Less than a year after the global emergence of the coronavirus SARS-CoV-2, a novel vaccine platform based on mRNA technology was introduced to the market. Globally, around 13.38 billion COVID-19 vaccine doses of diverse platforms have been administered. To date, 72.3% of the total population has been injected at least once with a COVID-19 vaccine. As the immunity provided by these vaccines rapidly wanes, their ability to prevent hospitalization and severe disease in individuals with comorbidities has recently been questioned, and increasing evidence has shown that, as with many other vaccines, they do not produce sterilizing immunity, allowing people to suffer frequent re-infections. Additionally, recent investigations have found abnormally high levels of IgG4 in people who were administered two or more injections of the mRNA vaccines. HIV, Malaria, and Pertussis vaccines have also been reported to induce higher-than-normal IgG4 synthesis. Overall, there are three critical factors determining the class switch to IgG4 antibodies: excessive antigen concentration, repeated vaccination, and the type of vaccine used. It has been suggested that an increase in IgG4 levels could have a protecting role by preventing immune over-activation, similar to that occurring during successful allergen-specific immunotherapy by inhibiting IgE-induced effects. However, emerging evidence suggests that the reported increase in IgG4 levels detected after repeated vaccination with the mRNA vaccines may not be a protective mechanism; rather, it constitutes an immune tolerance mechanism to the spike protein that could promote unopposed SARS-CoV2 infection and replication by suppressing natural antiviral responses. Increased IgG4 synthesis due to repeated mRNA vaccination with high antigen concentrations may also cause autoimmune diseases, and promote cancer growth and autoimmune myocarditis in susceptible individuals. In a relatively short period after the beginning of the COVID-19 pandemic, two mRNA vaccines, BNT162b2  and mRNA-1273 , were granted the first-ever emergency use authorization. These mRNA vaccines represented a new type of vaccine that comprises synthetic mRNA molecules that contain the coding sequence necessary to build the SARS-CoV-2 Spike protein, which is encased in the lipid nanoparticles (LNPs) to allow for the delivery of mRNA to cells. The main characteristic of the mRNA vaccine platform is that the proteins are synthesized within the host cells, mimicking a natural infection with SARS-CoV-2 [Contemporary investigations have contrasted the seriousness of symptoms in COVID-19 individuals infected with the SARS-CoV-2 Alpha, Delta, and Omicron variants, as well as the effectiveness of mRNA immunizations versus each variant among individuals admitted to hospitals in the United States from March 2021 to January 2022. COVID-19 vaccines were discovered to be quite efficient (90%) in avoiding intensive care unit (ICU) admissions caused by Alpha, Delta, and Omicron variants. However, three vaccine injections were needed to give protection against the Omicron variant, whereas two injections sufficiently safeguarded against the Alpha and Delta variants ,4,5,6.It is worth noting that there are conflicting pieces of information about the level of protection offered by these vaccines. Although the Center for Disease Control (CDC) in the United States has stated that throughout the pandemic, mortality rates have been higher in the unvaccinated than in the vaccinated , the datAlthough they can induce significant neutralizing anti-spike IgG and IgA responses, all three anti-COVID-19 vaccines: Pfizer, Moderna, and Astra Zeneca ChAdOx1,  appeared to be only transiently protective against SARS-CoV-2 infection and transmission ,11,12,13Lethal COVID-19 cases have been linked to higher levels of IgG4 antibodies ,29, and Several immunoglobulin classes and subclasses that constitute the antibody immune arsenal, including IgA, IgE, IgM, and IgG, are essentially identified by the structure of their heavy chain constant region. Human immunoglobulins G (IgG) are divided into four subcategories based on the immunogenicity of their heavy chains  ,33,34. IThe mechanism behind the reaction involving the replacement of one half of an antibody with another, also known as Fab arm exchange and specific to IgG4 antibodies, has been elucidated over the past twenty years . The heaThe majority of IgG4 molecules will have two distinct Fab arms because of the half-antibody exchange, making them “bi-specific” and operationally univalent for a particular antigen. As a result, far from the other IgG subclasses, IgG4 antibodies in circulation are unable to form immunological complexes with antigens. IgG4 antibodies have a limited theoretical potential for immunological activation due to their weak affinity for C1q and Fc receptors. The production of immune complexes stimulates the complement system and the action of immune effector cells. Furthermore, IgG4 antibodies may be able to block the inflammatory effects of IgG1 or IgE antibodies by dislodging the binding of those with comparable specificities. The anti-inflammatory characteristic may offer insight into another important fact that IgG4 antibodies are typically formed after prolonged contact with an allergen, hence reducing the level of chronic inflammation .The designation “IgG4-related systemic disease” refers to several clinical manifestations that were formerly thought to be completely distinct diseases. The list of organs linked to this illness is continuously expanding. Regardless of the organ involved, tissue biopsies show significant histological similarities. However, there are slight variations between organs as well. The hallmark pathology findings include widespread fibrosis, numerous IgG4-positive plasma cells, and disperse lympho-plasmacytoid infiltrates .IgG4′s reputation as a “blocking antibody” stems from its diminished capacity to elicit immune system effector reactions ,44. ThisIgG4′s lack of effector action and the phenomena of half-antibody interchange create complicated considerations about whether these antibodies are harmful or whether they act as a counter-regulatory reaction to an enduring immunologic illness . High coIgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder named after the presence of numerous IgG4+ plasma cells in damaged tissues and of high serum IgG4 concentrations in most, but not all, cases . SeveralThese results imply that increased IgG and/or IgG4 concentrations in IgG4-RD individuals may play harmful roles . BecauseIgG4-RD includes a “wide variety of diseases, formerly diagnosed as Mikulicz’s disease (MD) , autoimmAfter the identification of MuSK antibodies in 2001, it quickly became evident that their IgG4 subclass predominance and correlation between titers and illness severity were key findings ,81,82. HImmune checkpoint inhibitors, often known as cancer immunotherapy agents, prevent checkpoint proteins from attaching with their associated polypeptides, allowing cytotoxic CD8+ T lymphocytes (CTLs) to attack cancer cells. Immune checkpoint-blocking (ICB) agents include anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) and anti-PD-1 (programmed cell death protein 1) monoclonal antibodies ,88. ICB Karagiannis et al.  also fouLocally elevated levels of IgG4 in cancer tissue hindered antibody-mediated anticancer responses, assisted cancer in blocking the local immune response and indirectly aided in cancer progression. Three separate immune-potent mice models supported this theory. It was discovered that local administration of IgG4 dramatically sped up the growth of implanted colorectal and breast tumors as well as skin papillomas caused by carcinogens. Researchers also examined the IgG4 antibody Nivolumab, which is used in cancer immunotherapy, and discovered that it dramatically accelerated the development of cancer in mice when compared to phosphate buffer saline (PBS) and IgG1-treated groups .Researchers used models of immunologically competent mice to evaluate their hypothesis and further explore the mechanism mediated by such antibodies. One model involved injecting non-cancer-specific IgG4 into the subcutaneous inoculation site for breast cancer cells. In comparison to other groups of mice (injected with PBS or IgG1 without IgG4), this group’s cancer cell proliferation was dramatically accelerated, generating a significantly larger cancer mass by 21 days. Because IgG4 has no direct influence on cancer cell proliferation, these findings unambiguously indicate that cancer cells utilize the IgG4 antibody to block local immunological responses and thus allow cancer growth in vivo via immune escape. This could explain the recently discovered hyper-progressive syndrome that is occasionally linked to cancer treatment with PD-1 inhibitors .The immune system can detect cancers that might otherwise escape immune surveillance thanks to immune checkpoint inhibitory therapeutic antibodies that attach to the programmed cell death protein 1 (PD-1) receptor. Yet, IgG4 antibodies can also cause an autoimmune reaction by impeding the immune system’s ability to be suppressed by regulatory T cells . IntriguAn extensive review of the literature showed that mRNA vaccines are not the only ones that induce IgG4 antibody production. The HIV, Malaria, and Pertussis vaccines also elicited such a response. Overall, there are three critical factors determining the class switch to IgG4 antibodies: excessive antigen concentration, repeated vaccination, and the type of vaccine used.Compared to BNT162b2, the mRNA-1273 vaccine had a greater capability for inducing a prolonged IgG4 response. The amount and duration of the spike protein produced are presumably affected by the higher mRNA concentrations in the mRNA-1273 vaccine (100 µg) compared to the BNT162b2 vaccine (30 µg). Intriguingly, among the mRNA vaccines, the mRNA-1273 vaccine generated increased anti-S1 serum IgG4 concentrations in COVID-19-uninfected individuals with previously unknown repercussions on pathogen defense. Until day 270, uninfected people who received the adenovirus-based vaccine did not exhibit this long-lasting IgG4 response .The problem associated with vaccines designed to be injected with a low antigen concentration is a possible absence of immunological response, and traditionally there has been a strong connection to the “more is better” school of thought that persists, especially for the wide range of infectious diseases for which there are no trustable immune predictors of vaccine-induced protection (human immunodeficiency virus (HIV), tuberculosis (TB), hepatitis C virus (HCV), etc.) . A large(1) When excessive quantities of antigen are injected, it can cause cell death, resulting in the loss of a specific group of T cells; this phenomenon is known as clonal deletion.