Spike anchors are one of the most promising techniques to prevent or delay debonding in FRP reinforcement sheets. There are several parameters affecting the anchors’ capacity, such as the embedment length and dowel angle. Regardless of the anchors’ capacity, their contribution to the overall strength of the anchored joint is affected by a larger number of variables, including the bonded length behind the anchors, the number and arrangement of the anchors, and the contact surface between the anchor fan and the FRP sheet. This paper presents experimental results of 10 tests conducted on concrete beams. In the tests, anchored joints reached peak loads up to 155% of those of unanchored, bonded joints. The main finding of the research is that the bond length in front of and behind the anchors affects both the peak load and the overall behaviour, with unbonded anchored joints exhibiting a poor behaviour and premature slippage of the anchor, without achieving its failure due to fibre rupture. Fibre-reinforced polymers (FRPs) are broadly employed as a retrofitting method for existing reinforced concrete structures, due to the considerable advantages of these materials, such as their high strength-to-weight ratio ,2. HowevIn recent years, concern has arisen related to the poor FRP performance in the event of fire or elevated temperatures, as collected in different papers, such as ,17,18. TThe potential performance improvement of FRP sheets with spike anchors has been broadly highlighted in literature. However, lack of knowledge regarding some parameters affecting the performance of anchored joints has hindered their inclusion in international codes and design guidelines. The main results and analytical models for spike anchor’s behaviour have been collected in a recent review by Muciaccia et al. , indicatTests on isolated connectors allow identifying certain parameters that affect the strength of the anchors themselves when installed into predrilled holes, such as the embedded length, dowel angle, and bending radius ,21. AnchThe second approach comprises a range of experimental studies including single-shear, double-shear tests, and beam tests. In all these cases, anchors are subjected to shear stresses as the surface of the substrate is aligned with the tensile force. Shear tests allowed studying parameters, such as the bonded length in front of the anchor and behind the anchor, also referred to as end length ,26, the Numerical modelling has been used to evaluate the contribution of spike anchors to overall strength of anchored joint , but theThere is a severe scarce of beam tests, which makes it difficult to draw conclusions about whether the adherent joint performance may be affected by the actual orientation of the stresses in beams. Sun et al.  conducteZaki et al.  conducteFor narrow sheets with one anchor, the end length has been identified as the most influential parameter affecting the joint performance ,26. HoweIn this study, four series of tests were conducted in order to evaluate the influence of bonded length in front of and behind the anchor on the performance of anchored CFRP reinforcement sheets. Three series comprised a variation of the bonded length behind the anchor fan, while the fourth series was a control series used to compare the results of bonded and unbonded anchored joints. The aim of this research is to complement existing information regarding the influence of bonded length on the overall performance of anchored CFRP joints, while conducting a test that is able to reproduce the actual stressed in reinforced beams by means of including a flexural strengthening. The main significance of the study is the employment of beam tests instead of shear tests, with the aim at evaluating the influence of the deflection of the beam in the anchor’s performance. This motivated the monitorization not only of the sheet, but also of the anchor’s dowel, which is a main novelty with respect to the literature and will allow for better assessment of numerical modelling of complex situations of anchored joints. Additionally, Sun et al.  results This section comprises an explanation of the methodology employed in the research, together with the studied materials and parameters. The following flow chart summarises the methodology of the work.Three-point flexural tests were conducted to determine the interfacial strength of anchored CFRP sheets for concrete retrofitting. As mentioned above, the specimens were designed to study the influence of the bonded length behind the anchor fan on the joint strength, and the general influence of the adherent strength on the anchored joints. The test matrix is collected in The specimens were 150 × 150 × 700 mm, as shown in Five different series were evaluated, as collected in Concrete from a supply company, with mean compressive strength of 31 MPa  was used for all specimens. The classification of the concrete according to Spanish regulation EHE-08 was HA-25/B/IIa, this being equivalent to Eurocode S2 slump class for a XC2 environmental exposure. The following codes were employed for classification: UNE-EN, UNE-EN, resulting in the aforementioned mean compressive strength plus, and slump result of 7 cm. The slump result was obtained with the addition of plasticizer according to UNE-EN 934-2. The employed cement type was CEMI 42.5 R, according to EN 197-1. The aggregates were selected according to UNE-EN, with a maximum aggregate size of 20 mm and aggregate size distribution and characteristics were set according to UNE-EN 933. Water absorption by the aggregates according to UNE-EN 1097-6 was lower than 5% for fine aggregate and 6% for coarse aggregate. Sulphate and chloride content in the aggregates were controlled according to UNE-EN 1744.The Internal reinforcement consisted of B500S steel longitudinal rebars and double vertical stirrups; the longitudinal rebars were not connected in the midspan, nor was the anchorage length provided, to isolate the joint behaviour at each half of the beams. Quality of stirrups was controlled by means of UNE-EN ISO-1. The diameter for bending end hooks of reinforcement was four times the diameter of bent rebar/stirrup. The aim of the internal reinforcement arrangement was to prevent shear failure, while the concrete remains virtually unreinforced against bending moment so as to isolate the performance of the reinforcement. The arrangement of the internal reinforcement can be seen in A 20 × 20 mm notch was performed at the bottom of the midspan section of the concrete to control the cracking pattern and to assist the isolated behaviour of the two reinforced halves.2, and their longitudinal tensile strength is 2100 MPa.Sika Wrap-230C unidirectional carbon fibre fabrics with a nominal width of 300 mm were used as reinforcement. According to the manufacturer, the fibres have an elasticity modulus of 240 GPa, a tensile strength of 4800 MPa and a rupture strain of 2%. The product datasheet specifies a plate thickness with one ply of 0.129 mm, with an elasticity modulus of 220 GPa (average 225 GPa) and a tensile strength of 3200 MPa (average 3500 MPa). On the other hand, tests performed by De Diego et al., revealed that the average elastic module of one ply of the composite is 237 GPa, the average tensile strength is 4161 MPa ,40. In t®-52 Injection  was used, while Sikadur®-300  was used for the lamination of the reinforcement, FRP-to-concrete bond, and anchor fan-to-reinforcement bond. According to the manufacturer, Sikadur®-52 Injection has a tensile strength of 37 N/mm2, and an elasticity modulus of 1800 N/mm2; Sikadur®-300 has a tensile strength of 30 N/mm2 and an elasticity modulus of 4500 N/mm2.Two different bicomponent epoxy resins were employed: for the impregnation of the anchors and dowel length, SikadurConcrete was cast in wood open boxes with phenolic treatment, being the bottom face the one to which the FRP reinforcement was applied so that the free surface of the box is the upper face under compression during the test. The formwork fulfilled all requirements in terms of leak prevention, strength for bearing fresh concrete, and for compaction, geometry preservation, and cleanness of the inner panels. The use of first-use phenolic panels allowed demoulding without the need to use chemical products. The concrete curing process was controlled by keeping the upper surface wet in all specimens.Once the concrete reached 28 days, a precured FRP installation technique was used for all specimens in this research, following the procedure described in . The conFor all the anchored joints, the anchors were installed in predrilled holes which were cleaned according to the available guidelines for adhesive anchors, such as EAD-00-0601 . No edgeThe three-point bending test was chosen in this research because its results are easily applied to real beams, and to allow comparison with other experimental studies, such as . For the® KFH-10-120-C1-11L1M2R strain gauges were employed in the research, due to their grid size (10 mm). The extensometer box was calibrated for the strain gauge factor (2), for the nominal resistance (120 Ω), and for the configuration at quarter Wheatstone bridge. No relevant temperature variations appeared during the tests, which were conducted in a controlled room of a laboratory, and, consequently, no compensation was required for temperature adjustment of monitorization with the strain gauges.The FRP reinforcements and anchors were monitored by means of attaching strain gauges to the external layer of the reinforcements and to the anchor dowels. The location of the gauges can be seen in It should be noted that the monitorization of internal stresses serves for better identification of the contribution of the anchor to the overall performance at all times, by means of producing an independent load-strain curve for the reinforcement and the anchor dowel. It is noteworthy that monitorization of internal stresses in the anchor aimed at better identifying the contribution of the anchor to overall performance prior to debonding and as debonding progressed. Strain gauges were attached to the dowel region of the anchor prior to its insertion in the drilling, after the complete hardening of the matrix of the anchor dowel. The alignment of the strain gauges was controlled to guarantee that it corresponded to the longitudinal direction of the anchor.The load was applied through a hydraulic jacket, attached to a manometer that allows consulting intermediated loads. Intermediate values for load–displacement control were obtained every 1.25 kN, for assessment of proper measurement of the strain gauges as internal monitorization. The load was introduced in sustained steps of 5 kN, with continuous monitorization of the midspan deflection, and of the strains in the reinforcement and anchors. Load speed allowed intermediate measurement of deflections and load every 1.25 kN. The steps of 5 kN were employed to stop introducing load until the strain gauges were stabilized per each load step. The test set up is collected in The ultimate strength for control series (unanchored joints) was estimated by calculating the bond strength according to the model for inter-crack debonding proposed by fib90 bulletin . This moThe value corresponding to FRP rupture was fixed as a theoretical maximum for comparison of material exploitation with the FRP anchors. Additionally, the load corresponding to debonding failure was calculated for comparison with the results of the control series. −2. From this value it can be concluded that, if the rupture strain of the FRP is attained, the maximum strain in the concrete is 3.9 × 10−3, which is close but higher than the compressive strain of the fib90; in this case, in which concrete crushing is likely to occur and if we limit the strain in the concrete the normative value (3.5 × 10−3), the ultimate load would be 90.4 kN. The sectional equilibrium in this case would result in an ultimate load for debonding failure of 47.8 kN. The rupture strain of the FRP reinforcement according to the average values in ,35 for iA total of 10 beam tests were conducted to evaluate the impact of the bonded length behind the spike anchors, and to isolate the behaviour in the anchor fan-to-sheet interfaces when the reinforcement is unbonded. The results of three different positions of the anchor (B series) and of unbonded anchored reinforcements (U) were compared to a control series of bonded, unanchored reinforcements (C). The results are collected in The response of each specimen in terms of load-stress response is collected in The first observation is that concrete crushing (expected at a load of 90.4 kN) was not achieved in any specimen. This indicated that height of the beams were appropriated for the evaluated anchor and sheet arrangement, as high exploitation of concrete was obtained, but without compromising the hierarchy of failure modes. It should be noted that the desirable failure mode hierarchy in FRP-reinforced beams is as follows: i) debonding at the highest possible stress in the FRP sheet followed by ii) ductile behaviour with post-peak performance, promoted by the presence of anchors with anchor rupture (full exploitation of anchor), thus provoking iii) failure of the pre-cracked beam by loss of the tensile force of the sheet.As collected in All