These results demonstrate that this approach is expected to open a new avenue for design and preparation of high performance thermal management materials to address the heat dissipation of modern electronics.Construction of a vertically aligned and densely interconnected ordered 3D filler framework in a polymer matrix is a challenge to attain significant thermal conductivity (TC) enhancement efficiency. Fortunately, many biomaterials with unique microstructures can be found in nature. With inspiration from wood, artificial composites can be rationally designed to achieve desired properties. Herein, the authors report a facile and effective approach to fabricate anisotropic polymer composites by biotemplate ceramization technology and subsequent vacuum impregnation of epoxy resin. The hierarchical microstructure of wood is perfectly replicated in the cellular biomass derived SiC (bioSiC) framework by carbothermal reduction. Owing to the anisotropic architecture of bioSiC, the epoxy composite with vertically aligned dense SiC microchannels shows interesting properties, including a high TC (10.27 W m −1 K−1 corresponding to a significant enhancement efficiency, and a low coefficient of linear thermal expansion of 12.23 ppm K−1.The anisotropic wood microstructure is faultlessly duplicated into biomass derived SiC/epoxy composite by biotemplate ceramization technology and subsequent impregnation of epoxy resin. The composite exhibits a high thermal conductivity of 10.27 W m The conventional blending methods have been commonly used to prepare the thermal management materials by randomly dispersing fillers in the polymer matrix. However, a large amount of fillers (above 50 vol%) is always needed to attain a continuous and efficient heat conduction path and achieve the target TC values due to the inevitable agglomeration of fillers. Unfortunately, such a high loading usually leads to high cost, deteriorated mechanical properties and increased processing difficulty. Therefore, minimizing the content of fillers while achieving simultaneous high TC to obtain a significant enhancement efficiency remains a great challenge.With the rapid development of electronic technology and industry, efficient thermal dissipation has become a stringent necessity in modern electronic devices for stronger performance, higher reliability, and longer lifetime.2, 3 This thought could ensure that most of the energy is transferred through the 3D filler skeleton, thereby avoiding unnecessary polymer/filler interfacial thermal resistance. In other words, the 3D filler framework act as a macroscopic “motorway” for the rapid transport of phonons throughout the composite, which means that a high TC can be achieved in reduced loading concentration of fillers. Hao et al. reported the fabrication of a 3D alumina ceramic skeleton by compression molding and high temperature sintering method, followed by the impregnation of epoxy resin (EP). A remarkable TC of 4.356 W m−1K−1 in the porous alumina/EP composite was achieved at a filler loading of 43 vol%. Tian et al. developed a direct foaming method to prepare a 3D boron nitride porous architecture and then impregnated them with EP. The obtained epoxy composite possesses a high TC of 3.48 W m−1K−1 at a relatively low filler loading of 24.4 wt%. Although the TC of the above composites has been greatly improved compared to those prepared by the conventional methods, the TC enhancement efficiency is still not desirable enough. This is because the isotropic characteristics of these randomly interconnected and homogeneous 3D filler networks mean a zigzag heat conduction path, which was unable to maximize the TC enhancement efficiency. However, if given the anisotropic feature of the 3D filler network, construction of a vertically aligned and densely interconnected 3D filler framework in a polymer matrix is expected to make the heat transfer path straighter, and then further promote the heat conduction throughout the composite. In addition, modern electronic substrates also require the materials with low coefficient of linear thermal expansion (CLTE). Because the low CLTE substrate materials can reduce thermal evoked stresses and expansion mismatches between substrates and electronic components. The dense 3D filler skeleton can effectively restrict the thermal expansion of polymer matrix. As an example, the CLTE was remarkably decreased by ≈78% for BN/PMMA composite under filling with ≈56.1 wt% BN with respect to pure PMMA, which is ascribed to the embedment of ultralow expansion and tightly interconnected 3D BN skeleton. Meanwhile, the densely interconnected 3D filler framework can carry the load from the polymer matrix, thereby enhancing the mechanical properties of composites. Zhao et al. used alumina and cyanate ester to creatively synthesize ceramic/polymer composites with 3D interlocking skeleton structure. Such composites exhibit outstanding flexural strength (≈300 MPa), toughness (failure strain ≈5%), and superior specific strength (≈162 MPa (g cm−3)−1) simultaneously. What is more, the anisotropic functionality realized by the anisotropic structure can also expand the range of product applications, such as thermal insulation, thermal dissipation, and directional electrical conduction.As is known, the formation of continuous pathways of fillers is the key to achieve high TC in polymer composites. In recent years, introducing a prebuilt 3D filler network in a polymer matrix has been intensively studied with the purpose of significantly improving the TC enhancement efficiency.16 Thi By placing uniform aqueous slurry on the top of a copper pillar which was precooled in liquid nitrogen for unidirectional freezing, the ice crystals will first nucleate at the bottom of the slurry, and then grow along the temperature gradient to form the array of vertically aligned ice columns. At the same time, the fillers are expelled into the gap of adjacent ice columns and gradually templated. A vertically aligned 3D filler network with ordered long range continuous channels is obtained after removing the ice crystals by freeze‐drying. However, the anisotropic factors of 3D filler networks made from bottom–up methods are usually limited, since the pore channels show a poor long range continuity and a large quantity of horizontal branches bridged in the vertical direction. In addition, it is difficult for the fillers along the alignment direction to form a dense channel wall by physical extrusion. The existence of these structural defects will inevitably weaken the heat conduction. Moreover, complicated fabrication processes and expensive nano raw materials  also limit the scaling up of these materials. More rational process design and better selection of materials are required to optimize the anisotropic structure of 3D filler framework and the performance of its composites. Fortunately, many biomaterials with unique microstructures and anisotropy can be found in nature besides this method mentioned above. Millions of years, natural trees have used the vertically aligned cell channels for directional transportation of water and nutrients, and the unique architecture gives rise to anisotropic mechanical and thermal properties in wood. With inspiration from trees, artificial composite materials can be rationally designed to achieve desired properties. Wan et al. prepared a metallic wood with excellent anisotropic electrical, thermal, and mechanical properties by metal continuously filling the wood vessels. The composites boast a high TC of 5.23 W m−1K−1 at a Sn‐Bi metal filler loading of 31 vol%, and an extraordinary anisotropic TC ratio of 18. So far, the exploration of composite materials prepared by natural wood that utilize this anisotropic structure is still limited. Therefore, the development and utilization of structural and functional composites based on inexpensive and environmentally friendly natural wood exhibits strong potential and great significance.To date, a lot of efforts have been devoted to obtaining an anisotropic 3D filler framework. Among them, the ice‐templated assembly or so called unidirectional freeze‐drying is the most frequent approach owing to its stronger applicability to various materials.32 By  Generally, the biomass derived carbide ceramics (such as SiC and B4C) are fabricated through the following steps: 1) Preparation of carbon templates by pyrolyzing natural materials at high temperature. 2) Infiltration of the carbon template with ceramic precursors . 