To investigate the feasibility of retrospective prescription-based review and to describe the antibiotic prescribing patterns to provide information for an antimicrobial stewardship programme in Viet NamThis study was conducted in two provincial-level hospitals between February and April 2020. Reviews were done by a clinical team consisting of leaders/senior doctors of each ward to assess the optimal level  of antibiotic prescriptions. Mixed-effect logistic regression at prescription level was used to explore factors associated with optimal antibiotic use.The retrospective prescription-based review was accepted by study clinical wards with varied levels of participants. One hundred and eighty-three patients (326 prescriptions) in Hospital 1 and 200 patients (344 prescriptions) in Hospital 2 were included. One hundred and nineteen of the 326 (36.5%) antibiotic prescriptions in Hospital 1 and 51/344 (14.8%) antibiotic prescriptions in Hospital 2 were determined to be optimal by the review teams. The number of adequate antibiotic prescriptions were 179/326 (54.9%) and 178 (51.7%) in Hospital 1 and Hospital 2, respectively. The optimal level was lower for surgical prophylaxis antibiotics than for empirical therapy , higher in prescriptions in the ICU , higher in definitive antibiotic therapy  and higher in those with an indication recorded in medical records .This study provides evidence on the feasibility of retrospective prescription-based review, with adaption to the local situation. High and varying levels of optimal antibiotic prescriptions in clinical wards in hospitals were observed in Viet Nam. While new antimicrobial agents in the pipeline are expected to be effective against resistant pathogens,4 control and optimizing the use of existing antibiotics plays a pivotal role in combating antibiotic resistance.5Antimicrobial resistance (AMR) is a global concern as it poses a great threat to public health and a burden on healthcare facilities and society.7 Core elements of AMS programmes include: (1) leadership and commitment; (2) accountability and responsibilities; (3) AMS actions; (4) education and training; (5) monitoring and surveillance; and (6) reporting and feedback.7 Until now, AMS programmes have demonstrated their beneficial clinical and economic impact.8–11Antimicrobial stewardship (AMS) programmes have been promoted as one of the responses to the increasing use of antibiotics, with the aim to optimize antimicrobial use, improve patient outcomes, reduce AMR and healthcare associated infections.12 since the issuance of the Guideline for Implementation of AMS Programmes in Hospitals (Decision 772) in March 2016, by the Ministry of Health (MoH).13 Implementation has been at a slow pace, limited to guideline development and pre-prescription authorization, and affected by the COVID-19 pandemic.14 Review of antibiotic prescriptions is one of the recommended activities for AMS programmes. However, implementation of this activity is usually ad hoc and inadequate, as shown by our findings from a previous qualitative study in seven hospitals in our AMR network.15–17 Furthermore, there is a lack of understanding on physicians’ antibiotic prescribing patterns to inform AMS programmes. Studies have been mostly conducted in community settings, and for specific medical conditions  and populations (e.g. children).18 A point prevalence survey in 36 general hospitals in Viet Nam in 2008 showed that 1573/5104 (30.8%) antibiotic prescriptions for hospitalized patients were inappropriate.19 Studies conducted in other LMICs reported varying proportions of inappropriate prescribing in hospitals of between 15% and 70.3%.21 Details on how antibiotic prescriptions were assessed for optimal use were not included in many studies. Such information is valuable to inform AMS efforts to improve antibiotic use in hospital settings in LMICs.In Viet Nam, AMS programmes have been initiated in 47% of 655 hospitalsIn this study, we aimed to investigate the feasibility of retrospective prescription-based review as part of an AMS programme in clinical wards in two provincial-level hospitals to assess optimal antibiotic prescribing levels, identify areas that can be targeted in the hospital AMS programme, and provide feedback to prescribers to help improve their practices. Data from this study will also provide further understanding of antibiotic prescribing patterns and optimal levels in these settings and will be beneficial for AMS implementation in Viet Nam and other LMICs.22 The two hospitals were Viet Tiep Hospital and Dong Thap General Hospital. Viet Tiep Hospital is located in Hai Phong, a large port city (2.0 million people) in northern Viet Nam, a 2000 bed general hospital with 400 000 outpatient and 100 000 inpatient visits per year. Dong Thap General Hospital is in Cao Lanh, Dong Thap, a densely populated (494 people/km2) province in the Mekong Delta in southern Viet Nam with 1000 bed capacity, 710 000 outpatient and 6500 inpatient visits per year. The two study hospitals will be referred to as Hospital 1 and Hospital 2 (in no particular order) to avoid identification of hospital names in the data presented.This study was part of an AMS implementation programme to improve antibiotic use in two general provincial-level hospitals conducted by the Oxford University Clinical Research Unit (OUCRU) Hanoi, Viet Nam in collaboration with the Duke Antimicrobial Stewardship Outreach Network, NC, USA.At the time of this study, an AMS programme was newly established and the study was conducted before the implementation of AMS interventions in the clinical wards. Four clinical wards in each hospital  were selected by the hospital AMS teams for participating in this study. The selection was based on the discussions in the AMS team with two selection criteria: (1) the amount of antibiotics used was greater than the average of all wards in the hospital based on pharmacy reported data; and (2) willingness of the leadership in clinical wards to participate.Review of prescriptions was retrospectively conducted by a team consisting of the head/vice-head of each clinical ward and senior doctors. To minimize bias inherent in self-review, an AMS doctor validated a random selection of the records reviewed after being done by the review team. Training was provided for the review teams of the study wards in reviewing prescriptions and assessing antibiotic prescriptions by the AMS team and OUCRU research team. Training on analysis, interpretation and reporting review data was also provided by OUCRU to the AMS team to improve their skills in data use and feedback.The review team planned to retrieve and review the last 50 medical records with antibiotic treatment in February 2020 per ward. If lower than 50 medical records were retrieved in February, additional medical records were retrieved from January, March and April 2020 following the same procedure. In total, 200 medical records from four study wards per hospital were expected to be reviewed. Medical records were identified and retrieved by the administrative coordinator of the AMS team from the centralized storage unit, and were sent to the review team at each study ward. The inclusion criteria for selection were: (1) patient was admitted to the hospital in the evaluation month; (2) patient was prescribed antibiotics during hospitalization; and (3) patient was hospitalized for ≥72 h.23 ‘Optimal’ antibiotic prescription is defined as following national/locally endorsed guidelines optimally including antibiotic choice, dosage, route and duration. If endorsed guidelines are absent, ‘optimal’ is considered when the antibiotic prescription covers the likely causative or cultured pathogens and there is not a narrower-spectrum antibiotic/more appropriate choice, dosage, route or duration available, or this prescription has been reviewed and endorsed by an infectious disease doctor/clinical microbiologist. ‘Adequate’ antibiotic prescription is defined as when it is not optimal but a reasonable alternative for the likely causative or cultured pathogens  (See review form and assessment criteria in the JAC-AMR Online). The proportion of optimal antibiotic prescriptions, and proportion of prescriptions that were compliant with treatment guidelines  were identified as key indicators for tracking of antibiotic use over time as part of the AMS programme.Review forms were used to extract and record information on demographic characteristics, clinical details, microbiology culture results and antibiotic treatment regimens. Reviewers were asked to assess each antibiotic used and indicate any of the listed specific reasons for non-optimal prescriptions identified, including inappropriate antibiotic choice, spectrum, duration, dose/frequency, or route, allergy mismatch and microbiology mismatch. They were also asked to assess the overall optimal level and guideline compliance of antibiotic prescriptions. Optimal level was evaluated as ‘optimal’, ‘adequate’, ‘suboptimal’, ‘inadequate’ and ‘not assessable’ using definitions adapted from the National Antimicrobial Prescribing Survey—Australia.For the purpose of mixed-effects analysis, we used two terms: optimal  versus non-optimal (remaining categories). Below we presented data from the review before the implementation of AMS interventions.lme4 package in R. As one patient could be prescribed multiple antibiotics, we included patient as a random effect. To explore fixed effects, we included the following variables: patient’s demographics, clinical characteristics and antibiotic prescription characteristics. Details for each fixed effect are presented in Table P value ≤0.05 against the null model24 or described as having an impact on the outcome in previous studies. The fixed effect parameters were reported as OR and 95% CI.Data were analysed using R version 3.6.3. Continuous data were presented as median (IQR) and categorical variables were presented as count (percentage). To explore factors influencing the optimal level of antibiotic prescriptions, mixed-effects logistic regression was applied with the support of The study protocol was approved by the Oxford University Tropical Research Ethics Committee (OxTREC Reference 526-19), and the Ethics Committee of the National Hospital for Tropical Diseases (08/HĐĐĐ-NĐTƯ 31 May 2019). The conduct of this study conformed to the principles embodied in the Declaration of Helsinki.We observed variation in the levels of participation depending on the types of wards; more active participation by doctors in non-surgical wards was observed than by those in surgical wards. Senior doctors were assigned by ward heads to complete the review form when they were not seeing patients. The review teams required between 2 weeks and 1 month to complete one review round; more time was required for the surgical wards due to lack of staff time and a lower level of participation. The AMS team reminded the surgeons and engaged the surgical leads in frequent communication to maintain awareness and commitment. The AMS coordinator received the completed review forms and summarized data to the hospital AMS team and clinical wards in their monthly ward meetings. Hospitals