Antimicrobial resistance (AMR) has recently increased due to the overuse and misuse of antibiotics, and their use in animals (food-producing and companion) has also resulted in the selection and transmission of resistant bacteria. The epidemiology of resistance is complex, and factors other than the overall quantity of antibiotics consumed may influence it. Nowadays, AMR has a serious impact on society, both economically and in terms of healthcare. This narrative review aimed to provide a scenario of the state of the AMR phenomenon in veterinary medicine related to the use of antibiotics in different animal species; the impact that it can have on animals, as well as humans and the environment, was considered. Providing some particular instances, the authors tried to explain the vastness of the phenomenon of AMR in veterinary medicine due to many and diverse aspects that cannot always be controlled. The veterinarian is the main reference point here and has a high responsibility towards the human–animal–environment triad. Sharing such a burden with human medicine and cooperating together for the same purpose (fighting and containing AMR) represents an effective example of the application of the One Health approach.As warned by Sir Alexander Fleming in his Nobel Prize address:  In the present narrative review, the terms “antibiotic” and “antibacterial” are used instead of “antimicrobial” because they are specifically related to bacteria, which are the microorganisms considered in the review. Moreover, the term “antibiotic” and its derivations  are generally accepted.The discovery of antibiotics in 1928 revolutionized modern medicine, as they were deemed “miracle drugs”. In addition to their use to fight infectious  diseases, antibiotics have enabled remarkable medical improvements. Without them, major surgeries, organ transplantation, or cancer chemotherapy, would be impossible . Further“the use of antimicrobials can, and will, lead to resistance” [However, as warned by Sir Alexander Fleming in his Nobel Prize address, istance” . Bacteriistance” ,8.As this review demonstrates, the epidemiology of resistance is complex, and factors other than the overall quantity of antibiotics consumed may influence the level of AMR. The horizontal spread of antibiotic resistance genes (ARGs), inadequate sanitation, movements of humans, and the trade of live animals and meat are just some examples .“one of the ten global public health threats facing humanity” based on the predictions that, by 2050, it will be responsible for more than 10 million deaths per year, with a loss of more than 100 trillion dollars worldwide [Globally, the threat and costs of AMR are widely recognized. For example, antibiotic-resistant pathogens cause approximately 33,000 deaths per year in Europe and 4.95 million total deaths worldwide, resulting in EUR 1.5 billion in healthcare expenses and productivity losses annually . The Wororldwide ,12.In this context, to raise awareness about the AMR phenomenon and the appropriate use of antibiotics in animals, the European Union, as well as worldwide public or private organizations, highlighted in Regulation (EU) 2019/6 of the European Parliament and of the Council that its cross-border dimension, economic impact, and animal and human health consequences requires global intersectoral action to combat AMR .Veterinary medicine is concerned with the care and well-being of animals and, indirectly, that of humans. It should be noted that the term “animals” is very generic, encompassing terrestrial, aquatic, and avian species, which can be further divided into production, companion, and exotic/wild animals, all sharing different ecosystems with humans, directly or indirectly. These animals have many diseases in common with humans, even infectious ones , although they are usually caused by different etiological agents. Therefore, it is also common to share medications, including antibiotics. As underlined by Regulation (EU) 2019/6 , the AMRHowever, despite the acknowledged importance of the PK/PD approach and the responsible and prudent use of antibiotics, there are still many diverse aspects that remain uncontrollable .Focusing on the use of antibiotics in different animal species and its impact on animals, but also on humans and the environment, the purpose of this narrative review is to provide an overview of the AMR phenomenon in veterinary medicine, trying to explain its complexity.“global public health threat facing humanity”, as defined by the WHO.The literature is filled with valuable contributions to these topics , and given the nature of review (narrative review), only some particular examples are provided here to better understand the vastness of the issue. Finally, the authors’ intent was to address not only researchers and scientists, but also everyone involved  in containing this Antimicrobial resistance (AMR) is a natural phenomenon that appears when a bacterium  susceptible to an antibiotic, following its exposure to that antibiotic, becomes unsusceptible (acquired resistance).The consistent usage of antibiotics  creates a selective pressure on pathogenic bacteria but also on commensal bacteria  that can determine the prevalence of antibiotic-resistant bacteria (ARBs) and the spread of resistant bacteria or genes. Plasmids, bacteriophages, or integrative mobile genetic elements facilitate horizontal gene transfer; therefore, it is essential to reduce and to limit the use of antibiotics by following the “principles of responsible and prudent use” in order to preserve their efficacy ,15,16.It is important to keep in mind that AMR is a dynamic process: once bacteria become resistant, redeveloping susceptibility to antibiotics is not guaranteed; it takes time and only occurs when selection pressure decreases . In a baVertical  and horizontal  ARG transfers are well known and demonstrated . Due to Staphylococcus aureus (MRSA) [The transmission of resistant bacteria typically occurs from animals to humans through various routes, but it can also be of human origin, such as in the case of methicillin-resistant s (MRSA) ,27. Thres (MRSA) .Mostly through manure, antibiotic residues, ARBs, and ARGs are spread from food-producing animals, being of concern for the environment, wild fauna, and humans.The most commonly used antibiotic classes in food-producing animals are tetracyclines, β-lactams, quinolones, and sulfonamides, with oral administration being the most convenient route ,30. TetrAs previously mentioned, the land application of food-producing animal manure containing resistant bacteria and antibiotic residues may create an environmental reservoir of ARBs ,37,38, pFurthermore, the abundance of ARGs in the feces of people working in pig/broiler farms has often been linked to livestock AMR, potentially due to exposure to animal feces and dust in farms. This suggests that antibiotic residues in farm dust may also impact the gut microbiota by selecting for resistance . The fooAs is discussed in more detail later, aquatic environments may also become reservoirs of ARBs and ARGs from various sources, such as wastewaters, hospital effluents, agricultural contamination from animals, and aquaculture. Antibiotics in aquaculture are mainly administered through feed, immersion, or direct application into water ,43, withAntibiotic-resistant bacteria and antibiotic resistance genes, as well as multidrug-resistant bacteria (MDR), have emerged and spread among dogs and cats .S. pseudintermedius, (MRSP)/methicillin-resistant S. aureus (MRSA), and MDR Gram-negatives are hospital-associated pathogens that are currently spreading outside of healthcare facilities with high transmission ability, representing a serious risk to human health, especially for frail subjects  [Bacterial resistance to the most conventional antibiotics licensed for veterinary use poses a serious risk for animals and for humans. For example, Methicillin-resistant systems) .Moreover, the tight contact between companion animals and humans  as well as the home environment facilitate the transmission of antibiotic-resistant bacteria and genes .E. coli in dogs and cats in China. E. coli is one of the most common microorganisms in the intestinal flora and is continuously exposed to antibiotic selection pressure. The authors found a prevalence of antibiotic-resistant E. coli exhibiting a variety of antibiotic resistance patterns equivalent to 86.64% (higher than results from other studies) [E. coli had a higher prevalence in cats than in dogs, which differs from the findings of other research [E. coli isolated from dogs and cats is highly similar to human isolates, increasing the potential for transferring resistant strains between species [Zhou et al.  conductestudies) ,61,62,63research  hypothesresearch ,65. E. c species .Bacteroides spp., Capnocytophaga spp., Corynebacterium spp., Fusobacterium spp., Pasteurella spp., Porphyromonas spp., Staphylococcus spp., and Streptococcus spp. were considered the most common pathogens in dog bites. By mapping the genome of the dog saliva bacteria, the authors detected the genomes of the most relevant bacteria in dog bite infections, as well as the genes conferring resistance to aminoglycosides, carbapenems, cephalosporins, glycylcyclines, lincosamides, macrolides, oxazolidinones, penams, phenicols, pleuromutilins, streptogramins, sulfonamides, and tetracyclines. The identified antibiotic resistant genes have the capacity to establish themselves in the human body and bacteriota.As previously mentioned, Tóth et al.  underlinThe most frequently used classes of antibiotics in animals  are quinolones , aminopenicillins alone or in combination with potentiators, first- and second-generation cephalosporins, tetracyclines, sulfonamides alone or in combination with potentiators, and also third- and fourth-generation cephalosporins, macrolides, and glycopeptides, categorized as highest priority critically important antibiotics (HPCIAs) ,67.The “Terrestrial Animal Code”, issued by the Office International des Epizooties (OIE) in 2022 , represe“Assessment of the potential of antimicrobial agents to select for resistance”, consisting of (i) the concentration of either active antimicrobial agents or metabolites in the gut of the animal  at the defined dosage level, (ii) the pathway for human exposure to antimicrobial-resistant microorganisms, (iii) the degree of cross-resistance, and (iv) the intrinsic and pre-existing baseline level of resistance in the pathogenic agents of human health concern; (B) the “Establishment of acceptable daily intake (ADI), maximum residue limit (MRL) and withdrawal periods in food-producing animals”, concerning the safety evaluation, which should include the potential biological effects of the antibiotic residue on the intestinal biota of humans, referring to the values of minimum selective concentrations ; (C) the “Post-marketing antimicrobial surveillance”, since, among the information underpinning the pharmacovigilance programs, the lack of efficacy is of great concern to minimize AMR [In particular, the authorization process for new veterinary medicinal products containing antibiotics focuses on three key points for the responsible and prudent use of such drugs: (A) the mize AMR .Access to antibiotics, especially in the livestock sector, varies significantly around the world and sometimes within a single country, particularly in low-income countries. For instance, in many parts of Africa, there is evidence of the use of substandard and non-registered drugs. These antibiotics may be falsely branded or expired, therefore containing a lower (or no) amount of the active ingredient than indicated or even containing harmful ingredients . GeograpIn all situations where the administration of an antibiotic in animals is really necessary, the principles for its responsible and prudent use must be followed, including (i) using quality-assured products; (ii) avoiding the regular preventive use of antibiotics and, in livestock, their use as growth promoters; (iii) avoiding using HPCIAs for human medicine; (iv) only using antibiotics based on the diagnosis of disease (to know the pathogen causing the infection) by a veterinarian and only for the authorized indications; (v) in livestock, promoting the treatment of individual animals with the correct dose and duration, avoiding group treatments, especially through feed; (vi) whenever possible, selecting antibiotics