Infection near metal implants is a problem that presents challenging treatment dilemmas for physicians. The aim of this study was to analyse the efficacy of two treatment protocols for acute fracture-related infections.A and 32 from protocol B. Both protocols involve immediate surgical debridement and soft tissue coverage, but differ in antibiotic approach: (A) immediate empirical combination antibiotic therapy with rifampicin, or (B) postponed (1–5 days) targeted antibiotic therapy. The primary outcome of these protocols was success, defined as a fracture healing in the absence of infection. The secondary outcome was antibiotic resistance patterns. Logistic regression was conducted on patients and treatment-related factors in association with primary success.Seventy-one patients in two level-1 trauma centres in the Netherlands were retrospectively included in this study. These trauma centres had different standardised protocols for acute infection after osteosynthesis: 39 patients were selected from protocol A patients, in 47% of those in protocol B (P = 0.033), and with prolongation of treatment success was achieved in 90% and 78% of patients, respectively. Protocol A exhibited a better primary success rate  when adjusted for age and soft tissue injury. There was no significant difference in antibiotic resistance between the two protocols.Primary success was achieved in 72% of protocol Both protocols yielded high overall success rates. Immediate empirical antibiotics can be used safely without additional bacterial resistance and may contribute to increased success rates. Fracture-related infection (FRI) is a serious problem after operative fracture management. It is accompanied by increased morbidity, prolonged hospital stays, an increased number of operations and thereby a significant increase in healthcare costs . FRI hasTreatment regimens for prosthetic joint infections (PJI) are becoming increasingly well defined, but PJI differs significantly from FRI in terms of the soft tissue problems and the need for fracture stability that accompany it, and evidence-based guidelines for FRI are currently insufficient . UnfortuIn a previous study, the effect of an aggressive standardised approach to FRI, which consisted of immediate surgical debridement with hardware retention and combination antibiotics with rifampicin, produced promising results. High overall success rates were achieved, but the implications of empirical antibiotics in the context of emerging resistance remain the subject of debate .To contribute to the knowledge gap on this subject, we compared two standardised regimens that shared the philosophy of a uniform approach to all acute FRI, including all anatomic sites and fixation types. Both consisted of immediate aggressive debridement for source control, retention of orthopaedic implants and early soft tissue coverage, but differed in their antibiotic treatment guidelines. The aim was to analyse the effect of the regimens in terms of success rates, microbiological aspects and emerging resistance.A retrospective cohort study of patients who had been treated for FRI was performed in two level-1 trauma centres in the Netherlands. The inclusion period was from January 1, 2008  or January 1, 2011  until December 31, 2014. Patients were identified by diagnosis codes, operation registers and antibiotic administration. Patients of between 17 and 75 years of age with acute symptoms (< 3 weeks) of early and delayed FRI (< 10 weeks after fracture fixation) who had been treated according to the standardised treatment protocols were included in the study [Both protocols were followed in each hospital independently of the type of infection ([sub]acute or early/delayed), location or fixation type.B, a wound drain was used at the surgeon’s preference, while in protocol A, no drains were used. When primary closure could not be achieved, the alternative treatment in protocol A was to apply a vacuum dressing with secondary wound closure. In larger defects, secondary flap or skin transplants were considered. In protocol B, direct flap transplantation with or without a vacuum dressing was the preferred treatment.In all patients, an early and thorough surgical debridement was performed as soon as possible after a (suspected) diagnosis of FRI. Surgical debridement was repeated as often as required by the attending surgeon. Orthopaedic implants were retained when they were stable and sufficient. Primary closure after debridement was the aim in every patient. In protocol Protocol A Empirical antibiotic therapy started immediately after the first debridement when cultures had been obtained. This consisted of 10 days of intravenous administration of antibiotics. The antibiotic therapy began with a combination of vancomycin and rifampicin. Vancomycin was chosen because of its activity against most common pathogens of FRI and its synergetic effect with rifampicin [fampicin . VancomyProtocol B Antibiotic therapy started after culture data had become available (1–5 days) and consisted of a 14-day targeted intravenous administration period, followed by 4 weeks of oral antibiotic treatment. The type and administration  of antibiotics depended on bacterial identification and susceptibility data. Rifampicin was only administered when all cultured bacteria were susceptible.In both protocols, patients were given a peroperative antibiotic prophylaxis, which in most cases consisted of a one-time administration of cephalosporin after cultures had been sampled. In the case of repeated debridement, antibiotic therapy was continued in both protocols according to the culture results from the first debridement and was adjusted only when necessary. No additional preoperative antibiotic prophylaxis was administered at redebridement.From all patients, cultures  were obtained during initial surgical debridement and were repeated with each additional surgery. Isolates were cultured and identified using standard techniques. Susceptibility testing was performed on isolates using the Phoenix automated susceptibility testing system, disk diffusion and/or E-test strips.Initial resistance was defined as resistance before administration of the applicable antibiotic, while intrinsic resistance was not considered to be initial resistance. Follow-up resistance was defined as resistance after the administration of the respective antibiotic, regardless of whether that pathogen had been cultured before. Overall resistance was defined as the combination of both abovementioned types.The primary outcome measure was success. Primary success was defined as resolved signs and symptoms of infection and fracture consolidation on radiological follow-up, as assessed by the treating physician after a single protocol run. In some cases, fracture consolidation as assessed on routine X-rays took longer than the duration of one protocol run. Therefore, the moment of fracture consolidation on follow-up X-rays was counted as the moment of success. Inflammatory markers were not part of the criteria for success because of their low sensitivity and specificity in the diagnosis of FRI, and they are not routinely measured in either protocol . OverallThe secondary outcome measure was the emergence of resistance against administered antibiotics. Microbiological characteristics and susceptibility patterns were described.U-test. The statistical significance of categorical variables was assessed using a Chi-square or Fisher’s exact test. Next, multivariate analysis was performed. A binary logistic regression model was developed to identify the factors that were associated with success after a single protocol run. The model included covariates that showed an association in the univariate analysis of P < 0.5 or factors known to contribute to success from previous studies. A stepwise forward method was used to determine the optimal multivariate model. P values of < 0.05 were considered to be statistically significant. Unadjusted and adjusted odds ratios (OR) were reported with 95% confidence intervals (CI).Analyses were conducted using SPSS 24 . Baseline characteristics were compared between protocols, and descriptive analysis was used to report data per group. The statistical significance of continuous data—which were all non-parametric—between the groups was assessed using the Mann–Whitney A and 42 for protocol B. Ten subjects per protocol were excluded because of major deviation. The remaining 71 subjects were eligible for analysis. The majority (75%) of subjects were males, with a median age of 44 years. The pelvis and lower extremities were most often affected. The fractures were open in 45% of subjects, and most had been treated by nailing or plating . Furthermore, the median duration of both intravenous and oral antibiotic administration differed significantly between the protocols (P = 0.000). However, the median total duration of the antibiotic treatment was 80 days (7–202) and did not differ significantly  and did not differ between both protocols. Local antibiotics were used in 54% and did not differ between the two protocols. After debridement, 54% of the wounds were primarily closed. In protocol A and in 47% in protocol B (P = 0.033). The overall success rate was 90% and 78%, respectively, for each protocol. The time between trauma and success did not differ statistically between protocols, with a median duration of 7 months (range 2–37) in protocol A and a median of 16 months  in protocol B. In contrast, the time between infection and success differed significantly, with 5 months (range 2–25) for protocol A and 14 months (range 1–33) for protocol B . Treatment according to protocol A predicted a higher chance of success than with protocol B  and remained significant after adjustment for age and Gustilo grade . After adjustment for age and Gustilo classification, the administration of rifampicin contributed to higher success rates . Primary closure and the duration of antibiotic treatment did not contribute to different success rates  in the two protocols (P = 0.213), nor did the percentage of initial or follow-up resistance differ  for all or part of the cultured bacteria. Protocol A showed more rifampicin resistance and protocol B more amoxicillin/clavulanic acid resistance, corresponding to the antibiotics prescribed regularly in the respective protocols.Cultures were obtained from 70 subjects, of which five showed no growth. Of the positive cultures, 43 showed ia Table . Follow-A. However, as these elements are totally integrated in the protocols, their individual effects cannot be distinguished based on this data. Despite better logistics and earlier soft tissue coverage in protocol B, the primary success rate was significantly higher in protocol A (A = 72% and B = 47%), which could be attributed to the treatment protocol as a whole and the liberal use of rifampicin . As the antibiotic strategy was the most prominent difference between the two protocols in the logistic regression analysis, this supports the argument for the early use of empirical antibiotics in the treatment of acute FRI.The aim of this study was to compare the effect of two standardised treatment regimens for (sub)acute FRI that were similar in their philosophy for aggressive surgical debridement and implant retention, but differed in their use of antibiotics. The immediate administration of an antibiotic directed against the most common pathogens in combination with rifampicin seemed to contribute to a higher rate of success. In addition, an early change to oral antibiotics did not lead to worse outcomes in terms of success or antibiotic resistance in protocol S. aureus as the most common [S. aureus can begin to form a biofilm within 24 h. In a biofilm, bacteria form an extracellular matrix—which hinders antibiotic penetration—and enter a stationary growth phase, resulting in decreased antibiotic susceptibility [B, dormant infections led to the unnoticed maturation of biofilm before symptoms occurred. If this is the case, it could have contributed to the lower primary success rates in protocol B. It has been recognised that the successful treatment of mature biofilm infections consists not only of antimicrobial, but also of a surgical approach to reduce bacterial load, for which implant replacement is sometimes necessary [As evidenced in our study, the majority of bone and joint infections are caused by gram-positive bacteria, with t common , 9. Howet common , 14 and/t common . This cot common . Nonethet