planned to conduct this prescription-based review quarterly following the overall 1 year AMS implementation plan. However, based on the actual performance, a quarterly review was too intensive; a semi-annual review would be more feasible.In Hospital 1, one medical ward retrieved 33 medical records from January to March 2020. The other three wards retrieved 50 medical records from February 2020. In Hospital 2, 50 medical records were retrieved in four wards, mostly from February 2020. Details on the number of medical records per ward per month are presented in Table A total of 383 patients were included, 183 patients in Hospital 1 and 200 patients in Hospital 2 Table . Gram-neA total of 670 antibiotic prescriptions were reviewed . Cephalosporins were the most common antibiotics used in both hospitals: 135/326 (41.4%) and 226/344 (65.7%) prescriptions in Hospital 1 and Hospital 2, respectively Table .Regarding surgical antibiotic prophylaxis, the most common antibiotics used were third-generation cephalosporins  and fluoroquinolones  in Hospital 1, and third-generation  and second-generation cephalosporins  in Hospital 2  in Hospital 1; and 263/344 (76.5%) in Hospital 2. Specifically, the review team in Hospital 2 identified 52/344 (15.1%) with inappropriate spectrum (too narrow or broad), 43/344 (12.5%) with inappropriate dose or frequency, and 78/344 (22.7%) with inappropriate duration. In contrast, only 2/326 (0.6%) with inappropriate spectrum and inappropriate dose/frequency, and 1/326 (0.3%) with inappropriate duration were identified in Hospital 1  and 247/344 (71.8%) were compliant with the national/local endorsed treatment guidelines in Hospital 1 and Hospital 2, respectively. Thirty-eight of 326 (11.7%) antibiotic prescriptions and 26/326 (8.0%) in Hospital 1 compared with 3/344 (0.9%) and 4/344 (1.2%) in Hospital 2 were categorized as ‘no guideline available’ or ‘not assessable’, respectively. In Hospital 1, 22/26 (84.6%) ‘no guideline available’ prescriptions were in a surgical ward. Regarding optimal level, 119/326 (36.5%) antibiotic prescriptions in Hospital 1 and 51/344 (14.8%) antibiotic prescriptions in Hospital 2 were determined to be optimal by the review teams. The number of adequate antibiotic prescriptions were 179/326 (54.9%) and 178 (51.7%) in Hospital 1 and Hospital 2, respectively (Table n = 80) and urinary tract infections   Tables . The proThe results of multivariate mixed-effect logistic regression are presented in Table However, in multivariate analysis, only ICU admission, antibiotic indication documented, and treatment classification (definitive therapy and antibiotic prophylaxis) remained statistically significant. Antibiotics used in patients admitted to the ICU were more likely to be optimal  compared with non-ICU patients. Antibiotics used as definitive therapy in patients with known pathogens were also more likely to be optimally prescribed than in empirical therapy . Antibiotics prescribed as prophylaxis were more likely to be non-optimal than empirical therapy . Finally, documentation of antibiotic indication in medical records was associated with antibiotic prescriptions being more optimal .17 Innovative strategies are required to integrate AMS activities into the routine hospital work to achieve acceptability and sustainability in the long term.22In this paper, we described the process of conducting a retrospective prescription-based review as part of AMS implementation in hospital settings in Viet Nam. Despite recommendations in the national guideline for monitoring the quality of antibiotic prescriptions in hospitals, implementation remains challenging.7 The first and prioritized one is prospective audit and feedback (PAF); the second one is a retrospective prescription-based review with feedback. PAF provides prescribers with recommendations for each patient in real time and hence could be beneficial for patients while they are still in hospital. This approach might not be feasible for resource-limited hospitals where there are insufficient AMS staff capacity and information technology resources to perform PAF efficiently and effectively. The retrospective prescription-based review with feedback could be feasible because it requires fewer resources while still providing opportunities to improve prescribing practices of physicians, albeit not in real time. It can be done by self-revision by prescribers, which furthermore facilitates their autonomy and awareness of their antibiotic use.25 In our study, the review form, as well as assessment criteria, was developed with optimization to be less time-consuming yet adequate data to inform and evaluate the AMS programme.27 The implementation was well integrated into the medicinal wards while more efforts were needed in surgical wards. Identifying strategies to increase the involvement of surgeons in reviewing their own prescriptions and in AMS activities is important for the overall success of AMS programmes. Engaging surgical leads in integrated AMS and infection management discussions could potentially increase their involvement in the process.28Two audit interventions are recommended in the AMS practical toolkit issued by the WHO in 2019.21 but much higher than those reported in other studies: Turkey ,29 Viet Nam .19 Our data also indicated high levels of prolonged antibiotic use for surgical prophylaxis (>24 h) and use as postoperative prophylaxis, mostly in Hospital 2, with 62/67 surgical antibiotic prophylaxis prescriptions assessed as inappropriate duration, and 28/67 as inappropriate dose/frequency. As described elsewhere,31 this is possibly attributable to the doctors’ intentions to compensate for inadequate wound care and infection prevention and control procedures in the hospital, limited knowledge of spectrum of antibiotic activity and optimal timing of antibiotic prophylaxis.32–34 These prescribing patterns in surgical antibiotic prophylaxis do not yield any additional benefit in reducing surgical site infection but increase resistance rates and costs.35–37 AMS programmes in Viet Nam should specifically be tailored to prioritize the optimization of surgical antibiotic prophylaxis and integrate with infection prevention and control activities.We observed high levels of non-optimal antibiotic prescribing in the study wards in two provincial-level hospitals . This level is comparable to those reported from Pakistan ,38 Norway 39 and Australia ,40 In our study, ‘no guideline available’ prescriptions were observed mostly in a surgical ward, which provides most orthopaedics and traumatology care, thus local treatment guidelines should include more guidance on surgical patient populations, especially antibiotic prophylaxis.In Viet Nam, the MoH issued the Guideline for Antibiotic Treatment in 2015 and hospitals developed their local guidelines . Local treatment guidelines developed were based on MoH’s guideline, covering both internal medicine and surgery. The guideline compliance rate in our study was similar to other studies: Namibia ,42 From our findings, retrospective prescription-based review could also be a useful intervention for ICUs in LMIC settings.Our regression results showed that ICU-admitted patients were deemed to receive more optimal antibiotic therapy than non-ICU patients. This could be attributable to the fact that ICU doctors in our hospitals ordered microbiology culture for their patients more than those treating non-ICU patients . It is worth noting that AMS programmes in ICU settings have some unique consideration given the complex patients, high rate of AMR and heavy antibiotic consumption. Specific AMS interventions have been proven to be effective including de-escalation, pharmacokinetic/pharmacodynamic dose optimization, PAF and diagnosis test stewardships.43 Specifically, doctors expressed concerns about prolonged turnaround times for the microbiology cultures.17 Lack of laboratory infrastructure and capacity also poses a big challenge, as evident in one of our studied hospitals where blood cultures were performed manually and resistant mechanism identification (e.g. ESBL or carbapenemase) could not be performed. Lack of capacity, together with the common use of antibiotics prior to hospital admissions, might explain the low positivity rates in our study, as raised by the hospital staff in our AMS team discussions. The issue of limited resources in the microbiology laboratory setting, coupled with the scarce communication between doctors and clinical microbiologists, are the hindrance for improvement in microbiology testing practices.45Although our regression results showed that definitive therapy with known pathogens is more optimal than empirical therapy, low use of microbiology for antibiotic treatment guidance is common in hospitals in Viet Nam and other LMICs. There was only a small fraction of microbiology testing used to inform antibiotic decision-making despite a large number of test orders due to non-causative findings, non-relevant findings and a high rate of negative findings.This study has several strengths including representativeness of hospitals in terms of: geographical regions, size and provincial-level hospitals; the involvement of doctors in reviewing their prescribing practices that could facilitate behaviour change in AMS programmes; and the feasibility for the activity to be integrated into the routine hospital work. Nevertheless, interpretations of the study data need to be made in the light of its limitations. First, small sample sizes of medical records increased the feasibility of the activity but limited the statistical power in data analysis. Second, the fact that retrospective review was performed by the clinical team at each ward could generate some bias in the indicators of optimal antibiotic prescriptions and guideline compliance. However, engagement of clinical teams in reviewing their own prescriptions could be considered as an intervention in itself because through the review process, the clinical teams would become more aware of their issues and more likely improve their practices. Lastly, the application of appropriateness categories can vary between reviewers and between studies. Although we had an AMS doctor re-evaluate the reviewed medical records to minimize the last two limitations, this was only done in one hospital because this approach depends on the staff available at each hospital and would have high cost implications for the AMS programmes.In conclusion, retrospective prescription-based review could be integrated as part of hospital AMS implementation in LMIC settings in order to identify areas for potential antibiotic prescribing improvement. This success is linked to the fact that our programme is tailored to the local situation. Data from our prescription reviews showed wide variations in antibiotic prescribing practices in hospitals in Viet Nam. We identified parameters for improvement of antibiotic prescriptions including improving the content of hospital-specific guidelines, enhancing antibiotic use in surgery, and building microbiology laboratory capacity to support antibiotic decision-making.dlac144_Supplementary_DataClick here for additional data file.