for therapeutic use based on antibiotic susceptibility testing . It is iOther important factors to consider when setting up a correct antibiotic treatment in animals include (i) antibiotic use only when a primary bacterial infection has been proven; (ii) the severity of the infection and its likelihood to resolve without the use of antibiotics; (iii) especially in case of empirical prescription, knowing the spectrum of antibiotics (narrow spectrum antibiotics are to be preferred), their pharmacokinetics and pharmacodynamics, and potential toxicity or adverse effects; (iv) defining the most suitable route of administration  .The need to reduce the use of antibiotics in animals puts a great emphasis on the prescriptions of antibiotics by veterinarians to ensure their responsible and prudent use. Veterinarians can prescribe or dispense antibiotics based on defined criteria .Several studies have analyzed prescriptions of antibiotics for companion animals in veterinary university hospitals and private veterinary practices in different countries ,73,74,75Antimicrobial stewardship focuses on the approaches necessary to reduce the resistance selection and to preserve the clinical effectiveness of antibiotics, implying a wider concept than “prudent use” or “responsible use”. Good stewardship practices (GSP) is a guiding principle based on the active and dynamic process of the continuous improvement of antibiotic use that should be followed by everyone involved. The main actors are veterinary practitioners, but laboratory diagnosticians, owners, drug regulators, and pharmaceutical companies are relevant stakeholders .Antibiotics are administered to food-producing animals for several purposes, including therapeutic, metaphylactic, and prophylactic use, but they are also used as growth promoters. The latter involves administering low doses (sub-therapeutic) of antibiotics in feed or water over an extended period of time to improve growth and production efficiency . DespiteThe above previsions were confirmed by Tiseo et al. . The autConcerning Europe, the trend highlighted by Tiseo et al.  was confIn most cases, the antibiotics available for food-producing animals are the same used in human medicine and can contribute to AMR ,85, as wIn the therapy of pets, the extra-label use of drugs, and specifically of antibiotics, is frequent and more common than in food-producing animals . The reaThe regulations concerning the extra-label use of drugs show significant differences among countries; for example, while in the United States, the extra-label administration of drugs, and specifically of antibiotics, in companion species is legal, and in Europe, the extra-label use of drugs is strictly regulated .In the United States (but the situation is quite similar worldwide), more than 60% of households were associated with the ownership of various pet species . During S. aureus (MRSA), which is of human origin. Companion animals may be “transient carriers” of MRSA, but the source can only be from an infected human or a human carrier living in the same household. In conclusion, the authors agreed that the occurrence of MRSA in pets is most likely of human origin, with pets serving as transient carriers, but potentially affecting humans.Nowadays, humans and animals share most antibiotic classes, as well as ARBs and ARGs ,95; thusDespite the antibiotic use in companion animals being considerably lower than that in food-producing animals, the use of CIAs belonging to the AVOID USE and/or RESTRICT USE categories of the European Medicines Agency (EMA) classification is common in companion animals. For example, in Denmark, the majority of veterinary fluoroquinolone global consumption is intended for companion animals, despite that this represents only 1% of total veterinary antibiotics used ,101.In both human and veterinary medicine, defining the correct dosage regimen  is essential to ensure the health of patients with minimal adverse effects. This is especially true for antibiotics, which also have the additional purpose of countering or suppressing antimicrobial resistance. Therefore, the “correct” dose and dosing regimen for antibiotics is of the utmost importance. Antimicrobials must reach active  concentrations at the site of infection, the so-called “biophase”, and remain there for a sufficient amount of time to ensure healing.The knowledge of both pharmacokinetics and pharmacodynamics is essential, as is the definition of PK and PD parameters. The PK/PD approach, together with PK/PD indices, helps to integrate the two processes (PK and PD) and optimize the dosage regimens of drugs when systemic action is required.Concerning antibiotics, PK/PD indices are useful for determining the dose to be administered, but they are also necessary for establishing clinical breakpoints (CBSs) that should be considered as MIC values (mg/L) or zone inhibition diameters used to categorize antibiotics tested for their antimicrobial susceptibility as susceptible (S), intermediate or susceptible-increased exposure (I), or resistant (R) .PK/PD indices link antibiotic exposure to the antibiotic susceptibility of an infecting pathogen. Generally, the susceptibility is described as the minimum inhibitory concentration (MIC), which is the lowest concentration (mg/L) of an antibiotic that, under defined in vitro conditions, prevents the growth of a microorganism within a defined period (18–24 h). It is specific for a given microorganism and ultimately reflects the outcome of the antibacterial action (growth and kill/death of bacteria) ,103.MIC is widely accepted as a PD parameter in all PK/PD indices of antibiotics since it reflects the susceptibility of bacteria to antibiotics. Generally, for all drugs, the three parameters that describe the PD profile are efficacy, potency, and sensitivity, all of which are encompassed by MIC. Additionally, MIC is dependent on the assay condition and variability, making it a variable reflecting the three PD parameters rather than a PD parameter itself. MIC has been related to PD parameters by equations; thus, it can be regarded as a hybrid PD parameter ,105,106.The time–kill curve assay (TKCA) is another index describing the bacterial susceptibility to an antibiotic. It has two main purposes: (i) to categorize the antibiotic as concentration-, time-, or co-dependent; (ii) to calculate PK/PD indices, for example AUC/MIC, when the in vivo effects of the antibiotic depend on the highest achievable antibiotic concentration above the MIC for a pathogen to ensure maximal kill . The “matrix effect” represents the major limitation of TKCA ,107.Common PK/PD indices include: (i) the percentage of a 24 h period that the antibiotic concentration exceeds the MIC of the pathogen (at steady-state conditions) ; (ii) the highest concentration of the antibiotic to MIC ratio (Cmax/MIC); and (iii) the area under the antibiotic concentration-time curve over 24 h at steady-state  to MIC ratio  . Both AUMonte Carlo methods are stochastic computational algorithms (based on repeated random sampling) that are routinely used to support several aspects of antimicrobial PK/PD for different purposes: (i) the establishment of CBPs for antibiotic susceptibility tests ; (ii) thThe percentage of protein binding of a drug is species-specific, and it is susceptible to variations related to physiological or pathophysiological conditions of animals. Mzyk et al.  pointed During antibiotic treatment against a pathogen bacterium, the risk of emergence and propagation of antibiotic-resistant microorganisms should be considered, even though this emergence is limited ,116,117.Several studies, mostly in vitro and simulating antibiotic “therapeutic” dosing, suggest that exposure associated with an increased probability of therapeutic success may be insufficient to suppress the emergence of ARBs, particularly in Gram-negative bacteria ,117. DesE. coli, while for S. aureus, the ratio ranged from 9 (marbofloxacin) to 136 (difloxacin) [The Mutant Prevention Concentration (MPC) is defined as the MIC of at least one susceptible single-step mutant. MPC measures the MIC of the most resistant sub-population that may proliferate at concentrations higher than the MIC ,118,119.loxacin) .S. pseudintermedius isolates from dogs was in a narrow range from 5.3 to 6.8 [Similarly, the MPC/MIC90 ratio for ciprofloxacin, difloxacin, enrofloxacin, marbofloxacin, and orbifloxacin for 3 to 6.8 . Based o3 to 6.8 .The concept of MSW is currently applied only to fluoroquinolones, likely due to resistance developing through mutational alterations of the drug target. This approach is not applicable to other resistance mechanisms, such as plasmid-mediated, and therefore to other antibiotic classes . NeverthS. aureus exposed to garenoxacin, an AUC/MIC ratio of 100 is needed when the exposure time is two days, but the AUC/MIC ratio increases to 280 for an exposure of 10 days. The so-called “one-shot therapy” is a veterinary option that seeks to minimize treatment duration to prevent the emergence of resistance for quinolones by administering high doses of the drug. The goal is to kill the target pathogens as rapidly as possible, allowing the host’s natural defenses to eradicate the remaining bacterial population.Considering the duration of the therapy, thus the time of exposure of bacteria to the antibiotic, Tam et al.  found thSumi et al.  conducte(1)The exposures needed to suppress the emergence of resistance for Gram-negative bacteria varied depending on: the antibiotic assayed; the extent of the experiment; the bacterial species and the specific bacterial isolate tested ; th(2)As is described in more detail below, patient illness severity should be responsible for the high interpatient variability in antibiotic pharmacokinetics. Commonly, patients in Intensive Care Units (ICU) undergo important pathophysiological changes that have an impact on both the PD and mostly PK characteristics of antibiotics.(3)In vivo studies describing the emergence of AMR in anatomical sites different from the infected one  were not comprised by the systematic review ,131.In conclusion, Sumi et al.  suggest Patients  in Intensive Care Units (ICU) differ significantly from other patients due to their very serious organic conditions, frequent excretory organ deficiency, high complexity of drug regimens, and severe infection frequently caused by MDR-bacteria, often contracted at the ICU ,133. ForIn ICU patients, managing an antibiotic dosage regimen is a challenge due to the pathophysiological and/or iatrogenic factors that must be considered for the significant effects they may primarily have on kinetic processes. The main consequences are summarized below .(1)Infections are responsible for inflammation processes, which can increase capillary permeability, resulting in an increase of fluids in the interstitial space and a dilution of the systemic concentration of antibiotics. Antibiotics with a low volume of distribution  may especially result in under-dosing .