The epitaxialLSCO/LSMO bilayers were grown on (110)o-oriented NdGaO3 (NGO) substrates with a fixed LSMO (toplayer) thickness of 6 nm and LSCO (bottom layer) thicknesses varyingfrom 1 to 10 nm. Despite the small difference (∼0.2%) in latticemismatch between the two in-plane directions, [001]o and [11̅0]o, a pronouncedin-plane magnetic anisotropy was observed. Soft X-ray magnetic circulardichroism hysteresis loops revealed that for tLSCO ≤ 4 nm, the easy axes for both LSCO and LSMO layerswere along the [001]o direction, and theLSCO layer was characterized by magnetically active Co2+ ions that strongly coupled to the LSMO layer. No exchange bias effectwas observed in the hysteresis loops. In contrast, along the [11̅0]o direction, the LSCO and LSMO layers displayeda small difference in their coercivity values, and a small exchangebias shift was observed. As tLSCO increasedabove 4 nm, the easy axis for the LSCO layer remained along the [100]o direction, but it gradually rotated to the[11̅0]o direction for the LSMO layer,resulting in a large negative exchange bias shift. Therefore, we providea way to control the magnetocrystalline anisotropy and exchange biasby tuning the interfacial exchange coupling between the two FM layers.Controlling the in-planemagnetocrystalline anisotropy and interfacialexchange coupling between ferromagnetic (FM) layers plays a key rolein next-generation spintronic and magnetic memory devices. In thiswork, we explored the effect of tuning the magnetocrystalline anisotropyof La While it has been widelystudied on FM metals and alloys, magnetic perovskite oxides providedegrees of tunability which are absent in purely metallic materialsdue to interactions between the charge, orbital, spin, and latticedegrees of freedom.22 EB in perovskite oxides has not only been found in FM/AFM heterostructuresbut has also been observed at interfaces between hard and soft FMlayers.24Exchangebias (EB) is an effect broadly explored in ferromagnetic(FM)/antiferromagnetic (AFM) heterostructures2/3Sr1/3MnO3 (LSMO) has been extensively studied due to the ability tocontrol its MA properties.27 For example, Liao et al. demonstratedthe switch from interfacial magnetic anisotropy (IMA) to bulk magneticanisotropy (BMA) of the magnetic easy axis in ultrathin LSMO layersgrown on (110)o-oriented NdGaO3 (NGO) substrates by the insertion of an SrTiO3 (STO)buffer layer.27 Chen et al. further demonstratedthat MA in the LSMO layer could be probed through the symmetry ofthe Mn 3d orbitals, where the 3dx2–y2 occupancy showed a direct relationship with in-planeanisotropy.26 However, the EB effect couldnot be explored on the LSMO/STO system due to the diamagnetic propertiesof the STO layers. Although it has been reported that the magneticeasy axis of La0.8Sr0.2CoO3/LSMObilayer can be rotated from the out-of-plane to in-plane (IP) directionvia ionic-liquid gating, thus simultaneously reducing and reversingthe exchange bias,28 it is not clear whichlayer contributes to the EB effect from bulk magnetometry. In thisstudy, we present a new approach of tuning the bulk-like LSMO (∼6 nm) easy axis from BMA to IMA by changing the thicknessof the underlying La2/3Sr1/3CoO3 (LSCO)layer in LSCO/LSMO bilayers deposited on (110)o-orientedNGO substrates and utilizing soft X-ray magnetic circular dichroism(XMCD) hysteresis loops to gain insight of the properties of eachlayer. This approach allows for enhanced control over the EB behaviorof the LSMO layer.Tuning the magnetocrystalline anisotropy (MA)of different layersin a heterostructure offers the potential to influence the EB effect.Among the perovskite oxides, La3)0.3(Sr2AlTaO6)0.7 (LSAT) substrates and demonstratedthat exchange spring behavior was observed where the hard LSCO layer(h-LSCO) biased a composite soft layer.20 This compositesoft layer consisted of an interfacial soft LSCO layer (s-LSCO) characterizedby magnetically active Co2+ ions and an LSMO layer. Thiss-LSCO layer arose due to the formation of oxygen vacancies and interfacialcharge transfer,24 and as a result, theEB effect was only found when the LSCO thickness (tLSCO) exceeded a critical thickness. Unlike the cubic-structuredLSAT substrates where the substrate/film lattice mismatch is equalalong the two orthogonal in-plane directions, a small difference (∼0.2%)of lattice mismatch between the two in-plane directions exists in(110)o-NGO substrates.29 In a recent study, LSCO/LSMO bilayers on NGO substratesshowed a similar Co ion distribution throughout the LSCO thickness:a nonmagnetic layer characterized by Co3+ ions at the LSCO/NGOinterface, a bulk-like h-LSCO layer with mixed Co3+/Co4+ ions in the middle of the layer, and an FM s-LSCO layerat the LSCO/LSMO interface.30 Moreover,the formation of the Co3+/Co4+ ions was suppressedas tLSCO decreased, leaving only an s-LSCOlayer with strong ferromagnetism. However, the interfacial exchangecoupling behavior and MA for the bilayers on NGO substrates were notexplored.In prior studies, we reported on the exchangecoupling in LSCO/LSMObilayers grown on  symmetry with the a–a–c+ tilt patternin the Glazer notation31 and can be redefinedas a pseudocubic (pc) unit cell with a slightly rectangular in-planelattice .29 The LSCO layer exists under in-plane tensilestrain  on NGOsubstrates, while the LSMO layer is under in-plane compressive strain on NGO substrates where the in-plane strainis defined as ε = (afilm –asubstrate)/asubstrate. The BMA of LSCO and LSMO single layers on (110)o-NGO substrates is along the a- ([001]o) and b- ([11̅0]o) directions, respectively,corresponding with the smaller in-plane strain induced by the substrate.29 Based on the results of XMCD hysteresis loopstaken at the Co and Mn L-edges, we found that theeasy axes for the LSCO layers were always aligned along the a-direction regardless of tLSCO. Surprisingly, the LSMO sublayer clearly saw a transitionfrom an easy axis along the a-directionfor tLSCO ≤ 4 nm, to the b-direction for larger tLSCO values, despite the fact that the LSMO sublayer thicknessremains fixed at 6 nm, suggesting the influence of a unique IMA thatdiffers from the bulk properties. As a consequence, for tLSCO ≤ 4 nm, no EB effect was observed along the a-direction, while a small negative EB shiftwas observed along the b-direction.For tLSCO > 4 nm, a large negativeEBshift was found along both a- and b-directions due to the differing in-planeMA between the LSCO and LSMO layers. The preferred direction of theMn 3dx2 – y2 orbital occupancy was measured by element-specificX-ray linear dichroism (XLD) and correlated to the in-plane MA ofthe LSMO layer. Therefore, the interfacial coupling between the LSCOand LSMO layers strongly influences the IMA of the LSMO layer, enablingthe control of EB between the two FM layers.In this work, epitaxial LSCO/LSMO bilayers were grownon (110)22.1O-orientedNGO substrates by pulsed laser deposition from stoichiometric La2/3Sr1/3CoO3 and La2/3Sr1/3MnO3 targets. The LSCO layer thickness was designedto range from 1 to 10 nm, capped with 6 nm of LSMO, referred to asbilayers CxM6N . The chamber was pumped toa base pressure of 2 × 10–6 Torr then subsequentlyfilled with flowing O2 gas to a fixed pressure of 300 mTorr.During the deposition, the substrate temperature was held at 700 °Cand a KrF excimer laser (λ = 248 nm), with 1.0 J/cm2 laser energy and 1 Hz laser repetition rate was used for both LSCOand LSMO layers. The bilayers were cooled to room temperature in 300Torr O2 at a rate of 10 °C/min to ensure proper oxygenstoichiometry.The LSCO/LSMObilayers were grown on (110)2.2α1 X-rays (λ= 1.5406 Å). The out-of-plane lattice parameters of the bilayerswere obtained by fitting the XRD profiles using Leptos software.32 Due to the similarities of the densities ofLSCO and LSMO, the bilayers were further characterized using resonantXRR (RXRR) measurements at Beamline 2–1 of the Stanford SynchrotronRadiation Lightsource (SSRL). RXRR profiles were measured at the Co K-edge (7730 eV), Mn K-edge (6558 eV),and an off-resonance energy (8000 eV). The higher sensitivity of RXRRmeasurements was able to probe the structural properties of each layerin the bilayers.33 By fitting the RXRRprofiles at three energies to one structural model using GenX software,34 the thickness, roughness, and density of eachlayer were determined.The structural properties of the bilayers  were characterizedby X-ray reflectivity (XRR), high-resolution X-ray diffraction (XRD),and reciprocal space maps (RSMs) using a Bruker D8 Discover four-circleX-ray diffractometer using Cu K2.3L-edges at 80 K using Beamline 4.0.2of the Advanced Light Source (ALS) in total electron yield (TEY) mode,which probes the top 5–10 nm of the bilayer (correspondingto the entire LSMO layer and LSCO/LSMO interface region), limitedby the escape length of secondary electrons.35 For the acquisition of the XMCD spectra, the bilayers were fieldcooled to 0.3 T to ensure that all magnetic moments are aligned alongthe field direction. During the measurements, a 0.3 T magnetic fieldwas applied parallel to the incident X-ray beam which was 60°from the surface normal, and XA spectra were collected using right-and left-circularly polarized X-rays. XMCD spectra were calculatedas the difference between two jointly normalized XA spectra collectedwith right (IR) and left (IL) circularly polarized X-rays. The XLD spectra were acquiredwith the X-ray beam perpendicular to the sample surface, and the directionof the linear polarization vector was oriented with E⃗//a and E⃗//b. The XLD spectra were calculated as thedifference of the XA spectra obtained with the two linear polarizationdirections. Bilayers were zero-field cooled to 80 K before all XMCDhysteresis loop measurements. Unbiased Mn-XMCD hysteresis loops , XMCD, and XLD spectra) were acquiredat the Co and Mn is loops 2a–d and is loops 2e were m334 to determinethe individual layer thickness, roughness, and density parameters.RXRR curves for bilayer C4M6N are shown in Table SI. A thin carbon capping layer was added to the fitting modeldue to the extended exposure to hard X-rays in air during the measurements.Kiessig fringes can be seen in all curves, indicating smooth surface/interfaceregions. The density of each layer at the interface region is lowerthan the bulk values as listed in Table SI, suggesting the formation of oxygen vacancies at the interface.37 The total thickness of each layeris in a good agreement with expectations and the fitting results agreewith our previous studies on LSCO/LSMO bilayers.24The LSCO/LSMO bilayers were characterizedby RXRR and the curveswere fit using GenX softwareo reflection of the NGO substrates.Curves are vertically shifted with tLSCO values ranging from 1 to 10 nm. The LSMO and LSCO (002)pc film peaks are on the