The aim of this study was to determine and describe trends in antibiotics utilization in Serbia over a ten-year period. Data were retrieved from publicly available annual reports (2010–2019). The results were expressed as Defined Daily Dose (DDD) per 1000 inhabitants per day (DID). All calculations were performed using the DDD values for the 2020 Anatomical Therapeutic Chemical/Defined Daily Dose (ATC/DDD) version for each year of the study, to account for the DDD changes during the study period. Antibiotics were classified using the WHO Access, Watch, Reserve (AWaRe) classification. Total utilization of antibacterials for systemic use increased from 17.25 DID in 2010 to 28.65 DID in 2019. A statistically significant increasing trend in the use of the Watch category antibiotics was observed. A tendency towards use of broad-spectrum antibiotics, apparent by a statistically significant increase in the rate of utilization of broad-spectrum macrolides, quinolones and third-generation cephalosporins vs. narrow-spectrum ones, as well as a significant increasing trend in the use of quinolones was identified. Total antibiotic utilization was found to be well above the European average. Several specific problem areas were identified, which requires further efforts to improve antibiotic prescribing. The present study provides the information needed to facilitate antibiotic stewardship in Serbia further and proposes specific interventions to optimize antibiotic use in Serbia. Antimicrobial resistance (AMR) is one of the biggest challenges of the 21st century, identified by the World Health Organization (WHO) as one of the top 10 global public health threats humanity is facing . A core The use of antibiotics is one of the most important modifiable risk factors for the development of AMR. In Serbia, significant steps have been made over the past decade to reduce the irrational use of antibiotics. These include changes in legislation and a ban on over-the-counter antibiotic sales and better control of antibiotic dispensing ,5. In thMonitoring antibiotic consumption in both the in- and out-patient settings is of utmost importance as it provides the basis for the implementation and evaluation of antibiotic stewardship interventions. The Serbian Agency for Drugs and Medical Devices publishes yearly reports containing aggregated data on antibiotic consumption based on wholesale data , includiMore specifically, in 2019, the ATC Index with DDDs included substantial alterations in DDDs for eight antibacterials. The impact of the changes in DDDs on the patterns of antibiotic consumption differs, but in general, application of the new DDDs has the largest impact on consumption of penicillins, and comparing the trends in antibiotic use with reports published prior to this change in DDDs without accounting for this alteration leads to misinterpretation. A paper that reports on the impact of a change in amoxicillin DDD on the overall consumption of antimicrobials found that changes in total DID (Defined Daily Dose/1000 inhabitants/day) before and after the 2019 DDD adjustment ranged from 5.1% in Norway to as high as 19.2% in Spain . LogicalTaking into account the above, this study aimed to determine and describe the trends and patterns in antibiotic utilization in Serbia, while accounting for the recent DDD adjustments. Secondly, this paper aimed to identify potential problem areas in antibiotic use by employing the WHO Access, Watch, Reserve (AWaRe) classification of 2019. p = 0.089). A statistically significant increasing trend in the use of Watch category antibiotics  was observed. An overall increasing trend was observed, but without statistical significance for the Reserve  and Access  categories of antibiotics.The overall statistical trends for antibiotic utilization and shares of different categories according to the WHO AWaRe classification over a 10-year period in Serbia are shown in p = 0.035) was observed. An overall increasing trend in utilization of penicillins (J01C_DID), cephalosporins (J01D_DID) and macrolides, lincosamides and streptogramins (J01F_DID) between 2010 and 2019 was observed, but it was not statistically significant.The overall statistical trends for utilization of penicillins (J01C_DID), cephalosporins (J01D_DID), macrolides, lincosamides and streptogramins (J01F_DID) and quinolones (J01M_DID) expressed in DID are shown in p = 0.009), third- and fourth-generation cephalosporins  and fluoroquinolones  in total antibiotic utilization. The ratio of utilization of broad-spectrum to narrow-spectrum penicillins, cephalosporins and macrolides (J01_B/N) increased significantly , from 1.42 in 2010 to 4.16 in 2019. This finding is the consequence of utilization of narrow-spectrum penicillins, cephalosporins and macrolides remaining stable between 2010 and 2019 (3.29 vs. 3.26 DID), while there was a statistically significant increase in the utilization of broad-spectrum agents of these classes .Changes in the values of the quality indicators describing the relative use of beta-lactamase-sensitive penicillins (J01CE), penicillins, including beta-lactamase inhibitor (J01CR), third- and fourth-generation cephalosporins (J01DD + J01DE) and fluoroquinolones (J01MA), as well as the ratio of utilization of broad-spectrum to narrow-spectrum penicillins, cephalosporins and macrolides (J01_B/N) over a 10-year period in Serbia are shown in p = 0.001), cefaclor , tetracycline , roxithromycin  and gentamycin . A significant increasing trend was found in the utilization of 15 individual antibiotics, out of which 4 belonged to the Access group . A significant increasing trend was found for the 9 Watch category antibiotics , and for 2 antimicrobials belonging to the Reserve category .When trends in consumption of all individual agents were assessed , a signiConsiderable variation, both in the pattern and amount of antibiotics used at the beginning of the study (2010), year at which the total utilization peaked (2015) and the last available data (2019), was found when the drug utilization 90% (DU90%) profiles were determined . In 2010The share of the Watch category antibiotics in the total number of different agents was 53.30% in 2010 and 53.84% in 2019, and they contributed to 28.87% and 33.86% of the total utilization in 2010 and 2019, respectively. From the Access group, there were between 5 and 6 antibiotics within the DU90%, accounting for 56.67% and 56.33% of the total utilization in 2010 and 2019, respectively. There were no Reserve antibiotics within the DU90% in any of the years included in the study.Reporting on antibiotic utilization is an essential element of surveillance, providing important information in the global fight against AMR . To the According to the results of this longitudinal national study on the utilization of antibiotics in a ten-year period in Serbia, the overall increasing trend in total consumption of antibacterials for systemic use between 2010 and 2019 was observed. Even though the antibiotic utilization decreased from 29.66 DID to 21.60 between 2015 and 2017, this was followed by an increase to 28.65 DID in 2019. In the study period, there were no substantial changes in the burden of communicable diseases that might have driven the increase in antibiotic utilization. According to the “Report on Infectious Diseases in Republic of Serbia for 2018”, published by the Institute of Public Health of Serbia, the infectious diseases incidence rates show a decreasing trend in the period between 2010 and 2017 . SimilarA recent study demonstrated that the main reasons for the increasing trend in total consumption of antibiotics may lie in inappropriate prescription practices in primary care across low- and middle-income countries . To helpp = 0.037), with a maximal value in 2018 (42.5%). According to the abovementioned WHO report, the median proportion of Watch group antibiotics was 29% (IQR: 25–36%), with values ranging from less than 20% in the Nordic countries  to 52% in Georgia [In the present study, a statistically significant increasing trend was observed in the use of Watch category antibiotics between 2010 and 2019  but also fluoroquinolones (ciprofloxacin and levofloxacin) and second- and third-generation cephalosporins . The Watch-group antibiotics have a higher resistance potential when compared to the Access-group antibiotics , where aP. aeruginosa and E. coli to quinolones increased from 47% to 59% and 30% to 35%, respectively. In 2019, 56% of all P. aeruginosa isolates in Serbia were multidrug resistant. For K. pneumoniae, high levels of resistance, including carbapenems, more than 70% to quinolones and more than 80% to third-generation cephalosporins, were present in 2019. High levels of resistance were also reported for penicillin and macrolides in S. pneumoniae [Several findings clearly identify the area where there is the biggest room for improvement in antibiotic use in Serbia—over-use of broad-spectrum antibiotics. This finding is supported by the statistically significant increase in the use of Watch-category antibiotics, the statistically significant increase in quinolones use and the increase in the ratio of broad-spectrum penicillins, cephalosporins and macrolides compared to the narrow-spectrum agents of these classes. Furthermore, when the DU90% profile was determined, it was obvious that among the most commonly used antimicrobials, accounting for 90% of the total utilization, the share of the Watch-group antibiotics of the total number of different agents within DU90% was 53.84% (7/13), on the account of macrolides, quinolones and third-generation cephalosporins. An increasing trend in the utilization of fluoroquinolone was observed in Serbia (11.16% in 2019), which was also used at a high level compared to most other European countries. Based on this parameter, Serbia ranks 5th among all 33 countries with available data , with onThe Serbian government has put in significant effort to confine AMR through implementation of a series of policies and measures, including establishing a national program for the control of bacterial resistance to antibiotics, changes in legislation for antibiotic dispensing, public campaigns and national guidelines, yet the total utilization remains high above the European average. A tendency towards the use of broad-spectrum antibiotics, macrolides, quinolones and third-generation cephalosporins needs to be addressed. Exact factors driving these findings are difficult to completely grasp. Over 80% of antibiotics in Serbia are prescribed in the outpatient setting , and accAlthough our assessment of ten-year trends in antibiotic use has important policy implications, the study has limitations that need to be mentioned. The aggregate-level data used in this study provide no information about the length of treatment and the indication the drugs were used for, nor other specific patient-related data. The used quality indicators are intended for the outpatient setting, and despite efforts to exclude medicines solely available in an inpatient setting, there is a chance that, due to the nature of our data, there was a slight overestimation. Even though the use of DDD is a standardized measure, as with many calculations of an average, the DDD does not necessarily reflect the actual daily dosage. To surpass some of the limitations of the study, a ten-year period and several relative measures and their change over time were used to describe changes in patterns of antibiotic utilization. Therefore, even with several limitation of the study, the methodology adopted is widely used in similar studies and has been considered adequate to evaluate the antibiotic utilization trends.Information about consumption of medicines were retrieved from the annual reports available on the Agency for Drugs and Medical Devices of the Republic of Serbia for a ten-year period between 2010 and 2019. Only medicines classified in the Anatomical Therapeutic Chemical (ATC) classification J01 group  were included. The World Health Organization (WHO) ATC/DDD (Defined Daily Dose) methodology (Version 2020) was used to describe antibiotic utilization. The defined daily dose (DDD) is defined as “the assumed average maintenance dose per day for a drug used for its main indication in adults”  for seveTrends in antibiotic use were also analyzed based on the route of administration  and AWaRe classification categories. The AWaRe classification describes three categories—Access, Watch and Reserve. The Access category includes 48 antibiotics recommended as the first- and second-line drugs for various infections, which have lower potential for invoking AMR. Drugs classified in the Watch (110) and Reserve (22 antibiotics) groups should be the focus for stewardship programs . AntibioSeveral quality indicators developed by the European Surveillance of Antimicrobial Consumption project  were detThe statistical analysis was performed using the SPSS version 21.0  package. Results were presented as absolute values and percentages. Each of the antibiotic utilization series was explored independently for a trend over time by linear regression. All reported probability values were two-tailed and a 0.05 level of significance was considered to be appropriate. In Serbia, the total antibiotic utilization was found to be well above the European average. Several specific problem areas were identified, which requires further efforts to improve antibiotic prescribing. The present study provides information needed to facilitate antibiotic stewardship in Serbia further and stimulate policy makers to develop action plans, through identifying several problem areas that need to be addressed in order to optimize antibiotic use and tackle antimicrobial resistance.


