Acute febrile illness (AFI), a common reason for people seeking medical care globally, represents a spectrum of infectious disease etiologies with important variations geographically and by population. There is no standardized approach to conducting AFI etiologic investigations, limiting interpretation of data in a global context. We conducted a scoping review to characterize current AFI research methodologies, identify global research gaps, and provide methodological research standardization recommendations.Using pre-defined terms, we searched Medline, Embase, and Global Health, for publications from January 1, 2005–December 31, 2017. Publications cited in previously published systematic reviews and an online study repository of non-malarial febrile illness etiologies were also included. We screened abstracts for publications reporting on human infectious disease, aimed at determining AFI etiology using laboratory diagnostics. One-hundred ninety publications underwent full-text review, using a standardized tool to collect data on study characteristics, methodology, and laboratory diagnostics. AFI case definitions between publications varied: use of self-reported fever as part of case definitions , fever cut-off value , and fever measurement site . Eighty-nine publications (47%) did not include exclusion criteria, and inclusion criteria in 13% (24/190) of publications did not include age group. No publications included study settings in Southern Africa, Micronesia & Polynesia, or Central Asia. We summarized standardized reporting practices, specific to AFI etiologic investigations that would increase inter-study comparability.Wider implementation of standardized AFI reporting methods, with multi-pathogen disease detection, could improve comparability of study findings, knowledge of the range of AFI etiologies, and their contributions to the global AFI burden. These steps can guide resource allocation, strengthen outbreak detection and response, target prevention efforts, and improve clinical care, especially in resource-limited settings where disease control often relies on empiric treatment. PROSPERO: CRD42016035666. Acute febrile illness (AFI) is a common reason for people seeking medical care globally with potentially serious infectious etiologies. However, AFI has no current consensus standardized approach when considered as a syndromic case definition for public health surveillance or research, especially in global settings where AFI treatment is performed with limited diagnostic availability. Therefore, the aim of this review was to describe current methodologies in AFI research, identify gaps in research, and provide recommendations for standardization of AFI research. We screened abstracts and completed full-text reviews on publications found through an extensive search. A total of 190 publications were included in the final review, from which we collected data on study characteristics, methodology, and laboratory diagnostics. These collected data elements allowed us to identify where there were inconsistencies in reporting and investigative methods, which data elements were not regularly collected, and what laboratory testing methods were commonly used. Standardized reporting methods for AFI investigations, along with laboratory testing capacity for multiple pathogens, can improve our knowledge of the causative agents of AFI in certain regions of the world. This can help us determine where resources are needed, how to strengthen outbreak detection and response, and how to improve medical care, especially in regions with limited resources. Acute febrile illness (AFI) is often non-specific and used differently in clinical and public health settings. AFI in the clinical setting may simply refer to any illness with a fever. In public health surveillance and research, AFI has been frequently characterized as fever without an apparent localized site or cause of infection–a commonly occurring subset of febrile illnesses where empiric treatment guidance is needed.  EtiologiHowever, there are challenges associated with current AFI investigations. Variability in AFI case definition use, inclusion and exclusion criteria for study enrollment, level of health system studied, absence of a control group to calculate attributable fractions, and poor comparability of diagnostic assays used contribute to the lack of standardized methodology for conducting AFI investigations, hampering the ability to compare findings, trends, and proportional etiology between studies and geographic locations.  AdditionThe World Health Organization’s informal consultation on fever management in peripheral health care settings has called for a broad range of etiologic studies to identify the pathogens responsible for AFI.  Unlike iA scoping review of existing literature is used primarily as a means of summarizing evidence to understand the extent and depth of a particular topic. –14 This Publications identified from the literature search were screened as part of a title and abstract review process to determine which ones would continue to the full-text review . For incThe data characterization and collection form for the full-text review was created using Epi Info , and made available to all full-text reviewers through a web survey platform. Prior to data abstraction, specific instructions were provided, and publications were randomly assigned to reviewers.Data collection included three primary areas: study characteristics, study methodology, and laboratory diagnostic methods . Study cA total of 1,339 publications were initially identified for the scoping review; of these, 1,083 were identified through the keyword search and 256 were identified through references of review papers and the online repository of publications . After rThe geographic study setting with the most publications on AFI etiology was Southern Asia with 59 publications and 58,169 study participants; Southeastern Asia had the second highest number of publications with 42 publications and 71,554 study participants . There wOf 189 publications that reported on duration of study data collection, 125 (66%) had data collection duration <24 months, 47 (25%) had a data collection duration of 24–47 months, and 17 (8%) publications had a data collection duration ≥48 months. In 64 (34%) publications, the study population consisted of both inpatient and outpatient study enrollees; 21 (11%) involved study populations consisting of only facility-based outpatient participants, while 58 (30%) consisted of only inpatient enrollees. Five (3%) involved study populations in community (non-facility-based) settings . HealthcThere was great variation in exclusion criteria, inclusion criteria, and AFI case definition between publications . ExclusiPlasmodium spp., and Leptospira spp. were the most commonly investigated or identified, with each represented in 76 (40%), 53 (28%), and 53 (28%) publications, respectively (Pathogens that were included in at least ten publications are shown in ectively . The comectively . PathogeCoxiella burnetii to five (56%) of nine for Brucella spp. The proportion of publications that used at least one standard laboratory diagnostic test (defined in Brucella spp. to 51 (100%) of 51 for Plasmodium spp.The use of laboratory methods for identification of pathogens that were included in at least ten publications, except for those that were primarily identified by blood culture, was also evaluated . The proThis scoping review of published AFI etiology investigation methods highlights several gaps that can be addressed for a more cohesive and impactful global AFI surveillance strategy. We found wide variation in the AFI case definitions, including the fever cut-off value, inclusion and exclusion criteria, and in how findings were reported across existing AFI publications. Use of laboratory diagnostics not meeting widely accepted laboratory case definitions was common. The lack of AFI investigation methods and reporting in publications assessed prevents data aggregation across geography and time that could meaningfully guide public health action.Similar to existing reviews, we found gaps in the geographic distribution of study origin and in the demographics of the study populations. ,7 There Vibrio cholerae  of reviewed publications. By contrast, fewer studies examined other pathogens, such as cholerae . Several Africa. This review underscores a need for more comprehensive, multi-pathogen AFI etiologic studies paired with clinical presentation data. These etiologic investigations of AFI could be designed to unpack the circulating pathogens that contribute to AFI in geographic areas and quantify their attributable fractions, in order to ultimately guide empiric management and inform public health measures. Due to their specific and focused nature, single-pathogen studies provide limited evidence and data for actionable purposes or continue to reinforce pre-existing notions on the distribution of pathogens rather than document novel findings such as the presence of pathogens in new geographic areas or populations. Although there are many ongoing initiatives to characterize circulating causes of febrile illnesses, a paucity of evidence still prevails relative to that of etiologies responsible for respiratory and diarrheal diseases. ,19Unlike influenza and malaria, where extensive global efforts have been implemented to build diagnostic capacity, laboratory confirmation remains challenging for many other AFI pathogens. Obtaining paired sera, the issue of cross-reactivity, and limited availability of assays that are considered confirmatory or the gold-standards  or microagglutination test (MAT)) add additional layers of difficulty in laboratory confirmation.Mycobacterium tuberculosis, Plasmodium spp., Salmonella enteritidis serovar Typhi and four additional pathogens with local priority selected by each country. [Orientia tsutsugamushi. [Strengthening laboratory diagnostic capacity for common pathogens responsible for AFI in low- and middle-income countries directly improves routine surveillance systems and availability of actionable data to guide public health interventions. The WHO Collaborating Center for International Health Regulations (IHR) Implementation of National Surveillance and Response Capacity recommends that countries develop their capacity to perform 10 core tests related to influenza, poliovirus, HIV, country.  As many gamushi.  More recgamushi. New technological advances in the field of laboratory diagnostics can certainly play a role in addressing the aforementioned challenges surrounding laboratory confirmation. –25 IncreThese scoping review findings also highlight a lack of standardization in how methods and results from AFI studies are reported in the scientific literature. The need for standardized guidelines or even protocols for conducting AFI studies has previously been identified, and this lack of standardization continues to be a major impediment for being able to compare results from different studies and pool their results to develop national, regional or global burden of disease estimates. ,7,34 ForTo streamline AFI etiology reporting, minimize variation in key data elements, and improve our ability to fill existing knowledge gaps, we recommend the development and use of a checklist outlining specific criteria to be included in the methods and results sections of publications related to AFI studies in addition to use of existing checklists such as “Strengthening the Reporting of Observational Studies in Epidemiology” (STROBE) checklist.  A proposThis scoping review is subject to a number of limitations. Literature assessed for this study was limited to that published in the English language from January 1, 2005–December 1, 2017. In addition, the literature was also limited to articles published in peer-reviewed journals meaning that gray literature, white papers, and routine surveillance reports were also omitted from consideration. As a result, there is a potential for bias in the analysis of gaps in geographic distributions of AFI etiologic investigations, as well as pathogens that have been studied. At the same time, data analysis to determine gaps in research was limited to information contained in articles, opening up the possibility of reporting bias. Along the same lines, the content and quality of each publication included in the review differed, lending themselves to variable interpretation from one reader to the next. It is possible, also, that differences in HIV prevalence among regions could impact study results and, therefore, publication focus; HIV-specific comorbidity risks should be considered in settings with high HIV prevalence.AFI etiologic investigations are not only important for shining a light on the causes of what is still a somewhat unexplored clinical presentation in many parts of the world but also for building surveillance and diagnostic capacity in countries where common causative pathogens are circulating. Looking ahead, technological advances such as the validation of accurate multi-pathogen testing platforms combined with improvements in the availability and accessibility of diagnostic tools, as well as increased testing for etiologies that are not well understood or commonly tested for can contribute to bridging the global AFI knowledge gaps. At the same time, there is great variability in AFI etiologic investigation methodologies, and the absence of standardized case definitions and reporting hinders our ability to generate a complete global picture of the causative agents of AFI. A coordinated and standardized methodology for reporting could help mitigate these inconsistencies and generate a more comprehensive understanding of AFI etiologies and distribution, potentially with measurable global health security and AFI survival benefit.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S1 File(PDF)Click here for additional data file.S2 File(XLSX)Click here for additional data file.S3 File(DOC)Click here for additional data file.S4 File(DOC)Click here for additional data file.