(2) Immune tolerance may develop as a result of prolonged antigen exposure. T cells are an essential part of the immune system that detects and removes infections and other foreign objects. Yet, these T cells may become desensitized and lose their capacity to react to repeated exposures when they are exposed to large concentrations of antigens, such as during repeated vaccination. Immune tolerance is a condition that can also result in the persistence of infections or the emergence of autoimmune diseases.(3) T cells can undergo a process known as “terminal differentiation” when vaccines are given in high concentrations, at which point they become highly specialized, losing the capacity to divide and proliferate. The immune system becomes exhausted as a result and is unable to mount a successful defense against subsequent illnesses. This is a problem since it might undermine the protective advantages of vaccinations. To balance the advantages of immunological protection and the potential disadvantages of immune exhaustion, it is crucial to carefully determine the ideal dose of vaccines.(4) Adverse outcomes are more likely to occur in groups receiving greater doses.(5) The intensity of the reaction between an antigen and a T cell receptor or an antibody is referred to as avidity. The immune response is more effective in identifying and removing the target antigen when avidity is high. High antigen dosages, however, can result in “immune exhaustion,” a condition where the immune system’s cells become desensitized and unable to mount a successful defense. Helper T cell and antibody avidity may decline as a consequence, impairing the immunological response to the target antigen. To establish a strong and effective immune response, it is crucial to thoroughly assess the ideal antigen dosages utilized in immunotherapy .Billeskov et al.  providedResearchers have reported that quickly upon the administration of the first two mRNA vaccine doses, the pro-inflammatory subclasses IgG1 and IgG3 dominated the IgG response. Nevertheless, a few months following the second Pfizer vaccine shot, spike-specific antibodies were further enhanced by a third mRNA injection and/or new infections caused by the SARS-CoV-2 variant . Of all Such an increase in IgG4 levels was not observed in individuals who received either the same type or a different type of SARS-CoV-2 vaccine based on adenoviral vectors, proving that, in this study, the mRNA Pfizer vaccine was the only one to cause this response. Surprisingly, 7 months after the second inoculation, the IgG4 levels in the serum of approximately half of the vaccinees surpassed the lower limit of detection . To deteIn this regard, it was recently demonstrated that following the traditional vaccination scheme, the serum-neutralizing effectiveness in mice against the Delta and Omicron variants of the COVID-19 Pfizer vaccine was dramatically diminished after numerous booster doses . RepeateA study by Chung et al. contrasted repeated immunization with similar HIV vaccines in a scenario of an HIV vaccination trial. The protection (31.2%) afforded by one vaccine (RV144) was described by the authors as being linked with the production of IgG1 and IgG3 antibodies, whereas the protection of the other vaccine (VAX003) was negligible, and was associated with the production of IgG4 antibodies after multiple rounds of vaccinations . Since tSuch findings are similar to those recently reported after repeated mRNA vaccination; this IgG4 class shift was linked to a decreased ability of the spike-specific antibodies to promote complement deposition and antibody-dependent cellular phagocytosis . AdditioFrom these data, it is clear that IgG4 production in the VAX003 group was associated with repeated boosting (seven rounds of immunization vs. four rounds in the RV144 group), leading to reduced protection from HIV infection; moreover, this class switch to IgG4 may promote breakthrough infections due to the impairment in Fc-mediated antiviral responses . This suPlasmodium falciparum parasite, which causes Malaria. It was unclear, therefore, if antibodies to these antigens act as protective agents against clinical illness or only serve as exposure markers. In a group of 302 Mozambican children ages 5, 9, 12, and 24 months, highly specific tests were used to determine antibody responses to Plasmodium falciparum blood-stage antigens as part of a randomized, placebo-controlled trial between 2002 and 2004. The incidence of malaria throughout the follow-up period was found to be differently correlated with IgG subtype reactions to the EBA-175 antigen [P. falciparum antigens is essential, the prophylactic effect of IgG has been attributed to the neutralizing (IgG1 and IgG3) rather than the non-neutralizing subtypes (IgG2) (IgG2 and IgG4) [The merozoite surface protein 1 (MSP-1), the 175-kDa erythrocyte-binding antigen (EBA-175), and the apical membrane antigen 1 (AMA-1) are the three major objectives of the natural immune response to the  antigen . Since ind IgG4) ,119,120.While IgG4 reactivity was minimal in the first year but significantly increased by the age of 2 years, IgG3 reactivity remained moderate throughout the study period. IgG3 reactivity was stable throughout all time, while IgG4 was low during the first year but significantly increased at the age of 2 years. The study focused on the antibody responses of individuals at 5 and 12 months and investigated the incidence of malaria during two different periods of risk, from 5 to 12 months and from 12 to 24 months. In their analysis, they noticed a distinct pattern for IgG subclasses to the EBA-175 antigen: higher concentrations of particular antibodies known as neutralizing IgG1 and IgG3 were linked to a reduced likelihood of contracting malaria in the second year. As the levels of IgG1 doubled, the risk of malaria was reduced by about 50%, and when the levels of IgG3 doubled, the risk of malaria decreased by about 60% .It is important to note that the probability of contracting malaria increased by around three times when non-neutralizing IgG4 levels doubled. Up to the age of 24 months, IgG1 and IgG3 demonstrated 51% and 56% protective effects, respectively; however, IgG4 was linked to a higher risk of malaria infection throughout this age range . It is iIgG4 responses have been infrequently reported with other vaccines, even after numerous inoculations, including that of the tetanus toxoid (TT) vaccine and the respiratory syncytial virus (RSV) . These rA recently published study found that long-term IgG4 responses were produced by the mRNA vaccines but not by the vaccines using adenoviruses . It is iFurther analysis of the literature shows that only vaccines using a part of the virus produced an increase in IgG4 levels . Interestingly, Buhre et al.  found thRecent studies have raised concerns that inoculation with mRNA-based COVID-19 vaccines might result in the establishment of tolerance against the spike protein generated by host cells in response to vaccination. For example, a recent work by Irrgang et al. discovered that several months after the second immunization with the Pfizer vaccine, SARS-CoV-2-specific antibodies were mainly composed of non-neutralizing IgG4 antibodies, which were enhanced even more by a third mRNA vaccination and/or SARS-CoV-2 variant breakthrough infections . The autIt has been suggested that an increase in IgG4 levels could have a protective role similar to that occurring during successful allergen-specific immunotherapy by inhibiting IgE-induced effects . AllergeThis leads us to conclude that it is incorrect to compare the increase in IgG4 levels between allergy treatments and the reported increase in IgG4 antibodies after repeated vaccination or infection with SARS-CoV-2. The induced tolerance against the spike protein could produce an impaired immune response against the virus when these patients suffer a re-infection. Although the new Omicron subvariants have a high rate of transmissibility, the severity of infections has fortunately been reduced as a result of a change in affinity towards the upper respiratory tract ,134,135.A study by Gazit et al. found that when the initial event (infection or vaccination) happened during January and February of 2021, SARS-CoV-2-naive vaccinees exhibited a 13.06-fold , 8.08–21.11) greater risk for breakthrough infection with the Delta variant compared to the unvaccinated-previously-infected persons. The increased risk for symptomatic illness was also substantial. Evidence of waning naturally generated immunity was shown when the infection happened at any point between March 2020 and February 2021, albeit SARS-CoV-2 naive vaccinees still had a 5.96-fold (95% CI: 4.85–7.33) higher risk of breakthrough infection and a 7.13-fold (95% CI: 5.51–9.21) higher risk of symptomatic disease. This research also showed that immunity acquired through natural disease provides better protection against infection and disease symptoms caused by the Delta variant of SARS-CoV-2 than the immunity provided by two injections with the BNT162b2 vaccine .Even the protection that COVID-19 vaccines provide against severe symptoms and hospitalization is now being questioned following an outbreak in an Israeli hospital that resulted in the deaths of five individuals  who were fully immunized . This stIrrgang et al.  reportedThere is now compelling evidence that, among COVID-19 vaccines, only the mRNA vaccines  induced a remarkable increase in IgG4 levels, and such an increase was detected in SARS-CoV-2 uninfected individuals who received mRNA vaccinations before becoming infected with the virus, whereas for patients who had a previous infection before vaccination, IgG4 levels did not rise . This isThe HIV  and malaWe propose a hypothetical immune tolerance mechanism induced by mRNA vaccines, which could have at least six negative unintended consequences:(1) By ignoring the spike protein synthesized as a consequence of vaccination, the host immune system may become vulnerable to re-infection with the new Omicron subvariants, allowing for free replication of the virus once a re-infection takes place. In this situation, we suggest that even these less pathogenic Omicron subvariants could cause significant harm and even death in individuals with comorbidities and immuno-compromised conditions.