MET amplification plays an important role in the development of non-small-cell lung cancer (NSCLC) either de novo or in resistance to epidermal growth factor receptor tyrosine–kinase inhibitor (EGFR-TKI) settings. Fluorescence in situ hybridization (FISH) is the standard method for MET amplification. With more and more discoveries of oncogenic driver genes, next-generation sequencing (NGS) plays a significant role in precision oncology. Meanwhile, the role of NGS in MET amplification remains uncertain.MET amplification by FISH was defined as a MET/CEP7 ratio of  >  2.0 and/or copy number (CN)  >  5. MET amplification by NGS was defined as gene copy number (GCN)  ≥  5.Forty patients diagnosed with advanced NSCLC were included. FISH and NGS were conducted prior to MET inhibitors treatment. MET amplification identified by FISH showed the optimal predictive value. The partial response (PR) rate was 68.0% (17/25 with MET amplification) vs. 6.7% (1/15 without MET amplification); the median progression-free survival (PFS) was 5.4 months versus 1.0 months (P  < 0.001). MET amplification identified by NGS failed to distinguish significant clinical outcomes. The PR rate was 60.0%  vs. 40.0% ; the median PFS was 4.8 months vs. 2.2 months (P  = 0.357). The PR rate was 68.8% (11/16) and the median PFS was 4.8 months in patients with focal amplification by NGS.The concordance rate among FISH and NGS was 62.5% (25/40). MET amplification identified by FISH remains the optimal biomarker to identify suitable candidates for MET-TKI therapy. In comparison, amplification identified by NGS seems not as robust to be effective predictive biomarker. Further exploration is needed regarding the focal amplification by NGS in predicting the efficacy.The online version contains supplementary material available at 10.1186/s40164-021-00245-y. EGFR, ALK, ROS1, BRAF V600E, MET exon 14 skipping, RET, KRAS G12C, and NTRK) have been approved for the market  as a first-line treatment ). Written informed consent was obtained from each patient prior to sample collection. From March 2014 to June 2019, 40 NSCLC patients with MET amplification was defined as a mean gene copy number  ≥ 5 and/or MET to centromere of chromosome 7 ratio  > 2.0 and evaluated using the criteria established by Cappuzzo  and the median PFS (5.4 months vs. 1.0 months) were higher in the MET amplification group than in the non-MET amplification group (P  < 0.001). Our findings showed that FISH positivity remains as the “gold standard” for evaluating MET amplification, with high accuracy and good correlation with treatment outcomes. Several patients such as ID23, got progression although they were carrying MET-amplification by FISH. It was indicating that some co-occurring gene alterations have potential to affect response, including TP53 mutation, EGFR amplification.In our study, MET amplification identified by NGS failed to distinguish significant clinical outcomes. In the NGS group, the PR rate of MET amplification and non-amplification was 60.0% (6/10) vs. 40.0% (12/30); the median PFS was 4.8 months vs. 2.2 months (P  = 0.357) . Furthermore, neither tumor mutation burden nor co-occurring MET and EGFR mutations were significantly correlated with the size of the MET amplification. However, other co-occurring oncogenic drivers were associated with non-focal MET amplification [MET amplification using NGS. The results showed a focal MET amplification frequency of 48.5% (17/35). The PR rate was 68.8% (11/16) and the median PFS was 4.8 months in this patient group , suggesting that focal amplification identified by NGS and its clinical relevance warrant further research. Despite some meaningful findings obtained in this study, our small sample sizes require cautious interpretation of the results.Biological characteristics differ between focal and non-focal fication . Therefooup Fig. d. FurtheMET amplification identified by FISH remains the optimal biomarker to identify suitable candidates for MET-TKI therapy. In this small, exploratory series, MET amplification identified by NGS seems not as effective as a predictive biomarker for MET inhibitors. Further research is required regarding the role of focal amplification by NGS in predicting its efficacy.In conclusion, Additional file 1: Table S1. Range of GCN of total 59 patients at the preliminary.


Patients undergoing liver transplantation have a high risk of perioperative clinical deterioration. The Rapid Response System is an intensive care unit-based approach for the early recognition and management of hospitalized patients identified as high-risk for clinical deterioration by a medical emergency team (MET). The etiology and prognostic significance of clinical deterioration events is poorly understood in liver transplant patients. We conducted a cohort study of 381 consecutive adult liver transplant recipients from a prospectively collected transplant database (2011–2017). Medical records identified patients who received MET activation pre- and post-transplantation. MET activation was recorded in 131 (34%) patients, with 266 MET activations in total. The commonest triggers for MET activation were tachypnea and hypotension pre-transplantation, and tachycardia post-transplantation. In multivariable analysis, female sex, increasing Model for End-Stage Liver Disease score and hepatorenal syndrome were independently associated with MET activation. The unplanned intensive care unit admission rate following MET activation was 24.1%. Inpatient mortality was 4.2% and did not differ by MET activation status; however, patients requiring MET activation had significantly longer intensive care unit and hospital length of stay and were more likely to require inpatient rehabilitation. In conclusion, liver transplant patients with perioperative complications requiring MET activation represent a high-risk group with increased morbidity and length of stay. Liver transplantation (LT) remains a life-saving intervention for patients with acute liver failure, end-stage liver disease and hepatocellular carcinoma. Recent studies indicate that LT candidates are becoming older, have a greater comorbidity burden, and increasing Model for End-stage Liver Disease (MELD) score, all of which increase the risk of perioperative clinical deterioration and complications ,2. AlthoThe Rapid Response System (RRS) is a hospital-wide approach for the early recognition and management of inpatients identified as ‘high risk’ for acute clinical deterioration. The evolution of the RRS was prompted by evidence that deteriorating hospital patients commonly experienced ‘failure to rescue’ with subsequent development of serious adverse events, including death, cardiac arrest, and unplanned ICU admission . The RRSThe etiology of acute clinical deterioration events and their prognostic significance is poorly understood in LT patients. Only one previous study examined the frequency and characteristics of MET activation in LT patients. In a single-center retrospective study, 10% of LT patients required MET activation postoperatively, and these patients experienced an increased ICU and hospital length of stay, and higher in-hospital and one-year mortality compared to matched controls [The objectives of this study were to (1) describe the epidemiology of MET activation in patients during the hospital admission in which transplantation occurred, (2) to determine the patient factors associated with MET activation, and (3) to assess the association between MET activation and patient outcomes, including mortality, unplanned admission to ICU, and length of stay.We performed a cohort study of adult LT recipients (≥18 years) at the Victorian Liver Transplant Service at Austin Health . Eligible patients were identified from a prospectively collected database and included consecutive recipients of a de novo or repeat LT over an 84-month period from 2011–2017. Patients receiving multi-visceral transplantation were excluded. The Victorian Liver Transplant Service accepts referrals for LT from the states of Victoria and Tasmania, covering a catchment of approximately 11.7 million people. The ICU has a 23-bed capacity which manages more than 2200 admissions annually. It operates a closed model where only ICU physicians can prescribe therapy. Following transplantation, patients were systematically admitted to the ICU. Upon discharge from ICU, patients are managed in a dedicated transplant ward staffed by transplant surgeons and physicians.The MET was introduced at Austin Health in 2000 and is governed by the Department of Intensive Care Medicine. MET activations were designed to review medical emergencies and clinical deterioration except for cardiopulmonary arrest. A cardiopulmonary arrest was defined by loss of circulation or need for at least one of cardiopulmonary resuscitation, defibrillation, cardioversion, emergency pacing or emergency intubation, and this triggers activation of a Code Blue. The MET consists of an ICU registrar, internal  medicine registrar and ICU nurse equipped with materials and medications to recreate ICU care at the bedside within 5 to 10 min. The MET can be activated by any hospital staff member according to predefined physiological criteria  and stafThe primary outcome was MET activation, and the secondary outcomes were un-planned ICU admissions, length of stay, and mortality. We collected data on demographics, comorbidities, pre-LT location , length of stay, discharge destination, etiology of liver disease, MELD score at time of transplantation, liver disease complications , MET activation data , and patient disposition . Each MET activation was considered a separate event if a patient had >1 MET activation during admission. MET activations were further classified into those occurring pre-transplant (pre-LT MET) and post-transplant (post-LT MET).2, current hemodialysis, previous kidney transplantation or hepatorenal syndrome managed with terlipressin; and severity of chronic liver disease was based on the Child-Pugh classification and MELD scores. Congestive cardiac failure was defined as ejection fraction of <40% on echocardiography or a documented clinical diagnosis of heart failure.Comorbidity burden was assessed using the age-adjusted Charlson Comorbidity Index (ACCI), a validated metric that predicts one-year mortality . For theThe main data source was a prospective transplant database containing information on demographics, etiology of liver disease, MELD score, graft and donor characteristics, duration of LT surgery, and all pathology and radiology results. Two investigators independently reviewed medical records to identify MET activation and extract data. Discrepancies were arbitrated by an independent reviewer. A dedicated electronic MET reporting form is completed by the ICU team after each activation, which documents the indication for the MET activation, outcomes, and a provisional diagnosis of the medical condition responsible for the MET activation.p < 0.10 were initially