3) High temperature sintering to form ceramics. Despite the impressive results reported for biomass derived carbide ceramics synthesized by the existing routes, a few drawbacks still remain unaddressed. The mechanical properties are considerably deteriorated because of the degraded architecture compared with the original natural materials tissue microstructure. Moreover, silicon and boron impurities or residual carbon are always present in the products due to the uncontrollable degree of reaction. Besides it, complicate fabrication process is required for repetitious ceramic precursors infiltration into carbon template. In this work, using natural poplar wood as the template, we demonstrate a simple, rapid, and effective approach to fabricate a vertically aligned and densely interconnected 3D biomass derived SiC (bioSiC) skeleton via the carbothermal reduction of SiO vapor with a pyrolytic carbon template and then the impregnation of EP into this framework to obtain the final epoxy composite (bioSiC/EP). The wood tissue anisotropic microstructure is completely replicated in the bioSiC ceramic by employing this wood‐derived technique. As a benefit from this unique architecture, the prepared epoxy composite exhibits a dramatically improved TC (10.27 W m−1K−1) compared to that of pure EP (0.186 W m−1K−1) at a relatively low bioSiC loading of 21 vol%, corresponding to a significant enhancement efficiency of 259 per 1 vol% loading. Meanwhile, a high anisotropic TC ratio of 5.77 and an extremely low CLTE of 12.23 ppm K−1 are also achieved. These results demonstrate that this method exhibits strong potential for design and preparation of thermal management materials with high heat conduction efficiency. Moreover, we hope this work could provide a new avenue for boosting the development of high performance functional/structural ceramic polymer composites.SiC is a promising ceramic filler for polymer composites, which possesses high TC, low CLTE, excellent thermal stability, and remarkable chemical stability.45 Gen2Figure−3, a series of volume fractions of the bioSiC ceramic in the bioSiC/EP composite could be obtained based on different density values.As schematically illustrated in  After impregnation with EP, the body color of the bioSiC/EP composites became slightly darker, and its surface looked much smoother and denser. Furthermore, the bioSiC/EP composite could be easily tailored into various shapes and sizes according to the application requirements. The abundant, low cost raw materials and the facile preparation process ensured the scalable fabrication of the bioSiC/EP composite.The optical images of carbon template, bioSiC ceramics, and bioSiC/EP composites derived from poplar wood are shown in Figure 53 AftFigureThe blue dashed square in Figure The green dashed square in Figure Figure the width and length of SiC nanocrystals are ≈200 and ≈700 nm, respectively. The microstructure inherits the original structural directionality of the cellulose nanofibers of natural wood, indicating that the bioSiC ceramics were synthesized by the in situ carbothermal reduction. Moreover, there are a few micropores between the two cell walls of bioSiC ceramic, which were caused by the escape of CO gas from the initial carbon template during the carbothermal reduction. The thickness of the cell wall can be estimated to be about 700 nm, and unreacted carbon is not observed on it, indicating that a complete conversion from C to SiC occurs.A high magnification SEM morphology of the cell wall of bioSiC ceramic is shown in −1 for Si–C stretching, and the peak at 3646 cm−1 for O–H stretching is one of the features of raw bioSiC surface. After surface modification, the hydroxide group interacted with the hydrolyzed silane coupling agent in ethanol solution, and several functional groups appear on the FTIR spectra. Compared with raw bioSiC, three new absorption peaks at 2851, 2920, and 2951 cm−1 are assigned to the valence stretching vibration of aliphatic C–H. Meanwhile, the peak at 1053 cm−1 for Si–O–Si stretching is significantly increased, which reflects the dehydration condensation between the silane coupling agents. Unfortunately, the characterizations of O–H and Si–O–Si stretching are not accurate by FTIR spectra, therefore, the X‐ray photoelectron spectrum (XPS )was used to further analyze the bioSiC ceramic before and after surface modification  spectra of the functional groups on the surface of bioSiC ceramic before and after surface modification are characterized in Figure n Figure . As shown Figure . Among tn Figure , which iθ = 22.49° and 43.13° are visible in Figure θ = 35.74°, 41.50°, 60.09°, 71.83°, and 75.56°, which is consistent with the (111), (200), (220), (311), and (222) crystal planes of the β‐SiC phase card (PDF 00−029−1129), respectively, which confirm the high purity and high crystallinity features of bioSiC ceramic. The analysis of the SEM images from Figure ||/EP, bioSiC⊥/EP, and isotropic bioSiC/EP powders (crushed bulk composite) are performed as shown in Figure X‐ray diffraction (XRD) patterns are used to further characterize the bioSiC/EP composite properties. The two broad and large diffraction bands at approximately 2||) and radial  were carried out. Figure|| of bioSiC ceramics increases from 5.14 to 9.99 W m−1K−1, the TC⊥‐1 increases from 2.94 to 6.06 W m−1K−1, and the TC⊥‐2 increases from 0.99 to 1.69 W m−1K−1, respectively, which mainly benefited from the increasing number of heat transfer pathways. Moreover, low porosity results in the reduction of phonon scattering, which will be beneficial to phonon transport, and vice versa. On the other hand, the unique anisotropic microstructure of bioSiC ceramics results in an anisotropic TC, the TC|| is superior to that of the TC⊥, and the TC⊥‐1 is higher than the TC⊥‐2.To investigate the correlation between anisotropic microstructure and TC of the bioSiC ceramics and the bioSiC/EP composites, the TC measurements of axial  with same filler loading, which indicated that the vertically aligned bioSiC microchannels in EP matrix serve as a phonon “expressway” to facilitate thermal conductive in composites. At the same filler loading (≈21 vol%), the TC|| of bioSiC/EP composites slightly increases from 9.99 to 10.27 W m−1K−1, the TC⊥‐1 increases from 6.06 to 6.16 W m−1K−1, and the TC⊥‐2 increases from 1.69 to 1.78 W m−1K−1, respectively. This is because the bioSiC ceramics are equivalent to bioSiC/air composites, the TC of pure EP (0.186 W m−1K−1) is slightly higher than that of air (0.026 W m−1K−1). Therefore, the values of bioSiC/EP composites exhibit slight increase comparing with the TC of the bioSiC ceramics. These results indicate that the TC of bioSiC/EP composites is mainly provided by the 3D bioSiC framework, and most heat is quickly transferred through bioSiC. Therefore in our composites, the interfacial thermal resistance is mainly originated from bioSiC‐bioSiC interface not bioSiC–EP interface. To calculate the interface thermal resistance, as exhibited in Figure ||/EP composite . Some parameter values obtained by perfectly fitting the experimental data can be used to calculate the contact resistance (R) between adjacent bioSiC . The R of bioSiC||/EP composite can be estimated as 3.49 × 105 K W−1, which is 1–3 orders of magnitude smaller than the BNNS/EP composite prepared by freeze‐drying  is calculated. Here, η is defined as:K and Km are the TC of the bioSiC/EP composites and pure EP, respectively, and Vf is the volume fraction of bioSiC in composites. As shown in Figure η values of three orientations of the bioSiC/EP composites reach 40, 152, and 259 at a filler loading of 21 vol%, respectively.In addition, since the anisotropic microstructure of 3D bioSiC skeleton, the TC of bioSiC/EP composites also shows the anisotropic nature. The anisotropic TC, TC enhancement, and TC enhancement efficiency of bioSiC/EP composites with 21 vol% bioSiC are illustrated in Figure  results.58 The As shown in Figure ||/TC⊥‐2) in the bioSiC/EP composites is 5.77, which is much higher than that of natural wood (1.50), even higher than that of wood aerogel (4.30) with layered structure after chemical treatment. Benefiting from this anisotropic architecture, the anisotropic factor of bioSiC/EP composites is over 5 times higher than other SiC/EP composites. In addition, most of the reported epoxy composites fall in the anisotropic TC ratio range of 1.00–3.00, where the graphite nanoplatelet epoxy composite exhibits a relatively better performance with an anisotropic factor of 5.00, which is still less than the bioSiC/EP composite. For the epoxy composites prepared by freeze drying, their anisotropic TC ratios are usually relatively low due to poor long range continuity, such as graphite epoxy composites (2.51–4.44), CNT epoxy composite (4.87), Si3N4 epoxy composite (1.61), AlN epoxy composite (2.13), BN epoxy composites (1.19–2.56), and SiC epoxy composite (1.15) , which is even higher than some epoxy composites with high filler loading (>50 vol%). In addition, most of the reported epoxy composites fall in the TC range of 1.00–6.00, where the AlN honeycomb epoxy composite exhibits a relatively better performance with a TC of 9.48 W m−1K−1 at a filler loading of 47.26 vol%, which is still less than the TC||. On the other hand, the TC|| is much larger than that of SiC epoxy composites prepared by other methods. The η values of some typical thermally conductive epoxy composites are summarized in Figure  Most of the reported epoxy composites fall in the η range of 10−200, where the graphene‐multilayer graphene epoxy composite exhibits a relatively better performance with a η value of 244. It is worth noting that the vertically aligned and densely interlinked 3D bioSiC framework exhibits the highest η value of 259 among the reported fillers. There is no doubt that our bioSiC/EP composites simultaneously exhibit the highest TC and efficiency, indicating that the above structure has the better capability to improve heat transfer performance of epoxy composites.Many applications can benefit from the excellent anisotropic thermal properties of epoxy composite.61 As k Figure , includiIn order to visually demonstrate the heat conduction performance of the samples, the pure EP, three orientations of bioSiC ceramics with 81% porosity, random SiC/EP and three orientations of bioSiC/EP composites with 19 vol% bioSiC with dimensions of 20 mm × 6 mm × 6 mm were successively placed on the same heating platform at 100 ℃ for heating, during which their surface temperature variations were recorded by an infrared thermal imager, as shown in Figure  thereby the phonons need considerable time to pass through the EP matrix, resulting in a low TC of 0.186 W m−1K−1 , and the temperature at the bottom is fixed to 120 ℃, while all other outer boundaries are perfectly thermal insulated. Finally, transient finite element analysis methodology was established, the total time length is 0.03 s with a step length of 0.001 s. All the four models were set as the same conditions, when the bottom surface is exposed to a constant temperature heat source (120 ℃), convection is applied to the peripheral surfaces and the thermal conduction performance from the bottom