(2) mRNA and inactivated vaccines temporally impair interferon signaling ,143, pos(3) A tolerant immune system might allow SARS-CoV-2 persistence in the host and promote the establishment of a chronic infection, similar to that generated by the hepatitis B virus (HBV), the human immune deficiency virus (HIV), and the hepatitis C virus (HCV) .(4) The combined immune suppression  Repeated vaccination could also lead to auto-immunity: in 2009, the results of an important study went largely unnoticed. Researchers discovered that in mice that are otherwise not susceptible to spontaneous autoimmune disorders, repeated administration of the antigen promotes systemic autoimmunity. The development of CD4+ T cells that can induce autoantibodies , which had their T cell receptors (TCR) modified, was triggered by excessive stimulation of CD4+ T cells. The aiCD4+ T cell was generated by new genetic TCR modification rather than a cross-reaction. The excessively stimulated CD8+ T cells induced them to develop into cytotoxic T lymphocytes (CTL) that are specific for an antigen. These CTLs were able to mature further by antigen cross-presentation, so in that situation, they induced autoimmune tissue damage resembling systemic lupus erythematosus (SLE) . AccordiIt has been proposed that the amount and duration of the spike protein produced are presumably affected by the higher mRNA concentrations in the mRNA-1273 vaccine (100 µg) compared to the BNT162b2 vaccine (30 µg) . Thus, i(6) Increased IgG4 levels induced by repeated vaccination could lead to autoimmune myocarditis; it has been suggested that IgG4 antibodies can also cause an autoimmune reaction by impeding the immune system’s ability to be suppressed by regulatory T cells . PatientFinally, these negative outcomes are not expected to affect all people who have received these mRNA vaccines. Individuals with genetic susceptibility, immune deficiencies, and comorbidities are probably the most likely to be affected. However, this gives rise to a disturbing paradox—if people who are the most affected by the COVID-19 disease  are also more susceptible to suffering the negative effects of repeated mRNA vaccination, is it then justified to booster them? As Omicron subvariants have been demonstrated to be less pathogenic ,136,137,


To reduce the environmental damage caused by waste rubber, crumb rubber concrete (CRC) was prepared by replacing some fine aggregates with crumb rubber. The effects of elevated temperature as well as crumb rubber content on the mechanical properties of the prepared CRC were studied. The crumb rubber contents were 0%, 10%, and 20%, while CRC was subjected to atmospheric temperatures (AT) of 300 °C, 500 °C, and 700 °C. The concrete without crumb rubber content was used as the control group at the atmospheric temperature. The mass loss, thermal conductivity characteristics, compressive strength, splitting tensile strength, axial compressive strength, elastic modulus, and stress-strain characteristics of CRC at elevated temperatures were studied. The experimental results show that: (1) With the increase in crumb rubber content and temperature, the cracks on the surface of the specimen gradually widen while the mass loss of the specimen increases. (2) With the increase in crumb rubber content and temperature, the cube compressive strength, splitting tensile strength, axial compressive strength, and elastic modulus of CRC decrease, yet the plastic failure characteristics of CRC are more obvious. (3) The influences of elevated temperature on strength and elastic modulus are as follows: splitting tensile strength > elastic modulus > axial compressive strength > cubic compressive strength. (4) With the increase in temperature, the stress-strain curve of the CRC tends to flatten, the peak stress decreases, and the corresponding peak strain significantly increases. With the increase in crumb rubber content, there is a great decrease in peak stress, yet the corresponding peak strain is basically the same. The use of CRC can be prioritized in applications that increase toughness rather than strength. In the 21st century, humanity has entered the circular economy era, and the concept of a “circular society” has become established in countries around the world as an important path toward sustainable development ,4,5. RubSince the 1980s, many scholars have been adding waste tire rubber powder to concrete to prepare CRC ,11,12. TAlthough concrete has good fire resistance, its mechanical properties may deteriorate under elevated temperatures, leading to explosive spalling and irreparable damage to the structure, which endangers the overall safety of the structure ,36,37. T3, as shown in The cement is a 42.5-grade ordinary Portland cement produced by China Sunstone Group, and the physical and mechanical performance indicators of the cement are shown in As a nonpolar material, crumb rubber has weak bonding ability with cementitious materials. In addition, there are acidic substances on the surface of waste rubber that affect the bonding between crumb rubber and cement gel. In order to improve the bonding performance between crumb rubber and cementitious materials, the crumb rubber is immersed in a 3% NaOH alkaline solution to remove the acidic substances on the rubber surface, exposing the polar bonds inside the rubber that closely combine with the cement gel . The modCRC is prepared based on C30 concrete, using an equal volume of crumb rubber to replace fine aggregates with substitution rates of 0%, 10%, and 20%, respectively. The specimens are RC (reference concrete), CRC (crumb rubber concrete)-10, and CRC-20, as shown in To ensure uniform mixing of CRC, the preparation process is as follows: (1) The crumb rubber and fine aggregate are first mixed dry in a mixer for 5 min at a speed of 60 r/min, and the crumb rubber is evenly dispersed in the fine aggregate. (2) According to the mix proportion in Experience and experiments with fire have shown that the strength loss of concrete is relatively small before the action of 300 °C, and after exceeding 700 °C, the strength is basically lost. Therefore, in this experiment, three target temperatures of 300 °C, 500 °C, and 700 °C were selected to heat the concrete at elevated temperatures. Atmospheric temperature was used as a control group, and tests for individually determining the cube compressive strength, splitting tensile strength, uniaxial compressive strength, elastic modulus, and uniaxial stress-strain relationship of the CRC after elevated temperature were carried out. The number, size, grouping, and effective number of test pieces are shown in The KSL-30-12YSM track-type double door rapid heating high-temperature furnace was used in the elevated temperature test, as shown in To ensure the representativeness of the measured temperature, a thermocouple is buried every 50 mm along one end face of the specimen at the center of the cross-section, as shown in The microcomputer hydraulic universal testing machine produced by Shenzhen Xinsansi Company was used for loading, with the model CHT4106 and a maximum applied force of 1000 kN. The loading rates of cube compressive strength and splitting tensile strength are 0.3–0.35 MPa/s and 0.05–0.08 MPa/s, respectively. The TM-2 concrete elastic modulus tester produced by Yangzhou Hengtian Technology Development Co., Ltd. . was used for deformation measurement.When the test lasts for 15 min, the furnace temperature reaches 250 °C, and water vapor and a pungent odor overflow from the furnace door. At 25 min, the furnace temperature reaches 400 °C, and a large amount of water vapor overflows from the furnace door, as shown in At 300 °C, the surface of the specimen shows a reddish-brown color. The surface of the specimen mixed with crumb rubber shows holes of varying sizes and obvious microcracks, while the control group specimen does not show any cracks. At 500 °C, the specimen turns light gray, and some CRC specimens show obvious defects at the edges and corners. There are obvious holes on the surface of the specimens, and some of the holes still contain incomplete burnt crumb rubber residues. Cracks are formed between the holes, creating a clear sense of looseness. The control group specimens show subtle cracks. At 700 °C, the specimen turns gray-white. The edges and corners of the CRC specimen can be easily crushed by hand, resulting in a more pronounced sense of looseness and severe strength loss. The crumb rubber on the surface of the specimen has completely disappeared, leaving only white holes. Most of the surface cracks are interconnected, with these holes as the centers, as shown in After an elevated temperature, with the loss of free and bound water, the combustion or melting of crumb rubber, and a series of physicochemical reactions inside the concrete, the mass of the specimen is lost to varying degrees, as shown in Different temperature measurement points inside the specimen exhibit a temperature plateau at 100 °C, which has been discussed in previous literature ,49. WhenDuring the heating stage, a significant temperature gradient is formed inside the specimen. The closer it is to the heating surface, the faster its heating rate and temperature after reaching the constant temperature stage. During the constant temperature stage, the temperature inside the specimen continues to rise until the end of the constant temperature stage, and the temperature inside the specimen does not reach the set furnace temperature, indicating that the concrete has very obvious thermal inertia. During the cooling stage, the closer the specimen is to the heating surface, the faster the temperature drops, while the central position of the specimen remains at a relatively high temperature until the end of temperature