This study aimed to investigate the recycling opportunities for industrial byproducts and their contribution to innovative concrete manufacturing processes. The attention was mainly focused on municipal solid waste incineration fly ash (MSWI-FA) and its employment, after a washing pre-treatment, as the main component in artificially manufactured aggregates containing cement and ground granulated blast furnace slag (GGBFS) in different percentages. The produced aggregates were used to produce lightweight concrete (LWC) containing both artificial aggregates only and artificial aggregates mixed with a relatively small percentage of recycled polyethylene terephthalate (PET) in the sand form. Thereby, the possibility of producing concrete with good mechanical properties and enhanced thermal properties was investigated through effective PET reuse with beneficial impacts on the thermal insulation of structures. Based on the obtained results, the samples containing artificial aggregates had lower compressive strength (up to 30%) but better thermal performance (up to 25%) with respect to the reference sample made from natural aggregates. Moreover, substituting 10% of recycled aggregates with PET led to a greater reduction in resistance while improving the thermal conductivity. This type of concrete could improve the economic and environmental aspects by incorporating industrial wastes—mainly fly ash—thereby lowering the use of cement, which would lead to a reduction in CO Therefomissions ,4,5,6 ormissions ,8,9,10; The amount of municipal solid waste (MSW) in the world is increasing day by day, and it is estimated to be roughly 3.4 billion tonnes by 2050 , which pConsidering that the global aggregate production surpasses 40 billion tonnes annually , using r2 curing (accelerated carbonation) of recycled aggregates or the addition of pozzolanic micropowders, can offset the mentioned drawbacks and enhance the physical and mechanical characteristics of the artificial aggregates [Lightweight concretes have a lower density than conventional concretes, thanks to a system of voids in the matrix that replace natural aggregates in part or completely with LWA . The latgregates ,43.The use of lightweight concrete allows for excellent performance in terms of fire resistance and reduced weight for the structure, along with saving costs ,45. For In recent years, there has also been a significant increase in the use of lightweight concrete blocks to improve thermal insulation . It has Using recycled PET waste as an aggregate in Portland cement concrete/mortar in addition to geopolymer ones was recently studied. For instance, Akçaözoǧlu et al.  investig3. Nonetheless, there are still uncertainties about the quality of recycled aggregated concretes, and thus, the majority of standards and specifications recommend replacing up to 30% of recycled aggregates in structural elements [While some types of LWAs, mainly from CDW, have already become standardized according to EN13055  and ASTMelements . In view of what was mentioned above, further studies are still needed to promote the use of recycled aggregates obtained from wastes and byproducts with a higher percentage in cementitious products. While the majority of studies in the literature focus on the use of recycled aggregates from CDW and/or energy-intensive sintered and pulverized ashes/slags, in this study, the concrete includes artificial LWAs from the cold-bonding technique; PET sand was produced, and its mechanical and thermal properties were characterized. To this end, in the first part of this research work, washed MSWI fly ash (FA) was used together with GGBFS to replace cement in a properly evaluated mix design in order to perform a cold-bonding granulation process and obtain recycled aggregates. A further granulation process was carried out on the produced aggregates to improve the stabilization/solidification process, as described in depth in . The latThe chemical compositions of the main materials, including municipal solid waste incineration fly ash (MSWI-FA), ground granulated blast furnace slag (GGBFS), marble sludge (MS), and cement (CEM II/A-L 42.5R), used to perform the cold bonding granulation process are gathered in The produced single lightweight artificial aggregates (S-LWAs)  underwen3, which was higher than that in the present study, and they were considered to be normal-weight aggregates.As can be observed in 3 was provided by the company Vedelago Recycling Center Ltd. .Polyethylene terephthalate (PET) is a member of the polyester family of polymers; it is mainly a thermoplastic resin made of phthalates . PlasticRecycled aggregates with single- and double-step granulation processes were produced, and the mechanical and thermal properties of concrete containing such aggregates were investigated. Several samples of cubic concrete with a side of 10 cm were manufactured. Complete substitution of aggregates was performed to manufacture three concrete mixtures using single lightweight aggregates (S-LWA samples) and three samples using double lightweight aggregates (D-LWA samples). Each mixture was cast in a set of 3 conventional concrete specimen molds. The percentage distribution of the aggregates was about 25% of 4–8 mm (fine) aggregates, 50% of 8–16 mm (medium) aggregates, and 25% of 16–20 mm (coarse) aggregates.In order to obtain improved thermal properties, six further concrete mixtures were manufactured in the same way as the above-mentioned specimens, where 10% of the medium-diameter aggregates by volume were replaced with an equivalent quantity of PET (S-LWA+PET and D-LWA+PET). The 10% substitution was selected based on the results of a previous study . FinallyAll of the sample sets were cast in cubic steel molds (10 cm × 10 cm × 10 cm) and then covered with cellophane film. After 24 h, they were removed from the molds and cured for 28 days at room temperature. Compressive strength is the ability of a material or structure to carry loads on its surface without any cracks or deflections. The tested sample, usually in the form of a cube, prism, or cylinder, is compressed between the plates of a compression-testing machine by a gradually applied load. While the vertical direction shortens, the horizontal one expands, and cracks occur increasingly until the sample fails. The compressive strength of the examined cubic samples after 28 days of curing was determined according to UNI EN 12390-3  with a CThe thermal conductivity of the concrete samples was evaluated using an ISOMET 2114 portable thermal characterization analyzer , which wThe mean results of the compressive test evaluated for each mixture (three cubic specimens) are summarized in As can be observed in The decreased values of the compressive strength for the concretes with a 10% PET volumetric replacement ratio were mainly due to the shape and flexibility of the PET flakes , as well3; thus only D-LWC Mix1 met both requirements of strength and density to be considered as lightweight structural concrete.As most of the lightweight aggregate concrete samples had a 28-day compressive strength of less than 17 Mpa; according to the American Concrete Institute (ACI) , they caThe results of the thermal conductivity test are summarized in Moreover, the addition of PET to the mixtures containing single- and double-step aggregates resulted in a further conductivity reduction compared to the control samples. It can be noted that the 10% addition of PET in the S-LWC+PET samples showed reductions of 33%, 32%, and 34% compared to the decreases of 32%, 31%, and 34% obtained for the D-LWC+PET samples with respect to the reference sample. In fact, the addition of PET increased the porosity of the material, thereby lowering density, and the porous cementitious materials had a lower thermal conductivity and sound absorption coefficient, as reported in other recent studies ,90,91. TConsidering both the mechanical and thermal behaviors, the best mixture was provided by the double-step pelletized D-LWC Mix2 concrete, which exhibited higher resistance and lower thermal conductivity with respect to D-LWC Mix1 and D-LWC Mix3. In fact, Mix2 containing double-step pelletized aggregates without PET addition could improve the thermal conductivity of the conventional concrete by 26%, while the compressive strength was still satisfactory (19.06 MPa). The differences between the aforementioned mixes were minimal in the case of PET addition (D-Mix2-PET and D-Mix3-PET samples), which surely provided a beneficial effect to both mixes by further reducing the overall thermal conductivity of the concrete samples. In this case, the best overall thermal conductivity attained was 34% less than that of conventional concrete. This outcome and the fact that the addition of PET reduced the compressive strength of the two samples, bringing them to similar values , were considered. Thus, the mix designs with low PET content (10%) were considered to enhance the thermal properties while preserving the mechanical characteristics of the produced concrete as much as possible. However, PET would not properly bind to cement, reducing the compressive strength of the manufactured concrete, i.e., all of the PET samples had resistances lower than 16 Mpa and were, therefore, considered as non-structural concrete.The incorporation of recycled aggregates in construction products leads to less exploitation of natural aggregates and resources, as well as a reduction in the amount of waste disposed of in landfills. In this study, artificial aggregates made from industrial wastes—municipal solid waste incineration fly ash, slag, and marble sludge—were used to produce lightweight concrete (LWC) that could be oriented toward non-structural applications. A compression test on the LWC samples showed that the concrete had limited compressive strength and, on the other hand, a lower thermal conductivity when incorporating polyethylene terephthalate (PET) compared to that of its PET-free counterpart.Using artificial recycled aggregates with a 100% substitution