common . For exatibility . We atteecessary . Biofilmecessary . The appecessary –20. The ecessary . Thus, wRifampicin is an example of an antibiotic with favourable pharmacokinetic properties for biofilm infections because of its high bioavailability and capacity to affect bacteria in the stationary phase . A disadB, in line with the most frequent administration of this drug in the corresponding protocol. Resistance emerged twice in Escherichia coli. With high rates of the prescription of antibiotics in primary care facilities, the resistance of bacteria is a growing problem [E. coli has risen to 14% in the past decades [S. aureus and epidermidis, which have 5% and 14% resistance against rifampicin, respectively [Amoxicillin/clavulanic acid resistance was found most frequently in the patients who had been treated according to protocol  problem . Althoug problem . Studies decades . In addiectively . Taking Both protocols were intended to achieve early surgical debridement and wound closure at the initial fracture fixation. Several studies have described the benefits of primary closure in fracture treatment. Both Scharfenberger et al.  and JenkB. This has been considered in the literature to have both advantages (fluid and hematoma drainage) and disadvantages  [B and vacuum dressing in protocol A, with secondary wound healing or delayed flap coverage in extensive soft tissue damage. Direct flap coverage of severe soft tissue injuries that accompany fractures can be executed safely, whereas delayed (> 72 h) free flap transplantation may be associated with more wound complications [When primary closure was feasible, a drain was left in protocol ronment) . Parker ronment)  showed ironment) . When prications , 33. Conications . Vacuum ications . In thisA, as a whole, and the rifampicin treatment, as a separate element, were predicted to have higher success rates. However, due to the limited number of failures in this study and the incorporation of the rifampicin in protocol A, the aforementioned elements could not be analysed separately. Second, not all patients had routine follow-up cultures. Although all clinically relevant, redebridement or protracted infection follow-up tissue samples were obtained, additional samples from all treated patients could contribute to further insight into resistance patterns. Last, the follow-up time was significantly longer in protocol B. Although this is mostly explained by the prolonged inclusion period and longer time-until-success, it may lead to higher relapse rates and thereby result in lower success rates for protocol B. In addition to methodological limitations, since the execution of this study, a consensus on the definition of FRI has been reached and published [There are some limitations to this study. Since this was a retrospective cohort, although patients’ baseline characteristics were similar, fracture treatment characteristics were not standardised. This resulted in differences in, e.g., free flap transplantations (timing/frequency) and time until definitive fixation that could not be analysed separately because of their small numbers and integration in the rest of the protocol. This also applies to the analysis of the independence of separate elements of antibiotic treatment. The major differences between the two protocols were the timing of the start and the choice of antibiotics. Both, protocol ublished . AlthougIn conclusion, overall success rates were high in this setting, where source control and soft tissue coverage were the basis of both treatment protocols. Direct empirical combination antibiotic therapy that consisted of vancomycin and rifampicin yielded higher success rates than delayed narrow-spectrum antibiotics. It is also evident that the former treatment can be used safely, as both protocols had low rates of emerging bacterial resistance. Early combination antibiotics that are directed at the most common pathogens should be considered as the standard of care in acute FRIs.


This study investigated the effect of elevated temperatures on the mechanical properties of high-strength sustainable concrete incorporating volcanic ash (VA). For comparison, control and reference concrete specimens with fly ash (FA) were also cast along with additional specimens of VA and FA containing electric arc furnace slag (EAFS). Before thermal exposure, initial tests were performed to evaluate the mechanical properties  of cylindrical concrete specimens with aging. Additionally, 91 day moist-cured concrete specimens, after measuring their initial weight and ultrasonic pulse velocity (UPV), were exposed up to 800 °C and cooled to air temperature. Subsequently, the weight loss, residual UPV, and mechanical properties of concrete were measured with respect to exposure temperature. For all concrete specimens, test results demonstrated a higher loss of weight, UPV, and other mechanical properties under exposure to higher elevated temperature. Moreover, all the results of concrete specimens incorporating VA were observed before and after exposure to elevated temperature as either comparable to or slightly better than those of control and reference concrete with FA. According to the experimental results, a correlation was developed between residual UPV and residual compressive strength (RCS), which can be used to assess the RCS of fire-damaged concrete (up to 800 °C) incorporating VA and EAFS. Concrete is one of the most widely used construction materials on the face of Earth. Although concrete exhibits outstanding engineering performance in different extreme environments, it faces a significant challenge when exposed to fire due to improper design or as a result of an accident. Concrete is considered a semi-permanent material that neither burns nor emits toxic gases or smokes. Resistance to elevated temperatures and fire is one of the essential properties of concrete for maintaining its structural integrity . HoweverIn recent years, extensive research was carried on the potential use of naturally available materials and waste generated from various industrial and agriculture sectors in the production of high-strength and high-performance sustainable concrete ,9,10. ThVarious SCMs were evaluated against high temperatures including FA, VA, and GGBFS. Nasser and Marzouk conducted one of the first studies on FA-blended mass concrete exposed to elevated temperature in 1979 . They ob2 emission, which causes global warming and climate change-related issues [The per capita consumption of cement in the Kingdom of Saudi Arabia (KSA) has been recoded as one of the highest in the world . The cemd issues . Therefod issues . CurrentLike many other industry byproducts , VA is available in abundance around the globe, particularly in areas having active volcanos ,36,37,38Materials used in this study were ordinary Portland cement (C) from Saudi cement factory, commercially available FA (Class F), EAFS from Saudi Basic Industries Corporation (SABIC), Saudi Arabia, and locally available natural VA from Supper Burkanni Block Co. Jeddah, Saudi Arabia with an average particle size of 30 µm. The EAFS was obtained from SABIC in the form of small-size aggregates (up to 5 mm) and ground in the laboratory to achieve the desired fineness. The chemical composition of all the materials used was obtained by performing X-ray fluorescence (XRF) analysis as shown in 2), aluminum oxide (Al2O3), and iron oxide (Fe2O3) is 70% for both Class-N and Class-F pozzolanas. As demonstrated by the chemical analysis results  and FA (Class-F) was found to be 73.6% and 84.7%, respectively, which indicated the pozzolanic nature of both VA and FA. A more detailed investigation on the pozzolanic nature and reactivity of both VA and FA used in this study can be found in another study by Khan et al. [According to ASTM C618-15 , the min results , the sumLocally available hard limestone-based aggregate and desert sand were used in the preparation of high-strength concrete mixtures. The physical properties of both coarse and fine aggregates were tested according to the ASTM standards, as shown in A PULVERISWTTE 5/4 planetary mill classic line with four grinding bowl fasteners was used to grind the EAFS to change its physical state from small-size aggregates to powder form. The machine consists of four grinding bowls each with 250 mL capacity, made from hard metal tungsten carbide, with steel casing. Each bowl consists of five grinding balls (diameter 30 mm), made from hard metal tungsten carbide. Each bowl can grind up to 125 ± 1 g of material, which means that the planetary mill used in this study has the potential to grind up to 500 g of EAFS in one complete cycle. A measured quantity of 125 g of EAFS aggregates was poured into each bowl of the grinding mill and subjected to grinding for 30 min at a fixed rotation speed of 300 rpm. The grinding was performed in three consecutive cycles such that each cycle consisted of 10 min of grinding followed by a 10 min pause to lower the temperature of the grinding bowl. Each grinding cycle lasted for a total of 50 min. Finally, after completion of the grinding process, the ground EAFS after removing from the bowls was stored in sealed plastic bags to prevent any potential moisture transportation.As shown in The mixture proportions for HSC in this study were prepared following ACI 363.2R-11 , accordiAll the concrete ingredients were mixed by using a power-driven rotating pan mixer, according to the procedure specified in ASTM C192 . ImmediaFollowing the measurement of fresh properties, 42 cylindrical specimens (100 mm diameter × 200 mm height) were fabricated for each mix using steel molds according to ASTM C 39 . All theBefore exposure to the elevated temperatures, all the cylindrical specimens were first oven-dried at 100 °C until a constant weight was achieved. The purpose of the prior drying was to remove the capillary water and reduce the risk of potential concrete spalling . SubsequThe internal temperature of the furnace was set to increase from room temperature to different elevated temperatures . Due to the default variation in the rate of temperature increase in the furnace, the total time required to reach the maximum temperature was different for each elevated temperature. The actual time taken by the furnace to reach the specified elevated temperature  was recorded and is shown in First, the initial weight of each cylindrical concrete specimen used in destructive compression tests was measured before its exposure to elevated temperatures. Subsequently, the residual weight of each specimen after exposure to the specified elevated temperature  was measured to calculate the weight loss. The weight loss is reported as the ratio of residual weight of specimen after each elevated temperature exposure to its respective initial weight.Weight loss is commonly related to the loss of moisture present in different forms within concrete mass, such as free, capillary, absorbed, and chemically bound water. The weight loss at different elevated temperatures causes an alteration in the microstructure of cement paste, which directly affects the mechanical and durability properties of concrete. Therefore, the purpose of this test was to evaluate the impact of different elevated temperatures on weight loss of concrete containing locally available natural pozzolana (VA and its blend with EAFS) as compared to CC and reference FA-based concrete (VA and its blend with EAFS).Mechanical properties such as the compressive strength, elastic modulus, and split tensile strength of all concrete specimens were evaluated before and after exposure to elevated temperatures. At first, tests for mechanical properties on three identical specimens of all mixes  were perThe test for compressive strength of cylindrical specimens before and after exposure to elevated temperatures was performed according to ASTM C39 using a 1500 kN unconfined compression test machine (UCT 1500). The loading rate in the UCT was set to 0.2 MPa/s. The split tensile test on the cylindrical specimen was performed according to ASTM C 496 using a 300 kN universal testing machine (UTM) . The pacA well-known nondestructive UPV test on three identical concrete specimens of each mix before and after exposure to specified elevated temperatures was performed using a UPV tester, consisting of a transmitting and receiving transducer capable of generating and receiving 50 kHz ultrasonic pulse. To perform the UPV test, transducers were placed on smoothed