specimens with no anchor exhibited debonding failure, which occurred at several millimetres from the outer surface of concrete and provoked the shear rupture of the adhesive resin along the indentations.In most bonded specimens with anchors, the failure mode was debonding followed by anchor rupture, which occurred in the bending zone or in the beginning of the anchor fan. In The last failure mode, anchor slippage, occurred in unbonded specimens and implied that the test could not be completed up to the rupture of the anchor fibres. The test was stopped when the attained load decreased due to the slippage of the anchor in the drill. It is possible to observe from The control series exhibited complete debonding of the reinforcement followed by concrete rupture. This is consistent with results from literature and constitutes the expected failure mode for unanchored reinforcements, in which tensile strength of the fibres cannot be attained due to premature debonding from the substrate. The preparation of the substrate prevented to a noticeable extent the cohesive failure within the first millimetres of the substrate, which was largely replaced by tangential failure of the adhesive. Notwithstanding, the debonding value did not significantly differ from the calculated one , thus, it can be concluded that the preparation of the substrate allowed a proper development of the adherent strength according to the existing predictive models. The load-slip response of the control series is presented in It can be observed from the graphs presented in The bonded, anchored joints (B series) exhibited a common failure for anchor rupture due to stress concentration in the bending region. In these series, it is possible to observe differences in behaviour depending on the relative position of the anchor within the bonded length.In the literature, shorter bonded lengths behind the anchor have been related to lower utilization of the anchor’s properties. In Zhang et al. , it was It can be observed from The series was designed to reproduce the behaviour when bond loss has occurred, to isolate the anchor’s performance, and to calculate whether there is any by-effect of the adherence at initial loads steps. The objective was to evaluate to what extend the adherent mechanism is synergic with the anchorage systems in anchored, bonded FRP reinforcements.Series evaluated without adherent mechanism (U series) exhibited a particular failure mode which consisted of anchor slippage at low loads. The tests were interrupted when slippage occurred, which hindered the full exploitation of the anchors, as the load could not be sustained in time. In this sense, no anchor rupture was observed in this series. With this premature failure mode, the maximum loads were considerably lower than those of the B-series. The results are in good agreement with the impact on the anchorage system of partial loss of bond previously observed by Sun , and witIn It can be observed from All graphs from internal monitoring show the values per 5 kN step of load. This allows removing the strain gauges noise prior to stabilization at each sustained step. There was an almost linear behaviour among load steps, with changes in slope being clearly identifiable. This linearity was registered at every second in the strain gauges. In Following Cortez et al.’s approach , the behanc was the calculated value for the connector’s failure, PC-series is the average evaluated force of the control series, PU-series is the average evaluated force of the U series, 31.4 kN, and Pdb is the calculated value for the debonding force in the reinforcement. In the table, values greater than 1 for (P − Pdb)/Panc indicate the existence of a synergistic effect between the adherent mechanism and the connector’s behaviour.For the B series, there are slight differences in the positive impact of the bonded length behind the anchor. This may be caused by the bonded lengths that were installed in front of the anchors, the model having been calibrated against tests in which the bonded length in front of the anchor is lower than the effective bond length when there exists bonded length behind the anchors. According to the results of the unbonded series, and of the control series, it is possible to estimate the exploitation of the anchors when a sufficient bonded length is provided behind the anchor and/or in front of it. The results are collected in According to Test results have also been compared with previous beam tests by Sun et al. , in whicFrom FRP anchors enhance joint behaviour, with anchored FRP reinforcement sheets bonded to concrete beams, reaching peak loads up to 155% of the ones of the control series.The overall performance of the FRP anchored sheets seems to depend on the bonded length in front of the anchor and behind it. The best result was obtained with the anchor located closest to the midspan.The failure mode of the beams depends on whether there exists a bonded length. The beams with no bonded length exhibited slippage of the anchor, while all beams with bonded length presented fibre rupture in the bending area.There exists a synergistic effect of the contribution of the adherent mechanism and of the anchors to the overall strength of the flexural reinforced beams. The overall strength in bonded, anchored plates can be expressed as the addition of the bond strength plus the connector’s contribution, which is a fraction of the connector’s capacity.The installation of spike anchors in conjunction with the adherent mechanism allows fuller use of the sheets in concrete beams.The adherent performance of the FRP-to-FRP did not limit the anchor’s contribution to bond strength.Based on the experimental results, the following conclusions can be drawn:The eventual influence of the internal stirrups, which could not be fully addressed in the paper, may the object of future works, such as FEM modelling of the beams, to further study the possible effects of the confined concrete. Additionally, it should be noted that the tests are subjected to scatter due to the heterogeneity of the concrete material in specimens of the given size, with a greater influence of the aggregate diameter than that found in construction beams. Another limitation of the study is caused by the selection of the beam size. In this sense, additional research is required for concrete beams with greater height, in which equilibrium with FRP sheet is achieved with smaller compressive zone regions in the concrete.


Few studies have reported the cohesion and friction angle of concrete at a super early age. However, these two mechanical parameters are necessary to study the influence of engineering vibration on super-early-age concrete. In view of this, the mechanical properties of the super-early age-concrete are investigated in this work by direct shear testing. Firstly, the shear strength of the super-early-age concrete is measured by the direct shear experiment under different normal pressures at different times. Secondly, the cohesion and friction angle of the super early age concrete are calculated according to the Mohr–Coulomb criterion of failure. To overcome the great discreteness and randomness in the measured data, a new robust regression analysis algorithm is presented to replace the traditional regression analysis method to obtain more reliable and reasonable mechanical parameters. According to the experimental and theoretical analysis results, it is found that the friction angles of the super early age concrete are located in the interval of . The cohesion of the concrete is about 78.7 kPa at the initial setting state and about 190.9 kPa at the final setting state, respectively. It has been shown that the cohesion of the concrete at a super-early age tends to increase rapidly with time. The method and test results of this work can be used as a reference for relevant engineering practice. Specifically, the proposed regression method can be extended to the data analysis of other mechanical parameters of concrete, as well as other brittle materials such as rock. The test results of early concrete cohesion and friction angle can be used to analyze the adverse effects of vibration on newly cast concrete members in pile driving and blasting engineering. In the construction projects of civil engineering, great attention is paid to the physical and mechanical properties of the concrete at an early age ,2,3. TheTo determine early-age strength, Swaddiwudhipong et al.  carried For the early-age shrinkage and creep, Altoubat and Lange  found thHowever, few studies have reported the cohesion and friction angle of super-early-age concrete. In pile driving and blasting engineering, these two mechanical parameters are necessary parameters to study the influence of vibration on super-early-age concrete. Herein, the term super early age refers to the period between initial setting and final setting of the concrete. The cohesion and friction angle are important parameters to determine whether cracks occur in the super-early-age concrete under external vibration load such as blast, vehicle vibration, and so on. The research significance of this work mainly lies in two aspects. The first is to investigate the mechanical properties of the super-early-age concrete by direct shear testing. The obtained cohesion and friction angles of the early-age concrete can be used to evaluate the damage effect of vibration on fresh concrete members. The second is to propose a new regression algorithm to compute the cohesion and friction angle of the super-early-age concrete. This new regression approach can also be employed to analyze the other mechanical characteristics of the brittle materials. From the test and theoretical results, it is shown that the friction angle of the super-early-age concrete has little relationship with concrete age, but the cohesion is closely related to the age of concrete. Generally, the cohesion of concrete increases with the increase in concrete age. The framework of the study is presented as the following. As stated before, there are few reports on the experiments of cohesion and friction angle of the concrete at a super-early age. However, these two parameters may be used to analyze the influence of vibration on the concrete at a super-early age. To this end, direct shear experiments are carried out in this work to obtain the cohesion and friction angle of the concrete at super-early age. This experiment is implemented by the method similar to the soil direct shear test. As seen in At 8:50 a.m., the above materials were poured into the concrete mixer shown in b to begiThe setting state of the concrete can be determined according to According to the Mohr–Coulomb criterion of failure, the relationship between shear strength For each time point, the regression coefficients T” indicates the transposition process of a matrix. For the other time points, the regression coefficients Note that the values in Equations (4) and (5) are from From The From Equation (9), a diagonal matrix whose nonzero elements are weight coefficients can be defined as:Using Equation (12), the new solution of the regression coefficients From the above results, it was found that the friction angle of the concrete has little relationship with concrete age, but the cohesion is closely related to the age of concrete. Generally, the cohesion of concrete increases with the increase in age. From In this work, direct shear experiments are carried out to obtain the cohesion and friction angle of the concrete at a super-early age. A new robust regression analysis method is proposed to replace the traditional regression analysis method in order to analysis the measured data with great discreteness and randomness. From the test and numerical analysis, the following main conclusions can be obtained. (1) The existing regression algorithm using the least-square estimation is not suitable for computing some mechanical parameters of concrete, since the measured data are very discrete and random. (2) The proposed new regression algorithm can successfully overcome data discreteness and randomness, obtaining more reasonable and accurate calculation results. (3) It is found that the friction angles of the super-early age concrete are located in the interval of . (4) The cohesion of the concrete is about 78.7 kPa at the initial setting state and about 190.9 kPa at the final setting state, respectively. It is obvious that the cohesion of the concrete at a super-early age tends to increase rapidly with time. The theoretical and experimental results of this work can be used as references in related engineering practice. Specifically, the new regression method proposed in this paper can be extended to the data analysis of other mechanical parameters of concrete and can also be used in the data analysis of mechanical parameters of other brittle materials such as rock. The experimental results on the early cohesion and friction angles of concrete can be used to analyze the adverse effects of vibration on fresh concrete members in pile driving and blasting projects. It should be highlighted that this research is carried out only for one concrete mix. As the results are of practical importance, these tests can be continued in the future for different types of concrete and for different time parameters.