(2)Hypoalbuminemia  is frequently observed (humans: 35–40%) and should be taken into account when the antibiotic is highly bound (>80%), as this can lead to a decrease in the total plasma concentration ,136. How(3)Altered renal function, or augmented renal clearance (ARC), can result in an enhanced excretion of antibiotics mostly eliminated by the kidney  ,137,138.The inhibition or induction of drug metabolizing enzymes represent the most frequent drug–drug interactions in the ICU ,140. TheThe previous section highlighted the importance of the PK/PD approach, which is a pivotal aid in defining the “best” dose/dose regimen to administer to patients with a high probability of success, particularly for antibiotics. However, there are also factors, situations, or differences between antibiotics that make PK/PD underperform, especially in counteracting AMR. The following section provides examples, peculiar to veterinary medicine, to illustrate that AMR is a complex and threatening phenomenon that affects all ecosystems. AMR can only be addressed and contained by a One Health vision.Most antibiotic molecules are excreted unchanged and/or metabolized via feces and urine by humans or animals ,144 and Concentrations of antibiotics in both aqueous and solid-phase media  are of the order of “ng/L and μg/L” and “ng/g and μg/g”, respectively . AntibioThe research of Maghsodian et al.  intendedThe entry of antibiotics into aquatic environments from different sources may cause their accumulation and magnification in marine organisms . In general, the most frequently prescribed antibiotic classes in aquaculture, including amphenicols, or quinolones , tetracyclines , and sulfonamides (sulfamethoxazole and sulfamethoxazole/trimethoprim combination) all express high chemical stability in water. Conversely, penicillins are easily decomposed in the environment ,155,156.Worldwide, over two million tons of fish are produced annually. Although the main producing countries are Norway and Chile, the consumption of fish is increasing in the EU, USA, and Asia . AquaculSalmonella spp. and Vibrio spp. [tet genes) [As previously mentioned, approximately 80% of the antimicrobials used in aquaculture enter the environment in an active form . This cario spp. . Anotherrio spp. . Aquaticrio spp. . Furthert genes) ,161.The human intestinal microbiome is characterized by a complex group of microorganisms composed of bacteria, fungi, archaea, protozoa, and viruses. These microorganism are arranged in a community living in close relationship with the human GI tract environment and representing a good habitat for bacteria to exchange genetic materials , comprising ARGs .The commensal microbiota of the gastrointestinal tract or the skin of animals, as well as of humans, could be involved in AMR, and this is significant also from an ecological perspective. In animals, commensal microbiota are characterized by large biomasses  that significantly outweigh the biomass of pathogens harbored by animals . For exadenovo), and (ii) the lowest concentration that selects for a resistant, compared to a susceptible, strain (MSCselect) [Drug use is pivotal to treat diseases in food-producing animals; it is estimated that 80% of global terrestrial and aquatic livestock receive medication at least once during their lifetime. Similarly to any other drug, the use of antibiotics in food animals and in aquaculture can result in the presence of residues in edible tissues, as well as in milk and honey . Such asCselect) ,167.The results of the study  demonstrNeisseria gonorrhoeae. The MSCdenovo  was considerably lower than the quinolone concentrations found in foodstuffs. Even though a number of factors can affect the MSC, the authors affirmed that ciprofloxacin and quinolone concentrations in meat may be linked to the prevalence of ciprofloxacin resistance in N. gonorrhoeae, suggesting that it could be positively associated with quinolone consumption for animal husbandry [Bringing one more example, Gonzáles et al.  hypothesusbandry ,170,171.In assessing whether antibiotic residues equal to MRL in products of animal origin may facilitate AMR, several factors and variables should be taken into consideration: the combination of different antibiotics present in a particular foodstuff , the model of diet , and the cooking method used  ,165,172.Antibiotic residues in foods of animal origin are not as much of a direct public health concern; however, the long-term exposure of human intestinal microbiota to antimicrobial MSCs can favor the selection of resistant bacteria and enable the transfer of resistance genes in the human gut ,173.In veterinary medicine, using drugs, and specifically antibiotics, in a way not in accordance with approved label directions  is frequent, and it is more common in companion animals than in food-producing species. Papich  describeMany medicinal products are no longer marketed or available in all forms in the U.S. The indications listed on the label are generic and not relevant  or outdated, as well as dose regimens are not sufficient and accurate according to current PK/PD principles. Administering antibiotics that are not active against the bacteria listed on the label, or when the dose on the label is insufficient (due to AMR), results in unnecessary antibiotic exposure . Most ofThe Guidelines for the Prudent Use of Antimicrobials in Veterinary Medicine issued by the European Commission in 2015 state: “The off-label (cascade) use of antimicrobials not authorized in veterinary medicine to treat non-food-producing animals should be avoided, especially when the drugs are of critical importance for human health . Their use should only be considered in very exceptional cases, for example, when laboratory susceptibility testing has confirmed that no other antimicrobials will be effective and where there are ethical reasons to justify such a course of treatment” .The extra-label use of drugs is allowed “in particular situations”, meaning that a medicinal product can be exceptionally administered for non-authorized use in specific cases  under the veterinarian’s responsibility. This practice is well regulated by authorities (for Europe the Regulation 2019/6 ) and invThe procedures for the proper extra-label use of drugs in food animals are significantly more restrictive than those for companion animals . For exaSafe and effective drug dosing is essential, regardless of its purpose of administration. As the PK/PD approach applied to antibiotic therapy emphasizes, for such drugs, the “correct” dose is pivotal. When antibiotics are underdosed, the patient does not recover, and the risk of creating and spreading bacterial AMR is significantly increased.The dose extrapolation of drugs based on body weight (mg/kg) alone is not the most accurate approach. The relationship between the metabolic rate of an animal and its size must be taken into consideration. As the size of animal species increases, the body surface area in relation to body weight decreases, and all the physiological processes of a larger animal are slower than those of a smaller animal . In this context, the “metabolic rate” (closely related to body surface area) provides an index of how the rates of all the physiological processes involved in drug absorption, distribution, metabolism, and excretion scale across different species ,178.The application of this principle into practice, and thus into the need to extrapolate the dosage of a drug from one animal species to another , is based on the general consideration that the higher the body weight, the lower the doses of drugs (mg/kg). It is well known that the final therapeutic effect of a drug depends on its pharmacokinetic  and pharmacodynamic  processes. Some of these are related to the body surface area of the animal, while others are not .Sharma et al.  and NairProblems in the use of extra-label drugs are related to dosage forms, such as the concentration of the active ingredient, the type of preparation (solid or liquid), the size of solid forms  or the possibility to divide them, the type of excipients, and the organoleptic characteristics (taste or odor). These are just some of the many factors that must be taken into consideration when, especially in the case of antibiotics, a veterinary medicinal product labeled for a given species is used in a different one .To control the spread of AMR, action plans, recommendations, and guidelines on the responsible and prudent use of antibiotics were developed for food-producing animals and companion animals, but they appear to be lacking in exotic pets. This is likely due to the scarcity and/or lack of data and information on the use, overuse, or misuse of antibiotics in these species .First of all, most of the monitoring programs to assess the quantity of antibiotics used in animals are focused on food-producing animals, while data on companion animals  are scarce, and there is no information available on exotic pets . In the Enterobacteriaceae have been signaled in birds and rabbits, as well as in birds and turtles, respectively [MDR bacteria, such as methicillin-resistant staphylococci, and extended-spectrum β-lactamase-producing ectively ,181,182.In addition to the lack of information on the use of antibiotics in exotic pets, it should be noted that the possibilities of choosing among the available antibiotics for the different species are limited . Beyond The aforementioned challenges direct the choice towards veterinary medicinal products authorized for different animal species or for human use, compromising the selection of the right antibacterial in a specific bacterial infection in a particular patient. However, as with food-producing animals and companion animals, antibiotic treatments in exotic pets must be settled according to the responsible and prudent use approach.As previously mentioned, the use of drugs in food-producing animals and drug residues in tissues can affect wildlife and the environment. Drug residues have been detected in wild animals even when they were never treated. A high percentage of samples (29%) taken from carrion disposed of for feeding to endangered scavenger birds had antibiotic residues, with oxytetracycline (at the highest concentration: 1452.68 ng/g) and trimethoprim being the most common .Aquila chrysaetos) [Fluoroquinolones  and nafcillin were detected in vulture plasma. Enrofloxacin and marbofloxacin  were quantified in a high proportion of individuals (92%) in different colonies and on different dates . Similarysaetos) .Staphylococci strains in tawny owls, scops owls, and black kite owls [Enterococci (genus Enterococcus) are Gram-positive opportunistic pathogens that are part of the gastrointestinal microbiota of humans and animals. Alongside positive effects to the host , occasionally they act as pathogens and are able to acquire and transfer genes for AMR to different molecules [Enterococcus strains. All but one of the isolates were multi-drug-resistant (MDR); about 20% were categorized as extensively drug-resistant (XDR), and 3% was possibly pan-drug-resistant (PDR). Most of the assayed antibiotics were effective against less than 50% of isolates, and none of the antibiotics were effective against all the isolates. The high and diffuse resistances observed, especially for aminoglycosides and tetracyclines, were particularly notable. The highest percentage of Enterococcus isolates showed resistance to fluoroquinolones (70.87% to enrofloxacin and 51.46% to ciprofloxacin). The observed lower susceptibility to fluoroquinolones in enterococci from wild birds confirmed data described by other authors in raptors, common buzzards, and wild birds [The detection of MDR ite owls  proves tite owls ,191. Anoite owls . The autolecules ,199,200.ld birds ,197,199.ld birds , and as ld birds .The findings of Cagnoli et al.  pointed fil rouge of the review is the close relationship that exists between humans and animals, which is rooted in the fact that, despite the differences in species, both are complex organisms with similar biological processes. Starting from AMR, the authors focused on the use of antibiotics in animals, emphasizing the importance of responsible and prudent use, and the need for the veterinarian to be aware of the PK/PD approaches that can optimize dosage regimens, even in critically ill patients (ICU).Antibiotics are among the most important treatment options available in human and veterinary medicine, but AMR is a serious public health concern. This narrative review seeks to provide an overview of the state of AMR in veterinary medicine, considering both the advantages and disadvantages of using antibiotics in animals in relation to this global issue. The By citing specific instances , the authors intended to emphasize the complexity and resulting critical issues of the use of antibiotics in animals, which, particularly in food-producing species, has had and still has remarkable responsibilities. In this context, the veterinarian plays a key role, being called to carefully evaluate the consequences of its decisions and having the liability to educate everyone who administers antibiotics to animals .Antimicrobial stewardship involves coordinated approaches and interventions. It not only focuses on reducing antibiotic use, but it also encompasses infection control, clinical microbiology, the surveillance of antibiotic use and AMR, as well as pharmacovigilance, education, guidelines, and regulations. Most veterinarians are aware of AMR, but veterinary antimicrobial stewardship is a relatively new concept in veterinary medicine that needs to be further consolidated and pursued. However, as this narrative review clearly highlights, a shared commitment between the animal and human medicine worlds is an added value in the fight against AMR and represents an effective application of the One Health approach.