entered into the model, followed by variables with smaller odds ratios, while variables with p > 0.15 were removed. After all variables were considered, we retained variables with a p < 0.05. Models were compared using Akaike’s and Bayesian information criteria. Tests for interaction were conducted at a 1% level. We determined model calibration with the Hosmer-Lemeshow test. Model diagnostics included an assessment of the linearity of the logit of continuous variables, distribution of the model residuals, and the delta-beta method for influential cases. All analyses were performed using STATA 16.1 . A p < 0.05 was considered statistically significant.We report the mean and standard deviation (SD) for normally distributed continuous variables, and the median and interquartile range (IQR) if distribution was significantly skewed. We used a χ2 test to measure the association between categorical data, and the Mann-Whitney test for continuous data with skewed distributions. Logistic regression was used to determine the association between baseline clinical variables  and the primary outcome of MET activation. We used standard logistic regression as these clinical variables were time invariable in the context of this study, so patients experiencing >1 MET activation contributed only one unique data set. From univariable analysis, a modified stepwise approach was used to select variables into the multivariable model. Clinically meaningful variables with the largest odds ratios and a n = 381) are summarized in There were 383 patients in the LT database. Two patients were excluded as multi-visceral transplant recipients. Characteristics of the remaining patients  patients were recipients of donation after cardiac death. Split LT was performed in 19 of 381 (5.0%) patients. There were no ABO-incompatible transplants performed during the study period. The mean cold ischemia time for the cohort was 6.4 h , and mean warm ischemia time was 0.8 h . The mean LT operation time was 8.0 h . All LT patients had intraoperative cell salvage and autologous red blood cell transfusions. The median intraoperative red blood cell transfusion volume in the database was 1.20 L . All patients were routinely admitted to ICU postoperatively, where the median length of stay was 2.7 days . None of these LT characteristics were associated with a statistically significant probability of post-LT MET activation .During the index admission, 266 MET activations were recorded in 130 of 381 (34.1%) patients . Of these, 40% of MET activations occurred pre-LT and 60% occurred post-LT. Prior to LT, 106 MET activations occurred in 58 patients and post-LT, 160 occurred in 88 patients. Sixty-seven patients recorded a single MET activation, while 33, 10 and 20 patients recorded 2, 3 and >3 MET activations, respectively. Sixteen patients (4.2%) experienced a MET activation both pre- and post-LT. MET activation occurred a median of 11 days  prior to LT in the pre-LT MET group and 11 days  after LT in the post-LT MET group.p = 0.16). Further details of MET activation triggers, clinical observations and investigations are shown in The distribution of MET activations relative to the time of LT is shown in p < 0.001), with no other association found between etiology of liver disease and MET activation. Female patients were more likely to have MET activation . MELD score at LT was significantly higher in patients with pre-LT MET activations compared to those who did not receive a MET activation  or received a post-LT MET activation . The mean ACCI was lower in patients who experienced a MET activation ; however the absolute difference was small and of unclear clinical significance.In relation to baseline characteristics , patientp < 0.001), ascites  and spontaneous bacterial peritonitis  compared to patients with no MET activations. Furthermore, patients who recorded a MET activation had a higher incidence of pre-LT sepsis  and hepatorenal syndrome , in both cases accounted for by a significantly higher incidence in the subset of patients receiving pre-LT MET activation  and, as such, both variables could not be modelled together possibly due to collinearity. In the selected model, on average there was a 79% higher odds of MET activation in female LT recipients, an 18% higher odds of MET activation for every 5 points increase in MELD score and a 68% higher odds of MET activation in the presence of hepatorenal syndrome. The model was a reasonable fit for the data  but the predictive value was modest, with an area under the receiver operating curve of 0.66.In the multivariable analyses, several options were possible depending on whether the ACCI was considered. There was a moderately strong correlation between the ACCI and hepatocellular carcinoma (p = 0.026), spontaneous bacterial peritonitis  and greater pre-LT hospitalization days  were independently associated with a higher odds of MET activation. Patients with a higher ACCI had lower odds of MET activation . In the post-LT analysis, patients with a primary diagnosis of hepatocellular carcinoma had a lower odds for MET activation  but this was not independent of the ACCI or MELD scores .Logistic regression was also performed separately for patients who were hospital inpatients > 24 h prior to LT  and for p = 0.001) while post-LT MET activations had a higher incidence of hospital-acquired pneumonia . Bleeding complications were observed in 14.7% of MET activations and did not significantly differ between the groups.Blood tests and diagnostic imaging were performed in 62.0% and 61.7% patients respectively . In relap < 0.001)  vs. 65 h , < 0.001) .p < 0.001). No patient deaths were recorded during a MET activation. Overall inpatient mortality was 4.2%, with one additional death at 30-days post discharge. The inpatient and 12-month survival rates post-LT were 95.8% and 93.2% respectively. MET activation during the LT admission had no statistically significant effect on these survival rates. Patients who experienced MET activation were more likely to require inpatient rehabilitation rather than being discharged directly home, compared to patients without MET activation .We present the results of a large observational analysis of MET activations in patients undergoing LT and the association with clinical outcomes. In our cohort, 34% patients experienced at least 1 MET activation, most commonly due to respiratory disturbance. MET activation was associated with a 24% unplanned ICU admission rate, with the highest risk in the subset of patients experiencing a pre-LT MET activation. In addition, MET activations were associated with a prolonged post-LT ICU and hospital length of stay, but did not significantly affect inpatient or 30-day mortality.This study is the largest to investigate the epidemiology and clinical significance of RRS activation in LT patients and the first to analyze MET activations in patients hospitalized prior to transplantation. Significant hospital resources are allocated to RRS to identify patients at high-risk of clinical deterioration with a view to improving outcomes and preventing adverse events. Despite its widespread integration into healthcare systems, there remains a paucity of literature regarding the utilization and efficacy of RRS in the solid organ transplant population. Indeed, only one previous study has investigated the epidemiology of MET activations in LT patients. Parmar et al. published a small single-center series of 174 LT recipients, of whom 18 experienced postoperative MET activation . Like ouOne-third of patients in our cohort experienced clinical deterioration requiring MET activation during the hospital admission in which LT was performed. Importantly, this clinical deterioration could not be explained by an increased baseline comorbidity burden or older age, with a lower ACCI recorded in patients receiving MET activation. The MET activation rate of 698 per 1000 LT admissions in this study is significantly higher than other cohorts of medical or non-transplant surgical patients ,13,14, aConsistent with other studies, the most common trigger for MET activation in our cohort was respiratory disturbance, manifesting as hypoxia or tachypnea. Postoperative pulmonary complications are well described post-LT ,18,19,20Our study is the first to examine risk factors for clinical deterioration necessitating MET activation in LT patients during the hospital admission in which transplantation was performed. In our multivariable analysis, female sex, increasing MELD score and hepatorenal syndrome were independently associated with a higher risk of MET activation. The association between MELD score and patient outcomes is well described in LT patients ,23. PrevThe Victorian Liver Transplant Unit currently performs more than 100 LTs annually. The spectrum of liver disease and comorbidities of this LT cohort improves the generalizability of our findings to other transplant centers with a RRS using similar MET activation criteria. We also utilized a prospectively collected database of LT patients, which improved the reliability of clinical data while avoiding missing data. By reporting the rate of MET activation and the association with increased ICU and hospital length of stay, we have highlighted the need for enhanced surveillance and monitoring of LT patients both pre- and post-LT and the development of more effective early warning systems to detect patient deterioration. To our knowledge, analysis of pre-LT MET activation has not been previously reported and our study demonstrates a high rate of clinical deterioration in this cohort.This study has several limitations. Firstly, it is a single center study and MET activation data was retrospectively collected. Secondly, while the MET activation criteria at our institution are consistent with international guidelines, differences in activation criteria may limit generalizability. Rates of MET activation can also vary significantly between centers and are influenced by institutional factors and protocols. Thirdly, due to the study design, we could not exclude the possibility of missed MET activations (where a patient reached MET criteria without the MET being activated). However, previous hospital audits have demonstrated that a missed MET activation is rare (<5% of patients meeting MET criteria). Finally, as an observational study, it was not possible to establish causality in terms of the effects of the RRS activation on clinical outcomes.LT patients with pre- or postoperative complications prompting MET activation represent a high-risk group with increased in-hospital complications, ICU, and hospital length of stay. Female patients, and patients with hepatorenal syndrome and higher MELD scores are at particularly high risk of clinical deterioration during the hospital admission in which LT is performed. Early identification and correction of factors which predispose to MET activation in this population may lead to improved outcomes and a reduction in healthcare costs.


