to other metal–support combinations.For these purposes, overcoming intrinsic limitations in currentlyavailable characterization techniques will also be crucial to allowexperimental verification of predicted behaviors. To date, resolutionof the oxidation and coordination environment mainly relies on bulktechniques . As opposed to crystalline hosts such as metalsand metal oxides, the intrinsic inhomogeneity of amorphous carriersposes considerable challenges to the identification of active sitestructures.75 Recently, a facile irradiation-impregnationprocedure was developed to synthesize a range of Pt atoms supportedon NiFe-layered-double-hydroxide with various axial ligands . While experimentaland computational analyses uncovered their role in determining thePt atom valence state and d-orbital configuration, because of delocalizedelectrons. Another study based on machine learning proposed a distinctresearch direction, focusing on lanthanide–transition-metalcombinations.85 To design superior electrocatalysts, f–d orbital interactions offer goodprospects for a superior modulation of the d-bandcenter with enhanced stability by less orbital repulsive forces thantheir d–d counterparts.The metalatom coordination sphere can be further engineered by integratinga second metal atom. For over a decade, alkali metals have been knownto modify charge distribution in the transition-metal active sitevia electron density donation.2 monolayers for the oxygen evolution reaction(OER), exchanging interactions with neighboring Co sites incorporatedin the support in place of Ta atoms. The latter Co species increasethe spin density of the Co active sites on the support surface, eventuallyoptimizing the binding energy between surface Co and O species andpromoting the OER activity.86Interestingly, metal centers can also influence each other’sspin density. Evidence for this was observed in ferromagnetic Co SACson metallic TaS88 rationalization of intermetallic catalytic synergiesshould not overlook other structural features, such as local coordination,89 for accurate analysis of orbital hybridization and charge transfereffects.Althoughthe number of studies covering the integration of multiplemetal sites is rapidly increasing, reporting diverse electronic cooperativemechanisms between metal centers, general geometry-electronic propertyrelations have not yet been unraveled. While the intersite distancehas been proposed as a descriptor to quantitatively evaluate the electronicmetal–metal interactions,90 Future studies are encouraged to explore these aspects, holdingpromise for exciting discoveries.Finally, applying electromagnetic fields or controlledvoltagemay offer a promising strategy to tune the orbital configuration andspin state of the metal active sites.92 Aiming to gain atomistic insightsinto the active site structure, theoretical simulations often furtherintegrate these experimental techniques by predicting the thermodynamicstability of metal species in different potential oxidation and coordinationenvironments ,invalidating well-established catalytic descriptors  in extended metal surfaces. Unfolding thecomplex electronic structure of SACs and how the latter impacts themetal atom reactivity are nontrivial tasks that require a multitechniqueapproach. In this section, we comprehensively analyze advances andlimitations in resolving key electronic properties, such as the bandstructure or spin configuration (vide supra), of characterizationmethods both experimental, consisting of absorption, surface, andreflection spectroscopic techniques, and computational , usuallycomplemented by EXAFS to resolve the metal atom coordination environment4.4,91,92ronments 4.93 Furttational 4. Therea95 theirunderstanding in relation to the active site electronic structurestill represents a major challenge to the heterogeneous catalysisresearch community. Only in 2018, computational analysis screening15 different metal combinations revealed that many exhibited sharp d-band features near the Fermi level for the diluted metalatoms, pointing to such a feature as the cause of the remarkable reactivity.15 Following this study, pioneering work on AgCualloys demonstrated the electronic isolation of diluted Cu atoms inthe Ag matrix, introducing the concept of “free-atom-like electronicstructure”.16 For this purpose,characterization by ultraviolet photoelectron spectroscopy (UPS),which is particularly useful for determining the valence electronstructure of solid surfaces,6 was coupledwith analysis of the PDOS by DFT. While UPS spectra exhibited a clear,sharp narrowing in the d-band of the Cu atoms whendiluted in the Ag matrix, the PDOS showed that the Cu 3d line shape is nearly symmetric, indicating that the Cu 3d states do not strongly hybridize with the neighboringAg atoms. When adsorbates hybridize with narrow valence bands (suchas a d-band), the adsorbate state can split intolocalized bonding and antibonding states, resulting in an increasedinteraction strength with the catalyst surface.A primary example of the unique, andcomplex, electronic structure of atomically engineered materials areSAAs. Although the catalytic properties of diluted metal atoms supportedon a transition-metal matrix have been explored for a wide range ofapplications for almost two decades,d bandwidth in the AgCu SAAs, later studieson other SAA systems reported their influence on the catalytic performanceby enhancing reactive intermediate adsorption properties.97 In contrast, a recent theoretical study on SAAs demonstrated thatcritical shifts in the d-band center are associatedwith the formation of new electronic states in response to alloying,rather than with intermetallic charge redistribution.98 In the future, systematic studies investigating a rangeof metal–metal combinations are encouraged to unambiguouslyestablish descriptors for the SAA electronic structure of SAAs, requiringmandatory validation by theoretical models.Interestingly,analysis of the metal atom oxidation state by XPS, XANES, and DFTdisplayed charge transfer from the Ag matrix to the Cu single atoms,whereas EXAFS analysis of the metal bond length evidenced that theAg–Cu bond in the SAAs is longer than the Cu–Cu bondin bulk copper, suggesting the presence of strain effects. Nevertheless,while the effect of band narrowness on catalytic performance was uncovered,the role played by metal atom-support charge transfer and metal–metalbond length remains unclear. Albeit both factors were shown not toaffect the 51 as well as Bayesian learningof chemisorption processes.99 A recentDFT study examining the use of transition-metal-based SACs for theORR found that the activity of SACs with partially filled p orbitals is controlled by the position of the p-orbital energy levels relative to the Fermi level. Thissuggests that the electronic properties of the p orbitals,rather than just the d orbitals, play a crucial rolein determining the catalytic activity of these SACs.100To date, computationalefforts have been mainly directed to rationalizingand predicting metal site–adsorbate binding mechanisms. Theseencompassed the study of frontier molecular orbitals, highest andlowest unoccupied molecular orbitals of both adsorbates and singlemetal sites,17 By combining machine learning and DFT analyses, a varietyof catalytically relevant adsorbates was screened on a large set ofSAA surfaces, showing that the adsorbate interaction with the isolatedmetal site is maximized when the nd valence electrons of the dopant and the k valence electrons of the adsorbates sum up to 10: nd + k = 10. Undoubtedly,this simple 10-electron rule provides experimentalists with a straightforwardtool to identify suitable metal combinations when designing SAAs fortargeted applications. Nonetheless, one should be mindful that therule applies to systems that do not exhibit strong electrostatic interactionsbetween the adsorbate and the SAA surface nor that feature 3d isolated metal atoms.Although all the above-mentioned approaches are valuablefor understandingSAC reactivity, they still require expensive and complex simulationsthat are not easily accessible to researchers attempting to designefficient SACs for a specific reaction. Lately, an uncommonly simplemolecular orbital approach has been proposed for SAAs based on thekey concept that the interaction of adsorbates at their surface canbe described in terms of an electron counting rule.d metal single sites requires thorough investigation of the activesite oxidation and spin state, as well as investigation of its spinpolarization .101 While thesedescriptors can be evaluated by computational DFT methods, includingPDOS and Wannier function analyses, their assessment by experimentalcharacterization techniques is often hindered by the latter’sintrinsic limitations. For example, Mössbauer spectroscopyand electron paramagnetic resonance (EPR) spectroscopy can providevaluable insights into the spin polarization configuration  has been proposedfor the quantification of the metal site average spin state  provided experimentalproof of potential-induced changes in the Fe SAC spin state. Althoughthe number of studies on 3d metal-based SACs hasbeen increasing over the past few years, especially on Fe SACs, ourunderstanding of their electronic and catalytic properties