Worldwide, there is a shifting paradigm from immediate surgery with adjuvant treatment to a neoadjuvant approach for patients with resectable or borderline resectable pancreatic cancer (RPC or BRPC). Comparison of neoadjuvant and adjuvant studies is extremely difficult because of a great difference in patient selection. The evidence from randomized studies shows that overall survival by intention-to-treat improves after neoadjuvant gemcitabine-based chemoradiotherapy or chemotherapy (various regimens), as compared to immediate surgery followed by adjuvant chemotherapy. Radiotherapy appears to play an important role in mediating locoregional effects. Yet, since more effective chemotherapy regimens are currently available, in particular FOLFIRINOX and Gemcitabine/Nab-paclitaxel, these chemotherapy regimens should be investigated in future randomized trials combined with (stereotactic) radiotherapy to further improve outcomes of RPC and BRPC. The majority of patients with pancreatic neoplasms are pancreatic ductal adenocarcinoma (PDAC), containing 90% of the cases. Other subtypes include for example acinar carcinoma, pancreatic blastoma, or neuroendocrine tumors . The incThe main treatment of patients with RPC and BRPC is surgery, but up to 20%–25% of the patients who receive an exploratory laparotomy or laparoscopy do not get the intended tumor resection , 7. EvenThe efficacy of adjuvant chemotherapy has been investigated in various trials. Currently, it is regarded as the standard treatment for patients with RPC or BRPC after resection of the tumor, since it leads to an overall survival benefit compared to surgery alone –12. AdjuComparison between the results of adjuvant and neoadjuvant studies is challenging, since adjuvant trials only include patients with “resected” pancreatic cancer, fit for adjuvant treatment without progression of disease. In contrast, neoadjuvant studies usually include all patients with “resectable” pancreatic cancer, based on diagnostic imaging, before any treatment is given. Hence, these populations are prognostic incongruent. As stated above, many patients with resectable pancreatic cancer do not undergo the intended resection or are not fit enough for adjuvant chemotherapy after resection. Hence, adjuvant studies include the 40%–50% of patients initially diagnosed with RPC or BRPC with the best prognosis, whereas neoadjuvant studies include the entire population of RPC and BRPC. As this will inevitably result in confounding by indication, outcomes between adjuvant and neoadjuvant trials are not comparable. In fact, the only scientifically way to randomly compare the effect of neoadjuvant and adjuvant treatment is by comparing the entire population of RPC and BRPC on the basis of intention-to-treat (ITT). That is, based on the moment of diagnosis, whether or not they received the intended treatment.The outcomes by ITT of neoadjuvant treatment compared with those of adjuvant treatment in RPC and BRPC were previously analyzed in systematic reviews. One systematic review and meta-analysis published in 2018 reported the overall survival by ITT of 3,484 patients from 35 studies with RPC or BRPC who had been treated with immediate surgery or neoadjuvant treatment . The 1,7p = 0.015)  investigating the efficacy of neoadjuvant treatment. Three phase II/III RCTs have investigated the efficacy of neoadjuvant chemotherapy over immediate surgery. The Japanese phase II/III trial of neoadjuvant gemcitabine and S-1 versus immediate surgery, which randomized 362 RPC patients, was presented only as a conference abstract in 2019, and demonstrated a significant advantage of neoadjuvant treatment  . The pha= 0.015) . The mul= 0.015) . The wei= 0.015) , is 30.3= 0.015) Table 1.p = 0.028) (p = 0.56), suggesting a similar effect for both subsets with long-term follow-up. The weighted median overall survival of the RCTs investigating neoadjuvant chemoradiotherapy, calculated with the formula of Gillen et al., was 17 months after neoadjuvant chemoradiotherapy, compared with 14.4 months in patients treated with immediate surgery  . Because= 0.028) . In 2020= 0.028) . The ini= 0.028) . The PRE= 0.028) . In this= 0.028) , 39. The= 0.028) . With a  surgery Table 2.p < 0.001). Of the different neoadjuvant treatments, the 12-month survival estimate was 84% for the patients treated with FOLFIRINOX, compared with 79% in the gemcitabine/capecitabine group, 64% in the chemoradiotherapy group, and 42% in the patients treated by immediate surgery . This trial demonstrated a significant survival benefit for the neoadjuvant approach over the immediate surgery group  or immediate surgery . On the To conclude, there is currently a shifting paradigm worldwide, from immediate surgery with adjuvant treatment, to a neoadjuvant approach. The clinical evidence for neoadjuvant treatment is mostly based on the long-term results of the PREOPANC trial, which shows together with the earlier RCTs presented in the meta-analyses, an improvement in overall survival both in patients with RPC and with BRPC , 42.New chemotherapeutic regimens became available during accrual of the above-mentioned randomized studies. The trials providing the evidence for the neoadjuvant approach started before the era of FOLFIRINOX and Gemcitabine/Nab-paclitaxel and were mainly gemcitabine-based schedules that are currently considered old fashioned. Therefore, the optimal chemotherapy regimen for neoadjuvant treatment has not yet been established. In reviews, the use of FOLFIRINOX in the neoadjuvant setting has shown its benefit in patients with BRPC and locally advanced pancreatic cancer . As a reThe recently published abstract of the SWOG S1505 trial, comparing neoadjuvant modified FOLFIRINOX with neoadjuvant Gemcitabine/Nab-paclitaxel for patients with RPC, did not find a significant difference in survival between the two treatments  . The finYet, no phase III trial has compared neoadjuvant chemotherapy with neoadjuvant chemoradiotherapy. Currently, two RCTs are completed or still recruiting patients to answer this question; the PREOPANC-2 trial  and the In conclusion, the evidence reported so far suggests that chemotherapy should at least be part of the neoadjuvant approach. With a median overall survival that is reported to be longer as compared to RCTs performed with chemoradiotherapy (gemcitabine-based), RCTs on the efficacy of modern chemotherapeutic regimens, with or without concurrent radiotherapy, are warranted.The role of neoadjuvant radiotherapy is not yet fully understood. It is likely that radiotherapy results in more R0 resections, fewer lymph-node metastases, and lower locoregional recurrence rates , 34, 37.In patients with locally advanced pancreatic cancer, improved outcomes in terms of overall survival and local recurrences were demonstrated in patients receiving higher radiation doses  . The recIn the randomized phase II ALLIANCE A021501 trial, neoadjuvant chemotherapy followed by stereotactic radiotherapy has been investigated. In this trial, patients with BRPC were randomized between neoadjuvant extended chemotherapy (eight cycles of modified FOLFIRINOX) versus chemotherapy (seven cycles of modified FOLFIRINOX) followed by stereotactic radiotherapy (33–40 Gy in 5 fractions) or hypofractionated radiotherapy (25 Gy in 5 fractions) . RecentlOne other trial investigating the combination of neoadjuvant chemotherapy and stereotactic radiotherapy is the BRPCNCC-1 phase II trial, randomizing patients with BRPC between neoadjuvant Gemcitabine/Nab-paclitaxel versus neoadjuvant Gemcitabine/Nab-paclitaxel with stereotactic radiotherapy or neoadjuvant S-1 plus nab-paclitaxel with stereotactic radiotherapy. The dose of radiotherapy is 7.5–8 Gy per fraction, for 5 fractions . CurrentThe definitive results of the ALLIANCE 021501 trial and BRPCNCC-1 trial are awaited.In addition to stereotactic radiotherapy, the use of proton therapy in pancreatic cancer is not clear yet. Proton therapy can result in a sharp dose reduction behind the PTV, thereby reducing the dose to the OARs. However, these sharp dose gradients lead to great challenges in case of motion or position uncertainties. In particle therapy, such as carbon ion or muon, this is also the case. The use of muons, low-energy high-intensity particle therapy, on the other hand, is promising since this therapy results in high linear energy transfer (LET) radiotherapy, with a high biological effectiveness compared to photon or proton radiotherapy. This high-LET radiotherapy is characterized by a reduced oxygen enhancement ratio, leading to high efficacy in hypoxic tumors such as pancreatic cancer .Although improvements in survival have been observed in recent trials, a significant proportion of patients still develop progression during or soon after neoadjuvant treatment. Hence, tools for improving treatment effects are warranted.Since pancreatic tumors are known to be relatively resistant to chemotherapy and radiotherapy, due to dense stroma causing hypoxia, a complete pathological response has been reported in only 2.5%–7% of the patients –63. ThisSecond, molecular profiling at the time of diagnosis may guide the selection of individualized systemic treatment. The prospective phase II trial of Tsai et al. found that of the 130 patients with RPC or BRPC, more than 80% of the patients received their neoadjuvant treatment and surgery when molecular profiling was done before start of the therapy . Such hiThird, a better understanding of the PDAC immune environment may help to select new treatments to improve outcomes. The effect of immunotherapy in pancreatic cancer has been disappointing so far, probably due to the dense fibrotic stroma and immunosuppressive tumor microenvironment, and the low incidence of deficiency in mismatch repair pathways and subsequent microsatellite instability . There iThere is sufficient evidence from randomized trials to conclude that neoadjuvant treatment results in better outcome than immediate surgery, particularly in patients with BRPC. For RPC the evidence is accumulating. So far, all randomized evidence is based on gemcitabine-based chemo(radio)therapy schedules. Radiotherapy appears to play a role, particularly in pathological endpoints  and local control. Whether neoadjuvant FOLFIRINOX or Gemcitabine/Nab-paclitaxel is better than conventional chemoradiotherapy remains to be proven, as well as the role of radiotherapy in combination with these chemotherapy schedules. Future research should further explore on combinations of modern systemic therapies combined with  radiotherapy, and chemotherapy-enhancing treatment modalities, such as immunotherapy and hyperthermia.EV and GvT wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.JV-G has served as a consultant for Amgen, AstraZeneca, MSD, Pierre Fabre, and Servier, and has received institutional research funding from Servier (outside the submitted work). Johanna Wilmink: Research funding: Servier, Halozyme, Novartis, Celgene, Astra Zeneca, Pfizer, Roche, Merck, and Servier; Consulting/advisory role: Shire, Celgene, Servier, and Merck/MS (outside the submitted work).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.