Bioresource Technology was the most published and cited journal with 233 publications and 12,394 citations. Countries with the most publications and citations are Brazil, France, India, and Mexico. These findings suggest that research in the application of solid-state fermentation for bioprocessing of agro-industrial wastes has gained prominence over the past 50 years. Future perspectives and implications are discussed.This paper reviews the pertinent literature from 1970 to 2020 and presents a bibliometric analysis of research trends in the application of solid-state fermentation in the bioprocessing of agro-industrial wastes. A total 5630 publications of studies on solid-state fermentation that comprised of 5208 articles (92.50%), 340 book chapters (6.04%), 39 preprints (0.69%), 32 proceedings (0.56%), 8 edited books (0.14%) and 3 monographs (0.05%) were retrieved from Dimensions database. A review of the literature indicated that (i) fermentation of solid substrates is variously defined in the literature over the past 50 years, where “solid-state fermentation” is the most dominant research term used, and (ii) key products derived from the valorization of agro-industrial wastes through solid-state fermentation include, among others, enzymes, antioxidants, animal feed, biofuel, organic acids, biosurfactants, etc. Bibliometric analyses with VOSviewer revealed an astronomic increase in publications between 2000 and 2020, and further elucidated the most frequently explored core research topics, the most highly cited publications and authors, and countries/regions with the highest number of citations. The most cited publication between 2010 and 2020 had 382 citations compared to 725 citations for the most cited publication from 1970 to 2020. Ashok Pandey from India was the most published and cited author with 123 publications and 8,613 citations respectively; whereas  Agro-industrial residues; Bibliometrics; Bioprocessing; Microbial biotechnology; Solid-state fermentation. It is cSolid-state fermentation involves a series of steps that are characterized into upstream, midstream, and downstream processes . The ups(i)what are the major types of publications?(ii)what are the most frequently explored topics?(iii)what are the most highly cited publications and authors?(iv)what are the most highly cited journals? and(v)which country/region has the most cited publications?Solid-state fermentation has, over the decades, attained global recognition because of its potential to contribute significantly to solving some of the world's persistent problems, including malnutrition in humans and livestock, environmental pollution, climate change, hunger, and improving global food security . To this2th March 2021 in Dimensions (https://www.dimensions.ai), an online linked research knowledge system using the search term “solid-state fermentation”. The search was further modified to include other terms like “animal feed”, “biofertilizers”, “enzymes”, “antioxidants”, “biofuel”, etc., to extract specific scientific literature on the most frequently explored topics in solid-state fermentation based on the end-products. The following filters were manually activated for the search: (i) Relevance, and (ii) Title and Abstract. Dimensions automatically selected the following filters for the search: (i) Year of Publication, which ranged between 1970 and 2021 (ii) Researchers, (iii) Research Categories, (iv) Research Type, (v) Source Titles, and (vi) Journal List. Articles published between 2000 and 2020 were selected for a review of the literature. To determine the most highly cited publications and authors, and the research trends in the field between 1970 and 2020, automatically-generated statistical details of all cited publications  were retrieved in the “Analytical Views” section of Dimensions and processed with Microsoft Excel. All publications on solid-state fermentation between 1970 and 2020 were manually selected and exported to the Export Center of Dimensions. Subsequently, the Excel files were exported to VOSviewer (Version 1.6.17) for bibliometric analyses and network visualizations of the most cited author, the most cited journal, and the country with most cited publications as described by A comprehensive search of the primary scientific literature was conducted on 173solid substrate fermentation, (ii) solid state bioprocessing, (iii) solid substrate cultivation, (iv) solid state digestion, (v) solid state cultivation, (vi) solid-phase fermentation, (vii) solid state culture, (viii) surface cultivation, and (iv) surface culture  and actinobacteria species  are also employed in solid-state fermentation  and Lactobacillus sp. (bacterium) to enrich the nutrient content of cassava peels. Other similar studies have been conducted and cited in the literature Candida tropicalis, Saccharomyces cerevisiae, and Aspergillus niger Aspergillus niger Jatropha seed cake by the bacterium Pseudomonas aeruginosa Pleurotus ostreatus Aspergillus oryzae and Rhizopus oligosporus  unique specificity to substrates, (ii) the ability to speed up reactions that would otherwise be slow to complete, and (iii) are toxic-free . Microbi6.3The consumption of microorganisms is widely known as much as the use of mushrooms for food and food flavourings. In Germany, for example, during World War II (1939–1945), the diets of undernourished citizens were supplemented with yeasts and moulds as sources of protein . The wor6.4Generally, organic acids are produced by biological and chemical synthesis . HoweverA. niger is the most widely reported fungus used in the production of citric acid through solid-state fermentation . The result showed that rice plants treated with biofertilizers produced the highest plants height with the highest yield of rice in contrast to rice plants treated with chemical fertilizer, which produced the lowest plant heights with the lowest yields. Spent mushroom compost from Pleurotus eous used as biofertilizer to augment soil supported better growth in tomato (Solanum lycopersicon) and pepper (Capsicum annuum L.) under greenhouse conditions what are the major types of publications?(ii)what are the most frequently explored topics?(iii)what are the most highly cited publications and authors?(iv)what are the most highly cited journals? and(v)which country/region has the most cited publications?The term 7.1Based on literature search and analysis from Dimensions database, a total of 5630 publications (5208 articles (92.50%); 340 book chapters (6.04%); 39 preprints (0.69%); 32 proceedings (0.56%); 8 edited books (0.14%); 3 monographs (0.05) specifically on solid-state fermentation were retrieved. It is instructive to note that these 5208 articles included reviews that had been published in the field. Thus, research articles and reviews were the most common types of publications used to disseminate findings of studies in solid-state fermentation. This present search surprisingly revealed that no bibliometric study has been conducted nor published on solid-state fermentation as no record of such study was found in any of the databases . This provided an impetus to pursue the present bibliometric analysis of the literature on solid-state fermentation. To this end, data were analyzed by comparing the number of publications per year over the period under review. Interestingly, the data show that there has been a steady, consistent increase in the number of publications from 1970 until 2000, after which there was an astronomic increase till 2020 . This inBased on data from literature search and analysis, a total of 16 core research topics that relate to products obtained from solid-state fermentation were identified . “EnzymeSurprisingly, more than 2000 publications on the production of enzymes through solid-state fermentation were obtained from the search. This finding is key because it accentuates the continued efforts that are made to explore the possibilities of large-scale enzyme production using new sources and strains of microorganisms and available agro-industrial wastes . It is a7.2Agro-industrial wastes and their utilization using solid state fermentation: a review (C#207) and Recent developments and innovations in solid state fermentation (C#168), were respectively 3 and 4 years old at the time the literature search for this study was conducted on the 17th March 2021. Thus, an overwhelming 18 highly cited publications were more than 4 years , and Bioactive phenolic compounds: Production and extraction by solid-state fermentation: A review (C#368) ranked 9th and 10th in the 1970–2020 category, unlike in st and 2nd in the 2010–2020 category. This was because most publications in Engineering aspects of solid state fermentation ranked 13th with 353 citations. Another observation was that majority of the most highly cited publications in both categories were review articles, i.e., 12 review articles were among the top 20 publications between 2010 and 2020, whereas 18 review articles were among the top 20 publications between 1970 and 2020 the authors may have individual publications that have fewer citations, but collectively, these publications record a high total number of citations; and(ii)because recent publications tend to have fewer citations than older publications, authors with most recent publications may have been cited fewer times than those with older publications .A trend of interest is that most of the highly cited authors do not have any publication listed in the top 20 most highly cited publications Tables  and 9, ath most cited author who was located in Cluster 10 with 322 citation links and a total citation link strength of 786. This analysis further confirmed that Ashok Pandey has a more compelling citation profile on the list of most highly cited authors, and he is more prominently shown on the map than Marcio Antonio Mazutti  followed by Process Biochemistry . Further analysis of the data revealed that some of the journals with fewer publications were highly cited than those with a higher number of publications , the former is ranked 3rd with 5,698 citations, whereas the latter is ranked 4th with 4,790 citations  the kind of published materials included in the analysis of the database ; (ii) the kind of published materials that fall within the subject scope of the database (subject breadth); (iii) how much of scholarly output on solid-state fermentation was included in the database (subject depth); (iv) the possible exclusion of publications on solid-state fermentation that emanate from particular geographic regions (geographic coverage); (v) the use of only English-written publications exclusive of other key languages (language coverage); and (vi) depth of backfiles . Moreover, data could be impacted also by the unethical behaviour of authors such as Salami publishing, self-plagiarism, honorary authorship, and self-citation.9This paper highlighted the importance of the application of solid-state fermentation for the bioprocessing of various agro-industrial wastes for value addition. The production of enzymes remains the most dominant research interest in the field. Research on solid-state fermentation has increased exponentially between 1970 and 2020 as a result of increasing prospects of using solid-state fermentation to valorize a wide range of agro-industrial wastes into products of enormous industrial, agricultural, and health benefits to humans. There is a steady increase also in publications from emerging economies like China, India, and Brazil that suggests an immense interest by researchers to process agro-industrial wastes into useful domestic and industrial products, while remediating the environment from unwarranted pollution Microbiologists and scientists from allied fields should further explore new areas of interest, where collaborative, interdisciplinary efforts could be enhanced. The bibliometric analysis generated large quantitative data that revealed important research trends in solid-state fermentation. This approach of analyzing various types of data was crucial since one set of data was inadequate to understand research trends with bibliometric analysis. Most of the highly cited authors did not have any publication listed in the top 20 most highly cited publications and vice versa, a finding that emphasizes the need to analyze various data sets to obtain a comprehensive, comparable trend. Although a bibliometric study is quantitative, it involves qualitative analysis that requires subjectivity in decisions that consider what variables to analyze, and what constitutes a research topic as well as research trend. More bibliometric studies on other aspects of research on solid-state fermentation are required to augment the findings of this study.All authors listed have significantly contributed to the development and the writing of this article.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Data included in article/supplementary material/referenced in article.The authors declare no conflict of interest.No additional information is available for this paper.