remainsinadequate to derive general structure-performance relations. Forthis purpose, it will be pivotal to develop spin configuration characterizationtechniques that not only are applicable to all metals and under operandoconditions, but also enable one to gain insights into features, suchas the magnetic moment, that are currently accessible only via computationalanalyses.Because of their magnetic nature,the reactivity rationalization of SACs featuring 3guration 4.71,102 in state 4.103 By d-state electrons in Ru SACs, supported on Ni-and Fe-based layered double hydroxides, for the benzyl alcohol oxidationreaction.104 Nevertheless, probe moleculesthemselves can trigger changes to the SAC surface and active sites,offsetting the insights gained through IR characterization.105 Although preventive measures can be taken byconducting the IR analysis under cryogenic conditions, often quenchingactive site restructuring, it is recommended to resort to other complementarycharacterization techniques that do not require the use of probe molecules.In stark contrast, many experimental techniques areavailable to assess the electron density distribution in metal sitesupon interaction with reactive molecules. For example, in situ Fourier-transforminfrared (FT-IR) spectroscopy of CO chemisorption at room temperaturewas shown to be a convenient tool to disclose the population degreeof 109 However, it still suffers fromlimited resolution for highly diluted elements and scarce applicabilityto liquid-phase reactions.109 In contrast,XAS, including XANES and EXAFS, has been successfully employed todetermine the metal site oxidation and coordination environment undervarious reactive atmospheres. Over the past decade, an ever-increasingnumber of in situ and operando XAS studies has been performed on SACsin a variety of applications, encompassing thermochemical, electrochemical,and photochemical reactions.113 This has propelled the development and use of advanced techniques,including (i) high-energy-resolution fluorescence detection XANES,enabling the resolution of the metal site electronic structure evenin the most dilute samples under reactive atmospheres,115 (ii) combined operando XAS and X-ray powder diffraction (XRD) analyses,117 elucidating mechanisms for oxidation state and crystallographicstructural changes in the support that prompt metal active site restructuring,as well as (iii) processing methods for the large volumes of dataacquired in operando investigations.118Ambient pressure XPShas recently emerged for in situ and operando studies of the oxidationstate of surface metal sites in SACs.119 and ultimately uncoveringthe active site electronic structure and reaction mechanism. To thisend, experimentalists should attempt to obtain a better overview ofthe dynamic processes occurring in the catalytic material. To date,there is a lack of operando XAS studies probing at the same time thediverse elements present in the SAC under examination, which wouldunlock the investigation not only of metal–adsorbate and metal–supportinteractions, but also of adsorbate–support ones. This undertakingshould be further complemented by in situ and operando soft XAS analyses.These are sensitive to investigating the bond types and orbital hybridizationof light elements such as C, N, O, S, and Cl commonly encounteredin carbon-based hosts and exchangeable ligands.109 Furthermore, given research interests shifting toward morecomplex, multimetal SACs,120 multielementoperando XAS studies will be highly valuable for deriving robust structure–performancerelations.These remarkable advances pave the way for synergistic approachescombining operando spectroscopic analyses with computational simulations,rationalizing dynamic charge redistribution effects under reactiveenvironments,6 Another often overlookedexperimental approach to gain insights into the properties of activesites is probe reaction testing, as the adsorption strength of reactiveintermediates strongly depends on the metal atom electronic structure.123 Additionally, when combined with well-defined reference materialsand further complemented by operando spectroscopic techniques, probereaction testing targeting metal site exposure to selected atmospherescan enable the study of the dynamic evolution of the oxidation andcoordination environments under conditions that are relevant to awide range of applications.While advancedsynchrotron-basedX-ray absorption and diffraction analyses offer rich information onthe SAC oxidation and coordination environments, basic electrochemicaltechniques such as cyclic voltammetry, electrochemical impedance spectroscopy,and Tafel analyses can provide valuable insights, e.g., into the rateof electron transfer.126 Because of the sensitivity ofindividual techniques to specific catalyst properties and their limitations,127 extensive systematic investigations shouldbe conducted employing holistic approaches that combine multiple experimentaland computational techniques. This will be essential to comprehensivelyprobing all key electronic characteristics of SACs .130 In the case of Pt1/CeO2, the coordinative saturation of Pt atoms was linked to that oxidationstate of the support, in particular by the number of Ce3+ centers formed via electron transfer into the 4f orbitals of Ce4+.131 Lowercoordination to supports can potentially be induced by the adsorptionof reaction components if they create a stable environment for themetal.50The ability of metal atoms to chemisorbreactants relies on their coordinative unsaturation. A common misconceptionencountered in the SACs literature is that the dispersion of metalnanoparticles into single atoms will automatically result in the ultimatefraction of coordinatively unsaturated species following the behaviortypically associated with decreasing particle size. However, the coordinativeunsaturation of metal centers in SACs cannot be assumed, and severalexamples have emerged that reveal a strong dependence on the SAC compositionand synthesis method 5a. For e2, WS2, MoSe2, and WSe2) correlated the acidic/alkaline HER activity with the average oxidationstate of Pt single atoms, determined by XPS or XANES, and the H orOH adsorption ability, evaluated through analysis of the d-band center , depending on the electronic structure.133 In the heterolytic case, the proton is adsorbedon a neighboring N-group in the support. Distinct relationships withoxidation state have been reported in other applications. For example,a volcano dependence was observed for Os-based SACs in the HER, linkedto the adsorption strength of H atoms.134 A descriptor combining the valence electron number of metal, electronegativityof central metals, and radius of the metal ions was also proposedfor the activity in the electrocatalytic CO2 reductionreaction (eCO2rr), evidencing volcano-like correlationfor SACs based on a range of different transition metals,135 which was subsequently linked to a direct influenceon the bonding strength with intermediates.136As a readily experimentally determinable parameter,changes invalence states resulting from charge transfer to neighboring atomshave been reported to influence the strength, location, configuration,and electron transfer mechanisms of molecular adsorption 5b–d. Sevd center 6a.132 Ind-bandmodel is generally not suited for SACs, because of the chemical bondingthat typically occurs between isolated metal centers and their supports.11 Nonetheless, quantum chemical calculations havedemonstrated the importance of considering properties of the d-band structure as descriptors for adsorption, and theyhave highlighted the intimate dependence on the local atomic environment.137 The complexity of linking the electronic structureof SACs to the strength of reactant adsorption was shown by comparingsingle atoms of different metals occupying the same 2-fold coordination of a model Fe3O4 support surface at room temperature was linked to the cleavage of metal andO atoms in the lattice of the support upon adsorption of reductivegases (CO and H2) on the metal site.160 This change of the support structure induced a progressiveshift in the Pt charge from positive to neutral, and the resultingPt0 species aggregated into nanoparticles. Note that redoxphenomena might dynamically occur during catalytic processes withoutleading to catalyst deactivation. Simulations on reducible oxide-supportedAu nanoparticles for CO oxidation revealed that, upon CO adsorption,Au cations form and migrate onto the support to participate in thecatalytic cycle before reintegrating back into the nanoparticles aftercompleting the reaction.161While host engineering provides a key strategy for enhancing thestability of SACs, potentially detrimental impacts must be considered.122 Similarly, the protonation of N-functionalities and subsequentdeactivation upon complexation with counterions in the electrolyteis a prominent cause of catalyst degradation in the ORR reaction overFe SACs based on N-doped carbons, requiring the latter’s removalby thermal or chemical treatment for regeneration of the active site.165 However, the molecular-level origin of theseeffects is not always fully understood. It is noteworthy that theanchoring of metal atoms may also impact the support properties, havingpositive or negative