Assess urgent care (UC) clinician prescribing practices and factors associated with first-line antibiotic selection and recommended duration of therapy for sinusitis, acute otitis media (AOM), and pharyngitis.Retrospective cohort study.All respiratory UC encounters and clinicians in the Intermountain Health (IH) network, July 1st, 2019–June 30th, 2020.Descriptive statistics were used to characterize first-line antibiotic selection rates and the duration of antibiotic prescriptions during pharyngitis, sinusitis, and AOM UC encounters. Patient and clinician characteristics were evaluated. System-specific guidelines recommended 5–10 days of penicillin, amoxicillin, or amoxicillin-clavulanate as first-line. Alternative therapies were recommended for penicillin allergy. Generalized estimating equation modeling was used to assess predictors of first-line antibiotic selection, prescription duration, and first-line antibiotic prescriptions for an appropriate duration.Among encounters in which an antibiotic was prescribed, the rate of first-line antibiotic selection was 75%, the recommended duration was 70%, and the rate of first-line antibiotic selection for the recommended duration was 53%. AOM was associated with the highest rate of first-line prescriptions (83%); sinusitis the lowest (69%). Pharyngitis was associated with the highest rate of prescriptions for the recommended duration (91%); AOM the lowest (51%). Penicillin allergy was the strongest predictor of non–first-line selection  and was also associated with extended duration prescriptions .First-line antibiotic selection and duration for respiratory UC encounters varied by diagnosis and patient characteristics. These areas can serve as a focus for ongoing stewardship efforts. The rate of first-line antibiotic use in outpatient settings, including emergency departments and retail/urgent care clinics, has been reported as approximately 50%: lower than national goals even after accounting for treatment failures and documented penicillin allergy. Antimicrobial stewardship efforts often prioritize the decision of whether or not to prescribe an antibiotic for a given condition along with optimizing antibiotic selection. Duration of therapy is also an important antibiotic stewardship target and inappropriate antibiotic prescription durations have been described for a variety of outpatient conditions. Nationally, in all age groups, pharyngitis, sinusitis, and acute otitis media (AOM) account for over 50% of all outpatient respiratory antibiotic prescriptions and this figure is over 70% in children, highlighting the need to focus ambulatory stewardship efforts on respiratory encounters. Additionally, there have been calls to reduce antibiotic use by decreasing the duration of therapy for sinusitis and AOM.Most antibiotic use originates in the ambulatory setting and an estimated one-third of outpatient antibiotic prescriptions are thought to be unnecessary. Since 2019, UC centers have exhibited a 60% increase in patient volume, and this trend is forecast to continue in the coming years. Compared to other outpatient settings, UC encounters result in more overall and unnecessary antibiotic prescriptions. Respiratory tract infections, which are often associated with inappropriate antibiotic prescribing, are among the most common types of diagnoses evaluated in UC. While some studies have previously evaluated antibiotic selection and duration separately and in tandem for infectious conditions managed in pediatric UC settings, further understanding of these choices for UC sites that serve both adult and pediatric populations is needed.Urgent care (UC) centers have been one of the fastest-growing settings for outpatient care delivery in the United States (US). During this intervention, the Intermountain Health (IH) UC network reduced antibiotic prescribing in respiratory encounters from 48% to 33% over a 1-year period. Herein, we describe further opportunities for improvement by examining respiratory UC encounters where an antibiotic was prescribed during this period of decreased antibiotic prescribing. We assessed clinician prescribing practices and adherence to first-line antibiotic selection and duration of therapy recommended by institution-specific evidence-based guidelines for pharyngitis, sinusitis, and AOM. We also sought to identify factors associated with first-line and non–first-line antibiotic selection and extended-duration prescriptions to guide future stewardship efforts across our UC network.We have previously shown the impact of a multifaceted antibiotic stewardship intervention on reducing outpatient antibiotic prescriptions for respiratory UC encounters in a large integrated healthcare system.International Classification of Diseases, 10th Revision, Clinical Modification (ICD10) codes. We excluded clinicians and their encounters if they had fewer than 25 UC encounters during the study. Additionally, encounters with missing provider information were excluded. Sinusitis, pharyngitis, and AOM encounters in which an antibiotic was prescribed were assessed for first-line antibiotic selection and appropriate duration of therapy based on system-specific evidence-based guidelines using orders captured via the electronic health record (EHR). Prescription information, including the drug name and the duration of the prescription, was electronically extracted from the record. Antibiotic allergies were identified in the EHR along with patient demographic data. Race, ethnicity, and gender data are indicated by patients during the registration process for all encounters that occur throughout the IH system. Clinicians were characterized as either an MD/DO clinician or an advanced practice clinician (APC) ).This was a retrospective cohort study of pharyngitis, sinusitis, and AOM encounters in the IH UC network from July 1st, 2019 through June 30th, 2020. IH is a nonprofit, integrated, healthcare delivery system in the Mountain West and during the study period operated 38 UC clinics, which included 32 providing care for patients of all ages (“InstaCare”) and six providing care exclusively to children fewer than 18 years old (“KidsCare”). InstaCare is staffed predominantly by family medicine physicians while KidsCare is exclusively staffed by pediatricians. Pharyngitis , sinusitis, and AOM UC encounters were identified using a validated methodology based on the First-line therapy for pharyngitis was penicillin or amoxicillin and the recommended duration was 10 days. In patients with acute sinusitis, amoxicillin or amoxicillin-clavulanate depending on disease severity was considered first line and the recommended duration was 7 days in adults and 10 days in pediatric patients. In patients with AOM, amoxicillin or amoxicillin-clavulanate was the first-line therapy. For patients with AOM younger than 2 years old and those with severe AOM, the recommended duration was 10 days and 5–7 days in all other patients. In patients with a penicillin allergy, alternative second-line antibiotics were recommended. The recommended duration of therapy for penicillin-allergic patients receiving second-line antibiotics was the same as patients receiving first-line therapy except for those receiving azithromycin for pharyngitis or ceftriaxone for AOM. Because we were unable to assess disease severity in AOM, the shortest age-specific recommended duration  was considered appropriate in AOM encounters. Prescriptions exceeding the recommended duration were considered inappropriate while those equal to or less than the recommended duration were considered appropriate. Institution-specific guideline-recommended first and alternative second-line antibiotics for the conditions studied along with recommended durations for prescriptions are summarized in Table  A P-value of <.05 was considered statistically significant. The Institutional Review Board of Intermountain Health approved this study and waived informed consent.Descriptive statistics were used to characterize first-line antibiotic selection, appropriateness of duration of antibiotic prescriptions, and a combined outcome of first-line antibiotic prescriptions for an appropriate duration across each condition as well as provider (MD/DO vs APC) and clinic type (InstaCare vs KidsCare). To examine factors associated with first-line antibiotic prescriptions, appropriate duration prescriptions, and a combined outcome of first-line antibiotic prescriptions for an appropriate duration, we applied univariate and multivariable generalized estimating equation (GEE) models. GEE models allow for the analysis of correlated data by estimating the population-averaged effects of covariates on the outcome variables. Models here accounted for correlation within providers and multivariable models were adjusted for all factors examined.(Table ). 31,558 (58.4%) encounters occurred for female patients, 50,437 (93.7%) encounters were for White patients, and 47,690 (90.1%) occurred in non-Hispanic patients. 76.4% of clinicians were MD/DO and 23.6% were APC (NP/PA) clinicians. The majority occurred in InstaCare clinics (93.5%). Penicillin allergy was documented in 6,380 (11.8%) encounters in which an antibiotic was prescribed. The most commonly prescribed antibiotics for the included conditions were amoxicillin (61.5%), doxycycline (9.9%), amoxicillin-clavulanate (8.9%), cefdinir (7.3%), and penicillin VK (4.0%). Most patients received an oral antibiotic prescription, with only 1,092 (2.0%) patients receiving a parenteral antibiotic, and most of these (n = 887) were for pharyngitis. Patient and provider characteristics for all encounters associated with an antibiotic prescription are presented in Table During the study period, 98,510 encounters for sinusitis, AOM, or pharyngitis were identified. Of these, 94,228 met inclusion criteria and represented 83,886 unique patients which were seen by 270 clinicians. There were 27,601 (29.3%) encounters for sinusitis, 13,743 (14.6%) for AOM, and 52,884 (56.1%) for pharyngitis. A total of 54,072 (57.4%) encounters resulted in an antibiotic prescription, with AOM (94.5%) demonstrating the highest antibiotic prescription rate followed by sinusitis (84.3%), and pharyngitis (33.7%). For the antibiotic-treated population, the mean age of patients was 29.4 (SD 19.9) with 33.1% of patients ≤ 18 years old Overall, among encounters where an antibiotic was received, the rate of first-line antibiotic prescriptions was 74.5%. Sinusitis encounters received first-line therapy in 16,016 (68.9%) encounters, pharyngitis in 13,483 (75.6%) encounters, and AOM received first-line antibiotic therapy in 10,788 (83%) encounters. An appropriate duration was prescribed in 37,699 (69.7%) encounters. 6,665 (51.3%) AOM encounter prescriptions were for an appropriate duration compared to 14,893 (64%) sinusitis and 16,141 (90.6%) pharyngitis. Only 28,655 (53.0%) encounters received a first-line antibiotic for an appropriate duration. This varied by condition: 5,674 (43.7%) AOM encounters, 10,526 (45.3%) sinusitis encounters, and 12,455 (69.9%) pharyngitis encounters. MD/DO and APCs had similar rates of first-line antibiotic prescriptions for an appropriate duration (52.8% vs 53.8%). Among encounters with a documented penicillin allergy, 545 (8.5%) received a first-line antibiotic prescription compared to 39,742 (83.3%) without a documented penicillin allergy. Among those with a penicillin allergy, 4,771 (74.8%) received a recommended second-line agent and 1,064 (16.7%) received neither a first- nor second-line agent. The 5,835 encounters with a documented penicillin allergy that did not receive first-line therapy accounted for 42.3%  of all encounters that did not receive first-line therapy.