ends of the concrete specimen after applying silicone gel as required by ASTM C597 for the smooth transfer of signals through concrete specimens . The UPV2 to CaO and H2O. In the final heating phase (600 to 800 °C), the rate of weight reduction slightly dropped in CC and in ternary concrete samples, while a slight increase in rate of weight reduction was observed in binary concrete samples as compared to previous heating phase. Lastly, all the tested concrete samples experienced an almost identical net weight loss of 8.6% after heating to 800 °C except for V20S10 concrete samples. The net amount of weight loss in V20S10 concrete samples was lowest at 7.7%. The lowest amount of weight loss in V20S10 concrete could be because of no or lesser retention of water due to the simultaneous presence of VA and EAFS.In fact, the weight loss increased with the increase in exposure temperature irrespective of the type of tested concrete sample. In the first heating phase (20–200 °C), the CC specimens showed the highest weight reduction among all (3.7%), whereas the lowest was observed in V20S10 ternary concrete samples (2.2%). The weight loss in this heating phase is due to the moisture evaporation from the sample surface to the atmosphere. Interestingly, the specimens of ternary concretes containing pozzolanic materials with EAFS (V20S10 and F20S10) exhibited relatively lesser weight losses as compared to their corresponding binary concrete specimens without EAFS (V20 and F20). The current results of relatively lesser weight loss of ternary mixes than those of binary mixes are consistent with the findings of past studies on cement mortars . Moreove2.Consistent with past studies, the aforementioned weight loss phenomenon in all the tested concrete samples may be attributed to the changes in their stiffness and mechanical properties ,57. AccoBefore exposing the concrete specimens to elevated temperatures, the development of different mechanical properties of concrete such as compressive strength, tensile strength, and elastic modulus were calculated with aging at 7, 28, and 91 days. In addition, the UPV of concrete was also measured before elevated temperature exposure. The UPV test was conducted on 91 day cured specimens as the concrete mixtures containing pozzolana attain their maximum potential strength at later ages. A summary of test results before elevated temperature exposure is given in As with compressive strength, CC demonstrated the highest splitting tensile strength (STS) among all concrete specimens irrespective of aging . A slighAs presented in It can be seen in Unlike at 200 °C, the current results demonstrated that all the concrete specimens containing pozzolanic materials as a partial substitute of cement  showed an encouraging response under moderate (400 °C) and high temperatures (600 and 800 °C). It is evident from As shown in 2 to free lime. Because of these changes, the volume of cementitious products increases, which ultimately leads to a reduction in cohesiveness within the paste matrix and the generation of hairline cracks within the concrete mass, as well as on its surface. Consequently, the crack in concrete cause a reduction in the compressive strength of CC, as well as for concrete containing pozzolanic materials. 2, thus offering a higher resistance to degradation at elevated temperature. According to Khurram et al. [Due to a further increase in temperature (400 to 600 °C), a significantly higher rate of loss of compressive strength occurred in all tested concrete specimens. The RCS reduced nearly to 40% for V20, F20, and F20S10. For CC and V20S10, it reduced even further to nearly 36%. After exposure to such a high temperature, the stability of concrete is seriously affected, making it very difficult to differentiate between the effective roles of different pozzolanic materials. According to past research , such a m et al. , these pWith a further rise in temperature (600 to 800 °C), the trend of rapidly decreasing compressive strength continued in all concrete specimens in almost a similar manner to that when exposed to 600 °C. The rising temperature led to further physiochemical transformation and caused the re-crystallization of newly formed compounds. This phenomenon led to large numbers of cracks due to the rapid rate of expansion and shrinkage during heating and cooling phases, respectively. Similar to previous heating phases, the highest loss of compressive strength was observed in CC . In otheAs shown in Similar to the compressive strength (5–12%), only a slight drop in STS occurred (3–7%) due to a further increase in temperature (200 to 400 °C). Although the highest drop of STS was noted in CC (7%), it was still quite lower than its respective drop in compressive strength (12%). Interestingly, there seemed to be no negative effects of elevating temperature (200 to 400 °C) on the STS of concrete specimens containing FA (F20 and F20S10), while only a slight drop in STS was observed for those containing VA (3 to 5%). In fact, the similar compressive and tensile behaviors of concrete are evidence of a direct relationship between them even under elevated temperatures. This fact e = was further noted for the specimens exposed to high elevated temperatures up to 800 °C. For instance, as with the compressive strength, a significant drop in STS occurred due to the exposure of specimens under 400 to 600 °C. As shown in A general trend of slightly higher STS was noted for specimens of ternary concretes mixes containing pozzolanic materials with EAFS as compared to their respective binary concretes (V20S10 versus V20 and F20S10 versus F20) irrespective of the exposed elevated temperatures. However, an exception was observed at 600 °C, and we are keen to explore the specific reason for this reduced STS of ternary concrete mixes as compared to their corresponding binary mixes in future research.As with other mechanical properties, the elastic modulus of concrete decreased with increasing heating temperature. However, it was noted that the effects of increasing temperature on the reduction rates of elastic modulus were relatively faster compared to the respective compressive and splitting tensile strength of tested concrete specimens. As shown in As shown in A summary of the ultrasonic pulse velocity (UPV) results of all tested specimens before and after exposure to elevated temperatures is presented in As shown in R2 = 0.85). They also reported a high coefficient of variation (15%) for the prediction of RCS using their proposed power regression model [CS is the residual compressive strength in MPa, and RUPV is the residual ultrasonic pulse velocity in m/s. The coefficient of determination (R2) and the standard deviation for the above proposed equation are 0.987 and 4.24, respectively.A comparison of current experimental data with the results of linear regression by Awal and Shehu for control concrete  and poweon model . TherefoIt can be seen from Before exposure to elevated temperatures, HSC incorporating VA (V20 & V20S10) produced either comparable or slightly better results for all mechanical properties  to that of reference FA (F20 & F20S10) concrete, irrespective of aging. A slightly lower value of these mechanical properties was observed for the concretes containing pozzolanic materials (VA or FA) when compared to CC, particularly at early ages. This is attributed to the slow pozzolanic reactivity of these pozzolanic materials. However, due to a late pozzolanic reaction with aging, both VA and FA concretes possessed comparable results to that of CC at 91 days.Looking at the encouraging response of VA concretes at 91 days, specimens were subjected to elevated temperatures, and gradual losses of weight, UPV, compressive strength, and tensile strength were noted for all tested concretes up to 400 °C, while significantly high rates of losses were observed under high-elevated temperatures between 400 and 800 °C. However, unlike other properties, a significantly high loss of elastic modulus was observed even at low elevated temperatures, due to the formation of internal air voids and hairline cracks because of the evaporation of free water at low temperatures and chemically bound water at high temperatures.Up to 400 °C, the loss of compressive strength, tensile strength, elastic modulus, and UPV was in the range of 28–38%, 7–28%, 52–67%, and 20–24%, respectively. The highest losses were observed for CC, and a reasonably close agreement was noted between concretes containing VA and FA. The reason for lower losses among VA and FA concretes is their pozzolanic reactivity at relatively low elevated temperatures.2 to free lime. The relatively lesser loss among concretes with VA or FA than CC was due to their inherited ability to partly replace Ca(OH)2, thus offering a higher resistance to degradation at elevated temperatures.Between 400 and 600 °C, the respective losses of those properties were abruptly raised for all concretes to 58–64%, 47–58%, 80–81%, and 45–57%, with the highest loss for CC. At such a high temperature, the stability of concrete is seriously affected by the decomposition of CSH and dehydration of Ca(OH)Under high exposure temperature from 600 to 800 °C, the rate of high losses continued among all concretes, with values of 87–93%, 73–77%, 93–95%, and 75–77% for compressive strength, tensile strength, elastic modulus, and UPV, respectively. This is because of the large number of wider cracks and severe damage of concrete surfaces at such a high exposure temperature, irrespective of the type of concrete.For all concretes, an almost uniform trend of effect of elevated temperature exposure on residual UPV and RCS was noted. Therefore, a linear regression analysis was performed between the residual UPV and RCS of tested concretes. On the basis of the good correlation between the experimental data and regression line, an equation was proposed to use UPV as a nondestructive test to assess the RCS of fire-damaged (up to 800 °C) concrete incorporating VA, FA, and their blends with EAFS.The promising performance of concretes containing VA and EAFS before and after exposure to elevated temperature indicates that the use of these materials in construction as a partial substitute of cement can be very useful in terms of saving natural resources and protecting environment. However, it is suggested to extend this research to study the softening behavior of current concrete mixes at elevated temperature through their complete stress–strain curves. On this basis, a relationship between different concrete mechanical properties (strength and strains) can be proposed in terms of elevated temperature. In addition, other aspects of this research such as the influence of specimen dimension, heat conductivity, and heating/cooling rate on thermal damages need to be further explored.In this study, high-strength sustainable concretes using locally available volcanic ash were produced with and without incorporating EAFS. After determining the mechanical properties under normal curing, the concrete specimens were exposed to elevated temperatures up to 800 °C, and the influence of different heating regimes on the weight loss and mechanical properties of concrete were investigated. The values of UPV of concrete specimens before and after exposure to elevated temperatures were also measured and compared to the RCS of concrete. The following conclusions were made on the basis of this study:


Internationally, there are growing concerns about antimicrobial resistance. This has resulted in increased scrutiny of antibiotic prescribing trends – particularly in primary care where the majority of prescribing occurs. In England, antibiotic prescribing targets are set nationally but little is known about the local context of antibiotic prescribing. This study aimed to examine trends in antibiotic prescribing (including broad-spectrum), and the association with area-level deprivation and region in England.Antibiotic prescribing data by GP surgery in England were obtained from NHS Business Service Authority for the years 2014–2018. These data were matched with the Index of Multiple Deprivation (IMD) 2015 at the Lower Layer Super Output Area level Lower Layer Super Output Area (LSOA) level. Linear regression methods were employed to explore the relationship between antibiotic use and area-level deprivation as well as region, after controlling for a range of other confounding variables, including health need, rurality, and ethnicity.Over time, the amount of antibiotic prescribing significantly reduced from 1.11 items per STAR-PU to 0.96 items per STAR-PU – a reduction of 13.6%. The adjusted models found that, at LSOA level, the most deprived areas of England had the highest levels of antibiotic prescribing (0.03 items per STAR-PU higher). However, broad spectrum antibiotic prescribing exceeding 10% of all antibiotic prescribing within a GP practice was higher in more affluent areas. There were also significant regional differences – with the North East and the East of England having the highest levels of antibiotic prescribing (by 0.16 items per STAR-PU).Although antibiotic prescribing has reduced over time, there remains significant variation in by area-level deprivation and region in England – with higher antibiotic prescribing in more deprived areas. Future prescribing targets should account for local factors to ensure the most deprived communities are not inappropriately penalised. Antimicrobial resistance poses a significant challenge to modern day medicine and has been described by the World Health Organisation (WHO) as a global health security threat . Since tClostridium difficile infection. Optimizing prescribing practices is considered a key component of this strategy, which highlights the importance of understanding antibiotic prescribing patterns across different areas, although very few studies have reported this; the majority of research has focused on antibiotic prescribing in subsets of practices [In addition to targets for overall prescribing, particular focus has also been placed on reducing the prescribing of specific broad spectrum antibiotics, such as co-amoxiclav, the cephalosporins, and the quinolones, owing to their potential to cause severe adverse effects, such as ractices , 7 or acractices . Previouractices . It is nractices .local nature of antibiotic prescribing by primary care in England – especially in relation to area-level deprivation. It is well established that health need varies by area-level deprivation with higher rates of morbidity and mortality in the most deprived neighbourhoods [There is a need to understand the ourhoods . For exaourhoods . It is lThis study, therefore, aimed to: (1) examine the association between antibiotic prescribing and area-level deprivation; (2) analyse the proportion of broad spectrum antibiotics  prescribed by area-level deprivation; and whether (3) geographic region influences prescribing rates.Antibiotic prescribing data were obtained from the NHS Business Services Authority ePACT2 system (NHSBSA Copyright 2018). The data were downloaded for English General Practices (GPs) for the 4 years from April 2014–March 2015 to April 2017–March 2018. All GP practices open for the entire year were included in the analysis. Antibiotic prescribing was measured according to the items per STAR-PU (Specific Therapeutic Group Age-sex weightings Related Prescribing Units) weighting, which shows the amount of prescription items that have been prescribed, compared to what would be anticipated given the number and characteristics of patients registered in the practice. The numerator is the total number of prescription items for antibacterial drugs , and the denominator is the total number of oral antibacterial drugs  ITEM based STAR-PU. As such, it is possible to use STAR-PUs, instead of the number of patients, to allow for comparisons between General Practices. STAR-PUs adjust for age and sex in prescribing, but do not control for health need or area-level deprivation in the weighting. Lower values of items per STAR-PUs indicate less oral antibacterial prescribing. In addition, we also report when broad spectrum antibiotic prescribing  exceeds 10% of all antibiotics prescribed within a GP practice; the threshold of 10% is based upon NHS England targets . This meOverall, 29,631 GP surgeries were included in the analysis for antibiotic prescribing over the 4 years for which we have data (representing 7700 unique surgeries). Seven GP surgeries were excluded as they did not have a corresponding Index of Multiple Deprivation (IMD) decile, and a further 606 were removed as they represented the top and bottom 1% of antibiotic items per STAR-PU data . Deprivation data was derived from the IMD 2015 produced by the Department for Communities and Local Government. This index, constructed from seven domain indices were combined to produce an overall measure of deprivation, which ranks every LSOA in England from 1 (most deprived) to 32,844 (least deprived area). Ranks were converted to deciles to visually illustrate antibiotic prescribing by GPs in different levels of deprivation whereby 1 represents the most deprived areas and 10 represents the least deprived. The IMD 2015 data is used for all years in subsequent analysis as it is produced once every 4/5 years. Using their LSOA locations, the GP practices were also put into one of the nine English government office regions: North East, North West, Yorkshire & the Humber, London, East of England, West Midlands, East Midlands, South East and South West.https://www.nomisweb.co.uk) to determine the ethnic composition of each LSOA. We also included urbanity in the model (produced from the 2011 census), as it has previously been shown that GPs working in rural areas were less likely to delay prescribing of antibiotics [A number of variables were also included in our model specifications. We included ethnic composition, as it has previously been shown that different ethnic groups have different antibiotic consumption patterns , these dibiotics . In keepibiotics , 16, theibiotics . We usedibiotics , 19.To assess the impact of deprivation on the level of antibiotic prescribing, we used multiple bar graphs reporting items per STAR-PU and the proportion of broad spectrum antibiotics in each deprivation decile by year. To complement this graphical analysis, we also used a random-effects linear regression model to estimate the association between deprivation and antibiotic prescribing. This was seen as the most appropriate model specification, as the antibiotics prescribed per STAR-PU were approximately normally distributed (after removing the top and bottom 1% of data). The parameters were calculated using the XTREG command in the statistical software package Stata . The parOverall, the prescribing of antibiotic items decreased from 1.11 items per STAR-PU in 2014 to 0.96 items per STAR-PU in 2018 – a reduction of 13.5%. The reduced antibiotic prescribing was more pronounced in areas of high deprivation: a reduction of 0.17 items per STAR-PU (a reduction of 17.0%) was observed for GP surgeries located in the most deprived areas (IMD-1), compared with a reduction of 0.12 items per STAR-PU (a reduction of 13.1%) for GP surgeries located in the least deprived areas (IMD-10). Antibiotic prescribing in England over time by area-level deprivation is illustrated by Fig. Overall, the proportion of GP surgeries which prescribed over the target of 10% broad-spectrum antibiotics  in terms of total antibiotics prescribed has decreased from 48.4% in 2014 to 29.0% in 2018. In contrast to overall antibiotic prescribing, GP surgeries located in the most affluent areas generally had a higher proportion of prescriptions for broad spectrum antibiotics when compared with GP practices located in the most deprived areas .Two models were developed to understand the factors which drive antibiotic prescribing from English GP surgeries Table . Model 1p < 0.05). The model also showed that, over the 4 years for which we have data, all antibiotic prescribing has reduced by 0.18 items per STAR-PU (p < 0.01). GP surgeries located in areas where there were greater proportion of people of white ethnic origin (p < 0.01), and those found in rural areas (p < 0.01) also showed higher rates of antibiotic prescribing. Finally, compared to London, GP surgeries located in all other areas of England had significantly higher rates of antibiotic prescribing – with the East of England and North East of England having the highest levels (by 0.16 items per STAR-PU).When additionally adjusting for a proxy indicator of health need in Model 2, it was shown that living in the most deprived decile (compared to the least deprived) was still associated with increased antibiotic prescribing – albeit to a lesser extent, but it was only significant in the three most deprived deciles  as a percentage of total antibiotic prescribing by area-level deprivation. We identified three key findings that will be of importance to healthcare policy discussions around antimicrobial resistance and prescribing targets: (1) there were significant inequalities in antibiotic prescribing by deprivation – with GP surgeries located in the most deprived areas having the highest levels of antibiotic prescribing ; (2) there is also variation in the prescribing of broad spectrum antibiotics  with higher proportions of broad spectrum antibiotic prescribing occurring in more affluent areas; (3) there was also significant regional variation in antibiotic prescribing – with the highest levels of antibiotic prescribing observed in the East and North East of England.Area deprivation has multiple influences on health so the pathways linking deprivation and inequalities in antibiotic prescribing patterns are complex. There is a large international literature on the relationship between health and place which suggests that geographical health inequalities exist as a result of both the characteristics of places  and of the people who live there  . In termOur broad findings are in keeping with previous research. As mentioned previously, the study by Curtis and colleagues, who described antibiotic prescribing trends across England for the years 1998 to 2017, showed that there was significant geographical variation in prescribing: at a Clinical Commissioning Group (CCG) level, the variation in overall antibiotic prescribing was two-fold, while for cephalosporin prescribing, the variation was seven-fold . This stAnother study by Mölter and colleagues, who analysed antibiotic prescribing by GP practice in England, identified spatial clusters of high and low spots of prescribing  . The worGiven the emphasis and strategic importance – at both a national and international level – of developing and implementing antibiotic stewardship polices, our findings are timely and potentially have important implications for policymakers. The national strategy of reducing the use of antibiotics appears to be working, given that our data shows a reduction in antibiotic items per STAR-PU each year. This is in line with other work that also shows a similar reduction in antibiotic prescribing . HoweverWe believe our modelling results are robust; the residuals are normally distributed, and the VIF ratio is low (2.07) therefore homoscedasticity and multicollineararity are not considered problematic. However, we do acknowledge there are a number of limitations to our work. Firstly, we only assessed the amount of antibiotic prescribing according to items per STAR-PU; we did not consider the appropriateness of prescribing, nor did we consider the patient characteristics for whom the antibiotics were prescribed. It is possible, therefore, that the higher antibiotic prescribing observed in the most deprived areas were prescribed either unnecessarily or inappropriately. Indeed, Smith and colleagues showed that in an English primary care setting, most antibiotics are prescribed for conditions that only sometimes required antibiotics, which was dependent on patient specific indicators (e.g. co-morbidity) . Our stuDespite a reduction over time in antibiotic prescribing, there is still significant variation by area-level deprivation and English region in prescribing levels. Our analysis demonstrated higher overall antibiotic prescribing in more deprived areas, although the proportion of GP surgeries prescribing broad spectrum antibiotics was higher in more affluent areas. Health need is an important consideration in antibiotic prescribing, but it did not explain all of the variation. Future antibiotic prescribing targets should account for local factors, including deprivation, to ensure GP practices located in the most deprived communities are not inappropriately penalised.Additional file 1: Supplementary Figure 1. Histogram of antibiotic STAR-PU before (A) and after (B) trimming top and bottom 1% of data.Additional file 2: Supplementary Figure2. GP practice concentration by IMD decile.