How to start optimal antibiotic therapy before the results of cultures and antimicrobial susceptibility tests are available? Here, we use the law of total probability to present a probabilistic approach based on antibiograms of bacterial isolates from healthcare and community-acquired infections to optimizing empiric antibiotic therapy.Data on the microbiology of healthcare and community-acquired infections were analyzed from hospitals in Belo Horizonte, a three million inhabitants city from Brazil. Healthcare infections were defined by the National Healthcare Safety Network (NHSN)/CDC protocols. Only data obtained from infections with positive culture, both hospital and community, were considered. The success rate of an antibiotic (ATB) regimen, considering just one drug individually (monotherapy), was calculated by Law of Total Probability . In this sense, if a microorganism has not been tested for a specific antimicrobial, then, by definition, it was considered an antibiotic failure. For a regimen with more than one antibiotic, if the microorganism is sensitive to one of them, then it was considered a success of the scheme. For calculating the success probability of two or three antimicrobials A, B, and C, simultaneously , i.e., P(A and B) or P(A and B and C), the sensitivity to an antimicrobial was considered independent of sensitivity to any other. Then, P(A and B) = P(A) * P(B), and P(A and B and C) = P(A)*P(B) *P(C).Microbiologic data from hospital acquired infections (HAI) and community-acquired infections (CAI) are analyzed once a year. Empiric antibiotic therapy to HAI were proposed for urinary tract infections (UTI), bloodstream infections (BSI), and pneumonia . Empiric antibiotic therapy to community-acquired infections were developed for UTI, pneumonia, gastrointestinal system infection, bone and joint infection, and skin and soft tissue infection.We presented here a probabilistic approach to empiric antibiotic therapy. The next step is to validate all proposed regimens, that can be used to improve the success likelihood of empiric antibiotic decision making.All Authors: No reported disclosures.


Antibiotic resistance is an increasing problem worldwide. Dispensing antibiotics without prescription is a major contributing factor to antibiotic resistance. Pharmacists as healthcare providers are, in many studies, considered responsible for this practice. This study aims to explore Palestinian pharmacists' knowledge, attitudes, and practices concerning antibiotic resistance. A descriptive cross-sectional survey was conducted in 2021–2022. A random sample of 152 pharmacists was selected from the West Bank. Data were collected using a self-administered questionnaire that includes five sections: demographic characteristics, knowledge, attitudes, practices, and potential interventions. Results indicated that 60% of pharmacists dispense antibiotics without a prescription. A significant association between pharmacies' locality and antibiotic knowledge, attitudes, and practices was found. Pharmacists' knowledge-related responses indicated that 92.1% of the pharmacists agreed that inappropriate use of antibiotics can lead to ineffective treatment and 86.2% disagreed that patients can stop taking antibiotics upon symptoms' improvement. Only 17.1% disagreed that antibiotics should always be used to treat upper respiratory tract infections. Over two-thirds considered that they are aware of the regulations about antibiotic dispensing and acknowledged that antibiotics are classified as prescription drugs. Furthermore, 71.7% and 53.3% agreed that they have good knowledge of the pharmacological aspects of antibiotics and antibiotic resistance. Concerning attitudes, 75.6% agreed that antibiotic resistance is an important and serious public health issue facing the world, and 52% thought that antibiotic dispensing without a prescription is a common practice in the West Bank. Our findings indicate that pharmacists' locality and practices related to antibiotic dispensing without prescription are associated with the increase in antibiotics misuse and bacterial resistance. There is a need to design education and training programs and implement legislation in Palestine to decrease antibiotic resistance. Antibiotic resistance is becoming a global public health issue due to the increased morbidity, mortality, and healthcare costs attributed to resistant bacteria –4. AntibIrrational antibiotic use including overuse, suboptimal use in terms of dose and duration, and use with the wrong indication exacerbates the phenomenon , 6, 7. ADespite the legislations the Palestinian Ministry of Health issued regarding dispensing antibiotics without prescription, antibiotic overuse increased due to the lack of sufficient application of the regulations and the availability of antibiotics in the private market without prescription . ConsequA descriptive cross-sectional survey was conducted among Palestinian pharmacists between October 2021 and February 2022 to assess their knowledge, attitudes, and practices towards antibiotic resistance. Participants with a minimum of two-year work experience in pharmacy were selected. All participants only had either at least a bachelor's degree in pharmacy or Pharm D. A random sampling approach was used through a three-step sampling method to ensure generalizability and minimize selection bias. First, the total number of registered community pharmacies in the West Bank (1084 pharmacies) was determined . Next, aA validated self-administered questionnaire was developed based on a thorough literature search through web-based databases and related studies –26. The The final data collection instrument included questions to assess the sociodemographic characteristics of respondents, 19 questions to assess knowledge, 6 questions to assess attitudes, 10 questions to assess practices, and 3 questions regarding the potential interventions of the respondents towards antibiotic resistance.The sociodemographic characteristics include gender, geographical location, education, type of employment, working hours, the total number of employed pharmacists, the number of working pharmacists at once in the pharmacy, and years of experience.The knowledge assessment scale of 19 items using a Likert scale of 5 to 1  was used to assess the pharmacists' knowledge about antibiotics and antibiotic use, antibiotic resistance, legal aspects of antibiotic dispensing, and self-perception of their knowledge level.Attitudes were assessed by an 8 items' scale using a Likert scale of 5 to 1 . In addition, the section included a multiselection subsection on contributing factors to antibiotic resistance.The practices were assessed by a 6 items' scale using a Likert scale of 5 to 1 . Practices section also included three questions on the total number of dispensed antibiotics per day, the number of dispensed antibiotics per day with prescription, and the number of demanded antibiotics without prescription per day. Furthermore, the section included a multiselection subsection for sources of information used as guidelines/references for antibiotic dispensing.The negative statements were reverse scored during the analysis, and the responses to the knowledge, attitudes, and practices Likert scale questions were summed, so that higher scores reflect a positive direction towards antibiotic resistance, respectively.A Cronbach's alpha test was conducted to assess the internal reliability of the questionnaire: the alpha scores were 0.75 and 0.745 for knowledge and attitudes indicated moderate reliability for these sections, and an alpha score of 0.859 for practices indicated high reliability for the practices' questionnaire, respectively.Furthermore, three questions related to potential interventions, and the role of involvement in educational seminars about antibiotic resistance was included in the data collection instrument.The data were collected under the supervision of the Ministry of Health and Al-Quds University. Six trained field researchers who had received training in conducting field research visited the selected community pharmacies. They were provided with a data collection guideline. Before completing the study questionnaire, the study objectives were explained to participants and consent to participate in the study was obtained. Overall, 167 participants agreed to participate in the study, and 152 completed the questionnaire.p value of less than 0.05 was considered statistically significant.Data were coded, entered, cleaned, and analyzed using SPSS version 21.0 software . Descriptive statistics (frequencies and percentages) were used to summarize the data. The chi-square, univariate, and linear regression analysis were used, where indicated, to assess the relation between demographic characteristics and knowledge, attitudes, and practices towards antibiotic resistance. A Out of 167 questionnaires distributed, 152 participants (91.01%) completed the survey. The study participants consisted of 52% females and 48% males, and 50.7% aged <30 years. Around 51.3% of the participants resided in rural areas. A 40.8% of them had at least 10 years of experience, and 75.3%, 14.4%, and 10.3% had a bachelor's, postgraduate, and Pharm D degrees, respectively. Furthermore, around 64.5% were employees in their pharmacies, while the rest were managers. In addition, 71.1% of the pharmacists reported working part-time, and only 28.3% had a full-time workload. Around two-thirds of the pharmacies had up to 3 employed pharmacists and one pharmacist working at once . The demographic and professional characteristics of the participants are shown in The knowledge of Palestinian pharmacists regarding antibiotic use and antibiotic resistance were assessed using the knowledge scale. Most of the pharmacists agreed that inappropriate use of antibiotics could lead to ineffective treatment (92.1%). When asked about general antibiotic use, around 72% of the pharmacists disagreed that antibiotics could be used to alleviate pain. Furthermore, 86.2% disagreed that patients could stop taking antibiotics when their symptoms improved, and 66.5% acknowledged that keeping leftover antibiotics for use in another time was not a good practice. Interestingly, only 17.1% disagreed that antibiotics should always be used to treat an upper respiratory tract infection. Concerning antibiotics' side effects, two-thirds of the participants knew that antibiotics could kill normal flora in the body, thereby causing secondary infections, and around 83% agreed that antibiotics could cause allergic reactions. Regarding certain common medications, surprisingly, around 9% disagreed that amoxicillin is an antibiotic. In addition, around 6% agreed that Panadol and aspirin are antibiotics, and 6.6% were uncertain.Klebsiella pneumoniae is mainly enzymatic, while around 42% were uncertain of the mechanism of resistance in vancomycin-resistant Enterococcus faecalis. However, over two-thirds agreed that the wrong choice of antibiotics may lead a