Domestic and industrial wastewater discharges harbor rich bacterial communities, including both pathogenic and commensal organisms that are antibiotic-resistant (AR). AR pathogens pose a potential threat to human and animal health. In wastewater treatment plants (WWTP), bacteria encounter environments suitable for horizontal gene transfer, providing an opportunity for bacterial cells to acquire new antibiotic-resistant genes. With many entry points to environmental components, especially water and soil, WWTPs are considered a critical control point for antibiotic resistance. The primary and secondary units of conventional WWTPs are not designed for the reduction of resistant microbes. Constructed wetlands (CWs) are viable wastewater treatment options with the potential for mitigating AR bacteria, their genes, pathogens, and general pollutants. Encouraging performance for the removal of AR (2–4 logs) has highlighted the applicability of CW on fields. Their low cost of construction, operation and maintenance makes them well suited for applications across the globe, especially in developing and low-income countries. The present review highlights a better understanding of the performance efficiency of conventional treatment plants and CWs for the elimination/reduction of AR from wastewater. They are viable alternatives that can be used for secondary/tertiary treatment or effluent polishing in combination with WWTP or in a decentralized manner. Wastewater treatment plants (WWTPs) are a central distribution point where effluents are distributed to receiving water bodies. WWTPs are efficient for the reduction of many pollutants but have not shown efficiency for the removal of antibiotic-resistant bacteria (ARB) and antibiotic-resistant genes (ARGs) ,2. MunicThe United Nations Environment Programme identifies antibiotic resistance among the top emerging issues of concern , and theConstructed wetlands (CWs) are a sustainable “green” wastewater treatment option that can be used as an alternative to WWTP or as a component of conventional WWTP. They use natural processes, including substrates, plants, soils, and microbes, to filter and treat pollutants in water. Recent studies on CWs have gained significance due to their ability to treat pharmaceuticals ,25 from There is growing interest in the functionality of CWs for the reduction of antibiotic drugs ,39, ARBsGiven the urgent need to sustainably address antibiotic resistance, the potential for wastewater treatments as an antibiotic resistance critical control point, and encouraging data gathered to date on the potential of CWs for mitigating antibiotic drugs, ARB and ARGs in the waste stream, the present study was conducted with the specific objective to review and explore the performance efficiency of CWs towards multiple measures of antibiotic resistance, identify the major advantages/benefits CWs provide to the environment and compare CWs with conventional treatment plants for the reduction of antibiotic-resistant targets and other microbial pollutants. The present study will therefore provide a backbone for better understanding and evaluating the challenges faced by developing/low-income countries when managing and disposing of their huge amounts of wastewater, with a focus on antibiotic resistance outcomes.In order to understand the major problems associated with the disposal of wastewater in the context of antibiotic resistance in developing/low-income countries and to identify knowledge and research gaps, a literature search was conducted. We considered recently published articles for the abundance of ARGs in different environments between 2016–2021 and also included some significant studies reported during 1981–2015. The keywords used were CW AND ARGs AND bacteria AND WWTP AND mechanism of ARB in CWs AND AR in sludge AND AR in WWTP. Initially, articles and reviews based on effluents discharged from treatment plants (with/without tertiary units and chlorination), their characteristics and their impact on the environment were identified. We were also focused on antibiotic resistance associated with WWTPs, sludge being used as fertilizers without any post-treatment, CWs, treated effluents (both from treatment plants and CWs) and their effect on the receiving water bodies. There are no discharge standards for AR for effluents that are being directly discharged to water bodies and agricultural land for irrigation. Moreover, there is ignorance regarding the treatment of sludge used as fertilizer or disposed to nearby land. Then the question of concern/interest was framed in a detailed manner, reviewing the significance of each point dealt with in the study and its significance . The perPrevious literature was studied with a focus on papers describing measures of antibiotic resistance (including ARBs and ARGs) in CWs, WWTPs, wastewater, treated effluent, sludge, anaerobic digestion and activated sludge units of treatment plants, cattle feedlots and slaughterhouses . A briefn = 65), Web of Science (n = 55), Science Direct (n = 33), Google Scholar (n = 15) and also scanned references (n = 31). The total number of journals articles screened for the present review was 199. This included publications related to WWTPs (74), CWs (59), rural and urban wastewater (28), hospital wastewater (12), and aquatic and soil ecosystems (26). We then framed the question of concern regarding the protocols for antibiotic resistance, restrictive use of antibiotics, treatment of wastewater, effluent discharges and use and implementation of natural treatment system for ARG/ARB removal with a focus on ARGs in wastewater. Hotspots of antibiotic resistance in the environment and their pathway of exposure/disposal were identified. The recent studies were subdivided into (i) clinical studies based on case studies reported in humans, plants and animals, and (ii) environmental studies based on lab and field studies on water, soil, agricultural farms, poultry and anthropogenic activities. Then, information pertaining to the performance efficiency of WWTPs and CWs for the elimination of antibiotic resistance was consolidated. There is an increasingly robust body of literature on CWs and their potential technology that assists in the removal of antibiotic resistance. Studies reported during 2019 and 2021 demonstrate encouraging use of CWs for the reduction of general water and microbial pollutants. It is expected that the application of CWs may further increase in the near future due to its multiple benefits such as aesthetics, ability to reduce a variety of pollutants, and capacity for different configurations to suit stakeholders’ requirements.The present study is a literature review of studies related to antibiotic resistance in CW and WWTPs and its effluent discharge to water compartment, which is a major challenge in developing/less developed countries. Journal articles were identified in Scopus  causing infections is more or less the same [Antibiotic drugs are considered the main driver of antibiotic resistance, and they enter the wastewater stream via human, animal, medical, and industrial waste, along with heavy metals of different concentrations according to their sources. The sublethal concentration of antibiotics/heavy metals/biocides may alter/have a direct impact on microbial cell function as well as resistance properties . These wcarditis . Enterocycosides . They alycosides . Escherithe same .WWTPs are generally comprised of preliminary and primary treatment (screening and sedimentation basin) for the removal of suspended solids. The secondary treatment includes an activated sludge process and a biological contactor/filter process responsible for degrading/breaking organic compounds assisted by microbial metabolism. The tertiary treatment includes disinfection, CWs, sand filtration, a membrane bioreactor, etc. The treatment technology and use of tertiary treatment methods impact the prevalence of antibiotics, ARBs and ARGs.Dechloromonas and Thauera, that have been identified as typical denitrifying bacteria in wastewater treatment [2, ZnO, and CdS for photocatalysis has shown encouraging results for antibiotic removal due to their availability, nontoxic nature, low cost, strong oxidizing capability and use either as colloids or in an immobilized form [Antibiotics are chemical pollutants and include drugs such as β-lactams, cephalosporins, fluoroquinolones, tetracyclines and sulfonamides, among others. They find their path to the WWTP from domestic, industrial, clinical, pharmaceutical and other effluent discharges ,71,72. Ereatment . Variousreatment ,81. Revezed form .Various works of literature have reported that primary treatment is ineffective for the removal of antibiotics with a low reduction of antibiotic residues . ComplexInvestigations report that the removal efficiency of a particular antibiotic varies significantly even within the same type of process, such as activated sludge or anoxic/oxic (A/O) conditions. The use of only activated sludge may not show better results as compared to a combination of activated sludge with anoxic and oxic conditions. Therefore, a hybrid system employing both enhances the removal of antibiotics such as lincomycin in the range of 58–74% . It is a3 treatment. In this process, the antibiotics are oxidized by O3 molecules or hydroxyl radicles after O3 decomposition [Tertiary treatment involves disinfection methods that assist in the removal of microbial contaminants and often involve chlorination. They are also found to be efficient for the removal of tetracycline, trimethoprim, erythromycin, ciprofloxacin, sulfamethoxazole and norfloxacin. As reported by , when coposition . Employiposition ,96. Theyposition . The higposition . It has position , advanceposition , ozonatiposition , sulfateposition , and ionposition ,103 are E. coli and Enterococci are present in raw sewage and final treated effluent in WWTPs. These bacteria can display a range of antibiotic resistance phenotypes, and hence their removal in WWTP is of importance. The authors of [E. coli and Enterococci isolated from wastewater and found between 0.7–100% of the isolates in that study displayed at least one resistance phenotype. They also determined that bacterial species that are resistant to more than three antibiotics were about 25% in the influent and less than 20% in wastewater that was subjected to chlorination. A different study reported that the effluent of a WWTP consists of approximately 9.9% resistant E. coli and 0.2% total resistant coliforms. Based on previous reports, a two-log reduction of E. coli and Enterococci in WWTP is possible [ARBs such as antibiotic-resistant thors of  investigpossible ,106, incpossible ,108.There is a diverse community of ARBs present in the influent of WWTPs, including untreated wastewater and hospital wastewater, providing evidence for the presence of clinically relevant ARBs. In particular, there is a lack of studies reporting the reduction of ARBs in primary units. Though selective pressure due to the presence of heavy metals, antibiotic residues, and other pollutants has the potential to assist in the amplification and spread of ARBs to the receiving environment, appropriate technology can reduce or eliminate them in the final effluent. Physical processes such as primary screening, grit removal and sedimentation remove the majority of the suspended solids, along with adhered bacteria. Primary screening does not remove/eliminate any suspended ARBs, as the screens are used for removing larger floating materials in the wastewater. Sedimentation also does not support significant removal of ARBs, as reported by ,110. HowEnterococci species and E. coli in the raw influent was reported to be approximately 5.14 × 108, 2.45 × 107, 1.31 × 108, and 1.17 × 107 cfu/100 mL, respectively. Following activated sludge treatment, these numbers were reduced to 3.18 × 105, 5.12 × 104, 3.93 × 105, and 2.75 × 104 cfu/100 mL, with a log reduction of 3.21, 2.68, 2.52 and 2.62, respectively. This was comparable with the log reduction obtained after