effects without involving other modifiers.170Otherdetrimental effects due to support modifications reportedin different applications likely also result from a suboptimal electronicstructure. For example, heteroatom modifiers introduced in carbonsto enhance the metal–support interaction strength were linkedto coke deposition in acetylene hydrochlorination.2RR by integrating electron-donatingmethoxy groups in the protective phthalocyanine ligands.162 Similarly, the application of ionic liquidsas reaction solvents can enable regulation of the electron distributionat the active site through charge transfer between anions and cationswith both the metal sites and the support. This can ultimately leadto higher binding energy and resistance to leaching of the singleatoms, as recently reported for TiO2-supported Rh SACsfor hydroformylation reactions.163Finally, alternative approaches encompassing ligand engineeringand regulation of the reactive environment can also effectively modulatethe electronic properties, enhancing the stability of SACs. For example,irreversible and detrimental redox phenomena were successfully hamperedfor Ni centers catalyzing the eCOIn summary, the modulation of SAC electronic features is a complexundertaking that can enhance catalytic activity and selectivity andunlock stable performance. Still, the development of effective strategiesrequires detailed knowledge of the role of the material’s electronicproperties in fulfilling the catalytic cycle. To this end, futurestudies are encouraged to adopt holistic approaches investigatingthe active phase in its integrity, encompassing metal sites, ligands,and supports, as well as their potential interactions with the reactionmedia.Unlockingthe full potentialof single-atom catalysts requiresprecise knowledge of how to tailor their electronic structure andassociated stability, conductivity, optical, and magnetic properties.This Perspective has highlighted recent developments in understandinghow the electronic characteristics of SACs can differ from those ofsupported metal nanoparticles, synthetic and analytical approachesfor modulating their properties, and the potential catalytic impactsreported. Although various procedures are known for tuning the electronicproperties, these have often been proposed to explain observed behaviorrather than applied as design strategies. Attaining complete controlover the electronic structure of SACs remains nontrivial. Currentlyinterpretations are often based on simulations making certain structuralassumptions, for example, supposing regular active site structuresand neglecting potential dynamic effects. Furthermore, the simulationsoften rely on information derived from the ex situ analysis of SACs,which may not reflect the behavior of practical catalysts under reactionconditions. Despite these limitations, simulations play a valuablerole in guiding us to the potential range of accessible electronicproperty variations as a function of distinct structural features.Overcoming current synthetic and analytical frontiers will bringtremendous progress in the atomically precise design of catalyticmaterials. The analysis undertaken in this Perspective identifiedseveral priorities for moving forward. It emphasized the need formore dedicated efforts exploring the design of supports with well-definedcoordination site architectures that provide optimal environmentsto maximize the catalytic efficiency of anchored metal atoms. Desirablefeatures include the possibility to regulate orbital occupancy, bandedge energy levels, and spin states, providing multidentate structuresthat permit adaptive coordination during the catalytic cycle, andharnessing synergies with the support to enhance charge transfer andlight absorption properties. Alongside developing SACs with betterdefined structures, advances in smart characterization approachesseamlessly integrating computational modeling and experimental analysisinto efficient workflows guided by artificial intelligence can accelerateand improve the accuracy of discriminating the electronic structureof SACs through commonly applied techniques such as X-ray absorption,X-ray photoelectron, and electron paramagnetic resonance spectroscopy.


Mycobacterium tuberculosis transmission dynamics in high-burden settings are poorly understood. Growing evidence suggests transmission may be characterized by extensive individual heterogeneity in secondary cases , yet the degree and influence of such heterogeneity is largely unknown and unmeasured in high burden-settings. We conducted a prospective, population-based molecular epidemiology study of TB transmission in both an urban and rural setting of Botswana, one of the highest TB burden countries in the world. We used these empirical data to fit two mathematical models  that jointly quantified both the effective reproductive number,  Mycobacterium tuberculosis, is a major global epidemic with an estimated 10 million new cases and 1.5 million deaths annually1. TB incidence varies widely from country to country, ranging from less than 10 cases per 100,000 people in almost all high-income countries, to over 500 per 100,000 people in several low- and middle-income countries1. These remarkable disparities suggest substantial reductions in incidence are achievable if policymakers are able to identify population-specific factors that determine TB transmission and implement targeted preventive measures5.Tuberculosis (TB), an airborne infectious disease caused by 10. Such heterogeneity implies outbreaks are rarer but more extensive, and has profound implications in infectious disease control14. However, such research has overwhelmingly focused on individual outbreaks in low-burden settings, and the degree and population-level influence of individual heterogeneity in high-burden TB populations remains unknown15. Researchers have explicitly called for an improved understanding of individual heterogeneity in high-burden populations17.Understanding TB transmission dynamics is a notorious challenge given the marked variation in timing between infection and clinical TB disease. Limited evidence suggests TB transmission may be characterized by a high degree of individual heterogeneity, or differences in the number of secondary cases caused by each infectious individual18. This precludes our ability to reconstruct accurate chains of transmission  required to assess individual heterogeneity in secondary cases 19. However, molecular characterization of M. tuberculosis isolates combined with other epidemiologic  data has been shown to reasonably approximate entire TB transmission cluster sizes in high-burden settings, defined as the simple sum of all cases in a chain of recent transmission20. Since transmission chains give rise to transmission clusters, there exists an intrinsic relation between the distribution of individual secondary cases and entire cluster distributions23. Epidemiologic models have long exploited this relationship and have used the distribution of cluster sizes to infer the average number of secondary cases per each individual . We compared underlying transmission dynamics between settings by testing scenarios where model parameters were unique, partially similar, or identical. We used the best fitting model in each setting to examine the population-level impact of individual heterogeneity by calculating (1) the proportion of secondary cases attributable to infectious cases, (2) the probability of a large outbreak , and (3) the number of incident cases until the first large outbreak. We also evaluated the degree and direction of potential bias in empirical estimates by conducting a full simulation study modeling common limitations in TB observation, including missing cases, censorship, and imperfectly defined transmission clusters.Kopanyo study, “people gathering together” in local Setswana language)29. Study participants were recruited from two geographically distinct districts of Botswana: the greater Gaborone district, which contains the City of Gaborone and its surrounding suburbs, and the rural Ghanzi district. Gaborone is the political and economic capital and the most populated urban center of Botswana, with a population density of approximately 1400 people per square kilometer and a TB notification rate of approximately 440–470 cases per 100,000 population29. Ghanzi is a large, rural agricultural district in northwest Botswana with an estimated population density of 0.4 people per square kilometer and an estimated TB notification rate of 722 per 100,000 population29. The HIV prevalence in the general population in both regions at the start of the study timeframe was an estimated 17 percent30.We conducted a prospective, population-based molecular epidemiologic study aimed at identifying TB transmission networks within Botswana . Culture isolates were genotyped using a standardized protocol for 24-locus mycobacterial interspersed repetitive units—variable number of tandem repeats (MIRU-VNTR)31. Participants with matching MIRU-VNTR results were considered in the same genotypic cluster.All patients with a clinical or culture-confirmed TB diagnosis between 2012 and 2016 in Botswana’s greater Gaborone and Ghanzi districts were eligible for the study. Participants were recruited from