pathogen to lose its sensitivity towards a specific antibiotic, and that skipped antibiotic doses contributed to the development of antibiotic resistance. Additionally, around 40% thought that resistant bacterial strains could be spread in healthcare facilities.Concerning knowledge of antibiotic resistance, around 42% of the participants thought that prescribing broad-spectrum antibiotics is always better, despite the possibility of available narrow-spectrum antibiotics. When asked about the mechanism of resistance of certain types of bacteria, around 70% knew that the mechanism of resistance to beta-lactams in When asked about their knowledge of antibiotic dispensing without prescription, over two-thirds considered that they were familiar with the rules concerning the dispensing of antibiotics (with or without a prescription) in the West Bank and acknowledged that antibiotics are classified as prescription drugs. Furthermore, when asked about their perception of their own knowledge regarding antibiotic uses and resistance, 71.7% and 53.3% agreed that they have good knowledge of the pharmacological aspects of antibiotics and of antibiotic resistance, respectively. The attitudes section is comprised of questions within four conceptual categories: antibiotic dispensing, pharmacist/patient interaction related to antibiotic resistance, required education concerning antibiotic dispensing and resistance, and major contributing factors to antibiotic resistance. Result in The pharmacists were asked about the importance of education programs related to antibiotic use and resistance. Around 70.2% concurred that they are in need of attending educational programs to enhance their understanding of antimicrobial stewardship. In addition, around 52.6% indicated that the development of local guidelines would be more useful than the international guidelines.The results in Around 68% of participants referred to WHO guidelines, and 50.7% of participants reported the use of international guidelines as sources for antibiotic dispensing practices. Only 14.5% of participants used the national guidelines of the Palestinian General Directorate of Pharmacy's guidelines as a reference. Over half of the participants reported the use of the Internet (55.9%) and medical journals (25%), while others obtained information from senior, experienced colleagues and physicians (42.8% and 28.3%), respectively.When the participants were asked about their attendance at workshops on antimicrobials, only 17.8% reported having some training on the use of antibiotics. Moreover, 89.5% expressed their desire to acquire further education and training on antimicrobial use, resistance, and stewardship. Most of the pharmacists reported they would like to attend workshops and training programs (67.1%). Whereas fewer participants expressed their desire to participate as consultants (15.1%), developers of courses (12.5%), mentors to other pharmacists (9.9%) and leader of workshops and stewardship programs (4.6%).p = 0.014; p = 0.001; p = 0.001), where females , those living in urban areas  are more likely to have a higher knowledge score, and workers in pharmacies with a higher number of employees are more likely to have a lower knowledge score . The results showed no statistically significant effect of the number of working pharmacists at once (p = 0.736), education (p = 0.807), employment type (p = 0.540), age (p = 0.792), or years of experience (p = 0.988) on the knowledge score, however, pharmacists who are employees rather than managers and older pharmacists are 1.05 (95% CI = 05.03) and 1.03 (95% CI = 0–6) times likely to have slightly higher knowledge score, respectively.The overall pharmacists' knowledge, attitudes, and practices were estimated by summing the scales items scores. The overall mean knowledge score was 69.2 , and the mean attitudes score was 27.3 , whereas the mean practices score was 39.3 . Linear regression analysis was performed to assess for associations between the knowledge, attitudes, and practices' scores and demographic variables. p = 0.005), locality , gender (p = 0.296), total number of employed pharmacists (p = 0.321), number of employed pharmacists working at once (p = 0.312), employment type (p = 0.926), age and years of experience , respectively. However, pharmacists with a higher educational level and older pharmacists are 1.15 (95% CI = 0–1.87) and 1.17 (95% CI = 0–1.77) times more likely to have a higher attitude score, respectively. Female pharmacists, pharmacists who work in pharmacies with a larger staff, and those living in urban areas are 1.10 (95% CI = 0–2.3), 1.03 (95% CI = 0–1.72), and 1.08 (95% CI = 0–1.98) more likely to have better attitudes, respectively.As for attitudes score, the results showed no significant association with education level . The pharmacists working in pharmacies with a higher number of employees reported lower practices score , however those living in urban areas are more likely to have higher practices score . However, there were no significant differences in the practices score by gender (p = 0.191), number of employed pharmacists working at once (p = 0.498), employment type (p = 0.919), age (p = 0.121), and years of experience (p = 0.337). The odds of having a higher practices score are observed in females , more educated pharmacists , and more experienced pharmacists .Finally, the results of the practices score association with the demographic variables demonstrated that there was a significant association with the number of employed pharmacists and locality  countries where pharmacists are primarily the first line of contact for patients . This unThe study findings show that even though most of the pharmacists believe that antibiotic resistance is a worldwide public health issue, and over two-thirds are aware of the Palestinian regulations of proper antibiotic dispensing, around 60% of Palestinian pharmacists may dispense antibiotics without prescription with varying frequency , which is similar to the global estimate of antibiotic dispensing without prescription  and consThe key findings of this study demonstrate that pharmacists have an acceptable level of knowledge of antibiotic resistance in terms of general antibiotic uses, mechanisms of antibiotic resistance, and legality of antibiotic dispensing. Most of the study participants agreed that inappropriate use of antibiotics could lead to ineffective treatment, and over two-thirds acknowledged that it's an improper practice for patients to keep leftover antibiotics. However, an alarming key finding is that over 40% of the study participants agreed that upper respiratory tract infections (URTI) should always be treated with antibiotics, which is known in the literature to be mostly caused by viral infection . A recenOn the other hand, the study participants showed a higher level of perceived knowledge of antibiotics and the issue of bacterial resistance, and around one-third of the pharmacists reported that pharmacists' level of knowledge is one of the reasons for selling antibiotics without a prescription. This finding is consistent with a recent study in 30 EU/EEA countries, which has found that most pharmacists agree that they know what antibiotic resistance is . HoweverOur study results found a significant difference in the overall level of knowledge according to age and locality, where female and urbanite pharmacists having better knowledge of the matter. A recent scoping review in Southeast Asia has found that in comparison to males, females generally were found to have better knowledge of antibiotics and antibiotic resistance . In addiAn important observation of this study is the pharmacists' reported reasons for dispensing without a prescription. Over two-thirds of the pharmacists considered the patients' demand and improper use of nonprescription antibiotics of to be a major contributing factor to the issue. Indeed, this finding is consistent with a study in Egypt, which has found that around 55% of the participants believed that patients' personal choice of antibiotic use is one of the main causes of antibiotic resistance . AnotherNevertheless, over half of this study pharmacist also reported education of patients on antibiotic uses and indications. Furthermore, they also reported encouraging their patients to get medical consultations and prescriptions. These findings demonstrate the positive attitudes the Palestinian pharmacists have towards antimicrobial resistance. In this study, we have also observed significant differences in both attitudes and practices scores by the educational level and locality. Higher education was more likely associated with better attitudes and practices. A similar finding was observed in a study in Pakistan, in which practices significantly differed between pharmacists with bachelors' and masters' degrees, however, there was no significant difference in perceptions towards antimicrobial stewardship (AMS) . AnotherAnother key finding of this study is pharmacists' use of the international guidelines for antibiotic dispensing. Less than 20% use the Palestinian General Directorate of Pharmacy's guidelines as a reference for proper dispensing practice. This observation emphasizes the need for diligent regulation and application of regulations that apply in the Palestinian community. Additionally, the majority expressed the willingness to participate in educational programs about antibiotic resistance, mostly as participants, and to a greatly lesser extent, as mentors, developers, and consultants. This finding further emphasizes the pharmacists' perception of their contribution to the problem and their approval of the importance of laws and proper enforcement of legislations. This role is indeed recognized by pharmacists themselves in several studies , 42.Despite these findings, there is a need to emphasize that the issue of antibiotic resistance is not solely the responsibility of pharmacists. Many sectors of the community contribute to the issue, including physicians, veterinarians, dentists, and the public, respectively –47. ThisThe study has been limited by social desirability bias, which we aimed to control through anonymity. Anonymity is considered to lower social anxiety and social desirability bias . MoreoveThis study aimed to investigate the knowledge, attitudes, and practices of Palestinian pharmacists towards antibiotic resistance. Despite acceptable knowledge of antibiotic resistance and positive attitudes towards the issue, dispensing antibiotic without a prescription is high. Insufficient commitment to local regulations and guidelines were found. The study results showed significant differences in knowledge level by gender and locality and in attitudes and practices by education and locality. An intervention program directed mainly towards practices among pharmacists is imperative in improving antibiotic use and to minimizing the resistance. There is a need for an in-depth analysis of pharmacists' role in antibiotic resistance.