resulted in a decrease of more than 30% in compressive resistance with respect to the reference sample (REF), which was composed of 100% natural aggregates. Moreover, adding 10% PET to the mixture resulted in an additional average 22% reduction in compressive resistance.The majority of the lightweight concrete samples had compressive resistances below 17 MPa, making them suitable for non-structural applications.The addition of PET could improve the thermal conductivity of the samples, on average, by 10% and 33% for the PET-free and REF samples, respectively. Thus, adding PET led to lower mechanical properties while improving the thermal properties due to an increase in the trapped air and porosity. The amount of PET could be increased for possible specific application in which a lower thermal conductivity and a lower strength are needed, such as in concrete panels for façade cladding or partition walls.The lightweight concrete sample composed of the double-step aggregates (with the mix design of 75% fly ash) without PET demonstrated the optimal performance when considering both thermal and compressive behaviors.Specifically, the following conclusions are drawn from the results:2 curing in the production of this kind of aggregate, as well as the manufacturing of concrete samples with distinct replacement ratios of recycled aggregates.Therefore, using this type of artificial aggregate as a component of lightweight concrete can immobilize hazardous industrial waste  and promote a circular economy trend in the construction and building material industry. Future studies could employ CO


In this paper, we propose an end-to-end deep learning approach to realize channel state information (CSI) feedback and hybrid precoding for millimeter wave massive multiple-input multiple-output systems in the frequency division duplexing mode. Different from conventional approaches that treat the CSI reconstruction and hybrid precoding as separate components, we propose a new end-to-end learning method bypassing the channel reconstruction phase, and design the hybrid precoders and combiners directly from the feedback codewords (a compressed version of the CSI). More specifically, we design a neural network composed of the CSI feedback and hybrid precoding. Experiment results show that our proposed network can achieve better performance than conventional hybrid precoding schemes that reserve channel reconstruction, especially when the feedback resources are limited. Hybrid precoding is a promising technique for millimeter wave (mmWave) massive multiple-input multiple-output (MIMO) systems ,2,3,4,5,In recent years, with the rapid development of deep learning technologies, many new approaches have been realized successfully in CSI feedback ,19,20,21Most of the aforementioned works realize CSI feedback and hybrid precoding in separate modules. However, such a separate design may not fully explore the capabilities and advantages that can be provided by end-to-end deep learning ,30. In tA new deep learning-based end-to-end method of joint CSI feedback and hybrid precoding for FDD massive MIMO systems is proposed. Differing from the existing works that jointly optimize CSI feedback and hybrid precoding by using traditional algorithms, we adopt end-to-end deep learning techniques to solve the problem. Meanwhile, our proposed method bypasses channel reconstruction and directly designs the hybrid precoders and combiners from the feedback codewords for FDD massive MIMO systems, which is different from prior works that treat the CSI reconstruction and hybrid precoding as separate components and has been less investigated in the latest end-to-end works;A new end-to-end neural network structure for FDD mmWave massive MIMO systems is proposed in this paper. It consists of two parts: CSI feedback and hybrid precoding. The former, realized by CNN, transforms the channel matrices into feedback codewords and the latter, realized by DNN, transforms feedback codewords into hybrid precoders and combiners;The simulation results illustrate that compared with conventional approaches, which reserve channel reconstruction, our proposed method can significantly reduce the feedback overhead and achieve better performance, especially when the feedback resources are limited.In this paper, we investigate the joint design of CSI feedback and hybrid precoding for FDD massive MIMO systems. We propose a new neural network structure and an end-to-end learning framework, which bypasses channel reconstruction and directly designs the hybrid precoders and combiners from the feedback codewords. Specifically, our proposed neural network consists of two parts: CSI feedback and hybrid precoding. In order to train the network, we generate the input-output pairs where the input is the channel matrices and the output is the hybrid precoders and combiners. The main contributions of this paper are summarized as follows:Notation 1.We use We consider a point-to-point FDD mmWave MIMO system in which the TX with lth propagation path in the ith scattering cluster. U elements on the y-axis and V elements on z-axis, the array response vector can be expressed asd is the space between adjacent antennas.We consider a narrowband block-fading channel and the received signal can be written ash n∼CN0,σINR. The The decoded data streams Our objective is to design the hybrid precoders and combiners It is necessary for the TX to obtain the instantaneous CSI for optimal precoders and combiners design. For simplicity, we assume that the perfect downlink CSI has been obtained at RX via pilot-based training and only focus on the design of joint CSI feedback and hybrid precoding.M-dimensional codeword To reduce feedback overhead, the RX first compresses The TX receives In the following, we aim to jointly design F· in  and P· in . Such aIn this section, we describe the details of our proposd deep learning framework for the joint design of CSI feedback and hybrid precoding. Then, we describe how to generate the training dataset.M-dimensional codeword. This module is built with As assumed, the RX has obtained perfect CSI and needs to compress the downlink channel matrix on F· in . The inpQ units, which is used to generate the vector Under the assumption of an error-free feedback channel between the TX and the RX, the TX obtains the codewords on P· in . The codThe dataset of the proposed network is denoted as lated asmaximizeFlated asmaximizeFfined as0Fa=Fa(1)VD) of H .To reduce the complexity, the problem  can be dIn this case, the Euclidean distance between the optimal fully-digital precoder (combiner) and the hybrid precoders (combiners) is minimized, which will maximize the spectral efficiency of hybrid precoding. Once we solve  and 14)14) and oIn data generation, we generate the channel matrix rding to . We consJ denotes the size of the dataset. Stochastic gradient descent with momentum (SGDM) optimizer is used to reduce the loss and update the weight of the network. The epoch, batch size, and initial learning rate are set as 200, 400, and 0.0005, respectively. The learning rate is decreased after 20 epochs by a factor of 0.9.We implement the proposed neural network using MATLAB as a simulation environment. Notably, the channel matrices have been normalized before inputting the neural network. The typical mean squared error (MSE) between the label In this section, we evaluate the spectral efficiency of the proposed neural network and compare the performance with the following benchmarks:Benchmark 1: SVD with perfect CSI : Considering that the TX has obtained the perfect CSI, the TX performs hybrid precoding using a fully-digital precoder and combiner, which can be obtained from the SVD of the channel matrix Benchmark 2: MO-AltMin with perfect CSI [fect CSI : Given tfect CSI .Benchmark 3: SOMP with perfect CSI [fect CSI : Given tBenchmark 4: MO-AltMin with CsiNet [h CsiNet : In thisM is set as 25. It can be observed that the spectral efficiency of all considered algorithms increases monotonically with increasing SNR. The SVD with perfect CSI has the best performance. We observe that our proposed method can approach the performance of the MO-AltMin with perfect CSI, which means that our end-to-end neural network can effectively generate the precoders and combiners, which maximizes the spectral efficiency. In addition, our proposed scheme also has better performance than the MO-AltMin with CsiNet in the same codeword length, which verifies that our proposed end-to-end method can get better performance than the traditional separate design method in this situation. The SOMP with perfect CSI has the worst performance because it cannot select the optimal set of array responses from the dictionary.M is small, e.g., We further investigate the performance of our proposed method and conventional hybrid precoding design approaches versus the length of codewords. In Finally, we compare the computational complexity for our proposed method and different benchmarks. In this paper, we consider the joint design of CSI feedback and hybrid precoding for FDD massive MIMO systems. We propose a new deep learning-based end-to-end method that bypasses channel reconstruction and directly designs the hybrid precoders and combiners from the feedback codewords for FDD massive MIMO systems. We propose a new neural network that jointly optimizes CSI feedback and hybrid precoding. In order to train the network, we generate the input-output pairs, where the input is the channel matrices and the output is the hybrid precoders and combiners. Numerical results indicate the ability of the proposed network in reducing the feedback overhead and boosting the system performance in terms of spectral efficiency, especially in the case of the limited feedback resources. Future research directions include some other transmission modules, e.g., the downlink pilot transmission and quantized CSI feedback. Moreover, the performance of our proposed method in terms of energy efficiency is another promising direction for future works.