(Table ). Sinusitis  and pharyngitis  encounters were less likely to receive a first-line antibiotic prescription compared to AOM but AOM encounters were also least likely to receive a prescription for an appropriate duration  compared to pharyngitis. Older patients were less likely to receive a first-line antibiotic prescription, per 1-year increase in age  but no association was identified between appropriate duration prescriptions and age . Female patients were more likely to receive a first-line antibiotic prescription  as well as prescriptions for an appropriate duration . Compared to non-White patients, White patients were less likely to receive a first-line antibiotic prescription  or an antibiotic prescription for an appropriate duration . Non-Hispanic and Hispanic patients were similarly likely to receive a first-line antibiotic prescription however non-Hispanic patients were less likely to receive an antibiotic prescription for an appropriate duration . KidsCare UC centers were more likely to provide an antibiotic prescription for an appropriate duration  or a prescription for an appropriate duration .Univariate and multivariable GEE modeling, while accounting for correlation within providers, was performed to examine factors associated with first-line prescriptions and appropriate duration Table . Sinusi(Table ). Among diagnosis groups, pharyngitis encounters were most likely to have prescriptions fulfilling both criteria  while AOM encounters were least likely. With each 1-year increase in age, first-line antibiotic prescriptions for an appropriate duration became less likely . Female patients  and encounters at KidsCare UC centers  were more likely to receive first-line antibiotic prescriptions for an appropriate duration. Compared to encounters without a penicillin allergy, those with a penicillin allergy were less likely to receive a first-line antibiotic prescription for an appropriate duration .GEE modeling was also applied to examine factors associated with first-line antibiotic prescriptions for an appropriate duration Table . Among While 75% of encounters in which an antibiotic was prescribed were associated with a first-line antibiotic and 70% with an appropriate duration, only 53% of encounters were associated with a first-line antibiotic prescription for an appropriate duration. This indicates substantial opportunity to improve respiratory UC antibiotic prescribing beyond the decision to prescribe an antibiotic. Our analysis also revealed differences in first-line prescribing across age, gender, and race and differences in appropriate duration between gender, race, and ethnicity. could have a large effect on improving outpatient prescribing as previously reported. Interestingly, in our study 545 (8.5%) encounters with penicillin allergy received first-line therapy suggesting that some clinicians may have questioned the veracity of the documented allergy. Penicillin allergy also conferred a higher likelihood of an extended duration prescription despite guidelines suggesting similar durations of therapy for most alternative second-line agents recommended for penicillin-allergic patients. Further study is needed to understand this unexpected finding. One potential explanation could be that certain clinical characteristics differ between patients with and without allergy which in turn lead clinicians to treat penicillin-allergic patients with longer antibiotic courses. The differences we observed do not appear to be entirely related to allergy prevalence: penicillin allergy in non-White patients receiving an antibiotic was 8.3% compared to 12.0% of White patients. Prior studies have demonstrated higher rates of penicillin and beta-lactam allergy in adult and pediatric White patients. The rate of penicillin allergy in our overall population was 11.6%, similar to that of the general population.Unsurprisingly, a documented penicillin allergy impacted first-line antibiotic selection. In our study, penicillin allergy conferred the highest risk of receiving a non–first-line antibiotic. Collectively, patients with a documented penicillin allergy only accounted for 11.8% of encounters in which an antibiotic was prescribed, but more than 40% of non–first-line prescriptions. This suggests that delabeling penicillin allergies, many of which are inaccurate for a variety of reasons, Despite elderly patients being a small proportion of our population, these findings highlight the opportunity to further improve antibiotic prescribing in these patients. Our findings for pediatric patients, supported by age and clinic-type data, are consistent with existing literature. Gender and race were predictors for first-line antibiotic selection along with appropriate duration prescriptions, and ethnicity was also associated with appropriate prescription duration. There may be differences in patient expectations or demands not captured by our study contributing to these findings.Older patients were less likely to receive a first-line agent or a first-line agent for an appropriate duration. While patients ≥65 years old represented approximately 5% of our study population, only 39.1% of encounters in this age category received a first-line antibiotic for an appropriate duration. while others demonstrate similar prescribing rates for MD/DO and APC providers. We identified similar practices for both clinician types. While it was not a primary or secondary objective of our study, we noted similar interprovider variability for measured outcomes among both provider types . This finding could reflect the IH UC system involving all clinicians in education, tracking, and an organizational commitment to stewardship efforts. Both MD/DO and APC providers participate equally in education and tracking efforts and receive the same academic detailing communications. Recent data suggest shorter courses of therapy are sufficient for sinusitis and AOM in certain situations, and our findings emphasize the opportunity to improve the duration of antibiotic prescriptions among all clinicians.Some studies suggest higher prescribing rates by APCs Despite institutional guidelines suggesting durations of 5–7 days for sinusitis and AOM, encounters for penicillin-allergic patients were associated with a longer-duration prescription. These findings provide an opportunity to emphasize and reinforce first-line selection while also providing education regarding the appropriate duration of antibiotic therapy.Overall, the rate of first-line prescribing remained less than 80%. 80% has been proposed as the target rate for first-line antibiotic prescribing, providing some margin for when non–first-line therapy may be appropriate due to first-line failure and penicillin allergy. Our study has limitations. First, we relied solely on ICD10 codes and did not assess for concordance between coding and the clinical diagnosis despite using a validated methodology. Second, we defined the appropriate duration for AOM in patients older than 2 years of age as 7 days or less while our institutional guideline recommends 10 days of therapy for severe AOM. However, our data extraction methods were unable to account for severity which could have led to an underestimation of appropriate duration prescriptions. Similarly, for our analysis, we defined the appropriate duration for sinusitis as 7 days when our pediatric guideline recommended 10 days, though efforts are underway to update this guideline to recommend a shorter duration. The rates of sinusitis in the pediatric population were low (7.7%), but this also may have underestimated the rate of appropriate duration prescriptions. Patient-preferred language, geography, and socioeconomic variables not assessed could have created a differential impact on access to care or expression of expectations and thus affected antibiotic selection and prescription duration as well. We did not examine what percentage of non–first-line therapy was due to failure or adverse events on first-line antibiotics. However, 1,353 (2.5%) of all encounters with an antibiotic occurred within 30 days of a previous encounter with an antibiotic prescription. Of these, 528 (39.1%) received a first-line antibiotic. For these second antibiotic-associated encounters, we were unable to capture if the prescription associated with the initial encounter was filled, or how much of the initial prescription was consumed. While we did not exclude encounters occurring within 30 days of an initial encounter, the first-line prescribing rate for encounters where there was not a subsequent antibiotic-associated encounter within 30 days was 75.4%, similar to our findings when examining all antibiotic-associated encounters. Lastly, we did not examine the appropriateness of antibiotic initiation and it is possible a proportion of prescriptions were not indicated.While some of our study encompassed the COVID-19 pandemic, we did not observe an impact on antibiotic selection or prescription duration. Despite an increase in azithromycin use nationwide, we noted a decrease in azithromycin use from 4.5% in July 2019 to 1.2% in June 2020 and during March 2020–June 2020, azithromycin prescribing rates for respiratory UC encounters in our system remained less than 3%. there exist significant opportunities to improve prescribing practices beyond the Antibiotic Use for Respiratory Conditions Healthcare Effectiveness Data and Information Set (HEDIS) metric. Our findings emphasize the importance of delabeling antibiotic allergies when feasible and appropriate. Healthcare systems should also consider strategies such as prospective audit and feedback and peer comparison dashboards to improve the duration of antibiotic prescriptions given the success of these approaches in other areas of outpatient stewardship. First-line antibiotic prescriptions for an appropriate duration could also be a useful measure to evaluate antibiotic use for conditions where antibiotics may or may not be indicated while also being actionable and relevant to clinicians. Optimizing prescriptions for first-line antibiotics should not be considered separate from optimizing the duration of therapy: both are key components of antibiotic stewardship and a dual focus on antibiotic selection and duration should be considered as antibiotic stewardship interventions and metrics are further developed.Even in large vertically integrated healthcare systems with robust stewardship programs and amidst sustainable interventions that reduce respiratory antibiotic prescribing,Seibert et al. supplementary material