Escherichia coli” in the field of “Agricultural and Biological Sciences” from 2015 to 2019 to assess both research trends and scholarly networks in diverse research disciplines. The two keywords of “antibiotic resistance” and “Escherichia coli” were selected to search in the Scopus database. Each review article was categorized into materials, natural waters  and wastewater, journal name, and quartile in category of the journal, the year of publication, and the country. Bibliometric indicators and visualization maps were utilized to analyse the retrieved data quantitatively and qualitatively. A total of 1376 publications in the field of agricultural and biological sciences over the last 5 years were obtained using the keywords of antibiotic resistance and Escherichia coli. With additional keywords of freshwater and wastewater, 4 and 24 studies were obtained, respectively. Wastewater was found to be the most common working environment for the keywords of antibiotic resistance and Escherichia coli. It is also found that the studies of antibiotic resistance are mainly conducted in wastewater environments, focusing on human and food health. Working under “One Health” consisting of human, animal and agriculture, and environmental health could be the only permanent and effective approach to solving antibiotic resistance-related issues.The environment is the most important reservoir for both resistance mechanisms and gene transfer in biological science studies. This study gives a bibliometric overview of studies of “antibiotic resistance” and “The online version contains supplementary material available at 10.1007/s11356-021-14084-1. Escherichia coli transmitted to human beings from the environment via direct or indirect routes such as consumption of the contaminated food and water. A bibliometric study can provide a significant dataset to determine the frequencies and deficiencies of the studies. These bibliometric analyses, therefore, provide solutions to the spread and prevention of antibiotic resistance in the environment.Antibiotic was an important discovery which treats many infections and prevents the spread of infectious diseases. However, bacteria can rapidly evolve resistance to antibiotics  country (country of study), (ii) antibiotic names which are given as multidrug (more than five drugs in the articles) or their names (less than five drugs in the articles), (iii) environment such as seawater, wastewater, and freshwater, (iv) journals’ name, (v) quartile of category, and (vi) other information.For this study, data search and collection were retrieved through the Scopus database. The search strategy encompassed the titles, abstracts, and keywords of the articles that were searched from 2015 to 2019. The document type was limited to articles; however, international presentations and book chapters were also found that are not considered in this study. Furthermore, the subject field was limited to the category of agricultural and biological sciences. The obtained data over the last 5 years from 2015 to 2019 were provided as title–abstract and keywords of “antibiotic resistance” and “Escherichia coli are the first search terms that were used to search the articles in the abstract or title in Scopus. The obtained data over the last 5 years from 2015 to 2019 were provided as title–abstract and keywords of “antibiotic resistance” and “Escherichia coli”, the publication year of 2015, 2016, 2017, 2018, and 2019, and the subject area of agricultural and biological sciences. In this study, title and abstract were searched separately using the keywords. Afterwards, the articles compared found by searching separately and published by the same authors and same title were accepted as one article. Using these two keywords, articles were classified according to them including Escherichia coli or antibiotic resistance or both. There are more keywords on resistance in the various topics encountered while searching the database; however, in this study, we focused on only antibiotic resistance. The terms “antibiotic resistance”, “antimicrobial resistance”, and “bacterial resistance” were used for Escherichia coli as well as the keywords of “coliform” and “Enterobacteriaceae” in the search in Scopus.Antibiotic resistance and In this study, we analysed the studies of antibiotic resistance that were performed in the aquatic environment, but we did not analyse the studies that were done in other environments. The keywords of “freshwater”, “wastewater”, “seawater”, and “water” (other water environments) were used for the classification of water environments. Freshwater includes river, watershed, lake, waterways, groundwater, tap water, drinking water, and surface freshwater. Wastewater consists of sewage, sludge, environmental water, recycled water, drainage water, and reclaimed water. Seawater includes coastal, beach, marine, stream water, recreational water, and surface seawater. Where the publications do not have water media, they were grouped into animal, plant, human, soil, illness, food, and faeces. Soil was also added into this list where the soil is in contact with water. In the case of the publications, if they do not include any of these environments, these studies were classified as E (none). Furthermore, we searched for the country-based indicating the studies were conducted, or where the samples were taken. Where the country name was not presented in the abstract or title, the country names were presented as the country of the first author or corresponding author.The drug names were presented as “multidrug” or their names of “Antibiotic1”, “Antibiotic2”, “Antibiotic3”, “Antibiotic4”, and “Antibiotic5” when the articles have more than five antibiotics or fewer than five antibiotics given in the studies, respectively. Moreover, if an antibiotic name was not included in the abstract or title, but it was mentioned in the study, this antibiotic was accepted as multidrug resistance. The summary or title may not contain an antibiotic name; however, it may contain a resistance gene, and therefore the antibiotic name was included in which the resistance gene is effective.The bibliometric software plays a vital role in visualization of bibliometric analysis data. Distance-based and graphic-based mapping are being used in visualization of bibliometric analysis Garfield . While KEscherichia coli and the environment . Also, it has been visualized with figures for clarity. It provides information that can be considered when submitting publications to the journal by providing data about the related area.This bibliometric analysis covers the studies performed up until 20 April 2020 and 1376 articles in 2015, 2016, 2017, 2018, and 2019 were found within the criteria searched in the Scopus database. It was found that “multidrug” is to be mostly preferred in antibiotic selection. The results obtained were interpreted in the headings of the most relevant journal names, publications, and quartile categories that contributed significantly to the research on antibiotic resistance, Quartiles are categorized into the four quartiles of Q1, Q2, Q3, and Q4. This means that Q1 is occupied by the top 25% of journals in the list, Q2 is occupied by journals in the 25 to 50% group, Q3 is occupied by journals in the 50 to 75% group, and Q4 is occupied by journals in the 75 to 100% group. The most prestigious journals within a subject area are those occupying the first quartile, Q1, and the importance of the other journals declines as we move down through the quartiles , animal, and food having a cumulative percentage of 45 according to the data of agricultural and biological sciences as expected. Overall, the numbers of articles published in each of the environment categories are E (none) (345 articles), animal (343 articles), food (244 articles), illness (71 articles), and human (51 articles) are given. On the other hand, wastewater (47 articles), freshwater (47 articles), plant (42 articles), faeces (36 articles), seawater (23 articles), water (11articles), and soil (11 articles).Figure Escherichia coli studies were presented. The USA (24 articles), China (8 articles), and India (7 articles) are found to be the leading countries in the studies of antibiotic resistance and Escherichia coli in water environment. Nigeria is the fourth country on this list having 6 articles. Bangladesh and South Africa were both found to have 5 articles. These data match with the most productive authors and the countries where their institutes are located. Moreover, it is found that leading affiliations in antibiotic resistance and Escherichia coli studies in water environment are Universidade Regional do Cariri, Brazil, with 12 articles and USDA ARS Roman L. Hruska U.S. Meat Animal Research Center USA with 17 articles. Moreover, Universidad de La Rioja, Logrono, Spain, is listed on the top three author lists.From the results obtained by criteria considered in this bibliometric analysis, the first six leading countries in terms of the highest number of publications on antibiotic resistance and Escherichia coli publications in the field of Agricultural and Biological Sciences from 2015 to 2019 are given in Fig. Escherichia coli, resistance, and gene are noticeable as a cluster. It is found that all these frequently used keywords are interrelated and compatible.The network visualization map of countries and the research-topic network map for antibiotic resistance and Escherichia coli studies were retrieved in the field of agricultural and biological sciences from 2015 to 2019. Only 107 articles out of the 1376 articles were performed on antibiotic resistance and Escherichia coli, which cover only 7.77% of these studies. The drugs used were identified by using the titles, abstracts, and keywords in the bibliometric analysis in the field of agricultural and biological sciences.Research-topic density visualization map for publications is also represented in Fig. Escherichia coli is resistant to many drugs. Therefore, 75% of the studies were multidrug studies which corresponds to our expectations.From the results of the analysis, it is seen that multidrug is mostly preferred in antibiotic selection. The multidrug studies were expected to appear most often as Escherichia coli is closely associated with cephalosporins (third generation) resistance. However, it was observed that there was less focus on cephalosporin resistance compared to the resistance to other antibiotics. It was seen that these publications mostly focused on tetracycline, beta-lactam, and multidrug.As can be seen in Fig. Staphylococcus aureus in hospitals from 1995 to 2005 was performed by using data from newspaper articles, in which they reported inadequate hygiene in hospitals and health management errors  was carried out using Web-based searches  from 1961 to 2007. In the study, they stated that the leading country was the USA followed by the UK and Japan