to the top surface can be evaluated.In order to further study the thermal conduction behavior of the bioSiC/EP composites, the finite element simulation was carried out using COMSOL Multiphysics 5.4. As shown in −1K−1), while in bioSiC/EP composites, the heat transfers much faster from one side to another. It is worth noting that the bioSiC||/EP composite exhibits a faster thermal transfer with time in comparison with the bioSiC⊥/EP‐1 composite, but much faster than that of the bioSiC⊥/EP‐2 composite. The top surface temperature recorded in Figure ||/EP composite increases faster compared to bioSiC⊥/EP composite from the curves. The top surface temperature values of pure EP and three orientations of the bioSiC/EP composites are 20.00, 59.65, 81.67, and 100.10 ℃ at 0.01 s, respectively . For bioSiC⊥/EP‐2 composite as shown in Figure ||/EP composite as shown in Figure ⊥/EP‐1 composite as shown in Figure ⊥/EP‐2 composite and the bioSiC||/EP composite. In summary, the more direct and simple the heat transfer pathway is, the more efficient the pathway is, and the faster the heat transfer will be. Based on the parallel relationship between the microchannel alignment direction (including the cell plate) and the heat flow direction, the thermal interface material with anisotropic heat transfer performance can be easily customized.To further illustrate the heat transfer process, the temperature distribution and heat flow arrows of the sections of four models at 0.003 s are shown in Figure  The CLTE value is indicative of the dimensional stability, and is tested via thermo‐dilatometry measurements within the temperature range of room temperature to 180 ℃. The CLTE curves of pure EP, bioSiC ceramics, random SiC/EP, and bioSiC/EP composites as a function of temperature are shown in Figure−1. For bioSiC/EP composites with 19 vol% bioSiC, there are some slight fluctuations in the CLTE curves of three orientations with the variation of temperature, but the overall change is small. It could be seen that the CLTE of bioSiC/EP composites are much less than the curve of pure EP and close to the bioSiC ceramics. This is attributed to the well aligned 3D bioSiC structure stabilizing the whole framework of the composites. In addition, after further calculation, the CLTE values of three orientations of the bioSiC/EP composites reach 16.36, 14.67, and 14.22 ppm K−1 at a filler loading of 19 vol%, respectively. It is worth noting that the bioSiC/EP composites exhibit anisotropic CLTE in the axial and radial, and the CLTE values of bioSiC⊥/EP composites are lower than the bioSiC||/EP composite.The dimensional stability is an essential property for polymer composites, because the poor dimensional stability would bring severe impacts to the reliability of electronic devices.86 The−1. With the increasing addition of bioSiC, the CLTE values of bioSiC/EP composites show a significant decrease, which mainly because the 3D bioSiC framework exerts a stronger confinement effect on the motion of EP molecular chains. And the higher the volume fraction of bioSiC, the more obvious the inhibition. The minimum CLTE value of 12.23 ppm K−1 in bioSiC/EP composites is achieved with 21 vol% bioSiC, which is about 5 times lower than that of the pure EP. To further explore the effect of 3D bioSiC skeleton on CLTE, three classical models including Rule of Mixture (ROM), Turner, and Kerner are applied to estimate the theoretical CLTE values of bioSiC/EP composites . As shown in the inset of Figure  Both the 3D and random comparison samples show a tendency to decrease with extended filler loading. 3D filler network/EP composites present a lower CLTE, which attribute this reduction to the suppression of the volume change in the 3D structure between filler and EP in the interstitial space. In addition, the bioSiC/EP composites possess a lowest CLTE value of 12.23 ppm K−1, whereas the lowest values of BNNS aerogel/EP composites and oriented BN/EP composites are 24.00 and 22.70 ppm K−1, respectively. This consequence indicates that the vertically aligned and densely interlinked 3D bioSiC network with latticed structure exerts a stronger inhibition effect on the thermal expansion of EP.The effect of bioSiC loading on CLTE values of bioSiC/EP composites is discussed in Figure rmation).88 As z direction (0.0049%) is higher than that in the x and y directions (0.0041%). While for the model of multiple units, the same result can be observed in Figure z direction) is as low as 0.002316%, it is still higher than the in‐plane . From the section figures, it is obvious that the large thermal stress is still concentrated at the interface. In the in‐plane direction, the thermal expansion of EP is inhibited by the cell wall of bioSiC under normal stress, and the force of each cell wall is superimposed. Thus, the average displacement of the corresponding surface is relatively small. While in the through‐plane direction, the thermal expansion is restrained by the cell wall of bioSiC under shear stress. By contrast, the force of each cell wall is independent, thereby the average displacement of the top and bottom surface is relatively large. This result illustrates again that the bioSiC/EP composite is anisotropic during thermal expansion process, the linear expansivity of bioSiC||/EP composite (through‐plane) is higher than bioSiC⊥/EP composite (in‐plane).In order to further explain the anisotropy and internal stress of bioSiC/EP composites during thermal expansion process, the finite element simulation was carried out using COMSOL Multiphysics 5.4. The models of a single unit and multiple units with bioSiC volume ratio of 20% were created, respectively, the temperature of both models was fixed to 120 ℃. Figure  Thermogravimetric tests were carried out to investigate the thermal stability of the bioSiC/EP composites  curves of pure EP and bioSiC/EP composites all have two stage degradation behavior at 270−470 and 470−620 ℃, which correspond to the decomposition of the oxygen‐containing groups on the edge of EP and the pyrolysis of the carbon–carbon skeleton, respectively. Accordingly, the weight of bioSiC/EP composites at 620−800 ℃ can been used to characterize the content of bioSiC. The temperature at 10 wt% loss of the samples (T10%) provides vital information about thermal stability. As shown in the inset of Figure T10% of 360 ℃, as the bioSiC loading increases from 17 to 19 vol%, the T10% increases from 376 to 386 ℃, which indicates that the addition of bioSiC can retard the EP degradation, and the thermal stability of bioSiC/EP composites increases with increasing the loading fraction of bioSiC. It can be explained from the following three points: 1) The bioSiC exhibits higher thermal stability than EP. 2) The bioSiC possesses higher TC than EP, which makes it easier to absorb heat and results in the degradation of EP at higher temperature. 3) The 3D bioSiC framework possesses a barrier effect, which can inhibit the mobility of EP, delay the escape of volatile degradation products and prevent the transfer of oxygen.Thermal stability is an important consideration of thermal management materials, the limiting factor in being both production and applications.89 TheAs shown in Figure  Therefore, the flame resistance properties of pure EP, random SiC/EP, and bioSiC/EP composites were characterized by a butane spray gun  as a silane coupling agent was obtained from Shanghai Aladdin Biochemical Technology Co., Ltd, China. Bisphenol‐A EP was offered by Shanghai Resin Factory Co., Ltd, China. Methyltetrahydrophthalic anhydride (MeTHPA) and 2,4,6‐tris(dimethylaminomethyl)phenol (DMP‐30) were purchased from Sinopharm Chemical Reagent Co., Ltd, China, which were used as curing agent and curing accelerator, respectively.Natural poplar wood was purchased from a furniture factory in Guiyang, China. SiO powders with a purity of 99% and −1, resulting in the intact pyrolytic carbon template.Rectangular specimens in both the axial (||) and radial  orientations with dimensions of 100 mm × 40 mm × 40 mm were cut from natural poplar wood. The specimens were dried in an oven at 110 ℃ for 1 day to remove water before pyrolysis. Subsequently, the dried samples were pyrolyzed at 1000 ℃ for 4 h under nitrogen atmosphere with a low heating rate of 1 ℃ min−1 for 1200 to 1800 ℃.First, the carbon template was machined into various dimensions and shapes in both the axial (||) and radial  orientations. Then the samples and SiO powders were put into a closed graphite crucible, which was put into a sintering furnace  and sintered at 1800 ℃ for 4 h under argon pressure of 0.225 MPa. SiO vapor was generated via sublimation of SiO powders at high temperature, which reacted with the carbon template to form 3D bioSiC skeleton. The heating rate from room temperature to 1200 ℃ was 20 and 5 ℃ minThe 3D bioSiC scaffold was further infiltrated with EP under vacuum to prepare the bioSiC/EP composite. Before the impregnation, the samples were soaked in a hydrolysis solution (mass ratio of ethanol:water:KH‐560 = 95:5:0.57) of silane coupling agent at 80 ℃ for 3 h for surface modification. After that, the EP along with the curing agent and the accelerator were uniformly mixed at 55 ℃ for 40 min (EP:MeTHPA:DMP‐30 = 100:86:1). Subsequently, the functionalized 3D bioSiC framework was immersed into the resulted mixture under the assistance of vacuum for 4 h to ensure the complete filling. Finally, the composites were cured in an oven at 70 ℃ for 10 min, 135 ℃ for 3 h, and 180 ℃ for 4 h.