BackgroundPreoperative antibiotic prophylaxis is a method of administering antibiotics prior to surgical procedures to decrease surgical site infections. The Center for Disease Control and Prevention (CDC) guidelines recommend administering the chosen antibiotic within 60 minutes prior to incision. However, further research can be conducted to explore and determine a more precise and ideal time for preoperative antibiotic prophylaxis.MethodsThis paper explores the most used antibiotics within the Department of Neurosurgery at Arrowhead Regional Medical Center, which are cefazolin and clindamycin, and pinpoints the ideal time of preoperative antibiotic prophylaxis based on peak serum levels. It will present and discuss findings by analyzing the pharmacokinetic profiles of each antibiotic, focusing on the minimal inhibitory concentration (MIC), time to peak in the tissue, and duration of action to determine the appropriate time for redosing.ResultsOur findings indicate that based on the pharmacological profiles, the ideal time to administer preoperative antibiotics for cefazolin is 40 minutes prior to incision, and for clindamycin is 45 minutes prior to incision.ConclusionsThis study may help guide clinical decision-making and lead to minimizing the rate of infections and decreasing hospital stay. Surgical site infections (SSIs) have been the norm since the origins of surgery until the nineteenth century when the concept of antisepsis was developed . The firCurrently, the use of preoperative antibiotic prophylaxis has significantly decreased the incidence of surgical site infections. The Center for Disease Control and Prevention released guidelines for preventing SSIs in 2017 which discussed the use of parenteral antimicrobial prophylaxis prior to incision. The current timing guidelines for antibiotic administration are defined as within 60 minutes prior to incision. However, these guidelines fail to provide further details on the timing of antibiotic administration given the duration of therapy for the selected prophylactic antibiotic . While iThe parameters that are necessary to accurately assess antibiotics for the best window of application to minimize post-surgical infections include tissue half-life, minimal inhibitory concentration, and redosing interval. Half-life is the amount of time required for the plasma concentration of the drug to reduce by half. This paper is focused on tissue concentration over serum concentration as tissue concentration is more specific for surgical infections. The minimal inhibitory concentration (MIC) is the concentration of antibiotics at the site of infection that inhibits bacterial growth. The MIC90 is the MIC at which 90% or more of bacteria are inhibited. Furthermore, dosing interval is important to maintain a bactericidal level of antibiotics in the system and has been shown to be neglected. The dose interval is 1-2 times the half-life of the drug and is measured from the time of administration rather than the start of the procedure.The aim of our study is to investigate practices that would allow for the ideal timing of preoperative antibiotic prophylaxis. It is a quality metric that is nationally mandated and reported to the public by Medicare and Medicaid. Within our home department, the Department of Neurosurgery at Arrowhead Regional Medical Center (ARMC), the current policy is to follow the preoperative guidelines outlined by the CDC: 60 minutes prior to incision. ARMC practice reflects a dosing interval of 4 hours subsequently for both cefazolin and clindamycin. We believe that the ideal timing for administration of preoperative antibiotics will vary based on the pharmacological properties of each antibiotic and that it would be beneficial to begin surgical incision during the peak serum level specific to each antibiotic.Mechanism of action and pharmacokinetics of two antibiotic agentsProteus, Escherichia coli, Klebsiella, and Staphylococcus aureus [Cefazolin, a beta-lactam antibiotic, is a widely used first-line prophylactic agent for surgical procedures. It is the only first-generation cephalosporin in the United States and works by binding to penicillin-binding proteins, which play an important role in bacterial cell wall construction . By inhi aureus . Cefazol aureus . Cefazol aureus . It has  aureus ,7.Streptococci, Pneumococci, and Staphylococci. Clindamycin is dispersed throughout the body fluid and tissues, with the exception of non-significant levels in the cerebrospinal fluid (CSF). Clindamycin is also primarily excreted through urine . It is cTo analyze our proposal, we chose the most commonly used antibiotics within our home department, the Department of Neurosurgery at Arrowhead Regional Medical Center which were cefazolin and clindamycin. Our team obtained data from existing literature on cefazolin and clindamycin pharmacodynamics when administered intravenously in adults with normal renal function. The following factors were deemed relevant: serum half-life, time to peak serum concentration, minimal inhibitory concentration (MIC), time to peak in tissue, and dosing interval. All of these are parameters of time except for the minimal inhibitory concentration which is an important value because it represents the smallest concentration of antibiotic needed in tissue to remain bactericidal. It is dependent upon the bacterium, the affected (in vivo) human, and the antibiotic utilized to combat the bacterium . The afoTable Cefazolin has a narrower time frame for incision, as well as a shorter redosing interval Table . AccordiCefazolin and clindamycin differ in many ways, including their metabolism. Clindamycin is metabolized by the liver whereas cefazolin is cleared through the kidneys and has been known to cause acute interstitial nephritis in some cases ,21. AbnoS. aureus [Along with clindamycin and cefazolin, another commonly utilized antibiotic is vancomycin. However, we decided not to include vancomycin in our proposal because the dosing is heavily based on many factors including renal function, body weight, age, and gender. Vancomycin exists as a powerful antibiotic against gram-positive bacteria that should be administered slowly and monitored closely to avoid as best as possible nephrotoxicity and resistant . aureus . It has Possible future studies can feature both retrospective and prospective reviews. In terms of the retrospective studies, infection rates after surgical procedures can be compared to the timing of antibiotic administration. Additionally, data can be collected to observe the compared peak time of pediatric and adult patients without normal renal function. A statistical power ratio can be conducted to determine the necessity of administering preoperative antibiotics at ideal timing, maximizing their therapeutic output. As for prospective studies, it may be beneficial to explore the significance of preoperative antibiotic administration based on the ideal timing defined in our study. Additionally, a larger sample size would be necessary in order to implement a power ratio on the data for a more nuanced picture.We sought to decrease the rate of SSIs in all surgical procedures by utilizing the most used antibiotics within the Department of Neurosurgery at Arrowhead Regional Medical Center. Our findings indicate that the ideal time to administer preoperative antibiotics stands at 40 minutes prior to the incision for cefazolin and 45 minutes before incision for clindamycin because these antibiotics will be at peak levels in tissue. Furthermore, both antibiotics should be readministered during the earlier end of the redosing range to maintain a high tissue concentration. This information provides the basis for further research in the field of post-surgical infections, as we can help elucidate the true ideal time for antibiotic prophylaxis by further testing.


Moreover, after the same time of extraction, the concentration was reduced by 95% at the rebar surface, which could suggest that extraction rate was slower than chloride ion migration to concrete within the electric field. Using the migration coefficient for predicting the extraction time, as well as ignoring the variability of the extraction coefficient and the initial concentration over time, may result in too short or unnecessarily long extraction times.This paper presents a simple comparative method for evaluating the impact of concrete design on the effectiveness of repair with the electrochemical chloride extraction (ECE) process of reinforced concrete structures. This comparison covered two concretes with different types of used cement. Penetration of chloride ions to induce corrosion processes was accelerated with the electric field. However, the corrosion process itself occurred naturally. When the corrosion process was found to pose a risk to the reinforcement, the profile of chloride ion concentration was determined at the depth of concrete cover. Corrosion current intensity during migration and extraction processes of chloride ions was measured with the LPR method. Then, this serious condition for the structure was repaired with electrochemical chloride extraction. Rates of chloride extraction were determined from the derived concentration profiles. It should be noted that the critical concentration C The presence of chloride ions in de-icing agents and the coastal environment, as well as groundwater and municipal wastewater, is defined as the main cause of the risk of corrosion of reinforced concrete structures. Exceeding the critical concentration of chlorides at the depth of reinforcement leads to the initiation and development of a very dangerous type of steel corrosion, the so-called pitting corrosion. Chloride ions contribute to the destruction of the protective layer of passive reinforcing steel in concrete. Then, the mechanism of destruction consists of reducing the cross-section of the reinforcing bars and the accumulation of corrosion products at the surface of steel. The reduced cross-section leads to structural failure. On the other hand, the accumulated products of corrosion cause the bursting of the concrete cover. As the reinforcement is exposed to weather conditions, the corrosion processes accelerate .crit = 0.4% of cement by weight in reinforced concrete structures and Ccrit = 0.1% of cement by weight in prestressed structures are considered as the critical chloride content, at which corrosion process can develop. The American Standards /[OH−] ≤ 0.1.Taking into account the additional presence of hydroxide ions, it can be observed that using the Hausmann criterion and evaluating the results from measuring corrosion current in concrete C1, the whole process of migration and extraction of chloride ions is safe and should not reach the state of corrosion risk according to this criterion. However, the measurements of corrosion did not confirm this assumption. A totally different interpretation could be made for the results obtained for the limit value of corrosion risk for the ratio [ClA diagram in Concrete C2 demonstrated a similar trend. A more considerable drop in chloride ion concentration was noticed during the first phase of extraction than in the second one b. These Therefore, the extraction coefficient was expected not to be the constant value during electrochemical extraction of chlorides from concrete. Moreover, the concentration at the edge of the element was observed not to be constant, but it was decreasing as the extraction progressed. Moreover, the calculated values of chloride concentrations at the element edge did not agree with the values obtained from the chemical analysis. A drop in concentration at the element edge was caused by wetting the specimen with felt, which caused rediffusion of chloride ions at the edge of the test element. The equivalent shape of concentration curves is often based on tests on in situ diffusion of chlorides when chloride ions are eluted at the element edge because of periodic rainfalls.Based on the concentrations of chloride ions determined in the tested concretes with the method described in point 3.4, the coefficients of chloride extraction in the tested concretes were determined and their values are shown in Based on chloride ion concentrations at the test element edge, which were determined by the approximation method of computational curves expressed by the Equations (3) and (4), a simplified theoretical linear change in chloride ion concentrations for two time intervals from 1 to 10 days and from 11 to 21 days of extraction (nges cf. a. Similae (m2/s)) of the extraction coefficient at three different times (e (m2/s)) were calculated after the following extraction times: 24; 96; 120; 144; 192; 219; 240; 288; 384; 504 h using corresponding linear equations describing these changes  = 0.1%, which should be a safe value with no corrosion risk according to the standard [corr = 7.40 µA); C1.2(icorr = 19.40 µA) were characteristic for steel with moderate corrosion activity according to the criterion described in the papers [(x=20) = 0.01% from the model (and C(x = 20) = 0.02% from the tests). Both of these values were lower than the boundary values specified in the standards [corr = 3.96 µA); C1.2(icorr = 1.11 µA) obtained from the tests performed after 21 days of extraction, indicated low corrosion activity according to the criterion described in the papers [crit = 0.4% at the rebar surface was achieved after 21 days of the migration process. Moreover, after the same time of extraction concentration was reduced at the rebar surface by 95%, which could suggest that extraction rate was slower than chloride ion migration to concrete within the electric field.Based on the above values of concentration and the element edge, coefficients of chloride extraction and the Equation 2), the development of extraction of chloride ions over time was modelled by plotting concentration curves of these ions at the thickness of 2 cm corresponding to concrete cover thickness. , the devstandard ,4. This e papers ,30. Anote papers ,30. This(x = 20) = 0.3% (and C(x = 20) = 0.2% determined from the tests), which is a value posing a corrosion risk according to the standard [corr = 4.29 µA); C2.2(icorr = 2.91 µA) were characteristic of steel with moderate corrosion activity according to the criterion described in the papers [(x = 20) = 0.2% from the model (and C(x = 20) = 0.1% from the tests). Both of these values are specified in the standards [corr = 3.56 µA); C2.2(icorr = 3.07 µA) obtained from the tests performed after 21 days of extraction, indicated low corrosion activity according to the criterion described in the papers [crit = 0.4% at the rebar surface was achieved after 21 days of the migration process. Moreover, after the same time of extraction, the concentration was reduced at the rebar surface by 75%, which could suggest that the extraction rate was slower than chloride ion migration to concrete within the electric field.standard ,5. This e papers . Anothere papers . This prThe performed tests demonstrated that cement CEM III/A 42.5 N-LH/HSR/NA improves protective properties of concrete against corrosion of reinforcing steel as corrosion current values were lower at higher concentrations of chloride ions. On the other hand, chloride extraction from the structure built from this type of concrete should be longer to provide as effective extraction as for concrete with cement CEM I 42.5 R. This effect can be explained by the fact that the majority of chlorides in concrete C2 were probably bounded in the cement matrix, so the real concentration of chloride ions in pore water was lower than in this type of concrete. The effect of binding chloride ions in concrete with cement CEM III/A 42.5 N-LH/HSR/NA was also confirmed in the paper , in whice = (1−6)·10−10 (m2/s)) were about 7 times higher than the values determined for concrete C2 (De = (0.3−0.9)·10−10 (m2/s)), which could suggest extraction in concrete C2 was 7 times longer than in concrete C1. Moreover, the analysed model from crit = 0.01% and was the same as for concrete C1 after a 21-day extraction. However, it is known that too long extraction could deteriorate the mechanical properties of concrete and steel in the treated structure and increase the costs of the applied method.Furthermore, the determined coefficient of extraction in concrete must be considered with caution as the duration of the effective chloride extraction can be erroneously evaluated by comparing these coefficients without taking into account the distribution of concentration values at the concrete cover depth. The values of extraction coefficient in concrete C1 equal to  from concrete can be successfully used to compare the effect of the cement used in concrete on the speed of the extraction process.In another application, a rapid test on steel resistance to chloride ions can be performed using the drilled cylindrical specimen of concrete with fragments of reinforcement. This test uses the electric field to accelerate migration of chloride ions to concrete and then the densities of corrosion current are measured at the regular time intervals with the LPR method. A very important point here is that extraction is a longer process than migration of chloride ions into concrete. Hence, modelling the extraction process with the migration coefficient is incorrect and can lead to a too short duration of this process. As a result, this method may be ineffective.The limitations of this study: The method still needs to be tested on a larger number of different concretes.