left and right sides of theNGO substrate peak, respectively, due to the different strain statesbetween the film and the substrate. Though it is difficult to denotefilm positions because of the overlap between the two film peaks andthe substrate peak, the scans were fitted using Leptos software32 to obtain out-of-plane lattice parameter (c) and c/a ratio of each layer. Fit curvesare plotted in black, and the fitting results are listed in cLSMO/a values forthe LSMO layer are almost the same regardless of tLSCO but slightly larger than the values reported fora single-layer LSMO film on NGO substrates,39 suggesting that the underlying LSCO layer may affect the interfacialoctahedral tilt pattern/angles of the LSMO layer on top. For the LSCOlayer, an overall trend of increased cLSCO is observed as tLSCO decreased, whichcan be caused by a higher concentration of oxygen vacancies and Co2+ ions at the LSCO/LSMO interface24 which have a larger radius than Co3+ and Co4+ ions .41 The detailed information regarding Co ion spin and valence statesis discussed later in this article. RSMs were measured around the(103)pc and (013)pc reflections which are rotated by 90° from one anotherto probe the structural information along the two inequivalent in-planedirections of the orthorhombic NGO substrate. In tLSCO up to 10 nm.30 In addition, a small tilt is observed between the filmand substrate peak locations in the (103)pc RSM (marked as the white dashed line), indicating that the filmhas a unit cell angle deviation away from 90° along this direction.This deviation is only observed in the (103)pc RSM meaning that this angle variation is only occurring forone of the unit cell angles, resulting in monoclinic unit cells forthe LSCO and LSMO films on NGO substrates. The observed unit cellangle deviation has also been reported for other perovskite filmson orthorhombic substrates, such as SrRuO3 films on DyScO3 and GdScO3 substrates.43 Thus, the small tilt in the RSM suggests BO6 octahedralreconstruction at the heterostructure interfacial.45tLSCO, unbiased XMCD loops at the Mnand Co L-edges were acquired in TEY mode immediatelyafter zero field cooling to 80 K. Traditional bulk magnetometry cannotseparate the magnetic contributions of individual layers; however,by tuning the X-ray energies to either the Co or Mn L-edges enables such element-specificity from XMCD measurements. a- and b-directions with increasing tLSCO, and they provide information on the inherent LSMO magnetic anisotropywhile the LSCO layer is in the demagnetized state. The squarenessof these loops, defined as remanent magnetization (Mr)/saturation magnetization (Ms) is plotted in a-direction (about 0.9) than along the b-direction when tLSCO < 8 nm, indicating the magnetic easy axis of LSMO layer is alongthe a ([001]o) direction. However, the in-plane MA of the LSMO layer switchesto the b ([11̅0]o) direction when tLSCO increasesto 10 nm. For tLSCO = 8 nm, the loop shapeand squareness along a- and b-directions are almost equal,suggesting that either the magnetic easy axis lies between the a- and b-directionsor both in-plane directions are energetically degenerate. The trendof Mr/MS vs tLSCO along the two in-plane directions revealsthat the magnetic properties of the LSMO layer switch from IMA toBMA at a critical tLSCO of 8 nm. The tLSCO-dependent in-plane MA of the LSMO layeris shown schematically in o-NGO substrateis along the b-direction, due to slightlysmaller in-plane strain.29 The reorientationof the LSMO easy axis to the a-directionreveals that the strain state is no longer the dominant effect indetermining the LSMO MA. We propose that the interfacial interactionsbetween LSCO and LSMO layers plays a key role in explaining this behavior.To explore the in-plane MA of the LSMO and LSCO layers asa functionof L-edge weretaken along the a- and b-directions as shown in a-direction are much larger than those along the b-direction regardless of tLSCO as shown in a ([001]o) direction, which is in agreement with single layer LSCO onNGO substrates. In addition, a trend of increasing Hc (LSCO) as a function of tLSCO is observed ,similar to the behavior of single-layer LSCO on NGO and other substrates.46 Furthermore, in bilayers C1M6N and C4M6N, Hc (LSCO) is almost the same as Hc (LSMO) along the a-direction ), indicating that the LSCOand LSMO layers are magnetically coupled when tLSCO ≤ 4 nm. It has been reported thatLSCO and LSMO layers were fully magnetically coupled when tLSCO was below a critical thickness, as indicatedby a single magnetic switching event from bulk magnetometry.30 This interfacial coupling results in an increase of Hc (LSMO) values as shown in Figure S1 compared to that of single-layer LSMOon NGO and other substrates. Along the a-direction, Hc (LSMO) = 0.13 T in bilayerC4M6N, which corresponds to an enhancement of more than 60 times whencompared to the bulk value (∼0.002 T)48 and more than six times compared to the thickest bilayer C10M6N(∼0.02 T). Hc enhancement is commonlyobserved in FM/AFM systems due to the pinning effect50 or caused by the presence of defects in the FM sample48 but has not been widely studied in FM/FM perovskitesystems. Therefore, the modification of Hc values and change in the LSMO MA through interfacial coupling couldaffect the EB effect in LSCO/LSMO heterostructures.Similar unbiased XMCD loops at the Co a- and b-directions after zero-field cooling to 80 K as shown in L-edge, the bilayers were first biased at+1.8 T or −1.8 T so that both layers reach full saturation,then minor loops were measured between ±0.3 T. L-edge measured along the a-direction with tLSCO ranging from 1 to 10 nm. For tLSCO ≤ 4 nm, the absence of an EB effect in bilayersC1M6N and C4M6N along the a-direction,as observed by perfectly overlapping minor loops, can be attributedto the same MA and the magnetic coupling between the hard/soft FMlayers. Conversely, a small EB effect is observed along the b-direction in the two thinner bilayers ). For bilayers with tLSCO > 4 nm,asignificant lateral shift of the hysteresis loops in the directionopposite to the biasing field is observed along both in-plane directionsdue to the different in-plane MA and larger difference in Hc values between the LSCO and LSMO layers, resultingin a large EB effect. Such behavior indicates that the magnetic momentsof the soft LSMO layer are pinned by a hard FM layer, and the interfacialFM/FM exchange coupling is similar to the behavior at FM/AFM interfaces.52 Unfortunately, experimental limitations due to the extremely lowluminescence yield of NGO substrates30 andthe finite probing depth of TEY detection mode35 prevent us from acquiring reliable biased Co-XMCD loopsfrom the buried LSCO layer.The exchangebias effect of the LSCO/LSMO bilayers is exploredusing biased XMCD hysteresis loops measured in TEY mode along the shownin 4e,f, cauHc values fromMn-XMCD minor loopsand exchange bias field (HEB) values asa function of tLSCO are plotted in HEB values were found to increase as a functionof tLSCO, where HEB is defined as HEB = |(H1 + H2)/2|, and H1 and H2 are thevalues where the hysteresis loop intersects the left and right fieldaxes, respectively. In EB systems, the expectation is that HEB and Hc shouldshow similar trends.53 However, a reversedtrend of HEB and Hc is observed in HEB and Hc, and the enhancement of Hc values in LSCO/LSMO bilayers was previouslyreported, where the decrease in interfacial Co2+ ion concentrationand an increase of nonmagnetic Co3+/Co4+ ionswas observed with increasing tLSCO.23 Here we propose a similar tLSCO dependence of the hard/soft magnetic interfacialinteractions related to the details of the Co valence states in theLSCO layer, as discussed below.The L-edge XA spectra as shown in 2O4 (Co2+) and a single-layer LSCO film (mixedCo3+/Co4+), both in octahedral coordination,are plotted in Figure S2 for comparisonto the bilayer spectra. The Co-XA spectra of bilayer C1M6N shown in 2+ ions. For the thickest bilayerC10M6N, the Co-XA curve fully assembles the single-layer LSCO referencespectra where mixed Co3+/Co4+ ions dominateas shown in tLSCO increases to 8 nm, the prepeak intensity(shaded in pink color) decreases and fully disappears when tLSCO = 10 nm; (2) the intensity ratio of thedoublet peak (marked with “▼”) reduces as tLSCO increases from 1 to 4 nm; and (3) the Co-L3 peak positions shift to higher energies as tLSCO increases. These gradual changes in XAspectral shape indicate that the valence state of Co ions is graduallychanging from Co2+-dominated to mixed Co3+/Co4+-dominated with increasing tLSCO, which is consistent with the results in previous work.30 This tLSCO dependence again supports the result of decoupling of HEB and Hc, and the enhancementof Hc values in the LSMO layer as shownin 23Co ion valence states and bondingconfigurations in the bilayerswere probed by Co 2+ ions dominate is much stronger than thicker bilayers where mixedCo3+/Co4+ ions predominate, suggesting thatthe Co2+ ions are in a high spin state.54 Moreover, the decrease of Co-XMCD intensity as tLSCO increases from 1 to 8 nm indicates that the numberof Co2+ ions does not increase with tLSCO but rather is replaced by mixed Co3+/Co4+ ions that have lower magnetization. The existence of highspin Co2+ ions (larger ionic radius) in thinner bilayersis also supported by the observation of c-latticeexpansion shown in 2+ ions cannot be explainedby the charge transfer between Co and Mn ions due to the fact thatthe valence state of Mn ions stays almost unchanged with tLSCO as shown in Figure S3,thus we propose the contribution from oxygen vacancies at the LSCO/LSMOinterface to maintain charge neutrality.30Figure S4 displays the O K-edge spectra from the LSCO/LSMO bilayers, revealing a decreasingtrend of peak A  and an increasing intensity of peak B  with increasing LSCO thickness.56 These observations suggest the presence of more oxygen vacanciesin the thinner bilayers.The Co-XMCD spectra denote magnetically activeCo ions in the bilayers.The XMCD signal from bilayers C1M6N and C4M6N where Cod orbitaloccupancy in transition metal oxides which shows a direct correlationto MA.58 Here, we focuson probing the 3dx2–y2 occupancy because ofits direct relationship with in-plane anisotropy. Mn-edge XA spectrawere taken with X-rays perpendicular to the sample surface, whilethe polarization vectors have the geometry of E⃗//a and E⃗//b, as shown schematically in 59 but we can rule out the contribution from AFMordering because of the bulk-like ferromagnetic behavior of the LSMOlayer. The samples were demagnetized before the measurements, andno magnetic field was applied during the measurement. L-edge XA/XLD spectra measured along the a- and b-directions of bilayers C1M6Nand C10M6N, respectively. XLD