Therefore, in this study, we evaluated the initial mechanical properties of concrete in which cement was partially replaced with non-sintered hwangto (NHT). Specimens without NHT  and normal concrete (NC)) and specimens with NHT  and non-sintered hwangto concrete (HTC)) were prepared. NHT was substituted for 15% and 30% of cement. Two water-to-binder (W/B) ratios, 41% and 33%, were used to analyze the variation in the mechanical properties according to the cement and NHT content per unit volume of concrete. The compressive strength and ultrasonic pulse velocity (UPV) were measured. Experimental results indicated that compressive strength decreased with an increase in NHT content. The mortar with NHT substitution rates of 15% and 30% exhibited higher UPV than NM at a W/B ratio of 41%, in contrast to the behavior observed for concrete. The UPVs of most specimens were similar regardless of the NHT substitution rate. The correlation between the compressive strength and UPV of HTC was analyzed, and therefrom, exponential equations with a high correlation coefficient (R In particular, CO2 emissions from the cement firing process account for approximately 8.8% [2 emissions due to the cement firing process [The construction industry is responsible for 41% of total CO process ,6,7,8. A process , approxiIn particular, hwangto has been studied since the 2000s. Hwangto is easy to obtain because it is found in approximately 10% of the ground surface worldwide and has a chemical composition similar to existing cement admixtures, such as fly ash and blast furnace slag ,12; moreLow strength development may have a considerable impact on the construction period and quality in the early construction stage. In the early construction stage, it is important to evaluate the timing of form removal, and if a form collapse accident occurs during the construction process, it can result in significant human and property damage. In particular, the low strength of hwangto can have a significant impact on the construction period and quality in the early construction stages. Because concrete mixed with hwangto has lower strength compared to concrete mixed with 100% cement, evaluation at the time of form removal, such as with existing concrete, may cause problems such as form collapse. The vertical formwork demolding point is specified as 5 MPa in KASS and JASS and as 12 h after concrete pouring in the ACI and BS standards ,21,22,23The red shaded area is the part that did not reach the strength of 5 MPa and the time of 12 h, which is the point at which the vertical form was demolded, and the blue shaded area is the part that only reached 12 h. In addition, the blue dashed circle is the part where the form demolding strength and time have been reached, and the red dashed circle is the part where the form demolding strength has not been reached. After 12 h, which is the formwork demolding point, only the ACI estimation equation reached 5 MPa for concrete with a target strength of 45 MPa, whereas the other estimation equation did not. Since the difference in strength over time is significant in evaluating the formwork demolding point of concrete, confirming a developed strength of 5 MPa is considered a safe and quantitative decision criterion. Therefore, the formwork demolding point was evaluated using strength in this study .The compressive strength of concrete is part of the quality index and is also an index that predicts various strengths of concrete. It is believed that overlooking the compressive strength of concrete can have a direct impact on cost, construction period, and quality. It is necessary to evaluate the compressive strength at an early age in an accurate and quantitative manner. Fracture tests on specimens are necessary for an accurate evaluation of strength development in concrete. However, identifying the accurate strength development point is challenging because the mechanical properties of concrete can be affected by environmental factors, such as temperature and weather, and monitoring the concrete strength development mechanism is difficult. To address this problem, studies have investigated the identification of strength development point using ultrasonic pulse velocity (UPV), which is a non-destructive method ,26,27,28In existing studies, the correlation between the compressive strength of concrete and UPV was expressed as an exponential function or a linear function. Looking at the correlation between compressive strength and UPV, the degree of increase in compressive strength and UPV is minimal at first, but as time passes, compressive strength increases rapidly compared to UPV. When the correlation between the compressive strength of concrete and UPV was expressed as a linear function and as an exponential function, the correlation coefficient of the exponential function was high. Additionally, because the correlation graph between the compressive strength of concrete and UPV is similar to a quadratic equation, it is expressed as an exponential function. Therefore, in this study, hwangto, an eco-friendly material, was used as a construction material and compressive strength and UPV were measured from the initial age over time according to the replacement rate of hwangto as a cement substitute material. We would like to propose a strength prediction equation in the form of an exponential function by analyzing the compressive strength of concrete mixed with hwangto and the UPV results through correlation.3 and a fineness of 3200 cm2/g was used as the cement. Previous studies have shown that sintered hwangto is not suitable for reducing greenhouse gas emissions due to CO2 generation during sintering. Hence, herein, NHT with a density of 2.5 g/cm3 and a fineness of 3300 cm2/g was used [3, fineness modulus of 7.03, absorption of 0.68%, and maximum size of 20 mm was mixed. For the fine aggregate, river sand with a density of 2.54 g/cm3, fineness modulus of 2.54, and absorption of 1.6% was mixed. Polycarboxylic-based acid, a superplasticizer, was mixed to ensure workability.2 and Al2O3 content. In contrast, the SiO2 and Al2O3 content in NHT was higher than that of CaO. The chemical composition of NHT is similar to that of conventional cement admixtures [mixtures ,11,12.Recently, the target strengths of 45 MPa and 30 MPa have been continuously used in the construction industry, and W/B 33% and W/B 41% were set to represent the target strengths of 45 MPa and 30 MPa. Existing research results suggest that using ash and blast furnace slag as cement binders does not have a significant impact on the target strength of concrete. Therefore, in this study, experiments were conducted with NHT replacement content set at 15% and 30%.2 values of the exponential and linear functions were significantly lower than those of the logarithmic function, and the trends of the graph of compressive strength over time were consistent with the logarithmic function, so the trend line was expressed as a logarithmic function. At a W/B ratio of 41% , (2), and (3), and are expressed in the form of an exponential function. To compare with existing researchers’ prediction equations for the correlation between compressive strength and UPV, In this study, the strength of concrete mixed with NHT as a cement substitute was evaluated at early ages using UPV, which is a non-destructive method. In addition, the correlation between compressive strength and UPV was analyzed.The compressive strength of HTC41-15 was 37% higher than that of NC41 after 8 h, but it was 27% lower with a value of 6.58 MPa after 24 h. The compressive strengths of HTC33-15 and HTC33-30 were similar to that of NC33 until 15 and 10 h, respectively. The difference between the strengths of NC33 and HTC33 increased over time.At a water-to-binder (W/B) ratio of 41%, mortar mixed with NHT showed high UPV in contrast to concrete. However, at a W/B ratio of 33%, the UPVs of mortar and concrete were similar. As the NHT substitution proportion and W/B ratio increased, UPV decreased.2) for HTC41-30 and HTC33-30 were 0.88 and 0.94, respectively. In contrast, a high correlation coefficient of 0.95 or higher was observed for other specimens. Since the strength prediction formula showed a high correlation coefficient in this experiment, it is judged that it is possible to predict strength at an early age using the strength prediction formula.The correlation between compressive strength and UPV was analyzed. The correlation coefficients –(3) were derived through the correlation between concrete compressive strength and UPV. It is believed that it can be applied to quantitatively evaluate the compressive strength at the initial age of concrete mixed with NHT.In the scope of this study, a prediction model using compressive strength and ultrasonic speed was presented for the development of initial strength using NHT, but the analysis of hydration mechanism and tissue composition were somewhat lacking. We plan to confirm these aspects through additional research in the future, and through this, we believe that the use of eco-friendly materials such as hwangto will contribute to reducing the damage caused by current global warming.


Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) require multi‐modality treatment. Immune checkpoint inhibitors (ICIs) are now standard of care in management of recurrent/metastatic HNSCC. However, its role in the definitive and neoadjuvant setting remains unclear.A literature search was conducted that included all articles investigating ICI in untreated locally advanced (LA) HNSCC. Data was extracted and summarised and rated for quality using the Cochrane risk of bias tool.Of 1086 records, 29 met the final inclusion criteria. In both concurrent and neoadjuvant settings, the addition of ICI was safe and did not delay surgery or reduce chemoradiotherapy completion. In the concurrent setting, although ICI use demonstrates objective responses in all published trials, there has not yet been published data to with PFS or OS benefit. In the neoadjuvant setting, combination ICI resulted in superior major pathological response rates compared to ICI monotherapy without a significant increase adverse event profiles, but its value in improving survival is not clear. ICI efficacy appears to be affected by tumour characteristics, in particular PD‐L1 combined positive score, HPV status and the tumour microenvironment.There is significant heterogeneity of ICI use in untreated LA HNSCC with multiple definitive concurrent and neoadjuvant protocols used. Resultantly, conclusions regarding the survival benefits of adding ICI to standard‐of‐care regimens cannot be made. Further trials and translational studies are required to elucidate optimal ICI sequencing in the definitive setting as well as better define populations more suited for neoadjuvant protocols. Traditional surgical approaches to HNSCC can result in significant cosmetic and functional morbidity. Sequential technological advances and their application to surgery have resulted in less morbid operative approaches and surgical outcomes. This has been particularly highlighted by the increasing number of human papilloma virus (HPV) ‐driven oropharyngeal SCC which led to the development of transoral robotic surgery (TORS), now an accepted part of the treatment paradigm. However, patients who have extensive nodal involvement with extra‐nodal extension or incomplete resections often need adjuvant treatment. Thus there is significant room for neoadjuvant immune checkpoint inhibitors (ICI) to possibly reduce the need for adjuvant therapy.There is growing evidence for neoadjuvant ICI in multiple malignancies. This approach has demonstrated a high pathological response rate impacting relapse‐free survival rates in tumour streams such as melanoma, colorectal cancer, breast cancer and lung cancer.Several other systematic reviews on neoadjuvant ICI in HNSCC have been reported;2In September 2022, a literature search was conducted across five databases – Medline, PubMed, Cochrane Library, Embase and Google Scholar. Two authors (UN and JH) independently used the multiple combinations of search terms: “immunotherapy”, “immune checkpoint inhibitors”, “pembrolizumab”, “avelumab”, “nivolumab”, “head and neck cancer” and “squamous” to include all relevant articles to the topic. Our search strategy was as follows: “Head and neck cancer” AND  AND (“definitive” OR “neoadjuvant”).Our search included all published trials in English to date including early‐stage phase 1 single‐arm studies and abstracts. Our preliminary search identified 1083 articles from which 387 duplicates were removed and 696 were screened. In total, 588 abstracts were removed due to lack of relevance to the topic and 108 articles were retrieved for full review  were included in the final analysis Figure . We stra3.1Seven published trials investigated immunotherapy in the definitive setting combined with CRT.3.2p = 0.49). Locoregional control (LRC) appeared to be better in the Cetuximab‐RT arm than ICI‐RT (89% vs. 60% at 15 months). LRC was high at 100% at 16 months with the use of dual ICI (Ipilimumab and Nivolumab) in conjunction with RT in a small single‐arm Phase I trial.Definitive immunotherapy with radiotherapy alone has been investigated in five trials, with safety being the most common primary endpoint. Only one trial, PembroRad by Bourhis et al,3.3In the neoadjuvant setting, immunotherapy has been used in combination with radiation alone to explore pathological response rates and surgical delay. Currently, there are two published studies in this space. Leidner et al. investigated three doses of neoadjuvant nivolumab with RT followed by surgery and three doses of adjuvant nivolumab.3.4Concurrent ICI with chemotherapy in the neoadjuvant HNSCC setting has been investigated in two published trials. The first was conducted by Zinner et al. where combination nivolumab, paclitaxel and carboplatin were used in a mostly HPV‐negative LA HNSCC cohort.3.5Neoadjuvant ICI has been investigated in 13 published trials. Nivolumab monotherapy was investigated by Ferris et al. in both the HPV positive and negative setting.p = 0.02). Uppaluri followed this initial study with a similar protocol but with two doses of neoadjuvant pembrolizumab followed by surgery,In the HPV‐negative setting, Uppaluri et al investigated the role of single‐dose neoadjuvant pembrolizumab followed by surgery and adjuvant ICI and chemoradiotherapy.Wise‐Draper et al also investigated the benefit of neoadjuvant pembrolizumab followed by surgery, adjuvant CRT and adjuvant pembrolizumab to a total of seven cycles.3.6Among the 29 studies included, nine demonstrated a moderate risk of bias, while no study was found to have any serious or critical risks. The primary domain influencing bias was selection. Of these 29 studies, 13 unique inclusion criteria were used, resulting in significant heterogeneity in study populations and a unified understanding of results. Furthermore, 16 out of 29 trials are in abstract form alone. In these abstracts, no information could be elicited regarding bias resulting from deviation from planned intervention or bias resulting from missing data. However, no evidence of bias from these domains was found in the remaining 13 articles. The overall bias assessment has been summarised in Figure 4As demonstrated, multiple researchers have investigated the role of immunotherapy in the neoadjuvant and definitive setting for treatment of locally advanced HNSCC and this is a rapidly evolving field. Our paper provides a comprehensive overview of all currently published trials. Published studies show that adding immunotherapy to definitive chemoradiation or radiation alone does not appear to increase toxicity risks and can potentially increase locoregional control. For patients with PD‐L1 expressing tumours and those with p16 positivity, immune blockade is likely to improve pathological response further. However, significant work is needed to standardise treatment protocols , how response to treatment is defined  and populations where immunotherapy are most likely to be of benefit.Overall, the LA HNSCC space has significant heterogeneity regarding study populations and treatment protocols in published trials. Investigators have stratified inclusion criteria by HPV status, cisplatin eligibility and stage of disease, complicating the ability to provide recommendations on ICI usage in the neoadjuvant and definitive setting. In the definitive space, five different ICI have been trialled with two phase III studies, JAVELIN‐100 and Keynote‐412, currently published. One other current phase III study with preliminary toxicity results is the REACH study which is an ongoing investigation of the benefit of avelumab with either radiotherapy or cetuximab plus radiotherapy. PFS or OS data is not currently available for this study. Given these results, ICI use in the definitive setting lacks strong evidence to support its routine use compared with standard of care treatment. This recommendation may change pending the results of the REACH study.In the neoadjuvant setting, a recent meta‐analysis has demonstrated that in resectable HNSCC, neoadjuvant immunotherapy has favourable outcomes without surgical delay or increased toxicity.Patient selection is of significant importance in ICI use in LA HNSCC and predictive biomarkers are required to rationale ICI use in the neoadjuvant and definitive setting. HPV positive patients have increased pathological response to ICI in the recurrent/metastatic HNSCC setting and early signals from Zinner and Powell are also suggestive of this.Several trials questioned the timing of treatment and the amount of necessary immunotherapy to provide a response. Clump et al. demonstrated that sequential rather than concurrent ICI provided an improved 2‐year OS benefit of 94% versus 78% in the definitive space.On the other hand, Uppaluri conducted two trials investigating additional neoadjuvant ICI cycles demonstrating that two cycles of pembrolizumab compared with one increased pathological tumour response of >50% from 22% to 44%.Another important consideration is the heterogeneity of result reporting affecting bias in result interpretation in the neoadjuvant setting. Major pathological response (MPR) has been traditionally defined as viable residual tumour of less than or equal to 10% and is often used as a surrogate end point for survival in patients with multiple other solid organ malignancies such as lung cancer.p = 0.4).Lastly, the tumour microenvironment response is envisaged to play a role in the efficacy of neoadjuvant immunotherapy. Multiple trials have investigated T‐cell populations in patients with increased response to treatment.5There is a wide array of ICI use in untreated LA HNSCC with multiple definitive and neoadjuvant protocols with and without chemotherapy, radiation therapy, targeted therapy and metabolic drugs. As a result, definitive conclusions regarding ideal treatment modalities still require further research. Currently, in the definitive setting, although ICI use demonstrates objective responses in all trials, two large phase III study failed to show PFS benefit compared with standard of care CRT.Udit Nindra: Conceptualization ; data curation ; formal analysis ; investigation ; methodology ; writing – original draft ; writing – review and editing . Joshua Hurwitz: Conceptualization ; data curation ; formal analysis ; investigation ; methodology ; writing – original draft ; writing – review and editing . Dion Forstner: Conceptualization ; supervision ; validation ; writing – review and editing . Venessa Chin: Conceptualization ; supervision ; writing – review and editing . Richard Gallagher: Conceptualization ; supervision ; writing – review and editing . Jia Liu: Conceptualization ; supervision ; writing – original draft ; writing – review and editing .This research did not receive any specific grant from funding agencies in the public, commercial or not‐for‐profit sectors.The authors have no conflict of interest to declare.