all TB clinics and directly observed treatment centers in greater Gaborone (n = 24) and Ghanzi (n = 6). Only patients on treatment for 14 days or more prior to screening, incarcerated patients, or those refusing to consent were excluded from the study; additional details are available in the Supplementary Materials and a full protocol is available elsewhereIn December 2020, we retrospectively abstracted clinical encounter data from the Botswana Ministry of Health’s universal electronic medical record (EMR) database known as the Integrated Patient Management System (IPMS). IPMS contains detailed information on all clinical encounters in Botswana regardless of indication and it has been deployed to the vast majority of public and private clinics since the late 2000s . We abstracted all clinical encounters for Kopanyo participants in the IMPS database occurring between March 1, 2004 and December 31, 2018.32. We defined transmission sub-clusters as patients with the same genotype results identified in a geospatial cluster or having an epidemiologic link 33. Epidemiologic links (epi-links) were defined as patients with the same genotype results that frequented the same , resided at the same address, or had an overlapping clinical encounter during the putative infectious period . To relate epi-links more plausibly to recent transmission, only patients with one or more epi-links and enrolled within two years were considered a possible transmission link, with exceptions related to healthcare facilities . Cases with no established geospatial or epidemiologic link were considered isolated cases. Transmission clusters containing at least five participants with an incident case diagnosed within two years of the end of the study timeframe were considered censored .MIRU-VNTR-based clusters may contain multiple transmission sub-clusters and overestimate TB transmissionink Fig. . Geospat23. Briefly, each individual case in the population was assigned an associated individual reproductive number, denoted 11. 34. This Poisson-gamma mixture yields a negative binomial distribution of secondary TB cases (offspring distribution), also with mean https://github.com/jpsmithuga/UrbanRural_nbbpAnalysis.We developed two primary models, an urban and rural model, based on if the participant’s primary residence was in the greater Gaborone district or Ghanzi district, respectively. Both models were based on a classical Galton-Watson branching process35. We made mechanistic adjustments to account for two limitations common in cluster sizes, denoted 27. Instead, we conditioned the probability of a genotypic cluster reaching final size 22. This approach considers all possible ways 23. Confidence intervals (95% CI) were obtained through profile likelihood36. Using inferred parameters we also calculated the expected proportion of cases responsible for all secondary transmission .We used maximum likelihood estimation (MLE) to jointly infer negative binomial model parameters 37. Let 40. We compare model fit using the Akaike Information Criterion (AIC); the lowest AIC score determined the best fitting model. We then calculated information loss, which provides a measure of how likely the best fitting model explains the observed data relative to the comparison models42.Using model likelihoods we determined if there was statistical support for differences in transmission dynamics between the urban and rural populationsWe evaluated three primary sources of potential bias: the appropriateness of model assumptions, the definition of transmission clusters, and the sensitivity of parameter inference. Briefly, we compared models with two alternative distributional assumptions of mentclass2pt{minimThis study was approved by the Centers for Disease Control and Prevention (CDC) Institutional Review Board (IRB); the Health Research and Development Committee, Ministry of Health and Wellness, Botswana; and the University of Pennsylvania IRBs. All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all subjects and/or their legal guardian(s).A total of 4331 cases were enrolled in the study, of which 3736 (86%) had a validated geocoded primary residence, 3891 (90%) had EMR data linked from the IPMS database, and 2137 (49%) had culture-positive, pulmonary tuberculosis with genotyping data available; 1683 (39%) had combined genotypic, geospatial, and epidemiologic data suitable for analysis (Table The maximum likelihood estimates (MLE) of entclass1pt{minimaentclass1pt{minimaThe two populations had markedly different underlying mechanisms of TB transmission Fig. . The rurOf the six models developed to compare transmission dynamics in the two populations, the unrestricted model, which assumed the populations had entirely unique transmission parameters, best supported the observed data Table . The ideBoth models estimated that most secondary transmission was attributable to a minority of infectious cases, yet the proportion of cases responsible for secondary transmission varied considerably between models Fig. . For insOur assumption of a gamma-distributed entclass1pt{minimaentclass1pt{minimaity Fig. , yet stiOur cluster-based inference performed accurately and equally well under perfect surveillance conditions when compared to standard approaches using known individual-level data , with a median This analysis revealed remarkable differences in TB transmission dynamics between urban and rural populations in a high-burden TB and HIV setting. While we emphasize that both populations were characterized by extensive outbreaks of recent transmission . Fewer venues might concentrate a larger proportion of the population in these venues and result in a higher proportion of transmission relative to urban venues. Differences in social practices between populations may also provide insight; inhabitants of Ghanzi, like many populations in rural southern Africa, experience seasonal oscillating migration between their residence and towns and villages for employment and other economic and cultural reasons, often residing in temporary congregate lodging We performed multiple sensitivity analyses to evaluate model development and inference. We first compared multiple underlying assumptions of heterogeneity in the model, the evaluated differences between the populations using six comparison models. We also undertook a comprehensive simulation study both to verify that cluster-size distributions were sufficient for parameter inference and to evaluate the impact that imperfect surveillance has on the inference procedure. All analyses supported the primary findings that transmission in both populations was characterized by a high propensity for extensive transmission, and that rural populations had a higher probability of experiencing large outbreaks compared to the urban population. Importantly, despite a high degree of bias introduced, the models were able to easily distinguish between the urban and rural populations Fig. .50. Since missing genotypic data was not differential by population , demographic , or clinical characteristics , we evaluated the impact of this limitation in our simulation study using a binomial probability. While this revealed that estimates were slightly biased towards homogeneity, this approach assumes genotypic data were missing at random, an assumption that cannot be verified by the empirical data. This assumption would be violated if culture status was differential by genotype. However, to our knowledge, there is no biological rational for coding regions of genes to impact replicative fitness in culture media, and mycobacterial strains from differing lineages share similar growth kinetics.Our simulated study demonstrated that our method produced unbiased estimates, yet the accuracy of estimates depends on the data quality . MIRU-VNTR is a lower-resolution genotyping method than the more recent whole genome sequencing approach, and generally overestimates cluster distributionsentclass1pt{minima52. However, this assumption may be invalid if a substantial proportion of outbreaks occur in clustered pockets of vulnerable sub-populations  or in scenarios where the depletion of susceptible individuals may meaningfully impact outbreak trajectory . Recent studies incorporating heterogeneous susceptibility suggest estimates could be both over- and underestimated depending on the network structure and contact distribution patterns56. Future studies incorporating heterogeneous susceptibility, particularly those in high-burden settings, can extend these findings and deepen our understanding of population-specific transmission dynamics.All models are a simplified representation of disease transmission and are subject to inherent limitations. Branching process models assume transmission is independent and identically distributed. This assumption would be violated if Interrupting TB transmission in high-burden settings is fundamental to achieving TB elimination. This analysis developed well-characterized models quantifying TB transmission dynamics in a high-burden setting to estimate the propensity for extensive transmission. The results play a direct role in using surveillance systems to better understand the underlying mechanisms of TB transmission in high-burden populations.Supplementary Information.