β‐SiC powders (average size: 500 nm) were used for the preparation of random SiC/EP composite. First, the dried SiC powders were added to a hydrolysis solution (mass ratio of ethanol:water:KH‐560 = 95:5:0.57) of silane coupling agent and stirred at 80 ℃ for 3 h for surface modification. Subsequently, the modified SiC powders were obtained by vacuum filtration and drying at 80 ℃ for 1 day. Second, the modified SiC powders along with the liquid EP, the curing agent and the accelerator were uniformly mixed at 55 ℃ for 4 h under the assistance of vacuum to ensure no bubbles (SiC:EP:MeTHPA:DMP‐30 = 119:100:86:1). Finally, the random SiC/EP composites with 19 vol% SiC were obtained by curing in an oven at 70 ℃ for 10 min, 135 ℃ for 3 h, and 180 ℃ for 4 h.In order to be consistent with the bioSiC nanocrystals size, α radiation. The thermal diffusivity (α) and specific heat capacity (Cp) of the samples were measured by a laser‐flash diffusivity instrument  at room temperature, and the eventual TC (λ) was calculated by the equation: λ = ρ × α × Cp, ρ was the density of the specimens, each data was measured by a specimen, but three measurement points were selected for each specimen, each final value was averaged with three measurements. The temperature distribution image of the samples was recorded by an infrared thermograph . The CLTE of the specimens was tested by a thermomechanical analyzer  with a heating rate of 10 ℃ min−1 and a preload force of 0.02 N, each data was measured by a specimen. Thermal stability of the bioSiC/EP composite was performed by a TGA  at a heating rate of 10 ℃ min−1 under an air atmosphere. The flexural strength was measured by a universal testing machine  via three‐point bending method with a 16 mm span at a cross‐head speed of 0.5 mm min−1. Each final value was averaged over five measurements.The porosity and density of the samples were measured by the drainage method according to the Archimedes principle. The morphology and quantitative elemental analyses of the carbon template, the 3D bioSiC scaffold, and the corresponding epoxy composite were observed by a field emission scanning electron microscopy . FTIR  was used to characterize the functional groups on the surface of the 3D bioSiC network before and after surface modification. XPS were detected by a Thermo Scientific X‐ray photoelectron spectrometer . XRD analysis of the specimens was performed by an X‐ray diffractometer  with Cu K||/EP composite was fitted by Foygel model (K = K0(Vf − Vc)τ + C), other data were fitted by linear regression (K = AVf + B), which were analyzed with the goodness of fit (R2) and F‐test, statistical significance was defined as probability value (p) < 0.05. The CLTE values of pure EP, random SiC/EP, and bioSiC/EP composites in Figure In Figure The authors declare no conflict of interest.Supporting InformationClick here for additional data file.


More than 75% of neonatal deaths occurred in the first weeks of life as a result of adverse birth outcomes. Low birth weight, preterm births are associated with a variety of acute and long-term complications. In Sub-Saharan Africa, there is insufficient evidence of adverse birth outcomes. Hence, this study aimed to determine the pooled prevalence and determinants of adverse birth outcomes in Sub-Saharan Africa.Data of this study were obtained from a cross-sectional survey of the most recent Demographic and Health Surveys (DHS) of ten Sub-African (SSA) countries. A total of 76,853 children born five years preceding the survey were included in the final analysis. A Generalized Linear Mixed Models (GLMM) were fitted and an adjusted odds ratio (AOR) with a 95% Confidence Interval (CI) was computed to declare statistically significant determinants of adverse birth outcomes.The pooled prevalence of adverse birth outcomes were 29.7% (95% CI: 29.4 to 30.03). Female child , women attended secondary level of education , middle  and rich socioeconomic status , intimate-partner physical violence (beating) , big problems of long-distance travel , antenatal care follow-ups , multiparty , twin births , and lack of women involvement in healthcare decision-making process  were determinants of adverse birth outcomes.This study showed that the magnitude of adverse birth outcomes was high, abnormal baby size and preterm births were the most common adverse birth outcomes. This finding suggests that encouraging antenatal care follow-ups and socio-economic conditions of women are essential. Moreover, special attention should be given to multiple pregnancies, improving healthcare accessibilities to rural areas, and women’s involvement in healthcare decision-making.The online version contains supplementary material available at 10.1186/s12889-021-11113-z. According to the global report, about 2.9 million babies die in the first month of life, of which preterm births, complications during pregnancy, and sepsis are the leading causes of death –3. PartiOn top of that, about 15 million babies are born too preterm (often before 37 completed weeks of gestation) each year, of whom more than one million died immediately after birth due to complications and lack of appropriate treatment . Many ofApproximately, 2.6 million stillbirths occurred each year, of which about 50% of the incidents occurred just after the onset of labor . About 8A variety of intertwined maternal, nutritional, environmental, and healthcare system factors contributed to the occurrence of adverse birth outcomes. Thus, advanced maternal age, level of education, antenatal care, home delivery, and healthcare access problems, and economic conditions, maternal clinical conditions like anemia, malaria, chronic illnesses, and HIV were determinants of adverse birth outcomes Fig.  13–20].–20.13–20The government and stakeholders made tremendous efforts to curb the magnitude and impacts of adverse birth outcomes. Furthermore, the reduction of adverse birth outcomes like LBW, stillbirth, and preterm births are the parts of the Sustainable Development Goal (SDG) targeted under goals 3.1 and 3.2 . FocusedMost of the studies conducted previously had been single-centered and facility-based which was less likely to be representative. In addition, there is a need for quality, large, and population based-studies from SSA countries where a large share of adverse birth outcomes occurred. Hence, this study aimed to assess the pooled prevalence and determinants of adverse birth outcomes in SSA. A better understanding of the adverse birth outcomes could provide more generalizable evidence to justify the better quality of maternal healthcare and improving accessibility of health services in low-income countries. Moreover, evidence from this study could be helpful to design and integrated efforts at the regional level to hasten favorable birth outcomes.The most recent Demographic and Health Surveys (DHS) of ten Sub-African (SSA) countries  data were used to make analysis of this study. The DHS is a part of the measure DHS programs that collect national information on basic health measures such as mortality, morbidity, and maternal and child health service utilization. Using the Kids Record (KR file) dataset, all births in the preceding five years before the survey were the study population. In the selected enumeration areas (EAs) births that had data about birth weight, gestational age at birth, and perinatal death records were included in the study. During the measure DHS survey, a multi-stage (two-stage) stratified sampling technique was used to select study participants; children were nested within the enumeration areas. After the dataset was appended, the weighted sample size became 76,853 children and women who had given birth five years preceding the survey. The methodology section of the DHS report goes into great detail about the study participant selection and data collection .The main outcome variable of this study was adverse birth outcomes, which is defined as the presence of at least one or more of the following conditions in recent pregnancy  , 19. TheSocio-demographic characteristics , health service utilization and accessibility , and obstetrics related characteristics  were explanatory variables identified after thorough review of literatures , 24–31 .Short birth interval is defined as the time between two births which is less than 24 months . Also, wp-values were selected and entered into the multivariable mixed-effect logistic regression model. Adjusted Odds Ratios (AOR) with a 95% CI were calculated in the multivariable model to see the strength of association between independent variables and adverse birth outcomes. Variables with a 0.05 p-value in the final model being used as a statistically significant determinant of adverse birth outcomes.Before any statistical analysis, the data were weighted using sampling weight based on primary sampling unit, and strata to restore the representativeness of the survey and take sampling design when calculating standard errors and reliable estimates. Cross-tabulations and summary statistics were done using STATA software version 14 . The pooled prevalence of adverse birth outcomes with a 95% Confidence Interval (CI) was reported using a forest plot. The DHS dataset has a hierarchical structure that failed to meet the standard logistic regression model assumptions of independent observation and equal variance. Meanwhile, the children were nested within a cluster household, and children from the same cluster were more similar than from other clusters. Therefore, a mixed effect logistic regression model (both fixed and random effect) was fitted to account for cluster variability by using the advanced models. The outcome variable of the study was binary, a standard logistic regression and Generalized Linear Mixed Models (GLMM) were fitted step by step. Because the models were nested, model fitness was compared using the Intra-class Correlation Coefficient (ICC), Likelihood Ratio (LR), Median Odds Ratio (MOR), and deviance (−2LLR) values. As a result, the mixed-effect logistic regression model with the lowest deviance value was selected as the most parsimonious model.  