collection.At the initial loading stage of the specimen at atmospheric temperature, there was no significant change on the surface of the control group specimen. With the increase in load, subtle vertical cracks appear on the surface of the specimen, and the load continues to increase, rapidly expanding, leading to brittle failure. CRC exhibits obvious plastic failure characteristics. At the initial stage of loading, similar to the control group, there is no significant change on the surface. Approaching the failure load, subtle cracks appear on the surface of the specimen. The load continues to increase, the number of cracks increases, and they gradually widen, ultimately losing bearing capacity but remaining relatively intact. The larger the crumb rubber content, the more complete the specimen becomes after failure, as shown in The relationship between the heating temperature of the specimen and the cube compressive strength and reduction rate is shown in The internal structure of concrete is altered with crumb rubber. Due to the weak strength of crumb rubber itself, it also has the function of air entrainment during concrete mixing. At the same time, the bonding between nonpolar crumb rubber and cement matrix is weak, and there is a certain transition interface between crumb rubber and cement matrix, which has a significant impact on the strength of concrete. With the increase in crumb rubber content, the compressive strength of concrete shows a downward trend. At elevated temperatures, concrete undergoes a series of complex physicochemical reactions, causing the originally hard aggregates and cement stones to become loose. With the increase in crumb rubber content, additional, wider cracks appear on the surface of the specimen. As the weak part of the specimen, cracks penetrate under load, reducing the load-bearing capacity of the specimen.At the initial loading stage of the specimen at atmospheric temperature, there was no significant change on the surface of the control group specimen. When approaching the ultimate load, cracks appear along the splitting surface and then develop into wider cracks, and the specimen is split in two. When the CRC specimen approaches the ultimate load, small cracks appear on the splitting surface, and the cracks develop slowly. During failure, the specimen was relatively intact and did not split into two halves. The failure morphology of the CRC-20 specimen is more complete than that of the CRC-10 specimen, as shown in With changes in crumb rubber content and temperature, the internal morphology of the split specimen shows different changes, as shown in The relationship between the heating temperature of the specimen and the splitting tensile strength and reduction rate is shown in For the same crumb rubber content, the reduction rate of the splitting tensile strength of the specimen is obviously greater than that of the cube compressive strength. With the increase in crumb rubber content, the reduction rate is higher than that of cube compressive strength under the same condition. There are micro-cracks in the binding part of crumb rubber and concrete, and splitting tensile is sensitive to cracks. The influence of microcracks or defects on the splitting tensile strength of concrete is greater than that of the cube compressive strength. Similar conclusions are obtained in the elevated temperature test of ordinary concrete . TherefoAt atmospheric temperature, small longitudinal cracks appear in the control group with an increase in load. When approaching the ultimate load, the microcracks rapidly expand, one of the longitudinal cracks develops into the main crack, and the specimen rapidly loses its load-bearing capacity. The CRC specimens developed microcracks with the increase in load. When approaching the ultimate load, the microcracks develop into a more obvious crack, and the specimen loses its load-bearing capacity while there is no longitudinally penetrating main crack. The specimen is still intact after failure, and the specimen with 20% crumb rubber content is more complete than that with 10% crumb rubber content. With the increase in crumb rubber content, the specimen shows obvious plastic failure characteristics, as shown in The relationship between the heating temperature of the specimen and the axial compressive strength and reduction rate is shown in The relationship between the heating temperature of the specimen and the elastic modulus and reduction rate is shown in With the same crumb rubber content and temperature, the reduction rates of cubic compressive strength, axial compressive strength, elastic modulus, and splitting tensile strength increase successively, as shown in This test mainly records the rising section of the stress-strain curve of crumb rubber concrete, and the stress-strain relationship of specimens with different crumb rubber content at different temperatures is shown in As can be seen from The measured data are analyzed by multivariate nonlinear regression using Matlab. The measured stress-strain data of concrete with three different crumb rubber contents under atmospheric temperatures of 300 °C, 500 °C, and 700 °C are separately fitted. The relationship between stress-strain and crumb rubber content under uniaxial compression is shown in Compared with relevant studies ,51, it i(1)With the increase in heating temperature, the apparent color of the specimen becomes lighter, the surface cracks of the specimen become wider, and the mass loss of the specimen increases. With the increase in crumb rubber content, the cracks on the surface of the specimen become wider, the mass loss becomes larger, and the heat conduction rate of concrete decreases.(2)An elevated temperature has a great influence on the strength and elastic modulus of CRC. With the increase in heating temperature, the cube compressive strength of the control group increases slightly at 300 °C, while the cube compressive strength of the CRC decreases, and the split tensile strength, axial compressive strength, and elastic modulus of the control group and CRC all decrease. However, the integrity of the CRC specimen after failure is better, and the plastic failure characteristics are more obvious.(3)The cubic compressive strength, splitting tensile strength, axial compressive strength, and elastic modulus decrease more obviously with the increase in crumb rubber content. The degree of influence of elevated temperature on strength and elastic modulus is as follows: splitting tensile strength > elastic modulus > axial compressive strength > cubic compressive strength.(4)With the increase in heating temperature, the stress-strain curve tends to be flat, the peak stress decreases, and the corresponding peak strain obviously increases. At the same temperature, the peak stress decreases more with the increase in crumb rubber content, but the corresponding peak strain is basically the same. After multiple nonlinear regression analyses and the fitting of stress-strain data from three kinds of crumb rubber mixtures, the stress-strain fitting curves of specimens with different crumb rubber mixtures are obtained. The fitting results are basically consistent with the experimental results.The effects of temperature and crumb rubber content on the strength, elastic modulus, and stress-strain of CRC were analyzed by testing the experimental phenomena, mass loss, heat conduction characteristics, and mechanical properties of concrete with different crumb rubber contents under elevated temperatures. Compared with concrete without crumb rubber and at atmospheric temperature, the mechanical properties of CRC at elevated temperatures were clarified. The conclusions are as follows:


Non-small cell lung cancers (NSCLCs) can be treated with chemotherapy, radiotherapy, immunotherapy, or a combination before undergoing surgical resection. However, uncertainty remains regarding the overall outcomes of patients undergoing minimally invasive surgical (MIS) resection of the lung, following systemic treatment. As such, we studied the existing data on outcomes of this patient population via a comprehensive dive into the literature and performed a meta-analysis. Our findings indicate that MIS can be safely performed following systemic treatment in patients with NSCLC. Notably, MIS resection offers added benefits including significantly higher lymph node yield compared to open surgery. We also address the various complication rates of both open and MIS surgical approaches, underscoring the importance of surgeon preparedness to convert MIS approaches to open surgeries in precarious circumstances. Overall, this study provides valuable insights into the safety and efficacy of MIS resection post-systemic treatment for patients with NSCLC, offering potential improvements in patient outcomes and guidance to surgical decision making.Background: Minimally invasive surgeries for non-small cell lung cancers (NSCLCs) such as video-assisted thoracoscopic surgeries (VATSs) and robotic-assisted thoracoscopic surgeries (RATSs) have become standard of care for patients needing surgical resection in early stages. The role for neoadjuvant systemic therapy has increased with patients receiving neoadjuvant systemic chemotherapy and immunotherapy. However, there has been some equipoise over the intraoperative and overall outcomes for these patients. Here, we review the current data regarding outcomes of patients undergoing minimally invasive thoracic surgical resection after systemic chemotherapy, immunotherapy, or both. Methods: A systematic literature review of randomized controlled trials and observational studies presenting data on patients with NSCLC that underwent neoadjuvant systemic therapy followed by minimally invasive surgery was performed assessing complications, conversion rates, and lymph node yield. Results: Our search strategy and review of references resulted in 239 publications to screen with 88 full texts assessed and 21 studies included in our final review. VATS had a statistically significant higher lymph node yield in five studies. The reported conversion rates ranged from 0 to 54%. Dense adhesions, bleeding, and difficult anatomy were the most common reported reasons for conversion to open surgeries. The most common complications between both groups were prolonged air