The depletion of natural sand resources occurs due to excessive consumption of aggregate for concrete production. Continuous extraction of sand from riverbeds permanently depletes fine aggregate resources. At the same time, a major ecological challenge is the disposal of agricultural waste ash from biomass burning. In this study, an environmental friendly solution is proposed to investigate the incorporation of wheat straw ash (WSA) by replacing 0, 5, 10, 15, and 20% of sand in concrete. Characterization results of WSA revealed that it was well-graded, free from organic impurities, and characterized by perforated and highly porous tubules attributed to its porous morphology. A decrease in fresh concrete density and an increase in slump values were attained by an increase in WSA replacement percentage. An increasing trend in compressive strength, hardened concrete density, and ultrasonic pulse velocity was observed, while a decrease was noticed in the values of water absorption with the increase in WSA replacement percentages and the curing age. The WSA incorporation at all replacement percentages yielded concrete compressive strength values over 21 MPa, which complies with the minimum strength requirement of structural concrete as specified in ACI 318-19. Acid resistance of WSA incorporated concrete improved due to the formation of pozzolanic hydrates as evident in Chappelle activity and thermogravimetric analysis (TGA) results of WSA modified composites. Thus, the incorporation of WSA provides an environmentally friendly solution for its disposal. It helps in conserving natural aggregate resources by providing a suitable alternative to fine aggregate for the construction industry. Human activities have spread chaos in the sustainability of planet Earth. It is evident from the current state of our surroundings that rapid environmental degradation and increased consumption of geological resources have caused its everlasting depletion. Concrete is an extensively utilized construction material in the world that requires an enormous amount of aggregate. Natural resources are being consumed by materials extraction. According to Wiedmann et al. , 69.68 bAccording to statistics of the United Nations’ Food and Agricultural Organization, wheat produced globally was 743 million tons in 2017 , it is aConcrete usage has increased exponentially in the last three decades worldwide . Being aBinici et al.  reportedIn short, researchers found the incorporation of agricultural and industrial waste suitable for the achievement of sustainable concrete as it has disposal problems and depletion of natural sand associated with it. It is worth mentioning that WSA has been previously used as a cement blend and composite ,39,40. T2/g, respectively was used. Coarse aggregate was taken from the quarry site of Dorr River, Havelian (Pakistan) having a nominal maximum size of 19 mm, whereas Lawrencepur (Pakistan) river sand was used as fine aggregate. WSA was obtained from open-air burning (uncontrolled) of wheat straw, which was then used as a partial sand substituent in concrete.Cement, sand, WSA, and coarse aggregate were used in this research. Type-I cement satisfying the requirements of ASTM standard C150  along wiCharacterization of aggregate was conducted at the macro level to assess its suitability as fine aggregate. At the macroscopic level, particle size distribution, water absorption, organic impurities of WSA, and aggregate were conducted as per ASTM standard C136 , C40 4444, and CMicrostructural characterization of WSA was performed by conducting scanning electron microscopy (SEM), X-ray diffraction (XRD), and X-ray fluorescence (XRF) to determine micromorphology, crystallographic characteristics, and chemical oxide composition. However, Chapelle’s activity was determined to assess the pozzolanic potential of WSA that might contribute to strength development upon its incorporation in concrete. Wheat straw contains thin and elongated straws that are fibrous at the macroscopic level. Therefore, the micromorphology of both wheat straw and WSA was assessed using SEM using model JSM-5910 JEOL, Japan which are shown in The fibrous nature of WSA at the macroscopic scale has also been retained at the microscopic level which is evident in 2), alumina (Al2O3), and iron (Fe2O3) is 76.22% (>70%), which complies with the chemical requirement of pozzolan as per ASTM C618-15 [2O, which turns the color of these ashes to dark grey [2) was found at 2θ value of 38.27° (d = 2.35 Å) and 43.19° (d = 2.09 Å). However, qualitative analysis of WSA revealed the amorphous nature of silica. Stutzxnan and Centeno [2 fixed per gram of pozzolan. The pozzolanic activity of WSA found was 497.32 mg/g i.e., 50.70% greater than that of the standard sample (330 mg/g) which is shown in The oxide composition of WSA determined by XRF is listed in  C618-15 . The con C618-15 ,52. It hark grey . Crystal Centeno  state th Centeno . In this Centeno . The resThe control mix (W0) was formulated using the volumetric method with the design strength of 21 MPa in compression at 28 days. The concrete mixes were designated as W0, W5, W10, W15, and W20 after replacing 0, 5, 10, 15, and 20% of the volume of sand, respectively with WSA. The water absorption of WSA was compensated in mix proportioning to remove the fluctuation of the effective water-cement ratio that might be caused because of WSA’s higher affinity for water. However, water content varies along with the replacement levels but the effective water to cement ratio was affixed 0.5 for all mixes. The mix proportioning of the concrete is shown in 3) were cast at the relative humidity and temperature of 90% and 23 ± 4 °C respectively which also comply with the ASTM C 511 [Concrete cube samples  was determined. Thereafter, the concrete specimens were immersed in a 5% solution of hydrochloric acid and sulfuric acid separately for 28 days. The concrete specimens were oven-dried after removing from the acid solution and their weight was recorded as W2. The weight loss of the samples due to the deleterious action of acids was determined using formula given in Equation (1).All concrete formulations were assessed for various concrete properties in the fresh and hardened state. Fresh state properties including slump and fresh density were assessed as per ASTM standard C 143  and ASTMterature . The samThe early linear shrinkage response of the cement paste samples containing WSA as partial sand replacement is shown in The slump of concrete containing varying WSA content was determined to assess the effect of WSA addition on the workability of concrete. The result of slump values is shown in The compressive strength of concrete containing the specified WSA concentrations was determined to evaluate the effect of WSA addition up to 90 days of curing. The results of compressive strength analysis are shown in The hardened density of the concrete formulation with various incorporated percentages of WSA at varying ages of curing is shown in The trend between hardened density and curing age is shown in Exponential regression correlation between compressive strength and hardened concrete density is shown in The water absorption of concrete at 7, 28, 56, and 90 days of curing age is shown graphically in Several published studies  have alsThe concrete quality can be evaluated by determining the velocity of the ultrasonic wave in the cement paste matrix. Densified and enhanced microstructure corresponds to the higher value of UPV because of its lesser transit time. Therefore, the higher the values of UPV, the more durable, compact, impervious and less porous would be the concrete. The ultrasonic pulse velocity values of the WSA concrete formulations are listed in In literature , the resWhile A and B are empirical constants. The regression relation between the mentioned properties was determined which is shown in It is well-known that the travel time or velocity of an ultrasonic wave is affected by the nature of the propagating medium. Therefore, the density of the medium is of prime importance. Hence, the relation between unit weight and UPV is explicitly shown in Concrete has an alkaline nature which is vulnerable to acid attack. The binding phase (silicate phases) gets disintegrated while in contact with strong acids. Therefore, the performance of concrete formulations in a severe acidic environment was evaluated by keeping the concrete samples in hydrochloric acid and sulfuric acid for 28 days. After acid exposure, the weight loss results of control and WSA replaced concrete was determined and the results are shown in 2 was consumed by the WSA, confirming the pozzolanic activity. Similar trends of lower weight loss in the second region were observed in the published literature [The pozzolanic nature of WSA in concrete mixes was determined by the thermogravimetric analysis. For the ascribed reason, the TGA of the control mix (W0) and the mix having maximum compressive strength (W10) was determined at the curing age of 90 days. The weight loss and TGA curve for the W0 and W10 mixes are shown in terature ,88, whicterature . The low(a)Macro and microstructural characterization results of WSA revealed that it is pozzolanic in nature, well-graded with a fineness modulus of 2.76, free from organic impurities, and compliant with the ASTM C33 gradation requirement along with porous morphology due to the presence of tubules and microperforations.(b)Increasing slump values were observed with increased WSA replacement levels. This trend was predictable because of the lubrication effect of excessive availability of water absorbed by WSA, hence increased the fluidity of WSA concrete mixes. A maximum value of 85.36% reduction in total shrinkage response at 20% incorporation of WSA might be due to the readily available absorbed water that minimizes the self-desiccation of the cement paste matrix. The maximum decrease in fresh density was 9.5% compared to the control mix.(c)Increasing compressive strength values were attained with both increases in the age of testing and the WSA replacement percentage in concrete mixes. This increase was attributed due to the pozzolanic potential. At 28 days curing age, the compressive strength of all concrete formulations comply with the requirement of structural concrete as the minimal compressive strength of the mixes was higher than 17 MPa being specified in ACI 318, therefore it can potentially be used in various structural configurations.(d)The hardened concrete density of WSA incorporated concrete mixes increased along with the replacement percentages as a result of a pozzolanic reaction and filler effect. The water absorption of the concrete decreased upon the replacement of WSA due to suspected pore refinement by clogging of capillary voids which occurred due to synergic action of pozzolanic reaction and filler effect caused by WSA.(e)Like trends of hardened density, the pulse velocity values increased at all testing ages and replacement percentages. Based on the values of UPV, all WSA incorporated mixes fall in the category of excellent quality concrete. Therefore, higher UPV values show that the quality of the cement paste matrix has been enhanced upon the incorporation of WSA in concrete.(f)Weight loss of concrete containing WSA decreased with the increase in replacement percentage under the action of sulfuric acid and hydrochloric acid. The adverse effects of acids on concrete reduced with the addition of WSA due to densification in the microstructure. Therefore, the resistance toward deleterious agents increased with the increase of WSA incorporation in concrete.(g)The incorporation of WSA in the W10 mix has shown the lower value of weight loss in the second region which corresponds to the lower percentage of portlandite than that in control concrete. Thus, the WSA also shows pozzolanic activity when used as fine aggregate replacement in concrete.Environmentally friendly disposal of WSA by incorporating it as partial fine aggregate replacement in concrete has been proposed in this research. A few of the prime findings of this research are:Conclusively, environmentally friendly incorporation of WSA provides a solution for ash disposal and subdues ecological depletion, especially air pollution, which poses a serious hazard to human health. For the construction industry, it would help in the conservation of natural aggregate resources by providing a feasible source of raw materials.