The use of bacteria in the concrete was to increase the pH of the concrete by producing urease enzyme. This technique may help to maintain concrete alkalinity in high levels, even when the carbonation process occurs, because the CO2 accelerates to the concrete and then converts directly to calcium carbonate, CaCO3. Consequently, the self-healing of the cracks and the pores occurred as a result of the carbonation process and bacteria enzyme reaction. As a result of these reactions, the concrete steel is protected, and the concrete properties and durability may improve. However, there are several factors that control carbonation which have been grouped into internal and external factors. Many studies on carbonation have been carried out to explore the effect of bacteria to improve durability and concrete strength. However, an in-depth literature review revealed that the use of bacteria as a self-healing mechanism can still be improved upon. This review aimed to highlight and discuss the possibility of applying bacteria in concrete to improve reinforcement concrete.This study carried out a comprehensive review to determine the carbonation process that causes the most deterioration and destruction of concrete. The carbonation mechanism involved using carbon dioxide (CO CO2 is converted to dilute carbonic acid in the presence of moisture, which destroys concrete and lowers its alkalinity [2) in the atmosphere has been steadily increasing from 280 parts per million (ppm) in preindustrial times to 381 ppm today, and some models predict that it will double within the next century. This increase in CO2 concentration has been caused by human activity [2 existing in the atmosphere in varying concentrations enters the concrete, carbonates the CO2, and decreases the alkalinity of the concrete. The pH of the pore water in the cured cement paste will be decreased from roughly 13 to around 9.0 [2 has been carbonated, the pH will drop to around 8.3. At such a low pH, the protective layer is removed, exposing the steel to corrosion [The carbonation of concrete occurs when carbon dioxide from the air passes through the pores of the concrete and combines with calcium hydroxide to produce calcium carbonates . The actkalinity . The conactivity . The incactivity . The higound 9.0 . When al2 concentration, air pressure, relative humidity, and temperature. Internal factors, on the other hand, depend on physical characteristics such as the material size, surface area, and porosity of the concrete, or chemical properties such as the solid composition, calcium (Ca) contact, the Ca/Si ratio, the pH of the solid, and the availability of Pb, Cd, and Ni. The presence of CO2 in the environment surrounding the concrete is a significant factor that accelerates the carbonation process. To address these obstacles, self-healing approaches have been developed for improved outcomes. It is possible to improve the durability, compressive strength, and permeability of concrete. The ability to mend and seal concrete cracks was noted, and observations were made on the concrete’s permeability and its ability to mend cracks under pH-maintaining circumstances.According to the previous study that was done by , the fac3 precipitation through bio-mineralization [2 sequestration in the form of CaCO3 [2 and ammonia [Bio-concrete is a self-healing technique that fills the cracks and pores in concrete with bacteria by inducing CaCOlization . The accof CaCO3 . The minof CaCO3 . In this ammonia .3 precipitation: autotrophic and heterotrophic, both of which exhibit calcification and biomineralization [3 in concrete, only certain strains of alkaliphilic-based bacteria can be used [Microorganism-induced healing of concrete can be done by three various methods: by adding bacteria directly to the mix, by encasing bacteria in the mix to hold them inanimate until they are needed, or by spraying or injecting bacteria on the surface of the cracks . In eachlization . When it be used ,18. This2 in this process [This paper aimed to conduct a review on the role of bacteria and the self-heling process of carbonation on reinforcement concrete. At the same time, it reviews the mechanisms of the carbonation process, the factors affecting carbonation, and the effects of carbonation on concrete. In addition, the carbonation of concrete has a strong relation with the environment due to the role CO process .2” OR “carbon dioxide”), respectively. The number of author keywords that appeared three times, the total link strength, and clusters were 50, 288, and 8, respectively. The author’s keywords that occurred more than 5 times were 22, as shown in Bibliometric analysis was used as scientific metrics to give a strong indicator and highlight the research gap in this review. Bibliometric maps were analyzed for 282 articles from the Scopus database using 5 different categories of limitations, as follows: keywords, last 5 years, type of documents , English language. The keywords and their synonyms used were (“concrete”) AND  AND 2 to form CaCO3 with the availability of water. As can be observed in Equation (2) [2 is present, which results in the production of CaCO3 and silica gel. Due to that, the pH of the concrete starts to decrease, resulting in the destruction of the passivation coating and causing the steel reinforcement to corrode over the long term [As shown in Equation (1), carbonation in concrete is conducted by the chemical reaction between COtion (2) , the C-Song term .Ca (OH)According to Abdul-Baki , early cAs a carbon sink, early-age carbonation curing is a great advantage in the concrete industry as well . ClimateNumerous variables have an impact on the rate at which carbon dioxide is extracted from concrete. They have been divided into internal and external aspects as shown in 3) is formed through the carbonation process on the surface layer of cement-based materials. The CaCO3 generated is then deposited into the pore network through the hydrated cement matrix, causing a refinement in the carbonated layer’s pores [Calcium carbonate , thus making its reinforcement vulnerable to corrosion and leading to crack formation [The carbonated zone causes a chemical reaction to occur with the hydrated minerals in the concrete and decreases the alkalinity. Since carbonation penetration into the concrete is influenced by changes in the pH and CO content , a contiormation . This neormation . 2 penetration causes insoluble CaCO3 to be converted to soluble Ca(HCO3)2. The Ca(HCO3)2 is easily leached off, thereby resulting in the lowering of the porosity of the hydrated cement [In this process, calcium hydroxide will get dissolved more into the pour solution. After that, the alkaline materials including sodium hydroxide and potassium hydroxide will be consumed by carbon dioxide in the presence of moisture-forming carbonate. Carbonation-induced corrosion of rebars occurs as a result of the disintegration of the passive surface layer . Boualled cement . Carbon d cement ,57. Thisd cement .2 is usually delivered into a closed chamber and left for a particular amount of time and under specific conditions for the reaction to occur. Many studies have used a static carbonation system, as shown in 2 gas (99% purity) into a sealed chamber [Carbonation curing refers to the process of exposing concrete to carbon dioxide gas for an extended period. CO chamber . A gas r chamber ,64. The 2 sequestration, the samples were preconditioned in a 25 °C environmental chamber with a relative humidity of 50% for 6 h. Simultaneously, the air-cured specimens were put in the same laboratory conditions for 28 days [2 (99.5%) as opposed to flue gas (between 10–25% CO2 content) for reaction efficiencies [The pressure gauge for the tank ranged from 0 to 28 MPa with a 1 MPa precision, while the outlet gauge pressure range was from 0 to 1.4 MPa with a 0.05 MPa precision . Regulat 28 days . Most stciencies ,63. A cuciencies .By using the setup in ➢Pressurized carbonation curing2 gas was fed into the chamber without first vacuuming it for pressure-aided carbonation curing. The carbonation chamber was pressurized by keeping the valve open, as seen in The CO➢Vacuum carbonation curing 2 pressures was critical to a successful pilot-scale test.A venturi pump, as shown in Certain researchers have studied the curing procedures of carbonation in different batches using rectangular slab samples ,27. The For comparison, batches 1 to 4 are steam-cured, while batches 5 to 14 are carbonation-cured. Steam curing occurred in a steam cooker for 4 h, with a maximum temperature of 80 °C and relative humidity of 95% . InitialThe procedure for carbonation curing of paste and concrete samples have also been studied in the previous studies, and were broken into four steps ,67.Step 1: In-mold curing. Wet-mix concrete cannot be unmolded after casting because it has a higher slump. Therefore, it is important to carry out the initial hydration curing on the mold. The mixture proportions determine the time required for this step. A study by Zhang et al.  noted thStep 2: Off-mold preconditioning. After the first step, the cube samples were unmolded and left to fan dry on the bottom plates. This was done at a wind speed of 1 m/s for 5.5 h in a room of 25 °C and 50 ± 5% RH. This step is important because the conditioning removes more of the free water to allow for carbon dioxide penetration and the precipitation of carbonates.Step 3. Carbonation curing. The cube samples were placed in a pressure chamber with Co2 gas (99.8% purity) for carbonation under a constant pressure of 5 bar for 2, 12, and 24 h.Step 4. Subsequent hydration. Postcarbonation, the cubes were placed in a moisture room  for 27 more days after hydration. Preparation was also made for the hydration references. The curing was carried out in a sealed mold within the first 24 h, then unmolded, and further cured in the same moisture room for 27 days.According to Farah et al. , carbona3 [3 reduces the porosity and boosts the compressive strength. Similar reports were given by Vijay and Murmu [3 from the metabolic activity of bacteria to fill the pores, as seen in Water content may affect carbon dioxide diffusion.2 hydration and calcium carbonate deposition rates.Water content has a huge effect on bacterial survival, which may further affect COWater plays a major role in carbonation reactions.2 [Water is involved in the hydration process of steel slag to assess the water impact on the carbonation reaction and the survival of bacteria, and the concept of ‘residual water–cement ratio’ is presented. This idea was originally developed to research the precuring procedure for concrete with CO2 .Numerous approaches have been utilized in recent years to improve the carbonation rate and reduce the preparation cycle of carbonated steel slag, such as raising the carbonation pressure ,73, rais3 . This te3  after obnd Murmu  after diBacteria have been used in the majority of studies involving self-healing concrete based on its ability to generate calcium carbonate sediments using urea and calcium supplies via the catalysis of urea hydrolysis into ammonia and carbonate to generate urease ,88. BactThis paper discussed the self-healing of bacterial concrete as well as the effectiveness of the self-healing of fractures by encapsulated bacteria on the recovery of a variety of mechanical and durability qualities. The findings that can be drawn after a comprehensive investigation are that bacteria can contribute in protect steel in concrete via the self-healing process and maintain the level of the pH in concrete at a high level. However, there are many factors affecting the carbonation process, some which can be classified to two groups: internal factors and external factors. Therefore, bacteria alone cannot play a superior role if the role of these factors have been neglected. The bacteria can be considered as an additional material in the reinforced concrete if the bacteria used has the ability to produce the urease enzyme, which can help to in crease the pH of the concrete. In addition, the properties of the concrete improve especially the compressive strength and a reduction in the amount of water and chloride ion that can travel through a substance when bacteria are present.