leak, arrythmia, and pneumonia. VATS was found to have significantly fewer complications in three papers. Conclusions: The current literature supports VATS as safe and feasible for patients with NSCLC after neoadjuvant systemic treatment. Surgeons should remain prepared to convert to open surgeries in those patients with dense adhesions and bleeding risk. For the past few decades, lung cancer has been the leading cause of cancer-related death in the United States with non-small cell lung cancer (NSCLC) accounting for around 85% of all lung cancer cases . While tHistorically, surgery has been the primary treatment modality for early NSCLC, and definitive chemoradiation has served as the primary treatment for unresectable disease processes. For patients that present with more advanced disease at the time of diagnosis, neoadjuvant chemo- and immunotherapy has been theorized to treat micro-metastatic disease early and improve future ability to resect via downstaging . ResponsMinimally invasive (MIS) techniques such as video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracoscopic surgery (RATS) have become the standard of care over open thoracotomies for early-stage lung cancer ,8. The aIn this article, we review the current data regarding outcomes of patients undergoing minimally invasive thoracic surgical resection after systemic chemotherapy, immunotherapy, or both. We focus on operative complications, conversion rates, and the overall safety of those patients undergoing VATS or RATS resection compared to their counterparts who underwent open approaches.A systematic literature review was performed in line with the PRISMA checklist. The following search strategy was utilized and sourced from PubMed and relevant references:  AND (neoadjuvant chemotherapy OR neoadjuvant immunotherapy) AND . A search was conducted on the Cochrane Central Register of Controlled Trials with the following strategy: non-small cell lung cancer in All Text AND neoadjuvant in Title Abstract Keyword AND surgery in Title Abstract Keyword—with Cochrane Library publication date in the last 2 years, in Trials (Word variations have been searched). Inclusion criteria consisted of English-language randomized controlled trials and observational studies presenting data on patients with NSCLC that underwent neoadjuvant therapy followed by minimally invasive surgery. We excluded (1) case studies and reviews, (2) studies on staging or mediastinoscopy, (3) those that did not separate results by neoadjuvant treatment or surgical approach, and (4) ongoing trial data. Papers were screened by one reviewer, and two authors reviewed the full texts for inclusion.Publications were managed and screened using Covidence software. Extracted variables included stage, type of neoadjuvant treatment, amount of radiation, type of surgery, and time to surgery. Outcomes extracted include: rate of open surgery or VATS (including RATS), rate of conversion to open surgery, operative complications, and lymph node resection. Cause of conversion from VATS to open surgery was recorded. The number of lymph nodes harvested in VATS and open cases was collected along with significant differences if reported.Our search strategy and review of references resulted in 239 publications: among these, 6 duplicates were removed, 88 full texts were assessed, and 21 studies were included in our final review . The stup < 0.01) [Time to surgery was reported by nine publications. The mean time to surgery ranged from 26.5 to 93 days. Yang reported a significant difference in time to surgery between those receiving open surgery with a mean of 90 days and a range of 78–111 versus VATS with a mean of 93 days and a range of 77–114 ( < 0.01) . Zhang r < 0.01) .Four papers included only the VATS approach, and the majority included both VATS and open approaches. Three papers also included RATS as a subset of VATS ,25,29. OOf the 12 publications that reported the number of lymph nodes resected, five found statistically significantly more lymph nodes resected with an open approach compared to VATS . Other pThe reported conversion rate from VATS to open ranged between 0 and 54% with the exception of one paper that excluded converted cases  and one Nine papers reported the reason for conversion from VATS to open. Dense adhesions were the cause in 39 cases, bleeding and metastatic or fibrous lymph nodes were the cause in 12 cases each, and difficult anatomy/dissection was the cause in 4 cases. One paper reported 19 cases of conversion due to primary tumor invasion .There were zero 30-day mortalities reported in 10 publications, and 4 did not report on mortality. No significant differences by surgical approach were found across those that noted one or greater patient death ,26,29,30p = 0.042) [Operative time was compared by surgical approach in 6 publications ,20,26,30= 0.042) . Matsuokp = 0.02), Tian (100cc (30–200) vs. 200cc (300–525), p < 0.001), and Zhang (149cc (±57.9) vs. 321.2cc (±72.3), p = 0.021) [Estimated blood loss was found to be decreased in the MIS group by Kamel (100cc (50–150) vs. 150cc (100–250), = 0.021) ,30,35. M100cc 30–0 vs. 200= 0.021) . Yang fo= 0.021) .p < 0.05. Compared to the open approach, VATS had fewer respiratory and cardiac complications [Of the 10 papers that reported statistical comparisons of complications between approaches, three found significant differences with a ications , medicalications , or majoications . The mosAll papers concluded that VATS is safe and feasible for patients with NSCLC after neoadjuvant chemotherapy, radiotherapy, immunotherapy, or a combination of treatments.Since the adoption of minimally invasive surgery (MIS) into the repertoire of thoracic surgery, MIS has become increasingly prevalent for both benign and malignant diseases. The approach has been shown to have a multitude of advantages including reduced surgical trauma, decreased postoperative pain, shorter length of hospitalizations, and faster recovery times . MIS hasChemotherapy and immunotherapy have been increasingly implemented in the neoadjuvant treatment regimen in patients with locally advanced NSCLC. In comparison to adjuvant therapy, neoadjuvant treatment has the potential to increase the number of resectable tumors, improve surgical margins, decrease the size of resection, and promptly treat micro-metastatic disease. Additionally, compliance with systemic therapy is thought to be superior in the neoadjuvant setting, as post-surgical patients may not tolerate treatment should they have difficulty recovering from surgery. Compared to surgery alone, neoadjuvant chemotherapy with subsequent surgery has been shown to improve survival in patients with early-stage NSCLC especially in patients with stage II and III . OverallOperative safety, the ability to adequately visualize mediastinal structures, and lymph node yield are at the forefront of surgeons’ minds when contemplating minimally invasive versus open approaches in patients who have undergone neoadjuvant therapy. Safety and visualization are critical to ensuring an adequate surgery is performed with minimal complications. Thus, some surgeons choose to avoid MIS in later stages of malignancy, as mediastinal structures are reportedly distorted after receiving neoadjuvant chemotherapy and/or immunotherapy. These surgeons state that such distortion could lead to increased difficulty and complexity of lung and lymph node resection, which can prevent an oncologically sound operation. However, over the past few years, surgeon experience with video-assisted thoracoscopic surgery (VATS) is increasing along with the adoption of RATS and in addition to improvement in intraoperative technology and visualization. Therefore, minimally invasive approaches have been proven to be just as safe as open thoracotomy in patients who have undergone neoadjuvant systemic therapy.p < 0.01. In contrast, Muslim et al. found neoadjuvant treatment was not an independent predictor of conversion [In order to ensure patient safety and operative ease, there are instances in which surgeons must convert from a MIS to an open approach. In our review, we found a wide range of conversion rates from MIS to open (0–53%). This finding is consistent with a retrospective National Cancer Database analysis that found neoadjuvant chemotherapy to be associated with a higher conversion rate of 18.3% than those without neoadjuvant treatment with a nversion . Comparanversion ,17,33. Inversion . Positivnversion . HoweverAnother imperative point of comparison involves perioperative complications. Our review found that the most common complications in MIS and open approaches included prolonged air leak, arrythmia including atrial fibrillation, and pneumonia. Interestingly, all papers found MIS to have comparable or fewer complications compared to patients undergoing open surgery. Investigators have shown that those undergoing MIS after neoadjuvant therapy have a lower rate of postoperative pain and lower volume of chest tube drainage compared to the thoracotomy group ,26. UnsuIntraoperative systematic hilar and mediastinal lymph node assessment in early-stage NSCLC is necessary for proper staging accuracy, detection of early metastasis, and better survival ,43. IntrThrough our review of patients receiving neoadjuvant treatment for NSCLC in the literature, there appears to be a discernible difference of lymph node yield and approach to surgery after neoadjuvant therapy. We found four studies that reported a statistically significant higher lymph node resection in the open surgery over MIS. That being said, these studies noted comparable oncological efficacy despite there being a lower number of resected nodes with MIS ,33, the Among minimally invasive techniques, there are reported differences in lymph node yield. Toker et al. compared the effectiveness of lymph node dissection in the open, VATS and RATS approaches . In a reThere is increasing support that the lymph nodes themselves are affected by the neoadjuvant systemic treatment. Pathologists not only report residual viable tumors in the lymph node and primary site but also assess treatment effect and fibrosis. For this reason, it can be difficult to truly determine the number of lymph nodes, illustrating the need for very accurate hilar and mediastinal lymph node station assessment noted by