Immunologic hyporesponsiveness (HyR) is considered as an inability to mount immune responses to vaccination of at least the same degree as earlier doses. For meningococcal vaccines, HyR has classically been associated with unconjugated but not conjugated polysaccharide (PS) vaccine dosing, but the clinical relevance is unclear. To characterize meningococcal vaccine HyR, a PubMed search was conducted without date limits as follows: (hyporespons*) AND  AND (vaccine OR mechanism OR MOA OR causes). Papers from the authors’ files, including HyR insights with other vaccines, were included. Classic HyR with repeat unconjugated PS vaccine (MPV) dosing is thought to be associated with memory B-cell (BC) depletion, causing reduced responses on redosing with the same PS. This lack of immunologic memory and interference is seen years after MPV dosing across age groups. As data is added, other examples seem to fit the HyR definition but differ from the classical mechanism and its implications. First, passively transferred maternal antibodies (Abs) may interfere with neonatal adaptive immune response and ultimately those of childhood vaccination by binding to vaccine antigen (Ag) and inhibiting Ab production. Second, multiple dose schedules of meningococcal conjugate vaccines can show reduced responses to later doses in the series but memory is still established and amnestic booster response later achieved. Finally, carrier-induced epitopic suppression, occurring when PS Ag epitopes presented on a protein carrier are inhibited by prior/concurrent dosing with the same carrier, has also been reported. These 3 examples of alternative HyR mechanisms are not associated with memory BC depletion but are likely due to high circulatory Ab levels reducing responses, which is transient, reduces with Ab waning, immunologic memory remains intact, and is not clinically significant.This literature review identified HyR mechanisms other than the classic mechanism associated with memory BC depletion that may account for decreased immune response to subsequent vaccination. Understanding the type of HyR observed with meningococcal vaccines is crucial, as these mechanisms vary in terms of potential clinical significance and the duration of their impact.Jamie Findlow, PhD, Pfizer  Paul Balmer, PhD, Pfizer


Fiber-reinforced concrete (FRC) has become an alternative for structural applications due its outstanding mechanical properties. The appearance of new types of fibres and the fibre cocktails that can be configured by mixing them has created FRC that clearly exceeds the minimum mechanical properties required in the standards. Consequently, in order to take full advantage of the contribution of the fibres in construction projects, it is of interest to have constitutive models that simulate the behaviour of the materials. This study aimed to simulate the fracture behaviour of five types of FRC, three with steel fibres, one with a combination of two types of steel fibers, and one with a combination of polyolefin fibres and two types of steel fibres, by means of an inverse analysis based on the cohesive crack approach. The results of the numerical simulations defined the softening functions of each FRC formulation and have pointed out the synergies that are created through use of fibre cocktails. The information supplied can be of help to engineers in designing structures with high-performance FRC. Fiber-reinforced concrete (FRC) can be considered a composite material as it merges two materials seeking to improve the properties that they individually have. While the plain concrete matrix provides the stiffness and the compressive strength, the fibres enhance the reduced tensile strength and brittleness of plain concrete. The result of this combination is a material with a remarkable compressive strength and an improved flexural and tensile strength, ductility, toughness, and impact resistance among other characteristics. ,2,3. SevAmong all the available types of fibres suitable for being added to concrete, steel fibres, when added to concrete forming steel fiber-reinforced concrete (SFRC), have been the most used ones in structural applications such as footbridges, pavements, or tunnel linings ,9,10,11.As was mentioned in the previous paragraph, outstanding FRC properties might be obtained by mixing different types of fibers, but, in all cases, if a structural application is sought, the material properties must comply with certain requirements set in standards. There are national standards and structural design recommendations that establish the minimum mechanical properties that a certain type of FRC should meet to take advantage of the contribution of the fibres to the material properties ,21,22. HDue to the difficulties of developing such models, different theories have tried to describe the fracture process of concrete and FRC. Among them, the crack band theory  assumes To obtain such a relationship, some authors employed a numerical inverse approach that identified the mechanical and fracture properties required for performing an advanced analysis . Other aσ-w relation of the mentioned types of SFRC had to be determined. Moreover, once the previous tasks were fulfilled, the constitutive model of the same plain concrete with a binary and ternary cocktail of fibres was found. In addition, a discussion regarding the differences among the softening functions and their relationship with the fibre geometry was carried out.Following that rationale, this paper sought to numerically replicate the three-point bending fracture behaviour of the same plain concrete with 0.89% volume fraction of OL and 3D and 5D steel fibers, respectively, by using multi-linear softening functions . To achieve this goal, experimental data found in literature were employed. The volume fraction was chosen, according to , in ordeThe significance of this research relies on the potential optimization of the structural design that might be achieved by implementing the constitutive models in structural design software. Moreover, once the individual softening functions of each SFRC have been determined, the analytical deduction of the softening functions of the cocktails of fibres may be explored in future contributions. Another point that should be underlined is that the mentioned optimisation in the use of the material properties might result in remarkable reductions, or even a total substitution, of the steel-bar reinforcement without compromising the reliability of FRC structural elements. Besides, the reduction of the amount of steel used could suppose not only a decrease in the economic costs but also in an increment of the sustainability of the structure due to the savings in raw materials and safety and improvements of durability.This section will briefly present the manufacturing process of the concrete formulations, the fracture behavior of the mixes was simulated in the following sections. A detailed description of the materials used and the steps taken can be seen in .Five formulations of self-compacting FRC were prepared, adding several fiber combinations to the same plain concrete formulation. Such plain concrete was designed considering three aggregate types: two types of gravel with particle sizes between 4–8 mm and 4–12 mm, respectively, and one type of sand with particle sizes between 0–2 mm. The maximum size of the aggregates was 12.7 mm. In addition, limestone powder was employed, seeking to enhance the workability of the mixes. In all formulations a Portland cement-type EN 197-1 CEM I 52.5 was used as binder. A policarboxylic superplasticiser was added to the formulations pursuing to achieve the self-compactability of all types of concrete while in a fresh state. Tap water was also employed in concrete production. The proportions of all components can be seen in Three types of fibers  were used in order to obtain three types of SFRC. Such formulations were termed SFRC-OL, SFRC-3D and SFRC-5D, respectively. In addition, two fibre cocktails were employed in the other two formulations. One of the hybrid formulations, which was named H1, was obtained by mixing OL and 5D fibres. The other hybrid formulation employed OL, 5D, and polyolefin fibers (PF). This last formulation was called H2. The fibers’ characteristics and their appearance can be seen in The five concrete formulations were designed seeking to obtain high-performance concrete that was capable of surpassing the requirements set in the most common standards ,21,22 fo3 were also manufactured. All specimens were cured in a climatic chamber until 28 days of age. The cylindrical specimens were used to obtain the compressive strength, the modulus of elasticity, and the tensile strength following EN 12390-3 [All concrete batches were manufactured in a planetary mixer with vertical axis following the same scheme. A thorough description of the process can be seen in . From ea 12390-3 , EN 1239 12390-3 , and EN  12390-3 , respectAs can be seen in The fracture behaviour was determined following the process shown in . The resIn The fracture behaviour of the concrete mixes where cocktail of fibres were added can be seen in In Rf1, should be at least 40% of the load at the limit of proportionality (LOPf). Moreover, it should be also checked that the load at a CMOD value of 2.5 mm should be at least 20% of LOPf, usually termed Rf3. In In order to determine if it is possible to consider the contribution of the fibres in the structural design and, consequently reduce the amount of steel reinforcement,  sets of Similarly to what was mentioned in the case of the production process, a detailed description and discussion of the results can be found in .The concept of the cohesive crack zone ,38,39 wat transmitted across the crack faces was parallel to the crack displacement vector w . If the magnitude of the crack opening vector |w| does not decrease, the relation between both parameters can be stated as appears in (1)f(|w|) is the softening function for pure opening, which, in this manuscript, will be defined by multilinear functions, where unloading and reloading branches are aligned with the origin and the softening function is defined by a set of points.This approach considers that fracture takes place in mode I, and, hence, it was assumed that the cohesive stress vector The mentioned formulation is referred to as constant strain triangular finite elements that only have one integration point. It should be mentioned that only the directions parallel to the triangle sides are considered as cracking directions.t can be obtained asIf the element is cracked and, consequently, the crack direction is determined, the stress vector t is constant along the crack, with h being the triangle height, A representing the area of the element, L representing the crack length, σ representing the stress tensor, and n representing the unit vector normal to that side and to the crack. A more detailed explanation of the implementation can be found in [It should be mentioned that the stress vector found in .In the cohesive crack theory, it is assumed