We review our current understanding of adaptive immune responses to the fetoplacental allograft, emphasizing the divergent responses observed for trophoblast- versus fetal blood cell–derived antigens. We suggest these divergent responses arise from cell type–specific glycosylation programs that impart trophoblast-derived antigens with immunosuppressive properties. The paradox of fetomaternal tolerance has puzzled immunologists and reproductive biologists alike for almost 70 yr. Even the idea that the conceptus evokes a uniformly tolerogenic immune response in the mother is contradicted by the long-appreciated ability of pregnant women to mount robust antibody responses to paternal HLA molecules and RBC alloantigens such as Rh(D). Synthesizing these older observations with more recent work in mice, we discuss how the decision between tolerance or immunity to a given fetoplacental antigen appears to be a function of whether the antigen is trophoblast derived—and thus decorated with immunosuppressive glycans—or fetal blood cell derived. The conceptus, comprised of the placenta and the fetus proper, is not genetically identical to the mother yet fails to induce the rejection response traditionally observed for allogeneic organ transplants. Nearly 70 yr ago, Peter Medawar recognized this apparent paradox and posited three possible explanations: (1) the conceptus is kept physically separate from maternal immune cells; (2) the maternal immune system is generally suppressed; and (3) the conceptus does not express rejection antigens . These iThus, the paradox of fetomaternal tolerance has become focused on the more refined question of how an allograft that does express rejection antigens and does interact extensively with immune cells in an immune-competent host fails to elicit a traditional rejection response. Here we review our current understanding of systemic maternal B and T cell responses to the fetoplacental allograft, emphasizing the divergence in response apparent for antigens expressed by trophoblasts versus fetal blood cells and the potential role of cell type–specific protein glycosylation in explaining this divergence.Despite a varied architecture across mammals, the placenta forms an anatomic barrier between maternal and fetal circulation that separates fetal cells of nontrophoblast origin from the maternal immune system. However, in both humans and mice, antigenic quantities of fetal blood cells can enter maternal circulation and trigger maternal alloimmunization . In both− women) who are exposed to Rh(D)+ fetal blood during late gestation or delivery. HDFN, or Rh disease, as it is known when Rh(D) is the inciting antigen, can then occur when anti-Rh(D) IgG antibodies are transported across the placenta by the same pathway that provides protective passive immunization to the developing fetus. Maternal anti-Rh(D) antibodies then bind to fetal RBCs, which subjects them to antibody-dependent lysis. The clinical outcome is variable and ranges from mild anemia to fetal or neonatal death. Before the advent of preventive therapy, clinically significant HDFN occurred in ∼16% of gestations with maternal/fetal Rh incompatibility, or 1 in 1,000 total pregnancies, attesting to the pathogenicity of the response , which is caused by maternal B cells that have reacted to alloantigens expressed by fetal RBCs . Most caresponse . Althougstations .Like Rh(D) antigen, paternal HLA molecules can also trigger maternal B cell responses. Anti-paternal HLA antibodies directed against the full set of paternal HLA molecules  are identified in most multiparous women and are sometimes detectable in maternal plasma during the third trimester of a first pregnancy. This suggests that, in analogous fashion to the response to Rh(D), the anti-HLA response is driven by exposure to antigenic quantities of blood-borne, HLA-expressing fetal white blood cells as the result of placental microhemorrhage and/or delivery . It is aSomewhat surprisingly, the nature of the maternal CD4 T cell response to Rh(D) and fetal HLA antigens has not been thoroughly addressed. Because maternal anti-Rh(D) and anti-HLA antibodies are class-switched, it has been presumed that maternal CD4 helper T cell responses are also mounted to Rh(D) or a physically associated RBC antigen (since Rh(D) is a component of an integral membrane protein complex). Such CD4 T cell responses are also consistent with the correlation between the number of paternal HLA-derived epitopes predicted to be available to stimulate CD4 T cells during pregnancy and the probability of generating anti-HLA antibodies . MoreoveConsidering the grave pathogenicity of maternal B cells with specificity toward fetal RBC antigens, the field naturally wondered about the nature of B cell responses to trophoblast-expressed antigens. Experiments performed around 1980 uncovered the presence of “noncytotoxic” anti-paternal IgG1 antibodies in multiparous mice, but closer examination revealed that they arose only in some strain mating combinations and only after multiple gestations . SimilarThe behavior of maternal B cells with specificity toward a paternal alloantigen known to be expressed by trophoblasts was first directly examined in experiments using female mice bearing BCR transgenes encoding an IgM molecule with relative high affinity for a paternal strain H-2K . AlthougOur laboratory has recently examined the fate of the endogenous repertoire of peripheral B cells specific for a trophoblast antigen . This woN-linked glycans, a biochemical analysis revealed that t-OVA was more heavily glycosylated and that its glycans were terminated with α2,6-linked and α2,3-linked sialic acid residues (g-like lectins (Siglecs), a family of transmembrane proteins that typically inhibit immune cell activation  upstream of LYN, such as Siglec-G  within the decidua, which precludes input from these potent APCs in the uterine draining lymph nodes . InsteadH1) cells  cells . Howeverconcepti . These oconcepti , and parconcepti . The ideconcepti . In addic mating . A similed Tregs . Provocaed Tregs , thus liSurprisingly, our recent work on trophoblast glycans revealed that OVA-specific CD4 T cells are not disinhibited when Tregs are depleted during mOVA pregnancies, even though these pregnancies cause OVA-specific CD4 T cells to convert to Treg cells to some extent . We alsoIn contrast to the more classically tolerance-like maternal CD4 T cell response to trophoblast-derived antigens, the CD8 T cell response is best described as nonimmunogenic, since this response is characterized by neither tolerance nor immunity. Thus, while CD8 T cells do not become activated to t-mOVA, even when the mice are given adjuvants, mOVA-mated mice show robust CD8 T cell responses to OVA vaccination . MoreoveAlthough not the topic of this review article, mechanisms also exist to protect the conceptus from attack by T cells, should they happen to become activated, as well as mechanisms that prevent antibodies from damaging trophoblasts. These mechanisms rely on the unique tissue characteristics and immunology of the maternal–fetal interface  is diagnosed when, in the absence of infection, histologic examination of the placenta reveals a lymphocyte infiltrate in the stroma of the trophoblast-lined placental villi . This inDrawing on the divergence in maternal responses to trophoblast versus fetal blood cell antigens outlined above, we propose the following model for VUE pathogenesis that is based on the priming of maternal T and B cells specific for fetal blood cell antigens rather than trophoblast antigens. First, placental microhemorrhage exposes maternal T cells to fetal blood cells that express paternal allogeneic HLA. Maternal CD4 and CD8 T cells are then activated via the direct allorecognition pathway, with CD4 T cells also providing help for a B cell response. Second, there is focal damage to the usually impenetrable syncytiotrophoblast layer, perhaps via alloantibody binding and complement activation, and potentially involving the killing of trophoblasts. This allows CD8 T cells to gain access to the underlying villous stroma, where they encounter fetal fibroblasts, macrophages, and endothelial cells, which express the full set of paternal class I HLA, thus vigorously activating the T cells and reinforcing the inflammatory reaction. It is also possible that T cells gain entry to the villous stroma in focal areas where the syncytiotrophoblast layer has been damaged by a pathogen, or merely by compromised blood flow.Now is a very exciting time in reproductive immunology, as newly developed tools are allowing us to thoroughly dissect adaptive immune responses to the fetoplacental allograft. Based on the current literature, we have tried here to articulate a framework that explains why these responses appear to be so divergent, with trophoblast antigens inducing tolerance and fetal blood cell antigens driving immunity . This frMechanisms of increased trophoblast membrane protein sialylation are also an open area of research. As alluded to above, these mechanisms might include increased activity of sialyltransferases and sialic acid transporters, decreased activity of sialidases, and altered transit through the ER/Golgi processing pathway. Trophoblast antigen sialylation  might also be regulated in subtype-specific fashion and under the influence of paracrine factors. Indeed, recent evidence suggests that the glycan pattern of extravillous trophoblasts located in the uterine decidua might in part be regulated by cross talk with uterine natural killer cells and DCs . There m