was calculated as the difference betweentwo XA spectra (IXLD = Ia– Ib). The integrated areaunder XLD spectra (AXLD) around the Mn-L2 peak (from 649 to 660 eV) represents the preferreddirection of Mn 3dx2–y2 orbital occupancy.26 The negative AXLD from bilayer C1M6N reveals enhanced electron occupancy along the a-direction that aligns well with the magneticallyeasy axis of the LSMO layer. In contrast, a positive AXLD in bilayer C10M6N indicates favored electron occupancyalong the b-direction with the LSMOeasy axis along the same direction. To examine the relationship betweenin-plane electron occupancy and the magnetic easy axis, Co-edge XA/XLDspectra were taken on bilayer C1M6N under the same conditions. Theeasy axis of the LSCO layer was along the a-direction, while AXLD aroundthe Co-L2 peak (from 792 to 805 eV) wasnegative as shown in Figure S5. As a result,both Mn- and Co-edge XLD spectra reaffirm the direct correlation betweenthe 3dx2–y2 orbital occupancy and in-plane MA.Finally, XLD is an elemental-sensitivemeasurement technique fordetermining the preferred direction of 36 octahedral rotation and strain has been identifiedas theprimary factor that governs the MA of perovskite oxide heterostructures.43 In our study, no strain relaxation was observed with an increasein tLSCO from 1 to 10 nm. The LSCO layermaintains its magnetic easy axis along the a-direction, as the tensile strain state is smaller along thisdirection (0.57%) compared to that along the b-direction (0.78%). Conversely, we found that the BO6 octahedra at the heterostructure interface play a significant rolein determining the LSMO magnetic easy axis when tLSCO ≤4 nm. In contrast to the rhombohedral structurein bulk LSCO and LSMO, LSCO/LSMO bilayers exhibit a monoclinic distortion,leading to biaxially anisotropic B–O bond lengths, therebyinducing symmetry breaking of the Mn 3dx2–y2 orbitals. The presence of Co2+ ions, which have a largerionic radius, and oxygen vacancies can offer more degrees of freedomfor octahedral rotation, thus eliminating the strain effect at theinterface. Moreover, the FM exchange coupling between the soft LSCOand LSMO layers promotes the alignment of the LSMO easy axis to theLSCO easy axis, resulting in enhanced total magnetization of the LSCOlayer and enhanced cH values of the LSMOlayer. With further increase in tLSCO beyond4 nm, the concentration of Co2+ ions in the interface regiondecreases and the strain effect becomes the predominant factor influencingthe MA of the bilayers. Consequently, the easy axis of the LSMO layerswitches from IMA back to BMA, leading to a pronounced EB effect.Consistent with previous studies, the competitionbetween BO4tLSCO ≤ 4 nm, no EB effect is observedalong the a-direction due to the stronginterfacial magnetic coupling between the two layers that share thesame in-plane magnetic easy axis and Hc values. However, along the b-direction,a small negative exchange bias shift is observed because of the small Hc difference between the two layers. As tLSCO increases beyond 4 nm, the EB effect appearsdue to the difference in MA of the two layers, causing the easy axisof the LSMO layer to rotate back to the [11̅0]o direction as in bulk LSMO. With direct correlation to in-planeanisotropy, Mn-edge XLD spectra show different electron occupancyalong the two in-plane directions with increasing tLSCO. Thus, the interfacial exchange coupling betweenthe LSCO and LSMO layers facilitates the rotation of the LSMO easyaxis, allowing for the control of the MA and EB between the two FMlayers. Moreover, the ability to manipulate the MA of FM heterostructures,leading to thickness-dependent properties, makes magnetic perovskiteoxide heterostructures promising candidates for next-generation spintronicand magnetic memory devices.In conclusion, MA of a bulk-like LSMO thinfilm can be tuned byadjusting the thickness of the underlying LSCO layer in LSCO/LSMObilayers grown under biaxial strain on NGO substrates. For


Out of pocket (OOP) costs vary substantially by health condition, procedure, provider, and service location. Evidence of whether this variation is associated with indicators of healthcare quality and/or health outcomes is lacking.The current review aimed to explore whether higher OOP costs translate into better healthcare quality and outcomes for patients in inpatient settings. The review also aimed to identify the population and contextual-level determinants of inpatient out-of-pocket costs. A systematic electronic search of five databases: Scopus, Medline, Psych Info, CINAHL and Embase was conducted between January 2000 to October 2022. Study procedures and reporting complied with PRISMA guidelines. The protocol is available at PROSPERO (CRD42022320763).A total of nine studies were included in the final review. A variety of quality and health outcomes were examined in the included studies across a range of patient groups and specialities. The scant evidence available and substantial heterogeneity created challenges in establishing the nature of association between OOP costs and healthcare quality and outcomes. Nonetheless, the most consistent finding was no significant association between OOP cost and inpatient quality of care and outcomes.The review findings overall suggest no beneficial effect of higher OOP costs on inpatient quality of care and health outcomes. Further work is needed to elucidate the determinants of OOP hospital costs.This study was funded by Medibank Better Health Foundation.The online version contains supplementary material available at 10.1186/s12913-023-09941-3. Rising healthcare costs, coupled with changing healthcare needs, have led to patients being increasingly required to either fully, or partially, cover the cost of their healthcare . As a coRising OOP costs are recognised as a critical healthcare challenge. Several studies indicate that high OOP costs are associated with underutilisation of necessary healthcare services, lower treatment adherence, and increased hospitalisation and emergency department visits –11. ForgThe amount and nature of OOP payments varies considerably across countries and healthcare systems . In geneGiven the degree of burden imposed by OOP costs on consumers, it is imperative to understand the evidence available on the association between OOP costs and quality of care, particularly in hospital settings that attract higher OOP costs. It will also be beneficial to identify which characteristics make patients more vulnerable to OOP payments. Accordingly, the purpose of this systematic review is to synthesise and report evidence of the association between OOP costs and healthcare quality and health outcomes in inpatient settings to inform healthcare policy and consumer decision making. Specifically, the review aimed to examine whether higher OOP costs translate into better healthcare quality and outcomes for patients, in addition to identifying the population and contextual level factors that may contribute to the level of OOP cost incurred. The following research questions were addressed: 1. To what extent is there an association between OOP costs and care quality and health outcomes? 2. What population and contextual factors are associated with higher OOP costs?This review is reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) . The proStudies were eligible for inclusion if they used an observational or experimental design to examine the effects of OOP costs on quality and health outcomes in inpatient settings. OOP costs were defined as payment for inpatient medical care that was not covered by universal health insurance, private insurance or any other similar sources . OOP cosHealthcare quality outcomes investigated were care complications, unplanned readmissions within 28 days, and unintended intensive care unit (ICU) admissions. Health outcomes investigated were quality of life, function, disability, in-hospital death, and prolonged hospital length of stay (LOS). Prolonged hospital LOS was defined as a hospital stay longer than the 75th percentile of the entire sample .Studies were selected for inclusion if they were published in peer-reviewed journals, since 2000 and in English. Studies that examined OOP cost and quality in primary care settings, prescription-related OOP costs or OOP costs and treatment adherence were excluded. In addition, non-peer-reviewed articles, commentaries, case reports and conference abstracts were also excluded.BMJ Quality & Safety, were applied. Endnote reference management software (Endnote 20.2.1) was used for storing extracted studies and Covidence systematic review software was used for data screening.A systematic search of the academic literature was conducted between January 2000 to October 2022 using five electronic databases, namely Scopus, Medline, Psych Info, CINAHL and Embase. The search strategy was developed using the key concepts of OOP costs and healthcare quality and outcomes by developing keywords, synonyms and phrases. An initial search was carried out in Medline to identify all the possible synonyms of the main concepts included in the study. Table n = 2,795). In the third stage, 49 eligible articles were independently examined in full for their inclusion. Final agreement was made by consensus between the three reviewers. Any discrepancy between the reviewers was discussed and settled by the two further team members . RH and RM conducted a face validity check on the final set of included articles  involved in all the three stages. In the first stage, 3,483 identified studies were exported into Endnote and 639 duplicates were removed. In the second stage, titles and abstracts of the remaining 2,844 articles were reviewed for their eligibility for inclusion. Those studies considered not to be relevant were excluded  checklist , 34. TheThe information on the included articles in the data table were compared using a narrative empirical synthesis as a quantitative synthesis was deemed inappropriate due to the heterogeneity in the study design, population, OOP cost measurements and the outcome measures investigated. The narrative synthesis involved discussing the tabulated data by the team members and identifying the patterns of associations and consistent findings in terms of study objectives. Further exploration aimed to identify the relationships between study characteristics and findings, and the influence of different OOP measures and outcome measures and study settings on the findings.A total of nine studies were included in the review Table . Three wAdditional file A variety of quality and health outcomes were explored in the included studies in a range of healthcare contexts. The small number of studies and heterogeneity in the patient populations and outcomes explored