Incomplete and inconsistent reporting of adverse events (AEs) through multiple sources can distort impressions of the overall safety of the medical interventions examined as well as the benefit-risk relationship. We aimed to assess completed allergic rhinitis (AR) trials registered in ClinicalTrials.gov for completeness and consistency of AEs reporting comparing ClinicalTrials.gov and corresponding publications.We retrospectively examined completed randomised controlled trials on AR registered in ClinicalTrials.gov on or after 9/27/2009 to trials updated with results on or before 12/31/2021 along with any corresponding publications. Complete reporting of AEs in ClinicalTrials.gov were summarised in tables describing AE information, and complete reporting in publications was an explicit statement of serious AE, death or other AE. Difference in completeness, number, or description of AEs between ClinicalTrials.gov and publication was classified as inconsistent reporting of AEs.(P < .001). In 43 (95.6%) publications, there was at least one inconsistency in the reporting of AEs (P < .001). 8 (17.8%) publications had different number of serious AEs (P = .003), 36 (80.0%) of other AEs (P < .001) while deaths reporting was inconsistent in 8 (57.1%) publications (P = .127).There were 99 registered trials with 45 (45.5%) available publications. All published trials completely reported AEs in ClinicalTrials.gov, and 21 (46.7%) in publications The reporting of AEs from AR trials is complete in ClinicalTrials.gov and incomplete and inconsistent in corresponding publications. There is a need to improve the reporting of AEs from AR trials in corresponding publications, and thus to improve patient safety. The reporting of adverse events (AEs) to ClinicalTrials.gov has been mandatory since September 2009 . The SecGlobal health and at the same time economic problems can be attributed to allergic rhinitis (AR), for which drugs are the mainstay therapy, require numerous clinical studies . The datWe retrospectively analysed completed RCTs on AR shown in Fig. We searched ClinicalTrials.gov for completed RCTs using the following keywords: “allergic rhinitis”, “nasal allergies”, “rhinoconjunctivitis”, “hay fever”, and “atopic rhinitis”. We did not use Medical Subject Headings (MeSH) interventions. For trials with publications provided on ClinicalTrials.gov, we selected only those that reported the results of the current trial as the corresponding publications to the RCTs on AR. For trials without publications provided, we searched PubMed, Web of Science, Scopus and Google Scholar with the National Clinical Trial (NCT) identifier provided by ClinicalTrials.gov in the trial record that is usually listed in the abstract or main text of published articles . If the FDAAA: The Food and Drug Administration Amendment Act, FDA: The Food and Drug Administration.Flow diagram of retrospective cross-sectional study with inclusion and exclusion criteria. Inclusion criteria are shown in Fig. We primarily analysed the completeness and consistency of AEs reporting in ClinicalTrials.gov and the corresponding publications. The complete reporting of AEs in the registry were tables with the number of participants affected out of those at risk summarised for each AE, as required by the Final Rule . AdditioP < .05.Data extracted from ClinicalTrials.gov were coded and then entered into a Microsoft Excel spreadsheet. Percentages, medians with the 95% CIs were presented. Two-level categorical variables (no or yes) were different SAEs description, SAEs reported in a publication, SAEs reported as zero in a publication, OAEs reported as Treatment-emergent AEs (TEAEs) and as Treatment-related AEs (TRAEs) in a publication. The number of OAEs, frequency threshold and elapsed time from posting results to publication were treated as nonparametric. We categorised these nonparametric values based on a median split, where values were dichotomised as 0, when less than or equal to their respective median, and as 1 when greater than their respective median. Differences between ClinicalTrials.gov and publications in the completeness and consistency of reporting of AEs, their reported number or description were compared using the Chi-square test or Mann-Whitney U test. Frequencies were compared using Chi-squared tests. We used IBM SPSS Statistics 21  for the analyses. Differences were considered significant at a (P < .001). In 43 (95.6%) publications, there was at least one inconsistency in the reporting of AEs compared to ClinicalTrials.gov (P < .001). Table There were 99 registered trials with 45 (45.5%) available publications. Of the published trials, most were phase 3 (n = 21 [46.7%]), followed by phase 2 and 4 with 10 (22.2%) trials each. Furthermore, 34 (75.6%) of them were industry-sponsored trials, and 20 (44.4%)The withdrawal of participants due to AEs  was explicitly stated in most publications (n = 43 [95.6%]). In 5 (11.1%) publications, the number of patients withdrawn due to AEs differed from the corresponding number in ClinicalTrials.gov, and in most cases (n = 4 [8.9%]) was higher than in ClinicalTrials.gov.(P = .003), of which 1 (2.2%) publication reported a higher number than in ClinicalTrials.gov, and 7 (15.6%) had a smaller number. The number of patients with at least one SAE differed in 7 (15.6%) publications compared to the corresponding number in ClinicalTrials.gov (P = .006), and all 7 publications reported a smaller number than in ClinicalTrials.gov. In 15 (33.3%) publications the description of reported SAEs differed from the corresponding ones in ClinicalTrials.gov. Furthermore, trials in which less time elapsed from the posting of results in ClinicalTrials.gov to publication  were more prone to different descriptions of SAEs in publications, χ2 = 10.476, P = .001. Additionally, authors of publications corresponding to trials with zero reported SAEs in ClinicalTrials.gov were more likely to omit explicit reporting of SAEs in publications, χ2 = 4.746, P = .029.In 8 (17.8%) publications, the number of reported SAEs differed from the corresponding number in ClinicalTrials.gov (P < .001), of which 12 (26.7%) publications reported a smaller number than in ClinicalTrials.gov, and 24 (53.3%) had a higher number. In 37 (82.2%) publications, the description of reported OAEs differed from the corresponding ones in ClinicalTrials.gov.17 (37.8%) publications reported OAEs only as TEAEs2 = 14.400, P < .001 and χ2 = 9.000, P = .003, respectively. The number of patients with at least one OAE differed in 33 (73.3%) publications compared to the corresponding number in ClinicalTrials.gov (P < .001). Of these, a smaller number of patients with OAEs were reported in 7 (15.6%) publications, and a higher number in 26 (57.8%). The median reported frequency threshold in ClinicalTrials.gov was 5% (95% CI 2.77–4.09) and in publications 0% (95% CI 0.58–2.11) indicating a lower frequency threshold report in publications than in ClinicalTrials.gov. Furthermore, 26 (57.8%) publications had different frequency thresholds, mostly (n = 24 [53.3%]) lower than in ClinicalTrials.gov. Additionally, significantly more publications with a lower frequency threshold than registered had more reported OAEs than in ClinicalTrials.gov, χ2 = 6.259, P = .012.In 36 (80.0%) publications, the number of reported OAEs differed from the corresponding number in ClinicalTrials.gov (P = .001) (Table (P = .127).35 (77.8%) published trials were completed before the implementation of the Final Rule, and 10 (22.2%) after. 17 (37.8%) pre-Rule trials reported deaths in corresponding publications while only 2 4.4%) trials reported deaths as SAE and 2 (4.4%) through the ACM table in ClinicalTrials.gov. In contrast, all post-Rule trials reported deaths in ClinicalTrials.gov through the ACM table while only 4 (40.0%) corresponding publications reported deaths. Overall, 14 (31.1%) published trials reported deaths in ClinicalTrials.gov and 21 (46.7%) in publications. Thus, discrepancies in reporting of deaths was analysed for 14 (31.1%) published trials where we found that all of them reported deaths in ClinicalTrials.gov, and only 6 (42.9%) in corresponding publications as well .4% trialOur novel cross-sectional study on the discrepancies in the reporting of safety data from RCTs on AR showed incomplete and inconsistent AEs reporting in corresponding publications. Most published trials were phase 2, 3 and 4 (n = 42 [93.3%]) and were published in high-impact journals. Therefore such publications should contain consistent and complete data in relation to the registry as they have the greatest impact on clinical care and formulation of clinical practice guidelines . A similAlmost a quarter of the analysed publications did not explicitly report SAEs, and it is evident that publications mostly underreported SAEs as well as participants affected by SAEs in relation to ClinicalTrials.gov. As already stated in the results, one of the reasons for omitting explicit reporting of SAEs is definitely their absence during the trial, reported as zero in ClinicalTrials.gov. A number of other authors have found similar discrepancies in SAEs reporting between ClinicalTrials.gov and corresponding publications –6. The fJurić et al. ) had inconsistent reporting compared to ClinicalTrials.gov. Unlike SAEs underreporting, we found the overreporting of OAEs as well as participants affected by OAEs in the publications. One of the reasons for reporting more OAEs in publications is a lower frequency threshold at which to report OAEs in more than half of the publications. A similar conclusion was reached in the study by ć et al. . Discrepications . We haveications , but verThe analysis of the reporting of deaths differed from the analysis of remaining adverse events due to different regulations and requirements in their reporting during the analysed period. Therefore, discrepancies in deaths reporting has been analysed in less than a third of published trials, and the underreporting of deaths found in publications supports the results of other studies that analysed discrepancies in the reporting of AEs between trial registry and publications , 23. TheWe analysed trials only registered in ClinicalTrials.gov. There are currently 17 other primary registries in the World Health Organization (WHO) registry network that meet International Committee of Medical Journal Editors (ICMJE) requirements and therefore our analysed data may be incomplete and inaccurate . HoweverThe reporting of AEs from completed and published AR trials is complete in ClinicalTrials.gov and incomplete and inconsistent in corresponding publications despite all recommendations and guidelines. The SAEs and deaths were underreported in publications while OAEs were overreported. Inconsistent and incomplete reporting of AEs in publications compromises patient safety so there is a need for a more detailed comparison of registered and submitted AEs during the publication process.