High temperature rise mostly caused by a fire outbreak is currently becoming a threat that endangers concrete’s structural performance for buildings and the safety of occupants. The behavior of concrete after fire subjection has been of much interest for the structural materials design purposes. This study investigated the physical properties and the compressive strength of M25 concrete incorporating Neem Seed Husk Ash (NSHA), exposed to and through targeted different levels of temperature (200 °C to 800 °C) for a period of three hours in an electric furnace. The NSHA was produced by calcining neem seed husks at 800 °C for six hours and then sieved through the 125 μm sieve. Different amounts of NSHA were investigated while considering the plain concrete as the control sample. 150 concrete cubes of 150 mm sizes were cast and properly cured for 7 and 28 days. The experimental results show that the compressive strength of the 5% NSHA concrete exposed to temperatures up to 400 °C is 21.3% and 23.8% better than the normal concrete at 7 and 28 curing days, respectively. Surface cracks and spalling are noticeable at 600 °C and 800 °C for all samples considered in this study. Concrete is a composite building material comprised of coarse and fine aggregates glued together with cement paste that results in the desired structure upon hardening. It is a material of choice for applications that require high-temperature-resistant materials. However, concrete structures can only serve their intended purpose, provided that the threshold point is not exceeded upon exposing them to elevated temperatures, like those in case of fire accidents .2 is also produced, contributing to about 7% of the entire CO2 emissions worldwide [The current development of infrastructures due to urbanization has led to about 11 billion tons of concrete being consumed annually, and is likely to exceed 18 billion tons by the year 2050 [orldwide . Hence, the issues of materials sustainability and environmental pollution accelerated by the concrete industry need to be addressed. Many researchers of our century have been looking for eco-friendly materials that can partially or totally replace cement in the mix with the aim of handling the raised concern on depletion of raw materials, atmospheric pollution, global warming and waste disposal . HoweverCurrently, pozzolans from agro-wastes and industrial wastes have been of much interest in the field of building materials as they contribute to blended cement concrete with superior properties parallel to the reduction of the aforementioned environmental problems . With thMeanwhile, there are complications on the fire endurance ability of traditional concrete by itself due to dissimilar thermal characteristics of the components forming the composite material, porosity and moisture content . GeneralIn the present study, the OPC 42.5 N grade conforming to Tanzanian standard TZS727: 2002 in accordance with BS 12:1996 13 and Neem Seed Husk Ash (NSHA) were used. Their chemical composition and surface area will be presented and discussed under the results section.The OPC was acquired from local suppliers in Arusha city, Tanzania. The NSHA was obtained by burning the neem seed husk in an electric furnace at 10 °C/min heating rate to a temperature of 800 °C for six hours followed by grinding and sieving through 125 μm sieve as visually presented in The neem seed husks were locally collected from Singida, the central region of Tanzania. The moisture content was measured to be 1.8%, and they were oven-dried at 110 °C for six hours then ground to small size before calcining. X-ray fluorescence (XRF) used was to determine the chemical composition of NSHA, while the surface area was calculated with the Brunauer-Emmett-Teller (BET) method from nitrogen adsorption-desorption. The heating regimes were adopted from the previous study which assessed the pozzolanic activity of palm oil waste ash in response to calcining temperatures and retention time . The parThe properties of the used aggregates were determined, guided by the standards. The BS EN 933-1:2012  was usedIn this research work, natural river sand with fineness modulus of 2.6 was used as fine aggregates and crushed granite aggregates with a nominal maximum size of 20 mm were used as coarse aggregates. The particle size distribution and some of the measured properties of fine and coarse aggregates are presented in Portable tap water was utilized for mixing.Concrete was prepared by partially substituting cement by NSHA. The proportioning and the mixing of concrete ingredients were done as per BS 1881-125:1986  for all The concrete blends were prepared in an electric mixer. The weighed fine and coarse aggregates were put into the concrete mixer and moisturized in advance before adding water to their saturation. Afterward, water was added with the addition of cement together with the NSHA and thoroughly mixed for three minutes. Standard cubes of size 150 mm were used. A total of 150 cubes were cast from which three cubes from each series were considered for each exposure condition. After casting, specimens were allowed to set under room temperature of 25 ± 3 °C. After 24 h all the concrete specimens were demolded and then cured by submerging in water under identical environmental conditions. At the targeted ages of 7 and 28 days, cubes were taken out of the water and exposed for 24 h to naturally dry under laboratory environmental conditions.The prepared concrete samples were fired in a controlled electric furnace to different levels of temperature  at 10 °C/min, a methodology similar to an earlier study , for a pThe control samples were weighed and tested with no heat application. All specimens other than the control specimens were weighed before exposing them to elevated temperatures. After cooling, samples were then weighed again and observed for any spalling that might have occurred during the heating process. The recorded weights were then used to determine overall mass loss at each temperature similar to previous studies . Their rThe chemical composition of NSHA and the OPC were analyzed using X-ray Fluorescence (XRF). From the results presented in The reactivity of fly ash, when employed as a partial substitution of cement in concrete mixes, depends to a large extent on chemical composition and the particle size distribution. The fraction of ashes passing the 45 μm sieve is suitable for use in concrete production as the reactivity of fly ash increases with its fineness . Based oThe evaluation of impairment to the concrete structures exposed to high temperatures was thoroughly done to observe the changes occurring to the surface of concrete specimens. Visual observation of the color changes, as well as of the spalling and cracks on the surface of the concrete is considered to be the first step in assessing the damages of fired concrete. Visual observation of fired concrete which was considered as the first step assessment discovered a similar pattern of cracks and pits on the surfaces of both the 7 and 28 days cured concrete samples. The physical characteristics of concrete at various temperatures up to 800 °C are presented in The cube samples were respectively weighed before and after exposure to elevated temperatures for the purpose of evaluating the mass loss. 2 decomposition and the other hydrated cement products developed during the hydration process. A previous study by Janotka and Nürnbergerová [The mass losses for the 28 days cured concrete samples are shown in ergerová  observedergerová , who tesThe compressive strength for the cooled concrete samples after thermal treatment was determined. The residual strength for the 7 and 28 days cured concrete samples subjected to different elevated temperatures is presented in In the prior investigation, the compressive strength increased at 250 °C and had higher residual strength at 450 °C and 650 °C .The outstanding and reduced compressive strength for the heated concrete samples after 7 days curing period is demonstrated in The residual strength for the 28 cured samples with their respective standard deviations is presented in The observed early decrease of the compressive strength of concrete samples subjected to temperatures between 25 °C and 200 °C is due to the weakening of bonds likely to be ascribed by the swelling of water layers in the NHSA-cement paste . The addIn general, it can be concluded that the reduction in strength of NSHA concrete is initiated by the dense microstructure, which caused the build-up of high internal pressure as a result of the water-vapor transition in the water interlayer. For temperatures ranging from 400 to 600 °C, a severe strength loss for all the types of concrete was observed and recorded as 17.7%, 22.1%, 10.2%, 12.4% and 24.6 % of the initial values for OPC, 0% NSHA, 3% NSHA, 5% NSHA, 7% NSHA and 10% NSHA concretes, respectively.The cement paste contracts, and the aggregates expand upon exposing the concrete to high temperatures. Such a response leads to the weakening of the transition zone and bonding between aggregates and cement paste. This process, as well as the decomposition of the chemically formed hydration products, result in serious deterioration and strength loss in concrete exposed to elevated temperatures. An average strength loss of 70% was observed for concrete containing NSHA which deteriorated severely up to 800 °C due to the decomposition of C–S–H gel. Such an observation has been reported in previous studies ,38. Despite the improved early strength of concrete containing NSHA, a noticeable loss in compressive strength was observed at high temperatures as a result of built-up vapor pressure in a dense structure during the evaporation process of the physically and chemically bound water.For all concrete samples exposed up to 400 °C, there was no noticeable consequence on the surface. Significant fractures and localized spalling were noticed when the exposure temperature rose to 600 °C, and they were more pronounced at 800 °C. The color change was insignificant for all series of OPC and blended concrete considered.Specimens exposed to greater than 400 °C suffered spalling and mass loss. In previous findings by Bastami et al. , spallinThe compressive strength of specimens fell notably for both normal concrete and NSHA blended concrete samples when exposed to the temperature exceeding 400 °C. The drop in compressive strength of about 60% and 69% was observed at 800 °C for the 7 and 28 days cured specimens, respectively.2 content. Therefore, NSHA is worth being recommended as a pozzolanic material for structural applications in concrete structures, of which they will still perform at high temperatures up to 400 °C.Grounded in the investigated strength and physical properties of NSHA concrete, it is evident that 5% NSHA concrete performed better than control concrete for all mixtures for temperatures up to 400 °C. This implies that the reaction of pozzolans with portlandite is favored between 100 °C and 400 °C, resulting in a considerable decrease of Ca(OH)The present study examined the residual compressive strength and spalling effect of the cement-NSHA blended normal concrete (with characteristic strength of 25 MPa) subjected to elevated temperatures. The mixes containing NSHA exhibited greater compressive strength (33.2 MPa) than the control mix (26.7 MPa), implying that the inclusion of NSHA led to improved compressive strength both at ordinary and elevated temperatures. The blended concrete was found to perform better than the normal concrete when fired up to 400 °C. The strength decreased significantly for concrete specimens fired beyond 400 °C associated with higher mass losses due to spalling. The following deductions can be made based on the presented experimental results:


Pharmacoepidemiological research about antibiotics is supported by the World Health Organization (WHO), but data regarding antibiotic prevalence based on actual prescriptions and dosing patterns are insufficient. The aims were: (i) To estimate the prevalence and prescribed daily dose (PDD) of antibiotics in outpatients from Mexico City and (ii) to compare the PDD against the defined daily dose (DDD), as established by the WHO. The study included 685 prescriptions of antibiotics selected randomly from five geographical zones of Mexico City. Drug, dose, frequency, and duration of treatment were obtained from each prescription. PDD values of each antibiotic drug were calculated as the average of the daily doses. Sub-use and overuse were determined by the ratio PDD/DDD for each prescription. The most prescribed antibiotics to outpatients from Mexico City included six pharmacological groups: quinolones (28%), penicillins (23%), cephalosporins (17%), macrolides (10%), lincosamides (9%), and sulfonamides (4%). Both overuse and sub-use were high . In conclusion, most of the antibiotics with a high prevalence of prescription also had a high rate of either sub-use or overuse, with prescribed doses that significantly differ with their corresponding DDD. The dosing variation has important clinical implications since it denotes low prescription control. Antibiotic therapy has marked a threshold in modern medicine and the way infectious diseases are treated, but these drugs have represented a challenging issue since the beginning of their use in big populations, and therefore, global policies have taken place to reduce the actions that lead to an incorrect use ,2. As anIt seems that the best way to enclose antibiotic-related problems is to have a strict drug control ,6,13, anHowever, there is not a registry of any control in prescription, so there is still a long way to go until we could achieve good practices related to antibiotic use. In fact, there is poor evidence of antibiotic utilization in Mexico , and mosAntibiotic prescription is widespread in Mexico City and includes the utilization of 12 pharmacological groups . The mosThe PDD divided by the DDD was calculated to determine the discrepancy of dose utilization from a statistical point of view . We consp < 0.05). Some antibiotics had large discrepancies , including cefuroxime, clarithromycin, amoxicillin plus clavulanic acid, azithromycin, and lincomycin, while other antibiotics had small discrepancies , including levofloxacin, cefalexin, clindamycin, gentamicin, and fosfomycin.Prescription discrepancies related to doses are also described by their normalized values of PDD with respect to DDD . The norThere are only very few studies that assess the antibiotic prescription in Mexico ,20. For In this study, quinolones represented the pharmacological antibiotic group with the greatest prescription prevalence in Mexico City. This fact differs from other countries where penicillins are the most prescribed pharmacological group, as it is the case in Egypt , althougThe use of quinolones as the most prescribed drugs gives an interesting and overt pattern to future studies to relate the diagnosis with the pharmacoepidemiological results of prevalence in the outpatient setting, since it is necessary to further analyze the consequences of prescribing a given antibiotic for a determined infection. Pharmacoepidemiology establishes a specific methodology for this kind of study called prescription–indication ,28,29, wThe variability of prescription among the different pharmacological groups in this study was shown to be relatively low, as 7 out of 10 prescribed antibiotics in Mexico City belong to either a quinolone or beta-lactams , which is certainly a highlight when comparing our results to other regions around the world where diversity in prescription is wider . HoweverThe assessment of antibiotic utilization and the presence of problems related to them are difficult aspects to quantify. Nevertheless, the research in this subject should consider factors that involve both the prescriber and the patient and, in this sense, the differences that may be observed in antibiotic dosing after the statistical comparison of the PDD and the theoretical DDD might explain the point of view of the factors mentioned herein. For example, among general practitioners, several factors are associated with the antibiotic prescribing volume, including appointment duration, training practice, as well as the prescriber’s age and sex . On the Indeed, drug utilization has become a crucial matter regarding the assessment of antibiotics, especially when doses are considered into the evaluation, since it allows us to take adequate strategies into account to encourage health promotion to decrease and avoid antibiotic-related problems. Particularly, bacterial resistance has been identified as a globally recognized problem in public health related to the incorrect use of antibiotics ,26,32. BThe prescriptions did not include the diagnosis since it is not a requirement in the Mexican regulation and because of that, it was not possible to identify further reasons about the discrepancies between PDD and DDD, for example, if an antibiotic was prescribed for an indication different to the main one or if the patient was being treated concomitantly with other medications or was in a medical condition that oriented the physician to reduce the antibiotic daily dose .Antibiotic use, including prescription and administration, must reach adequacy as a key factor to avoid bacterial resistance. However, the correct utilization represents itself as a complex problem that involves the right antibiotic selection, proper posology, therapeutic adherence, and patient compliance. There is an urgent need in Mexico to continue researching about antibiotics to create a solid reference regarding the pharmacoepidemiology of antibiotics that aid future health decision-making processes . Thus, sThis study is part of the initial efforts in giving an overview and solution to antibiotic utilization in Mexico, focused on the outpatient population through the application of a formal pharmacoepidemiological methodology to get robust outcomes about drug utilization patterns and foresee better prescription practices that decrease adverse effects, inefficacy, and strongly avoid bacterial resistance. Nonetheless, considering the massive consumption of antibiotics, future studies are highly needed, especially those that explore the prevalence of antibiotics based on prescriptions in a multicentric fashion, since this ensures that the medication was actually dispensed to the patient, not in retailing sales, but also to encourage the research that explores the relationship between the antibiotic spectrum with the prescription  , the preThis study was retrospective, cross-sectional, descriptive, and observational, with a sample based on prescriptions from outpatients, and all data were retrieved from community pharmacies. There are not available databases in Mexico. Therefore, for creating the first database, we applied a sampling technique creating clusters to be able to sample data from a huge geographic zone, such as Mexico City with more than 8 million inhabitants, this technique is also useful to avoid bias since all data are randomly obtained with the same probability to be chosen and considers the population density at the moment of data collection, so representativity is guaranteed. For this study, Mexico City was divided into five geographical zones , then, 25 community pharmacies along the city were selected from a predetermined list of pharmacies using a table of random numbers . We proceeded to data collection once the pharmacies were selected, prescriptions being our unit of analysis, it is important to mention that there is not an electronic record of prescriptions in Mexico so the pharmacy must store the prescription in a hard copy (printed on paper). Previously, we calculated a sample size according to the proportions formula and considering a 20% loss in case of illegibility of prescriptions, those with incomplete posology data or prescriptions different from antibiotics or pediatric patients. Thus, the calculus was a total of 685 prescriptions which were divided equally in the 25 community pharmacies (77 prescriptions per pharmacy).Regarding the inclusion criteria, they were prescriptions delivered by physicians or odontologists, from adult patients (older than 18 years old) and with at least one antibiotic. All prescriptions were selected using random numbers generated by a computer. In this way, we could ensure that all obtained data were from outpatients from Mexico City.The protocol of the present study complies with the national and international ethical aspects as well as applicable confidentiality laws in Mexico. The Committee of Ethics for Research of the Medical Research Center CEBECI Farmacología Clínica, Sociedad Civil approved the study (protocol number ICE-1506-NIF).We extracted the whole posology from the prescription, considering the drug, the quantity of drug per dosage form, frequency of administration, and duration of treatment as independent variables. Afterward, the drugs were classified according to the anatomical, therapeutical, and chemical (ATC) coding, as indicated by the WHO, and