The main aim of this paper is to carry out the environmentally based enhancement of a concrete mixture containing recycled materials whilst considering natural resource consumption as well as mechanical and thermal property levels. The developed concrete is intended to be used in mortarless masonry wall structures. Ten concrete mixtures with different types and replacement rates of recycled masonry aggregate and recycled expanded polystyrene were prepared, and their mechanical and thermal properties were experimentally investigated. It was found that the use of recycled masonry aggregate led to better thermal properties while maintaining sufficient mechanical properties. On the contrary, the addition of recycled expanded polystyrene did not significantly affect the thermal properties of concrete, but the mechanical properties considerably declined. For this reason, the recycled masonry aggregate is suitable to use as an aggregate for concrete masonry blocks for wall structures. The effective use of construction and demolition waste (CDW) and its application in reusable structural elements can simultaneously reduce waste dumping and decrease the need to use primary resources, both of which are important environmental aspects to be considered in responsible sustainability management. This represents an important contribution to the solution of one of the core objectives of the 2030 UN Agenda on Sustainable Development—Goal 12: Ensure sustainable consumption and production patterns . In. In3, wihout EPS . The reshout EPS .Research on recycled materials as a partial or full replacement of NA in structural applications such as concrete blocks, paving blocks or floor blocks has already been published. The main reason for replacement of aggregate, which is the major component in concrete blocks, is the primary sources savings . There aThe use of RMA as a partial or full replacement of aggregate in structural concrete was examined for manufacturing precast prestressed beams , paving This paper presents the environmentally based optimization of a concrete mixture containing recycled materials for mortarless masonry wall structures. Due to the low thermal conductivity of RMA and EPS, their utilization could have great potential for manufacturing concrete blocks for mortarless masonry walls of low-rise buildings, despite the decline of strength. From technical and/or economic viewpoints, the principle of mortarless masonry permits easy wall deconstruction for the most effective reuse of structural elements after their end of life.In total, 10 concrete mixtures were prepared and tested in order to verify the properties of concrete made using recycled masonry aggregate. One of them was a reference mixture with a natural aggregate only, and other mixtures contained recycled masonry aggregate and recycled expanded polystyrene in various ratios as a partial or full replacement of natural aggregate.This research used one type of NA, two types of RMA, and one type of recycled EPS. Both types of RMA originated from construction and demolition waste and were delivered in fractions of 0–8 and 8–16 mm by a Czech recycling center see . For utiSelected properties of RMA were tested according to valid Czech standards. The properties most influencing the recipe design were tested. The basic physical properties of RMA are shown in 3 were prepared for laboratory measurements. One mixture of conventional concrete of strength class C30/37 only with NA of fraction 0–16 mm was manufactured as a reference to compare with the other mixtures in which NA was replaced in various ratios by RMA (five mixtures) and recycled EPS in addition (four mixtures). Two mixtures of RMA concrete (RMAC E and RMAC EPS D) only with RMA of fraction 0–8 mm was manufactured , mechanical (compressive strength and tensile strength), deformation (static modulus of elasticity in compression), and thermal .The mechanical properties, such as compressive strength, flexural strength, and static modulus of elasticity, were examined according to European and Czech standards. Water absorption capacity by immersion was tested on cubic specimens 100 × 100 × 100 mm. Specimens were treated by water, and after stabilization of weight, dried in an oven at a temperature of 105 ± 2 °C until stabilization of weight. The saturated surface-dried density and dry density were measured on these samples. Capillary water absorption was determined by measuring the rate of water absorption by capillaries. The ends of fractured prismatic specimens of 100 × 100 × approx. 150 mm, which were tested after the tensile strength test, were immersed in water up to a maximum height of 5 mm for 72 h or until their weight stabilized. The amount of water absorbed at different time intervals was measured by periodically weighing the surface-dried sample. Weighing intervals were 5 min, then 15 min for the first hour, then every hour for the first 6 h, and finally, every 12 h.Measurement of thermal properties was done by the portable hand-held system ISOMET 2114  for measurement of the heat transfer properties of the materials. This applies a dynamic measurement method, which enables reducing the measurement time in comparison with steady-state measurement methods. It is equipped with a surface probe for measuring solid and hard materials. A flat surface of at least 60 mm diameter is satisfactory for the probe. Demand for the accuracy of the surface flatness increases as the thermal conductivity value of the tested material increases. The expected minimal thickness of the evaluated materials ranged from 20 to 40 mm depending on their diffusivity (conductivity).Thermal conductivity λ (W/(m·K)): 0.04–6.00;2/s);Thermal diffusivity a (mρ (J/(m3·K)): 4.0 × 104 to 3.0 × 106;Volume heat capacity cTemperature T (°C): −15 to +50.Measured quantities and measurement ranges: The thermal properties were tested on three cube samples of concrete of dimensions 100 × 100 × 100 mm for each mixture see . The samThe water absorption of buildings materials is important to know due to its influence on durability ,81. The The compressive strength is the most important mechanical property of concrete blocks, which can be greatly enhanced by using recycled aggregate. The compressive strength of load-bearing wall blocks should not be less than 7 MPa . The comThe lightweight and thermal insulation properties are the important functional characteristics of wall blocks for buildings . The utiThe thermal conductivity of concrete mixtures with RMA was approximately three times lower in comparison with NAC see . The theIt was found that the thermal conductivity of concrete slightly depends on its density and compressive strength see . HoweverRecycled aggregate concrete has generally higher water absorption compared with conventional concrete. In this case, the water absorption by immersion and capillary water absorption were approximately two times higher. This aspect negatively influences the durability of concrete, especially freeze–thaw resistance. Nevertheless, it is not so important for insulated walls above ground level.The use of recycled masonry aggregate as a partial or full replacement of natural aggregate in concrete mixtures negatively influences the mechanical properties of concrete, such as compressive strength, modulus of elasticity, and so forth. Here, the decline of compressive strength was between 30% and 75% and the decline of static modulus of elasticity was between 42% and 68% depending upon replacement rates.The thermal conductivity of concrete with recycled masonry aggregate was approximately 70% lower than the value of the reference concrete with only a natural aggregate. The utilization of 30% recycled EPS for the concrete mixture with recycled masonry aggregate further decreased the thermal conductivity by about 5%. The volume heat capacity of concrete containing both types of recycled materials was similar to the volume heat capacity of concrete with natural aggregate.The decrease of the thermal conductivity of recycled aggregate concrete depends on the replacement ratio of recycled masonry aggregate in concrete. This dependence applies to the same type and fraction of recycled aggregate.In this study, the environmental optimization and experimental verification of the physical, mechanical, and thermal properties of concrete containing various amounts of recycled masonry aggregate were examined and discussed. The final conclusions that have been reached can be summarized in the following points:As it was mentioned in previous studies about concrete blocks with recycled materials, the replacement of aggregate by recycled materials with their unique characteristics can positively influence the properties of concrete blocks for special applications ,77,78,79


The results show that the dynamic mechanical properties of BSFRC are strain-rate sensitive. Both basalt and macro synthetic polypropylene fibers  have a strengthening and toughening effect on concrete. Their hybridization has a similar enhancement effect but the impact toughness of concrete is further improved and the best hybrid ratio is 0.05%(BF)–0.25%(SF). BSFRC with higher w/c ratio has a higher strain rate effect while the fiber hybridization effect is weakened. Besides, the proposed constitutive model can well describe the impact behavior of BSFRC. The hydration of cement in the interface transition zones is lower with more Calcium Silicate Hydrate and less Concrete in practical applications has to inevitably suffer various impact loads. Recent research indicates that the hybrid fiber reinforced concrete (FRC) has better dynamic mechanical properties compared to the mono FRC under impact loading. Based on macro-experimentation and micro-observation, the impact behavior of the hybrid basalt-macro synthetic polypropylene FRC (BSFRC) was investigated by using ∅74 mm SHPB, SEM, and EDS. The effects of fiber hybridization, strain rate, and  Concrete is a widely applied engineering material and measures to improve the performance of concrete are desperately needed. Fiber reinforced concrete (FRC) has been proven to have better performance than plain concrete (PC), especially in restraining microcracks propagation . Based oThere are few studies on the hybrid basalt-macro synthetic polypropylene FRC (BSFRC) at present, especially on its dynamic mechanical properties. However, other types of HFRC have also been studied. Yu et al.  studied Besides, most of the research is basically carried out at the macro scale now. However, some limitations exist when explaining the impact of fiber and strain rate upon the dynamic behavior of concrete material. Scanning electron microscopy (SEM) is an advanced processing method for observing sample surfaces and is widely applied for analyzing the microstructure characteristics of materials . It is gw/c ratio was investigated simultaneously with a split Hopkinson pressure bar (SHPB) device. Then, a proposed model for BSFRC was used to describe the mechanical behavior of BSFRC considering damage inside concrete. Finally, the microstructure characteristics of BSFRC were observed and analyzed according to the obtained microscopic appearance and element contents in the interface transition zones (ITZ). The methodological framework chart of this study is shown as This paper is devoted to analyzing the impact behavior and failure mechanism of BSFRC from both macro and micro perspectives. The effect of fiber hybridization, strain rate, and w/c ratios of 0.68, 0.54 and 0.44 were considered. Six groups of fiber hybrid content were designed which were PC (0%), BC (0.1% of BF), SC (0.5% of SF), BSC1 (0.05% of BF + 0.25% of SF), BSC2 (0.05% of BF + 0.5% of SF), BSC3 (0.1% of BF + 0.25% of SF). The strain rate was controlled by impact pressures in SHPB test which were 0.3, 0.4, and 0.5 MPa, respectively. The river sands were used as fine aggregates with the maximum particle size of 2.5 mm. The detritus was used as coarse aggregates with a particle size of 5–10 mm. The 42.5 ordinary Portland cement was used according to GB 175-2009 [The 175-2009 . The mix−5 MPa/s according to GB/T 50081-2016 [The size of cylinder specimens was an important factor in SHPB test. Li et al.  consider081-2016 .The SEM test was conducted to study the microscopic appearance of BSFRC with a JSM-6360LV digital scanning electron microscope , as shown in B. Hopkinson  in 1914 E and A are the elastic constant and sectional area of the input and output bars. The SHPB apparatus used in this study is illustrated in iformity . The spe (1)–(3) :(1)σ=EAAw/c ratios and fiber hybrid ratios. It shows that the strength of all types of concrete reinforced with fibers is higher than that of fiberless concrete. Giner et al. [w/c ratios of 0.44 and 0.54, the carrying capacity of BSC1 (0.5BC + 0.5SC) is higher than that of BC and SC which are increased by 9.6% and 12%, respectively. It indicates that the hybrid fiber has greater enhancement effect than mono fiber. However, the excessive fiber hybrid content (BSC2 and BSC3) produces inhibitory effects and the strength of concrete decreases. This is because too much fiber results in poor dispersibility and conglomeration. More defects of pores and weak interfaces are produced, leading to the weakness of enhancement effect of fibers. For w/c ratio of 0.68, bearing capacity of BSC1 is lower than that of BC and SC. Whereas, the strength of concrete continues to increase when the content of BF (BSC2) or SF (BSC3) is increased. This is probably because concrete with higher w/c ratio demands a higher fiber hybrid content. Concrete with low w/c ratio and high fiber content must use superplasticizers. Overall, the optimal hybrid ratio is 0.05% (BF)–0.25% (SF) for w/c ratios of 0.44 and 0.54, but higher fiber hybrid content is needed for a w/c ratio of 0.68.The static strength of concrete is an important factor in designing concrete structures and is the basis for analyzing the dynamic properties of concrete. r et al.  considerw/c ratio on the dynamic compressive response of BSFRC subjected to dynamic compressive loading is investigated. The dynamic characteristic parameters of SHPB test are defined in Here, the impact of fiber hybridization, strain rate and w/c ratios of 0.68 and 0.44 are approximated as straight lines. However, curves of w/c ratio of 0.54 have obvious inflection points. Some scholars call it as critical strain rate (Impact strength (te (ε˙c) . The impw/c ratio increases. It means that BSFRC with higher w/c ratio has a higher strain rate effect. R2 is the determination coefficient which can qualify the fitting results. Here, R2 close to 1 means that DIF and Dynamic increase factor (DIF) shows the change degree of impact strength with strain rate and it is defined as  (4)–(8) ,37,38,39w/c ratio, it shows from w/c ratio of 0.54 has the highest value but that of 0.44 has a downward trend. As is known, the brittleness of concrete increases when the w/c ratio decreases. It means that the strain-rate hardening effect is dominant as the w/c ratio of BSFRC is low.The impact strain indicates the deformation capacity of BSFRC under impact loading. The relationship between strain rate and impact strain is presented in w/c ratio increases. However, the fitted line becomes steeper as w/c ratio increases. It also indicates that BSFRC with higher w/c ratio has a higher strain rate effect.The impact toughness reflects the energy absorption capacity of BSFRC subjected to external loading. Herein, we use the energy method to analyze the impact toughness of BSFRC  has lower impact strength than BC and SC. However, it is similar to SC but higher than BC as the w/c ratio decreases. It indicates that higher w/c ratio will weaken the effect of fiber hybridization.w/c ratio of 0.54. But in general, it can be seen that concrete reinforced with proper amounts of BF, SF, and their hybridization has higher impact toughness which means that the two fibers can increase the impact toughness of concrete but their hybridization has better toughening effect compared to SF and BF used individually. However, BSC1 has higher impact toughness compared to BSC2 and BSC3. It indicates that too much fiber will play a weaken role which is more obvious in lower w/c ratio. Besides, the impact toughness of concrete, especially the ultimate toughness, shows a great variation in lower w/c ratio but has only a little difference in higher w/c ratio. It indicates that the fiber hybridization effect is more obvious at lower w/c ratio.m, a, m and a are the scale and shape parameter of Weibull distribution. The ZWT model , which wg et al.  considerw/c ratios. It shows that the stress fitted by the proposed model agrees well with the test data. The level of conformity in the rising phase is very high but declines in the dropping phase. It can be explained as the stress in SHPB test is not uniform when the internal stress reaches its maximum value. Overall, m increase while a decreases. It means that the dynamic elastic modulus of BSFRC is improved by strain rate. The increase of m has a greater effect upon D than a. D decreases with the increase of m and the decrease of a. The fitting result indicates that D is reduced which indicates that the microcracks propagation is restrained and the brittleness of BSFRC is improved with strain rate.Only part of the results is given because of paper length limitations. The fitted curves and parameters at various strain rates are plotted in The fitted curves and parameters with various hybrid ratios are plotted in in w/c ratio is an important factor affecting the failure mechanism of BSFRC. In this section, the microscopic appearance of mortar is studied with SEM equipment, as given in w/c ratio (0.68), the hardened cement hydrates are loosely structured with many 1.5–3 w/c ratio declines, the content of cement increases gradually and the internal defects decrease. When w/c ratio is 0.44, there are few obvious cracks and large aperture pores and the aperture of the pores is reduced to 0.5–1 w/c ratio decreases, there is not enough water to generate ettringite and the C–S–H gel impel cement to form a more compact structure. With fewer microcracks and pores inside, the performance of concrete is clearly improved.The ry pores . C–S–H wry pores , leadingw/c ratios has different degrees of damage in the ITZ. Concrete with the w/c ratio of 0.68 has apparent wide cracks and mortar is loosely bonded to aggregates. When the w/c ratio decreases, mortar of concrete with the w/c ratio of 0.54 has better encapsulation to aggregates but the mortar structure in the ITZ is relatively looser compared to that of concrete with the w/c ratio of 0.44. Besides, there is a significant difference between the microscopic appearance of ITZ and that of common mortar (CM) which is 500 The cement hydration products and coarse aggregates are essentially two different materials and there exist interfaces between them. First, we study the interface characteristics between mortar and detritus of PC, as shown in Herein, we study the fiber distribution and interface between mortar and fibers. After observing several different samples, we found that they showed broadly similar distribution of BF and SF, as given in w/c ratio caused by the penetration of water from mortar to aggregates surface and the thickness of ITZ is between 5 and 100 μm [w/c ratio near aggregates and w/c ratio of CM away from aggregates is lower and the content of C–S–H increases resulting in a compact structure. Therefore, the ITZ is an area with higher porosity and lower strength compared to CM.The formation of ITZ is because of the gradient of d 100 μm . Three sw/c ratio upon the impact behavior of BSFRC was studied experimentally in this paper. The microstructure characteristics of BSFRC material was observed and analyzed as well. The main conclusions obtained are as follows:w/c ratios of 0.44 and 0.54, but higher fiber hybrid content is demanded for w/c ratio of 0.68.BF and SF are able to increase the static strength and their hybridization has a greater strengthening effect. The best hybrid ratio is 0.05% (BF)–0.25% (SF) for w/c ratio has a higher strain rate effect. As the strength of concrete decreases with increasing w/c ratio, the research indicates that the reduction of the concrete strength increases its strain rate sensitivity.The impact test results indicate that BSFRC material is significantly affected by strain rate which can improve the dynamic mechanical parameters of BSFRC. The results show that DIF and w/c ratio will weaken the effect of fiber hybridization.Both fibers can improve the impact strength and toughness. Their hybridization has similar improvement effects on impact strength but can further increase the impact toughness and the best hybrid ratio is 0.05% (BF)–0.25% (SF). Higher m are sensitive to strain rate. The static and dynamic elastic constant of BSFRC are improved compared to plain concrete. The BF and SF hybridization can restrain the damage evolution of concrete more obviously.The proposed model can well describe the impact behavior of BSFRC. The fitted parameters of w/c ratio. Besides, degree of damage in the ITZ of PC decreases as well but is worse than that in the CM. BF and SF with proper fiber content can be evenly distributed in concrete. BF are mostly pulled apart while SF are mostly pulled out in fracture areas. The energy spectrum results show that the hydration of cement in the ITZ is lower with more C–S–H and less The mortar structure gets more compact with more C–S–H and less The impact of fiber hybridization, strain rate, and In practical applications, concrete-like material has to inevitably suffer various impact loads, such as an earthquake, explosion, and wave or wind power. The hybridization of BF and SF is able to combine the advantages of both BF and SF. The impact resistance of concrete with a suitable amount of BF and SF added is improved remarkably. In addition, the production cost of BF and SF is lower than that of some other type of fibers, such as steel fiber and carbon fiber. Thus, BSFRC has great potential in concrete application.


In several countries, especially in Africa, the dominant method of heroin intake is smoking a joint of cannabis laced with heroin. There is no data exploring the impact of smoking heroin with cannabis on treatment outcomes.To compare treatment outcomes between people who inject heroin and people who smoke heroin with cannabis.Three hundred heroin users were assessed on admission to inpatient rehabilitation and after treatment. We compared drug use, psychopathology, criminality, social functioning and general health between heroin injectors and heroin-cannabis smokers at treatment entry, and at 3 and 9 months after rehabilitation.p = 0.036). The median number of heroin use episodes per day was lower for IV users than heroin-cannabis smokers at both follow-up points (p = 0.013 and 0.0019). A higher proportion of IV users was HIV positive (p = 0.002). There were no significant differences in psychopathology, general health, criminality and social functioning between IV users and heroin-cannabis smokers at all three time points.The sample comprised 211 (70.3%) heroin-cannabis smokers and 89 (29.7%) heroin injectors. Eighty-four percent were followed up at 3 months and 75% at 9 months. At 9 months, heroin-cannabis smokers had a higher proportion of those who relapsed to heroin use compared with intravenous (IV) users (Heroin users who do not inject drugs but use other routes of administration may have increased risk for relapse to heroin use after inpatient rehabilitation and should therefore have equal access to harm reduction treatment services. Advocating a transition from injecting to smoking heroin in an African context may pose unique challenges. Injecting and chasing heroin are the most common methods of heroin use described in the literature. Injecting heroin is reported to pose the most harmful effects due to risks of overdose, transmission of blood borne viruses, more severe symptoms of dependence, longer heroin-using careers and higher rates of criminality and homelessness . ‘Chasinnyaope, whoonga and thai. Typically, a user rolls a joint of cannabis, pours over a bag of nyaope and smokes it [South Africa, Kenya and Tanzania have reported a significant proportion of heroin users who smoke heroin combined with cannabis –8. Data mokes it . The reamokes it , 10, 11.Different methods of drug use may however influence the severity of dependence and treatment outcomes. Furthermore, different methods of use may impact access to treatment. For example, in Kenya, access to opioid agonist maintenance treatment (OAMT) and other harm reduction services are reserved for injecting heroin users, and heroin-cannabis smokers have limited access . SimilarIn some African regions, much needed harm reduction services are slowly gaining impetus due to national HIV prevention and treatment campaigns for people who inject drugs. Whilst the roll-out of OAMT is much needed, it is also important to consider the larger heroin-using population and compare characteristics and treatment outcomes between heroin-cannabis smokers and heroin injectors. It is therefore worthwhile investigating different methods of heroin use and the biological, psychological and social sequelae thereof. These data may also help inform whether harm reduction campaigns that advocate a transition from injecting to smoking heroin would be advisable in areas where heroin is predominantly smoked with cannabis.Participants were recruited from two state-funded drug and alcohol rehabilitation centres in the Gauteng Province of South Africa. The programmes entailed 1 week of inpatient detoxification followed by 6 to 8 weeks of psychosocial rehabilitation. Upon completion, most participants returned home and were encouraged to see their local social workers for follow-up and attend community-based self-help groups such as Narcotics Anonymous. The study was approved by the University of Witwatersrand Human Research Ethics Committee (M1704100).have been using heroin in the months prior to admission,be older than 18 years of age,be willing to provide locator information for follow-up to occur,be able to provide informed consent.A convenience sample of new admissions whose primary drug of use was heroin was screened for inclusion and exclusion criteria. In order to be enrolled in the study, participants were expected toParticipants were assessed during rehabilitation and then followed up 3 months and 9 months after leaving inpatient rehabilitation. Participants were not compensated for their participation but were given 7 USD transport compensation if they returned to the research site for their follow-up interview. In some cases, the principal investigator (PI) did home and/or hangout-spot follow-up visits. Participants that were seen at home or hangout spots were not compensated. No telephonic interviews were done.All baseline and follow-up interviews were conducted face-to-face by the PI who is a psychiatrist. Recruitment and data collection were conducted between July 2017 and February 2019. The PI was not part of the treating team at the rehabilitation facilities. Participants did not read or answer any of the questionnaires on their own. At baseline, a detailed socio-demographic and past substance use questionnaire created specifically for the study was administered. The Opioid Treatment Index (OTI) , which iThe Mini-International Neuropsychiatric Interview (MINI) version 7.0.2 for DSM-5  was admiHIV status was determined by participants’ self-report from prior testing. Urine was collected for a Multi-Drug Urine Test (MDUT) for as many participants who were able to provide a sample. Urine collection was unsupervised; however, a research assistant was trained to identify any unusual changes in colour, temperature or smell. The MDUT tested for the presence of opioids, cocaine, amphetamines, methamphetamine, cannabis and benzodiazepines. Those who relapsed to heroin use after rehabilitation were classified as continued heroin users (CHU). CHU was determined by two factors: self-reported heroin use and/or positive for opioids on the MDUT. Therefore, in cases where no MDUT was available, self-reported substance alone was used to determine drug use.t test (for continuous variables); for the detection of a medium effect size (w = 0.3 and d = 0.5 respectively) with 80% power at the 5% level of significance, minimum sample sizes of 122 and 128 respectively are required. Sample size calculations were carried out in G*Power [Based on worst-case (for sample size) estimates of 50%, 5% precision and the 95% confidence level, a sample size of 385 would be required . A sampl G*Power .χ2 test. Fisher’s exact test was used for 2 × 2 tables or where the requirements for the χ2 test could not be met. Continuous variables were assessed by the independent samples t test. Where the data did not meet the assumptions of these tests, a non-parametric alternative, the Wilcoxon rank sum test was used. Comparison of heroin-cannabis smokers and IV users was carried out analogously. Comparison of binary outcomes at enrolment, 3 months and 9 months, was performed by a generalised estimating equation (GEE) with the outcome as the dependent variable, observation point as the independent variable and participant as the repeated measure. Data analysis was carried out using SAS version 9.4 for Windows [Comparison of follow-up status (those seen and those lost to follow-up) for categorical variables was carried out by the  Windows . The 5% p = 0.0062). The median age at first heroin use was significantly lower for IV users compared with heroin-cannabis smokers . The median duration of heroin use was 7 years (IQR 4–9 year). Further details of the baseline sample have been presented in previous reports [Over the recruitment period, 317 clients were screened. Eight did not fit the inclusion and exclusion criteria and five refused participation. A total of 304 participants signed consent and were enrolled in the study; however, four were withdrawn during baseline (BL) interviews as they were assessed as actively suicidal. The final sample thus consisted of 300 participants, 256 (85.3%) males. The median age at enrolment was 27 years , and 93.0% of the participants were Black/African South Africans . At 9 month follow-up, there were several significant differences between those seen and those lost to follow-up: those followed up successfully had a higher median duration of heroin use , lower proportion of those who used cannabis without heroin (p = 0.048), lower proportion of those with mental illness (p = 0.047), higher proportion of methaqualone users (p = 0.0098) and higher proportion of those living in formal housing (p < 0.0001).Two hundred fifty-two participants (84.0%) were followed up at 3 months, and 225 (75.0%) were seen at 9 months after leaving inpatient rehabilitation. The chief reason for loss to follow-up at 3 and 9 months was unknown whereabouts of participants as families reported they were uncontactable and living on the streets (41% of participants lost to follow-up at 3 months and 46% at 9 months). Over the study period, 12 participants were not interviewed as they were incarcerated at the time of follow-up interview and four participants passed away. At 3 months, there was no significant association between those seen and those lost to follow-up in regard to demographic variables, substance history, psychopathology and HIV status. However, those followed up successfully had a higher proportion of participants living in formal housing at enrolment, compared with those lost to follow-up (p = 0.073), heroin-cannabis smokers had a higher proportion of CHU compared with IV users at 9 months (p = 0.036). The median Q score for heroin was significantly higher for heroin-cannabis smokers compared with IV users at 3 and 9 months . The proportion of crystalmetamphetamine users (versus abstinence) was higher in IV users at 3 months (p = 0.049) and 9 months (p = 0.028). Of the 210 who were followed up at both 3 and 9 months, 34 (16.2%) were cannabis-only smokers (heroin abstinent) at the 3 -month follow-up. Of these, 50% went back to heroin use at 9 months.At 3 months, none of the participants had received OAMT. At 9 months, five participants received intermittent OAMT prescribed by a private general practitioner. MDUTs were done on 76.6% and 88.4% of participants followed up at 3 and 9 months respectively. At 3-month follow-up, 65.1% had continued heroin use (CHU), and 72.4% had CHU at 9 months. Whilst there was no significant difference in the proportion of CHU between IV users and heroin-cannabis smokers at 3 months (p = 0.06).For this analysis, we only used data from the 210 participants that were seen at all three time points. At the first follow-up, 42 (20.0%) were abstinent from cannabis and heroin. Of those who abstained from cannabis at 3-month follow-up, 29% went back to heroin  at 9 months. There was no significant difference between cannabis-positive and cannabis-negative users at 3 months and heroin use at 9 months , generalised anxiety disorder (26.0%) and post-traumatic stress disorder (17.1%). The prevalence of mental illness remained the same at 3 months and decreased at 9 months  but not at the 3 and 9 month follow-up points. Social functioning scores reflect data on accommodation, relationships and employment. At all time points, there were no significant differences between the median social functioning scores of heroin-cannabis smokers and injectors or in their median general health scores  (Table p = 0.01). Of those injecting heroin, 81% reported sharing needles at baseline, 82% and 89% at 3 and 9 months respectively. There was no significant change in the proportion sharing needles between baseline, 3 months and 9 months. At baseline and 3 months, 36% shared needles with three or more people and 43% reported the same at 9 months (Table There was a significant decrease in the proportion of IV users from 29.7% at baseline to 11.1% at 3 months (p = 0.002).Of the initial sample of 300, 47.0% did not have an HIV test in the preceding 6 months. Of those who knew their HIV status, 18.5% were HIV positive. The prevalence of HIV was higher in IV users than heroin-cannabis smokers  and Israel found that cannabis use in people receiving OAMT did not negatively impact heroin abstinence rates –25. In tIn our study, 50% of those who used cannabis only at first follow-up went back to heroin use 6 months later and 29% of those who abstained from cannabis continued heroin use later on. There was no significant difference in heroin abstention status at 9 months between those who used and did not use cannabis at the first follow-up. The data suggest that in this cohort cannabis use was not protective against heroin abstinence later on. Owing to the method of combination use, the risk for heroin relapse is expectedly higher in South Africa. There are however other challenges with relating international data to a South African cohort; from BL, a smaller proportion described using cannabis on its own (19.6%) and importantly our cohort received an abstinence-based approach and thus did not have the benefit of OAMT.Methods of heroin use have evolved at varying time periods in different countries , 30. TheThe median age at enrolment for IV users was lower and IV users began heroin use at a significantly younger age. This may reflect that IV users begin heroin use earlier however present sooner to rehabilitation presumably due to their concerns about the risks of injecting and sharing needles. Longer length of heroin use and higher frequency of heroin use episodes have been associated with poorer abstinence rates , 35. In Research has suggested that IV use may result in higher peak serum concentrations of heroin but faster metabolism. Smoking heroin on the other hand results in direct alveolar transfer of heroin to cerebral arterial blood which could facilitate greater and more distinct central nervous system toxicity . The impAmongst IV users, approximately 80% or more shared needles. Whilst this is in keeping with previous cross-sectional studies of IV users in South Africa , 39, it This study whilst novel and robust in its results has some limitations. Firstly, we were only able to compare short-term results between heroin-cannabis smokers and injectors. It would be valuable to follow the cohort over a longer period to assess whether short-term trends are maintained. Secondly, the drug use section of the OTI takes into account the last three occasions of substance use in the past month. In this cohort, the majority of participants consumed heroin and cannabis daily at all three time points. Therefore, the Q score for heroin and cannabis is largely reflective of the average use episodes in the 3 days prior to interview. Day to day substance consumption may be affected by variables such as availability of money, availability of the substance and socialisation. Therefore, some may argue that assessing past three occasions limits the overall interpretation of the quantity and frequency of use. Lastly, this study did not specifically assess severity of dependence using a separate tool or scale. It rather looked at drug use, social functioning, injecting behaviour, criminality, general health and psychopathology as key treatment outcomes after inpatient rehabilitation. Whilst data is available regarding the frequency of heroin use, occasions of heroin use do not necessarily signify exposure when comparing different methods of use.Compared to IV users, heroin-cannabis smokers had a higher proportion who had relapsed to heroin use 9 months post-rehabilitation. The findings therefore suggest that heroin-cannabis smokers should have equal access to OAMT and should be included in policy development towards harm reduction in heroin users. A harm reduction approach that supports injecting users’ transition to heroin smoking may increase the number of heroin-cannabis smokers in South Africa. Whilst this may decrease certain harms associated with injecting, it may unfortunately also pose further risks for more severe dependence on both cannabis and heroin.


To evaluate the effectiveness and safety at population scale of electronically delivered prescribing feedback and decision support interventions at reducing antibiotic prescribing for self limiting respiratory tract infections.Open label, two arm, cluster randomised controlled trial.UK general practices in the Clinical Practice Research Datalink, randomised between 11 November 2015 and 9 August 2016, with final follow-up on 9 August 2017.79 general practices (582 675 patient years) randomised (1:1) to antimicrobial stewardship (AMS) intervention or usual care.AMS intervention comprised a brief training webinar, automated monthly feedback reports of antibiotic prescribing, and electronic decision support tools to inform appropriate prescribing over 12 months. Intervention components were delivered electronically, supported by a local practice champion nominated for the trial.Primary outcome was the rate of antibiotic prescriptions for respiratory tract infections from electronic health records. Serious bacterial complications were evaluated for safety. Analysis was by Poisson regression with general practice as a random effect, adjusting for covariates. Prespecified subgroup analyses by age group were reported.The trial included 41 AMS practices (323 155 patient years) and 38 usual care practices (259 520 patient years). Unadjusted and adjusted rate ratios for antibiotic prescribing were 0.89  and 0.88 , respectively, with prescribing rates of 98.7 per 1000 patient years for AMS (31 907 prescriptions) and 107.6 per 1000 patient years for usual care (27 923 prescriptions). Antibiotic prescribing was reduced most in adults aged 15-84 years , with one antibiotic prescription per year avoided for every 62 patients . There was no evidence of effect for children younger than 15 years  or people aged 85 years and older ; there was also no evidence of an increase in serious bacterial complications .Electronically delivered interventions, integrated into practice workflow, result in moderate reductions of antibiotic prescribing for respiratory tract infections in adults, which are likely to be of importance for public health. Antibiotic prescribing to very young or old patients requires further evaluation.ISRCTN95232781. Overuse of antibiotics in medical practice is contributing to the emergence of antimicrobial drug resistance. The US Centers for Disease Control estimate that each year in the United States, at least two million people acquire antibiotic resistant infections and at least 23 000 people die as a direct result.A systematic review, updated to 2018, found that educational activities aimed at clinicians or patients, electronic decision support systems, and audit of antibiotic prescribing with feedback of results might be used to reduce unnecessary antibiotic prescribing.The present research focused on low cost interventions that can be readily integrated into routine practice workflow and scaled up through remote delivery using electronic media to a large sample of unselected practices. The research developed a multicomponent intervention that included a brief training webinar for prescribers, followed by monthly feedback reports of antibiotic prescribing at RTI consultations and decision support tools to inform appropriate prescribing. The primary objective of the present study  was to evaluate whether this multicomponent intervention was effective and safe at reducing prescribing of antibiotics when patients consult with RTIs, when delivered electronically into general practices over 12 months.The study was an open label, two arm, parallel group, cluster randomised trial with general practices as the unit of allocation. The target population for this trial was the general population registered with general practices in the United Kingdom, including England, Scotland, Wales, and Northern Ireland. The trial was conducted by use of the anonymised electronic health records of general practices contributing to the UK Clinical Practice Research Datalink (CPRD). The CPRD is one of the world’s largest databases of primary care electronic health records, and it includes data updated monthly from general practices throughout the UK. CPRD data have been extensively evaluated and employed for epidemiologicalThe protocol was approved by the NHS London-Dulwich research ethics committee (14/LO/1730) and by the CPRD independent scientific advisory committee (ISAC 14_130). Trial oversight was provided by independent trial steering and data monitoring committees. Each participating general practice gave written informed consent for participation. General practices were randomised between 11 November 2015 and 9 August 2016, and final follow-up was on 9 August 2017. The trial was stopped when the last general practices completed 12 months of follow-up. The study protocol has been reported previously,Cluster randomisation was used because intervention was delivered at the general practice level. CPRD staff (JS and KS) were responsible for recruiting practices to the trial and communicating allocations but had no access to the allocation procedure. Allocation to antimicrobial stewardship and usual care trial arms was done at King’s College London  by minimisation using the MINIM program,An intervention development study was conducted and is described in detail elsewhere.Decision support tools were deployed remotely into existing practice software to provide patient information sheets and advice on the positive indications for antibiotic prescription during consultations for RTI (supplementary figure 2). Patient information sheets were provided for common colds and upper respiratory infections, sore throat, otitis media, sinusitis, and cough and bronchitis (supplementary figure 3). Separate sheets for children were provided for otitis media and cough and bronchitis. Recommendations for positive indications for antibiotic prescription followed NICE guidance (supplementary figure 4).British National Formulary section 5.1. We determined whether antibiotics were prescribed on the same date as the RTI consultation. In order to focus on prescribing decisions at initial presentations for RTI, we excluded repeat consultations for RTI during the same episode using a 14 day time window. As sensitivity analyses, we evaluated whether estimates differed for a 10 day window or no time window. Outcomes for both trial arms of antimicrobial stewardship and usual care were evaluated by use of anonymised electronic health records of individual patients from CPRD. Consultations for self limiting RTIs were identified from medical codes for cough and bronchitis, otitis media, rhinosinusitis, sore throat, and common colds. Medical codes were drawn from the Read code classification (supplementary tables 6-7), which was in use in the UK at this time, including symptoms and medical diagnoses. Lower respiratory tract infections including “chest infections,” exacerbations of chronic bronchitis, and pneumonia were not included because they are subject to different treatment recommendations. Antibiotic prescriptions were identified from product codes for antibiotics included in the The primary outcome measure was the rate of antibiotic prescribing for RTI per 1000 patient years over the 12 month intervention period. Secondary outcome measures were the proportion of RTI consultations with antibiotics prescribed, the consultation rate for RTI per 1000 patient years, antibiotic prescribing for subgroups of RTI, and total antibiotic prescribing for all indications. Safety outcomes were identified by the data monitoring committee as new occurrences of a wide range of serious bacterial complications including pneumonia, peritonsillar abscess, mastoiditis, intracranial abscess, empyema, scarlet fever, pyelonephritis, septic arthritis, osteomyelitis, meningitis, toxic shock syndrome and septicaemia, and Lemierre’s syndrome. Interim analyses of safety outcomes were presented to the data monitoring committee in October 2016 and April 2017. The comorbidity status of patients consulting with RTI was classified as present or absent based on “seasonal flu at-risk” status including diagnoses of significant heart, lung, renal, liver, or neuromuscular disease, as well as cystic fibrosis, diabetes, and immunosuppression or immunosuppressive treatment.The primary outcome for the trial was the rate of antibiotic prescriptions for RTI per 1000 patient years. The sample size calculation was based on analysis of outcomes aggregated to cluster level; it was informed by data from our previous trialIndividual level patient data for primary, secondary, and safety outcomes were analysed according to the intention-to-treat principle. The original protocolThe trial dataset comprised full electronic health records data for all patients who consulted with RTI on one or more occasions during the trial baseline and intervention periods, together with denominator data for all patients registered at trial practices. For each registered patient, we evaluated the person time at risk during the 12 month intervention period of the trial. A random effects Poisson model was fitted using the “hglm” package in the R program,Data were visualised by calculating antibiotic prescribing rates for RTI by a single year of age and fitting smoothed curves using third degree polynomials. These empirical data were compared with estimates from a fully adjusted random effects Poisson model incorporating a third order polynomial term for age and the interaction with trial arm, with age 15 years used as reference.Safety outcomes were ascertained from CPRD clinical and referral files. The referral files include coded data for hospital referrals and discharge letters. We analysed safety outcomes adjusting for age group, sex, and comorbidity. A random effect for general practice was included for the most common outcome of pneumonia and for the composite, but this was omitted for the remaining outcomes.Interaction terms were tested and prespecified subgroup analyses were conducted. The statistical analysis plan included prespecified subgroup analyses by age group, sex, comorbidity, region, type of infection, and baseline antibiotic prescribing fourth. Age group was categorised from 0 to 14 years, then in 10 year bands, until 85 years and over. The subgroup effect was assessed statistically on this basis and the effect was summarised more simply in those aged 0-14 years classed as children, those aged 15-84 years, and those aged 85 years and over.Data on use of decision support tools was collected directly into the proprietary software used to deliver the tools. For each general practice, we estimated the proportion (%) of RTI consultations at which decision support tools were viewed, and we evaluated a linear trend for the primary outcome across fourths of decision support tool use adjusting for the same covariates.The trial procedure and proposed intervention were presented to a participation group of patients in primary care, and feedback and views were obtained on all aspects of the intervention including the way in which messages would appear on general practitioners’ screens, and information that would be presented to patients.Of 80 general practices recruited to the trial, one withdrew from CPRD before the start of intervention and the remaining 79 were included in the intention-to-treat analysis . The triThese imprecise estimates resulted from wide variations in antibiotic prescribing between general practices; the data appeared to be overdispersed with several extreme values. The coefficient of variation of general practice specific rates of antibiotic prescribing was 0.51. Adjusting for covariates reduced the standard error of the coefficient, which was largely accounted for by adjustment for practices’ antibiotic prescribing for RTI at baseline. In a sensitivity analysis, an overdispersed Poisson model gave an adjusted rate ratio of 0.86 , which confirmed conclusions. Sensitivity analyses, which compared the base case 14 day time window (for excluding secondary consultations) with either a 10 day time window or no time window, showed that the effect estimate was not sensitive to whether a time window was used or its length (supplementary table 1).We saw insufficient evidence for a difference between trial arms for the consultation rate for self limiting respiratory infections , proportion of consultations with antibiotics prescribed , and antibiotic prescribing for all indications .2=1.228, df=8, P=0.99); the adjusted rate ratio was 0.82 (0.44 to 1.51) for children and 0.99 (0.59 to 1.70) for people aged 85 years and older.2=65.5, df=8, P<0.001). Results of a prespecified subgroup analysis by age are shown in Subgroup analyses by individual patient characteristics are shown in 2=1.264, df=1, P=0.26) or comorbidity . Analysis by subgroup of practice level covariates (region and baseline antibiotic prescribing fourth) showed no consistent pattern of association (supplementary table 4). We saw no evidence of association of intervention with antibiotic prescribing for any subgroup of RTI separately (supplementary table 5).There was no evidence that the effect of intervention might differ by sex  more frequently. We saw no evidence that the intervention was effective at reducing antibiotic prescribing to children or people aged 85 years or older. The trial decision support tools specifically addressed common diagnostic concerns in children, including otitis media and cough and bronchitis, but prescribing to the youngest and oldest age groups could be more difficult to modify because safety concerns might be more salient at these ages.The trial was designed with the antibiotic prescribing rate as the primary outcome because such prescribing can influence subsequent consultation patterns for respiratory illness. Patients are more likely to consult for RTI if they have been prescribed antibiotics recently.The study did not find evidence that the intervention might influence the total use of antibiotics at these practices. Antibiotic prescriptions that are clearly associated with a documented RTI represented a substantial proportion of prescriptions, but nevertheless a minority consistent with another recent study,Analysis of electronic health records data for serious bacterial complications as safety outcomes showed no difference between trial arms. This study was considerably larger than most previous studies, but was nevertheless not designed to provide conclusive evidence concerning the safety of reducing antibiotic prescribing. Even a much larger study might have limited power to evaluate less frequent safety outcomes or vulnerable subgroups with precision.The trial was conducted in the context of national efforts to reduce unnecessary antibiotic prescribing in primary care that might have affected both trial arms with possible underestimation of intervention effects. Trial general practices represented all parts of the UK, but CPRD general practices in Scotland, Wales, and Northern Ireland were more likely to agree to participate in the trial than practices in England. General practices that agreed to take part might have been more motivated to reduce antibiotic prescribing. It is known that participation in research studies might cause individuals to alter their behaviour.The number of practices included was smaller than originally intended and several practices were unable to continue with the trial because they transferred to a different practice information system. In our previous study, allocation was stratified by practice list size and region,We saw wide variation in antibiotic prescribing for RTI between different general practices in both trial arms, which is consistent with data that we and others have reported previously.We found from analysis of data captured by the intervention delivery software that use of decision support tools was associated with effect size, which adds evidence of a causal association. Decision support tools were used at a minority of consultations but it is possible that learning from the tools might be applied in consultations in which they were not viewed. Decision support tools were necessarily triggered when prescribers entered medical codes into the practice system. Some general practitioners might record data after the end of the consultation, or might rely on free text entries, reducing the immediacy of this component of the intervention, this post-consultation exposure might contribute to the effect of the intervention over time. All prescribers also received antibiotic prescribing reports but we were not able to determine whether all prescribers read these each month. There is likely to have been variation among prescribers within practices, but we did not have consistent data for the prescriber level and no information concerning prescriber characteristics. We analysed data for antibiotic prescriptions issued by trial general practices. Patients might have received antibiotic prescriptions at consultations with walk-in centres and out-of-hours or emergency services, and these alternative patterns of antibiotic use might differ between trial arms. Additional data sources will be needed to evaluate this possibility. Altered diagnostic code selection might have occurred in order to justify antibiotic prescriptions,Previous studies of audit and feedback interventions across a range of indications show that these often have only small effects,Gjelstad and colleaguesHallsworth and colleaguesIn this cluster randomised trial, an antimicrobial stewardship intervention that was delivered remotely into practices and integrated into routine care delivery was associated with a 12% reduction in antibiotic prescriptions for RTI overall, with no evidence of increased serious bacterial complications. Although the absolute impact is moderate, it is likely to be important for public health in the drive to reduce antibiotic prescribing and the risks of antimicrobial resistance. We caution that the intervention might not be effective at reducing antibiotic use for children or people aged 85 or older. Interventions using data from electronic health records might be used to promote antimicrobial stewardship in primary care and might be readily scaled up. The needs of very young or old patients need specific consideration. Our trial results also suggest the need for further research into the safety of reduced prescribing.Widespread unnecessary prescribing of antibiotics is contributing to the emergence of antimicrobial drug resistanceA systematic review of antimicrobial stewardship interventions suggested that single interventions including patient and public education, point-of-care testing, audit and feedback, and electronic decision support might be associated with reduced antibiotic useThe relevance of previous trials to clinical practice is also unclear because of limited reporting of adverse clinical outcomes and lack of detail concerning possible effect modifiers, including patient characteristicsThis large UK study used data from electronic health records (EHRs) to evaluate effectiveness and safety of an antimicrobial stewardship intervention Overall, the intervention was associated with moderately reduced antibiotic prescribing, with no evidence of increased serious bacterial complications; the intervention reduced prescribing for adults but not for children or people aged 85 years or olderMultifaceted interventions, drawing on EHR data, could be scaled up to promote effective antimicrobial stewardship in primary care; the needs of very young or old patients require further consideration


In this paper, we present the synthesis, characterization, catalytic and computational studies of Composites of Platinum-Iridium Alloy Nanoparticles and Graphene Oxide (PtIr@GO) for dimethylamine borane (DMAB) dehydrogenation. The prepared PtIr@GO nanocatalysts were synthesized using an ethanol super-hydride method, and the characterization procedures for PtIr@GO alloy nanoparticles were carried out by various advanced spectroscopic methods like X-ray Diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Transmission Electron Microscopy(TEM) and high-resolution transmission electron microscopy (HRTEM). Additionally, catalytic activity, reusability, substrate concentration, and catalyst concentration experiments were performed for DMAB dehydrogenation catalyzed by PtIr@GO alloy nanomaterials. According to the results obtained in this study, PtIr@GO NPs catalyst was found to be active and reusable for the DMAB even at ambient conditions. Besides, DFT-B3LYP calculations have been utilized on PtIr@GO cluster to reveal the prepared catalyst activity. The calculated findings based on DFT was found to be a good agreement with experimental results. Hydrogen present in the structure of various sources, one of them ammonia borane, ammonia borane derivatives are preferred because of their high stability, hydrogen content, easiness of using and non-flammable properties3. Dimethylamine borane (DMAB) is an ammonia borane derivative and it has taken an extensive interest in the usage of hydrogen storage studies4. However, the ammonia borane derivatives should be used in combination with suitable catalysts. Hitherto, several studies6 have been conducted about the catalytic activity of ammonia borane and hydrogen release from their derivatives to find a proper solution for this issue. Hydrogen release in the result of the reaction of dimethylamine borane (CH3)2NHBH3, DMAB) reaction in the existence of a suitable catalyst has been achieved, and 3.5% by weight of hydrogen was obtained15. Although homogeneous catalysts16 showed the best activity, heterogeneous catalysts have been used widely in catalytic reactions, because they have some superiors such as stability, activity, recycle and having high catalytic lifetime21. The mentioned catalysts were prepared with their process and characterized various methods like using Raman, XPS, XRD, HRTEM, and TEM. However, so far, a catalyst having a sufficient catalytic activity and reusability has not been produced. Pt-based nanoparticles are important nanoparticles that have been used in the conversion of many inorganic and organic materials24. So far, we have conducted many studies on catalysts and about their catalytic studies, and it has been seen that platinum and graphene oxide-based catalysts are very important and active in these studies. Therefore, in this study, it is aimed to create a new nanocatalyst with graphene oxide support to combine the effects of iridium with platinum and to increase the efficiency of platinum. For this purpose, for the first time, the synthesis, characterization and kinetic activity of platinum and iridium supported graphene oxide (PtIr@GO) alloy nanoparticles were investigated for DMAB catalytic dehydrogenation. The catalytic reaction of DMAB is shown as shown below  and it has shown that the structure of Pt and Ir nanoparticles were highly crystalline and well decorated on graphene oxide. After that, PtIr@GO alloy nanoparticles was carried out for the dehydrocoupling of DMAB at room conditions. Thanks to this study, it was shown that PtIr@GO alloy nanoparticles could be used as an effective catalyst for catalytic dehydrogenation reaction of DMAB. Besides, DFT-B3LYP calculations have been utilized on PtIr@GO nanoparticles to reveal the catalytic activity of PtIr@GO in DMAB reaction.The preparation of PtIr@GO alloy nanoparticles was performed by reducing PtCl4 and IrCl3 compounds (0.25 mmol) and graphene oxide (25 mg/mL) were prepared and the reduction of Pt (IV) and Ir (III) to Pt (0) and Ir (0), respectively were performed using super hydride and ethanol according to the chemical reduction method25. The changing color of the resulting mixture to brown color indicated the formation of Pt (0) and Ir (0) on the surface of GO support and then the obtained solid sample was dried under an inert atmosphere at an oven.Composites of Platinum-Iridium Alloy Nanoparticles and Graphene Oxide have been synthesized by super hydride-ethanol reduction method. For this purpose, a mixture containing PtClThe catalytic reactions of the dehydrogenation of DMAB on PtIr@GO alloy nanoparticles were carried out in a cylindrical glass vessel connecting a scaled cylinder glass tube containing water as shown in Fig. 26 in this study. In theoretical works about catalytic studies of the prepared catalyst, the Gaussian 0927 software operate with B3LYP-Hybrid formalism process was used29. It has been known that one of the DFT methods for the high-quality procedure of theoretical calculations for organic chemistry is the B3LYP method. The LanL2DZ basis set was used in calculations for Pt and Ir metals. In theoretical works, the fasis set about the calculation of atoms like O, H, and C present in the cluster is 6–31 G.The theoretical calculations were performed using Density Functional Theory (DFT)30. One Pt and one Ir atom have been used to obtain PtIr@GO cluster that is to represent the PtIr@GO catalyst. These metal atoms have been located on p1 and p2 points on the GO cluster. A similar strategy in order to obtain Pt-decorated GO cluster has been utilized during DFT calculations in a study conducted about platinum decorated on GO for methane/methanol30. Two Pt atoms have been located on some points that are similar to the points used in that study30. In present work, atoms were entirely kept free.The graphene oxide (GO) cluster used for calculations has 40 C atoms and 10 Oxygen atoms meaning there are 10 epoxy groups. The structure of GO used is represented in Fig. 31. The calculated theoretical energy values were found as given below:Balance geometry calculations have been used to optimize geometries in adsorption energy studies. Additionally, zero-point energy (ZPE) and energy difference findings were also investigated. These values were computed by using the freq keyword in Single Point Energy (SPE) calculation. In addition, in Gaussian software vibrational frequency, thermal energy, enthalpy, and free energy data have been obtained by SPE calculations at 298 K and 1 atm pressureLUMO is defined as the lowest unoccupied molecular orbital energy and ϵHOMO is defined as the highest occupied molecular orbital energy. The equations have been based on the method of Koopman35 and given as follows.In these equations; H, E, G, T and S are enthalpy, thermal energy, free energy, temperature (K) and entropy in vibrational frequency data, respectively. HOMO geometric representation and LUMO geometric representation, and HOMO/LUMO energies s were found by using the population analysis. In order to have some info about the activity of cluster the values of chemical hardness and potential, the electronegativity and the electrophilicity were achieved. Here ϵ36. Moreover, atoms charges are known as Mulliken was found using Mulliken population calculations37.The theoretical methodology utilized here is given in Supporting Information. Multiwfn software is used to obtain the map’s distribution of electron localization functions (ELF) and the electron density (ED)Composites of Platinum-Iridium Alloy Nanoparticles and Graphene Oxide were easily prepared by the reducing of platinum (IV) and iridium (III) chlorine salts in a THF solution with the super hydride ethanol reduction method at ambient conditions. Upon reduction of Pt (IV) and Ir (III) to Pt (0) and Ir (0), respectively, the precipitation and agglomeration were formed without graphene oxide. Furthermore, the stability of the synthesized catalyst was tested and found to be stable. This stable structure is thought to be related to GO which is used as a support material in the catalyst. TEM, HRTEM, Raman, XRD, and XPS analysis were used for the morphological and structural distributions of PtIr@GO catalyst.39. As shown in Fig. The result of the XRD analysis is shown in Fig. 40.Further, the mean PtIr@GO particle size was calculated using the full width at half maximum of peaks in the P-XRD analyses Fig.  with the42 Fig. −1 and 1604 cm−1 ranges, and these peaks were assigned to the D band and the G band. The change in the D band is explained by the presence of PtIr nanoparticles in the graphene oxide material, which also indicates the formation of the composites of Platinum, iridium and graphene oxide.Raman spectrochemical analysis was carried out for further details about the chemical compositions and morphological changes for Pt@GO and PtIr@GO nanoparticles. Because Raman spectroscopy is a very suitable technique for this purposeIn addition, the platinum-iridium metals distributions on GO support materials and the average of PtIr@GO nanoparticles were investigated by TEM and HRTEM patterns. In order to count the average particle size of PtIr@GO alloy nanoparticles, about 100 particles present in TEM pattern Fig.  were cou5/2, as shown in Fig. 44. Some oxidized Pt patterns of Pt (II) and Pt (IV) were formed and these oxidized patterns may have probably been because of oxidized or unreduced nanoparticle samples. In Fig. Further, XPS analyses were performed to illuminate the electronic and oxidation status of palladium and iridium metals on GO supporting materials. 4f spectrum fields of Pt and Ir metals were examined by applying Gaussian Lorentzian technique. The densities of the species in the nanomaterials were calculated by counting by flattening the background in the graphs obtained from XPS analysis. The binding energy of C1s Fig.  was perf−1. When the same catalytic reaction was repeated with Pt (IV) and Ir (III) chlorine salts as pre-catalyst, it was observed seven minutes induction time and a 10–15% conversion of DMAB  were performed under room conditions, and their results are seen in Fig. The experimental findings performed using different DMAB amount are represented in Fig. −1), entropy (ΔS: −178.18 ± 2 J mol−1 K−1) and enthalpy (ΔH: 16.53 ± 2 kJ mol−1) were obtained using Arrhenius and Eyring equations and were presented in Fig. 49.Figure −1 K−1) of DMAB reaction catalyzed PtIr@GO alloy nanoparticles indicates the dissociative mechanism.Besides, the low and negative value of entropy change  reaching a stable state of GO (ii) forming an optimum size particle of PtIr@GO and (ii) synergy of Pt and Ir in the catalyst structure. Besides, explain the high activity of PtIr@GO catalyst, some of the theoretical calculations were performed. For this purpose, firstly EG calculation was used to optimize the GO cluster. The optimized structure of GO cluster is represented in Fig. 2 site is most favorable. Optimized geometry for adsorbed DMAB molecule on PtIr@GO cluster is depicted in Fig. With the determined optimized geometries of the obtained nanoparticle and moleculer structure of DMAB, adsorption of DMAB was examined on PtIr@GO cluster by EG calculations. Two possibilities (on Pt atom and Ir atom) for the adsorption of DMAB on PtIr@GO cluster have been utilized for EG calculations. Total energy values (including ZPE correction) for adsorption of DMAB on PtIr@GO cluster have been calculated to be −2670.547735 and −2670.498503 a.u. for these possibilities respectively, which designates that adsorption of DMAB on Ir atom on p51. In here, the values were computed by using Eqs 54.Adsorption energy, enthalpy, and Gibbs free energy were calculated by using Eq. 54. These data indicate that PtIr@GO cluster has a large chemical potential value for interaction with DMAB molecule. The activity of PtIr@GO cluster according to electronegativity, chemical hardness electrophilicity, chemical potential and data have been determined.Before DMAB adsorption, chemical potential values for α and β molecular orbitals were calculated to be 117.7 and 118.7 respectively by using Eq. 56.It was found that the computed chemical potential value of the nanocluster was related to the energy of the adsorption. Therefore, the chemical potential for Nano Material was found to be low and the adsorption energy obtained for DMAB was found to be a low valueAfter DMAB adsorption on PtIr@GO cluster, electrophilicity, chemical potential, chemical hardness, electronegativity data have decreased while HLG value have increased. The relative adsorption energy value for DMAB adsorption was −33.4 kcal/mol on PtIr@GO cluster meaning DMAB was strongly adsorbed on it. Furthermore, Gibbs free energy (ΔG) for DMAB adsorption on the cluster was calculated to be −21.6 kcal/mol, which designates adsorption of DMAB molecule occurs simultaneously on the PtIr@GO cluster.The HOMO-LUMO gap was extensively utilized as a pointer of kinetic stability, and it has been usually known that if the gap is small, the kinetic stability is low, and the chemical reactivity is high because it designates energetically favorable for the LUMO to gain electrons or for the HOMO to lose electrons. Based on the Table 60 has been shown in part c and d of Fig. 60. The ELF function helps to understand the empirical concept of the localization of electron, in particular the location of the paired electron. According to the ELF graph, the atoms where they showed larger values of the ELF in PtIr@GO cluster are Pt and Ir atoms. Besides, the negative and positive regions electrostatic potential (ESP) distribution  are localized on Pt and Ir atoms (mostly Ir atoms). This ESP distrubition is reliable with the charge distribution achieved by the analysis of Mulliken population. The charges values for Pt and Ir atoms are +0.072 and +0.323, respectively. It should also be noted that some positive (blue) regions of PtIr@GO cluster are positioned round the ending hydrogen atoms surrounding the PtIr@GO cluster. Nonetheless, it is inappropriate to consider these blue regions because these hydrogen atoms have been used to saturate the carbon atoms.In addition, parts a and b of Fig. 2]/dt = kobs [PtIr@GO]1.0721 [DMAB]0.6621. The activation parameters such as activation energy (Ea: 19.06 ± 2 kJ mol−1), entropy (ΔS: −178.18 ± 2 J mol−1 K−1) and enthalpy (ΔH: 16.53 ± 2 kJ mol−1) were obtained using Arrhenius and Eyring equations. Initial TOF value of PtIr@GO was calculated to be 225.64 h−1 for dehydrogenation of DMAB at 298 K, and this value is very high compared to the previous studies in literature as shown in Table Herein, the preparation, characterization of Composites of Platinum-Iridium Alloy Nanoparticles and Graphene Oxide, their catalytic activities and activation parameters were investigated for dehydrogenation of DMAB. The complete conversion of DMAB was obtained at ambient conditions. Some advanced process including TEM, HRTEM, XRD, Raman, and XPS, etc. were used to characterize PtIr@GO nanoparticles. The prepared platinum-iridium nanoparticles were determined to be highly active, reusable and durable for the catalytic dehydrogenation of DMAB. The reaction rate of catalytic reaction of DMAB include PtIr@GO nanoparticles was found to be −d [DMAB]/dt = +d[HSupplementary Information


The objective of this study is to describe the changes in prescribing practices of antibiotics to treat acute pyelonephritis (APN) in Korea.The claim data base of the Health Insurance Review and Assessment Service in Korea was used to select patients with ICD-10 codes N10  or N12  as the primary discharge diagnosis during 2010–2014. Consumption of each class of antibiotics was converted to Defined Daily Dose (DDD)/event.P = 0.002), but remained stable for outpatients (P = 0.066). The use of parenteral antibiotics increased for inpatients (P < 0.001), but decreased for outpatients (P = 0.017). As for the the antibiotic classes, 3rd generation cephalosporins (3rd CEPs) was the most commonly prescribed (41.4%) for inpatients, followed by fluoroquinolones (FQs) (28.5%); for outpatient, FQs (54.8%) was the most commonly prescribed, followed by 3rd CEPs (13.1%). The use of 3rd CEPs (P < 0.001), beta-lactam/beta-lactamase inhibitors (P = 0.007), and carbapenems (P < 0.001) increased substantially for the treatment of hospitalized APN patients. In particular, carbapenems use increased 3.1-fold over the 5 years.Throughout the five-year period, the average antibiotic consumption were 11.3 DDD per inpatient event and 6.0 DDD per outpatient event. The annual average antibiotic consumption increased for inpatients (Prescription of broad-spectrum antibiotics increased much for the treatment of APN in Korea during 2010–2014. Enterobacteriaceae are common uropathogen, and Escherichia coli is the most common among them. Uropathogens from APN have become resistant to several important antibiotics such as trimethoprim/sulfamethoxazole (SXT), fluoroquinolones (FQs) and the 3rd generation cephalosporins (3rd CEPs) and antibiotic resistance of uropathogens resulted in unfavorable clinical responses in community-acquired APN [rd CEPs among E. coli for community-acquired APN were 27.8, 21.3 and 9.3%, respectively, during 2010–2012 [Acute pyelonephritis (APN) is one of the most common community-acquired bacterial infections, which usually require antibiotic treatment . The annired APN . In Kore010–2012 . AntibioThe aim of this study is to describe the changes in prescribing practices of antibiotics used to treat APN during 2010–2014, using the National Health Insurance claim data in Korea, which may give a clue to the overall changes in prescribing practices of antibiotics used to treat common bacterial infections.International Classification of Diseases, Tenth Revision (ICD-10). Usually, there is a 1–2-month lag in billing for health insurance claims. We obtained the claim data for January 2010 to July 2015.The National Health Insurance System of Korea covers almost the entire population, including low-income families receiving medical aid: 98% of the population was covered in 2014 . We obtaWe included patients whose primary discharge diagnosis was APN from 2010 to 2014: ICD-10 codes N10  or N12 . Two or more claims during a 14-day period were regarded as a single event. The claims for the Veteran Health Insurance were excluded because beneficiaries of the Veteran Health Insurance could claim multiple times with a single event. The events with zero admission/visit day or zero medical cost and the events without antibiotic prescription were also excluded, as well as patients under 15 years of age  classification system, which does not include antifungal agents nor anti-tuberculosis agents. Systemic agents with per oral or parenteral administration route were included while topical agents were excluded. The consumption of each class of antibiotics was converted to Defined Daily Dose (DDD), following ATC classification system of the World Health Organization (WHO) . As for P < 0.05. All analyses were performed using SAS enterprise guide version 6.1 .Linear regression models with monthly measured variables were used to assess the trend of antibiotic consumption over time or age. Statistical significance was defined as A total of 845,656 APN events were identified during 2010–2014 in Korea . Most cases  met N10 code  in ICD-10. One out of 4.1 patients were hospitalized .P = 0.002). On the other hand, the average amount of antibiotic consumption per outpatient event was 6.0 DDD, which remained stable throughout the study period . Males received more antibiotics than females in both inpatient  and outpatient events . As for the antibiotic use by age, more antibiotics were prescribed for older patients  , but not in outpatient events . As for hospital type, the average amount of antibiotics usage was the highest among patients admitted to tertiary hospitals in both inpatient and outpatient events , followed by secondary hospitals .P < 0.001), but it mostly decreased for outpatients . As for per oral antibiotics, no significant change was observed in both inpatients (P = 0.075) and outpatients (P = 0.453).Figure rd CEPs  was the most commonly prescribed, followed by FQs  and beta-lactam/beta-lactamase inhibitors (BL/BLIs) . For outpatients, FQs  was the most commonly prescribed antibiotics, followed by 3rd CEPs  and 2nd generation cephalosporins (2nd CEPs) .Figure rd CEPs (P < 0.001), BL/BLIs (P = 0.007), and carbapenems (P < 0.001) increased every year over the study period; particularly, carbapenems use increased 3.1-fold, and 3rd CEPs use increased by about 25%. In contrast, the use of FQs (P = 0.010), 1st generation cephalosporins (1st CEPs) (P < 0.001), aminoglycosides (AGs) (P = 0.004), and penicillins (P = 0.014) declined every year. There was no noticeable change in antibiotic usage among the remaining classes including 2nd CEPs (P = 0.067), 4th generation cephalosporins (4th CEPs) (P = 0.162), and SXT (P = 0.575).Table rd CEPs (P = 0.049) and carbapenems (P = 0.001) increased gradually (Table st CEPs (P = 0.002), AGs (P = 0.002), and penicillins (P = 0.001). There was no noticeable change in antibiotics usage among the other antibiotics: 2nd CEPs, P = 0.124; BL/BLIs, P = 0.294; FQs, P = 0.555; SXT, P = 0.538.For outpatients, the use of 3 P = 0.00 increaseEnterobacteriaceae. Because the causative organisms of APN are easy to recognize, physicians can readily respond to antimicrobial resistance when they prescribe antibiotics in treating APN. Given that the local guideline for empirical therapy of urinary tract infections (UTI) did not change during the study period, APN is an appropriate disease to examine changes in antibiotic prescribing patterns under the presence of antibiotic resistance.APN is one of the most common infectious diseases caused by rd CEPs increased among APN patients from 1997 to 2001 [In the literature, two studies examined changing antibiotic prescription patterns in APN or UTI , 9. In t to 2001 . Howeverrd CEPs, BL/BLIs, and carbapenems were more prescribed in treating APN during the 5-year period than the traditional antibiotics. This probably happened for the following reasons. Firstly, the physicians were concerned about increasing multidrug-resistant pathogens in UTI. Secondly, resistance to traditional antibiotics in treating APN increased enough. Thirdly, broad-spectrum antibiotics occur more easily to the physicians’ mind.In Korea, broad-spectrum antibiotics such as 3E. coli isolated from blood in large Korean hospitals was 23.9% in 2006–2007 and then increased to 30.8% in 2011 [E. coli to FQs had increased from 21.3% in 2010–2011 to 33.5% in 2017–2018 among community-acquired APN patients [E. coli isolated from female uncomplicated cystitis, the study also demonstrated an increase in FQs resistance [FQs have been widely accepted as a first-line empirical antibiotic for APN in many countries , 11. How in 2011 . Similarpatients . In discrd CEPs  gradually increased. Carbapenems are generally used in hospital-acquired infections caused by multi-drug resistant organisms, however, our data implicates that those broad-spectrum antibiotics are more and more commonly used in mostly community-onset relatively simple infection.We found that carbapenems use increased by 3.1-fold among inpatients (from 0.28 to 0.87 DDD/event) and by 2.1-fold among outpatients (from 0.02 to 0.04 DDD/event), respectively. Also, the proportion of carbapenems use relative to FQs  and that to 3Considering the high prevalence of APN and ecological impact of the extensive use of carbapenems, this is a worrisome finding. Nationwide education and prescription control of broad-spectrum antibiotics for the treatment of common but not serious infections such as community-acquired APN should be reinforced. Other antibiotics which would replace carbapenems for the treatment of APN caused by extended-spectrum beta-lactamase (ESBL) producing organisms such as piperacillin/tazobactam or gentamicin should be studied more and recommended for the treatment of less severe APN patients , 19.rd CEPs and carbapenems increased in Korea since the last decade [Broad-spectrum antibiotic consumption is a common problem in many countries. Based on the data from the European Surveillance of Antibiotic Consumption (ESAC) projects, broad-spectrum penicillins and BL/BLIs were used more frequently than traditional penicillins throughout the EU countries . Carbapet decade . To breat decade . In Frant decade , 24. Fort decade . In addiThe main strength of the present study is documenting the increasing trend of broad-spectrum antibiotics use in treatment of APN which is a relatively simple community-acquired infection with identified pathogens in most cases. In addition, the present study is based on high-quality data source: the National Health Insurance data, which is the most representative health data in Korea. Using a large number of samples, our results show the overall changes in prescribing practices of antibiotics in a common bacterial infection clearly. Even though the reliability of diagnosis may be somewhat questionable as in other studies using administrative data, still there is no doubt that the data quality is high. APN has homogeneous pathology and simple diagnostic criteria to ease analyzing a large data set based on the entire population . We alsoDespite the above strength of this study in terms of data quality, there are also some limitations in this study. Firstly, administrative data do not contain laboratory-level microbiological data, and with the administrative data alone, we could not correlate the level of antimicrobial resistant pathogens with the increasing use of broad-spectrum antibiotic consumption. Also, due to lack of microbiological data, we could not differentiate complicated versus uncomplicated APN cases. Secondly, only the main discharge diagnosis of APN was included. Some cases might have been coded as sub-discharge diagnosis under other ICD-codes such as Gram-negative sepsis and adult respiratory distress syndrome. Thirdly, detailed information on the total duration and amount of each antibiotic use was not available, which made it impossible to analyze combined antibiotic therapies and calculate precise treatment duration for each event that are essential to judge the appropriateness of antibiotic therapies. Fourthly, using Korean data alone is certainly insufficient to shed light on the global antibiotic resistance trend in APN. Despite this limitation, learning about Korean experiences on antibiotic usage might be informative for other countries.rd CEPs, BL/BLIs and carbapenems were prescribed than traditional antibiotics for the treatment of APN in Korea.During the 5 years from 2010 to 2014, substantially more broad-spectrum antibiotics such as 3