created challenges for drawing out common findings between the studies, but several associations between OOP cost and quality were identified. The review identified fourteen associations between OOP costs, healthcare quality and patient health outcomes from the nine studies. These included associations examining multiple measures of OOP costs, quality of care as well as the differential analyses. Nearly two thirds (9/14) did not identify a significant relationship between OOP costs and healthcare-related quality and outcomes.Four studies examined the association between OOP costs and health-related quality of life (HRQoL) , 43, 45.Three included studies reported on associations between OOP costs and hospital LOS , 39, 42.Outcomes beyond length of stay that captured quality of care were examined in three studies. One study examined quality of care determined by the number of health checks performed and care complications experienced following birth , anotherDeterminants of OOP costs were examined in four studies , 44, 45.OOP costs were reported to be higher among individuals who were young adults (18 – 24 years) and also those who had higher monthly income (US $150 or higher) among patients using maternity services . ConversIndividual studies reported OOP costs as higher among individuals who had a higher level of education , who lived in urban areas as opposed to rural, by the level and type of health facility used  and by patients requiring more treatment numbers  , 45. StaMedical Costs Finder website that lists the median OOP costs for a selected specialities, services and regions [hospital price transparency policy in the US requires hospitals to disclose all payer specific negotiated rates for all items and services in a consumer-friendly manner [Health consumers around the world are increasingly seeking evidence to inform their decision-making regarding healthcare provider selection based on cost and quality information , 47. Imp regions . Similary manner . Privatey manner . HoweverThe current review identified nine eligible studies, indicating a paucity of evidence. The studies identified were heterogenous in terms of the population, health systems and outcomes investigated. Despite the critical need for evidence on the nature of the relationship between OOP cost and quality of care, the scant evidence available and substantial heterogeneity creates challenges in establishing the nature of any association between OOP costs and healthcare quality and outcomes. Nonetheless, the most consistent finding was no significant association between OOP cost and inpatient quality of care (nine out of fourteen associations). A previous systematic review looking at hospital cost or hospital price which focussed only on the quality of inpatient care reported no general relationship between hospital cost/price and quality .A negative association of OOP costs on patient health outcomes  were notable in studies exploring HRQoL in cancer and chronic kidney disease. In the context of cancer and chronic conditions, advanced stages, greater complexity and care requirements that are beyond the scope of private health fund allocation, could potentially be the contributing factors. Another potential explanation could be the association between financial burden caused by higher OOP costs imposed by these conditions and HRQoL –54.Longer LOS in hospital is often considered an indicator of poorer quality of care and health outcomes , 56. YetThe current review identified limited evidence in relation to the determinants of OOP costs and the quality of care. Age was the only variable explored across more than one study. Diverse study populations and clinical conditions demonstrated mixed findings with regards to age. OOP costs were reported to be higher in younger individuals accessing maternity services and among older patients who underwent elective hip arthroplasty procedure. A mixed association of age with catastrophic OOP costs depending on the clinical condition and complication levels were also reported by a previous systematic review looking at factors associated with the burden of household healthcare expenditures in Ethiopia .Health care delivery systems across the world are structured and financed differently and this may have an impact on the OOP cost-quality association. The degree of regulation between public and private systems is one of the main determinants of OOP costs and may have implications for health care quality. For example, in the US, lacking universal health insurance, multimorbid patients are reported to spend less time in hospital and are discharged quickly to rehabilitative facilities leading to longer combined LOS across acute and non-acute facilities compared to countries with more generous long‐term hospital coverage such as Canada, Sweden, and Spain . SimilarThis review is one of the first to synthesise information from the existing evidence to explore the association between OOP costs and healthcare quality and patient health outcomes in inpatient settings. Strengths include a systematic search strategy involving multiple data sources and reporting according to PRISMA guidelines. The findings have limitations including the low number of eligible studies available. A quantitative synthesis was not possible for this review due to the heterogeneity of the included studies. It is possible that some relevant studies were not captured by the search strategy. There remains a possibility of publication bias because non-English publications were omitted, and the grey literature was not searched. In addition, the focus of the review, specifically examining studies looking at the association between OOP cost and quality of inpatient care, could have resulted in not capturing studies examining general determinants of OOP costs.This review suggests no beneficial effects of higher OOP costs on inpatient quality of care and health outcomes. The review provides indicative evidence that the association of OOP costs and healthcare quality is likely to be influenced by the health conditions examined, the population case-mix and the healthcare context, particularly regarding an individual’s health insurance status. The different healthcare policies and health system funding models may have an impact on the OOP cost-quality association. There is also potential to further explore the determinants of OOP costs to aid in identifying populations who face the greatest OOP costs and focus research and policy action on these groups to reduce the financial burden imposed by high OOP costs.Additional file 1: Table S1. Quality assessment of selected studies using CASP cohort checklista. Table S2. Quality assessment of selected studies using CASP RAT checklistb.


Cardiac implantable electronic devices (CIED) are being inserted with increasing frequency. Severe surgical site infections (SSI) that occur after device implantation substantially impact patient morbidity and mortality and can result in multiple hospital admissions and repeat surgeries. It is important to understand the costs associated with these infections as well as healthcare utilization. Therefore, we conducted a population-based study in the province of Alberta, Canada to understand the economic burden of these infections.International Classification of Diseases (ICD) codes to identify complex (deep/organ space) SSIs that occurred within the subsequent year was applied to the cohort. The overall mean 12-month inpatient and outpatient costs for the infection and non-infection groups were assessed. In order to control for variables that may influence costs, propensity score matching was completed and incremental costs between those with and without infection were calculated. As secondary outcomes, number of outpatient visits, hospitalizations and length of stay were assessed.A cohort of adult patients in Alberta who had CIEDs inserted or generators replaced between January 1, 2011 and December 31, 2019 was used. A validated algorithm of There were 26,049 procedures performed during our study period, of which 320 (1.23%) resulted in SSIs. In both unadjusted costs and propensity score matched costs the infection group was associated with increased costs. Overall mean cost was $145,312 in the infection group versus $34,264 in the non-infection group. The incremental difference in those with infection versus those without in the propensity score match was $90,620 . Approximately 70% of costs were driven by inpatient hospitalizations. Inpatients hospitalizations, length of stay and outpatient visits were all increased in the infection group.CIED infections are associated with increased costs and are a burden to the healthcare system. This highlights a need to recognize increasing SSI rates and implement measures to minimize infection risk. Further studies should endeavor to apply this work to full economic evaluations to better understand and identify cost-effective infection mitigation strategies.The online version contains supplementary material available at 10.1186/s13756-023-01347-4. Cardiac Implantable Electronic Devices (CIEDs) are being prescribed with increasing frequency due to expanding indications and advances in technology . These dPrior studies assessing the economic burden of CIED infections have generally relied on the use of administrative data or insurer databases as the methods of tracking infection. However, these methods have not been adequately validated , 10, 11.The primary objective of this study was to assess the attributable cost of CIED infections in a Canadian population that was identified using validated administrative data as a method to track infections. The secondary objectives of this work were to explore healthcare utilization associated with CIED infections including length of stay (LOS) in hospital, number of admissions, and outpatient visits.This was a population-based cohort study in Alberta, Canada, a province of ~ 4 million people with a single healthcare system, Alberta Health Services (AHS), that included all patients who underwent CIED implantation, including those who subsequently developed a SSI. Patients were identified using a centralized CIED database (Paceart™) and these data were linked to AHS health administrative data that captures patient comorbidities and healthcare costs.International classification of Diseases 10th revision Canada (ICD-10-CA) codes  that were previously validated as able to identify complex CIED SSIs  with sensitivity and specificity > 90% [We identified a cohort of adult patients  who underwent a new CIED implantation (including pacemaker (PM), implantable cardioverter defibrillator (ICD), or cardiac resynchronization therapy (CRT)) or generator replacement between January 1, 2011, and