treatment with a septic tank system that ranged between 1.33 to 1.59 cfu/100 mL. The study also indicated that although there was a reduction of the bacterial population, there was an increase in the multidrug-resistant profiles of the isolates during wastewater treatment. It can be inferred that WWTP do provide a suitable environment for the proliferation of ARBs containing a high proportion of resistant bacteria. Berrios-Hernandez [E. coli, total suspended solids have been positively correlated with its removal, supporting the efficacy of primary and secondary treatment units for the removal of the microbial population. Activated sludge and novel aerobic granular sludge demonstrated somewhat similar removal efficiencies.Teshome  has inveernandez  inferredE. coli, C. perfringens, fecal enterococci and Sphingomonas by [E. coli along with chloramphenicol- and cephalothin-resistant bacteria [E. coli, Citrobacter and Enterococcus for their survivability at 0.5 mg/L of free chlorine concentration. Bacterial cells that survive chlorination can re-grow and remain a concern for public health [The relationship between chlorination and antibiotic resistance is complex. Disinfection in WWTPs includes the use of chlorine, UV irradiation and ozone. Chlorine is widely used in WWTPs due to its cost-effective nature and its beneficial oxidizing capacity for reducing the microbial population and pathogens in wastewater . Chlorinmonas by , or ampibacteria . The autbacteria  identific health ,124. UV c health  and theic health . UV radiE. coli, Staphylococcus and Enterococcus in the range of 0.8 to 1.1 log units when compared to flocculation filtration. Enterobacteria, Staphylococcus, Enterococci, and P. aurigonosa have demonstrated varying removal rates in the range of 60.2% to 98.9% at a concentration of 0.9 ± 0.1 g O3 DOC-1 (dissolved organic carbon), which is considered a regular dose applied for ozonation [E. coli present in WWTP [Enterococci by approximately 3.6 log units and Clostridia in the range of 1.2–1.7 log units [Pseudomonas, Enterococcus and E. coli [Ozonation has also been shown to impact the removal of ARBs by inactivation of bacterial populations (including antibiotic-resistant bacteria) due to the production of highly reactive radicles, though it is generally employed for the removal of organic micropollutants . Additiozonation . A log r in WWTP . A high og units . The res E. coli ,132. The E. coli , biologi E. coli  along wi E. coli , use of  E. coli , advance E. coli  and hybr E. coli . There rE. coli, Enterobacter species, and Salmonella species can be detected in treated effluent. The ARGs code for resistances associated with health risk threats and are especially concerning when associated with pathogens. The impact of WWTP-associated ARGs on environmental bacteria is unknown but is of potential concern.WWTPs provide suitable temperature, pH, nutrients, and environment for the growth and proliferation of bacteria, transfer of ARGs, and spread of both to the receiving water bodies or soil . GeneralAs reported by , a negliReports of ARG removal efficacy after secondary treatment are mixed and depend on a complex interaction of factors. Some reports have confirmed 1–2 log reductions of ARGs , while oint1 by 0.1 ± 0.4 log 10 copies/mL, tetA by 0.9 ± 0.6 log 10 copies/mL, ermF by approximately 0.1 ± 0.3 log 10 copies/mL, blaTEM by 0.4 ± 0.5 log 10 copies/mL, and int1 by 0.5 ± 0.4 log 10 copies/mL. They reported the same type of variation in another treatment plant, indicating a reduction in the abundance of ARGs. The final effluent of 2 WWTP released 3.3 ± 1.5 log 10 copies/mL and 3.4 ± 1.4 log 10 copies/mL of total ARGs and int1. Therefore, their results demonstrate that the conventional WWTPs using chlorination can be confidently used to avoid the proliferation of ARGs during treatment. ARGs are naturally carried within bacterial host cells, either chromosomally or on plasmids. Upon lysis of the host bacteria, ARGs are released into the environment where they persist until they are taken up by a new host or are degraded and lose their biological activity. However, even when chlorine and other disinfectants kill bacteria, they do not necessarily inactivate or degrade the ARGs [Tertiary treatment plays a significant role in lowering the abundance of ARGs. A recent study by  reportedthe ARGs . While ethe ARGs . The hydthe ARGs .2 min L−1) as compared to low CT (<10 mg Cl2 min L−1) than others [2/min/L . The residual chlorine in the effluent reactivates the development of ARGs [High CT favors the reduction of ARGs when they are present at high concentrations but is less effective when ARG targets are present in lower concentrations. For example, some evidence suggests that certain ARGs may be more easily inactivated by high CT , contact time with the wastewater and wastewater characteristics play a significant role [3 is relatively less effective than the other two disinfection methods, as O3 gets generally consumed by the organic matter in the effluent [Proper dosing of chlorine with CT (and focusing on by-products obtained) coupled with natural treatment systems  prevents the growth of pathogenic bacteria and is a useful option for effluent to be discharged to the environmental matrix ,155. Morant role ,65,156. effluent . When coeffluent . Despiteeffluent . Furthereffluent . Figure There is an emerging awareness of the value provided by biological treatment processes employing CWs ,161. CWsAntibiotic drug residues are released to the environment through WWTP and can affect the efficiency of the microbial communities essential to CW function. Antibiotics inhibit some types of bacterial growth , impact 4+-N) removal but increased the diversity and altered the community structure of bacteria. It is indicated that the antibiotics induce selective pressure on the bacterial population, rendering them resistant to a wide range of antibiotics.A growing body of work exists examining the efficiency of various CW systems to remove individual antibiotic drug targets. One theme that emerges from the work done to date is that the diversity of CW configurations, process parameters, and site-specific differences can impact drug removal efficiency. Li  evaluate4-N and organic matter [Vertical subsurface flow CWs (VSSFCW) are basically operated by providing intermittent feeding (of wastewater) from the top that drains to the bottom of a filter bed. The intermittent flow allows the process of nitrification in the unsaturated zone, promoting microbial degradation of antibiotics in a way that is superior as compared to HSSF-CW, which remains saturated all through . Hence, c matter . The denc matter  highlighc matter . Benefitc matter  comparedc matter  have evac matter  working c matter  demonstrPicta’  that was used for the treatment of urban wastewater. It was observed that the presence of antibiotics or pharmaceuticals and their transformation products had a direct impact on the floating plants and resulted in deterioration and decay, thereby showing phytotoxic activity. It was also concluded that despite high concentrations of antibiotics/pharmaceutical, the emergent macrophytic species, namely Gaint Miscanthus, in subsurface flow constructed wetlands (SSFCW) demonstrated no alterations in their physical appearance and suggested the use of hybrid systems for SSFCW and SFCW. Integrated flow constructed wetlands (IFCW) use a combination of different CW. IFCWs demonstrate better efficiency compared to a single unit of CW mainly for the removal of nutrients and other pollutants [Pharagmites australis and Triarrhena sacchariflora, which were found to efficiently remove sulfadiazine at rates up to 81.86%, sulfamethoxazole at rates up to 85%, sulfamethazine at rates up to 49.43% and trimethoprim at rates up to 2.32% with a retention time of 48 h. Chrysopogon zizanioides has also been used to remove antibiotics, especially tetracycline and ciprofloxacin, from secondary wastewater effluent in the presence of a high concentration of nutrients . The removal percentage varied between 89–100% for tetracycline and 60–94% for ciprofloxacin, and there was an inverse relationship between nutrient concentration and antibiotic removal [Ipomea aquatic based on its potential for remediation of 100% sulfamethoxazole in 30 h. It was observed that the primary mechanism of sulfamethoxazole elimination was biodegradation, which accounted for 82% of the observed reduction. Results demonstrated that Ipomea converted sulfamethoxazole into simple compounds like 4-aminophenol as its end product. Plant roots assisted in bioadsorption but accounted for only 0.77% of the drug removal, and leaves bioaccumulated up to 16.94% of the sulfamethoxazole. An 8% increase in chlorophyll and a 9% decrease in carotenoids was observed after 48 h of exposure to sulfamethoxazole, but this did not induce any toxic effect on the photosynthetic activity of Ipomea. It has a defense mechanism against toxicants and abiotic stress which is activated during the initial exposure to sulfamethoxazole. In a different study, the efficiency of CW planted with Juncus acutus was utilized for the removal of ciprofloxacin at rates of up to 93.9%, but no significant removal was observed for sulfamethoxazole [Juncus acutus is a halophyte tolerant to different stressors, specifically organic xenobiotics, heavy metals, endocrine-disrupting chemicals, pharmaceuticals and personal care products. This makes it a particularly good candidate for CW. Only 2% of plant species (of the known plant species) are halophytes that demonstrate good phytoremedial potential [J. acutus [Sochachi  evaluatellutants . Choi [1llutants  investig removal . Lab-bas removal , in a bahoxazole . Juncus otential ,190,191.. acutus .4, total nitrogen (TN), and a negative correlative between E. coli and total suspended solids (TSS), TP, COD and biochemical oxygen demand (BOD) [E. coli concentration decreased up to 50% in the effluent of a CW as compared to the influent. In the study, they compared the presence of E. coli, Enterococci, Bacteriodales (HF183) and ARG (erm(F) and int1) in the influent and the treated effluent. It was demonstrated that erm(F) and int were reduced by 13% and 67.2%. The study also found that there was no correlation between turbidity and ARG, though sediments act as a reservoir of ARGs. The growth of E. coli was affected by water temperature, sedimentation rate, pollution source and overall bacterial growth. At higher temperatures , the reduction of E. coli (that was present in 100% of the water samples) ranged between 31 and 70% and Enterococci between 70 and 99%. The temperature had an impact on microbial composition in treatment plants that affected bacterial removal rates. It was indicated that the microbes grow and survive at a pH range of 5.5–7.5 and are pH-sensitive [In addition to the ability to reduce the concentration of antibiotic drugs in wastewater systems, CWs have also been evaluated as a means to mitigate ARBs and ARGs. nd (BOD) . Lamori nd (BOD)  highlighensitive . High pHensitive  and the ensitive , during tet C, M, O, Q and W) and reported their complete removal by a CW, with 1 day of retention time, using Pharagmites australis. The CW demonstrated a reduction of up to 3 logs for ARGs, which increased with an HRT of 2–3 days. A comparative work recently reported by [sulI and tetracycline genes were found to be persistent due to the selective pressure by antimicrobial agents [int1 gene and ARGs, suggesting that MGE affects the dissemination of ARGs in CW. The fate of ARGs sulI, sulII (sulfadiazine), tetM, tetO, tetQ, tetW (from tetracycline) and 16S rDNA genes was evaluated in a HSSF-CW. It was found that the HSSF-CW performed better than the conventional treatment plant with aerated filters or UV disinfection. The reduction of ARG was in the order of 1–3 log units after treatment [Hien  investigorted by  investigl agents . Multipll agents . In anotl agents . There wreatment . Miller reatment  has reporeatment . Table 2The primary mechanisms of the removal of