each code has been linked with its corresponding value of DDD published on the WHO website in 2018 .All DDD values were present in the WHO database except for the combination of sulphamethoxazole and trimethoprim, for which the value used as DDD was the one of maximum daily dose, as published in the information to prescribe (ITP), this is in the technical document from the main pharmaceutical laboratory that manufactures the medication containing this drug combination . PDD was calculated as the product of the antibiotic dose per dosage form by the number of dosage forms indicated in each administration by the frequency in a day. This calculus was made for each one of the prescriptions of the same drug, and then the corresponding PDD mean was obtained and considered for the general statistical analysis.The antibiotic prevalence was calculated through the division of the number of prescriptions by the total number of prescriptions. The same analysis was made for the diverse pharmacological groups, and the results are presented as prevalence values and 95% confidence interval. According to Kolmogorov–Smirnov tests, most data did not have a normal distribution, and the results are presented as the median (percentile 25–percentile 75).The pharmacoepidemiological assessment of prescribed doses of antibiotics was done by comparing the values of medians of PDD for each ATC class against its corresponding DDD using the Wilcoxon signed-rank test. The ratio between PDD and DDD was also calculated for each prescription, to determine sub-use (defined as PDD/DDD < 1.0) or overuse (defined as PDD/DDD > 1.0) for all prescribed antibiotics. p < 0.05 was considered as significant.The doses were also normalized taking the PDD minus the DDD as the numerator and the DDD being the formula (PDD-DDD)/DDD and considering that there is no discrepancy between PDD and DDD if the value is zero as the denominator. The Wilcoxon signed-rank test was also performed comparing a value of zero against the median of the normalized value for each ATC class. The statistical analysis was performed using SPSS version 21.0 and a value of The analyzed prescription in this pioneering study in Mexico shows that most of the antibiotics with a high prevalence of prescription also had an elevated rate of either sub-use or overuse. The statistical value of the DDD reported by WHO when comparing to PDD does not necessarily reflect the quality of prescription, since the dose may vary according to the diagnosis and particular characteristics from the patient ,38, but The present study shows the utilization of antibiotics in an outpatient setting by the analysis of doses. Mexico does not have any record about this type of data, which is useful to prescribers for whom the knowledge in pharmacoepidemiological utilization tendencies may be a coadjutant daily clinical decision-making process related to prescription. This study and some others of the same class might justify to the Mexican health authorities the application of public strategies towards both health providers and patients to increase the rational use of antibiotics, and in this way, to contribute to the efforts that are globally taking place in other regions.


The role of central sensitization in refractory pain-related diseases has not yet been clarified.  We performed a multicenter case-controlled study including 551 patients with various neurological, psychological, and pain disorders and 5,188 healthy controls to investigate the impact of central sensitization in these patients. Symptoms related to central sensitization syndrome (CSS) were assessed by the Central Sensitization Inventory (CSI) parts A and B. Patients were categorized into 5 groups based on CSI-A scores from subclinical to extreme. The Brief Pain Inventory (BPI), addressing pain severity and pain interference with daily activities, and the Patient Health Questionnaire (PHQ)-9, assessing depressive symptoms, were also administered. p < 0.001). Medium effect sizes (r = 0.37) for CSI-A scores and large effect sizes (r = 0.64) for CSI-B disease numbers were found between patients and control groups. Compared with the CSI-A subclinical group, the CSI-A mild, moderate, severe, and extreme groups had significantly higher BPI pain interference and severity scores, PHQ-9 scores, and CSS-related disease numbers based on ANCOVA. Greater CSI-B numbers resulted in higher CSI-A scores (p < 0.001) and a higher odds ratio (p for trend <0.001). CSS-related symptoms were associated with pain severity, pain interference with daily activities, and depressive symptoms in various pain-related diseases.  CSI-A scores and CSI-B disease numbers were significantly greater in patients than in controls ( Our findings suggest that CSS may participate in these conditions as common pathophysiology. Central sensitization represents enhanced functions of circuits in nociceptive pathways and an abnormal state of the nociceptive systems, resulting from the remarkable plasticity of the somatosensory nervous system . Due to Central sensitization plays a role in fibromyalgia, a refractory pain disease in which alteration of central nociceptive processing occurs and pain can be worsened by psychological factors . In patiBased on these findings, central sensitization plays a key role in sustained and amplified pain observed in certain proportions of refractory pain-related diseases, and it can participate in the pathophysiology of pain chronification, contributing to pain-related disability and inducing comorbid psychiatric symptoms and nonspecific symptoms such as fatigue and dizziness. These consequences not only negatively impact daily activity and the quality of life of affected individuals but also reduce social productivity. However, the role of central sensitization in refractory pain-related diseases is not yet fully understood. Investigating the effect of central sensitization in various diseases requires a large sample of pain-related diseases with a multicenter collaboration.The Central Sensitization Inventory (CSI) is a self-administered questionnaire addressing symptoms associated with central sensitization and screening for several diseases related to central sensitization, including chronic headaches, restless legs syndrome, fibromyalgia, chronic fatigue syndrome, and multiple chemical sensitivity. CSI has been widely used and validated for the assessment of symptoms related to central sensitization syndrome (CSS) . In thisA total of 567 outpatients  were recruited from neurological psychiatric pain clinics in a multicenter setting between March 2018 and April 2019. Patient diagnoses in this multicenter study included migraine, tension-type headache, medication overuse headache, Parkinson's disease, stroke, restless legs syndrome, neuropathy, fibromyalgia, complex regional pain syndrome, cervical/lumbar spine disease, chronic fatigue syndrome, and depression. After excluding missing data on CSI, 551 outpatients  were finally included. Additionally, 6,135 residents as general healthy controls were recruited from Utsunomiya city located adjacent to Dokkyo Medical University Hospital. When they had undergone an annual health check-up, they answered the questionnaire. Excluding missing values for sex, age, and CSI, 5,188  were included in this study.The present study was carried out in accordance with the Declaration of Helsinki and was approved by the institutional review boards of Dokkyo Medical University Hospital and other participating facilities. All participants provided written informed consent to participate in the study.α coefficients of CSI-A scores were 0.902 in the patient group and 0.894 in the control group in the present study. Patients were categorized into 5 groups based on CSI-A scores: subclinical, 0–29; mild, 30–39; moderate, 40–49; severe, 50–59; and extreme, 60–100 [Participants completed questionnaires including smoking, caffeine intake, alcohol consumption, and body mass index. CSS-related symptoms were assessed by the Japanese version of the CSI, comprising parts A and B . CSI-A s, 60–100 , 20. A C, 60–100 . Patient, 60–100 . The Jap, 60–100 .t-test or Mann–Whitney U test for continuous variables where appropriate. To compare the CSI-A score and CSI prevalence (CSI-A ≥ 40 points) between patients and control groups, a matching dataset was obtained using caliper matching with a standard deviation of 0.25 times the propensity score calculated by age, gender, smoking, alcohol, and caffeine intake. The effect sizes between the patient and control groups were calculated by formula  for the Mann–Whitney U test or formula  for the chi-square test as follows formulas [Z is the standard test statics from the Mann–Whitney U test and n is the sample size.x2 is chi-square value, n is sample size, M is the value with the fewest rows and columns.Patient and control groups were compared using the chi-square test or Fisher's exact test for categorical variables and Student's  formula  (r ≥ 0.1formulas :(1)effecp values < 0.05 were considered statistically significant. IBM SPSS Statistics software version 24.0  was used for statistical analyses.For the patient group, one-way analysis of variance or the Kruskal–Wallis test was used for the analysis of continuous variables among groups where appropriate, and the chi-square test was used for the analysis of categorical variables. Post hoc tests with residual analysis and Benjamini–Hochberg test for a chi-square test and Bonferroni test for ANOVA or Kruskal–Wallis test were performed. The PHQ-9 score, BPI pain interference score, BPI pain severity score, and the number of CSS-related diseases (based on CSI-B) among the 5 groups classified by CSI-A scores were analyzed using analysis of covariance (ANCOVA) after adjustment for potential confounding factors followed by the post hoc Bonferroni test. The relationship between a number of CSS-related diseases (0–6) and CSI-A scores was also analyzed by ANCOVA followed by the Bonferroni test and multivariable logistic regression model after adjustment for potential confounding factors. Each missing value was excluded in every analysis. Two-tailed p < 0.001). Medium effect sizes (r = 0.37) for CSI-A scores and large effect sizes (r = 0.64) for CSI-B disease numbers were found between patients and control groups. Next, we performed a subanalysis comparing 526 patients and 523 propensity score-matched controls. The results replicated significant differences in CSI-A scores and CSS-related diseases on CSI-B among the groups . Additionally, compared with the 0 