Gastric cancer is a common and lethal malignancy worldwide. It lacks specific clinical symptoms during the early stages, and when detected, the optimal surgical opportunity is lost. Chemotherapy alone offers limited benefits in advanced inoperable disease or postoperative recurrence. Gastric cancer is a heterogeneous tumor involving multiple gene regulations; thus, multi-target combination therapy is the trend in research. The c-MET protein is a tyrosine kinase receptor belonging to the MET family, encoded by the MET proto-oncogene. After binding with its ligand, the hepatocyte growth factor, MET activates cellular signaling pathways in proliferation, motility, migration, and invasion. In addition, it may be abnormally activated in cancers via mutation, amplification, and protein overexpression.We report a 35-year-old male with advanced gastric cancer and bone metastasis who was intolerant to chemotherapy. He was in poor general condition, with thrombocytopenia and anemia.Next-generation sequencing (NGS) suggested MET gene amplification in the tumor. After savolitinib treatment, the condition improved significantly without noticeable adverse reactions and maintained a progression-free status for 14 weeks.This case report provides evidence for MET tyrosine kinase inhibitors in treating gastric cancer patients with MET gene amplification. It also shows that MET detection is a target in gastric cancer. In 2021, savolitinib was approved in China for treating patients who had progressed after platinum-containing chemotherapy and were intolerant to locally advanced or metastatic non-small-cell lung carcinoma (NSCLC) with a MET exon 14 skipping mutation (METex14m). In gastric cancer, the most common mechanism of aberrant activation of the MET pathway is high MET protein expression, and overexpression of MET protein suggests a poor prognosis. Xiao et al found that patients with positive c-MET expression had significantly shorter progression-free survival (PFS) and overall survival (OS) than those with negative expression. However, there is a lack of extensive reports on the efficacy of savolitinib in patients with MET-amplified advanced gastric cancer. We reported a case of advanced gastric cancer with bone metastasis. The next-generation sequencing (NGS) suggested MET amplification. The patient had an uncontrolled and rapidly-progressive disease after immunotherapy plus chemotherapy. Patients had performance status (PS) scores of 4 points and were intolerant to standard chemotherapy. The targeted therapy with savolitinib for 14 weeks showed that the PS score improved (by 1 point). Imaging suggested improved disease with no significant adverse effects, indicating a better quality of life and improved overall condition and prognosis. The positive outcome of this case provides a new treatment option for gastric cancer patients with MET amplification.Receptor tyrosine kinases (RTKs) and their downstream signaling pathways have attracted significant attention in the research for tumor target therapy. The mesenchymal‐epithelial transition (MET) factor protein is an RTK encoded by the proto-oncogene c-MET. The hepatocyte growth factor (HGF) binding secreted from stromal cells to MET influences biological processes such as cell proliferation, migration, and differentiation.A 35-year-old male was presented to the hospital with “choking, abdominal pain, and distension” after a meal. He had no significant past medical history. However, he had a family history of cancer. His maternal grand-uncle died of lung cancer, the grandmother died of breast cancer, one maternal aunt died of lung cancer, and another maternal aunt developed colon cancer.In October 2021, a gastroscopy and biopsy suggested a poorly differentiated adenocarcinoma of the gastric corpus, stage cT4N+Mx. On December 16, 2021, after 2-cycles of neoadjuvant therapy with camrelizumab plus SOX , the patient underwent radical surgery with total gastrectomy and adhesiolysis. Postoperative histopathology revealed ulcerative, poorly differentiated adenocarcinoma with signet ring cells mucinous carcinoma, stage pT4aN3bM1. In addition, the human epidermal growth factor receptor 2 (HER2) was negative, ki67 was 40%, MSS, Epstein‐Barr virus-encoded small RNA (EBER) negative, programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) < 1%, combined positive score (CPS) < 1%, low tumor mutational burden (TMB-L), with MET amplification (7)  count decreased to 20 × 109/L. A blood transfusion was administered. The lumbosacral pain aggravated, and the oxycodone hydrochloride was increased to 70 mg/12 h. On July 7, 2022, the red blood cell (RBC) count was 2.34 × 1012/L, Hb 6.6 g/dL, PLT 42 × 109/L, carcinoembryonic antigen (CEA) 73.6 ng/mL, cancer antigen 72-4 (CA72-4) > 250.00 IU/mL, and CA19-9 362 was U/mL. The CT revealed bilateral adrenal metastasis, the uneven density of lumbar-2 vertebral bodies, and abdominal and pelvic ascites , anemic face, pale conjunctivae, no obvious bleeding spots, and ecchymosis. The patient’s general condition was poor (PS 4 points), with intermittent fever of up to 38.5 ℃. The lumbosacral pain became worse. Bone marrow biopsy revealed no metastatic tumor cells. Repeated transfusion of RBCs, platelets, and TPO was administered to regulate the anemia and thrombocytopenia. The lumbosacral pain worsened, and he developed a pulmonary infection.In May 2022, lumbosacral pain appeared and gradually increased after six months of surgery and chemotherapies. He received five cycles of lumbosacral radiotherapy and one cycle of concurrent denosumab. Oxycodone hydrochloride 70 mg/day and topical fentanyl transdermal patch 4.2 mg/72h were provided for pain management. On June 15, 2022, the hemoglobin (Hb) was 3.0 g/dL and PLT 11 × 1012/L, Hb 9.0 g/dL, and PLT 221 × 109/L.On July 6, 2022, after nine months of surgery and chemo-radiotherapies, considering earlier intolerance to chemotherapy and MET amplification in the tumor, oral savolitinib 400 mg/day was started, together with supportive treatment for symptomatic relief. After seven days of savolitinib treatment, the lumbosacral pain was gradually relieved, pain medications were discontinued, anemia improved, and fever subsided. The general condition improved significantly (PS score was 1–2 points). The RBC was 3.3 × 1012/L, Hb 11.3 g/dL and PLT 137 × 109/L, carcinoembryonic antigen (CEA) 1.1 ng/mL, cancer antigen 72-4 (CA72-4) 41.4 IU/mL, and CA19-9 18.5 U/mL. The CT showed that the left adrenal nodule had reduced, the right adrenal nodule disappeared, the density of the lumbar-2 vertebral bodies was uneven, and the abdominal and pelvic effusion was less than before , and there was no pallor, bleeding points, or ecchymosis.After 39 days of savolitinib treatment, RBC was 3.85 × 10According to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the patient achieved partial response (PR), that is, a decrease in size of ≥10% or a decrease in tumor density (HU) ≥ 15% on CT, no new lesions, no obvious progression of the non-measurable disease. After 14 weeks of savolitinib treatment, during treatment, the patient survived and CT reexamination showed that the disease did not progress Fig. .This case report of a 35-year-old male with MET-amplified advanced gastric cancer and metastasis who was intolerant and did not respond to conventional chemotherapy showed a significant antitumor effect with improvement in general condition, better PS scores, relief of lumbosacral pain, and regression of bone and adrenal metastasis. The patient achieved partial response after using savolitinib, maintaining a progression-free status for 12 weeks. study demonstrated that in the PD-L1 CPS ≥ 5, the combination of nivolumab and chemotherapy (FOLFOX or XELOX) was associated with superior OS compared with chemotherapy alone (mOS 14.4 vs 11.1), with manageable adverse effects. A growing number of studies suggest that prognosis and treatment of cancer depend not only on type, differentiation, TNM stage, and others but also on the tumor-specific signaling pathways. The HGF/c-MET pathway is essential in regulating multiple processes involved in tumorigenesis and multiple pathways associated with cancer and is a promising therapeutic target.Currently, chemotherapy, targeted therapy, and immunotherapy are widely used for advanced gastric cancer. Recently, PD-L1 and PD-1 inhibitors have been the primary immunotherapies for lung cancer, malignant melanoma, and gastric cancer. In 2017, nivolumab was approved in Japan for patients with unresectable advanced or recurrent gastric cancer that had progressed after chemotherapy, becoming the first immunotherapy approved worldwide for gastric cancer. The results of the Check-Mate649 Surgery was performed on a patient with advanced lung adenocarcinoma diagnosed with stage IIIA (T2BN2M0) lung adenocarcinoma with METex14m after five weeks of treatment with savolitinib. The pathological response rate was 50%, and the postoperative pathological stage was PT1cN0N0. This suggests that preoperative treatment with savolitinib may prolong OS in patients with locally advanced operable NSCLC and provide the basis for a new direction in clinical management.Met genomic alterations include METex14m, MET kinase domain mutations, MET amplification, and MET fusions. Some solid tumors rely on MET gene activity for tumor cell proliferation and survival. METex14m is present in 1% to 3% of NSCLC patients, making the receptor less susceptible to ubiquitination and degradation by the proteasome, resulting in sustained HGF/c-MET pathway activation. Thus METex14m is an independent oncogenic driver that occurs in NSCLC patients. Savolitinib is a novel c-MET inhibitor that exhibits a high degree of antitumor activity. The drug is approved in China for treating patients with NSCLC who develop METex14m after platinum-based chemotherapy or who are intolerant to platinum-based chemotherapy. In phase II clinical trials conducted in China, 70 patients with NSCLC were treated with savolitinib; the ORR (objective response rate) after a follow-up of 17.6 months was 49.2%, the PFS was 1.4 months, the DoR (duration of response) was 8.3 months, and the DCR (disease control rate) was 93.4%. Median overall survival (mOS) was 12.5 months. Adverse reactions were mainly liver function impairment and allergy. In addition to lung cancer, savolitinib is used to treat PRCC and gastric cancer. A phase IB study that evaluated the safety and efficacy of savolitinib in advanced gastric cancer and NSCLC patients with c-MET abnormalities found that the ORR was 9.4 months, disease control rate (DCR) was 39.1% in all patients, and PR was expressed in all gastric cancer patients with MET amplification. Further analysis of the relationship between the curative effect and the copy number of the c-MET gene in gastric cancer showed that all patients with PR had a high MET gene copy number (GCN) expression.Primary MET amplification is seen in various solid tumors, most commonly in NSCLC (<1%–5%), gastric cancer (<1%–10%), type I PRCC  (13%), type II PRCC (3%), colorectal cancer (2%–4%), and with a lower incidence in esophageal and hepatocellular carcinoma.A clinical study (NCT03091192) comparing savolitinib with sunitinib in MET-driven PRCC demonstrated a strong antitumor effect with median progression-free survival (mPFS 7.0 vs 5.6) and a lower incidence of adverse events (52% vs 74%). Furthermore, circulating tumor DNA (ctDNA) MET gene copy numbers (GCN) can predict the efficacy of savolitinib. The higher the plasma MET copy number, the better the effect of the savolitinib treatment. In advanced gastric cancer, patients with a MET copy number greater than 10 had an ORR of 50% and a PFS of 4 to 6 months when treated with savolitinib monotherapy. This indicates that savolitinib has good efficacy in gastric cancer patients with MET amplification. An ongoing correlative study (NCT04923932) also evaluates savolitinib in patients with MET-amplified adenocarcinoma of the esophagogastric junction.The VIKTORY is the first and largest platform umbrella study with 10 phase II trials, the first and most extensive study of multiple biomarker screening-guided targeted therapy in gastric cancer, which showed that the efficacy of savolitinib monotherapy in MET-amplified gastric cancer was significantly better than conventional therapy (6-week PFS rate of 80%). The patient we report here had MET-amplified advanced gastric cancer with metastasis and responded rapidly with a significant response to savolitinib treatment.Interestingly, Ye et al reported an advanced MET abnormal gastric cancer patient with bone marrow infiltration and extensive metastasis, which improved rapidly after taking savolitinib. The general condition remained stable and progression-free for more than 15 weeks. This shows that c-MET is vital in tumor immune escape through the Ras-PI3K pathway and PD-L1 expression in renal cancer cells. Also, there are similar reports of esophageal and liver cancers.,13 Chen et al evaluated c-met and PD-L1 protein expression in gastric cancer tissues in a correlation study. They found that PD-L1-CPS (combined positive score) and PD-L1-TPS (tumor cell positive score) in gastric cancer tissues were positively correlated with c-MET protein expression .Balan et al found that both c-MET and PD-L1 could be significantly up-regulated and co-localized in renal cancer tissues and that using c-MET inhibitors could down-regulate the expression of PD-L1.Gastric cancer is a disease involving multiple genes, and combination therapy is a promising trend in research.This case report of a 35-year-old male with advanced gastric cancer, with bone and bilateral adrenal metastasis, MET gene amplification, and intolerance to conventional chemotherapy responded well with savolitinib treatment. He improved rapidly, with partial response, no progression at 14 weeks, and no noticeable adverse reactions.The authors would like to thank the patient’s family for providing the information about the patient.Medjaden Inc. for the scientific editing of this manuscript.The Internal Medicine-Oncology Ethics Committee of Shaanxi Provincial People’s Hospital approved this study, and the patient’s family members provided informed written consent to publish the case details and relevant pictures. The authors are also deeply indebted to all the tutors and teachers for their direct and indirect assistance and helpful advice. Special thanks to my friends who have put considerable time and effort into their comments on the draft manuscript. We thank Xin-cheng wrote the original draft and initiated the investigations. Gai-li An revised the manuscript and advised on the methodology.Investigation: GaiLi An, XinCheng He.Methodology: GaiLi An.Supervision: GaiLi An.Validation: GaiLi An.Writing – original draft: XinCheng He.Writing – review & editing: GaiLi An.


A reduction in the unnecessary use of antibiotic prophylaxis can prevent antibiotic resistance and adverse drug events. We aimed to evaluate the effects of implementing clinical pathways (CPs) on adherence to a systematic and appropriate duration of antibiotic prophylaxis. We identified 61 eligible CPs and a total of 44,062 patients who underwent elective surgeries associated with CPs. The Poisson mixed model with an interrupted time-series analysis frame was applied to the patient-level data. This enabled a comparison of the adherence rate before and after CP implementation. Furthermore, we examined the effect of application or completion of CP on the adherence rate after implementation. Adherence to the antibiotic prophylaxis guideline substantially increased , compared with that before implementation. Following the implementation into the electronic entry system, we observed an improved adherence not only in CP completion but also in attempted CP execution . The implementation of CP into the electronic prescribing system was associated with a significant increase in the appropriate use of antibiotic prophylaxis among patients who underwent elective surgeries. The results suggest that a computer-assisted CP system for electronic health records could improve antibiotic adherence without significant expense. According to a meta-analysis, surgical site infection (SSI) occurred in approximately 12% of all patients who underwent surgery2. Patients with an SSI have a higher risk of death than those without SSI4. Considering the ever-increasing volume of surgery, SSI prevention plays an important role in patient care. The estimated cost of SSI was $20,785 per patient care and $3 billion per year in the United States in 20125. Therefore, optimal care of patients undergoing surgery and the prevention of SSI are imperative even in terms of their economic impact.The estimated global volumes of surgeries in 2004 and 2012 were 234.2 million and over 300 million, respectively8. According to the American Society of Health-System Pharmacists Therapeutic Guidelines, prophylactic antibiotics should be administered within 60 min, prior to a surgical incision and should be continued for less than 24 h postoperatively9. However, the antibiotic prophylaxis guideline is not followed frequently in clinical situations12. For example, a German multicenter study reported adherence to the guideline in 71% of the cases10. A study on pediatric surgical cases reported an adherence rate of 40%11. In contrast, an Australian study on patients with breast surgery reported an adherence rate of 13%12. Various reasons contribute to the aforementioned low adherence rates. Incorrect wound classification, uncoordinated process, and the exaggerated perception of SSI risk by a physician were the major causes for non-adherence12.Antibiotic prophylaxis refers to the use of antibiotics before surgery to prevent surgery-related infections, including SSI. It reportedly reduces SSI in various surgeries13. Similarly, an Australian retrospective study concluded that non-adherence increased the risk of SSI14. In addition, the prolonged use of prophylactic antibiotics correlated with an increased risk of acquiring antibiotic resistance15.Proper adherence to antibiotic prophylaxis guidelines can lead to an improvement in the clinical outcomes. According to a study that used Taiwan claims data, adherence to the antibiotics prophylaxis guideline was associated with a shorter length of stay, fewer medical expenses, and lower 30-day readmission rates16. CP reportedly increased the adherence to an antibiotic prophylaxis guideline in a particular disease setting19. However, the systematic effect of CP implementation on adherence to an antibiotic prophylaxis guideline in a general clinical setting is rarely evaluated.The clinical pathway (CP) is a tool to improve the quality of healthcare by standardizing the care processThe objective of this study was to examine the long-term effects of CP integrated in an electronic health record (EHR) system on adherence to an antibiotic prophylaxis guideline. Our goal was to provide estimates of systemic changes over various diseases.A total of 44,062 patients were identified Fig. . The medAccording to the univariable and multivariable analysis, the adherence rate slightly increased a year before CP implementation. However, it sharply increased post-implementation . The enhanced effect of CP was maintained throughout the post-implementation period   Table . Further17. Furthermore, it increased the rate of administration of prophylactic antibiotics, within 60 min, prior to the incision from 87.4 to 99.2%. Moreover, the rate of discontinuation of prophylactic antibiotics within 48 h increased from 51.6 to 84.7%18. CP implementation was associated with less antibiotic use in a retrospective study on patients undergoing endoscopic retrograde cholangiopancreatography for common bile duct stones19. However, previous studies examined the effect of CP implementation on the use of prophylactic antibiotic under specific disease conditions. The strength of our study was that it evaluated the effect of CP implementation on adherence to the antibiotic prophylaxis guideline in a cohort including 61 and 44,062 CPs and patients.CP implementation increased the adherence to the antibiotic prophylaxis guideline, similar to previous studies. For example, it reduced the prolonged use of prophylactic antibiotics in patients undergoing