pollutants in CW are sedimentation, sunlight/UV radiation exposure, inactivation/death associated with unfavorable water chemistry, oxidation, biofilm interaction , predatiPhragmites australis in CW has shown encouraging removal of ARGs and 16sRNA levels compared to other plants. Other aquatic plants such as Cyperus alternifolius, Pontederia cordata and Myriophyllum verticillatum can also contribute to the removal of ARGs [Pharagmites australis shows a tolerance mechanism and biological response to ofloxacin and sulfamethoxazole residues at even a simulated condition of 1 mg/L. It was found that the growth of plants was not inhibited, and there was an improvement in root and photosynthetic activity. Low doses of antibiotics increased the transpiration and photosynthetic rate by stimulating the opening of stomata, which assisted the transportation of water and antibiotics and improved the efficiency of light utilization by acting upon the reaction center of the photosynthetic system. Individually, ofloxacin reduced the accumulation of reactive oxygen species in the plant. Both antibiotics accumulated prominently in the roots, then leaves, and finally the stem. Results demonstrated that Pharagmites is efficient in the removal of antibiotics from wastewater [Plant species, whether mono or mixed culture, are effective for the removal of antibiotic residues, ARG and other pollutants from wastewater, and accordingly, they can be selected on the basis of removal of a particular pollutant . Vegetat of ARGs . A recenstewater . Studiesstewater  reportedThe presence of antibiotic resistance in wastewater effluents has stimulated recent studies for understanding the abundance, occurrence, fate and potential control in WWTP. CWs are another option. CWs are quite efficient for the reduction of general water pollutants, nutrients, and emerging contaminants, including antibiotic drugs, ARBs/ARGs, and they have demonstrated encouraging results in recent studies. CWs are considered to be a flexible treatment technology with the potential to reduce a wide variety of pollutants. CWs can be used as decentralized systems where each individual housing unit can have its own pretreatment unit as a septic tank/sedimentation tank, allowing flow to the CW and then the discharge of treated water. They can also be integrated with secondary and tertiary treatment in conventional wastewater treatment plants as a viable option for the reduction of the microbial load. The treated effluent can be used for gardening purposes, agriculture, artificial groundwater recharge, as direct discharge to water bodies and in industrial usages, like washing, cooling, etc. CWs find their application particularly in developing/low-income countries, where there are failures for treating wastewater due to lack of treatment plants, tertiary units, electricity and manpower cost. CWs reduce the cost of conventional treatment plants and work on a non-mechanized system. Other factors include local availability, simplified operation, reduced construction cost, ability to maintain at an individual level, enriched aesthetics to the environment, and environmental restoration. Parks and gardens can be designed according to space availability for public awareness and acceptance. According to use, multistage or hybrid CWs can be designed that further increase the performance efficiency of the system. CWs treat wastewater and make it fit for reuse purposes, providing an alternative for large volumes of effluent from wastewater treatment plants. This would otherwise be difficult to manage and pose a potential threat to the receiving environment. Hence, the use of CWs as a flexible treatment technology is recommended, with the potential for reducing antibiotic resistance. Multistage and hybrid CWs are effective for treating raw urban wastewater. The technology, if adopted, will help in meeting the national action plans in developing and low-income countries, with options to use the treated effluent for multiple purposes. Investigations are further required in the relevant direction focusing on (i) the effect of antibiotic usage and its relationship with wastewater generated from the domestic and industrial sector, (ii) the impact of residual antibiotics in the influent on the selection pressure of ARG to promote resistance, (iii) the concentration of commonly used antibiotics in the influent/effluent of WWTP that is discharged into the water bodies/agricultural land, (iv) the detection of commonly available ARGs in terms of type and concentration by the latest techniques like qPCR, (v) the lacking correlation of different water quality factors and mechanisms, which needs to be explored further, (vi) the reactivation of ARG in the effluent after chlorination or treated effluent of CWs in the water or soil matrix and the overall impact of ARG disseminated, and (vii) identifying the mechanisms underlying the removal of ARG/ARB removal in CW that is essential for designing highly effective CWs for removal of antibiotic drugs, antibiotic-resistant bacteria, and ARG.


Immunoglobulin-G4-related hypophysitis is a rare inflammatory disease that can present as a tumefactive pituitary lesion mimicking hypophyseal neoplasms such as pituitary adenoma or craniopharyngioma. The literature on this entity is sparse, with fewer than 100 cases reported across 19 publications; a recent review found only 24 cases published from 2007 to 2018. Previous reports have described demographic differences, with immunoglobulin-G4-related hypophysitis in females tending to present in the second and third decades in association with other autoimmune disease, while males tend to present in the fifth and sixth decades of life without an autoimmune history.In contrast to the reported demographic trends, here we describe a unique case of immunoglobulin-G4-related hypophysitis in a 63-year-old white female with no history of autoimmune disease who presented with a rapidly enlarging sellar and hypothalamic mass causing headaches and cranial nerve palsies, prompting biopsy for diagnosis. The patient experienced rapid response to treatment with high-dose steroids and rituximab.The case contributes to the growing clinicopathologic description of immunoglobulin-G4-related hypophysitis and illustrates that this diagnosis should be a consideration even outside the conventional demographic setting. Primary hypophysitis is a rare disease, accounting for ~ 0.4% of all diagnosed pituitary lesions, and it may masquerade clinically as a mass lesion suggestive of a neoplastic process on radiologic studies . A definIgG4-related disease (IgG4-RD) is a fibroinflammatory process that can involve multiple organs, less commonly the pituitary, and is often but not always associated with elevated serum IgG4 levels . If therIn this case report, we present a unique case of IgG4 hypophysitis that will add to the medical literature. The presented case is an important addition to the literature as it is not a classic presentation of IgG4 hypophysitis since the patient had no autoimmune history, normal IgG4 serum levels, and is outside the typical age range for this disease. This case report will serve as an aid for physicians and surgeons to improve the timely diagnosis and treatment of this rare entity.A 63-year-old white female with a past medical history of hypertension and previous appendectomy presented after 2 months of progressive headaches, with magnetic resonance imaging (MRI) demonstrating a sellar and suprasellar mass that grew rapidly in 1 month’s time  and normal blood pressure (124/70 mmHg). On physical examination, she was alert, cooperative, and oriented to person, location, and date. She had a visual acuity of 20/25 in the right eye and 20/20 in the left with a partial left-sided cranial nerve VI palsy. She was otherwise neurologically intact. Her neck was supple and nontender, oral mucosa moist, lungs clear to auscultation, heart rate normal and with a regular rhythm, and her skin warm and dry.Initial outpatient laboratory studies showed an elevated antinuclear antibody (ANA) of 1:160  and normal inflammatory testing [erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP)]. Laboratory studies showed an 7 am serum cortisol 28.1 μg/dL (slightly elevated), concurrent plasma adrenocorticotropic hormone (ACTH) 29 pg/mL , free triiodothyronine (T3) 2.0 pg/m , follicle-stimulating hormone (FSH) 12.3 mIU/mL, luteinizing hormone (LH) 0.4 IU/L (low), Insulin-like growth factor 1 (IGF-I) 154 ng/mL, prolactin of 33.3 ng/mL , and IgG4 levels of 57.1 mg/dL . Lumbar puncture was obtained, which showed no organisms, white blood cell count (WBC) of 95 cells/cu mm, red blood cell count (RBC) of 4 cells/cu mm, 54% neutrophils, 42% lymphocytes, 55 mg/dL glucose, 154 mg/dL protein, and IgG 26.7 mg/dL. Repeat laboratory studies 1 month later showed a 7 am cortisol level of 2 ug/dL and free thyroxine (T4) level of 2.9 ug/dL . ACTH, growth hormone (GH), LH, FSH, thyroid-stimulating hormone (TSH), and prolactin levels were within normal limits. Her serum sodium was within normal limits , pointing to compensated diabetes insipidus. A water deprivation test was deferred at this time.An MRI of the brain with and without gadolinium was obtained at initial presentation and showed a 1.5 × 1.2 × 1.4 cm enhancing lesion involving the sella and adjacent structures, including the infundibulum, hypothalamus, and sphenoid sinus  for central hypothyroidism, high-dose prednisone (tapered over 1 year), and rituximab  postoperatively. Repeat MRI 5 days after biopsy showed significant improvement in the sellar and suprasellar enhancing lesion Fig. A, B. At Here we describe a unique case of IgG4 hypophysitis. The patient was outside the “normal age-range,” had no autoimmune history, and had normal serum levels of IgG4. All of these attributes make this an interesting case that will contribute to the literature and assist physicians and surgeons in the future in the diagnosis and management of this rare but potentially debilitating disease.Goudie and Pinkerton in 1962 were the first to report autoimmune hypophysitis in a 22-year-old female who developed amenorrhea and postpartum hypothyroidism . On autoPresentation of hypophysitis can vary; however, it typically has a component of hypopituitarism and sometimes diabetes insipidus, combined with mass effect from the increased size . Common The demographic characteristics of patients with IgG4-RH are not entirely clear, due to the paucity of reports of this entity. Of the 24 cases documented between 2007 and 2018, 12 patients were male and 12 female. Males and females in this cohort demonstrated different age of onset for this disease: females presented at a mean age of 28.5 years (range 14–55 years), compared with males, who presented at a mean age of 62.5 years (range 40–77 years) .Our patient is a 63-year-old white female with IgG4-RH that presented as a rapidly enlarging pituitary and infundibular mass. Since she has no past medical history of autoimmune disease and is not in the typical age range for female patients, her case is unusual and represents a unique clinical scenario that has, to our knowledge, not yet been reported . Our patC. acnes, is an odd phenomenon; it is unclear whether a protracted low-grade infection by this microbe could have triggered the hypophysitis. It is conceivable though that, as with many autoimmune diseases, an infection could be the initiating factor. Alternatively, the sinusitis may have been the result of the florid adjacent inflammation causing an obstruction in outflow and ensuing infection. Obviously, more case studies are needed to further investigate this hypothesis.The concomitant sphenoid sinus infection, predominantly caused by Pituitary involvement by IgG4-RD is a diagnostic challenge, especially in the absence of other organ involvement or elevated serum IgG4 levels. Criteria for diagnosing IgG4-RH on pituitary biopsy are currently not well defined. Suggestive histologic features include an elevated ratio of IgG4+/IgG+ plasma cells coupled with a minimum