were between the ages of 20 and 29 years. Nearly two-thirds of mothers (62.5%) lived in rural areas, 19.7% had no formal schooling, and 83.8% were married at the time of data collection. Whilst more than one-third (34.3%) of women experienced physical violence (beating) from the intimate partner due to the reason of refusals for sex, neglect of a child, and goes out of home without telling to the husband  women had greater than 24 birth months’ of the interval from the preceding births and 15.2% were on the birth order of 6th and above , women-autonomy, distance to the health facility, parity, and twin birth were associated with adverse birth outcomes. Thus, the odds of adverse birth outcomes decreased among middle  and rich socioeconomic status  compared to poorer women. Similarly, for women who attended secondary and above levels of education, the odds of adverse birth outcomes decreased by 13%  than those who had no formal education. Likewise, antenatal care visits and multiparity birth associated with 14%  and 12%  lower odds of adverse birth outcomes compared to those who had no follow-ups and those primiparous women, respectively. In addition, female child associated with 6%  lower odds of adverse birth outcomes than males. Whilst, mothers who experienced intimate partner violence (beating) had 1.18  times higher odds of adverse birth outcomes than women with no such history. In the same way, for women who didn’t participate in healthcare decision-making, the odds of adverse birth outcomes were 1.10  times higher than participated in decision-making. Similarly, women who perceived distance to health facilities as big problems had 1.08  times higher compared to the counterpart. Furthermore, twin birth was associated with 2.89  times more likely to had adverse birth outcomes than singleton birth . Stillbirth rate was 11.5 per 1000 births, with preterm birth, fetal low birth weight, and macrosomia accounted for 7.6, 14.7, and 25.1% of all births, respectively. A woman’s level of education, socioeconomic status, intimate partner physical violence (beating), sex of child, women autonomy for health care decision-making, distance travel, twin birth, multiparity, and ANC follow-up were determinants of adverse birth outcomes. The rate of stillbirth in this study was lower than the results of 48.5 per 1000 births in Southeast Asia . This coVarious maternal and contextual factors are associated with adverse birth outcomes, thus distance travel to health facilities associated with higher odds of adverse birth outcomes. This finding was consistent with those of studies in Africa , 37, 38.In contrast, birth interval above 24 months is associated with a decreased risk of adverse birth outcomes. This finding was consistent with those of studies SSA , 43–45. This study also revealed that twin pregnancies were associated with increased risks of adverse birth outcomes. This finding was in agreement with previous studies , 47. ThiLikewise, women who didn’t participate in healthcare decision-making were more likely to had adverse birth outcomes than participated in decision makings . This miOn the other hand, women who had antenatal care visits for the recent birth were associated with lower odds of adverse birth outcomes than those who had no follow-up visits. This finding was consistent with those of studies in SSA , 37, 45.Similarly, better socio-economic attributes like a better level of education and wealthy economic conditions associated with a lower risk of adverse birth outcomes. This finding was consist of previous results , 35, 48.This research has implications for mothers, healthcare planners, and maternal health program coordinators who are working to develop evidence-based approaches to help achieve the Sustainable Development Goals (SDG). Furthermore, increasing healthcare access to rural and hard-to-reach areas and encouraging women’s involvement in healthcare decision-making could help to minimize the extent of adverse birth outcomes. Furthermore, healthcare providers should pay more time and attention to women who had a history of partner physical violence, multiple pregnancies and have difficult labors.This study has the strengths of a large sample size from multiple countries that would help to assess the regional situation of adverse birth outcomes. In addition, factors identified from these pooled studies might be used areas interventions for stakeholders. However, due to reasons of secondary data sources, some important clinical parameters like gestational diabetes and chronic disease conditions were not assessed. In addition, this study included only a few countries from the Sub-Saharan region that leads to under representations. Moreover, adverse birth outcomes reported in this study were based on the recent pregnancies from the Demography and health surveys.This study showed that the magnitude of adverse birth outcomes was high, abnormal baby size and preterm births were the most common types. Problems of adverse birth outcomes were more common among women who experienced intimate partner physical violence (beating), distance travel, multiple pregnancies, and lack of involvement in the healthcare decision-making process. According to the findings, improving maternal health services such as antenatal care is critical in reducing adverse birth outcomes. Furthermore, this research emphasizes the importance of paying particular attention to women who have had multiple births, expanding healthcare coverage to rural areas, and promoting women’s participation in the healthcare decision-making process.Additional file 1: Supplementary file Table 1: Model comparison and random effect results.


Intraoperative ultrasound (IUS) localization for breast cancer is a noninvasive localization technique. In 2015, an IUS program for breast-conserving surgery (BCS) was initiated in a large, integrated health care system. This study evaluated the clinical results of IUS implementation.The study identified breast cancer patients with BCS from 1 January to 31 October 2015 and from 1 January to 31 October 2019. Clinicopathologic characteristics were collected, and localization types were categorized. Clinical outcomes were analyzed, including localization use, surgeon adoption of IUS, day-of-surgery intervals, and re-excision rates. Multivariate logistic regression analysis was performed to evaluate predictors of re-excision.n = 79) in 2015 to 28% of lumpectomies (n = 632) in 2019 (p < 0.001). Surgeons using IUS increased from 6% (5 of 88 surgeons) in 2015 to 70% (42 of 60 surgeons) in 2019. In 2019, 76% of IUS surgeons performed at least 25% of lumpectomies with IUS. The mean time from admission to incision was shorter with IUS or seed localization than with wire localization . The IUS re-excision rates were lower than for other localization techniques , and IUS predicted lower re-excision rates in a multivariable model .The number of BCS procedures increased 23%, from 1815 procedures in 2015 to 2226 procedures in 2019. The IUS rate increased from 4% of lumpectomies (In a high-volume integrated health system, IUS was adopted for BCS by a majority of surgeons. The use of IUS decreased the time from admission to incision compared with wire localization, and decreased re-excision rates compared with other localization techniques.The online version contains supplementary material available at 10.1245/s10434-021-10454-8. Localization techniques include invasive procedures, such as placement of wires or radioactive/nonradioactive seeds, and noninvasive methods, such as intraoperative ultrasound (IUS).5 However, the disposables and consoles are expensive, and placement still requires an invasive procedure by a breast radiologist.Non-radioactive seeds can be placed before the day of surgery to decouple cancer localization from the day of surgery, improving patient experience and facilitating surgery scheduling.14 Importantly, IUS can be used for small, non-palpable breast cancers, which comprise the bulk of early-stage disease.16In contrast, IUS does not require an additional invasive procedure and uses ultrasound (US) units, which many operating rooms and surgery offices already own. The benefits include improved patient satisfaction, ease of scheduling, decreased radiology utilization, and decreased costs.13A growing number of surgeons use point-of-care US in training and practice, but IUS has not been used as much as other wire- or seed-based methods. This may be due to concerns about the investment of time and money into learning a new technique, although the learning curve for IUS is relatively short, requiring only a few operations.Nearly all published reports of IUS are single-institution studies, and a method of implementing an IUS program across a large group of surgeons and variety of surgery practices has not been described to our knowledge.17 The pilot project was expanded to a program throughout Kaiser Permanente Northern California (KPNC) hospitals and provided support for surgeons to acquire training and equipment as needed. In this study, we evaluated the adoption of IUS during a 4-year period by TPMG breast surgeons to determine use and efficacy of the new practice.In 2015, the Permanente Medical Group (TPMG), a large, integrated health care system, launched a pilot IUS project demonstrating rapid adoption of IUS with favorable outcomes.18The Research Determination Committee for KPNC determined that the project did not meet the regulatory definition of research involving human subjects per 45 CFR 46.102(d), and an Institutional Review Board review was waived. As an integrated health care system, KPNC has 21 medical centers and more than 4.7 million members. Membership is racially and ethnically diverse and represents the demographics of the northern California population except at the extremes of income.19 The Breast Surgery Group treats more than 4000 new breast cancer patients annually and has consolidated