December 31, 2019. The infection group was identified using Discharge Abstract Database (DAD) and ty > 90% . All infCIED implantations were identified using the Paceart™ database which contains all device-related clinical encounters for patients followed within the province of Alberta, Canada. Paceart™ contains information regarding indications for device implantation, type of device, date of operation and basic demographic information including sex. Repeat procedures within a two-year period from the index surgical date were censored. This avoided double counting patient encounters months later as only the initial implant was counted as an index procedural date.AHS analytics data which provides healthcare information on all Alberta residents with an Alberta Health Care Insurance Plan  was used. This data repository provided records from both DAD which was used for tracking infection cases as described above. Both DAD and the national ambulatory care reporting system  were used to obtain demographic information about the patient cohort including comorbidities which were collected using a two-year retrospective review. Rural versus urban location and the Pampalon Deprivation Index was collected as well. The Pampalon Deprivation Index is a composite index using Canadian census data in order to create a measure of socioeconomic disparity,  and urbaA mix of gross costing and micro-costing was used to assess economic burden. Gross costing was used where micro-costing was not available . Gross costing is when aggregate resource use items are identified and expenditure data is collected at the organization level. Gross costs were identified from DAD and NACRS using resource intensity weights (RIW) for any healthcare encounter and were multiplied by the cost of a standard hospital stay (CSHS) in Alberta by year from the Canadian Institute for Health Information .Micro-costing data was available from AHS corporate finance for all inpatient admissions in Calgary and Edmonton. This is considered the gold standard of costing data. Patient level costs are provided and each component of resource use is estimated and a unit cost derived providing the most specific costing information possible . This daThe primary outcome was mean 12-month cumulative healthcare costs for all patients who had a CIED implant or generator replacement. Costs were also stratified into inpatient and outpatient costs. Additionally, healthcare utilization including number of inpatient and outpatient visits to any AHS facility were considered as well as LOS in hospital over 12 months. All outcomes were compared amongst those who did and did not develop a complex CIED SSI. All costs were inflated to 2022 Canadian dollars. The perspective taken was that of the pubic healthcare payer and therefore, patient-borne costs such as outpatient antibiotic prescriptions, were not included. Physician claims were not accessed for this work and thus were not included.Descriptive statistics, such as frequencies and percentages for categorical variables and means with standard deviation (SD) for continuous variables were used to describe baseline characteristics of patients with and without infections. For our primary method, we assessed the total mean costs, inpatient costs, and outpatient costs for all patients at one year after the index date of their implantation. Number of inpatient admissions, outpatient visits and total LOS were analyzed for all patients over the subsequent one year.In order to adjust for covariates, a propensity score match was conducted for comparing CIED patients who developed a complex SSI within one year of implantation to those who did not develop an infection. Propensity scores were estimated using a logistic regression model with observed baseline characteristics of age, sex, Elixhauser comorbidity index  and deviAs a sensitivity analysis we conducted generalized linear models (GLM) to identify the relationship between the outcomes and infection. We used GLM with Gamma distribution and a log link function for the costs, GLM with Poisson distribution and a log link for number of hospital admissions, LOS, and number of outpatient visits.All statistical analyses were performed using R Statistical Software (Version 1.4.0). This research was approved by the University of Calgary Health Research Ethics Board (REB20-2186).All patient characteristics are listed in Table Following propensity score matching, one infected patient did not have a match leading to a matched cohort of 319 (319 non-infection and 319 infection). Baseline characteristics between patients with and without infection were well balanced after matching on propensity score, as demonstrated by the standardized mean differences Table .Patients with infection had substantially more total mean costs at one year $145,312 (Standard deviation (SD) 188,279) compared to those without infection, $34,264 . These costs were largely driven by inpatient costs which accounted for 70% and 72% of costs in the non-infection and infection group, respectively . Again, this was caused mainly by inpatient costs with a mean incremental difference of $90,620  compared to a mean incremental difference of $3,508  for the outpatient costs (Table p < 0.001) and incremental costs of $49,350 for those that had a CRT compared to PM (p < 0.005). There were no significant differences in costs when looking specifically at hospital center or Pampalon deprivation index classification.Further sensitivity testing using GLM and including the variables of infection, device type, the five separate hospital centers of care for CIED implantations, and Pampalon deprivation index with an outcome of mean total 12 month costs, again demonstrated increased costs in the infection group. There was an additional $94,500 in costs for the infection group compared to non-infection group  surveillance is one known strategy to monitor rates of infection and the impact of infection reduction strategy . This tyStaphylococcus aureus (a common causative pathogen for infection), appropriate preoperative antibiotics and hand hygiene [A strategy to reduce complex SSIs may include IPC interventions such as perioperative bundles including pre-operative checklists, decolonization for  hygiene . A recen hygiene . More no hygiene . The worAs noted previously, the majority of costs associated with complex SSIs post-CIED implantation were found to be driven by inpatient hospitalizations with prolonged LOS. This is in keeping with previous literature demonstrating that prolonged hospitalizations are drivers of increased costs . This maThis work is unique in that it used validated administrative data to track complex SSIs that occurred after CIED implantation . This suThere are limitations that must be addressed. Infections were only tracked for one year, therefore complex SSIs occurring very late would not have been captured. There is always the possibility of errors in administrative data which relies on human coding. However, this provides one of the only ways to complete large population-based studies which would otherwise be prohibitively expensive and difficult. There are concerns associated with propensity score matching. One infection was excluded as a match could not be found; however, we do not believe that this introduced selection bias. There may be unobserved confounders that could influence the pairs and lead to bias in the matching, as all relevant differences may not be accounted for. Microcosting data was not available for all patients and given that many patients without infection were not re-admitted to hospital there would be more microcosting data available for the infection group. However, previous work on microcosting versus gross costing data specifically in Alberta exploring cardiac care demonstrated that microcosting and RIW performed similarly somewhat mitigating any risk of this discrepancy influencing costing outcomes . FinallyThis work has demonstrated the substantial economic burden associated with CIED complex SSIs. Largely driven by hospital admissions and prolonged LOS, these costs demonstrate a need to mitigate infection risk and work toward strategies for prevention. Now that the foundation has been completed through assessment of economic burden, these findings can be applied to future studies exploring cost-effectiveness for different infection prevention strategies. This work would be of relevance to healthcare providers, guideline development committees and policy-makers. Further studies should be completed in larger populations and explore individual factors contributing to increased costs in complex CIED SSIs, such as individual comorbidities, comorbidity indices and causative pathogens.Below is the link to the electronic supplementary material.Supplementary Material 1


Retrospective investigation of archived tissue samples from 3 lions displaying nonsuppurative meningoencephalitis and vasculitis led to the detection of rustrela virus (RusV). We confirmed RusV antigen and RNA in cortical neurons, axons, astrocytes and Purkinje cells by reverse transcription quantitative PCR, immunohistochemistry, and in situ hybridization. Rubivirus and the family Matonaviridae (Felis catus) showing clinical signs of staggering disease in Germany, Austria, and Sweden (Apodemus flavicollis) and wood mice (Apodemus sylvaticus) are assumed to be reservoir hosts of RusV , an RNA virus with single-stranded RNA genome of positive orientation, was considered the only virus of the genus Panthera leo) and tigers (Panthera tigris) kept in zoological gardens in Germany . The lack of viral RNA detection by ISH in the brain of lion 1, positive by qRT-PCR, could be a result of lower sensitivity of ISH (Immunohistochemical investigation for dsRNA revealed positive results in the brains of all investigated lions, regardless of their RusV infection status. Although it is possible that the RusV-negative lions were infected by other neurotropic RNA viruses, this scenario appears unlikely because no CNS lesions were observed in control animals 4–11. Thus, this method appears unsuitable for reliable detection of viral dsRNA in the brains of lions and perhaps other animals.In summary, our study reveals that RusV was present in northern and western Germany in the 1980s. Detecting RusV in lions indicates an even broader host range of RusV, encompassing a variety of different species (Additional information on rustrela virus as putative cause of nonsuppurative meningoencephalitis in lions.