number of IgG4+ cells, but thresholds for the values of these metrics may be tissue-specific, and it is not clear that criteria created for other organ systems can be directly applied to the pituitary. It remains an open question whether the characteristic features of IgG4-RD seen in other locations, including storiform fibrosis and obliterative phlebitis, should be required for a definitive diagnosis. It is plausible that such features could develop over time, but the small physical confines of the sella combined with the functional importance of the involved structures may lead to earlier presentation of hypophysitis in comparison with other sites of involvement such as the retroperitoneum. Similarly, the limited bulk of disease in the hypophysis may be insufficient to generate elevated serum IgG4 levels in the absence of involvement of other organ systems. Although a recent literature review suggests that the IgG4+/IgG+ ratio alone may not be specific for IgG4-RH, and proposes the inclusion of other organ involvement and/or elevated serum IgG4 as diagnostic criteria, the issue is far from resolved .et al. suggest that rituximab’s depletion of CD20-positive B cells, the cells that differentiate into plasma cells that produce IgG4, is what makes it an effective therapy for IgG4-related disease [IgG4-related hypophysitis, like lymphocytic hypophysitis, has historically been treated with corticosteroids owing to the similarity in presentation and histology to other autoimmune conditions. Postoperative treatment of IgG4-related sellar and suprasellar lesions has been varied. Most recently, there have been adjunctive postoperative biologic treatments that have been attempted. Corticosteroids were given in all cases; additionally, two patients received rituximab , one pat disease .et al. proposed that surgical intervention for biopsy is not mandatory for diagnosis, assuming that serologic and radiographic evidence coupled with clinical suspicion is present. Radiographic evidence is limited by a lack of standardized radiographic features [In 2011, Leporati features . In moreIgG4-RH remains a poorly understood clinical entity. This unusual case of IgG4-RH in a woman in her seventh decade of life with no past history of autoimmune disease, no systemic IgG4-RD, and normal serum IgG4 levels. Radiographically, she had a rapidly growing heterogeneous sellar lesion over a 1-month interval with signs and symptoms of mass effect. After biopsy of the sellar lesion demonstrated abundant IgG4+ plasma cells, she was treated with high-dose steroids and rituximab, leading to rapid symptomatic improvement and near-complete resolution of her imaging findings over the subsequent months. The case contributes to the growing clinicopathologic description of IgG4-RH and illustrates that this diagnosis should be a consideration even outside the conventional demographic setting.Although our patient showed rapid improvement that was sustained over months, the long-term efficacy of the therapeutic regimen over several years remains unclear. Furthermore, despite the absence of any concomitant autoimmune disease in our patient, the possibility that hypophysitis was the initial presentation of a systemic condition that could manifest in a delayed fashion cannot be excluded.


The main objective was to determine the deleterious potential of quartzite mining tailings subjected to different ASR alkali–silica reaction tests. The studies included petrographic analysis, chemical analysis of cements, expansion tests in mortar bars and concrete prisms, and microstructural analysis. Petrographic analysis of quartzites indicated high percentages of deformed quartz (95%), and were classified as potentially reactive. Two types of HES high early strength cement with alkaline equivalents of 0.749% and 0.61%, respectively, were selected. Of the 8 samples analyzed by the accelerated method in mortars, only 2 quartzite samples and 1 diabasium sample indicated potentially reactive behavior. The accelerated and long-term methods in concrete prisms proved to be effective and were consistent with the deleterious potential of the samples. All analyzed samples were diagnosed with the ASR gel. In the microstructural analysis, in addition to the ASR products, other expansive products of late ettringite were detected. Reaction mitigation methods are proposed so that quartzite waste can be used as an alternative aggregate in concrete, and thus contribute to the reduction of mine tailings and, consequently, reduce the negative environmental impact from mining. Brazil is one of the world’s largest producers and exporters of dimension stones. The state of Minas Gerais ranks second in the production of these materials, according to recent data , represeWaste generation is inherent to any process of production or transformation of materials and, in the context of sustainable development, more in-depth studies on waste have been intensified ,4,5,6. IIn this context, several geotechnical studies have been conducted with the aim of making quartzite mining tailings an alternative source of raw material for different purposes in engineering works or civil construction, for example, aiming to use this waste as aggregate in concrete ,13,14. MStudies carried out by Pinheiro  and CollBased on these premises, the general objective of this study was to identify the degree of deleterious potential of quartzite tailings from Minas Gerais in mortars and concrete attacked by alkaline solutions. The specific objectives are: to identify and classify the reactive minerals in different types of quartzite tailings through petrographic analysis; to determine the chemical composition and calculate the equivalent alkali in samples of Portland cement; to classify the deleterious potential of quartzites by means of laboratory expandability tests; and to investigate the presence of pathological products in the microstructure of mortars and concretes using SEM scanning electron microscopy.Samples of quartzite mining wastes used here were selected and collected from mining waste dumps located in the municipalities of STL São Thomé das Letras and ALP Alpinópolis, including previously crushed quartzites, and classified by a sector company. In the present study, a diabase exploited in a quarry located in the region of SSP São Sebastião do Paraíso was the reference rock for comparative purposes, as it is a material widely marketed as aggregate for concrete in the southwest region of the state of Minas Gerais, Brazil.Field surveys and preliminary recognition of the geological-geotechnical framework of the main exposures of quartzites mined in the STL and ALP regions, combined with the empirical denomination of miners to classify the waste, detected differences in tonality and texture of the materials according to the extraction site, and three geotechnical types of quartzites were categorized, commercially called soft, hard and glazed. The characteristics of these different types of quartzite tailings and the conventional diabase aggregate are listed in Importantly, each of the established test methods sets procedures with different temperatures, as the higher the temperatures, the more intense the chemical reactions between the alkaline components of the cement and the silica in the aggregates. The accelerated mortar bar method  uses a tThe two types of HES Portland cement were chosen for technological studies as they do not contain pozzolanic additions and steel slag in their compositions, which can contribute to ASR mitigation. In this way, there is a natural tendency for greater alkalinity in composition. Chemical analyses were performed to obtain the alkali content (Na and K) in the cement . StudiesBoth technical standard recommendations and recommendations from several researchers ,18,22 hi3 with a fixed mix ratio at 1:2.25:0.47 for each of the eight samples of aggregates and subjected to alkali attack in a NaOH solution at a temperature of 80 °C.The accelerated test method, recommended by NBR 15577-4  and ASTMAfter casting, bars remained at rest in a humid chamber. After the curing period, bars were removed from the molds, identified and the initial reading was made. Afterwards, bars were submerged in water and kept in an oven at 80 °C for 24 h. Then a new reading was taken and the bars were transferred and submerged in the standard solution with 1 N NaOH, and kept in an oven at 80 °C, accelerating the reactions and allowing the identification of results in a short period of time. Expansion readings were taken periodically, at 8, 16, 22 and 30 days, counted from the casting, and the results expressed in percentage of expansion, corresponding to the means of the three bars. For expansions of up to 0.19%, at 30 days, the aggregate was classified as potentially innocuous, and for expansions greater than 0.19%, as potentially reactive.During the production of some mortars, friability was observed in quartzite samples STL1, ALP1 and ALP3, which promoted the self-fragmentation of the materials during mixing in the mortar mixer. In the specific case of the ALP1 sample, in addition to altering the particle size of the aggregate, self-fragmentation resulted in an increase in the specific surface area, requiring a superplasticizer additive to promote the fluidity necessary for casting the bars.3 concrete; the water/cement ratio at 0.45; the dry coarse aggregate compact volume by 70%; the dry mortar content by 50%; and fineness modulus of fine aggregate at 2.7. For the alkali–aggregate potential reactivity test by the long-term and accelerated methods in concrete prisms, the procedures established by NBR 15577-6  and by N2Oeq) of the cements used to calculate and adjust the contents to 1.25% were made by adding NaOH to the concrete mixing water, using a conversion factor. STL3, ALP1 and ALP3 samples proved to be quite friable during concrete mixing and consolidation. The particles fragmented up, thus changing the particle size of the materials, and consequently the concrete consistency due to the increased specific surface of the aggregates. As an alternative to facilitate prism consolidation, without changing the w/c ratio, a superfluidizing additive was added to the mixtures. The ALP1 sample, even with the addition of the additive, was discarded for presenting a high porosity index and not meeting the consolidation conditions.To determine expansion by the long-term method, concrete prisms were kept in a temperature-controlled environment (38 ± 2 °C). The expansion readings were taken at 7, 28, and 56 days, followed by monthly readings from 3 to 12 months. Equivalent alkali , were also detected. Specific tests of sulfate attacks are recommended for a better diagnosis of this eventual problem, and we therefore propose mitigation methods for this reaction, such as the use of cement resistant to sulfates, for example.During the execution of microstructure analysis using SEM equipment, all tested samples were diagnosed with the presence of ASR expansive gels, indicating the need to use this method to perform a precise diagnosis of this pathology. In addition, expansion products typical of DEF developed on aggregate surfaces, which may have been developed with the rise in temperature during the test, added to the concentration of CaSOThe diagnosis of AAR in quartzites and diabase corroborated the importance of investigating the chemical reactions resulting from this pathology in concrete produced with these aggregates. In addition, this allows engineers and researchers to direct the correct use of these materials in different concrete structures, and warns against adopting techniques to minimize this reaction in structures that will be in contact with water, such as dams, dikes, bridges and retaining walls.In this way, quartzite tailings can be used as an alternative aggregate in mortars and concretes, and can contribute to reducing the amount of material destined for mining waste dumps, consequently mitigating the negative environmental impact in the south of the state of Minas Gerais, Brazil.