breast operations to high-volume surgeons who perform more than 50 breast operations per year and are committed to incorporating new evidence-based guidelines and techniques into their practices.In 2015, as part of an initiative to optimize subspecialty consistency and outcomes, TPMG established the Breast Surgery Group.21 and the adoption of nonopioid postoperative regimens19 are successful examples of this process.To optimize the quality and consistency of KPNC breast care further, the Breast Surgery Group developed a process that consists of initiating pilot projects at one or a few facilities, sharing findings with the remainder of the Breast Surgery Group, and then implementing best practices throughout KPNC. Both the KPNC Mastectomy Surgical Home Recovery program17 After determining that wire localizations could be decreased by 80% with similar re-excision rates and lumpectomy volumes, IUS was promoted as the most patient-friendly and operationally efficient method for locating breast lesions. Breast imagers across KPNC were requested to place US-visible clips into all lesions biopsied under US guidance and routinely include the o’clock position and distance from the nipple in their imaging reports to help orient surgeons and enable them to perform IUS.The IUS program was initiated in 2015 with a 10 month, four-facility pilot project (1 January to 31 October 2015). The project evaluated the feasibility of using IUS instead of wire-localization for nonpalpable, US-visible breast lesions, with larger goals of improving patient experience and operational efficiency.In addition, during breast cancer case conferences, breast imagers and surgeons reviewed the US images of patients with new diagnoses and indicated which patients were good candidates for IUS. The pilot-site surgeons created a tip sheet to assist breast surgeons in learning IUS . Suggestions included performing US in both the office and the operating room on all patients with superficial tumors larger than 1 cm to develop comfort and confidence with US visualization. To transition from wire localization to IUS, a stepwise sequence was recommended, starting with performing intraoperative US on US-visible tumors that had been wire-localized. This provided the security of the wire to guide surgical excision while enabling surgeons to develop confidence with US.When surgeons became comfortable visualizing wire-localized, US-visible lesions, the next stage was to request that breast imagers mark the skin overlying the tumor before surgery instead of placing a wire. When surgeons developed enough experience with skin-marked tumors, they progressed to IUS without a wire or skin marking. These practices helped avoid missing the tumor intraoperatively during the learning period.Discussions about IUS implementation were held during quarterly breast surgery leader meetings. Meanwhile, IUS champions within the Breast Surgery Group helped train other breast surgeons, both within and outside of their medical centers. Breast surgeons also were encouraged to take training courses. The Breast Surgery Group did not provide formal training courses, nor did it stipulate what type of training or how much training each surgeon needed to complete. Ultrasound units from 2016 onward were purchased for breast surgeons as needed by the KPNC Clinical Technology team, which develops contracts with vendors and purchases equipment for all KPNC facilities. Additional units were purchased by local facilities.We identified breast cancer patients who underwent breast-conserving surgery (BCS) during the pilot project period (1 January to 31 October 2015) and patients with BCS between 1 January and 31 October 2019 using the KPNC Breast Cancer Tracking Service (BCTS), which maintains a prospective database of all KPNC breast cancer patients. We included patients with a history of breast cancer, those who had undergone neoadjuvant chemotherapy, and those with oncoplastic procedures. Before 2018, we did not have distinct operating room procedure codes to differentiate between localization types, nor were non-radioactive seed localizations available in KPNC.The 2015 pilot project cohort provided the most accurate representation of IUS cases before 2018. In 2018, non-radioactive seeds became available in KPNC, and by 2019, operating room procedure codes had been established for IUS as well as for seed and wire localization, enabling reliable capture of these localization procedures. Cohort clinicopathologic characteristics were collected with KPNC HealthConnect electronic medical record (EMR) databases . The datapoints were age, race, body mass index (BMI), American Society of Anesthesiologists (ASA) physical status score, breast density, whether the patient’s diagnosis was determined after screening mammography or after a diagnostic exam for breast symptoms, history of breast cancer, receipt of neoadjuvant chemotherapy, and type of localization. Tumor characteristics included histologic type, tumor size, and receptor status.Outcomes included the extent of IUS utilization by individual surgeons. Other outcomes were time intervals on the day of surgery, with a focus on the time from admission to the time of incision; re-excision rates; and whether patients were able to continue with breast conservation or required a completion mastectomy.p value lower than 0.05. A multivariable logistic regression was used to determine independent predictors of re-excision and examine effects of patient and tumor characteristics, surgery, and localization type. We included all patients in 2019 with a localization procedure except for those with missing values.Clinicopathologic variables were summarized, and comparisons were made between the localization techniques using analysis of variance (ANOVA) for continuous variables and Pearson chi-square for categorical variables, with statistical significance defined as a p values higher than 0.1 in univariate regression and were not included in the multivariable analysis. All significant and clinically relevant variables were reported as significant if p was lower than 0.005 in the final model. All 230 statistical analyses were performed using SPSS Statistics version 22 .All the variables were placed into the model. Symptomatic presentation, BMI, and history of breast cancer had p <0.001; Fig. The number of breast-conserving operations increased 23%, from 1815 procedures in 2015 to 2226 procedures in 2019, and IUS lumpectomies increased from 4% to 28% of all lumpectomies (n = 14) used IUS for 50–100% of their localized lumpectomies, whereas 43% (n = 18) used IUS for 25–50% and 24% (n = 10) used IUS for 1–25% of these operations. Of the surgeons who adopted US in 2019, the total breast case volume in 2019 did not differ significantly from that of non-adopters , thus total surgeon operative volume did not appear to affect the decision to adopt IUS.We evaluated the distribution of IUS utilization among IUS surgeons and found that 33% of surgeons (p < 0.001) and a higher percentage of White patients . The localization cohorts also showed significant differences in breast density (p < 0.001). The percentage of patients with an ASA score above 2 was higher in the IUS cohort . A higher percentage of patients in the IUS group presented with symptomatic disease . Notably, the IUS group had a significantly lower percentage of patients with ductal carcinoma in situ (DCIS)  and a higher percentage of patients with T2 tumors  and invasive ductal carcinomas (IDC) . Finally, the IUS group had the highest percentage of hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancers .We compared the characteristics of the 2019 cohort by localization type (Table p < 0.001). In contrast, the time from incision to closure was significantly longer for IUS and seed than for wire .We evaluated the impact of localization type on different time intervals during the day of surgery Table . The timp < 0.001). The surgery day was significantly shorter for the lumpectomy patients and lumpectomy with sentinel node biopsy patients who had IUS or seed, and also shorter for the lumpectomy with axillary node dissection patients, although the difference did not reach statistical significance for the latter group.When we stratified by operation , we found similar trends with longer times for IUS and seed than for wire for each operation type, but these trends did not reach statistical significance. Despite the longer incision to closure times, the length of hospital stay from admission to discharge was significantly shorter for the IUS and seed patients than for the wire patients . The need for completion mastectomy was similar between the groups . The IUS margin re-excision rates for lobular carcinoma and DCIS were 32.1% (n = 53) and 26.2% (n = 42) respectively, both significantly higher than the 12.1% rate for IDC (n = 537) (p < 0.001). Finally, we evaluated differences in re-excision rates between the localization types Fig. . The IUSThe number of IUS cases per surgeon who adopted IUS ranged from 1–58 cases/surgeon in 2019, with a median of 13 cases. We evaluated the re-excision rate for each surgeon stratified by a case volume above or below the median of 13 cases. Those in the top 50% of IUS case volume had a mean re-excision rate of 12.5% (95% CI 8.4–16.6%), which was significantly lower than the mean re-excision rate of 20.6% for those in the bottom 50% (95% CI 8.6–32.6%).p < 0.001) than wire localization.We performed a multivariable logistic regression to determine predictors of re-excision Table . With thThis report describes the implementation of IUS for breast-conserving surgery in a large, integrated health care system. During a period of 5 years, the percentage of IUS lumpectomies increased from 4 to 28% of all breast cancer lumpectomies. In 2019, 70% of breast surgeons used IUS. The average