CSS-related disease group on CSI-B, the 1, 2, 3, and 4–6 CSS-related disease groups showed significantly higher odds ratios (ORs). The p value for the trend test was <0.001 among 5 CSS-related disease groups classified according to the cutoff point (≥40) of CSI-A scores.In In this study, we assessed symptoms related to CSS in patients with neurological, psychological, and pain disorders in a multicenter case-controlled setting. First, we showed that the CSI-A score and the number of CSS-related diseases on CSI-B were significantly greater in the patient group than in the control group. In addition, we calculated that the effect sizes for CSI-A and CSI-B between the patient and control groups were large. Next, we found that pain severity, the degree of pain interference with daily activities, and depressive symptoms worsened, and a number of CSS-related diagnoses increased as the CSI-A score increased across various pain-related conditions. Previously, the CSI-A score was related to pain intensity and pain interference in patients with musculoskeletal disorders . SimilarA large population-based study consisting of 8,930 respondents on a health survey showed that women reported poorer health scores than men did, particularly those aged between 30 and 40 years and over 70 years . TherefoOur finding that, as the CSI-A score increased, pain-related disability and depressive symptoms worsened even after adjustment for CSS-related diseases on CSI-B suggests that this impact of central sensitization was not specific to certain diseases. Alternatively, central sensitization may relatively uniformly impact pain-related disability and psychiatric symptoms in various pain-related conditions. Klyne et al.  reportedWe found a significant link between higher depressive symptoms and higher CSS burden (CSI-A scores) in this study. Brain limbic structures are innervated by serotoninergic median raphe neurons and noradrenergic neurons from the locus coeruleus, in which dysregulation of these neurons likely mediates features of psychiatric diseases such as depression and anxiety . Thus, iThe limitations of this study include a cross-sectional design in patient analysis, and CSS-related diagnoses were made by participants with CSI-B and not by physicians. Relatively few participants had more than 3 CSS-related diseases; thus, the 95% CI of the OR among the 3 and 4–6 CSS-related disease groups was wide. However, because the trend test for the OR among the 5 CSS-related disease groups showed significant differences, a relationship between the number of CSS-related diseases and a CSI-A score of ≥40 was more likely. Regarding potential confounding factors for lifestyle, smoking, alcohol, and caffeine intake were the only options for multivariate analysis. Further prospective studies and more confounding factors are warranted to show a longitudinal impact of CSS on disease progression in a patient group. Finally, we used a validated questionnaire to assess CSS-related symptoms (CSI) ; howeverWe revealed that CSS-related symptoms were associated with pain severity, pain interference with daily activities, and depressive symptoms in various pain-related diseases in a multicenter setting after adjusting for confounders. Our findings suggest that CSS may participate in these conditions as common pathophysiology and may be a target for future treatment of these disorders.


Escherichia coli (UPEC) strains both in vitro and in an experimental Galleria mellonella model. In vitro synergistic effects were observed in all 12 test strains by standard checkerboard and time-kill assays. Importantly, amikacin or nitrofurantoin at half of the clinical doses were not effective in the treatment of UPEC infections in the G. mellonella model but the combination therapy significantly increased G. mellonella survival from infections caused by all 12 study UPEC strains. Taken together, these results demonstrated synergy effects between nitrofurantoin and amikacin against MDR UPEC.Urinary tract infections (UTI) are common infections that can be mild to life threatening. However, increased bacterial resistance and poor patient compliance rates have limited the effectiveness of conventional antibiotic therapies. Here, we investigated the relationship between nitrofurantoin and amikacin against 12 clinical MDR uropathogenic  Escherichia coli (UPEC) and E. coli ST131 is the globally dominant multiple drug-resistant (MDR) UPEC clone that causes infections associated with limited treatment options (Urinary tract infections (UTI) are defined microbiologically as the inflammatory response of the urothelial to microbial pathogens and are some of the most common bacterial infections affecting 150 million people each year worldwide . UTIs ar options . These i options . The inc options . Therefo options .Carbapenems have been recommended for treating UTIs caused by extended spectrum β-lactamase (ESBL) producing bacteria but currently are being restricted due to increased resistance . HoweverE. coli in vitro . All tested strains were identified to the species level by MALDI-TOF MS (Axima-Assurance-Shimadzu) and https://cge.cbs.dtu.dk/services/) and ABRicate (https://github.com/tseemann/abricate).Genomic DNA from the 12 clinical isolates was subjected to 250 bp paired-end whole genome sequencing (WGS) using the Illumina MiSeq system  and the reads were assembled using SPAdes v3.6.2.  MLST andAmikacin (AMK), nitrofurantoin (NIF), meropenem (MEM), cefotaxime (CTX), tigecycline (TIG) and tetracycline (TET) were purchased from Yuan Ye Biological Technology . Ampicillin (AMP), fosfomycin (FOS), colistin (CST), ciprofloxacin (CIP) and sulfamethoxazole/trimethoprim (SXT) were purchased from Xiang Bo Biotechnology . Antibiotic stocks solutions were prepared according to the manufacturer’s recommendations.E. coli strain ATCC 25922 was used for quality control.Antimicrobial susceptibility assays were performed and interpreted according to CLSI guidelines  using the microdilution broth method except for fosfomycin. The MIC of Fosfomycin was tested using the agar dilution method in agar media supplemented with 25 mg/L glucose-6-phosphate. The checkerboard technique was employed to determine the Fractional Inhibitory Concentration Index (FICI) of nitrofurantoin/amikacin combinations as previously described . Briefly4 cfu/larva logarithmic-phase cells were incubated with amikacin in the presence and absence of nitrofurantoin and time–kill curves were compared to assess efficacy. Serial samples were obtained at 0, 3, 6, 9, and 24 h after incubation at 37°C. Bacterial counts were determined based on the quantitative cultures on MHA plates. Synergy was defined as achieving a ≥ 2 log10 cfu/mL reduction in bacterial growth at 24 h with the combination compared with the most active individual drug concentration used on its own . The optimal infection doses of the study test strains were determined using G. mellonella larvae that were randomly distributed into six experimental groups (n=10/group or ~250 mg). These were then infected by injection of 10 μL of logarithmic phase E. coli cells (~104 cfu/larva) into the last left proleg. After injection, the larvae were incubated in plastic Petri dishes at 37°C for 72 h and scored for survival daily. In all experiments, PBS injections were used as negative controls.A well-characterized lication . The G. in vivo efficacy of nitrofurantoin and amikacin alone and in combination were assessed in the same G. mellonella model caused by our study E. coli strains using the optimal infection doses as determined above (~104 cfu/larva). At 2 h post-infection, animals were randomized to receive no therapy or nitrofurantoin and amikacin alone, and in combination (n = 10/group) (The 0/group) . The ant0/group) . Larvae 10 values and the data were analyzed using Graphpad Prism 7.0 . P values were determined using a two-sided, Mann–Whitney U-test. A P-value of ≤ 0.05 was considered significant. All data were presented as means ± SD.Bacterial counts were transformed to logE. coli  in the presence of increasing amikacin concentrations (1/4−1×MIC). The addition of nitrofurantoin to amikacin increased in vitro bactericidal activity compared with nitrofurantoin alone. Similarly, the addition of amikacin to nitrofurantoin also significantly increased in vitro bactericidal activity  but the combination therapy resulted in 80–90% survival after 72 h. The combination therapy also significantly increased survival from infections with the E4396 and E3759 strains . Similarly, nitrofurantoin monotherapy significantly increased G. mellonella survival from infections caused by two strains; E4181 and E68071. Therefore overall, amikacin or nitrofurantoin given at subinhibitory concentrations was not effective in the treatment of UPEC infections in the G. mellonella model. In contrast, the amikacin/nitrofurantoin combination significantly increased survival from infections caused by all 12 study UPEC strains. More importantly, the combination therapy significantly increased survival compared with amikacin or nitrofurantoin monotherapies with 11/12 of the test strains (p < 0.05). Only one UPEC strain E68071 generated a non-significant P value (0.0957). Overall, we found increases in survival with the combination therapies that increased survival against challenge by our UPEC test strains from 40 to 70%  previously been reported can improve the sensitivity of UPEC to Nitrofurantoin after treatment  can be found below: NCBI BioProject [accession: PRJNA678682].Clinical strains isolated from humans in this study were provided by the Third Affiliated Hospital of Sun Yat-sen University. This study was carried out in accordance with the recommendations of ethical guidelines of South China Agricultural University. SCAU Institutional Ethics Committee did not require the study to be reviewed or approved by an ethics committee because we are not involved in the isolation of bacteria.Z-XZ and Z-HC contributed equally in this study. JS, Y-HL, and X-PL designed the study. Z-HC, Z-XZ, TT, X-JL, Z-JZ, and W-NN carried out the experiments. JS, Z-HC, YY, and Y-FZ analyzed the data. JS, Z-HC, L-XF, and Z-XZ wrote the draft of the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by National Natural Science Foundation of China (31972735), the National Key Research and Development Program of China (2016YFD0501300), the Program for Innovative Research Team in the University of Ministry of Education of China (IRT_17R39), and the 111 Project (D20008).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.