To construct effective prediction models for neoadjuvant radiotherapy (RT) and targeted therapy based on whole-tumor texture analysis of multisequence MRI for soft tissue sarcoma (STS) patients.1-weighted with fat saturation and contrast enhancement (T1FSGd), T2-weighted with fat saturation (T2FS), and diffusion-weighted imaging (DWI) sequences and their corresponding apparent diffusion coefficient (ADC) maps. According to the postoperative pathological results, the patients were divided into pathological complete response (pCR) and non-pCR (N-pCR) groups. pCR was defined as less than 5% of residual tumor cells by postoperative pathology. Delta features were defined as the percentage change in a texture feature from pre- to post-neoadjuvant RT MRI. After data reduction and feature selection, logistic regression was used to build prediction models. ROC analysis was performed to assess the diagnostic performance.Thirty patients with STS of the extremities or trunk from a prospective phase II trial were enrolled for this analysis. All patients underwent pre- and post-neoadjuvant RT MRI examinations from which whole-tumor texture features were extracted, including TFive of 30 patients (16.7%) achieved pCR. The Delta_Model (AUC 0.92) had a better predictive ability than the Pre_Model (AUC 0.78) and Post_Model (AUC 0.76) and was better than AJCC staging (AUC 0.52) and RECIST 1.1 criteria (AUC 0.52). The Combined_Model  had the best predictive performance (AUC 0.95).Whole-tumor texture analysis of multisequence MRI can well predict pCR status after neoadjuvant RT and targeted therapy in STS patients, with better performance than RECIST 1.1 and AJCC staging.MRI multisequence texture analysis could predict the efficacy of neoadjuvant RT and targeted therapy for STS patients.• Texture features showed incremental value beyond routine clinical factors.• The Combined_Model with features at multiple time points showed the best performance.• The online version contains supplementary material available at 10.1007/s00330-022-09362-6. Soft tissue sarcoma (STS) is a relatively rare malignant tumor of mesenchymal origin, accounting for 1% of all malignant tumors –7. MeanwHowever, the optimal efficacy evaluation criteria for neoadjuvant therapy for STS are still unclear. As the most commonly adopted clinical evaluation criteria for solid tumors, the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1  does notMagnetic resonance imaging (MRI) has high tissue resolution and is recognized as the most accurate modality for STS. Texture analysis (TA) can extract and calculate the grayscale changes in pixels or voxels from medical images and analyze quantitative image features to reflect the deep heterogeneity of tumor tissue . It has However, there is no research about the prediction accuracy of MRI-based radiomics for patients receiving neoadjuvant RT and targeted therapy. Therefore, this study aimed to incorporate comprehensive MRI sequences to predict the pCR status of neoadjuvant RT and TKI in STS. We also compared the predictive performance of our models with that of the RECIST 1.1 criteria and AJCC stage.Patients were enrolled from a prospective phase II trial investigating the safety and efficacy of neoadjuvant RT and targeted therapy (a multi-targeted TKI) for STS , with a prospective collection of MRI images before and after neoadjuvant RT. A total of 30 patients with STS admitted to the radiotherapy department of this research institution from July 2020 to April 2022 were enrolled in this study. The following inclusion criteria were applied: ① patients were older than 18 years; ② STS was pathologically proven, with an intermediate to high grade, maximum tumor size ≥ 5 cm, and deeply located tumor (≥ 2 items met); ③ neoadjuvant RT was required after multidisciplinary treatment (MDT) discussion; ④ no regional nodes or distant metastases were present; and ⑤ MRI was performed before and after neoadjuvant RT, and the image quality was good. The exclusion criteria were as follows: ① RT was not completed as planned; and ② MRI images before and/or after RT were missing or could not be compared. This study was performed in accordance with the Declaration of Helsinki, and informed consent was obtained from all subjects. The treatment and clinical efficacy assessment are detailed in the Supplementary Materials. The flow diagram of the study cohort is shown in Fig. 1FSGd, T2FS, diffusion-weighted imaging (DWI), and their corresponding apparent diffusion coefficient (ADC) maps. The contrast agent used was gadoterate meglumine (Gd-DOTA), with a dose of 0.1 mmol/kg body weight, intravenously injected at a flow rate of 2.0 mL/s and then flushed with 20 mL of normal saline. The delayed images of enhanced scanning were collected 2 min after the injection of contrast agent. The details of all sequences are listed in Table S1.All patients underwent MRI before and at the end of neoadjuvant RT. All MRI examinations were performed on a 3.0-T system  with an eight-element phased-array wrap-around surface coil. Both the field of view and the matrix matched the location and size of the tumor. The sequences included Twww.itksnap.org) software and reviewed by an expert radiologist with 20 years of STS imaging diagnosis experience who was blinded to the clinical or pathological information. Regions of interest (ROIs) were delineated on each sequence independently. The scope of the ROI included the entire tumor and avoided peritumoral edema.The whole tumor was manually delineated slice-by-slice by two radiologists (with 3 years and 5 years of STS imaging diagnosis experience) using ITK-SNAP  for each patient. Each image had 107 texture features, including 14 shape features, 25 first-order features, 22 gray level co-occurrence matrix (GLCM) features, 16 gray level run length matrix (GLRLM) features, 16 gray level size zone matrix (GLSZM) features, and 14 gray level dependence matrix (GLDM) features. All texture features were obtained from open-source PyRadiomics (http://www.radiomics.io/pyradiomics.html) as recommended by IBSI [XPre − XPost) / XPre, where XPre is the pre-neoadjuvant RT texture feature and XPost is the post-neoadjuvant RT texture feature. The processes of tumor segmentation and feature extraction are shown in Fig. First, each MRI scan of each patient was normalized with  by IBSI . Delta fr < 0.8) were screened out. Finally, the statistically significant texture features were further screened out through logistic regression, and the Pre_Model, Post_Model, Delta_Model, and Combined_Model were established. In addition, the predictive ability of AJCC staging and RECIST 1.1 was assessed to compare the performance of various models.Data reduction and feature selection processes were performed to select the most relevant features for constructing the models. pCR status was defined as less than 5% of residual tumor cells by postoperative pathology. First, the texture features on pre, post, and delta images that were significantly different between the pCR group and the non-pCR (N-pCR) group were screened out. Second, the diagnostic efficacy of the above features was assessed by correlation tests and the area under the curve (AUC) method, and texture parameters with a high diagnostic efficacy and low correlation between groups (http://www.Rproject.org) and MedCalc . All data were assessed for a normal distribution using the Kolmogorov–Smirnov test. The t test was used to compare the differences between continuous variables, while the chi-square test or Fisher’s exact test was used to compare the differences between categorical variables. p values were corrected for multiple comparisons by Bonferroni. The intraclass correlation coefficient (ICC) was used to investigate interobserver agreement. The correlation between groups was judged by calculating the Pearson correlation coefficient, and r > 0.8 indicated a high correlation. Multivariate binary logistic regression analysis was conducted with a forward stepwise approach to select variables and construct models. The Mann–Whitney U test was used to evaluate the difference in the RadScore between the pCR group and the N-pCR group for each model. Receiver operating characteristic (ROC) curves were applied to evaluate the diagnostic performance. The Youden index was used to determine the optimal threshold, and the AUC, sensitivity, specificity, and accuracy were calculated. The DeLong method was used to compare the AUC values of all models. The Hosmer–Lemeshow test was used to assess the goodness-of-fit of the models. Decision curve analysis (DCA) was performed according to the method of Vickers et al [p value < 0.05 was considered statistically significant.The data were analyzed using R software  were included in this study, of which 5 patients (16.7%) showed pCR on postoperative pathology. All clinical and pathological data are shown in Table p < 0.05). Details of the texture features are shown in Table r > 0.8 between the two groups was carried out, and the texture features with lower AUCs were excluded. There were 3, 2, and 5 pre, post, and delta texture features, respectively, that met the requirements; see Tables S2–S4 for details.All parameters showed good interobserver agreement (ICC > 0.8). Among pre, post, and delta texture features, there were 4, 2, and 6 texture features, respectively, which were significantly different between the pCR and N-pCR groups . The performance and ROC curves of each model are shown in Table p < 0.05), respectively. Even with the Delta_Model alone, the AUC values were also significantly higher than those of AJCC and RECIST 1.1 .The differences in the RadScore between the pCR and N-pCR groups for each model are shown in Fig. To our knowledge, this is the first study to construct efficacy prediction models based on multisequence and whole-tumor texture parameters at multiple time points  of neoadjuvant RT and TKI for STS. The Combined_Model, in which all texture parameters of all time points were incorporated, had the highest diagnostic performance (AUC 0.952), followed by the Delta_Model (AUC 0.92), compared to routinely used RECIST 1.1 criteria and AJCC staging. Multisequence whole-tumor texture analysis can better predict the pCR results of neoadjuvant RT and TKI for STS.We primarily focused on the early response prediction of STS patients receiving neoadjuvant RT and TKI. In the modern era, TKIs have played an emerging role in the treatment of STSs as radio-sensitizing agents –7. Altho1FSGd, T2FS, and DWI) and ADC maps to predict the efficacy of neoadjuvant RT and TKI for STS. Gao et al [2WI) before and after treatment. The sequences in Peeken’s study [1FSGd and T2FS [1FSGd and T2FS sequences, similar to the results of Peeken et al’s [This study included three sequences , and the Flatness texture feature was also statistically significant in Crombé’s study (p < 0.05). Flatness shows the relationship between the largest and smallest principal components in the ROI shape. SizeZoneNonUniformity measures the variability of size zone volumes in the image, with a lower value indicating more homogeneity in size zone volumes. Both these features reflect tumor heterogeneity in morphology, while another texture parameter in our study, ClusterShade, reflects the stability of the tumor grayscale. Although we focused on different neoadjuvant therapies for STSs, it seems that there was some consistency in the efficacy prediction by texture features. We also discuss some advances in the clinical and pathological evaluation of neoadjuvant therapy for STS, as detailed in the Supplementary Materials.The Combined_Model in our study, which incorporated the image textures at all time points, had the best diagnostic performance (AUC 0.952), and the Delta_Model also had good performance (AUC 0.92). Compared with that of Peeken et al