The production of concrete leads to substantial carbon emissions (~8%) and includes reinforcing steel which is prone to corrosion and durability issues. Carbon-fiber-reinforced concrete is attractive for structural applications due to its light weight, high modulus, high strength, low density, and resistance to environmental degradation. Recycled/repurposed carbon fiber (rCF) is a promising alternative to traditional steel-fiber reinforcement for manufacturing lightweight and high-strength concrete. Additionally, rCF offers a sustainable, economical, and less energy-intensive solution for infrastructure applications. In this paper, structure–process–property relationships between the rheology of mix design, carbon fiber reinforcement type, thermal conductivity, and microstructural properties are investigated targeting strength and lighter weight using three types of concretes, namely, high-strength concrete, structural lightweight concrete, and ultra-lightweight concrete. The concrete mix designs were evaluated non-destructively using high-resolution X-ray computed tomography to investigate the microstructure of the voids and spatially correlate the porosity with the thermal conductivity properties and mechanical performance. Reinforced concrete structures with steel often suffer from durability issues due to corrosion. This paper presents advancements towards realizing concrete structures without steel reinforcement by providing required compression, adequate tension, flexural, and shear properties from recycled/repurposed carbon fibers and substantially reducing the carbon footprint for thermal and/or structural applications. Taterials ,9,10,11.aterials . Among taterials ,14. Theraterials ,15,16,17aterials ,19. A coaterials ,21. Furtaterials ,23,24. Aaterials .Aggregates such as manufactured sand (M sand), consisting of crushed sand, have been investigated as a sustainable aggregate due to their lower cost and have been used in high-strength concrete structural applications, including mix designs with lightweight aggregates ,27,28,29Fiber-reinforced cementitious and concrete have been investigated to explore sustainable solutions for structural applications ,38,39,40As carbon fibers have higher tensile strength and modulus than steel fibers, they can carry higher tensile forces in concrete ,69. A. BCarbon fiber has not yet realized its full potential commercial utilization cost for market entry, which has limited its use outside of high-performance applications such as aerospace and high-end performance vehicles. The conversion of a precursor, such as polyacrylonitrile (PAN), to carbon fiber is energy- and cost-intensive, and a significant amount of waste carbon fiber is disposed into landfills when end-of-the-lifecycle-part stage is reached ,81,82,83Studies have shown the use of recycled CFRP in concrete. Ogi et al. investigated the flexural and compressive strength and fracture behavior of concrete reinforced with recycled CFRP pieces . AdditioThe surface of the carbon fiber can play an important role in the fiber-to-cement bond. Fibers with a rough surface have a stronger attachment to the cement than those with a smoother surface ,104,105.X-ray computed tomography (XCT) is an effective technique to evaluate complex geometry, including lightweight concrete, M sand, and high-performance concrete, by detecting microstructural features of interest such as air voids, fiber, and concrete phases ,112,113.The main knowledge gaps in the literature involve the consideration of recycled carbon fibers which dramatically reduce the carbon footprint by capturing the high embodied energy needed to manufacture virgin carbon fibers and identifying them for augmenting tensile properties to minimize or eliminate reinforcing steel rebars. High performance concrete is being considered currently by many state and federal transportation projects and this paper provides an alternative to replace steel fibers with much more durable and environmentally friendly recycled carbon fibers. In addition to structurally demanding applications, concrete is utilized extensively for other applications that require improved thermal insulation. This paper addresses these critical knowledge gaps and also overcomes the limited studies that exist on the structure–process–property relationship of carbon fibers utilized in ultra-lightweight, structural lightweight, and high-strength concrete. Thus, there is a need for a comprehensive study of the microstructure of the interfacial bonds between the fiber, fiber sizing, and surrounding concrete matrix, including microstructural features such as voids. In this study, a multiscale analysis experimental program was developed to evaluate the influence of rCF-reinforced concrete on three concrete mixes made from three aggregate types compared to a commercially available steel fiber reinforcement. The three concrete mix designs incorporating rCF were high-strength, structural-light, and ultra-light concrete. The rCF-reinforced concrete designs were evaluated for their mechanical properties, such as compression, tensile, and flexural strength. The crystal lattice parameters of the rCF were calculated using a WAXS technique to provide insight into the structural–mechanical performance of the fibers. The surface morphology of the fibers was examined using SEM, and the elemental chemical composition of the fibers was observed using energy dispersive X-ray spectroscopy (EDS). Furthermore, high-resolution micro X-ray computed tomography (µ-XCT) was utilized to analyze the pore geometry content spatially in 3D to investigate porosity structure in relation to each concrete mix design’s mechanical performance. The thermal conductivity of the tensile samples was measured to investigate the relationship between the porosity obtained from µ-XCT for each concrete mix design. The thermal conductivity results were compared with reconstructed 3D volumes obtained through µ-XCT to investigate how the voids and fiber distribution affect the thermal conductivity of the different concrete mixes. The surface of mechanically failed tensile samples was imaged using SEM to observe the failure mechanism of the fibers and concrete. This study highlights novel insights on the effects of rCF when incorporated into various concrete mix designs for lightweight and high-strength concrete structural applications, including the microstructure and porosity effects of the final concrete mix, thermal insulation effects, and the fiber reinforcement failure mechanisms of the concrete mix.A multiscale analytical experimental program was used in this study to characterize the concrete mix design and was divided into three stages. The first stage involved characterizing the fibers for their structural properties. The microstructure of the fibers was examined using SEM, and the chemical elemental composition of each fiber type was identified using EDS. Additionally, the structure of the recycled carbon fibers was evaluated for their crystalline structure using a WAXs technique. In the second stage, the concrete mix design was evaluated non-destructively using µ-XCT to investigate the void volume content spatially and the effects of void formation from incorporating fibers in the concrete mixes coupled with the resulting reinforcement mechanisms between the host concrete matrix and surrounding the fibers . The thiThis study involved the use of rCF and steel fiber as reinforcement for concrete. The rCF used for this study was supplied by Carbon Fiber Recycling LLC  and was used as received. The steel fibers were manufactured in accordance with ASTM A820 type 1 with a 13 mm length . Figure ® MA15, Carl Zeiss, Oberkochen, Germany) was used to examine the surface topography of the tensile briquette samples after mechanical failure with an accelerating voltage of 20 kV using variable pressure [The surface morphology of the fibers was examined using SEM, specifically, a ThermoFisher Scientific Apreo S SEM instrument  with an accelerating voltage of 20 kV. Additionally, the chemical elemental composition was observed using EDS. The fibers were Au sputter coated using a sputter coater  for 40 s. An environmental SEM (Zeiss SEM EVOpressure .a), and stacking height (Lc) were calculated using the following two relationships based on Bragg’s law (Equation (1)) and the Debye–Scherrer equation (Equation (2)):λ is the wavelength, θ is the Bragg angle in radians, and id is the interlayer distance between the crystalline planes determined from the peak position of the diffracting planes 002 and 100 as illustrated in n (Lc or La) are based on Bragg’s law, and K is Scherrer shape factor constant corresponding to a value of 0.9 for Lc and 1.8 for La. β is the FWHM corresponding to 002 and 100 reflections or peaks corrected for instrument broadening [WAXS was performed to examine the crystalline microstructure of the fibers for two different batches of rCF and a reference commercial carbon fiber (T700). The scanning was performed on a Xenocs GeniX 3D microfocus instrument equipped with a Cu K-alpha 1.54 Å X-ray source with a voltage of 50 kV and a current of 0.60 mA over a 2θ angular range of approximately 0 to 55 degrees. The d-spacings, crystal size  rotary stage  was used to mount and scan nine samples cored from the tensile briquette sample (approximately 18 mm in diameter by 25 mm in length). Each sample was scanned over an angular range of 360 degrees with a voxel resolution of approximately 12 µm using a voltage of 150 kV and amperage of 137 µA . A total of 3001 12-bit 2D projections (2316 × 2316 pixels) were collected and normalized, and sinograms were obtained to reconstruct 2D slices using a commercial reconstruction algorithm . Additionally, artificial artifacts such as ring artifacts and beam hardening were reduced using correction methods applying the aforementioned reconstruction algorithm ,132. EacAn upper- and lower-threshold grayscale value was applied manually as a first step in image segmenting to create masks for the concrete, pore (air), and fiber phases within the reconstructed 3D volume. To further enhance the segmenting, concrete and voids geometries flood-fill algorithms were applied. Overlapping masks were subtracted to unambiguously identify concrete and void phases within the 3D reconstructed volume using Boolean operations . The 2D ® TPS 2500 S, Göteborg, Sweden) consisting of a 6.403 mm radius Kapton sensor in accordance with ISO 22007-2 [®, an electrical current is passed through the sensor to the samples with sufficient current to generate heat up to several degrees, and it records the resistance or temperature as a function of time. This temperature change rate of thermal transport from the sensor to the materials is “highly dependent on thermal transport properties of the surrounding material” [In this study, the thermal conductivity of the mixes was measured to investigate how porosity and different fibers affected the concrete mix design. Thermal conductivity measurements were performed on two halves of tensile briquettes for each concrete mix design using a transient plane source instrument  for a time-dependent temperature increase for the Transient Plane Source technique:According to Hot DiskP0 from the sensor, α represents the overall radius of the disk, D(τ) is a dimensionless time dependent function, and ᴧ represents the thermal conductivity of the tested samples. The D(τ) function has the following relationshipt represents the measured time from the start of the transient recording. The characteristic Θ is defined as the following:κ represents the sample’s thermal diffusivity. A computation plot is generated of the recorded temperature increase versus D(τ) to obtain a straight line, where iT is the intercept. Due to both Θ and κ are not known prior to the experiment, the thermal conductivity is calculated through a iterative process [the total output power  process .Statistical analysis was performed for each concrete mix design to compare the measured physical, mechanical, and thermal conductivity properties. The average and standard deviation values were calculated for the flow, compression, tension, and flexural properties, in accordance with ASTM standards. The average and standard deviation values were calculated for the thermal conductivity properties. Since only two density measurements were obtained for each concrete mix design, the two density values were reported. It must be noted that density values are averaged for the Results and Discussion portions of this study to compare the density for each concrete mix design. 