The transmission of viral aerosols poses a vulnerable aspect in the biosecurity measures aimed at preventing and controlling swine virus in pig production. Consequently, comprehending and mitigating the spread of aerosols holds paramount significance for the overall well-being of pig populations. This paper offers a comprehensive review of transmission characteristics, influential factors and preventive strategies of common swine viral aerosols. Firstly, certain viruses such as foot-and-mouth disease virus (FMDV), porcine reproductive and respiratory syndrome virus (PRRSV), influenza A viruses (IAV), porcine epidemic diarrhea virus (PEDV) and pseudorabies virus (PRV) have the potential to be transmitted over long distances (exceeding 150 m) through aerosols, thereby posing a substantial risk primarily to inter-farm transmission. Additionally, other viruses like classical swine fever virus (CSFV) and African swine fever virus (ASFV) can be transmitted over short distances (ranging from 0 to 150 m) through aerosols, posing a threat primarily to intra-farm transmission. Secondly, various significant factors, including aerosol particle sizes, viral strains, the host sensitivity to viruses, weather conditions, geographical conditions, as well as environmental conditions, exert a considerable influence on the transmission of viral aerosols. Researches on these factors serve as a foundation for the development of strategies to combat viral aerosol transmission in pig farms. Finally, we propose several preventive and control strategies that can be implemented in pig farms, primarily encompassing the implementation of early warning models, viral aerosol detection, and air pretreatment. This comprehensive review aims to provide a valuable reference for the formulation of efficient measures targeted at mitigating the transmission of viral aerosols among swine populations. The significance of biosecurity in farms is increasingly acknowledged due to the significant challenges posed by the ASFV to the global pig industry, particularly in Asia, where conventional interventions such as vaccines or drugs have proven ineffective in addressing these issues , 2. In tBioaerosols, characterized by the presence of small droplets or particles measuring less than 5 μm suspended in a gaseous medium, possess the capacity to transport pathogenic microorganisms and facilitate the transmission of diseases . The preThis review comprehensively summarizes the latest characteristics of aerosol transmission for various common swine viruses Table , includiIn this section, we summarize the characteristics and influential factors of aerosol transmission of various prevalent swine viruses. The transmission distance of viral aerosols holds significant importance, as evidenced by a scholarly report suggesting that a spatial separation exceeding 150 m between structures can effectively mitigate the risks associated with airborne transmission . ConsequAphthovirus genus within the Picornaviridae family, is an enveloped, single-stranded positive-sense RNA virus with a diameter of approximately 26 nm. It primarily causes vesicular diseases affecting the oral mucosa, hoof parts, and udder skin in pigs, cattle, and sheep, which is also a zoonotic disease [3 TCID50 [5.8–106.4 TCID50 of the virus into the air within a 24-h period [FMDV, belonging to the  disease . The air disease –16. Thes disease . Moreove disease . It is b disease , 17, 19.3 TCID50 , 21. And3 TCID50 , 23. An 3 TCID50 . Under eh period . FurtherArterivirus genus within the Arteriviridae family, is an enveloped, single-stranded positive-sense RNA virus with a diameter of approximately 60 nm. It primarily causes reproductive disorders in sows and respiratory difficulties in piglets [Mycoplasma hyopneumoniae (MHYO) 232, and the air samples collected at a distance of 9.2 km from the pig population remained infectious [Actinobacillus pleuropneumoniae exhibited an increased frequency and duration of sneezing and coughing, indicating a higher potential for aerosol transmission of pathogens [2 (0.4–0.7 μm) to 5.1 × 104 (9.0–10.0 μm) copies/m3 [PRRSV, belonging to the  piglets . Researc piglets , 29, whe piglets . The pri piglets . Researc piglets , 33. On fectious . Additioathogens . Other iopies/m3 . The halopies/m3 , which iInfluenza A genus within the Orthomyxoviridae family, is an enveloped single-stranded negative-sense RNA virus with a diameter of 80–120 nm. It primarily causes a zoonotic respiratory disease characterized by coughing, respiratory distress, and fever [4–107 copies/m3), persisting for 20 days [IAV, belonging to the nd fever . The airnd fever . And, IA 20 days . Further 20 days , indicat 20 days . Under e 20 days .There is a limited amount of literature available regarding the aerosol transmission factors impacting swine influenza virus. Nevertheless, there exists a substantial body of research on other species that can be utilized as a point of reference. The primary factors influencing the capacity of IAV airborne transmission are viral strains, environmental conditions, and sizes of aerosol particles. Mubareka et al.  discoverCoronavirus genus within the Coronaviridae family, is an enveloped, single-stranded positive-sense RNA virus with a diameter of approximately 95-190 nm. It primarily causes severe enteric diseases with high mortality and watery diarrhea in 7-day-old piglets [6 (0.4–0.7 μm) to 3.5 × 108 (9.0–10.0 μm) copies/m3, and the aerosols with viral particles can survive in the environment for up to 9 months [7 PFU/mL) resulted in typical PED symptoms in 5-day-old piglets [PEDV, belonging to the  piglets , 50. Aer piglets . The aer piglets . PEDV ca9 months , 53. Res9 months . Further9 months . Li's re piglets . However piglets .Varicellovirus genus within the Herpesviridae family, is an enveloped double-stranded DNA virus with a diameter of approximately 225 nm. It primarily causes an acute infectious disease characterized by high fever, abortion, and neurological symptoms not only in pigs, domestic livestock, and various wild animals [5.3 TCID50 within 24 h [PRV, belonging to the  animals . Donalds animals . Each PRhin 24 h . Grant ehin 24 h . Under fhin 24 h –62. HowePestivirus within the Flaviviridae family, is an enveloped, single-stranded positive-sense RNA virus with a diameter of 24–26 nm. It mainly causes acute fever and bleeding in pigs [1.2 to 103.0 TCID50/m3 (moderate virulence) to 101.6–103.8 TCID50/m3 (high virulence) [CSFV, belonging to the genus  in pigs . A study in pigs . Gonzale in pigs . Lu et a in pigs . Two stu in pigs , 68. Wee in pigs . Additiorulence) . Moreoverulence) .Asfivirus genus within the Asfarviridae family, is an enveloped double-stranded DNA virus with a diameter of approximately 200 nm. It is also the only known DNA arthropod-borne virus [3.2 TCID50/m3 found in aerosol samples collected from rooms with ASFV-positive pigs [ASFV, belonging to the ne virus , 73. ASFne virus , 75. Wilne virus . Europeane virus . Accordine virus . And secne virus , 80. Undive pigs . The preCircovirus genus within the Circoviridae family, is a non-enveloped single-stranded DNA virus with a diameter of approximately 17 nm. It primarily targets and impairs the immune system of susceptible animals [7 copies/m3 [PCV, belonging to the  animals , 83. Veropies/m3 . Anotheropies/m3 . Additioopies/m3 . HoweverEnterovirus genus within the Picornaviridae family, is a non-enveloped, single-stranded positive-sense RNA virus with a diameter of approximately 24–26 nm. It primarily causes vesicular diseases affecting the hooves, oral cavity, nostrils, and mammary glands in pigs [1.4 TCID50 (< 3 μm) to 102.6 TCID50 (> 6 μm) [2.4 TCID50 [SVDV, belonging to the  in pigs , 88. Und(> 6 μm) . SVDV vi4 TCID50 . It is s4 TCID50 . And SVD4 TCID50 , 91. HowFlavivirus genus within the Flaviviridae family, is an enveloped, single-stranded positive-sense RNA virus with a diameter of approximately 45–50 nm. It primarily causes a zoonotic disease characterized by high fever and neurological symptoms [2 TCID50/mL [JEV, belonging to the symptoms . JEV trasymptoms , 94. In CID50/mL , and eveCID50/mL . The afoCID50/mL .Coronavirus genus within the Coronaviridae family, is an enveloped, single-stranded positive-sense RNA virus with a diameter of approximately 100–160 nm. It is a natural deletion mutant of the enteropathogenic TGEV [1.87 PFU/m3 [7 TCID50, and successfully infected 1-week-old piglets by inoculating them with the collected aerosols [PRCV, belonging to the nic TGEV –100. PRCnic TGEV , 102. Conic TGEV . Researc7 PFU/m3 . Cox et aerosols . Anotheraerosols . It is waerosols . CurrentAbove all, the primary evidence concerning the transmission of viral aerosols is derived from field and laboratory studies. Detecting aerosol transmission under field conditions, especially in the early stages, poses significant challenges. Mathematical models based on epidemiological surveys and case reports play a crucial role in understanding long-distance virus transmission and the emergence of new viruses. Extensive research has been conducted on the utilization of mathematical models in the context of FMDV –16, and Airborne transmission plays a pivotal role in the containment of animal diseases and is equally significant in the dissemination of zoonotic diseases. Consequently, it is imperative to prioritize endeavors aimed at preventing airborne transmission. However, given the scarcity of research on the prevention of aerosol transmission in pig farms and the current reliance on relatively simplistic preventive measures, here, we propose integrating insights from studies on viral aerosol transmission diseases in humans to propose potential preventive and control strategies that could be implemented in pig farms.The implementation of a real-time early warning monitoring system or regional risk maps for viral aerosol transmission is crucial for disease prevention, control and the improvement of biosecurity measures for pig farms. The establishment of an early warning model for West Nile virus provides a valuable reference . FirstlyMonitoring viral aerosols in pig farms can function as a proactive measure to mitigate airborne transmission . HoweverThe process of air pretreatment involves the elimination of pathogens from the air prior to its entry into the barn, with the aim of ensuring its safety. A viable approach entails the implementation of air filtration systems to purify the air entering pig barns, a strategy that has been extensively employed in global large-scale pig farms, demonstrating its efficacy in disease control, particularly in the case of PRRS , 117. HoOther methods, such as the reduction of dust levels in pig barns and the establishment of disease-free zones, hold potential for the prevention and control of viral aerosols , 8. AddiIn conclusion, this review provides a systematic classification and summary of prevalent airborne-transmitted viruses in pig production. As shown in Fig.