Chemoimmunotherapy is the first-line standard treatment for patients with non-small cell lung cancer (NSCLC). However, there are few reports on the efficacy of chemoimmunotherapy in patients with NSCLC who harbor the MET exon 14 skipping mutation. We report the case of an 81-year-old male patient with lung adenocarcinoma with a MET exon 14 skipping mutation who was treated with chemoimmunotherapy and achieved a durable response. Chemoimmunotherapy may be a promising treatment option for patients with a MET exon 14 skipping mutation. However, further studies are needed to characterize the objective response rate and response duration in these populations. A MET exon 14 skipping mutation is a rare oncogenic driver mutation in non-small cell lung cancer (NSCLC) . In JapaChemoimmunotherapy has shown to be superior to cytotoxic anticancer drugs and has become one of the standard treatments for NSCLC -8. MoreoAn 81-year-old man presented with bloody sputum. He previously smoked 40 cigarettes per day. He had hypertension and old myocardial infarction. The patient’s performance status score was 1. Computed tomography revealed a large right lower lung mass with right adrenal and multiple lymph node metastases. A transbronchial biopsy was performed on the lung mass. Immunohistochemistry revealed positive thyroid transcription factor-1 (TTF-1), Napsin A, and programmed death-ligand 1 (PD-L1) expression (tumor proportion score = 75%) and negative p40 and synaptophysin expression. Therefore, the patient was diagnosed with lung adenocarcinoma ). The patient’s general condition was good; however, because of rapid tumor progression, chemoimmunotherapy was promptly started as the first-line treatment. Carboplatin (area under the curve = 5.0), pemetrexed (500 mg/m2dL), and pembrolizumab (200 mg/dL) were administered to the patient every three weeks as the first-line treatment. After four cycles of induction chemotherapy, tumor lesions in the right lower lobe and multiple enlarged lymph nodes almost disappeared, while the tumor lesion in the right adrenal gland was significantly reduced ). The Oncomine Dx Target Test Multi-CDx system detected 2739 reads of the MET(13)-MET(15) product. After four courses of induction therapy followed by two courses of maintenance therapy, the patient developed grade 1 pneumonitis. Although the treatment was discontinued, no recurrence was observed for six months. So far, disease control has been achieved up to 11 months after the initiation of chemoimmunotherapy.Treatment response evaluation indicated that a partial response was achieved. During chemoimmunotherapy treatment, an exon 14 skipping MET mutation was detected by the Oncomine Dx Target Test Multi-CDx system and confirmed by the ArcherMET test (Home-Invitae (Here, we report a case of a patient who received chemoimmunotherapy for lung adenocarcinoma with a MET exon 14 skipping mutation and achieved a durable response. To date, there have been two case reports of patients with the pulmonary sarcomatoid subtype of NSCLC, together with MET exon 14 skipping mutation, who received chemoimmunotherapy , 11. ICIIn this case, chemoimmunotherapy was initiated as the first-line treatment to start treatment as soon as possible. However, in the Japanese Guidelines for Diagnosis and Treatment of Lung Cancer/Malignant Pleural Mesothelioma/Thymic tumor, MET inhibitors are recommended as first-line treatment for patients with MET exon 14 skipping mutation positive lung cancer . TherefoIn our case, the patient developed grade 1 pneumonitis, which improved with treatment discontinuation. His general condition remains good. Careful re-administration of ICIs or MET inhibitors can be performed at the time of relapse. It is known that tumors with MET exon 14 skipping mutations occur more frequently in elderly patients , 16, whoIn conclusion, chemoimmunotherapy may be a potentially effective treatment option for patients with MET exon 14 skipping mutation. Further clinical studies are needed to evaluate the efficacy and safety of chemoimmunotherapy in patients with a MET exon 14 skipping mutation.


As a transfer member at the discontinuous place of vertical load, the deep beam has a complex stress mechanism and many influencing factors, such as compressive strength of concrete, shear span ratio, and reinforcement ratio. At the same time, the stress analysis principle of traditional shallow beams is no longer applicable to the design and calculation of deep-beam structure. The main purpose of this paper was to use the strut-and-tie model to analyze its stress mechanism, and to verify the applicability of the model. Nine high-strength concrete deep-beam specimens with longitudinal reinforcement with an anchor plate of the same size were tested by two-point concentrated loading method. The effects of shear span ratio , longitudinal reinforcement ratio , horizontal reinforcement ratio , and stirrup reinforcement ratio  on the failure mode, deflection curve, characteristic load, crack width, steel bar, and concrete strain of the specimens were analyzed. The results showed that the failure mode of deep-beam specimens was diagonal compression failure. The normal section cracking load was about 15 to 20% of the ultimate load, and the inclined section cracking load was about 30~40% of the ultimate load. The shear span ratio increased from 0.3 to 0.9, and the bearing capacity decreased by 32.9%. When the longitudinal reinforcement ratio increased from 0.67% to 1.25%, the ultimate load increased by 42.6%. The shear span ratio and longitudinal reinforcement ratio have a significant effect on the bearing capacity of the high-strength concrete deep beams with longitudinal reinforcement with an anchor plate. The shear capacity of nine high-strength concrete deep-beam specimens with longitudinal reinforcement with an anchor plate was calculated by national standards, and the results were compared with the calculation results of the Tan–Tang model, the Tan–Cheng model, SSTM, and SSSTM. The analysis showed that the softened strut-and-tie model takes into account the softening effect of compressive concrete, and is a more accurate mechanical model, which can be applied to predict the shear capacity of high-strength concrete deep-beam members with longitudinal reinforcement with an anchor plate. Deep beams are generally used as transfer components at discontinuous vertical loads in buildings and bridge structures. The stress mechanism of deep beams is complex and there are many factors affecting the bearing capacity, such as compressive strength of concrete, shear span ratio, longitudinal reinforcement ratio, and web reinforcement ratio. Many scholars ,4,5,6,7 Previous studies have shown that the shear span ratio is one of the important influencing factors on deep-beam components . Tan et In the face of different influencing factors, the calculation methods of shear capacity of deep-beam members can be classified into two categories: one is the empirical-formula method based on experimental research results and statistical theory; one is a mechanical model based on the force mechanism of deep beams, such as the strut-and-tie model. The Chinese Code for Design of Concrete Structures GB50010-2010  is basedAt present, domestic and foreign scholars have conducted a large amount of research on deep bending components, but their influencing factors and data dispersion are relatively large. There is little research on the system of high-strength concrete deep-beam components with longitudinal reinforcement with anchor plates. It is of practical significance to study the mechanical performance mechanism of high-strength concrete deep beams with longitudinal reinforcement with anchor plates, and propose reasonable design methods and bearing-capacity calculation formulae. Therefore, this article describes the design and manufacture of nine high-strength concrete deep-beam components with anchor plate longitudinal reinforcement; analyzes the influence of shear span ratio, longitudinal reinforcement ratio, and web reinforcement ratio on the failure mechanism of the components; analyzes their failure process and mode; and discusses the applicability of various calculation methods, in order to provide theoretical reference for the practical engineering application of such components.In order to study the influence of shear span ratio, longitudinal reinforcement ratio, horizontal reinforcement ratio, and stirrup reinforcement ratio on the bearing capacity of high-strength concrete deep beams with longitudinal reinforcement with an anchor plate, a total of nine specimens were designed and manufactured. The size was 1660 mm × 600 mm × 200 mm, and the specimens were divided into Groups a–d , according to the different influencing factors. Specimen DBH-2 was the control specimen. The detailed reinforcement information and design parameters of the specimens are shown in In this experiment, nine specimens were poured with C60 concrete. At the same time, six groups of the same batch of pouring test blocks were reserved, and the specimens were cured with the same curing conditions until the beginning of the test to ensure the accuracy of the material test. According to the relevant provisions in GB/T50152-2012  and GB/TIn this test, the bottom longitudinal reinforcement was an HRB600 steel bar with diameter of 16 mm, 20 mm, and 22 mm, and the web reinforcement was an HRB400E steel bar with diameter of 8 mm. The material test of steel bar is determined according to the relevant provisions of GB/T228.1-2010 , and theFirstly, the bearing capacity of the specimen was estimated. The single jack device was used to carry out symmetrical concentrated loading through the distribution beam. The size of the plate at the loading point and the support was 80 mm × 200 mm, and the gap between the plate and the deep beam was filled with fine sand to ensure the average force on both sides. The loading device of the test is shown in The main data collected during the loading process are as follows: (1) deflection: three displacement meters were arranged at the middle position of the bearing and the bottom of the beam to measure the vertical displacement of the specimen; (2) characteristic load: including normal section cracking load, inclined-section cracking load and ultimate load; (3) concrete strain: oblique and vertical strain gauges were arranged evenly on both sides of the specimen and the vertical part of the beam span to measure the concrete strain; (4) longitudinal reinforcement strain: strain gauges were arranged at equal intervals on the bottom longitudinal reinforcement to measure the strain of the bottom longitudinal reinforcement and clarify the effect of the longitudinal reinforcement; (5) strain of web reinforcement: strain gauges were arranged at equal intervals on the web reinforcement in the shear span area to measure the strain of web reinforcement and clarify the shear resistance of web reinforcement; and (6) crack width development: the occurrence of cracks and the width of existing cracks were recorded after each stage of loading. The arrangement of displacement meters and strain gauges on the specimen is shown in The process from loading to failure is basically the same, and can be divided into the elastic stage, normal-section cracking stage, inclined-section cracking stage and ultimate failure stage. From the beginning of formal loading to the first normal-section crack, the specimen was in elastic working