the COC Intraoperative standard 5.8 .Preoperative radiation has been debated, and many clinicians opt for solely chemotherapy and immunotherapy as the mainstays for neoadjuvant treatment. However there are multiple phase II trials that report higher response rates, more pathologic response, and increased downstaging with the inclusion of radiotherapy to the neoadjuvant regimen ,52. ThatRadiation treatment in particular is associated with an increased conversion rate due to the subsequent edema, dense adhesions, and fibrotic changes. Huang et al. reported a 37.5% conversion rate where all but one patient received preoperative radiotherapy . The onlImmunotherapy, specifically immune checkpoint inhibitors, has shown great promise in improving overall survival in both metastatic and locally advanced NSCLC patients . A multitude of studies have shown increased overall survival and disease-free survival in the metastatic setting when utilizing immunotherapy along with chemotherapy rather than chemotherapy alone. The PACIFIC trial illustrated that immunotherapy increases survival in early-stage unresectable lung cancer with the addition of Durvulumab after chemoradiotherapy . For resIn an attempt to describe the utility of nivolumab immunotherapy as a supplement to neoadjuvant chemotherapy, Forde et al. conducted a recent phase III clinical trial (Checkmate 816) comparing those receiving standard of care neoadjuvant chemotherapy versus those receiving neoadjuvant chemoimmunotherapy . RelevanUtilizing immune checkpoint blockade in the neoadjuvant setting likely provides an early opportunity to enhance the patient’s immune response against their tumor, as the tumor is left in situ, allowing for the larger response. However, this response may make the future resection more difficult due to the newly unleashed anti-tumor immunity that serves as a principal driver of organ inflammation and fibrosis .Although well tolerated in the majority of cases, immune checkpoint blockade can result in side effects known as immune-related adverse events (irAEs), which can affect multiple organ systems, including the lungs . PD-L1 sp = 0.027); odds ratio 0.095 : 0.014–0.809) [While rare, pneumonitis should be carefully considered when evaluating patients for surgery if administering immune checkpoint blockade in the neoadjuvant setting. Yet detecting checkpoint inhibitor pneumonitis, and accurately predicting post-operative outcomes, prior to surgical intervention has remained challenging. A CT radiomics-based predictive model was recently shown to provide reasonable predictions of immunotherapy-associated pneumonitis in tumors treated with PD-L1 inhibitors  . While p4–0.809) . Lower DWith the increased implementation of immunotherapy in lung cancers, surgeons should be aware of the increased risk of fibrosis and not have any hesitation to start with minimally invasive surgery. That being said, surgeons should be ready to convert to open surgery to not compromise an oncologically sound operation after immunotherapy. Over the next few years, further studies being conducted along with the increased use of neoadjuvant immunotherapy will truly give us an idea of the adoption, complications, and conversion rates of minimally invasive techniques with the use of neoadjuvant immunotherapy outside of clinical trials. While the strengths of this review include the number of randomized-controlled trials included, broad search strategy, and systematic screening of papers, the limitations include the inclusion of observational studies that impart risk of bias and the lack of true randomized controlled trials in this setting. Future reviews will be needed as ongoing trials of neoadjuvant treatment for NSCLC utilizing MIS approach are released. Additional studies could report further details on reasons for conversion and complications along with the increased use of robotics in patients following neoadjuvant therapy.Minimally invasive thoracic surgery (MIS) has become the standard of care for lung cancer resection due to faster postoperative recovery. It has been studied extensively in cases amenable to upfront resection. However, limited data exist with regard to the efficacy of minimally invasive thoracic surgery following neoadjuvant therapy. In this discussion, we summarize the existing data on VATS and robotic surgery following neoadjuvant therapy. The extent of lymphadenectomy and feasibility of resection following neoadjuvant therapy will always be at the forefront of these discussions, as they are critical to determining the overall prognosis of the patient. More studies will be required to determine what is the best approach to surgical resection following neoadjuvant therapy.


Spot). FTOESpot correlated with CSI, as did the change in FTOE during tilts, but CSI’s correlation with impaired CA did not reach significance. Larger trials are indicated to validate CSI, allowing for noninvasive CA measurements and measurements in outpatient settings.Infants with congenital heart disease (CHD) may have impaired cerebral autoregulation (CA) associated with cerebral fractional tissue oxygen extraction (FTOE). We conducted a pilot study in nine CHD neonates to validate a noninvasive CA measure, cerebrovascular stability index (CSI), by eliciting responses to postural tilts. We compared CSI to an invasive measure of CA and to FTOE collected during tilts (FTOE Infants with congenital heart disease (CHD) have poorer neurodevelopmental outcomes compared to their healthy counterparts ,2. This 2), during postural tilts in which CHD infants are moved from a supine to sitting posture. We calculated CSI as an average change in rcSO2 over the postural tilts.This study explores a novel noninvasive measure of CA, cerebrovascular stability index (CSI), as a proxy for an invasive method. CSI uses cerebral near infrared spectroscopy (NIRS), a device that measures cerebral oxygenation, to measure regional cerebral oxygen saturation, , would correlate with CSI. Additionally, we investigated an exploratory hypothesis that FTOE would increase from baseline during postural tilts. Validating CSI will promote early identification of impaired CA in CHD infants and those at risk of poor neurodevelopmental outcomes by enabling CA to be measured regardless of clinical status or hospitalization.This study aimed to address this clinical gap by validating a noninvasive method of measuring CA . We hypothesized that our novel CSI measure would correlate with an invasive CA measure, and that FTOE calculated during spot collection of CSI data, . We excluded any neonates who: had hemodynamic instability, were intubated, had additional congenital abnormalities, or were > 14 days old, to allow for postural tilt measures and to eliminate confounding variables.2), measured via pulse oximeter, and rcSO2 via cerebral NIRS, recorded using an INVOS™ cerebral oximetry infant-neonatal sensor .We collected continuous hemodynamic data pre-operatively for up to 72 hours, which included MAP, measured via pressure transducer connected to an indwelling arterial catheter, pre-ductal systemic arterial saturation  5 minutes of rcSO2 in a supine position, (2) 5 minutes of rcSO2 in a sitting position, and (3) 2 minutes of rcSO2 for two subsequent tilts in both supine and sitting postures. We calculated average rcSO2 values using the last two minutes while supine prior to the tilt and the first two minutes while sitting for all three tilts. We calculated the change score as the average sitting minus average supine rcSO2 values. We calculated CSI as the average change score over the three postural tilts.We collected CSI using a postural tilt method in which neonates were manually moved from a supine (0°) to sitting posture (90°) with one hand placed on the infants’ back and another supporting the neck . We collx) as a moving, linear correlation coefficient between MAP and rcSO2 collected using 30-paired 10-second samples over a moving 300-second window via ICM + Cambridge software  [x correlation coefficient > 0.3 and the percentage of time spent with impaired CA was defined as the CA measurement for each infant [et al. and given the wide use of COx as an indicator of cerebral oxygenation in neonatal and pediatric populations [We calculated cerebral oximetry index  . Impaireh infant . We defiulations .2 via pulse oximetry and the equation FTOE = (SpO2 – rcSO2)/SpO2. FTOE was calculated both continuously, as an average over the pre-operative monitoring period, FTOECont, and as a spot check during the postural tilts, as an average of each 2-minute period that CSI data were collected in the sitting posture, FTOESpot. FTOEChange was calculated as FTOESpot – FTOECont.We calculated FTOE using SpOSpot. Kendall’s tau tested the associations between FTOECont and FTOESpot, and between CSI and FTOEChange.We used SPSS v28 for analyses. We analyzed CSI, CA, and FTOE variables for normality. Pearson’s correlation analyzed the associations between CA and CSI, and between CSI and FTOEWe collected CA and CSI data on nine CHD neonates. Sixty-six percent of the neonates were female and 100% of the neonates were of Latinx background. The average gestational age at birth was 38.7 weeks with an average birth weight of 3.1 kg. Eighty-eight percent of the neonates had cyanotic CHD and 44% had single ventricle CHD. Sociodemographic information, birth characteristics, average time monitored, and CHD diagnosis type are detailed in Table r = 0.40, p = 0.28). CSI was moderately associated with FTOESpot,  and FTOEChange, , respectively . Furthermore, FTOESpot was greater than FTOECont for all neonates except one. Individual FTOE values and total time monitored are detailed in Table CA was moderately associated with CSI, as demonstrated in Fig. Spot, and CSI and FTOEChange, provide promising support for the use of CSI, despite the association between CSI and CA not reaching statistical significance. With validation of our novel CSI measure, CSI may be implemented as a noninvasive CA measure in CHD neonates and can be extended as a tool for use in other vulnerable populations. This will allow comparisons of brain health to be made between neonates both with and without CHD and between other susceptible populations. Furthermore, early recognition of impaired CA may help identify individuals at risk