3) was approximately 4.8% lower than the neat mix design (2.37 g/cm3) and approximately 6.1% lower than the steel mix design (2.37 g/cm3). For the structural-light concrete, the compressive strength of the rCF mix design (28.4 MPa) was approximately 73.2% lower than the neat mix design (61.2 MPa) and approximately 20.8% lower than the steel mix design (35.0 MPa). The tensile strength of the rCF mix design (2.90 MPa) was approximately 14.8% higher than the neat mix design (2.50 MPa) and approximately 48.8% lower than the steel mix design (4.77 MPa). The flexural strength of the rCF mix design (2.57 MPa) was approximately 82.8% lower than the neat mix design (6.20 MPa) and approximately 118.3% lower than the steel mix design (10.02 MPa). The neat mix had the highest flow, at 84.4%, followed by the steel fiber mix, with a flow of 20.3%. Unfortunately, due to low workability and poor cohesion in the concrete mix, the rCF mix design crumbled during the test, leading to an invalid test or an effectively 0% flow. The average density of the rCF mix design (1.53 g/cm3) was approximately 10.5% lower than the neat mix design (1.70 g/cm3) and approximately 15.7% lower than the steel mix design (1.79 g/cm3). For the ultra-light concrete, the compressive strength of the rCF mix design (21.7 MPa) was approximately 13.7% lower than the neat mix design (24.9 MPa) and approximately 62.4% lower than the steel fiber mix design (41.4 MPa). The tensile strength of the rCF mix design (3.21 MPa) was approximately 72.6% higher than the neat mix design (1.50 MPa) and approximately 58.6% lower than the steel fiber mix design (5.87 MPa). The flexural strength of the rCF mix design (5.62 MPa) was approximately 48.7% higher than the neat mix design (3.42 MPa) and approximately 97.5% lower than the steel fiber mix design (16.32 MPa). The flow of both the neat and the steel fiber was 150+%, with rCF having a flow of 1.6%. The average density of the rCF mix design (1.48 g/cm3) was approximately 2.0% lower than the neat mix design (1.51 g/cm3) and approximately 12.7% lighter than the steel fiber mix design (1.68 g/cm3). 3) than in the neat structural-light (average: 1.70 g/cm3) and neat ultra-light (average: 1.51 g/cm3) mixes. Additionally, unambiguous detection of the microstructure granularity within the concrete phases and pore phases within the 2D-reconstructed cross-section for each concrete mix design demonstrates the effectiveness of this µ-XCT technique. Additionally, it is interesting to note the interconnectivity of the pores observed for the structural-light and ultra-light concrete mix designs. Due to the interconnectivity of voids and the segmentation procedure used in this work, individual voids could not be quantified for a pore size distribution. However, this demonstrates the effectiveness of using the µ-XCT technique to obtain void volume content spatially and quantitative information including the effects of the fiber reinforcement of the concrete. As shown in The mechanically failed tensile samples for each of the nine different concrete mix designs were examined using SEM to investigate the failure mechanisms for the fibers and surrounding host concrete matrix, as shown in Investigation of the structure–process–property relationships between the rheological behavior, porosity, and influence of rCF on the mechanical performance for all the considered concrete mix designs was the primary aim of this study. The SEM surface morphology  and EDS It can be observed in 3) are much denser then the aggregates (2.71–0.37 g/cm3) or the rCF (1.81 g/cm3) they are replacing. The ultra-light mix illustrates this the best as the steel-fiber-reinforced mix (1.68 g/cm3) was 0.2g/cm3 denser than the rCF-reinforced mix (1.48 g/cm3). Therefore, rCF reinforcement could be ideal in applications where the density of the concrete is critical. It should be noted that while the rCF-reinforced structural-light mix (1.53 g/cm3) had a much lower density than the other structural-light mixes (1.70–1.79 g/cm3), this was mostly because the poor flow traps air and creates voids during mixing and casting. It can be seen in As shown by the thermal conductivity measurements presented in in The mechanism involved with optimizing concrete mix design with carbon fibers involves lengths of chopped fiber to be long enough to provide bridging of tensile cracks in the cement composite phase and sufficient fiber volume fraction to augment the mechanical properties. For workability, the fiber volume fraction should be such that the rheology is not too far from the neat mix design. For optimal load transfer, one needs to optimize the interfacial shear strength between the carbon fiber surface and the cured cement phase using appropriate physical and chemical coating. For thermal insulation, increasing the trapped air/void phases uniformly distributed and small enough in size to minimize strength loss is targeted. For improved ductility, one needs to optimize fiber length distribution and fiber bridging without clumping in a well-dispersed state. Though, all of these features were not realized in this paper, we have provided controlling mechanisms and example mix designs to realize strong, light, and multifunctional concrete mix designs utilizing durable, lightweight, and low carbon footprint recycled carbon fibers.In this study, recycled carbon fiber was evaluated for its mechanical properties  for high-strength, structural-light, and ultra-light concrete mix designs. The mechanical performance of the recycled carbon rCF-reinforced concrete mix designs was compared to traditional commercial steel-fiber-reinforced concrete and neat mixes. Scanning electron microscopy was used to examine the surface morphology of fibers coupled with energy dispersive X-ray spectroscopy to identify the elemental chemical composition of the recycled carbon fiber and steel fiber. Additionally, wide angle X-ray scattering was performed on the recycled carbon fibers to examine the crystalline parameters of the fibers. The concrete mix designs were evaluated non-destructively using high resolution micro X-ray computed tomography to visualize the voids spatially within the concrete tensile samples and to provide quantitative information on the porosity effects on mix design and the influence of incorporating recycled carbon fibers. Thermal conductivity was performed on the concrete mix designs to evaluate the effect of porosity, inclusion of recycled carbon fiber and steel fiber, and concrete mix design type. The results of the thermal conductivity were correlated with the porosity obtained from micro X-ray computed tomography and the compressive, tensile, and flexural strength. Incorporation of recycled carbon fibers into the three concrete types can increase the tensile and flexural strength of neat concrete.The recycled carbon-fiber-reinforced concrete has slightly higher ductility compared to the neat concrete for tension and flexural strength but lower than the steel-fiber-reinforced concrete mix designs.The recycled carbon fibers tended to increase the void content in the concrete, with the exception of the ultra-light mix where the fibers constrained the aggregates and allowed for their more uniform dispersion.An increase in void volume content is the primary factor affecting the decrease in thermal conductivity for the concrete mix designs.The addition of fibers increases the thermal conductivity of the concrete; however, the additional voids caused by the fibers can negate the effects.The following general conclusions can be drawn for the incorporation of the recycled-carbon-fiber-reinforced method into the three concrete mix designs considered in this study:It can be observed across the different mix designs that recycled carbon fiber improves the tensile and flexural strength of the concrete while not significantly decreasing the compression strength in most cases. It was observed that the steel fibers performed better in compression, tensile, and flexural strength across the board but had a higher density than the recycled carbon fiber and neat mixes. Furthermore, it was observed that the flow of the concrete mixes was significantly reduced with the addition of recycled carbon fiber, and the effects on flow were significantly magnified when the cement content was reduced. This result suggests that the fiber volume content in the concrete mixes should be based on the cementitious material volume content as opposed to the total mix volume. It is theorized that when the fibers are mixed into the volume, they are mixing into the cementitious portion of the mix and not the aggregate portion. It must be noted that there is a need for continued studies on the microstructural and chemical properties of fiber sizing and interfacial bonding with concrete mixes to enhance flowability and mechanical performance. Overall, recycled carbon fibers are a viable reinforcement for fiber-reinforced concrete and are particularly effective when incorporated in structural-light and ultra-light applications.