condition. There was no obvious deformation or crack on the surface of the specimen, and the strain of the steel bar was small. The stress state of the specimen conformed to the elastic state, and the specimen was in the elastic stage. As the load continued to increase, the first bending crack appeared near the mid-span, with a width of 0.02 mm–0.07 mm, and the specimen entered the normal-section cracking stage. After that, the cracks continued to develop, and multiple cracks appeared near the first crack. The crack density increased, the height gradually extended to 1/6–1/3 of the beam height, the crack extension angle gradually pointed to the mid-span position at the top of the beam, the crack width increased slowly, and the bending moment in the shear span area increased. Group a specimens showed that the crack development was due to the bending effect at this time, and the bending effect became more and more obvious with the increase in the shear span ratio. The crack generation and development were caused by the tension at the bottom of the beam. When the load reached 30% to 40% of the ultimate load, the first diagonal crack appeared at the support, and the crack developed rapidly from the bottom to the top along the connection between the support and the loading plate on the same side. Then, diagonal cracks appeared at the same position on the other side of the specimen, and the specimen entered the diagonal-section cracking stage. The height of the mid-span bending crack eventually reached half of the beam height as the load increased, and individual specimens reached 2/3 of the beam height. Under the influence of bending and shearing in the shear span area, the cracks continued to extend, and multiple parallel cracks appeared near the cracks. The crack density in the compression bar area increased and the cracks penetrated each other, and the crack width increased. After that, the crack development rate decreased, and the stress state of the specimen tended to be stable, forming an obvious force transmission mechanism of the STM. After that, the concrete had a splitting sound as the load increased, and the specimen entered the ultimate failure stage. Finally, with a loud noise, the specimen was destroyed, and a penetrating oblique crack was generated on one side of the specimen. The concrete at the support at the bottom of the crack was partially broken, and the crack width was also increased to 0.7 mm–1.6 mm. The specimen had obvious brittle failure.Taking the specimen DBH-2 as an example, the specimen showed a typical failure mode as a control specimen, as shown in The failure results of each group in the experiment are shown in The characteristic load curve of Compared with the cracking load of the inclined section in each group, the cracking load of the inclined section in the same group changed little, but the increase in the horizontal reinforcement ratio and the longitudinal reinforcement ratio decreased the Compared with the ultimate load in each group, the ultimate load decreased with the increase in shear span ratio. Compared with λ = 0.3, the ultimate load decrease by 18.5% when λ = 0.6, and decreased by 32.9% when λ = 0.9. The reason for this was that the inclination angle of the strut bar decreased with the increase in the shear span ratio, which mad the shear force longer along the force-transmission path of the strut bar, reducing the force transmission mechanism of the STM, and reducing the ultimate bearing capacity. The ultimate load increased with the increase in longitudinal reinforcement ratio. When the longitudinal reinforcement ratio increased from 0.67% to 1.05% and 1.25%, the ultimate load increased by 18.2% and 42.6%, respectively. This is consistent with the conclusion in . The reaThe mid-span deflection curve of each group in the test is shown in From The crack-width curve of each group of oblique sections in the experiment is shown in The steel bars distributed in the deep beam were divided into horizontal reinforcement and longitudinal reinforcement. The longitudinal reinforcement affected the bearing capacity of the beam through the dowel action. The longitudinal stressed steel bar not only inhibited the development of the oblique crack, but it also improved the performance of the shear force transfer between the crack interface. At the same time, the longitudinal reinforcement acted as a tie rod in the STM, which is one of the important components in the model. In addition to directly bearing part of the shear force, the horizontal reinforcement indirectly limited the development of cracks and enhanced the aggregate bite force of the abdominal concrete. The horizontal reinforcement passing through the diagonal compression reinforcement improved the strength of the concrete diagonal compression bar and also affected the bearing capacity of the deep beam.The longitudinal reinforcement strain curve of each group in the experiment is shown in The strain curves of horizontal bars in each group are shown in The specimen DBH-2 is taken as an example, as shown in At present, the calculation methods of shear bearing capacity of deep flexural members in various countries are mainly divided into two categories: one is the semi-empirical and semi-theoretical formula obtained by regression of various influencing factors through big data, such as GB50010-2010 “Code for Design of Concrete Structures” , the othTan, K. H. et al.  proposedAfter cracking, the compressive strength of concrete has a significant decreasing trend. Cracked concrete produces a large tensile strain perpendicular to its compressive direction. These tensile strains have the opposite effect to the compressive strain (constraint effect), resulting in the strength of concrete being lower than that of concrete under the standard test. This phenomenon is called softening of concrete. The current national specifications for the application of the STM refer to the reduction coefficient g et al.  proposedg et al.  has simpjd is the distance between the center of mass of the compressive concrete of the deep beam and the center of mass of the tensile longitudinal reinforcement; and Macro model: Due to the bending moment balance equation, the relationship between horizontal shear force and vertical shear force can be determined, that is Equation (1)D is the pressure of the strut rod, Force balance: According to the stress analysis, the horizontal shear force and vertical shear force in the deep beam are:The maximum compressive stress Constitutive relation: The constitutive model of cracked concrete adopts Equations (5)–(7)Deformation compatibility: The two-dimensional membrane element should satisfy the Mohr’s circular strain compatibility condition, Equation (8):The strut of reinforced concrete in the SSSTM is defined as The horizontal pull rod index is:The vertical tie rod index is the same.Nine deep-beam specimens were calculated by using the proposed method of national codes, the model proposed by Professor Tan, and the softened strut-and-tie model. The calculation results and comparative analysis are shown in The mean value of the ratio of the experiment value to the calculation results of the method recommended by the GB50010-2010, ACI318-19, European code, and the CSAA23.3-19 was 1.529, 1.309, 1.313, and 1.473, respectively, and the variance was 0.043, 0.027, 0.026, and 0.022, respectively. It was shown that the ACI318-19 was close to the experiment results, which indicates the accuracy of the STM, and the Chinese code has a larger safety reserve.The mean values of the ratio of the experimental values to the calculated results of Tan–Tang model and Tan–Cheng model were 1.359 and 1.318, respectively, and the variances were 0.007 and 0.006, respectively, indicating the accuracy of the model proposed by Professor Tan. The model takes into account the size effect and the data deviation was small.The calculated results of the softened strut-and-tie model method were in good agreement with the experimental results. The average ratios of the experimental values to the calculated values of the softened strut-and-tie model and the simplified softened strut-and-tie model were 1.295 and 1.282, respectively, and the variances were 0.010 and 0.007, respectively. The softened strut-and-tie model takes into account the softening effect of compressive concrete, and is a more accurate mechanical model, which can accurately predict the shear capacity of high-strength concrete deep beam with anchor plate longitudinal reinforcement.The calculation results of this paper were compared with the literature ,5, and tThe failure process of the specimens was the same, and the failure mode was the diagonal compression failure of the concrete strut crushing, showing obvious brittle failure. The cracking load of the normal section was about 15~20% of the ultimate load, and the cracking load of the inclined section was about 30~40% of the ultimate load. The shear span ratio had a significant effect on the failure mode of deep beams.The shear span ratio is an important factor affecting the ultimate bearing capacity of deep beams. When the shear span ratio increased from 0.3 to 0.9, the bearing capacity decreased by 32.9%. The longitudinal reinforcement ratio had no obvious effect on the cracking load of the normal section of the specimen, but had a significant effect on the cracking load and ultimate load of the inclined section. When the longitudinal reinforcement ratio increased from 0.67% to 1.05% and 1.25%, the ultimate load increased by 18.2% and 42.6%, respectively. The increase in longitudinal reinforcement ratio can increase the bearing capacity of concrete.The reinforcement ratio of the web reinforcement will also have an impact on the bearing capacity of the deep beam. The steel skeleton formed by the combination of horizontal reinforcement and stirrups can effectively constrain the strain of the concrete, improve the ductility of the deep-beam member, and increase the effective cross-sectional area and strength of the concrete pressure bar, and the web reinforcement can also be used as a force-transmission path to improve the bearing capacity of the component. The increase in the reinforcement ratio of the web reinforcement can reduce the concrete strain, thereby reducing the width of the inclined crack. The web reinforcement is the same as the longitudinal reinforcement, which had little effect on the cracking load of the component, and the restraint effect on the concrete did not increase linearly;The shear bearing capacity of reinforced concrete deep-beam specimens was calculated by using the calculation method recommended by the specification and the Tan–Tang model, Tan–Cheng model, SSTM, and SSSTM based on the strut-and-tie model. The results showed that the ACI318-19 code was similar to the test results, and the Chinese code has a greater safety reserve. The model proposed by Professor Tan takes into account the size effect and the data deviation was small. The calculation results of the softened strut-and-tie model method were close to the experimental results. The softened strut-and-tie model considers the softening effect of the concrete strut bar, and has a clear mechanical calculation model, which can reasonably reflect the stress mechanism of the components.In this paper, the failure mechanism and shear capacity calculation method of deep beams were analyzed by systematic experimental study on nine high-strength concrete deep-beam specimens with longitudinal reinforcement with an anchor plate. The Tan–Tang model, Tan–Cheng model, SSTM, and SSSTM based on the STM were used to calculate. The main conclusions are as follows: