Chemoprophylaxis (antibiotic prophylaxis) is a long relied-upon means of opportunistic infection management among HIV/AIDS patients, but its use represents an evolutionary tradeoff: Despite the benefits of chemoprophylaxis, widespread use of antibiotics creates a selective advantage for drug-resistant bacterial strains. Especially in the developing world, with combined resource limitations, antibiotic misuse, and often-poor infection control, the emergence of antibiotic resistance may pose a critical health risk. Extending previous work that demonstrated that this risk is heightened when a significant proportion of the population is HIV/AIDS-immunocompromised, we work to address the relationship between HIV/AIDS patients’ use of antibiotic chemoprophylaxis and the emergence of resistance. We apply an SEIR compartmental model, parameterized to reflect varying percentages of chemoprophylaxis use among HIV/AIDS+ patients in a resource-limited setting, to investigate the magnitude of the risk of prophylaxis-associated emergence versus the individual-level benefits it is presumed to provide. The results from this model suggest that, while still providing tangible benefits to the individual, chemoprophylaxis is associated with negligible decreases in population-wide morbidity and mortality from bacterial infection, and may also fail to provide assumed efficacy in reduction of TB prevalence. The use of antibiotic prophylaxis has long been relied upon to reduce morbidity and mortality due to opportunistic infection among the HIV/AIDS-immunosuppressed–especially when access to antiretrovirals is limited –6. HowevThe rapidity with which antibiotic resistance can develop represents a worldwide threat to infection prevention and treatment, manifesting on the scale of months or even weeks –10. The Mycobacterium tuberculosis and Staphylococcus aureus, the incidence of bacterial infections, despite the use of broad-spectrum chemoprophylaxis to combat them, is indicative of the emergence of resistance [Our previous study relied on the simplifying assumption that antibiotic use referred specifically to targeted antimicrobials, since the high prevalence of bacterial infections that is characteristic of the developing world necessitates frequent use of the use of curative antibiotics –26. Howesistance , 27–30. sistance –33.) GivEven when antibiotics are used correctly, widespread antimicrobial use for the treatment of active infections selects for the emergence of resistance , 26. BasThere is ample evidence that misuse of curative antibiotics, which includes overuse, self-medication, and inconsistent dosing, is the greatest predictor of emergence , 40–49. Holding HIV/AIDS prevalence constant at 0.46% and 27.4% for Indonesia and Swaziland , 22, resGiven the time-scale of interest for bacterial infections, we do not focus on host HIV/AIDS status as an epidemiological process. We note that susceptibles are categorized based on immune status as follows: those who are fully immunocompetent ; those whose immune function is compromised by active AIDS; and those who are HIV or AIDS+, but whose consistent use of HAART enhances their immunocompetence such that their risk of succumbing to complications of AIDS-defining illness is low –55. The superscript to dually describe HIV and HAART status; and we use a subscript to describe both bacterial infection status and adherence to antibiotics. In addition to the previously defined notational designations, we also adopt the subscript combination “+-” to describe infection-negative, prophylaxis-positive, susceptibles, thereby distinguishing them from hosts using antibiotics to treat active infection . Values for ϕ  vary basWe make two conservative assumptions: First, we assume that those susceptibles prescribed chemoprophylaxis are completely adherent to their dosing instructions. Second, we assume that those who develop resistant infections while using chemoprophylaxis are then also completely adherent to the targeted antibiotics used to treat the active infection.   and SwazPneumocystis carinii. However, since this refers to a specific patient population (HIV+ susceptibles not yet considered AIDS-immunocompromised) from the developed world, we suspect that it is unlikely to be representative of treatment percentages within the developing world. We therefore investigated the impact on emergence of varying the percentage of HIV/AIDS+ susceptibles being treated prophylactically in 10% increments from 0–100%, with the trial in which chemoprophylaxis is not used acting as a negative control. In the absence of any data regarding the prevalence of chemoprophylaxis use in the developing world, we based this range on reported adherence to targeted antibiotics. Adherence varies based on factors such as age, socioeconomic status and the drug’s side-effect profile [In surveying a subset of HIV+ Italians, Napoli, et al.  found th profile –63. VaryWhen infections occur in HIV/AIDS+ susceptibles despite the intended effects of chemoprophylaxis, they likely arise out of drug-resistant mutations within the host. Within this initial exploration, we make the simplifying assumption that resistant strains do not circulate within the population, though follow-up efforts will explore competition between sensitive and resistant strains.To quantify the relative contributions of both broad-spectrum chemoprophylaxis and targeted antibiotics to the emergence of resistance, we established a composite probability of the emergence of resistance for each possible combination of treatment and immune status. The values for this parameter are informed by the TB literature, and are designated as When we compared the expected emergence of antibiotic-resistant TB in Swaziland to that in Indonesia, we observed a drastic difference in the impact of chemoprophylaxis. In Swaziland, irrespective of initial TB prevalence, there was a negligible difference in expected emergence among actively immunocompromised  HAART-treated patients . Given tContrary to the results from Swaziland, we note a sharp decline in risk of prophylaxis-associated emergence in Indonesia, where, among the actively AIDS-immunocompromised, we observed a nearly 60% reduction in risk when 100% of HIV/AIDS+ susceptibles are prophylactically treated. Among those who are HIV/AIDS+ and HAART-adherent, the impact was even greater; risk of emergence was reduced by approximately 80%. These results occurred irrespective of initial TB prevalence . DespiteRecall that in both Indonesia and Swaziland we have made the conservative assumptions that prophylactically-treated susceptibles adhere completely to dosing instructions, and that they continue to do so once they become infected with a bacterial pathogen resistant to broad-spectrum chemoprophylaxis and must change antibiotics to treat the infection. We may therefore be conservatively underestimating total emergence, but we do not expect that this will qualitatively impact the results of our model.Using expected TB incidence under conditions of 0% chemoprophylaxis use as a baseline, we analyzed the factor change in population-wide infectivity that results from varying the percentage of HIV/AIDS+ susceptibles using chemoprophylaxis. While we did observe a decline in population-wide TB incidence Swaziland, as chemoprophylaxis use was increase from 0–100%, it was not as pronounced as we might have expected, given the reliance upon chemoprophylaxis as a means of minimizing opportunistic infection risk among HIV/AIDS patients . Under cWe note that, when 100% of HIV/AIDS+ susceptibles are treated prophylactically, 27.4% of the population should be protected . We woulOur mortality results mirrored those from the analysis of TB incidence in Swaziland. Again, despite a goal of chemoprophylaxis being to reduce bacterial infection-related mortality among the HIV/AIDS-immunocompromised, the decline in mortality as percent chemoprophylaxis treatment increased was nearly undetectable (<1%), irrespective of immune status or initial TB prevalence.Consistent with our findings regarding emergence in Indonesia, we also observed a more noticeable effect of chemoprophylaxis when we examined TB-incidence and TB-associated mortality among HIV/AIDS-affected individuals. As chemoprophylaxis use among HIV/AIDS+ susceptibles increased from 0–100%, we observed a corresponding decline in TB incidence. Relative to the baseline, TB incidence among HIV/AIDS+, HAART- hosts is reduced by 60% when initial TB prevalence is low, and by 58%, when initial prevalence is high. TB-attributable mortality among HIV/AIDS+, HAART+ hosts is reduced by 81% in the low TB condition, and by 78% in the high TB condition.As would be expected given the decline in TB incidence, TB-associated mortality also decreased with increased chemoprophylaxis treatment. When initial TB prevalence was low, and 100% of HIV/AIDS+ susceptibles were prophylactically treated, HIV/AIDS+, HAART- hosts benefitted from a 60% reduction in mortality; and mortality in HIV/HAART+ hosts declined by 80%. Under the high TB condition, mortality was reduced by 55% among the actively AIDS-immunocompromised, and by 74% among those receiving HAART. We note, however, that our analysis of per capita mortality among HIV/AIDS patients demonstrated that those with active AIDS experience twice the risk of TB-associated mortality as those who are HAART-treated .––, I+–, and I+ +. In each of the eight possible combinations of Swaziland vs Indonesia, high TB prevalence vs low, and with or without AIDS, we compiled 100 000 samples using Latin hypercube sampling. From these samples, we tested most parameters of the system against the disease burden outcomes to determine which of those parameters were most influential. Note that some of these parameters are basic parameters, from which other parameters are derived.  indicates that intervention strategies with partially-adherent individuals may not be effective , but that strategies targeting untreated individuals may be. The particular impact of The results of this analysis can be compared to the analogous analysis from existing work focusing on a simpler model : “Most odtb, itb, hh, and θ– / in the high TB scenario (with or without AIDS) in Indonesia (a significant change).The new sensitivity analysis reflects a greater accounting for longer-term behavior and the differentiation of bacteria types when compared with , with inSee Chemoprophylaxis has long been considered to be a valuable infection management strategy among the HIV/AIDS-immunocompromised . DespiteGiven that 27.4% of Swaziland’s adult population is HIV/AIDS+,  , we wereThe results of our initial work on the relationship between HIV/AIDS-prevalent host populations and antibiotic resistance demonstrated the potential for heightened emergence . Due to Among HIV/AIDS+ patients in Indonesia, the benefits of chemoprophylaxis were much more noticeable, with category-specific TB incidence declining by as much as 80% when 100% of HIV/AIDS+ susceptibles are treated. Given this decrease in observed incidence, we also noted a corresponding decrease in emergence of resistance and TB-associated mortality. These findings reflect the characteristics of the population: While pathogen persistence is typically constrained by the availability of susceptibles (as seen in Swaziland) , 70, IndDespite these positive findings for HIV/AIDS patients, we must acknowledge that, contrary to Swaziland, the majority of TB cases in Indonesia occur among otherwise immunocompetent hosts. This isHaving examined the risk of prophylaxis-associated emergence, versus the protective benefits it provides, we determined that the magnitude of its impact as an infection control measure varies depending on the prevalence of HIV/AIDS+ susceptibles within the population. In Swaziland, where more than a quarter of the population is HIV/AIDS+, and where 77% of TB cases occur in HIV/AIDS+ hosts , 23, theThese findings suggest that policy decisions regarding TB infection management should take into account the prevalence of both HIV/AIDS and HIV-incident TB in the target population, since the effectiveness of chemoprophylaxis is affected by both of these conditions. We also emphasize that, while chemoprophylaxis initially appears not to be contributing significantly to the rate of emergence of novel resistance, our follow up work will evaluate the impact of strain competition using a longer-term model.S1 AppendixDetails of the model, including the abstract construction of the model, the equations derived from the abstraction, and the details  used) of each parameter.(DOCX)Click here for additional data file.S2 AppendixComplete details of the analysis of the disease burden (infective counts of each type) and its sensitivity to each parameter.(DOCX)Click here for additional data file.


Procalcitonin is a biomarker that supports clinical decision-making on when to initiate and discontinue antibiotic therapy. Several cost (-effectiveness) analyses have been conducted on Procalcitonin-guided antibiotic stewardship, but none mainly based on US originated data.To compare effectiveness and costs of a Procalcitonin-algorithm versus standard care to guide antibiotic prescription for patients hospitalized with a diagnosis of suspected sepsis or lower respiratory tract infection in the US.C.difficile infections, and costs per antibiotic day avoided.A previously published health economic decision model was used to compare the costs and effects of Procalcitonin-guided care. The analysis considered the societal and hospital perspective with a time horizon covering the length of hospital stay. The main outcomes were total costs per patient, including treatment costs and productivity losses, the number of patients with antibiotic resistance or C.difficile infection. Total costs in the Procalcitonin-group compared to standard care were reduced by 26.0% in sepsis and 17.7% in lower respiratory tract infection .Procalcitonin -guided care for hospitalized patients with suspected sepsis and lower respiratory tract infection is associated with a reduction in antibiotic days, a shorter length of stay on the regular ward and the intensive care unit, shorter duration of mechanical ventilation, and fewer patients at risk for antibiotic resistant or C.difficile infections.Using a Procalcitonin-algorithm to guide antibiotic use in sepsis and hospitalised lower respiratory tract infection patients is expected to generate cost-savings to the hospital and lower rates of antibiotic resistance and  C.difficile infections, and poses an increasing burden on healthcare resources  aFor the US, a limited amount of research on the effectiveness of PCT-guided ABS was available. The FDA, for example, cleared high-sensitive PCT for the management of antibiotics in LRTI and sepsis based on a meta-analysis of several European trials, which showed a safe reduction in antibiotic days of -3.2 and a change in length of stay of 1.1 days on the ICU (an increase in the PCT-group) and -1.4 days on the general ward. Still, in our analysis, all but one of the most influential input parameters  were based on US data.Huang et al. recently published the ProACT study and found no difference for the number of antibiotic days and the number of adverse events . It shouOur paper has limitations regarding the data that was used in the model. The data underlying the main parameters in our model were based on either one or a few studies. As a systematic literature review was conducted to identify all data available and suitable for the model, the results show the cost-savings that can be expected given the best evidence available at that time. The study by Bishop et al. 2014) [ [14], e.For some parameters, data was not available specifically for the US and therefor based on European data. All non-US data used in the model were validated for their applicability to the US healthcare setting by the four clinical authors of this study. From a multi-country study, the US-specific data was requested but not received. The change in antibiotic resistance infections, depending on the change in antibiotic days, was based on two studies. As long-term data are lacking, we conservatively projected the impact on ABR solely based on the reduction in days of AB exposure and LOS. Mortality was not included in our model; however, it should be noted that multiple RCTs established PCT being safe . In a reFurther, while the study by Bishop et al. 2014) [ [14] is C.difficile infections, and the impact on other outcomes such as bloodstream infections and health-related quality of life need to be studied.For analysing the cost impact of PCT using data that is completely based on patients with the specific disease, future research should present the results of patients with different diseases separately. Still, the model is based on the best evidence that is currently available. In addition, more US-based research on the effect of PCT-testing is needed to include the results of more studies in the model. Finally, the long term impact of PCT on ABR and C.difficile infections were reduced considerably, however, this was based on very few studies. Considering the growing public health concern related to antibiotic resistance infections and C.difficile infections, future investigations should focus on impact of PCT-guided ABS on the number of patients with antibiotic resistance infection and C.difficile infection.Our results showed that using a PCT-algorithm to guide antibiotic use in sepsis and hospitalised patients with lower respiratory tract infections reduced the total costs, including treatment costs and productivity losses, in the US by $11,311 and $2,867, respectively. The cost drivers were shown to be the patients´ length of stay, the costs of the hospital stay, and, for patients with LRTI, the percentage of patients receiving antibiotics. The number of patients with antibiotic resistance infections and S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


The X-ray structure revealed that two cycloalkane moieties can be simultaneously encapsulated in the hydrophobic cavity of the Q[8] host to form a ternary complex for the first time.The host-guest interaction of a series of cyclohexyl-appended guests with cucurbit[8]uril (Q[8]) was studied by  Later, N-ethylcyclohexylamine (NECyA), N-cyclohexylethanolamine (NCyEA), and N-(3-aminopropyl)cyclohexylamine (N3ACyA), were selected as the guests for binding to the Q[8] host. 1H NMR titration experiments clearly indicated that the cyclohexyl moieties on these guests can be included into the cavity of the Q[8] to form host-guest interactions (1H NMR spectra of the N3ACyA guest in D2O (pD = 2.45), which was recorded in the absence and presence of different concentrations of Q[8]. The free N3ACyA guest peaks were well-resolved when no Q[8] was added. After the addition of the Q[8] host to the guest solution, new peaks appeared at 4.10 ppm, 5.43 ppm and 5.67 ppm, which are ascribed to Q[8] . The binding constant (Ka) for the complexation was determined to be 1.55 × 107 M−1 at 298.15 K, which is much larger than that of previously reported ternary complexes involving alkyl groups inside the Q[8] cavity (Ka on the order of 105 M−1) [18]. In such cases, alkyl groups such as a butyl were appended to a 4,4′-bipyridinium core, and the resulting ternary complex most probably stemmed from the contribution of the ion–dipole interactions between the positively charged nitrogen atoms of the 4,4′-bipyridinium and the Q[8] portal carbonyl oxygen atoms. The ITC data indicated that the Q[8] cavity-based ternary complex involving an alkyl group is mostly enthalpy driven. In the present study, as mentioned above, the host-guest interactions are driven by both enthalpy and entropy factors. Negative enthalpy changes may result from the ion–dipole interactions between the protonated nitrogen atoms on the guest, the carbonyl oxygen atoms at the portals of the Q[8] cavity, and the non-classical hydrophobic effect from the desolvation of the Q[8] host cavity releasing ‘high-energy’ water trapped in the cavity. The positive entropy is mainly derived from the classical hydrophobic effect of the guest, such as the cyclohexyl moiety in aqueous solution. Notably, the binding constants for these four inclusion complexes are in the range of 106~107 M−1, indicating that the cyclohexyl-based ternary complex inside the Q[8] cavity is more stable compared with an alkyl moiety, and even with aromatic groups ·N3ACyA at room temperature. As shown in 1H NMR spectroscopy. The shortest distance between the two encapsulated cyclohexylamine moieties in the Q[8] cavity is around 2.28 Å. Notably, apart from the ion-dipole interactions between the ammonium guest and the carbonyl groups of the host portal, it is evident that the presence of each guest is further stabilized by the C−H···π interactions (bond distances in the range 3.131 Å–3.368 Å) between the included cycloalkane and C=O group of the Q[8] host. Hydrogen bonding between the outside terminal ammonium group of the guest and the carbonyl-laced portal of the Q[8] host will also contribute to the formation of the ternary inclusion complex of Q[8]·N3ACyA.In an effort to gain more detailed binding information on the host-guest interactions between Q[8] and the cyclohexyl-appended guests, we successfully obtained the X-ray crystal structure of Q[8]·N3ACyA. The slow evaporation of a hydrochloric acid aqueous solution containing a 1:2 mixture of the Q[8] host and N3ACyA in the presence of CdClN-Ethylcyclohexylamine, N-Cyclohexylethanolamine, and N-(3-Aminopropyl)-cyclohexylamine were purchased from TCI  Development Co., Ltd. Other chemicals were commercially available and used as received without further purification.Cyclohexylamine, ITC measurements were carried out using a Nano ITC  isothermal titration calorimeter at 298.15 K. The heats of reaction were corrected for the heat of dilution of the guest solution determined in separate experiments. All of the solutions were degassed prior to titration by sonication. Computer simulations were performed using the Nano ITC analyze software.3) was taken up in paraffin oil and mounted on a Bruker SMART Apex II CCD diffractometer  equipped with a graphite monochromated Mo-Kα radiation source  operating in the ω-scan mode. Data were corrected for Lorentz and polarization effects using the program SAINT . The structure was solved by direct methods, and was refined against F2 using the full-matrix least-squares method using SHELXL-2016 , Mr = 3321.02, triclinic, space group P-1, a = 17.499(12) Å, b = 17.654(12) Å, c = 18.005(13) Å, α = 70.891(9)o, β = 81.545(10)o, γ = 65.968(9)o, V = 4799(6) Å3, Z = 1, Dc = 1.149 g cm−3, F(000) = 1694, R1 = 0.0944 (I > 2σ(I)), wR2 = 0.2930 , GoF = 0.985.Crystal data for the host-guest complex: 2(C105H114N66O32 Cd2Cl8 (%): C 37.98, H 3.46, N 27.84; found: C 36.91, H 3.85, N 26.96.Anal. Calcd. for C1H NMR spectroscopy, ITC, and X-ray crystallography. All of the results suggested that the Q[8] host can simultaneously hold two cyclohexyl in the hydrophobic cavity. In particular, the solid state structure of the ternary complex suggests that the high binding constant of Q[8]·N3ACyA likely results from the multiple cooperation of the ion-dipole interactions, hydrophilic effects, and C–H···π interactions between the guest and the host.In summary, the selective host-guest binding behavior of Q[8] with a series of cyclohexyl group-appended guests has been evaluated by


In this study, environmentally friendly ground granulated blast furnace slag (GGBFS) based alkali activated materials and basic oxygen furnace slags (BOFs) were used as bonding materials and aggregates, respectively, to produce novel, environmentally friendly GGBFS based porous concrete. Porous concrete with a particle size of 4.75–9.5 mm and 9.5–19.00 mm was used as an aggregate. The “liquid-to-solid ratios” (L/S) variable was set at set at 0.5 and 0.6, and the “percentage of pore filling paste ratio” variable was controlled at 40%, 50%, and 60%. The curing period was set at 28 d, and the relationship between connected porosity and permeability, as well as that between unit weight and the pore filling paste ratio percentage were explored using analysis of variance. The results showed that the porous concrete had a maximum compressive strength of 8.31 MPa. The following results were obtained. An increase in percentage of pore filling paste ratio increased compressive strength. Permeability was measured at 4.67 cm/s and was positively correlated with porosity. An increase in porosity increased permeability, in which porosity was positively correlated with the percentage of pore filling paste ratio. The maximum splitting strength achieved during the 28 d was 1.46 MPa, showing a trend similar to that of compressive strength. Porous concrete—made from zero or traces of fine aggregates, as well as a mixture of coarse aggregates, water, and insufficient cement—is an environmentally friendly paving material  that feaBasic oxygen furnace slag (BOF) is a byproduct created during the steelmaking process and is the solid waste created when iron ore are converted in a basic oxygen furnace . BOF fea4]4− and [AlO4]5− tetrahedrons. Alkali activated materials display excellent fire-resistance, heat-insulation, and acid and base-resistance abilities, as well as mechanical properties [Alkali activated materials, introduced by French scientist Joseph Davidovits in 1978, are a new, green, and environmentally friendly material that has emerged in recent years. These materials are primarily made by placing aluminum silicate materials in an overbased alkaline solution to produce silicon and aluminum colloids, which are then dehydrated and hardened to form interconnected [SiOoperties ,24,25,26Yeih et al.  manufactThis study used BOF as aggregates for making environmentally friendly porous concrete. The particle sizes used were 4.75–9.5 mm and 9.5–19.0 mm, and the physical and chemical properties of the BOF are shown in Because no standardized ratio and design method are currently available for making porous concrete, the volumetric method was adopted. This method involves first finding the porosity, relative density, and unit weight of BOF with particle sizes of 4.75–9.5 mm and 9.5–19.0 mm. The porosities of the two different aggregates are shown in In this study, a cylindrical specimen that measured 10 cm and 20 cm in diameter and height, respectively, was used. Subsequently, a bonding material  and the BOF were placed inside a mixer and mixed for 1 min. Next, an alkali solution was slowly added, and the mixture was mixed for 2 min. Then, porous concrete was introduced and rammed. After the porous concrete was thoroughly mixed, a unit weight experiment was performed using the American Society for Testing and Materials (ASTM) C138 , and a hThe connected porosity and permeability of porous concrete are correlated. 3 (3–1900 kg/m3).The novel environmentally friendly GGBFS-based porous concrete had a unit weight of approximately 2011–2260 kg/m3 , which sThe permeability coefficient is a crucial indicator of the permeability of concrete. According to the Japan Concrete Road Association, Tokyo, Japan (1996), porous concrete must feature a permeability greater than 0.01 cm/s. The compressive strength of the porous concrete measured in the 28 d was the most critical indicator of its mechanical properties. In general, typical porous concrete has a compressive strength of 2.8–28 MPa. Because porous concrete has many internal pores, its compressive strength is lower than that of general concrete. In this study, the compressive strength of the porous concrete in the 28 d was 5.38–8.31 MPa, which satisfied general porous concrete intensity requirements. The linear regression of the compressive strength at the flexural strength and the radish ratio of 0.5 and 0.6 is shown at 7 days, 28 days, and 56 days of age in The British pendulum tester can be used as an indicator of the slip resistance of porous concrete. A low BPN indicates poor slip resistance. 1,1,0.05 = 18.51 and F = 173.86 > F1,2,0.05 = 19. Conversely, when the BOF particle size was 9.5–19.0 mm, F=16.47 < F1,1,0.05 = 18.51 and F = 264.51 > F1,2,0.05 = 19. This result indicates that the pore filling paste ratio had a stronger effect on GGBFS-based porous concrete.The correlations between pore filling paste ratio, liquid-to-solid ratio, and compressive strength were estimated using an analysis of variance. A table of the mathematical models used in the regression analysis is shown in The novel environmentally friendly GGBFS-based porous concrete had a connected porosity of 28.7%–34.3%, in which the connected porosity of GGBFS-based porous concrete with a particle size of 9.5–19.0 mm exceeded that of GGBFS-based porous concrete with a particle size of 4.75–9.5 mm. Compressive strength decreased and increased as the particle size and percentage of pore filling paste ratio increased and increased, respectively.The optimal component ratio was achieved when the pore filling paste ratio and aggregate particle size were 60% and 4.75–9.5 mm, respectively. It yielded a compressive strength and permeability of 8.31 MPa and 4.67 cm/s, respectively, in 28 days.The permeability coefficient and connected porosity of the novel, environmentally friendly GGBFS-based porous concrete decreased as the pore filling paste ratio increased. The permeability coefficient and connected porosity can be represented by the equation Y = 0.46534X – 8.09947.The compressive and splitting strengths of the novel environmentally friendly GGBFS-based porous concrete decreased as permeability increased. The use of porous concrete with a particle size of 4.75–9.5 mm increased mechanical strength but decreased permeability because the percentage of filling increased.


In order to study the fractal characteristics and energy dissipation of concrete suffered freeze-thaw cycle actions and impact loading, C35 concrete was taken as the research object in this paper, and freeze-thaw cycle tests were carried out with a freeze-thaw range of −20 °C~20 °C and a freeze-thaw frequency of 0~50 times. The degradation characteristics of concrete material and the variation rules of basic physical parameters under various freeze-thaw cycle conditions were obtained consequently. By using the SHPB (separated Hopkinson pressure bar) test device, impact compression tests of concrete specimens under different freeze-thaw cycle actions were developed, then the process of impact crushing and the mechanism of damage evolution were analyzed. Based on the screening statistical method and the fractal theory, the scale-mass distribution rules and fractal dimension characteristics of crushing blocks are investigated. Furthermore, the absorption energy, fracture energy and block kinetic energy of concrete under different conditions were calculated according to the energy dissipation principle of SHPB test. The relationship between the energy consumption density and the fractal dimension of fragments was established, and the coupling effect mechanism of freeze-thaw cycle action and strain rate effect on the fractal characteristics and energy consumption was revealed additionally. The research results show that the concrete under different freeze-thaw cycle conditions and impact loading speeds has fractal properties from the microscopic damage to the macroscopic fracture. The energy dissipation is intrinsically related to the fractal characteristics, and the energy consumption density increases with the increase of the fractal dimension under a certain freeze-thaw cycle condition. When at a certain loading speed, with the growth of freeze-thaw cycles, the energy consumption density reduces under the same fractal dimension, while the fractal dimension improves under the same energy consumption density. Concrete is the most widely used building material in the fields of national defense, civil defense and civil construction engineering . In receThe essence of the impact failure of materials is the energy consumption process, in which the internal damage cracks continue to expand and extend under the drive of external energy, eventually leading to material instability and failure ,3. The nSince C35 concrete is commonly used in the concrete engineering in China, the impact compression test of C35 concrete suffered from different freeze-thaw cycles , was conducted on the Φ 50 mm SHPB system in this paper. Through screening statistics of broken blocks under different conditions, the scale-mass distribution rules were gained. On the basis of the fractal theory and the energy dissipation principle of SHPB test, the fractal dimension and energy consumption characteristics of concrete fragments were analyzed, the relationship of energy consumption density and fractal dimension was established, and the influence mechanism of freeze-thaw cycle action and load speed was revealed.C35 concrete was used in this paper, and its specific mixing ratios was calculated according to “the design rules of mixing ratio of ordinary concrete” (JGJ55-2011), as shown in 3 and moisture content of about 5%. (5) Water reducing agent. The PH value of the water reducing agent was 7–9 and the water reduction rate was about 20–35%. Prepared solutions with a concentration of 26–28% were used. (6) Water. Laboratory tap water, in compliance with standard requirements.The specific parameters and performance of the ingredients used to produce the mixture were shown as follows: (1) Cement. The cement was ordinary Portland cement with the strength grade of P.0.42.5 produced by Shaanxi Qinling Cement Building Materials Co., Ltd., Xi’an, China, and the physical and chemical properties were just as shown in The well-mixed concrete materials were poured into the molds and maintained for 28 days in the standard curing room with a temperature of 20 °C and humidity of 95%. Through coring and cutting, the concrete was made into cylinders of Φ 48 mm × 25 mm. The upper and lower surfaces of the specimens were polished using a grinder during the specimen processing. The processing accuracy was strictly controlled to ensure the errors of both the surface planeness and the vertical deviation of upper and lower surfaces were within ±0.02 mm . After sWhen developing the freeze-thaw cycle test, the saturated concrete specimens were firstly put into the automatic low-temperature freeze-thaw test box (Model: CLD-1. Temperature measurement accuracy: ±0.5 °C. Temperature range: −40~+50 °C), and then the freeze-thaw cycle tests were conducted with freeze-thaw temperature varying from −20 °C to +20 °C and freeze-thaw cycle numbers changing from 0 to 50 times. The process of per freeze-thaw cycle was as follows: at first, the temperature was slowly reduced from 20 °C to −20 °C (this process took 120 min), keeping a constant temperature for 240 min, then rapidly rising to room temperature of 20 °C (this process took 30 min), keeping constant temperature for 240 min. The total time of one freeze-thaw cycle is 630 min, and 10 freeze-thaw cycles are defined as a phase.After different freeze-thaw cycles, the internal defects of concrete specimens propagated, expanded, gathered and penetrated continuously, and eventually developed from microscopic damage to macroscopic fracture. The apparent crack propagation and development of concrete specimens under different freeze-thaw conditions were shown in According to the above analysis of the apparent deterioration characteristics and damage evolution processes of concrete under the freeze-thaw cycle actions, the mechanism of freeze-thaw cycle deterioration of concrete is as follows: the concrete is a kind of non-homogeneous material and there exists internal microcracks and micro pores. The internal freeze-thaw damage of concrete specimens starts from the freezing and thawing of the water in internal initial pores of materials, and the external apparent degradation begins at the aggregate-colloid interface. As the cracks grow and extend continuously, the damage develops further to the spalling of aggregates, colloids, and even concrete blocks. This is because after the water inside the concrete freezes, the specimen volume expands and the frost heaving force causes continuous development of internal pores; the water in the pores further increases, then the specimen volume continues to expand, resulting in the more severe deterioration and the loss of integrity.In the freeze-thaw test, the mass and the volume of specimens were measured, and the porosity was calculated per 10 freeze-thaw cycles. Finally, the variation rules of the mass, volume and porosity of concrete under different freeze-thaw cycle actions were gained as shown in As found in As indicated in In this paper, directed to the concrete specimens suffered from different freeze-thaw cycles , the dynamic uniaxial compression tests were carried out on the Φ 50 mm separated Hopkinson pressure bar (SHPB) device In order to reduce the dispersion effect caused by the transverse inertial movement of bar particles and extend the time before incident pulse reaches the peak value, the waveform shaping should be considered to ensure there is sufficient time for specimens to achieve the stress uniformity before failure . In thisDynamic failure modes and stress-strain curves of concrete under different conditions were shown in The results of freeze-thaw cycle test and impact compression test indicated that, after experiencing the freeze-thaw cycle action, the internal damage defects of concrete deviated from the equilibrium state under the external impact loading. In order to dissipate the energy transferred from the outside world and reach a new balance state, cracks inside the specimen were forced to change their own structure state, continuously multiplied and gathered, and gradually developed from the disordered distribution to the orderly development, finally leading to a macroscopic catastrophic fracture. This was the impact crushing process and mechanism of concrete under freeze-thaw conditions.As can be seen from In addition, it was also shown in The variation rules of dynamic peak strain with freeze-thaw cycles and impact loading speed were shown in the As can be seen from The concrete crushing blocks were collected after the impact test and the screening statistical test was conducted on the ZBSX-92a standard vibrator . The diameter of the sieve holes are 0.5 mm, 1 mm, 2.36 mm, 4.75 mm, 9.6 mm, 16 mm and 19 mm respectively. The pendulum instrument shakes 221 times and vibrates 147 times per minute, with the swing of 25 mm. The motor is 1400 revolutions per minute. Fragments of all particle sizes can be effectively separated through the sieve. Taking the condition of 0 freeze-thaw cycle with loading speed of 5.4 m/s as an example, the crushing blocks of different particle sizes were shown in The screening test results of concrete crushing blocks under different freeze-thaw cycle conditions and loading speeds were shown in It can be seen from It also can be found from In conclusion, due to the effect of the freeze-thaw degradation and the impact energy, the freeze-thaw action and loading speed had a significant correlation with the scale-mass distribution rules of crushing blocks. Moreover, the more freeze-thaw cycles the concrete suffered, or the higher the loading speed was, the more serious the crushing degree of specimens would be, and the larger the mass proportion of the small and medium size fragments would be. The mechanism of this phenomenon was as follows: when freeze-thaw cycles are less or the loading speed is lower, only those microscopic cracks that consume less energy during the expansion have practical effects on the impact crushing of concrete. The propagation and penetration of these microscopic cracks will lead to concrete fracture failure before the absorption energy increases enough to cause other microscopic cracks to crack and form the main crack. When more freeze-thaw cycles or a higher loading speed is experienced, the energy absorbed by the concrete reaches a higher level before the mesoscopic crack is penetrated, so that more mesoscopic cracks can expand and participate in the crushing process, leading to a smaller size of specimen broken blocks.According to the mass-frequency relationship , the disTake the natural logarithm on the both sides of Equation (2) to getr–ln r/MT){WI=AIgnoring the energy loss caused by the friction between the specimen and section of incident/transmitted bar, then the total energy absorbed by the concrete specimen during the impact crushing process isur parts : fracturAccording to the research result of literature , the relIn order to eliminate the influence of the specimen size, the energy consumption density, namely the absorbed energy per unit volume of the specimen, was introduced to reflect the energy consumption characteristics of concrete materialsThe results calculated by Equations (6)–(9), including the incident energy As shown in Both The difference in the dissipation of the external impact energy and that in the failure patterns of crushing blocks, are the essential internal cause and the macroscopic representation respectively of the concrete crushing characteristics under different freeze-thaw cycle conditions and impact loading speeds ,12. TherThe relation fitting curves of the energy consumption density and the fractal dimension of concrete specimens under different conditions were shown in As can be found in (1) The impact crushing mechanism and process of concrete under freeze-thaw conditions are as follows: after experiencing the freeze-thaw cycle action, the internal damage defects of concrete deviate from the equilibrium state under the external impact loading. In order to dissipate the energy transferred from the outside world and reach a new balance state, cracks inside the specimen are forced to change their own structure state, continuously multiply and gather, and gradually develop from the disordered distribution to the orderly development, finally leading to a macroscopic catastrophic fracture.(2) The freeze-thaw cycle action and the impact loading speed have a significant effect on the scale-mass distribution rules of crushing blocks, and the more freeze-thaw cycles the concrete suffered, or the higher the loading speed is, the more serious the crushing degree of specimens will be, and the larger the mass proportion of the small and medium size fragments will be.(3) The concrete material has fractal properties from the microscopic damage to the macroscopic fracture. The fractal dimension increases significantly with the increase of the impact loading speeds and improves generally with the growth of the number of freeze-thaw cycles. The increment of the fractal dimension reaches the maximum under the 0 freeze-thaw cycle condition. The distribution rules of concrete dynamic peak stress varying with fractal dimension is coupling affected by the freeze-thaw cycles and the loading speeds.(4) The impact fracture of concrete under different freeze-thaw cycle conditions and loading speeds is a fractal evolution process driven by the external impact energy. The energy dissipation is intrinsically related to the fractal characteristics, and the energy consumption density increases with the increase of the fractal dimension under a certain freeze-thaw cycle condition. When at a certain loading speed, with the growth of the freeze-thaw cycles, the energy consumption density reduces under the same fractal dimension, while the fractal dimension improves under the same energy consumption density.


EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have achieved remarkable outcomes in the treatment of patients with EGFR-mutant non-small-cell lung cancer, but acquired resistance is still the main factor restricting their long-term use. In addition to the T790 M mutation of EGFR, amplification of the MET (or c-MET) gene has long been recognized as an important resistance mechanism for first- or second-generation EGFR-TKIs. Recent studies suggest that a key mechanism of acquired resistance to third-generation EGFR-TKIs (such as osimertinib) may be MET amplification and/or protein overactivation, especially when they are used as a first-line treatment. Therefore, in patients resistant to first-generation EGFR-TKIs caused by MET amplification and/or protein overactivation, the combination of osimertinib with MET or MEK inhibitors may be considered. Lung cancer is the leading cause of cancer-related death in humans, accounting for approximately one-third of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) is the main type and accounts for more than 80% of lung cancer cases, with an overall 5-year survival rate of approximately 18% [The proportion of EGFR mutations varies from race to race and is not the same in Western and Asian NSCLC populations, in which it is approximately 15 and 40%, respectively . EGFR muApproximately 60% of acquired resistance to the first generation of EGFR-TKIs results from EGFR exon 20 T790 M mutations. In addition, several studies have found that amplification of the MET  gene is also an acquired resistance mechanism that leads to the failure of EGFR-TKI treatment , 5. TherOsimertinib (AZD9291 or TAGRISSO™) is representative of the third generation of EGFR-TKIs and has been approved by the FDA for patients with locally advanced NSCLC or NSCLC patients who are positive for the EGFR T790 M mutation. Currently, it is also approved as the first-line treatment for patients with NSCLC harboring EGFR mutations (exon 19 deletion or exon 21 L858R mutation). Although osimertinib has achieved great clinical success, it still cannot avoid acquired resistance. Apart from some of the mechanisms involved in C797S mutations and MET amplification, the mechanism of resistance is largely unknown . For theMET is a proto-oncogene located in the long arm of human chromosome 7 7q21–31); it is approximately 125 kb in length and contains 21 exons . Its pro1; it is The role of MET amplification and protein hyperactivation in conferring resistance to third-generation EGFR-TKIs was assessed. We found that the EGFR mutation NSCLC cell line (HCC827/ER) resistant to erlotinib had MET gene amplification and protein overactivation and was cross-resistant to osimertinib and rociletinib. In addition, HCC827 cells (HCC827/AR), which have acquired resistance to osimertinib, also show MET gene amplification and protein overactivation. Compared with the parental cell line, the p-MET level is increased, and these cells are not only resistant to rociletinib but also to erlotinib . With smRecent studies have reported similar results. Many laboratories constructed HCC827 cell lines resistant to erlotinib with MET amplification and protein overactivation, and the cells were resistant to osimertinib . H1975-PDysregulated MET expression and activity in human cancer tissues can be detected at the gene and protein levels. The following assays were performed to determine MET dysregulation. Fluorescence in situ hybridization (FISH): the MET gene copy numbers were obtained by detecting the site number of MET and CEP7 (as the control). Its advantage is high accuracy, good repeatability, good correlation with the curative effect, and use of fewer specimens; however, MET protein expression on the cell surface but not MET amplification could be detected . DropletP = 0.0002). The study included ctDNA sequencing results from 438 patients and analyzed the relationship between MET expression and clinicopathological parameters. The results showed that MET ctDNA alterations were associated with a poorer prognosis and higher numbers of genomic abnormalities and bone metastases [A recent study showed that liquid biopsy to detect MET is feasible. MET changes occurred in 7.1% of patients on liquid biopsy, which was higher than the frequency found in tissue , medium  or high (≥ 5), A MET/CEP7 FISH ratio of 5 or higher is defined a “MET-positive” group with no oncogenic overlap. As this method and criteria are also associated with the highest response rate to MET inhibition, they represents the clearest definition of a MET copy number gain-addicted state , 28.MET overexpression can be caused by gene amplification, gene mutation, transcriptional enhancement, or posttranscriptional mechanisms. Immunohistochemistry (IHC) can be used to detect the overexpression of MET in tissue specimens. In different studies, the proportion of MET overexpressed in NSCLC varies greatly from 15 to 70% due to differences in experimental reagents and threshold settings.MET amplification was detected in third-generation EGFR-TKI-resistant EGFR-mutant NSCLC, but the results from different studies were not identical. Le et al.  detectedCurrently, most studies have focused on the resistance mechanisms of osimertinib and other third-generation EGFR-TKI second-line treatments. There are few studies on the first-line treatment of EGFR mutation-positive advanced NSCLC with osimertinib, which may be related to its recent approval. A study presented at the 2018 European Society for Medical Oncology (ESMO) annual meeting used NGS technology to analyze 91 plasma samples from patients undergoing first-line treatment with osimertinib; MET amplification was detected in 15% of the samples and EGFR in 7% of the samples. The C797S mutation suggests that MET amplification is the most common acquired resistance mechanism .The underlying mechanism by which MET amplification leads to EGFR-TKI resistance is associated with the activation of the EGFR-independent phosphorylation of ErbB3 and the downstream activation of the PI3K/AKT pathway, providing a bypass signaling pathway even in the presence of EGFR-TKIs . TherefoIn addition, the inhibition of MEK by small molecule MEK inhibitors such as trametinib (GSK1120212) is also an effective and feasible solution to overcome MET-induced acquired resistance to osimertinib . StudiesCurrently, two small molecule c-MET inhibitors, cabozantinib and crizotinib, have been approved by regulatory authorities for the treatment of selected cancer types, but several novel c-MET inhibitors are currently in trials for different settings , 36–38. Immunotherapy has emerged as a new topic in advanced lung cancer research and has made breakthroughs in the first-line and second-line treatment of advanced NSCLC –49. HoweA significant correlation between MET receptor overexpression/hyperactivation and poor outcomes has been demonstrated in different solid tumors, including NSCLC. Many new molecules that either target MET or act as multitarget inhibitors are emerging and exhibit antitumor activity. MET inhibitors have shown promising antitumor activities in preclinical and early phase clinical trials of several tumor types, although the results of most phase III trials with these agents have been less encouraging. But with the efforts of translational and clinical research, an increasing number of MET-targeted therapies will surely have a positive impact on lung cancer outcomes, and these treatments should be included as one of the possible therapeutic options for patients with NSCLC.Osimertinib is currently approved by the FDA for the treatment of EGFR-mutant NSCLC with a T790 mutation after relapse following first- or second-generation EGFR-TKI therapy (second-line). However, approximately 20% of these patients are not sensitive to treatment with osimertinib. Based on our findings, we believe that it is necessary to detect the MET status prior to osimertinib treatment. Patients with EGFR-mutant NSCLC may be insensitive to osimertinib or other third-generation EGFR-TKIs. Combination therapy with a combination of MET or MEK inhibitors may be considered for these patients. In the last few years, anti-PD1/PD-L1 drugs have become a new paradigm in oncology, and based on current research, anti-PD1 and anti-PDL1 antibodies combined with a MET inhibitor may finally represent an effective treatment of EGFR-mutant NSCLC.MET amplification and MET protein expression are often detected in clinical practice, but there are few studies on p-MET. MET-amplified EGFR-mutant NSCLC cell lines not only have high levels of MET but also have high levels of p-MET . Therefo


Vibrio parahaemolyticus was isolated from a tropical estuary in Rio de Janeiro, Brazil. Genome sequencing was conducted to establish the molecular basis of antibiotic resistance in this organism. The genetic content of this strain revealed it to be a non-virulent lineage that nevertheless possesses several antibiotic resistance determinants.A multi-resistant strain of  Vibrio parahaemolyticus are responsible for several global outbreaks of gastroenteritis caused by the ingestion of contaminated seafood.,,,,V. parahaemolyticus have been reported,,,V. parahaemolyticus, hereby named strain JPA1, from the waters of the Jacarepaguá lagoon system situated in the city of Rio de Janeiro, Brazil. The local population often comes in contact with the waters at this site either directly for recreational purposes or indirectly through the consumption of seafood retrieved from the lagoon system. Despite this, the Jacarepaguá lagoons receive massive amounts of untreated sewage daily; a factor that contributes to the high abundance and diversity of antibiotic-resistant bacteria in this habitat.,Virulent strains of The antibiotic susceptibility profile of strain JPA1 was determined by measuring the minimum inhibitory concentration (MIC) of 16 drugs against JPA1. This organism was resistant to eight out of the 16 tested antibiotics . JPA1 shV. parahaemolyticus strain JPA1 was assembled into 793 scaffolds  and displayed a G+C content of 45.1%. Gene prediction was carried out using Prokka,DNA was prepared for sequencing using the Nextera XT DNA library prep kit following manufacturer’s recommendations. Genome sequencing was conducted using the Illumina MiSeq platform that yielded 1,461,209 reads (average length = 250 bp and average Phred score = 37). Reads were subjected to a hybrid assembly using A5V. parahaemolyticus often carry genes that encode a type three secretion system (T3SS) for a thermostable direct haemolysin (TDH) and/or TDH-related haemolysin.,V. parahaemolyticus JPA1, suggesting it to be non-virulent to humans. Yet the JPA1 genome encoded genes that were involved in resistance against several classes of antibiotics -Ib encodes an aminoglycoside-3’-phosphotransferase capable of inactivating aminoglycosides through phosphorylation, CARB-18 encodes a β-lactamase, and catB8 encodes a chloramphenicol acetyltransferase that inactivates amphenicols. Target protection proteins work by impairing the contact between antibiotics and their targets. Gene dfrA3 encodes an alternative dihydrofolate reductase that is less sensitive to the action of trimethoprim. Genes otrA, tetW, and tet32 encode peptides that perform non-covalent modifications to bacterial ribosomes, rendering them resistant to tetracyclines. Furthermore, qnrC and qnrVC5 also contribute to target protection mechanisms that confer resistance to quinolones.Three genes encoding proteins capable of antibiotic inactivation were also detected: ,Upon infection, human pathogens are often challenged by antibiotic therapy, which favours strains that possess antibiotic resistance determinants. Many potentially pathogenic bacteria possibly have a free-living lifestyle that includes surviving in soils, water bodies, and associated to non-human hosts. JPA1’s genetic content indicates that it is non-pathogenic to humans, despite possessing a broad array of antibiotic resistance genes. Antibiotic resistance genes precede the advent of antibiotic therapy,V. parahaemolyticus. In the environment, horizontal gene transfer is often mediated by plasmids and other mobile genetic elements. However, the resistance mechanisms identified in the JPA1 genome were not found to be associated with such elements. Nevertheless, horizontal gene transfer can also take place through the direct uptake of exogenous DNA or via phage-mediated transduction. In the advent that antibiotic resistance genes from JPA1 are mobilised to other bacteria through the aforementioned mechanisms, this strain could play a role in the spread of antibiotic resistance genes in aquatic ecosystems.Vibrio cholerae, Shigella spp., and Pseudomonas aeruginosa.Thus, we conclude that the JPA1 genome has a broad array of antibiotic resistance genes that confer upon it a multi-resistant phenotype. Horizontal gene transfer has been implicated as a mechanism for the acquisition of virulence


Rapid risk and outbreak assessments Rapid risk assessment: Monkeypox cases in the UK imported by travellers returning from Nigeria, 2018Date of publication: 21 September 2018https://ecdc.europa.eu/en/publications-data/rapid-risk-assessment-monkeypox-cases-uk-imported-travellers-returning-nigeria Rapid risk assessment: Cholera outbreak in Algeria, 2018Date of publication: 7 September 2018https://ecdc.europa.eu/en/publications-data/rapid-risk-assessment-cholera-outbreak-algeria-2018 Rapid risk assessment: Severe respiratory disease associated with Middle East respiratory syndrome coronavirus (MERS-CoV), 22nd updateDate of publication: 29 August 2018https://ecdc.europa.eu/en/publications-data/rapid-risk-assessment-severe-respiratory-disease-associated-middle-east-11 Rapid risk assessment: Early large increase in West Nile virus infections reported in the EU/EEA and EU neighbouring countriesDate of publication: 13 August 2018https://ecdc.europa.eu/en/publications-data/rapid-risk-assessment-early-large-increase-west-nile-virus-infections-reported Rapid risk assessment: Ebola virus disease outbreak in North Kivu and Ituri Provinces, Democratic Republic of the CongoDate of publication: 9 August 2018https://ecdc.europa.eu/en/publications-data/rapid-risk-assessment-ebola-virus-disease-outbreak-north-kivu-and-ituri-provinces Rapid risk assessment: Public health risks related to communicable diseases during the 2018 Hajj, Saudi Arabia, 19–24 August 2018Date of publication: 2 August 2018https://ecdc.europa.eu/en/publications-data/rapid-risk-assessment-public-health-risks-related-communicable-diseases-during-0 Rapid outbreak assessment: Multi-country outbreak of Salmonella Agona infections possibly linked to ready-to-eat foodDate of publication: 26 July 2018https://ecdc.europa.eu/en/publications-data/rapid-outbreak-assessment-multi-country-outbreak-salmonella-agona-infections Rapid risk assessment: Carbapenemase-producing (OXA-48) Klebsiella pneumoniae ST392 in travellers previously hospitalised in Gran Canaria, SpainDate of publication: 11 July 2018https://ecdc.europa.eu/en/publications-data/rapid-risk-assessment-carbapenemase-producing-oxa-48-klebsiella-pneumoniae-st392 Rapid risk assessment: Dengue outbreak in Réunion, FranceDate of publication: 6 July 2018https://ecdc.europa.eu/en/publications-data/rapid-risk-assessment-dengue-outbreak-reunion-france-0 Listeria monocytogenes serogroup IVb, multi-locus sequence type 6, infections linked to frozen corn and possibly to other frozen vegetables – first updateRapid risk assessment: Multi-country outbreak of Date of publication: 3 July 2018https://ecdc.europa.eu/en/publications-data/rapid-risk-assessment-multi-country-outbreak-listeria-monocytogenes-serogroup-ivb Scientific advice Public health guidance on prevention and control of blood-borne viruses in prison settingsDate of publication: 23 July 2018https://ecdc.europa.eu/en/publications-data/public-health-guidance-prevention-control-bloodborne-viruses-prison-settings Technical reports Monitoring the use of whole-genome sequencing in infectious disease surveillance in Europe 2015–2017Date of publication: 18 September 2018https://ecdc.europa.eu/en/publications-data/monitoring-use-whole-genome-sequencing-infectious-disease-surveillance-europe Generic protocol on enhanced surveillance for invasive pneumococcal disease at the EU/EEA levelDate of publication: 12 September 2018https://ecdc.europa.eu/en/publications-data/generic-protocol-enhanced-surveillance-invasive-pneumococcal-disease-eueea-level Hepatitis B and C epidemiology in selected population groups in the EU/EEADate of publication: 11 September 2018https://ecdc.europa.eu/en/publications-data/hepatitis-b-and-c-epidemiology-selected-population-groups-eueea Handbook on tuberculosis laboratory diagnostic methods in the European Union - 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Aconitum carmichaelii, commonly known as Fuzi, is a typical traditional Chinese medicine (TCM) herb that has been grown for more than one thousand years in China. Although root rot disease has been seriously threatening this crop in recent years, few studies have investigated root rot disease in Fuzi, and no pathogens have been identified. In this study, fungal libraries from rhizosphere soils were constructed by internal transcribed spacer (ITS) sequencing using the HiSeq 2500 high-throughput platform. A total of 948,843 tags were obtained from 17 soil samples, and these corresponded to 195,583,495 nt. At 97% identity, the libraries yielded 12,266 operational taxonomic units (OTUs), of which 97.5% could be annotated. In sick soils, Athelia, Mucor and Mortierella were the dominant fungi, comprising 10.3%, 10.1% and 7.7% of the fungal community, respectively. These fungi showed 2.6-, 1.53- to 6.31- and 1.38- to 2.65-fold higher enrichment in sick soils compared with healthy soils, and their high densities reduced the fungal richness in the areas surrounding the rotted Fuzi roots. An abundance analysis suggested that A. rolfsii and Mucor racemosus, as the dominant pathogens, might play important roles in the invading Fuzi tissue, and Phoma adonidicola could be another pathogenic fungus of root rot. In contrast, Mortierella chlamydospora, Penicillium simplicissimum, Epicoccum nigrum, Cyberlindnera saturnus and Rhodotorula ingeniosa might antagonize root rot pathogens in sick soils. In addition, A. rolfsii was further verified as a main pathogen of Fuzi root rot disease through hypha purification, morphological observation, molecular identification and an infection test. These results provide theoretical guidance for the prevention and treatment of Fuzi root rot disease. Aconitum carmichaelii Debx. is a typical TCM herb that has been clinically used for almost two thousand years [A. carmichaelii Debx., has been extensively used as a cardiotonic, analgesic, anti-inflammatory, and diuretic agent for the treatment of colds, polyarthralgia, diarrhoea, heart failure, beriberi, and oedema [A. carmichaelii (Fuzi). More than two thousand hectares of Fuzi, which is considered an important daodi herb and economic crop, were cultivated in Jiangyou and Butuo in Sichuan Province in 2015. Some East Asian countries, such as Japan, Korea, Mongolia and India, import a large quantity of this traditional medicine from China.nd years , 2. Fuzid oedema . As a reHowever, large-scale planting encourages mortal threats, and the Fuzi crop yield per unit area has been reducing each year. For instance, ten years ago, 15,000 kg of Fuzi could be harvested per hectare, but only approximately 11,000 kg per hectare can be harvested at present. This decrease is due to root rot disease, which is difficult to remedy using traditional methods. Once one Fuzi plant is infected by the root rot pathogen, its leaves turn brown (or reddish purple) and droop, and its stems eventually wilt. In severe cases, strands of white hyphae are visible on the ground, and a reddish brown sclerotium forms approximately a week later. Underground lateral roots eventually show skin lesions and tissue decay. The normal infection speed of this disease can reach 0.5–1 metres per day. Plants in the same farm or farm located near the disease sources soon become sick, and this resulted in the infection of more than 50% of the area of Fuzi farmlands by root rot fungus in 2016.Fusarium in cereal plants, Rhizoctonia bataticola in chickpea plants [Phytophthora nicotianae in pepper crops [Cylindrocarpon destructans in Panax ginseng [Magnaporthe grisea, M. oryzae, Colletotrichum graminicola, Leptosphaeria maculans and Cercospora beticola, also infect the roots of their hosts to cause root rot [P. nicotianae includes 255 plant genera in 90 families [C. destructans can also cause disease symptoms in the roots of species other than P. ginseng, such as strawberry [Root rot is generally regarded as the primary disease caused by soil-borne pathogens, such as the genus a plants , Phytopher crops , and Cyl ginseng . Other proot rot . Crop plroot rot , but thefamilies . C. destrawberry , 9 and grawberry . On the rawberry , indicatFew studies have investigated the pathogens of Fuzi root rot, and neither the invasion process nor prevention and control methods are known. Moreover, the pathogens leading to Fuzi root rot have not yet been reported; therefore, the encouragement of fundamental research studies on Fuzi root rot is crucial for solving the problem of pathogen invasion. In this study, we used high-throughput sequencing technology to screen the fungal community in sick soils and identify potential pathogens for Fuzi root rot disease. In addition, the fungal colonies of sick roots were isolated, purified and identified based on ITS sequences. Additionally, a pathogen infection test was performed to determine which fungi could cause the disease. Through this research, we aim to provide theoretical guidance for the prevention and treatment of Fuzi root rot disease.Aconitum Good Agricultural Practice of Medicinal Plants and Animals (GAP) planting bases in China. In Jiangyou, the Da-Hua leaf-type Fuzi is the main type of Fuzi plants cultivated, and the Xiao-Hua leaf type was cultivated to a lesser degree. Compared with Xiao-Hua, Da-Hua leaf-type Aconitum has a higher yield, larger root tubers and weaker resistance to root rot disease.In this study, sick soils refer to soils attached to Fuzi roots around which sclerotia emerge. Samples of rot-infected Fuzi and sick soils were harvested from Jiangyou in Sichuan Province, which is the core area of the The following four groups of root surface soils were obtained: healthy soils , healthy Da-Hua Fuzi , diseased Da-Hua Fuzi  and healthy Xiao-Hua Fuzi . Each group of dry soil was approximately 300–500 g (100 g for each replicate), and 17 soil replicates were prepared respectively as described by Miao . The sam2O. The reaction conditions were 98°C for 1 min, 30 cycles of 98°C for 10 s, 50°C for 30 s and 72°C for 30 s, and 72°C for 5 min, and the ITS primer sequences used were ITS5-1737F (5’-GGA AGT AAA AGT CGT AAC AAG G-3’) and ITS2-2043R (5’-GCT GCG TTC TTC ATC GAT GC-3’).Genomic DNA was extracted from each soil using the CTAB reagent, and PCR was then performed using specific barcode primers. The reaction contained 15 μl of PCR Mix (2× Phusion® High-Fidelity PCR Master Mix with GC Buffer), 3 μl of each primer (2 μM), 2 μl of gDNA (1 ng/μl) and 10 μl of H® DNA PCR-Free Sample Preparation Kit was used to construct cDNA libraries of the fungal communities in the soil samples. After the libraries were quantified by qRT-PCR and Qubit 2.0, a HiSeq 2500 PE250 instrument was used to sequence their ITS nucleotides. The high-throughput data was analysed using Qiime . After removing primers, tags, adaptors and low-quality nucleotides, the MUSCLE programme  was used for sequence alignments to identify the phylogenetic relationships and representative sequences of all OTUs. The OTUs were assigned at the 97% identity level. The community composition of each soil sample was calculated at each classification level, including kingdom, phylum, class, order, family, genus and species. The OTU counts were normalized into relative abundances (%). Statistical analyses were conducted with SPSS , and curve fitting was performed with SigmaPlot . Unless otherwise stated, P values ≤0.05 were considered significant.The TruSeqTo evaluate the species richness of rhizosphere fungi in each soil sample, an α-diversity analysis was performed using Qiime software (Version 1.7.0) with the Shannon index.The focus of this study was the differences in fungal diversity between sick and healthy soils. Qiime software was used for an unweighted pair-group method with arithmetic means (UPGMA) analysis based on the UniFrac distance. The soil groups were clustered in a weighted UniFrac tree based on their relative fungal abundances at the phylum level. A principal component analysis (PCA) of the soil fungi in the four groups of soils was performed using the ade4 function in R software (Version 2.15.3).2 pieces, and the square blocks of Fuzi were incubated on PDA medium  at 32°C. Once the hyphae grew to approximately 2–3 cm, they were purified three times.Fresh samples of rotted Fuzi were washed and sterilized with 75% ethanol. The interior milky tissue was sliced into 0.5-cm5’-CTT GGT CAT TTA GAG GAA GTA A-3’) and ITS4B (5’-CAG GAG ACT TGT ACA CGG TCC AG-3’). The PCR reactions contained 25 μl of PCR Mix (SsoFast TM EvaGreen® Supermix), 2 μl of ITS1F, 2 μl of ITS4B, 1 μl of gDNA and 20 μl of ddH2O. The reaction programme was 94°C for 3 min, 35 cycles of 94°C for 40 s, 55°C for 40 s, and 72°C for 90 s, and 72°C for 5 min. Sequencing was finished by the Chengdu branch of Biological Science and Technology Co., Ltd.ITS barcode PCR, sequencing and nucleotide blast analysis  were performed to identify the pathogens isolated from rotted Fuzi tissues. The DNA of the pathogens was extracted using a Plant Fungal DNA Extraction Kit with the ITS sequence primers ITSlF (http://www.megasoftware.net/) with the default parameters.After ITS sequence alignment with the NCBI database, the pathogens in rotted Fuzi tissue were identified with homology >90%. A phylogenetic tree was then constructed based on the neighbour-joining (NJ) method using MEGA 4.0 software  and dropped from the plant starting from the bottom. In addition, white hyphae were distributed unevenly in the soil, usually in visible clusters, and reddish-brown sclerotia arose and gathered near the soil surface (this type of soil is denoted “sick soil” in the manuscript). The series of symptoms observed was similar to that described in previous reports [Diseased is study . Once th reports , 13.To explore the pathogenesis of Fuzi root rot disease, 17 soil replicates from four group of samples were used to construct fungal databases. In total, high-throughput sequencing produced 996,653 reads from the 17 soil samples. After removing the barcode primers, these were combined into 975,213 reads, and 948,843 ITS tags (95.25%) were obtained after the QC and Nochime analyses, yielding a total of 195,583,495 nt and an average length of 206 nt for each tag .. The Q3Mortierella, Talaromyces, Penicillium, Athelia and Mucor  were unique, and each soil sample provided an average of 722 OTUs . For annnd Mucor .For the diversity analysis, a visualized UPGMA tree was constructed with the fungi in sick (G3) and healthy soils . The results revealed various diversities at every taxonomic level. At the phylum level, G3 contained the least abundances of Chytridiomycota, Ascomycota and Zygomycota fungi but the highest abundance of Basidiomycota fungi. The fungi in the G4 samples, which were obtained from rot-resistant Fuzi, mostly included Chytridiomycota, Zygomycota and Glomeromycota, with a lower abundance of Basidiomycota .Talaromyces (6.66%), Mucor (6.62%), Mortierella (5.63%), and Athelia (3.87%) (Penicillium (9.4% in G2 and 9.1% in G3). However, the Athelia content in sick soils (G3) contributed 10.3% of the fungal biomass, which is 2.6-fold higher than that found for G2. In addition, the abundances of Mucor and Mortierella in sick soils were 1.6- and 5.41-fold higher than those in G2, respectively  showed the highest species richness , and the fungal community was mainly composed of  (3.87%) . The rhiectively . High dei plants , which di plants . In parti plants . Based oA. rolfsii, Mucor racemosus, Mortierella chlamydospora and P. simplicissimum were detected at levels higher than 5% ,  than 5% . A. rolfl plants , 15, 16.y tomato . Mortierhabitats . This fu signals .Phoma adonidicola and Epicoccum nigrum in DV1 and Cyberlindnera saturnus and Rhodotorula ingeniosa in DV4 are shown in Phoma genus are the causal agents of brown root rot, which causes severe root lesions in alfalfa, soybean and other perennial forage legumes [P. adonidicola than healthy soils (T1-T5). It is noteworthy that the other three fungi that were enriched in sick soils appear to play competitive and antagonistic roles against the rot pathogens in Fuzi. A few E. nigrum isolates have been reported to significantly reduce the radial growth of both Pythium debaryanum and P. ultimum [Cyberlindnera fungus has been proven to exhibit antagonistic activities against a range of pathogenic and saprophytic filamentous fungi [Rhodotorula can protect sugar beets against the soil pathogen Rhizoctonia solani [Some fungi that were not identified as the main constituent species in sick soils (G3) were nevertheless found to be enriched in these soils compared with healthy soils. For example,  legumes . This ph ultimum . A Cyberus fungi . Additioa solani , 22. ThuA. rolfsii and Mucor racemosus, as the dominant pathogens, play important roles in the invasion of Fuzi tissue and the induction of root rot symptoms, and increases in the P. adonidicola abundance would worsen the disease. In contrast, M. chlamydospora, P. simplicissimum, E. nigrum, C. saturnus and R. ingeniosa might antagonize the pathogens in sick soils around Fuzi roots.These findings suggest that In this study, the rotten tissue of diseased Da-Hua Fuzi plants was used for pathogen isolation, and one strain of white fungus was obtained after purification. Its white, slender and crossed hyphae spread rapidly in the PDA medium, as a rate of approximately 2–3 cm per day . The funA. rolfsii strains in the NCBI database Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.


To reduce the environmental impact of concrete production, supplementary cementitious materials such as fly ash, blast furnace slag, and silica fume are commonly used as  cement replacement materials. However, these materials are industrial by-products and their availability is expected to decrease in the future due to, e.g., closing of coal power plants. In addition, these materials are not available everywhere, for example, in developing countries. In these countries, industrial and agricultural wastes with pozzolanic behavior offer opportunities for use in concrete production. This paper summarizes the engineering properties of concrete produced using widespread agricultural wastes such as palm oil fuel ash, rice husk ash, sugarcane bagasse ash, and bamboo leaf ash. Research on cement replacement containing agricultural wastes has shown that there is great potential for their utilization as partial replacement for cement and aggregates in concrete production. When properly designed, concretes containing these wastes have similar or slightly better mechanical and durability properties compared to ordinary Portland cement (OPC) concrete. Thus, successful use of these wastes in concrete offers novel sustainable materials and contributes to greener construction as it reduces the amount of waste, while also minimizing the use of virgin raw materials for cement production. This paper will help the concrete industry choose relevant waste products and their optimum content for concrete production. Furthermore, this study identifies research gaps which may help researchers in further studying concrete based on agricultural waste materials.Concrete production utilizes cement as its major ingredient. Cement production is an important consumer of natural resources and energy. Furthermore, the cement industry is a significant CO Worldwide, increasing amounts of waste generated are a major concern for a sustainable environment. According to a report by the World Bank, ~2.01 billion tons of solid waste was generated in cities worldwide in 2016 alone, amounting to a footprint of 0.74 kg per person per day [Typically, the excesses from growing and processing of raw agricultural products such as fruits, vegetables, meat, poultry, dairy products, and crops are classified as agricultural waste . These w2 [One of the options for using agricultural waste is in concrete production ,7,8. It 2 . ResearcIt should be noted that agricultural wastes can successfully be used in combination with binders other than ordinary Portland cement, such as lime and MgO cement. For example, Stevulova et al.  developeThis section describes the general processes involved in the conversion of agricultural wastes into usable materials for concrete production. It also provides the general properties of the selected agricultural wastes relevant for concrete production. Comparison of their properties with ordinary Portland cement and other relevant concrete constituents is also provided to highlight the likelihood of their use as cement replacement material.Palm oil fuel ash (POFA) is an important cash crop in several tropical countries, particularly Malaysia and Indonesia ,20. The 2 compared to cement. Due to its pozzolanic behavior, POFA has been used by researchers in cementitious materials either to replace the binder or as filler materials [POFA can be used in concrete either as aggregates, supplementary cementitious materials or as filler material ,24. Typiaterials ,24,26. TThe ash should be sieved in order to remove the organic and uncombusted matter. Furthermore, the reactivity of the ash may be increased by reducing the particle size by e.g., milling . A scannRice is one of the three major food crops in the world and Asian countries like China, India, Indonesia, Vietnam, and Bangladesh are the leading rice producers . Rice hu2), which can be used as alternative binder for concrete [When completely incinerating the rice husk in appropriate conditions, the residue  contains 90–96% amorphous silica  [2/g) [Rice husk ash resembles silica fume in some aspects: it has a large specific surface area and a high content of amorphous silica . However2/g) , rice hug) [2/g) ,48. Thisg) [2/g) . In addig) [2/g) . AccordiApproximately 60–70% of total sugar is produced from the sugarcane world-wide. Sugarcane production in countries such as Brazil, India, China, and Thailand is increasing every year. However, every 1000 kg of planted sugarcane produces around 231 kg (28%) of bagasse and 430 kg 52%) of solid waste % of soli. In the 2 [2O3, Fe2O3, and CaO as shown in 2O3, Fe2O3, and CaO in SCBA make it a good candidate as an alternative binder to cement in concrete production [The chemical composition of SCBA shows that a large proportion (> 65%) of it is SiO2 , which ioduction . Other coduction ,24,25,26Similar to palm oil fuel ash, the reactivity of the sugarcane bagasse ash can be improved by reducing its particle size, e.g., by milling or grinding ,58. In F2 (~76%), and shows high pozzolanic reaction when used as binders for producing concrete [2 content in BLA can expedite the reaction of calcium hydroxide crystal by forming more calcium silicate hydrate. Thus, BLA can also be an alternative binder for concrete production in developing countries and reduce their dependency on cement. The annual production of bamboo is ~20 million tons, of which more than 10 million tons are produced in India, China, and Japan ,60. Bambconcrete ,62. Othe2 negative footprint.From the above discussion it can be seen that the physical and chemical properties of POFA, RHA, SCBA, and BLA are in many ways similar to the traditional binders such cement, fly ash, and slag of cement-based materials. Therefore, it is worth doing research on these materials and scrutinize their different properties before they can be used as a supplementary cementitious material. Successful uses of these materials in concrete production may improve the basic material properties and at the same time reduce the CODue to pozzolanic reactivity of the agricultural wastes discussed, various investigations on the behavior of the ashes generated from these wastes as cement replacements or aggregate replacements have been conducted. Favorable results have widely been obtained as discussed in this section.The use of palm oil fuel ash (POFA) as partial cement replacement has a great influence on the microstructural development of concrete ,64,65,66Utilization of POFA in concrete has an effect on its fresh properties. The influence of different percentages of ultrafine oil palm ash (max size 11 μm) replacement in concrete slump was investigated by Zeyad et al. , as showA study of Tangchirapat et al.  showed tPOFA can also be used as aggregate in concrete production, having different effects on the slump. Kanadasan and Razak  investigUse of palm oil fuel ash has an impact on the initial and the final setting time of concrete . With inStudies on the compressive and tensile strengths of concrete when POFA was used show a reduction in strength with increase in the POFA content in the mix, as illustrated in At lower water-to-binder (w/b) ratio , concrete made with 30% cement replacement by POFA showed a similar range of compressive strength as concrete without POFA . In thisLong-term and durability properties of concrete are also affected by addition of palm oil fuel ash as partial cement replacement. It has been shown that POFA has a positive effect on durability: it decreases the chloride diffusivity of the mix ,72,73, lAlthough some properties of concrete (most notably strength and setting time) are adversely affected by POFA, research has shown that it can be used in many applications. As such, it can be a great resource in developing countries. Future research needs to promote its use in structural applications.Considering that rice husk ash has a very high specific surface area, it has an important effect on the hydration of blended concrete ; it has Use of RHA as supplementary cementitious material affects the fresh properties of concrete. While some studies showed that the addition of rice husk ash was found to increase slump compared to reference  concrete , others The addition of RHA to concrete causes an increase in compressive strength, as shown in In another study , naturalDurability of concrete was found to improve with incorporation of RHA as partial cement replacement. This can be attributed to the refinement of the pore structure caused by the pozzolanic activity. Concrete with RHA has shown to be more resistant to chloride ingress ,87,94, tOther concrete properties such as thermal conductivity and autogenous shrinkage were also investigated when RHA was incorporated in the concrete mix ,100. AltLike the other waste materials discussed, sugarcane bagasse ash influences the hydration and microstructural development of blended concrete. Sugarcane bagasse ash has pozzolanic properties ,104,105.Workability of concrete reduces with the increase in the amount of SCBA content in the concrete mix . The losIn case of mechanical properties, a study with SCBA replacement in concrete showed equal or marginally better strength than the control mix of concrete, even at early age of three days . At 28 dThe addition of sugarcane bagasse ash has a positive effect on concrete durability. The durability performance of concrete with different SCBA content against chloride, gas and water penetration was also investigated by the researchers ,114. ResFrom the above discussion, it can be said that the SCBA influences the quality of concrete. It has a good chemical composition and physical properties such as fineness, setting time and compressive strength. However, there is uncertainty about the optimum content of SCBA in concrete as the current results show variability in concrete strength with SCBA replacement ranging from 5% to 25%. Nevertheless, the use of SCBA in addition to the concrete is a very feasible option in improving the mechanical properties of the concrete, besides providing a suitable destination to agroindustrial by-product .The use of bamboo leaf ash in concrete is less studied compared to other agricultural wastes discussed. Singh et al.  investigIn terms of concrete workability, the higher the percentages of BLA replacement, the lower the slump was observed . At a giWhen the mechanical properties of BLA concrete are concerned, the majority of studies reported that the strength of concrete reduces with increase in the BLA content ,116,117.Concrete durability properties such as acid resistance and chloride resistance are considerably improved at 10% replacement of cement with BLA . The capAgricultural waste is widely available in developing countries, and its use as fuel is attractive from an economic point of view. The ashes produced from the fueling process have little industrial use. However, if these wastes are burnt under controlled temperature and time, they are proven to have pozzolanic properties . This en2 emission. Therefore, research needs to concentrate to find out the actual benefit of reusing these waste materials in concrete. This is in addition to potential technical benefits, the use of agricultural waste as alternative binder can lower production cost of concrete, lower cement consumption and thus CO2 emission [One of the major issues with the agricultural wastes is that often these need to be treated such as burning at high temperature or grinding for having the desire shape and size. However, this process requires lot of energy and also contributes to the COemission .So far, limited research has focused on the production and processing costs of these waste materials . In geneThis article provides an overall summary of research devoted to utilization of various agricultural wastes in concrete production, especially in developing countries. For the various waste sources discussed, it was found that they can be used as partial cement replacements or aggregate materials in concrete. If properly treated, the ashes have pozzolanic properties and contribute to the hydration and hardening of concrete. If properly designed, such concretes are not inferior to OPC concretes and, in fact, they can show improved workability and long-term durability, together with reduced heat of hydration. This makes such wastes suitable candidates for various specific applications, e.g., for creating durable concrete or massive concrete structures.At the moment, it can be considered that the feasibility of use of agricultural waste materials in concrete has been proven. Although more studies need to focus especially on long-term properties, progress is needed first and foremost in production technology and quality control of these materials. Only when ashes of constant high quality can be produced at low financial and environmental costs will their use in engineering practice become more widespread. This is important, as for many developing countries these are the only SCMs available.