The prevalence of chronic diseases has become one of the most significant global health threats of the 21st century. These conditions have a significant toll on people’s quality of life and create both societal and economic burdens. Inflammation is a normal biological defense against infection and tissue damage. Under normal circumstances, the inflammatory response quickly ends after the clearance of infection and injurious agents. However, when inflammation becomes self-perpetuating, it can result in chronic or long-term inflammation and trigger inflammation-mediated damage that contributes to the pathogenesis of several chronic diseases. Growing evidence suggests a close link between inflammation and many chronic health conditions . TacklinJiang et al. reported the potential activity of Gaudichaudione H, a natural compound isolated from the plant Garcinia oligantha Mer., in inhibiting the inflammatory response in macrophages and dextran sodium sulfate (DSS)-induced colitis in mice mainly through the modulation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, suggesting its potential application in IBD and macrophage-related inflammatory disease in general. da Rocha et al. reported the results of a combined in vitro and in vivo study to explore the modulation effect of pioglitazone, a PPARγ ligand, on IBD inflammation. They demonstrated the pivotal role of Annexin A1 (AnxA1), a glucocorticoid-modulated anti-inflammatory protein, as a mediating factor for the therapeutic properties of pioglitazone against IBD. Moreover, the in vitro data from macrophages indicated that the therapeutic action of pioglitazone depends on extracellular signal-regulated kinase (ERK) phosphorylation, which involves AnxA1. Intestinal barrier homeostasis is involved in many diseases at different levels, including the pathogenesis of recurrent urinary tract infections. Stepanova’s mini-review article highlights the importance of the cross-talk between intestinal barrier dysfunction and the recurrence of urinary tract infection to guide experimental and controlled studies to clarify the mechanisms underlying the interaction between these conditions. Chronic low-grade inflammation has also been associated with metabolic disorders such as insulin resistance triggered by the excessive production of leukotriene B4 (LTB4), a potent inflammatory lipid mediator, in combination with its receptor BLT1. In this context, Gong et al. examined in vitro the effect of berberine on the LTB4–BLT1 axis in the development of inflammation and insulin resistance. Their results suggested that berberine might interfere with BLT1 and alter the LTB4–BLT1 axis, leading to decreased insulin resistance and inflammation. Clinically, septic liver injury is associated with severe systemic inflammation and multiple organ dysfunction syndromes. Yu et al. investigated the pharmacological effect of dexmedetomidine (DEX), a highly selective α2-adrenoreceptor agonist, against septic liver injury. Their results suggested that DEX might protect against cecal ligation and puncture (CLP)-induced liver injury, highlighting a novel mechanism in which DEX improves autophagy, which reduces the inflammatory responses in CLP-induced liver injury by regulating the adenosine monophosphate-activated protein kinase/Sirtuin 1 (AMPK/SIRT1) signaling pathway.The articles contributed to this Research Topic cover different aspects related to inflammatory-based diseases by highlighting the underlying mechanisms and diverse pharmacological strategies. Intestinal chronic inflammations, including inflammatory bowel disease (IBD), are among the diseases showing more pronounced increases. These diseases are widespread and impose burdens on healthcare systems worldwide. Experimental studies have also revealed the link between these conditions and other systemic diseases. As the pharmacological options to treat these conditions are limited, research to identify new therapeutic strategies is of great interest. In this Research Topic, Finally, the Guest Editors thank all the authors who have contributed to this Research Topic and provided interesting ideas, approaches, and results, which offer a platform upon which other researchers can build.


No significant technical errors were detected with deployment on over 550 devices.•VPExam QI intervention was associated with a 30-day hospital readmission rate of 9.52% from a baseline readmission rate of 15.9%, with a relative risk reduction 40.16%. Readmission rates fell precipitously, to 0%, for the last 4 consecutive months of VPExam QI. Thirty-day mortality rate was 4.76%.•VPExam QI provides supporting quality and feasibility data for increasing adoption of virtual care platforms with minimal barriers. Actionable physical exam and structured data optimize quality of transitional care, allowing for significant reductions in readmissions and mortality.Heart failure (HF) is a leading cause of morbidity and mortality in nearly 5.7 million Americans. With improved survival and an aging patient population, the cost associated with HF management is expected to reach close to $70 billion by 2030.,The COVID-19 pandemic has increased utilization of telemedicine for HF management. Telehealth is a growing field of importance owing to value-based care and population management incentives, as well as increased acceptance in the general and medical population since the COVID crisis. Numerous meta-analyses have demonstrated that compared to conventional care, the addition of telemedicine in HF management leads to reduced hospitalization and mortality.Telemedicine platforms have traditionally presented numerous obstacles, including affordability of equipment, difficult-to-use technology requiring extensive training, lack of standardization, and patient privacy issues. These barriers are especially challenging to SNF and home care populations, who often have significant comorbidities, functional impairments, and barriers to transportation and access.Telemedicine can offer these populations improved access, but this is typically at the expense of clinical data such as a comprehensive physical examination and other structured data including vitals, medication reconciliation, and laboratory results. Many of the most common and expensive cardiopulmonary diseases rely on physical examination for detection of decompensation or exacerbation .Figure 1VPExam is a Health Insurance Portability and Accountability Act (HIPAA)–compliant medical device data system that assists in overcoming barriers to traditional telemedicine using a combination of augmented reality–based guidance leading a minimally trained nurse or medical assistant (MA) through appropriate camera positioning for video capture based on anatomical landmarks. VPExam augmented reality–guided overlays, combined with sample videos as well as text and audio instructions, teach users how to obtain optimal video recordings of clinical findings such as evaluation of jugular venous distention and degree of lower-extremity edema in a reproducible manner.VPExam is integrated with Bluetooth-enabled stethoscopes, including the Eko Duo with single-lead electrocardiogram (ECG), to capture a full heart and lung exam with active user instruction . VirtualVPExam app data acquisition creates a partnership between minimally trained users (nurses or MAs) and physicians to efficiently gather and transmit relevant medical data to the Physician Portal. On average, nurses/MAs required a single 20-minute training session before becoming clinically proficient to use the platform in clinical practice. VPExam nurse assessment was completed in under 5 minutes on average. VPExam data were reviewed by the managing physician using the Physician Portal in under 2 minutes on average prior to proceeding to real-time video encounter with the patient and saved in the electronic medical record (EMR). Time-efficient review of asynchronous, clinically relevant patient management data has proven critical for ongoing physician engagement when using virtual care telemedicine.In addition to physical exam data, VPExam allows nurses to transmit structured data including manual transmission of vitals, voice recognition–based virtual history and review of systems, medication reconciliation with photographs of pill bottles, and a document scanner to transmit laboratory results, orders, logs, ECGs, etc . ProvideVPExam routinely transmits digital physical exam data for comprehensive assessment of volume status, cardiopulmonary auscultation, ECG detection of arrhythmias, and structured data including vitals, medication reconciliation, and labs. VPExam Partner Portal allows physicians to collaborate with partners at SNFs and home care to schedule VPExam follow-up post discharge. VPExam Partner Portal sends automated e-mail notifications to administrators or directors of nursing at partner facilities. SNFs and home care have HIPAA-compliant access to coordination-of-care data as well as prepopulated electronic home care or SNF orders sent by physician users .VPExam also offers additional remote patient monitoring (RPM) using Apple Health and Google Fit Health Kit data transmission to the VPExam Provider Portal, including blood glucose, body mass index, cardio fitness, blood pressure, ECG, heart rate, oxygen saturation, walking heart rate, and weight . VPExam VPExam QI was designed as a single-arm prospective comparative community case study recruiting patients admitted for HF at University Hospitals Regional Medical Centers with anticipated discharge to SNFs or home care as well as those requiring urgent cardiology consultation with VPExam intervention. Primary outcomes included the degree to which unique VPExam digital physical exam data to assess volume status, cardiopulmonary