To describe pediatric outpatient visits and antibiotic prescribing during the coronavirus disease 2019 (COVID-19) pandemic.An observational, retrospective control study from January 2019 to October 2021.Outpatient clinics, including 27 family medicine clinics, 27 pediatric clinics, and 26 urgent or prompt care clinics.Children aged 0–19 years receiving care in an outpatient setting.Data were extracted from the electronic health record. The COVID-19 era was defined as April 1, 2020, to October 31, 2021. Virtual visits were identified by coded encounter or visit type variables. Visit diagnoses were assigned using a 3-tier classification system based on appropriateness of antibiotic prescribing and a subanalysis of respiratory visits was performed to compare changes in the COVID-19 era compared to baseline.Through October 2021, we detected an overall sustained reduction of 18.2% in antibiotic prescribing to children. Disproportionate changes occurred in the percentages of antibiotic visits in respiratory visits for children by age, race or ethnicity, practice setting, and prescriber type. Virtual visits were minimal during the study period but did not result in higher rates of antibiotic visits or in-person follow-up visits.These findings suggest that reductions in antibiotic prescribing have been sustained despite increases in outpatient visits. However, additional studies are warranted to better understand disproportionate rates of antibiotic visits. At the same time, primary-care delivery transformed with the rapid increase in use of telemedicine. More recently, children returned to in-person school for the fall semester of 2021 during a surge in COVID-19 cases due to the severe acute respiratory coronavirus virus 2 (SARS-CoV-2) δ (delta) variant and an atypical summer–fall peak of respiratory syncytial virus (RSV). Antibiotic use is an important contributor to the development of antimicrobial resistance, and ∼30% of outpatient antibiotic prescribing is unnecessary. Understanding changes to antibiotic prescribing due to nontraditional viral respiratory patterns and novel care-delivery strategies is valuable for understanding and implementing outpatient antibiotic stewardship efforts.The coronavirus disease 2019 (COVID-19) pandemic and resultant mitigation strategies, social distancing, and mask mandates, have had a substantial impact on the epidemiology of other pediatric infections. Virtual encounters, while offering numerous benefits, also have the potential to impact the quality of antibiotic prescribing, especially for conditions that benefit from physical exam and laboratory testing. Early studies showed significant reductions in antibiotic prescribing associated with the COVID-19 pandemic in the United States, and a recent study found sustained reductions in antibiotic prescribing in pediatric primary-care offices through June 2021, primarily driven by reductions in respiratory encounters. However, less is known about alternative outpatient settings, the influence of more recent changes in viral respiratory patterns (RSV and COVID-19 variants), return to in-person school, variations by patient or visit characteristics, and appropriateness of antibiotic prescribing. The primary objective of this study was to describe changes in antibiotic prescribing during the COVID-19 pandemic across a range of outpatient site and provider types. Secondary objectives were to evaluate changes in visit types, including (1) visits where antibiotics are sometimes, always, or never appropriate; (2) respiratory visits, the most common indications for outpatient antibiotic prescribing in children; and (3) telehealth visits and associated in-person follow-up visits.In many outpatient settings serving children, the COVID-19 pandemic resulted in rapid implementation of telehealth visits.This retrospective control study utilized electronic health record (EHR) data from pediatric outpatient visits at Norton Healthcare, a large healthcare system serving the greater area of Louisville, Kentucky, and southern Indiana. Outpatient visit data were included for children aged 0–19 years from 27 family medicine or primary-care clinics, 27 pediatric clinics, and 26 urgent-care or retail clinics. In March 2020, 3 academic pediatric clinics were added to Norton Healthcare; in addition to expanding pediatric outpatient care, these are the only practice sites that include medical trainees. No formal outpatient antibiotic stewardship programs or interventions were conducted at Norton Healthcare during the study period. Visits were excluded if the provider type of record did not have authority to prescribe antibiotics  or for encounter types not typically associated with medication prescribing . Outpatient visits were defined as virtual based on encounter and visit types, as coded in EHR variables, and we did not include telephone encounters. Virtual visits were counted as having a follow-up visit if any in-person visit type  for the same patient occurred within 48 hours. Beginning March 16–20, 2020, schools and daycare facilities were closed, and social distancing recommendations were implemented. In January 2021, schools were permitted to reopen for in-person learning, and legislation required in-person classes to resume by March 29, 2021. We defined a “baseline”  period of January 1, 2019, to March 31, 2020. The “COVID-19 era” included April 1, 2020, to October 31, 2021. To calculate an absolute reduction in visits and antibiotic prescribing, we also compared corresponding periods of April–October in 2019, 2020, and 2021.A state of emergency was declared in Kentucky on March 6, 2020, in response to the COVID-19 pandemic.A). Additional secondary outcomes of interest included changes in proportion of visit types, assessed by antibiotic appropriateness, all respiratory visits, and virtual visits. Visits were further sorted by diagnostic categories using International Classification of Diseases, Tenth Edition (ICD-10) codes. Visit appropriateness for antibiotic prescribing was defined using a previously described, mutually exclusive, ICD-10 classification scheme in which a diagnosis is classified as “always” appropriate for an antibiotic , “sometimes” appropriate for an antibiotic , or “never” appropriate for an antibiotic . To identify a single diagnosis for each visit, modified clinical classification software categories were prioritized using a similar tiered classification scheme. Classification was hierarchical such that if any of the listed medical diagnoses should always be treated with an antibiotic, the “always” diagnosis was prioritized over diagnoses for which antibiotics are sometimes or never indicated, respectively. For indications for which antibiotics are never indicated, we prioritized reporting of the following infectious categories of interest: acute upper respiratory infection, acute bronchitis (including bronchiolitis), influenza, and COVID-19. If >1 diagnosis was identified per tiered category, the first reported diagnosis field was selected. COVID-19 visits were defined using ICD-10 codes for diagnosis, exposure, screening, or personal history . Respiratory visits of interest were identified using modified clinical classification software categories and included bronchitis, COVID-19, influenza, otitis media, pharyngitis, pneumonia, sinusitis, tonsillitis, and other upper respiratory infections . A full list of diagnosis classifications is available in Supplementary Table B.All included outpatient visits were queried for associated antibiotic prescribing through the EHR. The primary outcome of this study was percentage of antibiotic visits, defined as any visit with an associated oral antibiotic or select intramuscular antibiotic agents commonly used for pediatric infections , month, visit diagnoses of interest, and virtual visits with in-person follow-up within 48 hours. Reductions in the percentages of antibiotic visits in the COVID-19 era for respiratory visits were calculated as relative reductions compared to the baseline era.We applied multivariable logistic regression models to identify which characteristics were associated with antibiotic prescribing in respiratory visits during the study period. The following factors were included in the analysis: period (baseline vs COVID-19 era); visit type ; sex, age group ; race or ethnicity ; insurance (Medicaid vs private); department ; and provider type . Odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated. All statistical analyses were carried out using SAS version 9.4 software .During the study period, 984,244 outpatient visits were included among 198,315 unique patients. From April to October 2019, there were 197,253 outpatient visits, compared to 158,497 visits in the same period of 2020 and 244,189 visits in 2021. In the same monthly periods (April–October), there were 40,140 visits during which antibiotics were prescribed in 2019, compared to 16,396 antibiotic visits in the same period of 2020. These data represent a 59.2% reduction in antibiotic prescribing from 2019 to 2020. During the follow-up period of April–October 2021, there were 32,820 antibiotic visits, an 18.2% reduction in antibiotic prescribing compared to the baseline. The percentage reduction in antibiotic prescriptions during respiratory visits during only the corresponding April–October periods were larger: 71.2% in 2020 and 23.2% in 2021.The proportion of visits by children who were younger, non-White, and insured by Medicaid increased during the COVID-19 era, as did visits to pediatric clinics  and COVID-19 (20.6%). However, AOM had a follow-up rate of 6.1%, sinusitis had a follow-up rate of 7.1%, and other diagnoses had a follow-up rate of 7.1%.There were 8,652 virtual visits during the study period: 437 (5.1%) were in the baseline period and 8,215 (95.0%) were in the COVID-19 era. Also, 715 (8.3%) of all virtual visits had in-person follow-up visits within 48 hours  have been shown to directly correlate with seasonal increases in antibiotic prescribing both before and during the COVID-19 pandemic. However, the changes detected in May–September 2021 are novel. For instance, initial declines in AOM diagnoses were likely because AOM is most frequently a consequence of viral upper-respiratory infection, and viral infections decreased due to social distancing and masking. AOM cases increased again in summer 2021when acute upper-respiratory infections peaked.Our findings show dramatic changes in respiratory diagnoses over the study period but minimal changes to nonrespiratory diagnoses Fig. . Similar Evaluating national prescribing data, Chua et al reported a 55.6% reduction in antibiotic prescribing to children in April–December 2020 compared to the corresponding period in 2019. More recently, investigators described a 72.7% reduction in antibiotic prescriptions within a study period from January 2019 through June 2021 in pediatric primary-care practices associated with the Children’s Hospital of Philadelphia. Our study expands on the existing