MET amplification and exon 14 skipping are currently clinically recognized biomarkers for stratifying subsets of non-small cell lung cancer (NSCLC) patients according to the predicted response to c-Met inhibitors (c-Metis), yet the overall clinical benefit of this strategy is quite limited. Notably, c-Met protein overexpression, which occurs in approximately 20–25% of NSCLC patients, has not yet been clearly defined as a clinically useful biomarker. An optimized strategy for accurately classifying patients with c-Met overexpression for decision-making regarding c-Meti treatment is lacking. Herein, we found that SYK regulates the plasticity of cells in an epithelial state and is associated with their sensitivity to c-Metis both in vitro and in vivo in PDX models with c-Met overexpression regardless of MET gene status. Furthermore, TGF-β1 treatment resulted in SYK transcriptional downregulation, increased Sp1-mediated transcription of FRA1, and restored the mesenchymal state, which conferred resistance to c-Metis. Clinically, a subpopulation of NSCLC patients with c-Met overexpression coupled with SYK overexpression exhibited a high response rate of 73.3% and longer progression-free survival with c-Meti treatment than other patients. SYK negativity coupled with TGF-β1 positivity conferred de novo and acquired resistance. In summary, SYK regulates cell plasticity toward a therapy-sensitive epithelial cell state. Furthermore, our findings showed that SYK overexpression can aid in precisely stratifying NSCLC patients with c-Met overexpression regardless of MET alterations and expand the population predicted to benefit from c-Met-targeted therapy.Genomic  EGFR, ALK, ROS1, NTRK, etc. The response rate to EGFR inhibitors (EGFRis) is approximately 70% in patients with EGFR mutations,2 who account for 15–40% of patients with non-small cell lung cancer (NSCLC). However, the scenario in patients with MET alterations is quite different. c-Met alterations in lung cancer include gene mutation, amplification and protein overexpression.4 Recent studies reported a response rate of 40–70% in patients with MET exon 14 skipping mutation (MET ex14Δ).7 However, such MET alterations are only present in a rare subtype of NSCLC, accounting for only 3–4% of NSCLC cases.6 A much more limited response was observed in patients with MET amplification10 or c-Met overexpression.12 While c-Met overexpression occurs in approximately 20–25% of NSCLC patients,14 it has not yet been clearly defined as a clinically useful biomarker. Efforts to identify predictive biomarkers, especially in the c-Met protein overexpression subtype, might help precisely expand the population that would benefit from the clinical use of c-Met inhibitors (c-Metis).Targeted therapies have greatly improved clinical outcomes and reshaped the treatment standards for patients with genomic alterations in 17 Epithelial-mesenchymal transition (EMT) is recognized as one of the best examples of cancer cell plasticity; EMT is the process by which epithelial cancer cells dedifferentiate into a highly motile and mesenchymal tumor phenotype. It is also an important mechanism for inducing resistance to kinase-targeted therapy.18 Generally, an epithelial state rather than a mesenchymal state is more often associated with therapeutic response to kinase-targeted therapy.19 Therefore, key factors that inhibit EMT have the potential to become new sensitive predictive biomarkers that, when combined with existing therapies, may lead to better and more durable clinical responses. Here, we hypothesized that such factors facilitating the epithelial cell state might also account for the sensitivity to c-Metis in the c-Met-overexpressing patient subset.With advancement in research on cancer mechanisms, phenotypic plasticity and disrupted differentiation have been recognized as discrete hallmarks that are highly involved in sensitivity to anticancer therapy.20 SYK plays a crucial role in hematological malignancies, particularly B-cell lineage lymphomas. Accumulating data also suggest that SYK is involved in carcinogenesis and tumor progression in solid tumors, acting as either a tumor-promoting or tumor-suppressive factor according to the biological context and tissue lineage.21 Here, we assessed the epithelial cell state and performed comprehensive omics analysis in c-Met-overexpressing cell lines, with lung cancer cell lines harboring EGFR mutations as positive controls, as the appearance of mesenchymal features is well recognized to be associated with resistance to EGFR inhibitors26; we validated the results in patient-derived xenograft (PDX) models and NSCLC patient cohorts. We found that SYK regulated the epithelial cell state, enabling the selection of SYK-high NSCLC patients in the c-Met-overexpressing group as a population that may benefit from c-Meti therapy.Spleen tyrosine kinase (SYK) is a cytoplasmic kinase that couples immune cell receptors to induce intracellular signaling pathways and plays a central role in adaptive and inflammatory immune responses.27 and profiled 14 lung cancer cell lines harboring MET amplification with EGFR mutation or ALK translocation as positive controls. We found that 315 genes were significantly associated with sensitivity to c-Metis, EGFRis and ALK inhibitors (ALKis) at the transcriptomic level  databasevel Fig. . We thenUC1 Fig. . SYK, a nse Fig. . Togethe31 with four individual epithelial/mesenchymal signature gene sets30  (Supplementary Table p < 0.05) 05) Fig. . However05) Fig. . All theWe then assessed the association of SYK with the therapeutic response to c-Metis, EGFRis, and other kinase inhibitors for the treatment of NSCLC, such as ALKis and RET inhibitors (RETis), in 15 cancer cell lines Fig. . Cancer MET-amplified EBC-1 cell line, EGFR-mutant PC-9 cells, HCC827 cells and ALK-translocated H2228 cells. We found that SYK knockdown led to decreased sensitivity to c-Metis, EGFRis, and ALKis  of RNA-seq data comparing the SYK shRNA group to the nc control group, and we found that SYK depletion was positively associated with the mesenchymal signature  but negatively associated with the epithelial signature   Fig. . Real-ti25) Fig. . Furtherlls Fig. , indicatEMT Fig. .35 indicated that in breast cancer cells, SYK was able to downregulate the transcription factor FRA1, which acts as a key EMT switch as well as a drug resistance mediator in cancer.36 We then investigated whether FRA1 was downstream of SYK in our scenario. We found that depletion of SYK increased FRA1 expression in representative cell lines with MET amplification or EGFR mutation , which indicated the limitation of low SYK expression alone in predicting resistance. Since a highly mesenchymal cell state is commonly associated with resistance,15 we assessed a mesenchymal signature gene set by Gene Ontology (GO) enrichment analysis. We found that the extracellular matrix term gene set, including LTBP1/2, TGF-Β1I1, BGN, DCN and SERPINE1/2, was the top-ranked gene set  or EGFRi (gefitinib) once a day consecutively  exhibited resistance (YM-01-0555)  Fig. . These fels Fig. . To veriels Fig. .Fig. 4SYEGFR mutation-positive NSCLC who received first-generation EGFRis (Supplementary Table de novo resistance). The receiver operating characteristic (ROC) curve showed that the optimum diagnostic cutoff score for SYK was 2, and this score had a specificity of 100% ).To explore the translational implications, we first used an EGFRi-treated NSCLC cohort as a proof-of-principle cohort and to define the criteria for SYK-positive status. This cohort included 31 patients with advanced MET amplification  who were treated with the c-Meti crizotinib or capmatinib was selected ; 66.7% of patients with positive SYK expression exhibited high E-cadherin expression , upregulation of AXL correlates with the emergence of EMT features, which has been shown to underlie erlotinib resistance. Both AXL inhibition and knockdown restored sensitivity to erlotinib.58 These findings encouraged the ongoing clinical exploration of combination therapy with AXL inhibitors and EGFRis.59 In the present study, we focused on the therapy sensitivity-associated epithelial cell state. SYK itself was reported as part of the epithelial core signature,29 and here, by integrating epithelial cell state scoring with comprehensive omics analysis, SYK was found to regulate the epithelial cell state, dictating sensitivity to c-Metis in c-Met-dysregulated preclinical cancer models and a patient cohort. Furthermore, we revealed the importance of the TGFβ1-Smad2/3-SYK-FRA1 mechanistic axis in epithelial-mesenchymal state regulation and its corresponding role in the response to c-Metis. Decreased SYK expression with shRNA or TGF-β1 treatment accompanied with increasing FRA1 expression, was associated with an enhanced mesenchymal state and decreased sensitivity of cancer cells to c-Metis. In contrast, FRA1 knockdown reversed the mesenchymal cell state and the reduction in inhibitor sensitivity induced by SYK depletion. In addition to downstream canonical Smad2/3 signaling, TGF-β1 can induce a mesenchymal state through noncanonical β-catenin signaling.61 Sporadic preliminary preclinical studies showed upregulation of β-catenin in c-Meti-resistant NSCLC cells, and β-catenin siRNA increase c-Meti sensitivity.62 Our findings together with other reports in cancers with c-Met alterations strongly indicated that the above canonical or noncanonical pathways that could enhance the mesenchymal cell state may be potential therapeutic targets, and intervening in these pathways has the potential to increase drug sensitivity in patients with c-Met alterations who did not respond to c-Meti therapy, which needs further clinical exploration. It appears that comprehensive analysis to identify key regulators of cancer cell epithelial-mesenchymal plasticity may reveal markers related to mesenchymal or epithelial dependency that indicate therapeutic vulnerability and could serve as targets to overcome resistance or as biomarkers for predicting the treatment response; these markers would have important implications in the precise application of anticancer drugs, particularly kinase-targeted therapies. Further extensive exploration may help test this hypothesis to guide anticancer therapy.EMT is a dynamic and reversible process, and reversal of EMT may sensitize tumor cells to treatment, leading to a more durable response.Our research shows that SYK has important translational significance and application potential in kinase-targeted therapy.+/SYK+”, as a new stratification biomarker, could substantially expand the population of patients predicted to benefit from c-Meti treatment. Our PDX-based parallel trial showed that high SYK expression predicted a therapeutic response to c-Metis in the context of c-Met overexpression, regardless of MET gene status (amplification or wild type).First, we revealed that “c-Met14 It is usually assessed by IHC with the SP44 antibody and is scored from 0 to 3+ using a semiquantitative approach. There is no agreed-upon cutoff for defining high c-Met expression. In some studies, c-Met staining with moderate (2+) or strong (3+) intensity in ≥50% of tumor cells was used.63 Thus far, c-Met overexpression by IHC has not been determined to be an effective clinical biomarker with a clear cutoff. The reported response rate in this subpopulation is consistently very low.12 Intriguingly, in the present study, c-Met overexpression (defined as ≥50% of tumor cells with strong 3+ staining intensity) coupled with SYK overexpression identified a subpopulation of NSCLC patients with a high response rate (73.3%) to c-Metis. This subset of patients also tended to experience a longer PFS time than other patient subsets.Notably, c-Met overexpression is found in approximately 20 to 25% of NSCLC cases.We thus suggest that both SYK and c-Met could be assessed for c-Meti response prediction, as populations overexpressing both SYK and c-Met (c-Met + /SYK + ) are likely to be responsive to c-Meti treatment Fig. . MoreoveEGFR-mutant and ALK-translocated NSCLC, respectively. Similar enrichment was further validated in a cohort of advanced NSCLC patients harboring EGFR mutations. When substratified by SYK-high status, all EGFR-mutant-positive NSCLC patients responded to EGFRis , and their response rate was much higher than the response rate of patients stratified by EGFR mutation alone . The SYK-plus strategy may expand the population of patients with kinase alterations predicted to benefit from kinase inhibitor treatment.Second, SYK has the potential to be a generalizable and sensitive biomarker for other kinase inhibitors in the context of kinase-addicted tumors. We utilized database analysis, cancer cell assays and PDX models and revealed that SYK stratification consistently enriched the population of patients