that outside the crack the material remains elastic. The stress tensor can be obtained using Equation (3), where the inelastic behaviour is subtracted to correct the elastic deformation of the element by including the crack displacement.E stands for the elastic tangent tensor, αε is the apparent strain vector obtained with the nodal displacements, and +b is the gradient vector corresponding to the shape function of the solitary node, as appears in Equation (4):In Equation (3), t = σ n and also using Equations (1) and (3), the following expression could be obtained.1 stands for the identity tensor. If an iterative algorithm is used, w could be found to satisfy Equation (5).If it is considered that ctf), the element behaves elastically. The tensile strength influences the limit of proportionality of the experimental curves, being greater as ctf increases. Nevertheless, if such value is exceeded, the direction of the maximum principal stress is found and a crack perpendicular to such direction is introduced. From that point onwards, the behaviour of the element is governed, if strains keep growing, by the softening function of the material, which relates the stress and the crack opening relation (σ-w). Apart from the tensile strength, the subroutine requires the modulus of elasticity of the material E. Although it is true that the presence of fibres in concrete changes the post-peak behaviour of the material when subjected to compressive stresses, given that for high crack widths the material behaviour is mainly under tensile stresses, no compressive damage was considered in the material implementation. Moreover, no experimental data appeared in [The approach previously explained was introduced in a material subroutine in a commercial finite element code (ABAQUS) seeking to reproduce the material behaviour. An external file with the coordinates of the nodes and the elements is required to feed the subroutine with the geometry of the elements. If the material has not reached the tensile strength  curves. If the numerical behavior does not reproduce the experimental behaviour, the points that define the softening function are modified and the next iteration starts again. If the numerical behaviour simulates with a certain degree of accuracy the experimental behavior, the points proposed in the first step are considered valid.In order to reproduce the material behavior, a plane mesh with plane stress conditions was employed. The mesh was composed of constant strain triangles, which are finer in the whereabouts of the notch. An image of one of the meshes can be seen in In Similarly to In In this work, not only the experimental curves of the three-point bending fracture tests of the formulations with the addition of one fiber were simulated but also the formulations with an addition of cocktail of fibres. In the case of the formulation H1, the cocktail of fibres was composed by OL fibres and 5D fibres. At this point, it should be mentioned that the fracture curve was simulated following the same iterative process that was applied to the concrete formulation with only one type of fibre. Consequently, although the softening functions of SFRC-OL and SFRC-5D were known, the softening function of H1 could not be inferred from them.In Regarding the fracture behaviour of H2, in The accuracy of the simulations performed in all the concrete mixes was assessed by comparing the fracture energies that were obtained in the experimental tests and the numerical simulations. In the last column of In After the first stretch, the softening function of the SFRC-OL fibers continued to develop a progressive unloading until the failure of the material took place. It should be mentioned that the slope of the rest of the unloading stages was much more progressive than the first stretch. This feature conferred SFRC-OL a certain ductility. Regarding the remaining part of the SFRC-3D softening function, it can be seen in In the case of the softening functions of H1 and H2 formulations, it can be observed in A comparison among the points that define the softening functions of the five mixes analysed can be seen in This study implemented multi-linear softening functions in a user material subroutine of a finite element code (ABAQUS) in order to simulate the three-point bending fracture behaviour of three SFRC and two FRC with cocktails of fibres. The results obtained showed that the methodology used is a robust and efficient approach to simulate the fracture behaviour of the concrete mixes analysed.The mentioned approach reproduced the fracture behaviour of the five concrete types studied with accuracy, obtaining less than a 2% difference between the experimental and the simulated fracture energy.The analysis of the softening function corresponding to SFRC-5D showed that the presence of the double-hooked end in the 5D fibres might not provide an increment of the fiber–matrix anchorage for reduced CMOD values. However, in the case of 3D fibers, no load drops appeared at initial crack widths of the softening function. Regarding SFRC-OL, its softening function boasted a progressive unloading of the material. Lastly, no relationship was observed between the length of the fibres and the maximum crack width of the softening functions found.Regarding the softening functions of H1 and H2, the presence of OL and 5D fibres in both cocktails explains the presence of an unloading stretch and a re-loading stage. The synergies that appeared when combining several types of fibres generated an increment of the maximum crack width both in H1 and H2. However, a further analysis should be performed for a better measurement of the enhancement that the combination of fibers can provide.


Holothuria glaberrima, for its capacity to regenerate the whole intestine after ejection from its internal cavity. We explored the antibiotics’ effects on several intestinal regeneration processes. In parallel, we studied the effect of antibiotics on the animals’ survival, toxicity, and gut bacteria growth. Our results show that tested antibiotics perturbed key cellular processes that occur during intestinal regeneration. Moreover, this happens at doses that inhibited bacteria growth but did not alter holothurian’s metabolic activity. We propose that antibiotics can perturb the cellular events of intestinal regeneration via their impact on the microbiota. These results highlight H. glaberrima as a promising model to study the importance of the microbiota during organ regeneration.The impact of the microbial community on host’s biological functions has uncovered the potential outcomes of antibiotics on host physiology, introducing the caveats of the antibiotic usage. Within animals, the digestive function is closely related to the microorganisms that inhabit this organ. The proper maintenance of the digestive system requires constant regeneration. These processes vary from self-renewal of some cells or tissues in some species to the complete regeneration of the organ in others. Whether antibiotics influence digestive organ regeneration remains unknown. We employ the sea cucumber, Holothuria glaberrima. For this, holothurians were eviscerated and left to regenerate for 10 days in seawater with different penicillin/streptomycin-based cocktails (100 µg/mL PS) including: 100 µg/mL kanamycin (KPS), 5 µg/mL vancomycin (VPS), and 4 µg/mL (E4PS) or 20 µg/mL (E20PS) erythromycin. Immunohistological and histochemical analyses were performed to analyze regenerative processes, including rudiment size, extracellular matrix (ECM) remodeling, cell proliferation, and muscle dedifferentiation. A reduction in muscle dedifferentiation was observed in all antibiotic-treated animals. ECM remodeling was decreased by VPS, E4PS, and E20PS treatments. In addition, organisms subjected to E20PS displayed a significant reduction in the size of their regenerating rudiments while VPS exposure altered cell proliferation. MTT assays were used to discard the possibility that the antibiotics directly affect holothurian metabolic activity while bacterial cultures were used to test antibiotic effects on holothurian enteric microbiota. Our results demonstrate a negative effect on intestinal regeneration and strongly suggest that these effects are due to alterations in the microbial community.The increased antibiotics usage in biomedical and agricultural settings has been well documented. Antibiotics have now been shown to exert effects outside their purposive use, including effects on physiological and developmental processes. We explored the effect of various antibiotics on intestinal regeneration in the sea cucumber  The use of antibiotics has increased drastically over the last decades. Their wide use in human and veterinary medicine has been attributed to their many beneficial effects including the prevention and treatment of pathogen-associated diseases. Moreover, the use of antibiotics has extended to other farming activities, including agriculture and aquaculture ,2 to impApostichopus japonicus are treated to prevent diseases such as Skin Ulceration Syndrome caused by Vibrio sp.  was done to determine the IC50 or EC50 of these doses using GraphPad PRISM. A Spearman correlation test was performed, in addition to Wilcoxon t-test to compare each group against the appropriate controls, the Krustal–Wallis test was also used to compare all the groups, for in vivo experiments. A Wilcoxon t-test analysis as well as Krustal–Wallis (KW) test was performed to analyze toxicity assays. Results are reported as mean ± SD or SEM (specified in figures legends). Statistical significance is represented with asterisks (*) and p-value (p).Statistical analyses were performed using Mann–Whitney (MW) p = 0.4774)  .H. glaberrima, animals were subjected to various antibiotics for 10-dpe following evisceration. Several parameters associated with intestinal regeneration were assessed, including the size of the regenerating gut and the extent of ECM remodeling, cell dedifferentiation, and cell proliferation.To test whether exposure to antibiotics alters the intestinal regenerative process of the sea cucumber t-test p = 0.0262). The effect of erythromycin was only observed at the higher dose since animals treated with erythromycin at the lower concentration of 4 µg/mL (E4PS) did not show a significant decrease in the regenerating rudiment’s area  their actin filaments into spindle-like structures (SLS) . This prp = 0.0012, VPS vs. PS p = 0.0004, E4PS vs. SW p = 0.0012, E4PS vs. PS p = 0.0004, E20PS vs. SW p = 0.0012, E20PS vs. PS p = 0.0004, KPS vs. SW p = 0.0011, KPS vs. PS p = 0.0225 PS vs. SW p = 0.0201) as shown in p = 0.0022, suggesting a perturbed cell dedifferentiation in animals treated with antibiotics.As expected, in rudiments from 10-dpe non-treated animals SLSs and muscle fibers had already been eliminated from the area close to the forming rudiment but were observed in the mid region of the mesentery and close to the body wall B. Interet-tests) reports that both the animals treated with vancomycin or erythromycin have significant collagen fibers