auscultation, ECG detection of arrhythmias, and structured data of vitals, medication reconciliation, and labs would impact individual transition-of-care management as well as VPExam impact 30-day all-cause rehospitalization rates. The design also sought to assess feasibility of transition-of-care workflows within SNFs and home care, compliance with follow-up, technical stability of the platform, nursing staff satisfaction with the platform, and financial analysis of virtual care networks.The study design attempted to overcome common barriers to traditional telemedicine. Training barriers were reduced using user-friendly VPExam augmented reality–guided overlays to guide new nurse and MA users through how to obtain optimal video recordings of clinical findings such as jugular venous distention and degree of lower-extremity edema. The VPExam platform was cost-effective, requiring only a tablet and Bluetooth stethoscope at each sending site, allowing for rapid scaling within the health system. VPExam was approved by a thorough institutional Information Technology (IT) Architecture review process by University Hospitals of Cleveland IT Department to ensure HIPAA and HITECH compliance.The goal of VPExam QI was to explore potential clinical benefits to active physician-directed disease management using the VPExam technology and workflows for patients undergoing transitions of care. VPExam QI focused on gathering data on patients being discharged to SNFs or home care from a community-based hospital. VPExam QI evaluated whether a comprehensive virtual care platform can enhance the quality of transitions of care. Three SNF and 1 home care partners were selected with the highest numbers of HF patients being discharged to their care from the 2 medical centers before initiation of the pilot to increase data acquisition. University Hospitals of Cleveland’s IT department successfully deployed VPExam on over 550 hospital-owned devices and University Hospitals home care.Prior to deployment of VPExam QI, baseline hospital HF outcome data were collected. From June 2020 to June 2021, patients discharged from University Hospitals of Cleveland Regional Medical Centers received guideline-directed HF therapy in accordance with the American College of Cardiology expert consensus guidelines for HF management and follow-up. The same cardiologist and advanced practice providers managed the control population from June 2020 to June 2021, as well as the study population from July 2021 to December 2021, with VPExam acting as the primary intervention.The prospective single-arm community case study of VPExam QI used convenience sampling to recruit patients admitted with HF who met eligibility criteria from University Hospitals of Cleveland Regional Medical Centers. Twenty-one patients with 25 independent patient encounters received virtual care intervention using VPExam technology and established workflows. VPExam QI focused on patients who were being discharged to 3 partner SNFs or follow-up from University Hospitals home care. VPExam QI recruited patients for the 6-month period from July 2021 through December 2021. All patients approached agreed to participate. Once patients were enrolled in the VPExam QI, encounters were completed as routine follow-up appointments within 1–3 weeks of discharge. Partners were also permitted to enroll urgent encounters as part of VPExam QI in coordination with the research team to allow for urgent cardiology consultation.The intervention of VPExam was compared to historical community matched controls. The control group data were derived from historical community patient data from the hospital system in the months and year immediately prior to VPExam intervention. The control group received guideline-directed HF therapy without routine follow-up at their SNF or home care visits with cardiology-led telemedicine with physical exam data from the same cardiology team as the intervention group.To identify potential patients, a daily automated list was generated from the EMR of patients admitted to the 2 hospitals for HF, known as the “Currently Admitted Patients with Heart Failure” from Allscripts Sunrise EMR.HF patients were identified based on brain natriuretic peptide (BNP) of greater than 300 or left ventricular ejection fraction (LVEF) of less than 40%. The team emphasized enrollment of patients who had been readmitted to the hospital within the last 30 or 90 days, as well as patients’ being active on cardiology consultation services. The team enrolled patients being discharged to 1 of 3 SNF partners or eligible for University Hospital Home Health with VPExam capabilities.Exclusion criteria included the following: (1) those not meeting the definition of HF patients used in VPExam QI; (2) severe dementia preventing the patient’s participation; (3) patients who are unable or unlikely to comply with telemedicine encounters.VPExam QI’s primary objective was to determine the degree of significance of physician-directed disease management based on unique VPExam data including volume status assessment, cardiopulmonary auscultation, ECG arrhythmia detection, and structured data transmission, as well as the downstream impact on 30-day all-cause rehospitalization rates.Outcome measures included the following: (1) identifying the degree of significance of disease-altering care  based on VPExam virtual care data ; (2) 30-With each encounter, demographic data points were collected including sex, body mass index, tobacco abuse history, Charlson Comorbidity Index, NYHA classification, days since previous hospitalization, relevant echocardiogram data with LVEF, degree of valvular disease and pulmonary hypertension, and laboratory data including BNP and glomerular filtration rate trends .Table 2DDemographic and functional characteristics were measured using descriptive statistics. Continuous variables were expressed as mean ± standard deviation if normally distributed, or otherwise as median (interquartile range).The intervention was implemented as a virtual care practice change to improve the quality of care. Data were collected and stored using a HIPAA-compliant, web-based data collection tool stored in a restricted-access folder on a secure server. All participants received information about the purpose of the study, agreed to consent before participation, and were free to withdraw from the study at any time. Informed consent was obtained from the individuals or from minors’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.The community case study recruited 21 patient participants with 25 independent encounters for patients discharged to SNFs or home care from 2 community hospitals, University Hospitals of Cleveland Regional Medicals Centers. At baseline, patients were on average 79.2 (SD 13.4) years old , 40.9% oNursing satisfaction overall rating of using this platform was 4.8/5 (± 0.22) for 25 surveys of nursing staff that participated. Staff were also interviewed regarding technical difficulty encountered with the use of the platform on a 6-point Likert scale, with 0 meaning no technical error and 5 meaning unable to use the platform owing to technical error. For all nursing staff involved in the study, the score was zero. No technical errors were detected across partners at 3 SNFs and deployment on over 550 home care–owned medical devices.VPExam QI patients received clinical follow-up for approximately 2–3 weeks’ duration and data collection for 3 months following VPExam encounter. There were no patients who declined participation and there were no dropouts. All 21 patients and 25 scheduled encounters at partner SNFs and home care nurses were compliant with VPExam visits coordinated by communication via VPExam Partner Portal. A total of 19% of study encounters occurred with home care services and 81% of encounters occurred at SNFs. During the 6-month pilot, 33.8% of all hospitalized HF patients at University Hospitals of Cleveland Regional Hospitals were enrolled into VPExam QI. Cardiology management was based on guideline-directed therapy. Over 95% of patients were on beta-blocker therapy. A total of 38% of patients were on renin-angiotensin inhibitors and 9.5% of patients were on mineralocorticoid receptor antagonists on follow-up visits during the study. The most common documented reason for deferring renin-angiotensin inhibitors or mineralocorticoid receptor antagonists was acute renal failure, followed by allergy, including angioedema, followed by hyperkalemia.Sixteen percent of patient encounters required only mild or less significant clinical modification of care, while 84% of patient encounters required moderate-significance changes in clinical modification based upon VPExam follow-up . The mosPrior to deployment of VPExam QI, baseline hospital HF outcome data were collected. From June 2020 to June 2021, patients discharged from University Hospitals of Cleveland Regional Medical Centers received guideline-directed HF therapy in accordance with the American College of Cardiology expert consensus guidelines involving medical/procedural management and follow-up. The same cardiologist and advanced practice providers managed the control population from June 2020 to June 2021, as well as the intervention population from July 2021 to December 2021, with VPExam acting as the primary intervention.The historical control population of HF patients discharged from University Hospitals of Cleveland Regional Medical Centers from June 2020 to June 2021 had an average monthly all-cause readmission rate of 15.91%, with 158 total encounters. Following intervention with VPExam QI interventions, 30-day hospital admission rates