for future brain injury or neurodevelopmental delays.The significant associations found between CSI and FTOEet al., identified that cerebral NIRS can determine precise changes in cerebral blood volume when children undergo a postural change from sitting to standing [The relationship between postural changes, alterations in blood pressure, and subsequently cerebral blood flow has been elucidated in several studies ,11. Kim standing , indicat2 declined when moved upright), CA would be more positive . This would indicate that as neonates lost adequate cerebral oxygenation via CSI, they would concurrently demonstrate impaired CA. However, we found that CA did not significantly associate with CSI. This may be due to our small sample size where outliers have significant effect, or it may indicate that greater cerebral oxygen extraction during a postural tilt may not correlate with one’s baseline risk for impaired CA.Therefore, we expected similar findings in CHD neonates and anticipated that our CSI measure would provide a sensitive method of measuring CA, given their cerebral vulnerabilities are comparable to preterm infants . We predet al., determined that fast doppler assessment of the basal ganglia can reliably measure cerebral blood flow velocity as a proxy for cerebral tissue perfusion and consequently autoregulation in preterm infants [Previous studies investigated using noninvasive fast doppler sonography as a method to assess CA and have compared transcranial dopplers (TCDs) to cerebral NIRS ,14. Peep infants . Elting et al. demonstrated increased cerebral oxygen extraction due to an aberrant autoregulation response in CHD infants leads to decreased cerebral oxygenation [2 when non-sedated, indicating greater difficulty maintaining adequate cerebral perfusion when active [Spot compared to FTOECont. We attributed this to a greater proportion of time spent awake and upright during positional changes while FTOESpot was collected as compared to FTOECont which was collected while largely supine. Additionally, we found FTOESpot and FTOEChange both had significant associations CSI. This suggests that the cerebral saturation decline elicited during postural tilts is related to greater cerebral oxygen extraction, i.e., FTOESpot, resulting in a greater change from baseline, i.e., FTOEChange. The lack of correlation between FTOECont and FTOESpot may underlie the lack of association between CSI and CA, as baseline measures may not be indicative of the neonatal response to change provoked by moving to an upright posture.Prior studies established that greater FTOE associated with impaired CA in CHD infants –4. Lynchn active . Thus, wSeveral limitations are of note in this study. First, to collect the two types of hemodynamic data, measures were taken in clinically stable, non-intubated neonates with arterial lines. Thus, our sample was limited to a small subset of our overarching study, as only nine CHD neonates fit both the inclusion and exclusion criteria. This lowered the statistical power of detecting significant associations. Second, our sample was recruited from the Los Angeles area and every neonate was of Latinx background, limiting the generalizability of our study. Future studies may utilize a larger and nationally representative sample to gain statistical power and demonstrate a significant association between CSI and CA to validate the use of CSI. Furthermore, replication of CSI in other studies will help establish confidence in this noninvasive technique.We found significant associations between CSI and FTOE while infants were in a sitting position, and that cerebral oxygen extraction increases from baseline during a postural tilt in most CHD infants, providing promising evidence for the use of the CSI measure in clinical practice. Although our main hypothesis regarding the association of CSI and the percent time spent with impaired CA was not statistically significant, we provide further evidence that FTOE, impaired CA, and CSI are linked. Our study, however, was restricted by a small sample size. Validation of the CSI method may help improve clinical practice as it would allow for measures of CA to be obtained in healthy infants, in outpatient settings, and in vulnerable infants without arterial lines.


At present, studies have found that c-Met is mainly involved in epithelial-mesenchymal transition (EMT) of tumor tissues in urologic neoplasms. Hepatocyte growth factor (HGF) combined with c-Met promotes the mitosis of tumor cells, and then induces motility, angiogenesis, migration, invasion and drug resistance. Therefore, c-Met targeting therapy may have great potential in urologic neoplasms. Many strategies targeting c-Met have been widely used in the study of urologic neoplasms. Although the use of targeting c-Met therapy has a strong biological basis for the treatment of urologic neoplasms, the results of current clinical trials have not yielded significant results. To promote the application of c-Met targeting drugs in the clinical treatment of urologic neoplasms, it is very important to study the detailed mechanism of c-Met in urologic neoplasms and innovate c-Met targeted drugs. This paper firstly discussed the value of c-Met targeted therapy in urologic neoplasms, then summarized the related research progress, and finally explored the potential targets related to the HGF/c-Met signaling pathway. It may provide a new concept for the treatment of middle and late urologic neoplasms. Renal cell carcinoma (RCC), prostate cancer (PCa) and bladder cancer (BCa) are the most common urologic neoplasms, which are a major tumor system threatening human health. RCC is the 12th most common cancer worldwide . BCa is In recent years, with the promotion of early screening, early detection of tumors and the development, application of tumor diagnostic markers, the diagnosis and treatment of urologic neoplasms have made rapid progress –6. BecauC-Met, as a tyrosine kinase receptor, is overexpressed in multiple tumors and exerts an active function in tumor progression as an oncogenic factor . BecausePrevious studies have demonstrated that c-Met overexpression exists in hepatobiliary tumors, so the treatment targeting c-Met has been carried out more frequently in the treatment of hepatobiliary tumors –16. HoweIn adult kidney, c-Met is expressed in renal tubular epithelial cells, and its main physiological function is to stimulate the growth of renal tubular cells , 18. ProNumerous studies have demonstrated that c-Met is overexpressed in RCC tissues and is closely related to pathological grade, stage and prognostic survival. It may have potential for prognostic assessment and targeted therapy –24. J. HIn addition, the expression of c-Met in chromophobe renal cell carcinoma (CRCC) and its prognostic significance have also been studied. F. Erlmeier et al.  evaluatein vitro and in vivo. It was found that epithelial cells began to express c-Met protein with the development of tumor malignancy. Therefore, the study have shown that the stromal cells of PCa may form an autocrine c-Met loop, which may act together with HGF expressed by cancer cells to promote tumor progression.C-Met expression can be detected in normal prostate basal epithelial cells, but it is generally not expressed in peripheral and transitional zone epithelial cells . C-Met pTo further explore the role of c-Met in the prognosis of PCa, D. Strohmeyer et al.  demonstrIn addition, other researchers have investigated the correlation between c-Met protein expression and Gleason grade. F. Jacobsen et al.  successfAs early as the 1990s, a study confirmed that the HGF/c-Met pathway was involved in the progression of BCa in animal models . Since tK. Yamasaki et al.  retrospeIn addition, the correlation between c-Met and programmed death ligand 1 (PD-L1) in tumor tissues was investigated. Y. Mukae et al.  demonstrC-Met is a transmembrane tyrosine kinase receptor that is activated by HGF to regulate the expression of related downstream genes. This process is essential for cell migration under normal and pathological conditions. Current studies have demonstrated that c-Met is mainly involved in EMT in many types of cancer. HGF combined with c-Met promotes the mitosis of various tumor cells, and then induces motility, angiogenesis, migration and invasion. In recent years, many studies have been conducted on the oncogenic mechanism of c-Met in urologic neoplasms Table 1.At present, numerous studies have demonstrated that HGF can regulate the expression of VEGF and promote tumor angiogenesis through its receptor c-Met , 48, 49.In recent years, researchers have conducted some studies on the specific mechanism of EMT in PCa. B. Yin et al.  confirmePCa consists of secretory cells and immature cells. C-Met was found to be specifically expressed in immature prostate cells. G. J. van Leenders et al.  determinIn addition, aberrant HGF/c-Met upregulation and activation were found to be frequently observed in BCa and correlated with cancer progression and invasion. W. J. Sim et al.  found thDue to the role of c-Met in promoting the progression of urological neoplasms, c-Met targeting therapy have great potential in the treatment of urological neoplasms. Researchers have conducted a large number of preclinical studies in recent years, and preliminary results have been achieved Table 2.For the past few years, chimeric antigen receptor T cells (CAR-T) therapy has revealed remarkable efficacy in cancer immunotherapy, especially in the treatment of B-cell malignancies. To apply this technique to RCC, J. I. Mori et al.  developeStudies have shown that hormone-independent PCa is highly resistant to most conventional therapies, including radiation therapy, which is a major obstacle in the treatment of such patients. H. Yu et al.  shown thin vivo could inhibit c-Met and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in osteoblasts, thereby reducing the expression of RANKL and M-CSF, and was associated with tumor-induced reduction of osteolysis. Other researchers have found similar results, J. Eswaraka et al.  and as a first-line treatment option when ICIs are contraindicated . CabozanThe progression of PCa requires androgen support, and this characteristic determines that the treatment of PCa should not be without anti-androgen therapy. Therefore, most