in or adjacent to the rudiment compared with control groups . In addition, the Kruskal–Willis test showed a p < 0.0005 which suggests that both vancomycin and erythromycin hinder the process of ECM remodeling.A significant remodeling of the ECM takes place during intestinal regeneration, which can be followed by observing the disappearance of collagen fibers in a graded process that begins near the forming rudiment and moves toward the mesenterial end attached to the body wall . The effOur results show a 9% average proliferation in the coelomic epithelium and 3% in the connective tissue of the SW group animals . Thus, ap = 0.0429)  with no significant differences when compared to controls . In the  0.0429) .p = 0.0048), and not observed in the experimental groups. This result suggests that all antibiotics tested perturbed the characteristic pattern of cell proliferation in 10-dpe regeneration intestines. A further statistical analysis comparing the proliferation rate in between the connective tissue and the mesothelium of each group showed that decreased cellular proliferation ratio in the connective tissue was only significant in non-treated animals  and −0.8545 (p = 0.0015) respectively). After a non-linear regression “log(inhibitor) vs. response -Variable slope” curve fit determines the IC50 for cells incubated with this antibiotic is 1.29 µg/mL and 7.41 µg/mL for 48 and 72 h, respectively. A Kruskal–Wallis test showed significant decreased activity in cells treated with doses from 25 µg/mL compared with non-treated controls, for both 48 and 72 h  (p = 0.0496)  . On the ctively) . However 0.0496) .p 0.0017) and an IC50 2.52 µg/mL at 48 h (p = 0.0002). Meanwhile, when kanamycin cocktails were added, neither an inhibitory nor agonistic effect could be detected (Addition of erythromycin-PS cocktails reflect a negative correlation of r = −0.92 ( at 48 h . Consequdetected .p = 0.0032) showed that the dose of kanamycin 10 μg/mL increased the tissue metabolic activity, supported by Dunn’s multiple comparisons test, but exposure to vancomycin significantly decreased it . Even though there was no apparent correlation, various PS doses significantly increased the enzymatic activity of muscle explants . Moreover, when antibiotic cocktail effects were analyzed, a negative correlation for VPS treatments  at 100 μg/mL was observed  (p = 0.05) and a significant increase at 500 μg/mL  was observed  F. The no 0.0234) H. Meanwhobserved D. Conseqobserved D. The reobserved .H. glaberrima intestinal detritus were isolated. Gram-negative, Gram-positive, or a mixture of both were used to determine bacterial growth inhibition. MIC was performed to identify the antibiotic concentrations necessary to perturb the growth of bacteria. Treatments included penicillin/streptomycin, vancomycin, erythromycin, and kanamycin. Doses were selected based on the MTT results  and KPS affected only the cell dedifferentiation process. E4PS-treated organisms presented a perturbed cell dedifferentiation and delayed ECM remodeling, and E20PS treated sea cucumber revealed the most dramatic results, also showing smaller rudiments in comparison to those of non-treated animals. Because ECM remodeling and cell dedifferentiation are processes that show similar temporal and spatial profiles, it is interesting that the drugs that delay the ECM remodeling , are also characterized with the most dramatic effect  on the degree of cell dedifferentiation compared to non-treated organisms. In addition, the proposed delay in cell dedifferentiation and in collagen depletion in VPS treated rudiments may impair the cell division pattern in regeneration intestines , where the presence of a bacterial group (Proteobacteria) suppressed the regenerative ability of the organism and resulted in tissue degeneration in healthy worms [Two other studies might prove relevant to our findings. The first is a study of elopment . The sechy worms , showingH. glaberrima’s commensal bacteria in the early stages of regeneration influences primarily the cell dedifferentiation. We venture that not only the microbial target of antibiotics on the holothurian intestine, but also the dose administered will explain the extent of this perturbation. For example, the sole addition of a third antibiotic amplifies the effects of the broad-spectrum PS, but the effect of PS is intensified if the added drug is a Gram-positive targeting antibiotic and the dose is increased. These effects may alter processes dependent on cell dedifferentiation, as well as restructuration of the ECM components, epithelial to mesenchymal cellular transition, cell proliferation, and, lastly, the formation of the intestine. This might indicate that the effect of the antibiotics depends on their target mechanism and causes different results on the chronology of how the microbiota regulates intestinal regeneration. Though the mechanism of how the microbiota influences the homeostasis and regenerative response on the intestine has not yet been entirely deciphered , our resPS-based cocktails were found to alter regeneration-associated cellular events such as cell dedifferentiation, ECM remodeling, and proliferation. Interestingly, neither significant survival rate of regenerating animals, nor differential metabolism in holothurians tissues was observed upon treatments of PS-based cocktails. In contrast, antibiotics decrease the growth of enteric bacteria obtained from holothurian guts , Table 1Future experiments should aim at the characterization of the microbial community in regenerating sea cucumbers treated with antibiotics and their comparison to control animals. Such experiments will be crucial to test the effectiveness of antibiotics against the microbial ecology of sea cucumbers. Moreover, evaluation of differential expressed genes during antibiotic treatments, may validate the cellular events that are affected upon antibiotic treatments as well as to support our toxicity assays results.


Surgical antibiotic prophylaxis has been widely used for prevention of surgical site infections (SSI’s). World Health Organization (WHO) global guidelines strongly recommend the administration of pre-operative prophylactic antibiotic, depending on the type of surgery, to reduce SSI’s. However, within Gulf Cooperation Council (GCC) countries, antibiotic resistance has been rising due to unregulated prescribing practice. We aimed to assess adherence to local/international guidelines in the plastic surgery unit of Salmaniya Medical Complex.st of January 2019 to 30th of April 2019. Recommendations and guidelines were provided by South Australian Guidelines for Surgical Antimicrobial Prophylaxis, NHS Greater-Glasgow Foundation Trust. Salmaniya Medical Complex Guidelines were also taken into consideration. This was followed by an implementation of standardized guidelines and a re-assessment period for another four months.This study was a retrospective review of adults’ undergoing plastic surgery between the dates of 1There were 106 patients who met the inclusion/exclusion criteria throughout the primary cohort. With respect to choice and dose of antibiotics, only 21 (19.8%) of the procedures were adherent to global/local guidelines. Similarly, only 11.5% of those cases have met the recommended timing for pre-operative antibiotic administration. After the implementation period, adherence to guidelines regarding choice and time of antibiotic administration has increased to 36.8% and 32.6% respectively. SSI decreased from 1.8% to 0.08%.Practice in SMC in plastic surgery pre-operative antibiotic prophylaxis shows poor compliance to both local and international guidelines in terms of choice, dose, and time of administration. We were able to significantly improve adherence to international/local practice in both areas by implementing an integrated protocol in liaison with the medical staff involved in the plastic surgery unit and operating theatres. As one of the most important medical measures to reduce SSIs, the WHO global guidelines strongly recommend the administration of pre-operative prophylactic antibiotic depending on the type of surgery2.Surgical Site Infection (SSI) refers to an infection that takes place post-operatively involving the part of the body where the surgery took place. SSI is a main factor that increases hospitalization being the third most frequent cause of nosocomial infection and affecting 16% hospitalized in-patients. In surgical patients, SSIs accounted for 77% of deaths due to post-operative complications3-6. One particular study has illustrated that in clean contaminated procedures, prophylactic antibiotics prevents wound dehiscence, bone mal-union, stitch and septal abscesses7. One prospective observational study shows that the incidence of postoperative infections in non-antibiotic groups reach up to 42% compared to 8.9% in antibiotic groups3. Within the literature, the effectiveness of pre-operative antibiotics in preventing post-operative infections in plastic surgery operations has been widely demonstrated 8. Within Gulf Cooperation Council (GCC) countries, antibiotic resistance has been rising compared to European countries, due to unregulated prescribing practice and unaudited use of antibiotics9. As a result, there is a definite need to regulate the use of prophylactic antibiotics through implementing local/international guidelines. Despite that, there is a growing antibiotic crisis with new strains of drug resistant bacteria encountered in wounds10-12. In addition, there is evidence that antibiotics are not recommended for clean procedures 10-13.In plastic surgery surgical prophylaxis, there is a customization of guidelines in different countries and hospitals based on local resistance patterns and types of pathogens. However, there are some common relations between most guidelines. Many guidelines, like the National Health Service (NHS) and South Australia guidelines, agree on the need of antibiotic prophylaxis on clean-contaminated, contaminated and dirty procedures We aimed to evaluate the adherence and accuracy of giving peri-operative antibiotic prophylaxis in plastic surgery with respect to local/global guidelines, in the largest hospital in the Kingdom of Bahrain, Salmaniya Medical Complex. Design and standardsst of January 2019 and the 30th of April 2019. The local guidelines on surgical antibiotic prophylaxis by Salmaniya Medical Complex was used as the main standard in this study14. Recommendations provided by NHS Salisbury15, NHS Greater Glasgow Foundation Trust guidelines16, and South Australian guidelines for Surgical Antimicrobial Prophylaxis17 were adopted where the local guidelines were insufficient.This study was a retrospective, standards based clinical review, evaluating peri-operative antibiotics given to all the patients who underwent operations in the plastic surgery unit in Salmaniyya Medical Complex between the 1Study settings and inclusion and exclusion criteria st of January 2019 and the 30th of April 2019 were reviewed. Guidelines were implemented after the initial assessment period and were re-assessed between the dates of 1st September 2019 to 31st December 2019.Patients who underwent surgery under local anesthesia, received antibiotics as treatment, had incomplete data; were excluded from the study. All adult and pediatric cases (of 1 year or more), who underwent plastic surgery operations under general anesthesia, over the four-month period between the 1Data collection and analysis The data collection included three main categories. The first category was patient demographics and medical background. This included patient identification, age, ethnicity, weight (in kilograms), known allergies and history of adverse reactions to antibiotics, colonization with resistant organisms and chronic comorbidities. The second category was operation details; where details of the operation performed, classification, type of anesthesia used, name of operating surgeon, time of the surgical incision and duration of the operation were noted. The third category was the choice of antibiotic prophylaxis (peri-operative and post-operative) administered including the name, dose, time of administration and reason for administering/withholding a particular drug as antibiotic prophylaxis.Data from electronic and written hospital files were directly plotted into an Excel spreadsheet by the authors.National ID numbers of cases in the inclusion criteria were recorded from the plastic surgery department and were used to access patient files. Data analysis was completed through Excel (2016 version).Implementation period and re-assessment st September to 31st December 2019. Results obtained during the first study period were used to design a quality improvement strategy. An implementation period of three months was given, after which, a retrospective re-assessment was conducted using the same methodology from 1The study took place over a period of one year, which included a three-month period for quality improvement strategies implementation. A total of 236 patients were admitted to the Plastic Surgery Department in Salmaniyya Medical Complex. Out of these cases, 112 had undergone operations/procedures under general anesthesia and received prophylactic antibiotics. After removal of patients with incomplete documented data, a total of 106 patients were included in the primary study. During the 3 months from Sep to Dec 2019, 117 patients met the criteria and were included in the re-assessment period. Operation Classification Within plastic surgery, operations are generally classified into four types: clean, clean-contaminated, contaminated, and dirty. For the purpose of this study, clean procedures have been further divided into aesthetic , uninfected burns (with or without skin grafts), and others . The procedures analyzed during the study period are described in table one . Choice of prophylactic peri-operative antibiotics In all operations accounted for in the primary study, only 19.8% of the cases were given appropriate antibiotic prophylaxis consistent with local and international guidelines . In specClean operationsIn peri-operative prophylaxis of aesthetic procedures, our local hospital guidelines encourage a single dose of cefazolin 1g IV as a STAT dose. Out of 69 patients undergoing aesthetic surgeries in the primary study, 65 patients were prescribed antibiotics pre-operatively as required. However, the antibiotics prescribed in all cases were not the antibiotic of choice. All cases were prescribed either ceftriaxone (third generation antibiotic) or cefuroxime (second generation antibiotic) . AdditioIn aesthetic operations and uncomplicated burns, our facility’s practice was not adherent to current practice. On the contrary, other simple clean procedures had adherence of 83% to guidelines during the primary study . During Clean-contaminated and Dirty Procedures  With regards to clean-contaminated procedures, our facility was not adherent to guidelines during the study period. Three cases of cleft lip/cleft palate were considered within this category; all of given cefuroxime . All casTime of administration of prophylactic antibioticsIt is recommended that IV peri-operative antibiotics are to be administered within 1 hour prior to surgical incision according to local hospital guidelines. Within the plastic surgery department in our treatment facility, there was significant non-compliance with regards to this element. Only 11.5% of operations were adherent to timely administration of antibiotics . The NHSRe-assessment Period Following the re-assessment, we observed a significant improvement, with a 36.8% adherence to the recommendations in total procedures, in comparison with 19.8% total adherence within the primary study . Further18-29. Even though abdominoplasties are classified as clean procedures, the use of prophylactic antibiotics is recommended within most guidelines, taking into consideration the prolonged operation time, extensive dissection and significant dead space15.The prescribing practice of prophylactic antibiotics within plastic surgery has been an area of controversy, due to the lack of randomized controlled trials examining the role of prophylactic antibiotics in plastic surgery. Evidence has supported the use of prophylactic antibiotics in various contaminated surgeries and clean breast surgeries30. In clean aesthetic operations, cefazolin 1g IV stat is recommended, yet our hospital had limited supply of the drug. On the other hand, in the majority of the surgeries involving uninfected burns not covered by prophylactic antibiotics, increasing the chances of surgical site infections. We observed a pattern of over-prescribing in elective aesthetic surgeries, including the use of broad-spectrum antibiotics and prescribing a course of antibiotics post-operatively, which could be a result of common practice and surgeon preference to reduce a feared risk of complications in an elective surgery. Similar practice was also noted in a cross-sectional study, surveying surgeons on their prophylactic antibiotic use17 However, our facility used cefuroxime in most of these operations.Within our hospital, most antibiotic use that was not adherent to the recommendations was due to the inappropriate choice of the antibiotic being used. For example, according to current best practice, it is recommended that co-amoxiclav for prophylaxis is used for cleft lip/palate procedures.30. More to the point, we observed a preferential tendency towards the use of broad-spectrum antibiotics, especially third generation cephalosporins. Global Point Prevalence Survey of Antimicrobial Consumption and Resistance  in 2017 revealed high rates of use of cephalosporins in general at our hospital and third generation cephalosporins in the surgery department in particular, which explain the significantly high use of third generation cephalosporin within our studied populationClostridiumdifficile infections, causing a burden on both the patient and the healthcare system31.The excessively inappropriate use of antibiotics has been a major cause of resistant bacterial strains and Staphylococcus aureus bacteria isolated from blood samples, had isolates susceptible to oxacillin (a narrow- spectrum b-lactam). This suggests that the use of narrow-spectrum beta-lactams such as the recommended flucloxacillin would still be effective in the majority of cases. It was also reported that resistance pattern to cephalosporin included 50% of E. coli and 45% of K. pneumoniae. Unfortunately, insufficient data was available to calculate the Drug Resistance Index of cephalosporin in Bahrain18. Resistance and sensitivity pattern in the local population needs to be studied for better antibiotic use guidance. It is well-known that the recommended administration of the antibiotic is prior to incision, in order to obtain the required level of antibiotic at the site of surgery19. The majority of cases at our hospital received prophylactic antibiotics after the incision was made, creating a risk of surgical site infection. Global Antimicrobial Resistance and Use Surveillance System (GLASS) Report published in 2020 by the WHO showed that 64.5% of patients from Bahrain who had Quality improvement strategies After conducting the primary study, we studied the areas of improvement in our practice. The results of the study were revealed and discussed within the plastic surgery department in the form of a meeting and summary leaflets were distributed to all plastic surgeons for feedback. Weekly summaries of the practice were reviewed in the morning meeting at the end of each week during the implementation period, during which points of improvement and common mistakes were further reinforced. Theatre staff played a role in ensuring that prophylactic antibiotics were given during the recommended time pre-operatively. We included a section on timing of preoperative antibiotic prophylaxis, adopted from the WHO Surgical Safety Checklist, within our local preoperative checklist and the supply of cefazolin was discussed with the pharmacy department. We observed a deficiency in the recommendation details within our local guidelines in the following areas: burns needing surgical intervention, clean operations not involving grafts or open fractures and clean-contaminated procedures. The importance of adding the mentioned areas within our local guidelines were discussed with the head of the plastic surgery department. The main limitation to our paper as a retrospective study in the initial phase was the quality of documentation and incomplete records, in some cases. The short duration of time had a significant impact on the number of procedures within each category, with some categories having very limited cases affecting the overall compliance result. A re-dose of an antibiotic was not considered as most of the operations in our unit and within this study, did not surpass the 3-hour window required an additional dose. Lastly, a larger sample can be used to produce a statistically significant result for future studies. The main aim of the study was to identify areas of improvement within the current practice of preoperative antibiotic use in the plastic surgery department at our hospital. We achieved an increase of 17% and 21.1% in adherence to recommendations regarding choice and time of antibiotics given respectively. The SSI rate decreased from 1.8% to 0.08% after the protocol intervention. As a result, we contributed to the development of strategies that would aid in encouraging adherence to the guidelines within our department. The success of implementing our quality improvement strategies was aided by a multidisciplinary approach between plastic surgeons, microbiologists, anesthetists and nursing staff; this included opportunity for regular feedback on current practice and the implementation of the required areas in our local preoperative checklist and guidelines. No sources of funds, products, substances, or devices were used in conducting this article. There are no financial or commercial relationships/associations related to any of the authors. The authors have no conflicts of interest to declare.