Since their first documentation in 1952, plaque reduction neutralization tests (PRNTs) have become the choice of test for the measurement of neutralizing antibodies against a particular virus. However, PRNTs can be performed only against viruses that cause cytopathic effects (CPE). PRNTs also require skilled personnel and can be time-consuming depending on the time required for the virus to cause CPE. Hence, their application limits large-scale studies or epidemiological and laboratory investigations. Since 1978, many surrogate PRNTs or immunocolorimetric assay (ICA)-based focus reduction neutralization tests (FRNT) have been developed. In this article, ICAs and their utility in FRNTs for the characterization of neutralizing antibodies, homologous or heterologous cross-neutralization, and laboratory diagnosis of viruses of public health importance have been discussed. Additionally, possible advancements and automations have been described that may help in the development and validation of novel surrogate tests for emerging viruses. Renato Dulbecco was the first to demonstrate the presence of ‘virus plaques’ on a monolayer of chicken embryo fibroblasts, specifically for Western Equine Encephalomyelitis and Newcastle Disease viruses . These fFor the first time, Okuno’s group has described peroxidase-anti-peroxidase (PAP) staining-based NTs, and afterwards, immunostaining-based methods on various cell substrates have been standardized for other viruses of public health importance ,16,17,182 incubators, reducing the overall assay cost and saving time with an increased output. The precipitation of viral foci on cell substrates by primary and secondary antibodies used in FRNTs results in a faster NT than plaque staining using crystal violet or other stains. Though both FRNTs and PRNTs showed similar sensitivity with inter-assay variation (Nt-Ab titers) of two- and three-fold, respectively, FRNTs offer the advantage of speed, reduced sample volume, and the possibility of automation using 96-well plates [A PRNT measures the level of virus-specific Nt-Abs in a serum or plasma sample by determining the ability of various dilutions to block the production of viral plaques on cell monolayers by a known amount of live virus . A PRNT l plates ,22. Othel plates . Thus, FGenerally, for the characterization of the qualitative and quantitative immune responses against wild-type and vaccine strains, in-vitro NTs are the preferred methods. For various viruses, viral plaque or focus reduction-based NTs have been standardized, validated with established virus-specific IgG Enzyme Immuno-Assays (EIAs), and employed to measure the Nt-Abs response. NTs have been utilized for confirmation of recent or past infections (with known or unknown etiology). In addition, modified NTs based on the principle of fluorescence detection and pseudo-viruses or recombinant-viruses have also been explored. The level of Nt-Ab titers that protect against the acquisition of viral infection and development of clinical disease have been documented using a sensitive PRNT for mumps and measles viruses ,65. ThroThere are methods in place to characterize functional Nt-Ab responses to the Poliovirus and Yellow fever virus, for which well-tested and proven vaccines are available ,19,49,67Similarly, various types of NTs, i.e., FRNTs, micro-NTs, fluorescent-FRNTs, immunostaining based PRNTs, PAP-NTs, and automated versions of FRNTs, have been established by various investigators for Hantavirus, Bourbon virus, West Nile Virus (WNV), Zika virus (ZIKV), Dengue virus (DENV), and Chikungunya virus (CHIKV), either for vaccine developments, epidemiological investigations, sero-prevalence studies, or laboratory diagnoses ,63,71,72Previously, many sero-epidemiological investigations of viruses of public health importance, i.e., DENV, CCHFV, Rift Valley fever virus, WNV, Usutu virus, CHIKV, Bourbon virus, Hantavirus, ZIKV, and SARS-CoV-2, have been carried out to confirm the presence of virus-specific IgM and IgG antibodies, and subsequently, case confirmation using gold standard PRNTs or by virus isolation ,82,83,84n = 2996) from Philippines was studied using IgG ELISAs and FRNTs. Although high sensitivity and specificity (>90%) were documented for ELISAs, their false-negative and false-positive results limit their use for pre-vaccination screening [n = 53) referred for MeV diagnosis were tested using FRNTs, of which 47.1% of cases showed a correlation with measles IgM antibody detection [n = 80), where 58.8% of serum samples showed positivity in all three tests, i.e., IgM ELISA, IgG ELISA and FRNT [The comparative dengue seroprevalence in children , B.1.167.2 (Delta), and B.1.1.529 (Omicron) strains . Interesn = 50) obtained from symptomatic, asymptomatic, and non-infected subjects, suggesting the possibility of a strain-specific neutralization pattern. Similarly, cross-neutralization studies using MuV genotypes A, F, H, and I challenge viruses have been carried out from Korea, which revealed that post-vaccination FRNT titers in the vaccine recipients (MMR one dose) were significantly lower against wild types compared to vaccine strains [A study from Iran measured homologous and heterologous Nt-Abs to MeV A, B3, D4, and H1 genotypes among measles-immunized children, indicating sufficient levels of Nt-Abs titers against the circulating genotypes . Such st strains . Such st2 = 0.95) between manual and automated methods with Nt-Ab titer differences within two-fold [2 = 0.94) with the CPE-based NT [Recently, various types of liquid handling systems have become available in the market that can be utilized for NTs. In addition, viral plaques or foci stained with various dyes or fluorescent reagents can be captured using high-resolution digital cameras, and results can be recorded using advanced instrumentation systems. In-built statistical formulas in the software can be used to obtain Nt-Ab titers, enabling results to be recorded in a digital format. An automated colorimetric micro-NT was developed for WNV which utilizes the principle of neutral red dye retention and records results on a spectrophotometer using advanced software . An imprtwo-fold . A similtwo-fold . A rapidbased NT . Similarbased NT . A studybased NT . A replibased NT . Recentlbased NT . Recentlbased NT . Both prA large number of commercial companies are producing monoclonal antibodies against various viruses using different approaches; thus, the cost of such antibodies may be lowered, and ultimately, the assay expenses could be reduced. In addition, the use of secondary IgG antibodies may be excluded by conjugating virus-specific monoclonal antibodies directly with different peroxidases or other enzymes, which will ultimately help in reducing the assay time. Moreover, there is a great need for the development of ‘universal’ cell-fixative and permeabilization reagents, blocking buffer solutions, and very specific primary/secondary antibodies that can efficiently bind to target virus surface proteins. However, optimization of various steps  is critical during standardization of immuno-staining protocols and ICA-based NTs. Studies on bovine herpesvirus 1, indicated virus-serum incubation  as crucial step for accurate measurement of antibody levels ,94. Thus


It is unknown whether using pegfilgrastim biosimilars is cost saving in a real-world setting.To compare medical costs including pegfilgrastim drug costs and febrile neutropenia (FN) treatment and management costs between pegfilgrastim biosimilars  and originator users for primary prophylaxis of febrile neutropenia.A retrospective cohort study using 2019 IBM MarketScan Commercial and Medicare Supplemental databases was conducted in adult patients with cancer initiating myelosuppressive chemotherapy courses. At least 2 diagnoses of the same cancer (at least 7 days apart) were required within 30 days of the chemotherapy initiation date. Pegfilgrastim (excluding on-body injector) costs included drug costs only (excluding administration fees). FN-related costs included all FN-related health care utilizations that were defined as having neutropenia, fever, or infection diagnosis. Per-patient per-cycle (PPPC) out-of-pocket (OOP) costs, health plan costs, and total costs were compared between originator (excluding on-body injector) and biosimilars users in the first cycle. A generalized linear model and a 2-part model were used.P < 0.0001 for both comparisons). However, there was no difference in health plan costs  and total costs. In addition, no difference was observed for adjusted PPPC FN treatment and management OOP costs, health plan costs, and total costs in the first cycle. FN treatment OOP costs were $192 for originator, $197 for pegfilgrastim-jmdb (P = 0.958), and $240 for pegfilgrastim-cbqv (P = 0.680). FN treatment health plan costs were $2,804 for originator, $2,970 for pegfilgrastim-jmdb (P = 0.692), and $2,745 for pegfilgrastim-cbqv (P = 0.879).A total of 1,930 patients were included, of whom 884 (45.8%) used pegfilgrastim originator, 427 (22.1%) used pegfilgrastim-jmdb, and 619 (32.1%) used pegfilgrastim-cbqv. Adjusted PPPC OOP pegfilgrastim costs in the first cycle were significantly lower for the biosimilars vs the originator ($182 for pegfilgrastim-jmdb and $159 for pegfilgrastim-cbqv vs $299 for originator, In a commercially insured population, using pegfilgrastim biosimilars in the first cycle for primary prophylaxis of FN led to cost savings for patients but not payers. No difference in FN-related costs was observed. In this study, we found that among commercially insured patients with cancer receiving chemotherapy in the first cycle, using pegfilgrastim biosimilars instead of originator for primary prophylaxis of febrile neutropenia was associated with 47%-59% lower costs for patients. Using pegfilgrastim biosimilars was not associated with lower costs for payers. Implications for managed care pharmacyIn the context of primary prophylaxis for febrile neutropenia, patient out-of-pocket costs were lower for pegfilgrastim biosimilar users compared with originator users, and 67%-83% of patients paid nothing for treatment in the first cycle. Although no difference in costs was observed for payers, rebates and discounts were not considered in the present analysis. For managed care pharmacies interested in adopting pegfilgrastim biosimilars, prices offered by the manufacturers after considering all discounts and rebates is a determining factor.1 According to National Comprehensive Cancer Network (NCCN) guidelines,1 use of G-CSFs for primary prophylaxis is recommended when the overall FN risk is greater than 20% following myelosuppressive chemotherapy, and secondary prophylaxis is recommended following FN or a dose-limiting neutropenic event. Off-label use of G-CSFs for FN treatment is not recommended. G-CSFs are available in both short-acting  and long-acting  products. For FN prophylaxis, filgrastim requires daily administration until the neutrophil level recovers, whereas pegfilgrastim is given once per cycle. Owing to its ease of use, pegfilgrastim has dominated the G-CSF market since its introduction, accounting for more than 97% of G-CSF use as recently as 2019.2 Although both agents are effective in reducing the risk of FN, the high costs make them significant drivers of expenses in oncology care, and lack of reimbursement to practice and concerns about insurance coverage are the main factors why high-risk patients may not receive prophylaxis with G-CSFs.3 The approval of biosimilars for G-CSF products presents a promising opportunity for expanded access to this therapy and cost savings for both patients and payers.Granulocyte-colony stimulating factors (G-CSFs) are essential for oncology supportive care. They are used to reduce the duration of neutropenia and the incidence of febrile neutropenia (FN) for patients with cancer receiving myelosuppressive chemotherapy, allowing maintenance or increase of chemotherapy dose intensity.2Competition from biosimilars has emerged for filgrastim and pegfilgrastim since 2015 and 2018, respectively. As of September 2021, there are 2 filgrastim biosimilars and 4 pegfilgrastim biosimilars on the market, including filgrastim-sndz and filgrastim-aafi for filgrastim as well as pegfilgrastim-jmdb, pegfilgrastim-cbqv, pegfilgrastimbmez, and pegfilgrastim-apgf for pegfilgrastim. Uptake of biosimilars has been rapid. In Q4/2019, biosimilars accounted for about 56% of filgrastim and 30% of pegfilgrastim use among commercially insured populations.4 Current economic evidence for the impact of biosimilars is thus far limited to filgrastim7 or other simulated