literature by including fall 2021 data, which included return to school and increases in circulating respiratory viruses as previously described. We also included nonpediatric primary-care settings such as family medicine and urgent care and retail practices.Previous studies showed similar declines in respiratory diagnoses and antibiotic prescribing during earlier stages of the COVID-19 pandemic. However, in 2021, the RSV peak and SARS-CoV-2 δ (delta) variant produced unseasonably high rates of viral illness in summer–fall months. Therefore, we chose to report percent reductions in antibiotic prescribing in respiratory visits, to account for fluctuations in respiratory visits throughout the study period.Additionally, we identified disproportionate changes in antibiotic prescribing by patient characteristics, prescriber type, and practice settings. Earlier publications evaluating antibiotic prescribing during the pandemic have reported on monthly trends and relative changes in antibiotic prescribing beyond expected, using monthly matched time periods. Additionally, prior to the COVID-19 pandemic, White children were prescribed antibiotics at higher rates than Black or non-White children. Although the reduction in antibiotic visits could represent reduced inappropriate prescribing, it could also potentially represent undertreatment and/or limitations in access to care. The racial discrepancy identified in our study may represent another example of how racism has caused widened health disparities through the COVID-19 pandemic and warrants further study because this factor could have greater implications for other areas of pediatric care.The COVID-19 pandemic has disproportionately affected adults and children by race and social status with regard to illness, use of telemedicine, and ability to practice social distancing.Our study also showed greater decreases in antibiotic visits for older children aged ≥3 years, possibly due to virtual learning and masking or shifts in parental expectations for antibiotics in the setting of viral illness. For instance, caregivers could be more focused on obtaining testing for COVID-19 for return to school and less likely to expect antibiotics for a child’s respiratory illness. These findings suggest that there could be a favorable shift in culture and expectations surrounding outpatient visits for acute upper respiratory infections, representing a reduction in unnecessary antibiotic prescribing. Continued monitoring and reporting of antibiotic prescribing trends are warranted. We also saw disproportionate changes in practice settings, likely reflective of the addition of academic pediatric practices that joined the healthcare system in March 2020. Similarly, trainees are only involved in outpatient care in the newly added pediatric clinics and therefore had an increase in respiratory visits during the COVID-19 era.Differences in relative reduction of antibiotic visits by practice setting and provider type could be attributable to several changes throughout the pandemic. For instance, reductions were greatest in urgent care and retail clinics which could be due to such settings being more frequently visited for COVID-19 tests as the primary focus of the visit. Physician assistants also experienced greater reductions in antibiotic visits compared to nurse practitioners and physicians; however, physician assistants are uncommon in pediatric primary care at our institution and results likely reflect the prescribing practices of a few providers. Although virtual visits in our study sample were low, our findings suggest that antibiotic prescribing for respiratory diagnoses was less common in virtual visits (Table Prior to the COVID-19 pandemic, studies evaluating antibiotic prescribing in virtual visits compared to in-person visits had conflicting and controversial results.ts Table . AdditioThis study had several limitations. Our study sample included pediatric visits to a single healthcare organization, and findings may not be generalizable to other organizations or geographic settings. We were unable to quantify any changes in pediatric visits due to patient relocation or care-seeking behaviors. We utilized ICD-10 codes to identify visit diagnoses, a common practice for database research in antimicrobial stewardship; however, accuracy between diagnostic billing and clinical diagnosis cannot be guaranteed. We utilized respiratory visits to compare changes in antibiotic prescribing and in the regression model, to standardize time periods for seasonal variations. We chose to include COVID-19 visits because COVID-19 may present with respiratory symptoms similar to other viral indications for which antibiotics are commonly prescribed inappropriately. However, inclusion produces lower rates of antibiotic visits in the COVID-19 era. We included medical practices that were added to our organization during the study period; however, sensitivity analyses revealed that the addition of these practices did not impact odds of an antibiotic visit. Finally, we included all visit types for our virtual follow-up visit analysis, which could have included routinely scheduled visits and, therefore, we may have overestimated the rate of in-person follow-up visits.In conclusion, we report decreases in antibiotic prescribing during the COVID-19 pandemic, with disproportionate changes among patient groups by age, race or ethnicity, insurance status, and practice setting. Additional qualitative studies are needed to better understand changes in culture and expectations surrounding antibiotic prescribing during this unprecedented time. Tracking and reporting of antibiotic prescribing is a key component of outpatient stewardship initiatives. Efforts should be made for organizations to share such data with prescribing clinicians to continue to promote favorable trends in judicious antibiotic use.


A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). Several MET exon 14 skipping alterations have been identified, but different MET exon splice variants tend to have different clinical outcomes which deserve concern. Herein, based on NGS panel analysis, we firstly described a 61-year-old woman with lung adenocarcinoma who harbored a novel MET exon 14 skipping (c.3004_3028+3del) concurrent MET amplification (copy number: 3.91) and benefited from Savolitinib treatment. Moreover, CytoTest MET/CCP7 FISH Probe (c-MET/CCP7 Ratio:1.41 and mean gene copy number:6) and qPCR which based on ABI 7500 also were performed to confirm these two MET alterations. After 2 months of Savolitinib treatment, the clinical evaluation was a partial response (PR). In summary, our finding not only expanded the spectrum of the MET exon14 variant (METex14). Targeted NGS analysis could improve detection of MET alterations in routine practice. The mesenchymal–epithelial transition (MET) receptor tyrosine kinase binds the hepatocyte growth factor to activate downstream cell signaling pathways involved in cell proliferation, survival, and migration. Several genetic mechanisms can result in aberrant activation of this receptor in cancer cells. One such activating mechanism involves the acquisition of gene mutations that cause MET exon 14 skipping variants (METex14) during mRNA splicing. Mutations leading to METex14 are found in approximately 3–4% NSCLC patients. Accumulating evidence suggests that METex14 is a true, independent oncogenic driver in NSCLC, and also being an independent prognostic factor for poorer survival in patients with NSCLC . SavolitA 61-year-old woman was admitted to our hospital because of respiratory irritation, dry cough, and breathing difficulty. The patient has no history of smoking, but had occasional alcohol. A computed tomography (CT) scan found a space-occupying lesion in the upper lobe of the left lung. Brain magnetic resonance imaging (MRI) showed left frontal lobe occupation  and generated 150 bp paired-end reads. Then base calls from the Illumina NovaSeq6000 were conducted to FASTQ files. Then a BWA-MEM (v.0.7.17) algorithm was performed to align to the reference genome (UCSC’s hg19 GRCh37). SNVs/InDels were called and annotated via VarDict (v.1.5.7)   and InteA splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in patients with NSCLC. MET exon 14 alteration has been implicated as an oncogenic driver in NSCLC and has been proposed as a potential therapeutic target . AlthougInterestingly, we found that this patient also harbored MET amplification. Since the definition of MET amplification and high copy number amplification based on NGS is still controversial, we performed the MET/CCP7 FISH probe to validate the amplification which showed that the c-MET/CCP7 ratio = 1.41, mean c-MET gene copy number/cell = 6. Previous retrospective studies demonstrated that patients with METex14 both with and without MET amplification have responded to MET TKIs , 10. MarBrain metastases (BrMs) are associated with significant morbidity and are found in up to 50% of patients with advanced NSCLC. It has been recognized that patients with brain metastases comprise a heterogeneous population. With regard to brain metastases from NSCLC, the disease-specific graded prognostic assessment (GPA) has identified patient groups for which median survival ranges from 3 to 14.8 months . ClinicaHowever, there are also some limitations in our present study. There is only a one-patient case report. Whether sensitivity to Savolitinib in this patient was conferred more by the METex14 mutation or by MET amplification is unclear. Prospective clinical trials will be necessary to determine if certain METex14 mutations are more responsive to c-Met inhibition than others and whether concurrent MET amplification predicts increased sensitivity to c-Met inhibitors. Secondly, more prospective clinical trials are urgent to analyze the efficiency of MET-TKI in MET14ex alterations positive patients with BrMs. In summary, our case report expands the spectrum of METex14 skipping alterations. A targeted NGS analysis could improve the detection of METex14 mutations and MET amplification in routine practice.We firstly described a lung adenocarcinoma patient harboring a novel MET c.3004_3028+3del benefited from Savolitinib treatment. Our case report expanded the spectrum of METex14. A targeted NGS analysis could improve detection of MET alterations  in routine practice. The opportunity to implement precision medicine in oncology has grown in parallel with the increasing use of NGS. This case is an excellent example.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.JL, YT, QZ, and QQD prepared the manuscript and the literature search. JL and YF reviewed and edited the manuscript. JL treated and observed the patient. JL performed the histopathological, immunohistochemical examinations. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.YT, QQD, and QZ are employed by Jiangsu Simcere Diagnostics Co., Ltd. and Nanjing Simcere Medical Laboratory Science Co., Ltd.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.