According to the rapid response system’s team composition, responding teams were named as rapid response team (RRT), medical emergency team (MET), and critical care outreach. A RRT is often a nurse-led team, whereas a MET is a physician-led team that mainly plays the role of an efferent limb. As few multicenter studies have focused on physician-led METs, we comprehensively analyzed cases for which physician-led METs were activated.We retrospectively analyzed cases for which METs were activated. The study population consisted of subjects over 18 years of age who were admitted in the general ward from January 2016 to December 2017 in 9 tertiary teaching hospitals in Korea. The data on subjects’ characteristics, activation causes, activation methods, performed interventions, in-hospital mortality, and intensive care unit (ICU) transfer after MET activation were collected and analyzed.In this study, 12,767 cases were analyzed, excluding those without in-hospital mortality data. The subjects’ median age was 67 years, and 70.4% of them were admitted to the medical department. The most common cause of MET activation was respiratory distress (35.1%), followed by shock (11.8%), and the most common underlying disease was solid cancer (39%). In 7,561 subjects (59.2%), the MET was activated using the screening system. The commonly performed procedures were arterial line insertion (17.9%), intubation (13.3%), and portable ultrasonography (13.0%). Subsequently, 29.4% of the subjects were transferred to the ICU, and 27.2% died during hospitalization.This physician-led MET cohort showed relatively high rates of intervention, including arterial line insertion and portable ultrasonography, and low ICU transfer rates. We presume that MET detects deteriorating patients earlier using a screening system and begins ICU-level management at the patient’s bedside without delay, eventually preventing the patient’s condition from worsening and transfer to the ICU. The rapid response system (RRS) was first introduced in Australia and the United States in the mid-1990s . CurrentThe RRS aims to prevent unexpected patient death and cardiac arrest resulting from unpredictable deterioration of the patient’s condition in the general ward and emergency room. The RRS is composed of two limbs—an afferent limb that can quickly recognize a patient’s sudden deterioration and risk situation and an efferent limb that triages patients, performs resuscitation, and stabilizes the patients at the bedside . Mainly,Currently, more than 10 years later, various types of the RRS are operating worldwide, and the RRS is well established in many hospitals. As few recent studies have focused on METs, and most RRSs were physician-led METs in Korea, in this study, we retrospectively analyzed cases for which physician-led METs were activated. Data on subjects’ characteristics, activation causes, activation methods, outcomes, and interventions by the MET through a cohort from nine tertiary teaching hospitals were collected and reviewed.This multicenter retrospective cohort study included subjects over 18 years of age who were admitted to general wards in 9 tertiary hospitals in Korea from January 2016 to December 2017. Only the first MET activation during each hospitalization was included. If a MET directly reviewed the patient’s medical record, made a clinical decision, or treated the patient, it was judged as MET activation. Subjects without information regarding in-hospital mortality were excluded from the analysis.Each hospital’s MET operated differently from each other. Among the 9 hospitals, 3 operated their METs 24 h a day, 7 days a week, whereas 6 operated their METs part-time—2 hospitals operated their METs during regular working hours on weekdays, another 2 hospitals operated their METs extending to night hours on weekdays, and the remaining 2 hospitals operated their METs extending to the weekend. The MET was activated using a screening or calling system. The screening criteria of the nine hospitals were slightly different. Six hospitals used a single-parameter trigger system, two hospitals used the Modified Early Warning Score or National Early Warning Score (NEWS), and one hospital used a single-parameter trigger system along with NEWS. A single parameter, including abnormal blood pressure, high or low respiratory rate, tachycardia or bradycardia, fever or hypothermia, oxygen desaturation on pulse oximetry, neurological deterioration, threatened airway, lactic acidosis, hypoxemia, hypercapnia, and metabolic acidosis on arterial blood gas analysis, can also trigger the MET. The parameters were collected from the electronic medical charts of all subjects. Furthermore, the triggering threshold was slightly different among the hospitals see . A call After the MET activation, a doctor or nurse in the activated team completed a standardized sheet related to the activation event. The following data were included: age, sex, date of admission, department of admission, diagnosis at admission, comorbidities, date and time of MET activation, interval between admission and MET activation, clinical department at the time of activation, method of activation, cause of activation, do-not-resuscitate (DNR) order before and after MET activation, MET interventions, and results of MET activation. The types of activation methods were screening, doctor call, nurse call, CPCR, and others , and the causes of activation were sepsis, shock, respiratory distress, cardiopulmonary arrest, arrhythmia, altered mental status, metabolic acidosis, and others. In addition, the ICU discharge date, hospital discharge date, and death date in subjects with MET activation were collected. The data extraction time (time zero) was based on the MET activation time in the medical record, and if there was no recorded value at the time of MET activation, the MET on-site arrival time was used. In the absence of both data, the recorded value of the closest point among the recorded values between 24 h before and after MET activation was collected. Interventions directly performed by the MET were collected.Variables were presented as either mean with standard deviation or median with an interquartile range (IQR), as appropriate. We compared the subjects who died with those who survived after MET activation; Student’s t-test was used to compare continuous variables, and the chi-squared test or Fisher’s test was used to compare categorical variables. All p values were two-tailed, and p values of less than 0.05 were considered statistically significant. Statistical Package for the Social Sciences  was used for all statistical analyses.The study protocol was reviewed and approved by the Institutional Review Board of the National Cancer Center (IRB #2018–0181), which waived the requirement for informed consent because of the retrospective nature of this study.Among the 12,803 cases of MET activation, 12,767 cases were analyzed in this study, excluding 36 cases without information regarding in-hospital mortality. Among the 12,767 cases, 9,299 survived and 3,468 died. The median age of the subjects was 67 years, and 58.7% were males . SubsequConcerning the activation method, 59.2% of the subjects were activated by a screening system, 25.2% by a doctor’s call, 11.7% by a nurse’s call, and 3.7% by CPCR announcement . In the The most common interventions were arterial line insertion (17.9%), intubation (13.3%), and portable ultrasonography (13.0%), and interventions were performed more in subjects who later died . The METAmong 12,767 subjects, 29.4% were transferred to the ICU after MET activation and stayed in the ICU for a median of 5 days . The meaSince MET has been introduced more than 10 years ago, we expect that the proficiency of METs has increased and its role in the hospital has been solidified. In addition, the performance of METs may have been improved along with the developments in medical technology and equipment. Furthermore, we thought that the characteristics of physician-led METs are different from other RRS types; thus, we compared the cohort in this study with those of other studies. In this cohort, most subjects were admitted to the medical wards and the most common cause of MET activation was respiratory distress, followed by shock. METs were activated by an electronic medical records-based screening system more than half of the time, and the commonly performed procedures were arterial line insertion, intubation, and portable ultrasonography at the bedside. Moreover, 29.4% of the subjects were transferred to the ICU, and 27.2% died while hospitalized.The results of this study show higher intervention rates than those reported in other studies on the RRS. Above all, the interventions examined in this study excluded basic interventions, including fluid resuscitation, chest X-ray, arterial blood gas analysis, and medications other than intravenous antibiotics and vasopressors; therefore, the percentage of subjects who had received interventions more than once may be underestimated. However, the cohort in this study shows higher intervention rates when comparing by item. In the large-scale study by Lyons et al. that included 151,400 cases of RRT activation in major hospitals in the United States, the rate for intubation was 4.6% (vs. 13.3% in the cohort of this study), bedside ultrasonography was 0.3% (vs. 13% in the cohort of this study), and newly started antibiotics was 1.5% (vs. 6.6% in the cohort of this study), which were lower than those in this study . In the Among the subjects in this study, 70.4% had been hospitalized in the medical department, which was a result similar to that reported in previous studies ,15, but In our cohort, in-hospital mortality among the 12,767 patients was 27.2%, which is similar to the mean value of 26% (range 12%–60%) in a systematic review of 17 studies that reported the in-hospital mortality of RRT activation cases . Among tThis study has some limitations. First, we investigated the causes of MET activation at the time of MET acting, so we did not account for the subjects’ additional identified problems or diagnosis after being transferred to the ICU. We included subjects with septic shock based on sepsis II definitions. Second, this study was not a before-and-after study—we did not have any comparable data before MET introduction. As we did not know the in-hospital mortality or ICU transfer rate before MET introduction, we compared our results with those reported in other studies instead. Third, this study was conducted in nine tertiary teaching hospitals; therefore, the subjects had several comorbidities and more severe disease than those in nonteaching, nontertiary hospitals. Therefore, the results may not be representative of all hospitals. Nevertheless, this study is meaningful because it demonstrated the well-established physician-led MET in Korea and is a model for other hospitals that are attempting to introduce the RRS.The results of this study confirmed high intervention and low ICU transfer rates. We presume that our MET detects the deterioration of the condition of patients earlier by a screening system and begins ICU-level management at the patient’s bedside without delay, eventually preventing the patient’s condition from worsening and transfer to the ICU.S1 File(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.