predicted to be responsive to EGFRis and ALKis among those with low subtype was inconsistent; there was one case of PD (indicating resistance) and 4 cases of SD  in this cohort. Further stratification by TGFβ1 expression revealed resistance (PD) in the TGFβ1high group  were further stratified based on TGFβ1 expression, and all the cell lines in the SYKlow/TGFβ1high group exhibited resistance , a highly selective c-Met inhibitor, was granted breakthrough therapy designation by the China National Medical Products Administration (NMPA) for the treatment of patients with MET ex14Δ-positive metastatic or advanced NSCLC in 2021 (No. CXHB1600071) and orphan drug designation by the FDA for treatment for NSCLC with MET genomic aberration in 2022 (https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=858221). The New Drug Application (NDA) for SCC244 was submitted to the NMPA in 2022. We hope our ongoing clinical study of SCC244 will help standardize the use of IHC staining and refine reference ranges for clinical or mechanistic studies.In addition, in the c-Met-dysregulated NSCLC cohort, the response to c-Meti in the SYKoup Fig. . In Fig.nce Fig. . These rls Figs. , low exp64 And STMN-2, markedly up-regulated in HCCs, could activate Smad2 independent of TGF-β1 stimulation.65 Therefore, whether TGF-β1-independent Smad regulator is involved in Smad-downregulated SYK in NSCLC needs further exploration.In addition, in the mechanism exploration, we confirmed that Smad2/3-mediated downregulation of SYK, which triggers the resistance to c-Metis, is TGF-β1 dependent. However, in our case, we also found that loss of Smad2/3 enhanced the basal level of SYK without TGF-β1 stimulation only in NCI-H1993 cells, which suggested that Smad2/3 might regulate SYK independent of TGF-β1. Some previous reports have provided similar results. For example, advanced glycation end products (AGEs) could activate Smad2/3 early phosphorylation through ERK/p38.MET and EGFR alterations, which are high-frequency typical genetic alterations in lung adenocarcinoma (LUAD) and are rarely detected in lung squamous cell carcinoma (LUSC).66 The molecular genomic alterations are quite different between LUAD and LUSC,66 the predominantly histologic subtypes of NSCLC. Whether SYK expression is associated with the response to inhibitors of other targetable alterations, including typical LUSC alterations, and the underlying mechanism need to be further studied.Furthermore, in the present study, we mainly focused on http://www.broadinstitute.org/ccle). Lung cancer cell lines with MET amplification, EGFR mutation and ALK translocation were selected. The protein expression and drug sensitivity data for NCI-H3122 cells were not available on the CCLE. NCI-H3122 is a known ALKi-sensitive cancer cell line; therefore, it was classified as inhibitor-sensitive. Transcriptomic profiling of significantly differentially expressed genes between cancer cell lines considered sensitive versus resistant to specific kinase inhibitors was performed with R using the edgeR package.We obtained gene expression, protein expression and drug sensitivity data from CCLE_DepMap_18Q4_RNAseq_log2 (TPM + 1), CCLE_RPPA_20180123.csv, and CCLE_NP24.2009_Drug_data_2015.02.24, respectively, from the CCLE portal (37 HCC827 and HCC827/GR6 cells were kindly provided by Pasi A. Jänne (Dana-Farber Cancer Institute). As described in his previous study,67 to generate cell clones resistant to the EGFR inhibitor gefitinib, parental HCC827 cells were exposed to increasing concentrations of gefitinib for 6 months. Six clones isolated from single cells were resistant to gefitinib, one of which was HCC827/GR6. Other cell lines were purchased from the American Type Culture Collection . All cell lines were cultured as instructed and were authenticated via short tandem repeats (STR) analysis with the latest test in November 2021  or single-nucleotide polymorphism (SNP) analysis with the latest test in 2022 . All cells were routinely tested for mycoplasma and found to be free of contamination. Detailed information on these cell lines is listed in Supplementary Table PC-9 cells were purchased from the European Collection of Authenticated Cell Cultures (ECACC). NCI-H3255 cells were purchased from CoBioer (China). NCI-H3122 cells were purchased from the National Cancer Institute (NCI). SPC-A1 cells were purchased from the Cell Bank of the Chinese Academy of Sciences (China). MKN45 and EBC-1 cells were purchased from the Japanese Collection of Research Biosources Cell Bank (JCRB). EBC-1/SR is a cell line with induced acquired resistance to the c-Met selective inhibitor SGX523; it was generated in our lab from the EBC-1 parental cell line by exposure to increasing concentrations of SGX523 for 6 months7 cells per mouse), EBC-1-nc/shSYK cells (5 × 106 cells per mouse), or MKN45-nc/shSYK cells (5 × 106 cells per mouse) were subcutaneously injected into the right flanks of 5-week-old immunocompromised female BALB/c nude mice. Tumor volume was measured twice per week with a caliper in most tumor models, except for MKN45-nc model which was measured every two days, and quantified by the modified ellipsoidal formula (tumor volume = ½ (length × width2)). The mice were randomly assigned to groups when the mean tumor volume reached approximately 100–250 mm3 and then given the indicated treatment as described below once daily for a period of time. For the PC9 xenograft model experiment, gefitinib (5 or 10 mg per kg) was suspended in 0.5% sodium carboxymethylcellulose (CMC-Na) and administered daily by oral gavage. Mice in the vehicle groups were treated on the same schedule but were only treated with 0.5% CMC-Na. For the EBC-1 and MKN45 xenograft model experiments, INCB28060 (1 or 3 mg per kg) was suspended in 95% 0.5% methyl cellulose (0.5% MC) and 5% dimethylacetamide (DMAC) and administered daily by oral gavage. Mice in the vehicle groups were treated on the same schedule but were only treated with 95% MC and 5% DMAC.PC9-nc/shSYK cells  and Crown Bioscience . The mice were given vehicle alone or the indicated compound via oral gavage once daily for 13–35 days. Tumor size was measured twice per week using a microcaliper.Animal studies using NSCLC PDX models were conducted by WuXi AppTec  . Animal studies using PDX models were approved by the Institutional Animal Care and Use Committees of WuXi AppTec  and Crown Bioscience .EGFR mutations were included. Patients with simultaneous T790M mutations were excluded. The patients were 76 years old or younger, and all had measurable disease. Approval was obtained from institutional research ethics boards at the following institutions: Renji Hospital, School of Medicine, Shanghai Jiao Tong University; the Affiliated Hospital of Xuzhou Medical University; and the Central Hospital of Minhang District. Informed consent for biomarker analysis was obtained from each patient. EGFR mutations were detected using amplification refractory mutation system (ARMS) real-time PCR analysis with tumor tissue obtained via bronchoscopy, percutaneous lung biopsy, or surgical resection. The clinical parameters of all patients, including sex, age, smoking status, pathomorphological diagnosis, disease stage, EGFR gene mutation type, and prior treatment, such as surgery or chemotherapy, were collected. All patients received first-generation kinase inhibitors .Thirty-one patients with advanced NSCLC harboring activating EGFR mutations, ROS1 rearrangements or ALK rearrangements were excluded. All patients had measurable disease. Research approval was obtained from the institutional research ethics board at Guangdong Provincial People’s Hospital. Informed consent for the biomarker analysis was obtained from each patient. MET gene amplification was assessed by fluorescence in situ hybridization (FISH), and c-Met protein overexpression was assessed by IHC with an SP44 antibody, as previously described.11MET amplification was defined as either MET gene copy number (GCN) ≥ 6 and/or a MET/centromere ratio of ≥2.0. c-Met overexpression was defined as ≥50% of tumor cells with strong staining intensity (3+). Clinical parameters for all patients, including sex, age, smoking status, histologic diagnosis, disease stage, and prior treatment information, were collected. All patients received the c-Meti crizotinib at a dosage of 150 mg daily orally.Twenty patients with advanced NSCLC who had c-Met protein overexpression and were treated with crizotinib or capmatinib were included . Staining intensity was scored on a scale of 0~2 . The H-score included scores of 0~4 and 6 and was calculated by multiplying the staining percentage score by the intensity score, resulting in a negative  or a positive  expression value for SYK and a negative  or a positive (4 and 6) expression value for TGF-β1. The antibodies used for IHC were anti-TGF-β1 antibody (ab92486)  and anti-SYK antibody (4D10) (sc-1240) .p > 0.05; *p < 0.05; **p < 0.01; and ***p < 0.001.The data are presented as the mean ± SD for in vitro data or the mean ± SEM for in vivo data. Data were analyzed using unpaired two-sided t tests (two groups) or one-way ANOVA (≥3 groups) using GraphPad Prism software. Pearson’s correlation was used to analyze the relationships between the indicated groups. Pearson’s chi-square and Fisher’s exact tests were used for comparative analysis using SPSS version 23. Statistical significance was determined based on the P value: not significant (NS), Supplementary manuscript


The structures were analyzed by the combination of characterization experiments and theoretical calculation, and the formation mechanism of polymorphism was discussed. The obtained results of in vitro evaluation showed that MET–RHE had a similar hygroscopicity with metformin hydrochloride (MET·HCl), and the solubility of the component of RHE increased by approximately 93 times, which laid a foundation for improving the bioavailability of MET and RHE in vivo. The evaluation of hypoglycemic activity in mice (C57BL/6N) indicated that MET–RHE exhibited better hypoglycemic activity than the parent drugs and the physical mixtures of MET and RHE. The above findings demonstrate that this study achieved the complementary advantages of MET and RHE through the multicomponent pharmaceutical salification technique, and provides new possibilities for the treatment of diabetic complications.This study aimed to develop an effective treatment for diabetes and diabetic complications, based on the advantage complementary strategy of drug–drug salt, by designing and synthesizing the multicomponent molecular salts containing metformin (MET) and rhein (RHE). Finally, the salts of MET–RHE (1:1), MET–RHE–H According to the statistics of the International Diabetes Federation in 2017, the prevalence of diabetes in the world is gradually increasing, and more than 90% of patients with diabetes mellitus experience Type 2 diabetes (T2D) . In addia = 12.4 [Metformin  and RHE (pKa = 3.2) were greater than 3, allowing the prediction of the potential for multicomponent salt formation between MET and RHE [First, according to the ΔpKa rule , the pos and RHE . MoreoveET pKa = .4 and RH and RHE ,45 and d and RHE ,51,56,61 and RHE , while t and RHE . From an2O (1:1:1), MET–RHE–ethanol–H2O (1:1:1:1), and MET–RHE–acetonitrile (2:2:1). The prepared multicomponent pharmaceutical salts were