length of the surgery day was significantly shorter with IUS than with wire localization, although operations with IUS required more time than wire-localization operations. The re-excision rates were lower for IUS than for any other localization technique. Overall, the implementation of IUS across our health system has been successful and effective.23 or pilot studies with only a few centers.17 In contrast, our study describes the largest reported cohort of IUS patients (n = 632) and surgeons (n = 42). Consistent with our findings, prior studies have compared IUS to wire localization and found significantly lower rates of re-excision with IUS.26 However, our study expanded on previous studies by examining an additional method of localization (non-radioactive seeds), evaluating the impact of localization type on time intervals on the day of surgery and evaluating predictors of re-excision.Previous studies have described single-institution experiences with small numbers of surgeonsNotably, the IUS program developed largely through voluntary adoption of this technique by breast surgeons throughout Northern California in partnership with their local breast-imaging teams. In contrast to other studies, this study had no standardized protocols, formal training, or defined patient selection criteria. Tumor size, depth in the breast, breast size, and density were not strictly used as criteria for IUS, but ability to visualize the clip and/or mass in the office at the initial consultation by the surgeon was required.The decisions about speed of progression through the steps to independent IUS and candidacy for IUS were at the discretion of individual surgeons. Utilization of IUS was based on surgeons’ confidence as they gained experience with the technique. The distribution of IUS utilization among surgeons in 2019 may reflect differences in level of experience. More experienced surgeons may have had the confidence to use IUS rather than wire or seed localization for a larger percentage of their lumpectomies. Adoption of IUS did not appear to be related to breast surgeon case volume, and may have been driven more by non-surgeon-specific factors .25The majority of IUS patients had tumors easily visible with US, most IUS patients (92%) had T1 or T2 tumors, and 85% had IDC. We hypothesize that some surgeons used IUS in conjunction with palpation, which may have accounted for the decrease in palpation-guided lumpectomies from 27% in 2015 to 19% in 2019. In addition, IUS may have helped improve re-excision rates for these tumors, similar to a report by investigators who conducted a randomized prospective trial evaluating the use of IUS for palpable lesions.In contrast to the patients with IDC and T1 or T2 tumors who comprised the majority of the IUS cohort, only 7% of the IUS patients had DCIS. Furthermore, only 28% of all the DCIS patients underwent IUS, whereas the remaining 82% had wire or seed localizations. These findings likely reflect the fact that most DCIS patients present with calcifications, which typically are not US-visible, although US-visible clips are placed after stereotactic biopsies at some KPNC facilities. We anticipate that as more breast imagers place US-visible clips for stereotactic biopsy of calcifications and more surgeons become comfortable visualizing the clips and smaller tumors, more patients with small tumors or DCIS will become candidates for IUS.p < 0.001). We hypothesized that selection bias may have contributed to the low IUS re-excision rates because 85% of the IUS patients had IDC, while only 8% had ILC and 7% had DCIS. With IDC, which typically presents with a well-defined tumor, clear surgical margins are easier to obtain than with the more diffuse ILC and DCIS patterns.27 Furthermore, a larger percentage of IUS patients presented with symptomatic tumors and T2 tumors. The ability to palpate the disease during the lumpectomy probably improved the rates of successful surgical clearance. Despite selection bias, the fact that re-excision rates were not worse with IUS than with other techniques and the finding that IUS was a predictor of low re-excision rates in the multivariable analysis suggest that IUS is an oncologically safe alternative to wire and seed localization techniques.The magnitude of the difference in re-excision rates between IUS and the other techniques was unexpected  to assess whether levels of anxiety and overall levels of satisfaction differed between the different localization types. We also lacked PROs regarding pain associated with localization and/or the breast operation or satisfaction with aesthetic outcomes. The Breast Surgery Group currently is developing and testing PRO tools to capture these data for future studies.In conclusion, implementation of an IUS localization program is efficient and feasible for a large, high-volume, multiple medical center practice. Adoption of an IUS localization program required coordinated system changes between surgeons and breast imagers, resulting in significant increases in utilization of IUS over time. The benefits of IUS include avoiding an additional invasive procedure, freeing up breast-imaging department time and personnel to perform other services, and decreasing the length of stay on the day of surgery. Intraoperative ultrasound can be used for the majority of breast cancers, and in this study resulted in lower re-excision than wire or seed localization. We will continue to evaluate how IUS improves patient satisfaction and operative outcomes and anticipate expanding its utilization as surgeons mature in their IUS practices.Tip Sheet for starting an intraoperative ultrasound (IUS) localization program. Supplementary file1 (DOCX 16 kb)Below is the link to the electronic supplementary material.


As indicated by the World Health Organization, preterm birth is a relevant public health issue, being one of the leading causes of death in children under five years of age. Its incidence has been increasing in most countries, with inequalities in terms of survival rates and negative outcomes around the world ,2. PreteThe articles included in this Special Issue will add new considerations on prematurity, focusing on: (a) the effect of preterm birth on developmental outcomes from early life to adulthood, taking into account risk and protective factors; (b) the role of parenting and social environment; and (c) interventions that can promote the well-being of preterm children and their families.The first section of articles explores the effect of preterm birth on developmental outcomes from infancy to adulthood. Some articles reveal that preterm participants show significant differences with respect to normative values and control groups. A higher incidence of learning impairments in very preterm children , compared to normative values, is described at the end of primary school . Delays These studies confirm the need to overcome the notion of impaired versus intact domains suggesting that, as proposed for other populations with atypical development, scores in the normal range or the absence of differences between preterm and control groups do not necessarily provide evidence of typical developmental trajectories . In addiA second section of the studies analyses the role of parenting and social environment in modulating the effect of preterm birth on developmental outcomes. Concerning parenting, a first study analyses the complex relationship among gestational age (32–41 weeks of gestation), attention capacities, and maternal sensitivity at 18 months and receptive and expressive language at 24 months, revealing an effect of gestational age on receptive language, both direct and indirect, through the child’s alerting attention, and a direct effect of maternal sensitivity on expressive language . A seconThe studies grouped in this second section stress the importance of identifying the factors that may mediate the effect of preterm birth on developmental outcomes, opening up new research challenges on possible cascading effects in the preterm population . In addiThe last section includes two articles that describe interventions to support families and promote the child’s skills. Preterm birth has an important impact on parents and families, especially when it occurs before 28 weeks of gestational age. Indeed, in the first year at home, the parents of children born in Sweden report prolonged worries for the child and their own emotional state, and they appreciated a post-discharge home-visiting program to support parent–child interaction and encourage well-being for parents and children . A seconThe promising results of both studies suggest the relevance of proposing short, ecological and cost-effective programs for preterm children and their families in order to enrich their environment, modify constraints, and increase protective factors .In conclusion, this Special Issue confirms that an interdisciplinary approach is mandatory to understand the complexity of the risk factors affecting preterm birth and to promote protective factors in order to support the families and children’s developmental trajectories. Only by integrating the results of studies carried out in collaboration among different professional areas of expertise, including paediatricians, psychologists, therapists, educators and teachers, can we improve the care of preterm children by taking into account their family and educational context. Secondly, multiple assessment points, integrating standardised assessment and observation in ecological contexts and emphasizing longitudinal design and multimethod approaches are the best way to grasp the complexity of the phenomenon. Finally, this Special Issue addresses the need to support vulnerable populations, improve follow-up programmes, and develop new interventions to promote the well-being of preterm born children and their families.