of the clinical trials of TKIs targeting c-Met are combination therapy. A. Tripathi et al.  conducteAt present, olaparib has been clinically approved for the treatment of PCa, but cytotoxicity and DNA damage limit its clinical application. Z. Wang et al.  found thPrevious studies have shown that HGF/c-Met signaling pathway exerts a crucial function in the progression of urologic neoplasms. Therefore, targeting HGF/c-Met signaling pathway is a hopeful approach for the treatment of urologic neoplasms. Besides, more and more studies have confirmed that HGF/c-Met signaling is also regulated by other targets. Some studies have also confirmed that tumor progression can be inhibited by inhibiting these targets. Therefore, targets that regulate the HGF/c-Met signaling pathway may also have potential value for targeted therapy Figure 2in vitro and in vivo in RCC. These results suggest that SOX18 may be a valuable target for the treatment of RCC. Previous studies have shown that circRNAs are involved in the occurrence and development of many cancers. J. Yang et al. (Cullin 4B (CUL4B) is a structural protein encoding ubiquitin ligase complex, which is normally involved in physiological and developmental processes of the body. In recent years, it has been found that it is overexpressed as an oncogene in various solid tumors –79. S. Cg et al.  found thg et al. . L. Songg et al.  also fouin vivo studies and found that TMPRSS2 inhibitors inhibited PCa metastasis in vivo. Meanwhile, T. Yoshioka et al.  family has been shown to be involved in tumorigenesis. Studies have shown that Sp1 can regulate TGF-β, c-Met, PSA and α-integrin in PCa. These results indicate that Sp1 has potential value in targeted therapy for PCa because of its important role in PCa progression  can achieve better clinical efficacy. Therefore, it also indicates that the current TKIs targeting c-Met are more suitable for adjuvant therapy of advanced urologic neoplasms.C-Met interacts with other oncogenic molecules (such as EGFR and RON) to activate downstream pathways, thereby mediating tumor progression and drug resistance . SimilarFor the past few years, monoclonal antibodies against PD-1/PD-L1 and VEGF have been approved for clinical application in anti-tumor therapy. Besides, monoclonal antibodies against c-Met, such as Onartuzumab and Emibetuzumab, have been applied to digestive system tumors, and have shown good tolerance and clinical response rate , 96. HowIn addition, tumor killing by CAR-T cells technology depends only on the targeting of the target, not on the mechanism of the target. As a membrane protein specifically expressed in tumor cells, c-Met is suitable for tumor therapy using CAR T cell technology. CAR-T cells targeting c-Met have been studied in gastric cancer , 98, livIn conclusion, c-Met is involved in the progression of urologic neoplasms. It is highly expressed in tumor tissues and is associated with poor clinical prognosis. Due to the interaction mechanism between c-Met and other molecular signals, the use of targeting c-Met alone has limitations, while the combination of other antitumor methods showed better tumor killing efficacy. In the future, with the in-depth research on the mechanism of c-Met in urologic neoplasms and the optimization of CAR-T cells technology, it is believed that the targeted therapy of c-Met in the treatment of urologic neoplasms will surely make breakthrough progress.PS and XK also performed literature management and produced tables and graphs. All authors contributed to the article and approved the submitted version.


Targeting high-volume prescribers for stewardship efforts is a practical approach to reducing outpatient antibiotic prescribing that also captures inappropriate use.Inappropriate antibiotic prescribing to pediatric Medicaid patients was compared among high-volume and non-high-volume prescribers. High-volume prescribers had a higher percentage of inappropriate prescriptions than non-high-volume prescribers (17.2% versus 15.8%,  Antimicrobial resistance (AMR) is a growing public health threat, and a key driver of resistance is antibiotic use . The WorKentucky has consistently had one of the highest rates of outpatient antibiotic prescribing in the nation since annual statewide reporting became publicly available from the CDC in 2011 ,7. PriorThe CDC provided a subset of state public health departments, including the Kentucky Department for Public Health (KDPH), with a list of the top 10% of antibiotic prescribers, by specialty type, identified using 2019 IQVIA Xponent data. IQVIA is a commercial entity with a focus on data analytics, technology, and clinical research in the healthcare sector . The XpoHigh-volume antibiotic prescribers identified in the IQVIA Xponent data were matched to the Medicaid data using NPI numbers. “High-volume prescribers” were defined as those included in the top 10% list from IQVIA data. Any prescribers included from the Kentucky Medicaid data that were not included in the “High-volume prescribers” category (identified by the IQVIA top 10% data), were categorized as “non-high-volume prescribers”. The provider type was obtained from Kentucky Medicaid claims and categorized prescribers into one of the following groups: general practitioner, nurse practitioner, physician assistant, pediatrician, and other. Dentists were excluded from both prescriber lists, as associated dental diagnoses are not reliably available in our Medicaid data files. Descriptive statistics were used to summarize the cohort, with frequency and percentages used for categorical data, and median and interquartile range (IQR) utilized for continuous variables. Non-parametric Mann–Whitney U tests were used to compare the distributions (or median percentages) of inappropriate antibiotic prescriptions between prescriber groups. There were 1083 providers identified as high-volume prescribers in the 2019 IQVIA Xponent data, 878 (81.1%) of whom were included on the Medicaid prescriber list. There were 5149 prescribers on the Medicaid list, of which 878 (17.1%) were on the IQVIA list (of high-volume antibiotic prescribers). Overall, high-volume prescribers provided a median of 245 (IQR 107-428) antibiotic prescriptions to children insured by Kentucky Medicaid in 2019, compared to non-high-volume prescribers who provided a median of 46 antibiotic prescriptions (IQR 22-106). A total of 676,476 Medicaid antibiotic prescriptions were included, 133,662 (19.8%) of which were determined to be inappropriate. High-volume prescribers wrote 293,330 (43.4%) of all antibiotic prescriptions included. Among antibiotic prescriptions written by high-volume prescribers, 62,557 (21.3%) were inappropriate, representing 46.8% of all inappropriate prescriptions.p = 0.005) (p < 0.001). There was also a trend toward higher inappropriate antibiotic prescribing for high-volume antibiotic prescribers in the “other” category .Considering all prescribers, across provider groups, high-volume antibiotic prescribers had a higher percentage of inappropriate prescriptions to pediatric Medicaid patients than did non-high-volume prescribers  . There w= 0.005) . The perHigh-volume antibiotic prescribers, who made up 17% of all prescribers evaluated, were responsible for nearly half (47%) of all inappropriate antibiotic prescriptions to children insured by Kentucky Medicaid. Although rates of inappropriate prescribing by high-volume and non-high-volume antibiotic prescribers were similar for most provider types, targeting the top 10% of prescribers by volume for stewardship efforts has the potential to be a high-impact approach to reducing unnecessary outpatient antibiotic prescribing given the high proportion of overall antibiotic prescriptions written by this group. This approach may be particularly useful if complementary data are available to allow an emphasis on high-volume prescribers with a higher likelihood of inappropriate prescribing . In order to reduce unnecessary antibiotic prescribing and the subsequent development of antimicrobial resistance, much work in outpatient antibiotic stewardship has focused on reducing inappropriate antibiotic prescribing ,12,13,14Our study found that high-volume prescribers had significantly higher rates of inappropriate prescribing, particularly among general practitioners. Among children insured by Kentucky Medicaid, general practitioners prescribe approximately 30–40% of all antibiotics, compared to approximately 10% of prescriptions by pediatricians , highligEnterobacteriaceae [Unnecessary and inappropriate antibiotic prescribing can directly impact individuals and can influence levels of resistance noted in the population. For example, a study evaluating the initial diagnosis of a urinary tract infection in children found that children with recent exposure to amoxicillin were more likely to have a urinary pathogen with ampicillin and amoxicillin-clavulanate resistance . Similareriaceae . From theriaceae . Such fiA similar study in adults found that the top 10% of antibiotic prescribers wrote 24.4 million (41%) of the 59.4 million antibiotic prescriptions for Medicare Part D beneficiaries in the US in 2019 [In 2021, the KDPH, along with other states, utilized the top 10% IQVIA provider lists to send informational letters to top antibiotic prescribers. The current study, a collaboration among stewardship researchers and KDPH, suggests volume-based antibiotic use reporting is a practical approach to target state outpatient antibiotic stewardship efforts as it captures a substantial proportion of inappropriate prescribing. Additionally, including general practitioners and nurse practitioners in pediatric stewardship efforts has potential for high-impact reductions in unnecessary antibiotic prescribing. Efforts to reduce excess antibiotic prescribing are necessary and important in addressing the national and global threat of antimicrobial resistance. Further, implementing antibiotic stewardship efforts, such as prescriber feedback, on a broader scale  has greater potential to impact the overall threat of resistance. Medicaid claims and prescription dispensing data are useful for broad-scale outpatient antibiotic stewardship efforts. Targeting high-volume prescribers is a practical approach to provider feedback and also captures inappropriate prescribing.