dropped to 7.98% for the entire HF population, with 62 total encounters. Within the 21 encounters of VPExam QI, the all-cause 30-day hospital admission rate was 9.52%. VPExam was associated with a 40.1% relative risk reduction for 30-day readmission compared to historical community matched control. Of note, fewer than 25% of VPExam QI patients were recruited in months 1 and 2 of the pilot when the readmission rate for the hospital system remained similar to historical averages. However, by months 3–6 of the pilot more than 75% of VPExam patients were recruited and readmission rates fell precipitously to 0% for 4 consistent months .Figure 6Across HF subtypes, patients with HF mortality rate following hospitalization is approximately 10.4% at 30 days, 22% at 1 year, and 42.3% at 5 years.The VPExam QI used the ongoing results for a rapid-cycle improvement strategy via Plan-Do-Study-Act cycles. Continually implementing improvements enables providers to better serve the highest-risk patients and improve quality for transitions of care. Plan-Do-Study-Act cycles also help hospital systems overcome resistance to new virtual-care technology workflows.,,,Significant barriers identified in literature review preventing successful integration of quality improvement initiatives include the following: (1) the presentation of HF can be nonspecific and make it difficult to diagnose; (2) guideline-directed drugs are underused owing to doubt on their utility and safety concerns; (3) SNF providers can be uncomfortable managing HF owing to complexity and autonomy at end-of-life decisions; (4) there is mistrust and lack of timely communication between SNF staff, patients, and their families; (5) there are limited resources in terms of diagnostic studies and access to specialists for care of patients; and (6) there are poor information sharing and transfer capabilities.VPExam QI reveals that unique VPExam tools overcome many of these barriers while creating a successful local virtual care network between hospital systems and partner SNFs and home care.VPExam deployment to SNFs and home care is feasible, scalable, and cost-effective. VPExam virtual care networks enable high compliance with follow-up, with high satisfaction from nursing staff. A major value for moderate-level-complexity patient management involved structured data transmission of the platform linked to moderate modification in clinical management over 95% of encounters. Structured data transmission of vitals improved detection of uncontrolled hypertension, hypotensive episodes, and tachyarrhythmias often missed in traditional telemedicine. Structured data transmission of medication reconciliation often identified high-risk transition-of-care errors. Structured data transmission of labs including renal function, BNP trends, and blood count stability improved the quality of medical decision making.VPExam is also uniquely suited to improve clinical decisions with unique physical exam data. Volume status including jugular venous distention and lower-extremity edema influenced moderate modification management in 50% of encounters. Synchronous and asynchronous stethoscope auscultation of the heart to detect murmurs, rubs, gallops, and irregularity, as well as auscultation of the lungs to detect wheezing and rhonchi, influenced moderate modification management in over 31% of encounters. Synchronous and asynchronous single-lead ECG transmission for arrhythmia detection including atrial fibrillation influenced moderate modification management in over 13.6% of encounters.The results demonstrate that virtual care in transitions of care to SNFs and home care offer a large opportunity to improve quality of care and mitigate risk of errors for cardiopulmonary patients. VPExam was associated with improved adjustments in medication dosages based on physical exam data, correcting errors in medication reconciliation, and educational reinforcement of medication compliance. Despite a relatively small cohort, the reduction in 30-day hospitalization and mortality supports the hypothesis that unique VPExam virtual care data empower care providers to optimize transitional quality of care beyond traditional guideline-directed therapy.Beyond quality improvement encouraging adoption of virtual care, there are also financial considerations for various stakeholders. Transfer of SNF residents to emergency departments is linked to increased morbidity and mortality, as well as significant cost.VPExam helps reduce the cost of transporting patients to specialists and hospitals, including ambulance cost and nursing time expenses. Virtual care also helps reduce the risk of contracting infectious diseases such as COVID while visiting the health care facility, as well as the unforeseen burden to the patient, including potential need for quarantine.In addition to the financial incentivization to using virtual care to mitigate the cost of readmissions, the platform can also increase individual provider productivity. VPExam data were correlated to a higher level of complexity per encounter on average, increasing CPT 99454 to CPT 99457 with an average increase in reimbursement of approximately $50 and 0.9 work relative value units (wRVU). Furthermore, VPExam services are eligible for RPM billing using CPT codes 99453, 99454, 99457, and 99458 with recurring monthly payments. VPExam QI service received RPM reimbursement from diverse payors, including Medicare A, United Healthcare Medicare HMO, Humana Gold Choice, CareSource MyCare Ohio, and United Healthcare Medicare HMO, throughout the pilot.VPExam QI is a quality and feasibility study during an unprecedented COVID crisis. We suspect that launching similar transition of virtual care programs in other hospital systems at a larger scale as a formalized quality initiative will be beneficial to ensuring high-quality outcomes across the continuum of care. Virtual care offers earlier detection of clinical decompensation to underserved communities and better decisions by clinicians, resulting in reduced risk of hospital admission and mortality on discharge. In turn, improved transitional care assists health care systems in preventable penalties, unnecessary care escalation, and more efficient utilization of limited inpatient and intensive care unit beds.A significant limitation of the VPExam QI is the relatively small scale of a 21-patient single-center observational trial owing to the resources needed to deploy technology, train staff, and allow for adequate data collection in a relatively condensed timeline. This made a case series study with descriptive statistics the most appropriate format for analysis. The interventions were deployed from community-based hospitals in suburban areas that may not be applicable to more urban or rural health care settings. Scalability may be resource constrained by access to technology, especially for smaller health systems. Partnership for VPExam technology deployment was made with 3 high-volume SNFs and a hospital-operated home care agency. Of note, the United States has trended toward decreasing discharges to SNFs in favor of discharging patients home with home care services. Patients discharged to SNFs and home care on average have significantly greater comorbidities and barriers to care than patients discharged to home without such services. Therefore, the intervention of VPExam QI was indirectly focused on the higher-risk HF population.The research team included 2 board-certified cardiologists, 2 internal medicine residents, 2 cardiology nurse practitioners, and 1 registered nurse. Cardiologists with HF-specific training were available during all VPExam QI encounters to improve standardization of data analysis and guideline-directed therapies. VPExam QI encounters were completed as routine follow-up appointments or urgent consultations. One of the major reasons for a lack of emergent significance modification of clinical management in the VPExam QI was that the small size of the study team made it impossible to provide consistent 24/7 access to cardiology care for urgent decompensations. Therefore, an emergent VPExam workflow was not consistently established with partner SNFs and home care. The value of VPExam technology in these types of emergent encounters can likely be better studied in the future by deploying the platform with a significantly larger clinical team supporting these types of encounters and offers greater potential quality-of-care impact.Implementing virtual care to improve transitions of care in the underserved SNF and home care patient populations represents a promising measure to address high readmission rates in HF patients. VPExam offers capabilities to efficiently transmit virtual physical exam cardiopulmonary and volume status assessments with supplemental structured data, including vitals, medication reconciliation, and labs critical to HF management. Noninvasive virtual-care platforms offer novel interventions to optimize quality of care, impacting readmission and mortality rates.Virtual care in HF management is a rapidly evolving intervention with high-yield quality returns for SNF and home care patients, who traditionally have poor access to specialist care. Future projects should not only focus on how virtual care can be integrated to provide better quality of care, but also address the paradigm of cost-effective health care delivery given the growing challenges of health care resource scarcity. Ongoing government and hospital support for digital innovation research allows physicians the opportunity to define the way developing technologies will be used in future workflows to optimize efficiency and quality of care.