characterized by single-crystal X-ray diffraction analysis (SXRD), powder X-ray diffraction analysis (PXRD), and thermal analysis (DSC-TGA). On the basis of mastering the processes of crystal formation and transformation from the solvates to MET–RHE, the stability, hygroscopicity, and solubility of MET–RHE in vitro and its hypoglycemic activity in mice were evaluated systematically. The experimental results of this thesis showed that MET–RHE not only optimized the solubility of RHE and reduced the hygroscopicity of MET, but also ameliorated the hypoglycemic activity in mice, thus providing a material basis for the further synergistic effects of MET and RHE to alleviate diabetic nephropathy.Based on the above salification strategy, four multicomponent pharmaceutical salts and their solvates were obtained, including MET–RHE (1:1), MET–RHE–HThis study shows that the multicomponent pharmaceutical salt based on the strategy of complementary advantages can improve the physicochemical properties shortcomings of the single component and synergistically enhance the efficacy, which provides a new way to improve the bioavailability of the original drugs in vivo and to maximize their multiple potential pharmacological activities to a greater extent.MET·HCl  and RHE  were purchased from Nine-Dinn Chemistry Co., Ltd.  and Hubei Wande Chemical Co., Ltd. , respectively. The reagents used were of analytical grade. The solid drug delivery device (patent number: 201010219220.5) was developed and prepared by the National Drug Screening Center of the Institute of Materia Medica, Chinese Academy of Medical Sciences.Metformin hydrochloride was dehydrochlorinated by acid–base neutralization method, and the final metformin sample was obtained. First, 3.31 g (20 mmol) of metformin was accurately weighed and dissolved in an appropriate amount of isopropanol, to which 0.80 g (20 mmol) of sodium hydroxide was added. The mixture was stirred at 300 rpm at room temperature overnight. The solution was filtrated, and the product was spun dry to obtain the metformin sample for the experiment at 60 °C and −0.01 MPa.For MET–RHE (1:1), 0.2 mmol of MET (25.8 mg) and 0.2 mmol of RHE (56.8 mg) were accurately weighed into a mortar, 2 mL of ethanol was added, and the solid was manually grounded at 25 °C for 1 h. The solid was dried at 25 °C for 4 h to obtain an auratus powder sample. The obtained sample was dissolved in 6 mL of methanol, and then filtered. The filtrate was air-dried at 25 °C, and faint yellow massive crystals were obtained after 6 days.2O (1:1:1), 0.5 mmol of MET (64.5 mg) and 0.5 mmol of RHE (142.0 mg) were accurately weighed into a vial, 5 mL of acetone/water  mixed solvent was added, and the mixture was stirred at 25 °C at 300 rpm for 3 h. The solvent was quickly removed using a rotary evaporator, and the resulting solid was dried at 50 °C for 2 h.For MET–RHE–H2O (1:1:1:1), 0.1 mmol of MET (12.9 mg) and 0.1 mmol of RHE (28.4 mg) were accurately weighed into a mortar, and 3 mL of ethanol/water  mixed solvent was added and ground manually at 25 °C for 2 h. A brown powder was finally obtained. The resulting sample was dissolved in 8 mL of ethanol and filtered. The filtrate was air-dried at 25 °C. After 5 days, yellow massive crystals suitable for single-crystal X-ray diffraction were obtained.For MET–RHE–ethanol–Hv/v, 3:1) mixed solvent. The mixture was stirred at 25 °C at 300 rpm speed for 48 h, and then filtered. The filtrate was air-dried at 25 °C, and tangerine block-like crystals were obtained after 7 days.For MET–RHE–acetonitrile (2:2:1), 0.5 mmol of MET (64.5 mg) and 0.5 mmol of RHE (142.0 mg) were accurately weighted into a vial, and added to 12 mL of methanol/acetonitrile , which was equipped with a Cu–Kα radiation source set at 40 kV and 150 mA. In this paper, the diffraction data were collected in the 2θ range of 3–80° with a scan rate of 8°/min. All the data were analyzed using Jade 6.0 software.−1 with a flow of 50 mL/min of N2.DSC characterization of the experimental samples were performed in this study using a Mettler Toledo DSC/DSC 1 . The specific method is to accurately weigh the sample into an alumina crucible, start heating from 30 °C, and complete the whole experiment at a heating rate of 10 °C min2 flow of 50 mL/min.The TGA analysis for this study was performed by a Mettler Toledo DSC/TGA1 . An appropriate amount of sample was weighed in a crucible using 40 µL alumina and warmed to 500 °C at 10 °C/min starting at 30 °C under a NThe STAR software package  was used for the processing and analysis of DSC and TGA results in this experiment.SCXRD was carried out on a Rigaku MicroMax-002+ diffractometer  with Cu–Kα radiation (λ = 1.54178 Å) at the temperature of 293 K. The structures of qualified single crystal samples obtained in this study were solved by direct method and refined with the full-matrix least-squares technique. The nonhydrogen atoms were refined using anisotropic displacement parameters, and hydrogen atoms were placed at the calculated positions and refined using a riding model.The counterpoise-corrected interaction energies in the salts were investigated by density functional theory using the Gaussian 16 program . The geoIn order to investigate the transformation process from the solvates to MET–RHE salt, the MET–RHE solvates were desolvated at a temperature of at least 20 °C above the corresponding solvent peak temperature in DSC curves. The products were analyzed by DSC and PXRD in comparison with the MET–RHE salt, respectively.To investigate the stability of MET and MET–RHE, powder samples were placed in high-temperature (60 °C), high-humidity , and illuminated (4500 lx ± 500 lx) environment for 10 days. The stability of samples was evaluated via PXRD analysis.The hygroscopicity of MET and MET–RHE was studied by dynamic vapor sorption experiment . The samples were studied at 25 °C in the humidity range of 20–95% relative humidity (RH). Each humidity step was performed when a change in weight of less than 0.02% occurred within 10 min, with a maximum retention time of 120 min.Prior to the in vitro dissolution and solubility study, the samples were processed with a 100-mesh sieve in advance to minimize the influence of sample particle size on the experimental results. In addition, the aqueous equilibrium solubilities of ionizable drugs are measured in buffered solutions, considering that their solubilities are a pH-dependent parameter , and thev/v); detection wavelength, 254 nm; flow rate, 1.0 mL/min; column temperature, 30 °C; injection volume, 10 μL. The experiment was repeated three times and the average value was taken.Afterward, precisely weighed RHE (30.0 mg) and MET–RHE  were added to a dissolution vessel containing 450 mL of buffer medium (pH = 7). Samples were stirred at 100 rpm at 37 °C, and 1 mL of sample was obtained at 0, 5, 15, 30, 50, 75, 105, 150, 210, 270 and 390 min, while the same volume of buffer was replenished. The samples were analyzed for dissolved concentration by HPLC  after filtration through 0.22 µm PTFE filter. The liquid-phase conditions were as follows: Welch Ultimate AQ-C18 ; mobile phase, methanol–0.2% formic acid . Mice with fasting glucose level over 11 mmol/L were selected as diabetic mice models. In addition to the normal control group, the diabetic mice were divided into five groups, including the diabetic model group, MET·HCl group , MET–RHE group , physical mixture of MET and RHE group , and RHE group . All drug dosages were converted to 0.6 mmol/kg. The mice from different administration groups were administered with drugs by gavage after 4 h of fasting. Normal control and diabetic model groups were filled with equal doses of normal saline. Blood glucose levels were measured at 0, 1, 2, 4, 6 and 8 h after administration.Male C57BL/6 mice (7 weeks old) purchased from Vitaliver  were used in this study and placed under environmentally controlled conditions with a light/dark cycle for 12 h at a temperature of 22 ± 3 °C and a humidity of 55 ± 5%. Mice were injected intraperitoneally (i.p.) with 120 mg/kg streptozotocin  after fasting for 16 h to induce diabetic models. The control animals received an i.p. injection of an equal volume of vehicle only . Seven days after the administration of STZ, the 4 h fasting blood glucose levels of mice were measured with an ACCU-CHEK2O, MET–RHE–ethanol–H2O, and MET–RHE–acetonitrile . However, the PXRD pattern of MET–RHE–H2O and MET–RHE–acetonitrile has no characteristic peak that can prove the remaining MET. Therefore, the endothermic peaks at low temperatures of MET–RHE–H2O, MET–RHE–ethanol–H2O, and MET–RHE–acetonitrile correspond to the presence of solvents in their structures.As a sensitive thermal analysis technique, DSC can be used to analyze the formation and purity of new phases. The DSC results for MET, RHE, and multicomponent salts are provided in 2O, MET–RHE–ethanol–H2O, and MET–RHE–acetonitrile correspond to the solvent endothermic peaks of their DSC curves, while the percentage of solvent weight loss steps is quite close to the theoretical percentage  B. The die c-axis C. On the2B–H2BB···O6B and N1A-H1AA···O5B hydrogen bond, while the acetonitrile molecule is connected with the MET molecule through N1Y–H4AB···N4A hydrogen bond  and span of deviation from plane (SDP) parameters, and the results are listed in 2O, MET–RHE–ethanol–H2O, and MET–RHE–acetonitrile , MET·HCl (B), RHE (C), and MET–RHE (D) was evaluated in high-temperature, high-humidity, and illuminated environments by weighing 50 mg samples for PXRD characterization on days 0, 5 and 10, respectively . During Optimizing the hygroscopicity of MET is the main improvement target in the salification strategy of MET . Therefo−1) is much higher than that of RHE (0.48 µg/mL⋅min−1) based on the comparison of the slope of the first 5 min of the dissolution experiment. Satisfactorily, the in vitro solubility test (Considering that water solubility is one of the important factors affecting drug absorption and bioavailability ,72, the ity test B showed ity test  of MET–Rity test , MET is Based on the excellent physicochemical properties of MET–RHE in vitro, its hypoglycemic activity in mice was evaluated. As shown in Optimizing the physicochemical properties of drugs, improving their bioavailability, and enhancing efficacy are some of the important topics for pharmaceutical researchers. The important contribution of this paper is the design and preparation of four multicomponent pharmaceutical salts via salification. SXRD and other methods were used to characterize structures of the salts, and the solvent removal experiment of multicomponent salt solvates was completed under PXRD monitoring. In vitro stability and solubility experiments showed that the solubility of RHE was improved by about 93 times, while the stability of MET was optimized, indicating the complementary advantages of multicomponent pharmaceutical salts. The hypoglycemic activity of MET–RHE in mice showed that MET–RHE exhibited a certain hypoglycemic advantage compared with MET·HCl and the physical mixture of raw ingredients. In addition, given that both MET and RHE exhibit some activity in alleviating diabetic nephropathy, the above studies provide a new approach to the development of new agents for the combined treatment of diabetes and diabetic complications to some extent.