data.12 One study evaluated the costs for a pegfilgrastim on-body injector (OBI).13 There are no real-world data focused on pegfilgrastim biosimilar medication costs from the patient and payer perspectives in addition to the costs for FN treatment and management. Thus, it is unknown whether cost savings are realized from adopting pegfilgrastim biosimilars. This study addresses this knowledge gap by analyzing and comparing pegfilgrastim costs to the patient and payer as well as the downstream costs associated with FN treatment and management for patients with cancer receiving myelosuppressive chemotherapy.Biosimilars should offer the same therapeutic benefits with lower prices for market competition. The prices of originators decreased following the entry of biosimilars, potentially narrowing the gap in price between the originator and biosimilar.Supplementary Table 1, available in online article) and used any of the 3 pegfilgrastim products—pegfilgrastim originator (prefilled syringe), pegfilgrastim-jmdb, and pegfilgrastim-cbqv—for FN prophylaxis were included.A retrospective cohort study was conducted using 2019 IBM MarketScan Commercial and Medicare Supplemental databases. These databases were HIPAA-compliant, fully integrated, longitudinal data sources of inpatient, outpatient, and prescription drug claims for individuals covered under commercial health plans and Medicare supplemental insurance plans. Patients with cancer  who received selected myelosuppressive chemotherapy regimens .2 Patients were required to have 180 days of continuous enrollment and 90 days without any chemotherapy administered prior to the index date to identify the start of the chemotherapy courses. Furthermore, 2 or more cancer diagnoses at least 7 days apart within 30 days before or after the index date were required (Supplementary Table 3). Patients who were on weekly chemotherapy regimens were excluded because use of pegfilgrastim with weekly chemotherapy is not recommended by NCCN guidelines.1Adult patients aged 18 years and older were required to receive at least 1 chemotherapy agent. The date of the first chemotherapy administration was defined as the index date (day 1). The chemotherapy regimen was determined based on all chemotherapy agents a patient received from day 1 to day 7. Regimens were then categorized into high FN risk (≥ 20%), intermediate FN risk (10%-20%), and low FN risk (< 10%) according to NCCN guidelinesSupplementary Table 4.Other exclusion criteria included (1) evidence of 2 or more primary solid cancers or acute myeloid leukemia within ± 30 days of the index date; (2) evidence of autologous peripheral blood progenitor cell collection, bone marrow transplantation, or hematopoietic stem cell transplantation during the period beginning 30 days before the index date and ending 10 days after that; or (3) evidence of the use of more than one G-CSF product , pegfilgrastim-OBI, or pegfilgrastim with an unknown route. Codes for exclusion criteria are shown in Supplementary Table 5). To be considered FN prophylaxis, patients were required to receive pegfilgrastim within 3 days from chemotherapy completion. Patients were followed from the index date (day 1) to the day prior to the next chemotherapy administered between day 12 and day 60 (end of cycle 1). If no chemotherapy was administered between day 12 and day 60, follow-up was considered censored on day 35, disenrollment, or the end of the study period, whichever occurred first. Patients whose followup ended because of disenrollment or the end of the study period were considered to have an incomplete cycle 1 and were excluded from the study. Pegfilgrastim and febrile neutropenia costs were only compared in cycle 1 because risks for FN are highest in the first cycle and we do not expect difference in costs between pegfilgrastim originator and biosimilars to change significantly across cycles. Study design diagrams are shown in Supplementary Figures 1 and 2.Pegfilgrastim product use was identified in medical claims using Healthcare Common Procedure Coding System and pharmacy claims using National Drug Code , patient out-of-pocket (OOP) costs, health plan costs, and total costs were analyzed separately. Patient OOP costs were calculated as the sum of coinsurance, copayments, and deductibles.Per-patient per-cycle (PPPC) pegfilgrastim costs, FN treatment costs, and FN management costs were estimated in cycle 1. Pegfilgrastim costs included medication costs only. FN treatment costs include all FN-related health care utilizations, including emergency visits, outpatient visits, and hospitalizations. FN management costs were calculated as the sum of pegfilgrastim costs and FN treatment costs. FN treatment–related health care utilizations were defined as having Descriptive statistics were summarized for all study variables . Patient characteristics were compared between biosimilar and originator users by the Student’s t-test for continuous variables and chi-square test for categorical variables.18 PPPC costs were estimated using either a generalized linear model or 2-part model19 after adjusting for covariates presented in Multivariable regression models were used to evaluate differences in all cost outcomes. Pegfilgrastim-jmdb and pegfilgrastim-cbqv were compared against the originator. The modified Park test was performed to determine the distributions of the cost data and to select the most appropriate regression model.P < 0.001]; pegfilgrastim-cbqv: 53.0 years [P < 0.001]; and pegfilgrastim originator: 56.3 years). They were also more likely to be commercially insured than covered by Medicare supplemental insurance . More than 40% of patients resided in the South. Breast cancer was the most common cancer type. Originator users were more likely to have a preferred provider organization health plan type (54.4% for pegfilgrastim originator vs 46.1% for pegfilgrastim-jmdb and 44.1% pegfilgrastim-cbqv). Biosimilar users were less likely to have a history of neutropenia  received pegfilgrastim originator, 427 (22.1%) received pegfilgrastim-jmdb, and 619 (32.1%) received pegfilgrastim-cbqv. Biosimilar users were significantly younger than the originator users (pegfilgrastim-jmdb: 53.4 years [P < 0.0001) for pegfilgrastim-jmdb, and $159 USD  for pegfilgrastim-cbqv (P = 0.511) for pegfilgrastim-jmdb, and $5,845 USD  for pegfilgrastim-cbqv (P = 0.048) for pegfilgrastim-jmdb, and $6,412 USD  for pegfilgrastim-cbqv in the first cycle (Adjusted PPPC OOP costs were significantly lower for biosimilars compared with originators. OOP costs were $299 USD (95% CI = 268-331) for the originator, $182 USD  for pegfilgrastim-jmdb, and $240  for pegfilgrastim-cbqv. Adjusted PPPC health plan FN treatment costs were $2,804  for pegfilgrastim originator, $2,970  for pegfilgrastim-jmdb, and $2,745  for pegfilgrastim-cbqv. Adjusted PPPC total FN treatment costs were $3,085 USD  for pegfilgrastim originator, $3,162 USD  for pegfilgrastim-jmdb, and $3,283 USD  for pegfilgrastim-cbqv in the first cycle.No significant differences were observed for FN treatment costs  between patients who used pegfilgrastim originator and biosimilars in the first cycle. Adjusted PPPC OOP FN treatment costs were $192 (95% CI = 78-307) for pegfilgrastim originator, $197 , and $426 USD (95% CI = 196-656) for pegfilgrastim-cbqv (P = 0.679). Adjusted PPPC health plan FN management costs were $8,469  for pegfilgrastim originator, $8,854  for pegfilgrastim-jmdb, and $8,758  for pegfilgrastim-cbqv. Adjusted PPPC total FN management costs in cycle 1 were $9,830 USD  for pegfilgrastim originator, $9,397 USD  for pegfilgrastim-jmdb, and $9,893 USD  for pegfilgrastim-cbqv.Likewise, there were no differences in FN management costs between pegfilgrastim originator and biosimilars users in the first cycle. Adjusted PPPC OOP FN management costs were $490 USD (95% CI = 323-656) for pegfilgrastim originator, $337 USD (95% CI = 165-510) for pegfilgrastim-jmdb . Although it is tempting to assume that lower OOP expenses could make pegfilgrastim more affordable to patients and payers could drive biosimilar adoption using differential cost sharing structure, 67%-83% of patients were paying zero OOP for the pegfilgrastim. This would limit the potential of using differential cost sharing structure to drive biosimilar adoption and expand pegfilgrastim use. One reason why a high proportion of patients are paying nothing for pegfilgrastim is likely because of the patient assistance program, such as Coherus COMPLETE and Amgen ASSIST 360, offered by the manufacturers. Another reason could be that pegfilgrastim users likely reached their OOP limits for the year because of chemotherapy treatment.20 we were unable to detect differences in health plan costs and total costs between the pegfilgrastim biosimilars and originator. This may be due to the small sample size of our analysis or the inability to capture rebates and discounts in the claims database. Future studies using larger samples will further address the saving potential of pegfilgrastim biosimilars. Regardless, our findings for pegfilgrastim costs align with previous studies comparing filgrastim costs between biosimilars and originator users showing modest to no difference in costs.7Although wholesale acquisition costs and average sale price are 33% and 6%-11% lower for pegfilgrastim biosimilars compared with the originator,4 Product differentiation strategy from the branded manufacturers in response to competition from biosimilars, such as development of OBI, can also benefit patients by reducing provider office time and patient travel burden, although several studies have shown that the pegfilgrastim-OBI device is subject to failure at a rate of 1%-6.9%.24 Proactively removing legal and regulatory barriers for biosimilars will help mitigate the problem of escalating costs for biologics and advanced technology.Despite the absence of differences in total costs for pegfilgrastim between biosimilar and originator users, the availability of biosimilars may have other financial and clinical benefits to the health care system and patients through increased competition. Studies have shown that the net price  of both filgrastim and pegfilgrastim originator has dropped since the availability of biosimilars.13 As pegfilgrastim biosimilars gain a larger market share, comparisons on specific cancer type and chemotherapy regimen as well as in the context of secondary prophylaxis are needed to advance our understanding on the cost-saving benefits of using biosimilars.Our study has limitations. First, using a claims database has inherent limitations. For example, because measuring chemotherapy dose is unreliable in claims data, regimens were categorized into 3 FN risk categories based only on the chemotherapy agents received and the cycle length. The possibility of FN risk level misclassification cannot be ruled out. Moreover, although we used a nationally representative commercial claims database, we limited our study sample to patients with certain cancer types, predominately breast, lung, and non-Hodgkin lymphoma, who received selected chemotherapy regimens. Our findings can only be generalized to these patients. We were also unable to capture rebates in claims database, which would result in overestimation of the pegfilgrastim health plan and total costs. Next, we assessed costs in the first cycle only, because we believe this is the most straightforward way of comparing both pegfilgrastim costs and FN treatment costs between biosimilars and originator; it is unclear how the costs incurred later differ from those in the first cycle. Moreover, our analysis was performed in a study population comprising newly and previously diagnosed patients, which may influence the risk of FN and the pegfilgrastim product choice. Although we measured multiple FN risk factors and adjusted for them , residual confounding cannot be ruled out. Lastly, we excluded patients who used pegfilgrastim-OBI in the present analysis because we believe that the benefits OBI brought to patients and providers makes it incomparable to pegfilgrastim prefilled syringe, either biosimilar or originator. Regardless, a previous study found that there is no significant difference in costs between pegfilgrastim-OBI and pegfilgrastim originator.Use of pegfilgrastim biosimilars was associated with lower patient OOP costs but not lower health plan costs. No significant differences in FN treatment and management costs between biosimilars and originator were found. These findings are only applicable to patients with cancer types and selected chemotherapy regimens included in this study.