laparoscopy-assisted vaginal hysterectomy19. However, the orders in CP should be specific as they are entered into an electronic order entry system. In other words, every CP order is not narrative but a specifically defined element. For example, a CP containing an order of ‘vital sign check every 8 h’ is different from that of ‘vital sign check every 4 h.’CPs were defined diversely in previous studies. Most CPs comprise an algorithm consisting of evaluations, interventions, and standardized care plans. Furthermore, they facilitate an ambiguously defined element, such as ‘routine nursing’Considering the detailed definition of a CP, the system provided flexibility to a physician to decide about its application on a patient. Therefore, it is recommended not to apply a CP to an unusual patient such as one for whom an intensive care unit admission is anticipated. This can be attributed to the calibration of the usual orders of a CP for an ordinary patient. Therefore, a CP was not applied to some patients, following its implementation into the system. In addition, despite the application, we permitted termination of CPs. For example, CP orders should not be applied to a patient with complications as they were designed for one without complications.20. Moreover, the strength of the study includes the level of specification (narrative recommendation vs. element-wise systematic order) and the use of the electronic order entry system.CP application and completion also increased adherence to the prophylaxis guideline. Our study findings are unique in that most previous studies did not distinguish CP implementation from its application. Furthermore, they did not define CP completion21. Furthermore, the prophylactic antibiotic might exceed the limit. Therefore, we examined the effects of CP on antibiotic prophylaxis in a cohort including patients on whom it was not applied.The electronic order entry system allowed a physician to use his or her discretion for not applying CPs to eligible patients. Therefore, our attempts to estimate the CP effect only in patients in whom it was applied could be misleading. A physician might specifically apply a CP to an ‘simple’ patient and use the prophylactic antibiotic for a short duration. However, the CP might not be applied to a ‘complex’ patient22, patient conditions23, and organizational constraints25. Second, the change in the guideline by the National Hospital Evaluation Program or government-driven policies might have affected the adherence rate26. These external effects were not incorporated into the model. Third, the institutional guideline permits the use of prophylactic antibiotics over 24 h postoperatively, which is less strict than the external guidelines. Despite estimating the trend of the adherence rate, the overall rate at the institute was presumably higher than that in other institutes. Fourth, we did not evaluate direct clinical outcomes, such as changes in the SSI rates. Finally, because this study was conducted in a single center, the results may have been influenced by the specific hospital setting.Our study had several limitations. First, implementing CPs alone has limitations for effective antibiotic use control because adherence to guidelines is affected by comprehensive factors such as reminders, educationAntibiotic stewardship programs aim to optimize antibiotic use and ultimately enhance patient care by combining activities such as CP implementation, intervention, tracking, reporting, and education. In this study, we compared the antibiotic adherence rates before and after CP implementation in an EHR system. The adjusted adherence rate was 8% before CP was implemented, after which it increased to > 60% within two years. When measured during the same time frame, the adjusted adherence rate after CP use was 1.5 times as high as that before CP. The results of this study suggest that a computer-assisted CP system for EHR could improve antibiotic adherence without significant expense.27. This single-site time series was set at the office of the Quality improvement and Process, an institutional government in charge of CP development and monitoring.This study was conducted at a tertiary university hospital in the Seoul metropolitan area of Korea. The hospital developed a high-level EHR system. Furthermore, it operates a comprehensive system comprising more than 264 CPs as of 2020CP typically comprises detailed sets of orders that describe how a patient should be cared for, from the time of admission to discharge. CP includes orders on vital signs, activity, diet, intervention, personalized frequency and dosage of medication, fluid administration based on height and weight, and laboratory tests. However, it does not generally contain intraoperative and anesthesia orders.The dose and duration of prophylactic antibiotics for each CP are tailored down to a specific surgery type. For example, an intravenous injection of 2 g cefazolin is recommended in most CPs; however, 1 g cefotetan is used in the CP for a large bowel resection.This predetermined dose and duration of prophylactic antibiotics are guided by the Antibiotic Stewardship Program (ASP) of the Seoul National University Bundang Hospital. This consists of a multidisciplinary group, including infectious disease specialists and physicians from various departments. The ASP aims to optimize the use of antibiotics and prevents the overuse of prophylactic antibiotics. Prophylactic antibiotics were previously administered more than a week. The ASP recommended gradually decreasing the duration from 5 to 3 and 2 days. It currently allows the use of prophylactic antibiotics for more than 24 h only if the physicians insist on a prolonged use under certain clinical situations.A physician or the entire medical department may propose a new CP of detailed orders for a list of eligible surgeries. The proposed CP is reviewed by a multidisciplinary team, including infection specialists, nursing team members, insurance/reimbursement team members, and other physicians, before being implemented into the electronic order entry system.Most CPs are developed in a hierarchical fashion such that a CP for an upper level surgery can be used interchangeably for a subcategory of the surgery. For example, a list for a CP named ‘laparoscopic hysterectomy’ could include surgery names, such as ‘total laparoscopic hysterectomy’ or ‘laparoscopy-assisted vaginal hysterectomy.’ A physician can apply the ‘laparoscopic hysterectomy’ CP to the patient having ‘total laparoscopic hysterectomy’ or ‘laparoscopy-assisted vaginal hysterectomy’ as the scheduled surgery name.Before 2016, a physician had to manually assign a CP to a patient. For example, to assign a CP to a patient expected to undergo 'total laparoscopic hysterectomy,’ the physician had to open a screen containing the list of all CPs and select ‘laparoscopic hysterectomy.’ The system was flexible enough that physicians did not have to prescribe a CP, for example, a patient was reserved to be admitted to the intensive care unit postoperatively.A new system was launched in 2016, which recommends CPs based on the surgery scheduled for each patient. It generates a list of the recommended CPs for each patient. Upon the authorization of an electronic signature by a physician, the chosen CP is activated. This is followed by an entry of the orders of the selected CP into the EHR system. Therefore, the study period was set from 2006 to 2015 to exclude the system-specific effect.Physicians can modify the preselected orders of CP adapted to a patient situation, if necessary. For example, physicians prescribe other antibiotic medications based on their experience of a patient with fever of an unknown cause with suspected infection. In addition, they can stop applying a CP for various reasons, such as development of postoperative ileus or inability to consume the scheduled diet. Furthermore, CP application is automatically terminated when the duration of admission surpasses the predefined limit. Therefore, the completion of a CP refers to the status that the CP is terminated on schedule; however, it allows for a maximum difference of 2 days.The monitoring team organized at the office of the Quality improvement and Process defined and monitored the institution-wide metrics for CP usage. The application rate is defined as the number of CP applied patients divided by the number of CP eligible patients (a person who underwent a surgery from the list of eligible surgeries). The completion rate is defined as the proportion of patients who completed a CP among those for whom CP was applied. The monitoring team investigates the causes and provides feedback to the associated department on a quarterly basis on observing a low application or completion rate.c = 80), CPs without an antibiotic prophylaxis (nc = 13), and those with an extremely high or low adherence rate (< 10% or > 90%) (nc = 21). Therefore, a total of 61 CPs were eligible for this study.Our study protocol was approved by the Seoul National University Bundang Hospital institutional review board (B-1612-375-105) and the study methods were carried out in accordance with the Declaration of Helsinki. Furthermore, the need for informed consent was waived off by the aforementioned institutional review board. We selected all 175 CPs with available metrics for an elective surgery. We excluded CPs of an insufficient number of patients , short period of observation (< 2 years before and after each CP implementation) (nWe selected patients who met the following criteria: 1) included in one of the 61 CPs and (2) admitted between 2 years, before and after the implementation date of each CP  in the analysis.28. Despite the binary adherence outcome, we selected a Poisson model with robust variance estimators because of the high rate of overall adherence. We established a core part of the mixed model for the ith CP as follows to assess the effect of CP implementation:We used a mixed-effect piecewise Poisson regression with a random slope to model the adherence rateIn the aforementioned equation, The model included the effect of CP attempted and not completed and the effect of CP completed (