The main aim of the paper was to assess whether the lightweight concrete with a new type of sintered fly ash aggregate can be used as a structural material for post-tensioned elements subject to high effort. This purpose was achieved by comparison of the properties of lightweight aggregate concrete with Certyd aggregate (LWAC) and normal-weight concrete with dolomite aggregate (NWAC) of similar strength in terms of their suitability for use in prestressed members. Special emphasis was placed on long-term, relatively rarely performed tests of rheological properties such as shrinkage and creep. The research was conducted on standard specimens as well as on plain and post-tensioned beams of bigger scale, which could reflect better the behavior of the materials in a destined type of structural members. The carried out tests showed that, despite the expected lower density and modulus of elasticity, LWAC revealed comparable tensile strength and lower shrinkage and creep in the whole time of observations (ca 1.5 years) in comparison to NWAC. Moreover, the total loss of prestressing force for beams made of LWAC was slightly lower than for NWAC. Estimations of tensile strength and modulus of elasticity values according to the standard Eurocode EN-1992-1-1 for both concrete types turned out to be satisfactory. However, the rheological properties of the tested lightweight concrete seemed to be considerably overestimated. Lightweight aggregate concrete (LWAC) as a structural material was already used in ancient times. The technology of this type of cement composite was developed by the Romans, who applied concrete with crushed bricks or volcanic rock aggregates such as pumice to construct both buildings and engineering facilities. One of the most famous and admirable buildings from that time that has survived to this day is the Pantheon in Rome. In modern times, the first structural application of lightweight concrete made of manufactured aggregate was in 1928, when LWAC was used to add eight additional floors to a skyscraper of Bell Telephone Company in Kansas City [3 and not more than 2000 kg/m3. This concrete should be characterized by a closed structure and be made with the use of only or partly lightweight aggregate of mineral origin. In comparison to normal-weight concrete (NWAC), such lightweight concrete is usually characterized by greater structural homogeneity resulting from a more similar modulus of elasticity of the aggregate and the cement matrix, their better mutual adhesion, and more uniform shape and size of the manufactured LWA. Due to the different structures, lightweight aggregate concretes usually behave differently under load and show a different mechanism of failure compared to NWACs. In the case of LWAC, there are no three characteristic stages of crack development as in normal-weight concrete . For typical NWAC with rock aggregate subjected to compressive load, the stress limit between stage I and stage II is about 35–45% of concrete strength, while stage II changes to stage III at stress of about 70–90% of the compressive strength. Meanwhile, in concretes with lightweight aggregate, the first cracks appear even at the stress corresponding to 85–90% of the strength [According to standard EN-1992-1-1 , structustrength . This apstrength . As Younstrength ,13,14,15strength ,17,18. Ostrength ,22,23 thstrength ,25,26 asThe concept of using lightweight concrete for prestressed structures may turn out to be a very good alternative to normal-weight concrete. Due to the application of LWAC instead of NWAC, the amount of concrete and prestressing steel can be reduced . Mayer aThe aim of tests reported by Bymaster et al. in  was to cTests of prestressing force losses in beams made of various types of concrete were also carried out by Chen et al. . In thisIn turn, Vázquez-et al.  reportedWu et al.  analyzedThe main aim of the research was to assess whether lightweight concrete with a new type of sintered fly ash aggregate can be used as a structural material for post-tensioned elements subject to high effort. This purpose was achieved by comparison of the properties of LWAC and NWAC of similar strength in terms of their suitability for use in prestressed members. Due to the destiny of these concretes, special emphasis was placed on long-term tests of rheological properties such as shrinkage and creep specified on bigger elements and in much longer time than in the case of all studies referred above. As these characteristics have a direct impact on the value of rheological losses and deflections of prestressed elements, a longer time of observation could make the comparison more reliable. An additional purpose of this paper was also to verify the estimations of the structural properties values for lightweight and normal-weight concretes in accordance with the standard Eurocode EN-1992-1-1 . Two typTests were carried out on two types of concretes of comparable compressive strength levels suitable for prestressed members: lightweight aggregate concrete and normal-weight concrete as a reference composite.24h) before application for concrete. Such a procedure protected fresh concrete from workability loss and too high cement content.Lightweight concrete was made with Certyd aggregate . It is aNormal-weight concrete was made of dolomite coarse crushed aggregate. Its rough texture and uniform structure enabled the formation of a very good bond between the aggregate and the cement matrix. Owing to better concrete homogeneity, this type of dolomite aggregate has typically been used for structural composites, especially for prestressed structures such as viaducts and bridges. The properties of the used dolomite are compared with lightweight Certyd in –cement coefficient in comparison to NWAC. Compositions of both concretes are presented in The rest of the constituent materials applied for the production of both concretes were natural quartzite sand, Portland cement CEM I 42.5R, potable water, and superplasticizer. The compositions of lightweight and normal-weight concretes were designed in such a way that both composites had the same consistency in fresh conditions (V4/V5) and comparable strength in the hardened stage (45–55 MPa). Additionally, lightweight concrete density was assumed to be classified as D1.8. As a result, the composition of LWAC was characterized by a higher content of cement and superplasticizer and a lower nominal waterThe consistency of the fresh concretes was tested according to EN 12350-5 , as the Tests of density, compressive strength, modulus of elasticity, and tensile splitting strength were carried out according to European Standards procedures ,37,38,39In the case of testing, shrinkage and creep much bigger than typical standard specimens, i.e., beams 200 × 200 × 1000 mm, were used. For each concrete type, six beams were cast: three massive beams and three with inner ducts formed for post-tensioning. In the middle of the length of each beam, two 200 mm long measuring bases were installed on opposite sides to measure deformations. The scheme of beams for shrinkage and creep testing with the arrangement of prestressing cables and sensors for measuring deformation is given in Strain readings were taken with the mechanical sensor Demec over a period of 559 days for lightweight concrete and 489 days for normal concrete. The difference in measuring time for LWAC and NWAC beams resulted from different times of execution of these beams see . For eacFor both LWAC and NWAC, the Vebe time was 5–6 s. According to National Annex PN-B-06265  to EN 203, while in the case of NWAC, it was 2330 kg/m3.The density of fresh LWAC was 1990 kg/mMean densities of hardened concretes in saturated, natural, and oven-dry conditions at 28 days are presented in The obtained density of lightweight concrete in a dry condition classifies it according to EN 206  to densiThe mean values of compressive strength determined at the age of 14, 28, and 90 days on standard cylindrical specimens are shown in Comparing the test results after 28 days, it should be stated that, regardless of the type of specimens used for the strength determination, similar average compressive strengths were obtained for both concretes, and their values corresponded to the assumptions. The average compressive strength of normal-weight concretes was only 4% and 11% higher than that of lightweight concretes, respectively, when determined on cubic and cylindrical specimens.Nevertheless, the strength development of both concretes over time turned out to be different, especially in ages later than 28 days. Between the age of 28 and 90 days, NWAC showed a significant 25% increase in strength, while during this time, LWAC strength increased only by 3%. A negligible increase in the compressive strength of lightweight concrete after 28 days is due to the limiting effect of lightweight aggregate. The low strength of LWA, which is the weakest component of the concrete, prevented the use of the potential of a stronger cement matrix in the further development of the composite’s strength. Such observations regarding the strength development of lightweight aggregate concretes are consistent with the research reported in ,14.cm,cube) and cylindrical specimens  indicate very good structural homogeneity of both concretes. In the case of typical structural normal-weight concretes and lightweight concretes, their compressive strength at 28 days determined on cylinders is usually lower than the strength tested on cubes by about 20% and 10%, respectively [cm,cyl to fcm,cube for the tested LWAC was 6%, while the tested NWAC showed no scale effect et al., which was probably caused by the application of a very homogeneous dolomite aggregate with a rough texture. Such results confirm the reports [Small differences between the compressive strength determined on cubic  determined at the age of 14, 28, and 90 days on standard cylindrical specimens are shown in The mean values of tensile splitting strength  determined at the age of 14, 28, and 90 days on standard cylindrical specimens are shown in The mean values of the secant modulus of elasticity  than that of normal concrete. It should also be noted that for both LWAC and NWAC, the standard estimations differ only slightly from the obtained test values, which confirms the reliability of the estimations according to Eurocode EN-1992-1-1 [4% than tThe increase in compressive strength, tensile strength, and modulus of elasticity between 28 and 90 days of curing is much greater for normal-weight concrete than for lightweight concrete. A smaller increase in the mechanical characteristics of LWAC is caused by the limiting effect of the porous aggregate, which is weaker than the cement matrix.The shrinkage of lightweight concrete in the initial period of its curing (up to about 100 days) revealed a much less dynamic development in comparison to normal-weight concrete. The reason for this different rheological behavior of LWAC was probably a significant amount of water accumulated in the porous aggregate. Later, the shrinkage of lightweight concrete increased linearly, but by the end of the tests , it did not reach stabilization, and its value was still as much as 36% lower than for normal-weight concrete. Such behavior of tested LWAC turned out to be different from that reported in the available thematic literature, indicating that in the vast majority of cases, the shrinkage of lightweight concrete after about a year reaches the value of shrinkage of NWAC of comparable strength. Due to the lack of shrinkage stabilization for the tested LWAC, it can be expected that it will eventually reach higher values compared to NWAC. However, confirmation of the above would require a much longer observation period.The course of shrinkage of the tested normal-weight concrete turned out to be consistent with the estimations of Eurocode EN-1992-1-1 , and theThe final creep deformations of the tested lightweight concrete were more than two times lower than those of the corresponding normal-weight concrete despite significantly lower final strength.The course and values of the lightweight concrete creep coefficient calculated according to EN-1992-1-1  are signDiscrepancies in values of both rheological properties, shrinkage and creep, determined in tests and estimated according to Eurocode EN-1992-1-1  for lighThe carried out research program and the conducted analyses give the basis for formulating the following conclusions:The above conclusions from experimental tests allow us to assess that lightweight concrete with Certyd aggregate is characterized by properties, in particular rheological characteristics, suitable for using this material in prestressed structures and can be considered a favorable alternative to normal-weight concrete. In order to verify this thesis, long-term rheological tests were carried out on full-size 6 m long prestressed beams made of both types of concrete. The results of these studies will be the subject of the next publication.