Leiomyoma is the most common benign uterine tumor in reproductive-age women. Increasing numbers of studies are focusing on the effects of environmental exposure on the incidence and progression of tumors. One major step taken in the food industry is the addition of food preservatives to maintain freshness. Butylated hydroxytoluene (BHT) is a synthetic phenolic antioxidant, which is widely used as an additive to develop fat-soluble characteristics, as well as in cosmetics and rubber. Previous studies also highlighted that BHT may be related to increased fibrosis capacity and carcinogenic effects. In this study, we explored the effects of the commonly used food additive BHT on leiomyoma progression, and the related mechanism. The exposure of the ELT-3 leiomyoma cell line to BHT for 48 h increased the proliferative effect. Since leiomyoma progression is related to increases in extracellular matrix (ECM) accumulation and matrix metalloproteinase (MMP), BHT could effectively increase ECM-related protein expression, as well as MMP-2 and MMP-9 protein expression. This increase in ECM, in response to BHT, may be linked to the activation of the phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) signaling pathway. Through PI3K inhibition, BHT’s effect on leiomyoma progression could be partially modulated. These results suggest the harmful effect of BHT exposure on leiomyoma progression may relate to PI3K modulation. However, an in vivo study is necessary to confirm these findings. Leiomyoma (aka uterine fibroids) are the most common benign uterine tumors in reproductive-age women, with an incidence rate of more than 70% ,2. CliniAlthough the pathogenesis of uterine leiomyoma is still not entirely clear, one of the most commonly accepted hypotheses is the accumulation of extracellular matrix (ECM) ,8. ExtraLeiomyoma cells express significantly higher levels of ECM components than normal uterine smooth muscle cells . Under nWith the progression of ECM deposition, intracellular signaling pathways are triggered, such as the mitogen-activated protein kinase (MAPK) and PI3K/Akt (protein kinase B (PKB)) pathways, which increase proliferation and cell survival and maintain the ECM’s deposition microenvironment in leiomyoma ,16.Considering the rapidly increasing consumption of food additives, more and more studies are revealing their potentially harmful and toxic effects. To preserve food freshness, antioxidant additives are widely used. Butylated hydroxytoluene (BHT) is one of the most commonly used antioxidant additives, which can improve the stability of fat-soluble vitamins and cosmetics and prevent spoilage . As food2) [The Eker rat-derived uterine leiomyoma ELT3 cell line was provided by Dr. Lin-Hung Wei . Cells were cultured in Dulbecco’s modified Eagle medium/Ham’s F-12 Medium in a 1:1 ratio , supplemented with 10% fetal bovine serum , 100 units/mL penicillin , 100 μg/mL streptomycin, sodium bicarbonate , and 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid  under cultured conditions  . The cells were starved in serum-free medium for 24 hours and then treated with BHT in 1% FBS medium for 24, 48, and 72 h.The effect of BHT  on cell viability was analyzed using the MTT  assay. After treatments, 1 mg/mL MTT in phosphate-buffered saline was added and incubated for an additional 3 h. The formazan crystals were dissolved in 100 μL dimethyl sulfoxide . The optical density was measured using a VERSA Max microplate reader  at 570 nm and 630 nm. We used the absorbance of the control group as the denominator to calculate the cell viability percentage.Cells were seeded in 6-well plates (500 cells/well) and treated with different concentrations of BHT for 48 h. After 48 h, we removed the medium and replaced it with a completed medium, which we then cultured for 1 week. The colonies were fixed with methanol  and stained with 0.5% crystal violet (Sigma-Aldrich) . We thenAfter the treatments, the cells were fixed in 4% paraformaldehyde (Sigma-Aldrich) for 10 minutes at room temperature, treated with 0.5% Triton X-100 in PBS for 10 minutes, and then blocked with 5% bovine serum albumin (BSA for 30 minutes at room temperature), following with previous study . The celCell lysates were homogenized with ice-cold RIPA buffer containing protease  and phosphatase inhibitor . Following quantification, 30 μg of protein was boiled for 5 minutes, then separated using 10% or 15% SDS–polyacrylamide gel electrophoresis and transferred to polyvinylidene fluoride membranes (0.22 µm). Nonspecific binding sites were blocked with blocking buffer (5% BSA) for 1 h at room temperature, and the membranes were incubated with the primary antibodies for proliferating cell nuclear antigen (PCNA) , matrix metallopeptidase 9 (MMP-9) , MMP-2 , collagen type I (COL1A1) , alpha-smooth muscle actin (α-SMA) , PI3K , p-Akt , Akt , extracellular-signal-regulated kinase (ERK) , p-ERK , p38 MAPKinase , p-p38 , and glyceraldehyde-3-phosphate dehydrogenase (GAPDH)  at 4 °C overnight. The membranes were washed and incubated for 2 h with anti-rabbit/mouse IgG coupled with alkaline phosphatase  and then washed with TBST buffer. The bands were detected using ECL and visualized with the eBlot Touch Imager tm . The values shown were normalized to the internal control GAPDH and analyzed via the ImageJ software. t-test and one-way analysis of variance (ANOVA), and we used Tukey’s test for post-mortem analysis. p < 0.05 indicates a statistically significant differenceData are expressed as mean ± standard deviation. Statistical analysis was performed with Graphpad Prism version 9 , using Student’s We used MTT as the cell proliferation assay to evaluate the changes in cell viability following BHT exposure in ELT-3 cells. The ELT-3 cells were seeded in a 96-well plate for 24 h. After starvation for 24 h, they were treated with a graded concentration of BHT (0.1–25 µM) for 24 and 48 h. All the concentrations used for the 48 h treatments could significantly increase leiomyoma cell viability A,B, indiTo investigate the long-term effect of BHT on ELT-3 cell proliferation and its ability to stimulate stem cell characteristics, such as colony formation, a colony formation assay was performed after BHT exposure for 48 h and the replacement of the complete medium. The results show that BHT could significantly increase colony formation E, as eviImmunofluorescence was used to measure the protein expression of MMP-9 and MMP-2 following 48 h of BHT exposure. The intensity of fluorescence was significantly increased in both MMP-9 and MMP-2, indicating that BHT enhanced the levels in live cells A–C.Matrix metalloproteinases act as a regulator of ECM accumulation. Western blot analysis confirmed that BHT exposure could significantly increase MMP-9 D and MMPImmunofluorescence was used to measure the protein expression of α-SMA and COL1A1 following 48 h of BHT treatment. The intensity of fluorescence was significantly increased in both α-SMA and COL1A1 A–C.The overexpression of extracellular matrix-related proteins contributes to leiomyoma progression. Therefore, we explored ECM-related protein expression in response to BHT treatments, including COL1A1 and α-SMA as confirmation for previous immunofluorescence results. Our results were consistent with the fluorescence intensity results. Moreover, BHT exposure induced the significant protein expression of COL1A1 and α-SMA D,E. Collp-Akt/Akt protein expression , and modulates cancer cell survival, proliferation, and apoptosis, therefore playing an important role in cancer progression  and in lThe pathogenesis of uterine leiomyoma is still not clear, but leiomyoma growth is estrogen- and progesterone dependent, which indicated hormone dependence plays an important role in leiomyoma progression ,33. StudFood additives maintain quality, taste, and freshness . For fooStudies exploring the toxicity of BHT have been inconsistent. One study highlighted its positive effects based on its antioxidant activity, ability to increase intracellular antioxidant enzyme levels , and antBHT was found to be harmful to metabolic- and reproductive-related diseases. In reproductive disorders, the exposure of mouse Leydig cells (TM3) with BHT suppressed cellular proliferation, altered the cell cycle, and changed the cytosolic and mitochondria calcium homeostasis . In addiAntioxidant enzymes could eliminate oxidative stress. Manganese superoxide dismutase (MnSOD), on the other hand, could act as a tumor suppressor  and promStudies showed that BHT interacts with PI3K/Akt and MAPK signaling modulation and enhances fibrosis . An injeIn the current study, BHT’s role in leiomyoma progression was explored for the first time. BHT increased proliferative effect, increased ECM-related protein expression, and induced ECM accumulation, which is essential to leiomyoma progression. Additionally, in vitro experiments showed that BHT exposure could alter protein expression, in addition to activating the PI3K/Akt and MAPK signaling pathway. The study shows, for the first time, that BHT exposure could increase the leiomyoma progression, indicating that it may participate in PI3K and MAPK signaling pathways. However, the in vitro study used could not fully explain the role of BHT in leiomyoma. The metabolites of BHT may play different roles in leiomyoma progression; therefore, further animal studies are needed to realize its effect in the future.Environmental exposure to BHT could be associated with several disease disorders and disadvantages. Using the ELT-3 rat leiomyoma cell model, the results shed light on BHT’s potential in enhancing leiomyoma cell proliferation, colony formation, and ECM accumulation in a mechanism that might involve modulation of PI3K/Akt and MAPK signaling pathways . It is t