Concrete with crushed concrete aggregates (CCA) shows lesser compressive strength than reference concrete with natural aggregates. The goal of this study is to improve the strength of structural concrete with 53% and 100% CCA replacements without increasing the cement content. Thus, improvements in CCA quality are induced by combining mechanical and pre-soaking pre-processing techniques. Mechanical pre-processing by rotating drum is separately pursued on fine and coarse CCA for 10 and 15 min respectively. Results show, adhered mortar content and CCA water absorption reduces as pre-processing duration increases. Pre-processing influences CCA particle grading, flakiness index, shape index, void-content, unit-weight and density, jointly seen as packing density, which increases with pre-processing duration. Water amount to pre-soak CCA before concrete mixing is stable despite grading modifications, due to reduced water absorption resulting from mechanical pre-processing. Compressive strength and workability for pre-processed CCA50 and CCA100 concrete are comparable to reference concrete and show similar trends of improvement with packing density. Packing density markedly shows the quality improvements induced by pre-processing on CCA, maybe considered as one of the quality assessment indexes for CCA. Packing density should be investigated for other recipes to see the stability of the trend with workability and compressive strength. Crushed concrete aggregates (CCA) originating from structural concrete completes a closed-loop recycling when reused again in structural concrete. Using CCA originating from structural applications for low-utility applications, such as road backfilling, degrades the material value of CCA. By quality improvements, CCA is improved to suit high-utility applications like structural concrete, thus retaining material value. The efforts for the CCA quality improvements are necessary to channel larger amounts of CCA for structural concrete production, which as of 2018 is only 6% of the total 2.38 million tons of mineral waste from the construction sector in Sweden [Several studies show that by improving CCA quality the mechanical properties of the CCA concrete can match up to the properties of concrete with gravel or crushed rock—which is usually the parent concrete for the CCA. The quality improvements in coarse CCA fractions by mechanical pre-processing are shown to produce concrete with similar compressive strength as concrete containing aggregates of crushed stone or gravel .Quality of CCA is affected by the surface-adhered mortar giving CCA a higher porosity than natural gravel and crushed rock . A high The mechanical preprocessing techniques cause abrasion of CCA by milling either in a stationary drum containing a paddle on a rotating axis or in a rotating drum. Equipment such as eccentric rotor mill  has a roThe mechanical preprocessing of concrete rubble results in two major effects: firstly, abrasion of adhered mortar and secondly the comminution of low-density CCA or the abrasion of aggregate material from high density CCA. Screw abrading crusher and eccentric mill are seen to cause comminution of about 70% of the low-density CCA, reducing it to fine fractions . With auMechanical pre-processing in literature are either carried out on coarse ,10 or fiThe mechanical pre-processing of CCA is followed by washing on sieve to remove the abraded mortar particles to densify the CCA . Mechani3 [3, mechanical pre-processing after crushing results in an improved particle grading towards reference aggregate grading [Mechanical pre-processing by primary crushing causes the particle grading of fine CCA to be distant from natural aggregates ,17. Mech grading  as not j grading , the cloMechanical pre-processing additionally influences the CCA shape as seen in studies that use multiple crushing stages to pre-process the CCA to acquire a rounder shape similar to reference aggregates ,20. The Mechanical pre-processing influences properties—such as density, flakiness index, shape index, and particle grading—prominent in assessing aggregate quality for structural concrete according to standards SS-EN 12620 . These pImprovements in flakiness index and particle grading induced by crushing methods are shown to increase the concrete compressive strength and workability ,22, alsoBesides improving CCA density by mechanical pre-processing, there exist other pre-processing methods in literature that address the water absorption need of CCA, pre-processing by pre-soaking CCA with water ,30. A coThe novelty of this study is the mechanical pre-processing of both fine and coarse CCA to induce adhered mortar removal in comparison to previous literature where pre-processing is carried out in either coarse or fine fractions.A drum fitted with ribs with a rotating speed of 50 rpm is used to mechanically pre-process fine and coarse CCA separately in laboratory conditions. The mechanical pre-processing is evaluated for two durations of 10 and 15 min, considered optimum by literature for the CCA investigated in the respective studies ,11. MoreThe pre-processed aggregates are washed on sieves to remove the abraded adhered mortar or aggregate material. The pre-processing efficiency is determined firstly by the amount of adhered mortar loss along with the material damage occurring on CCA. This can be seen as a new contribution to literature, which solely addresses the adhered mortar loss in CCA by pre-processing. The improvements in CCA properties—such as density, water absorption, flakiness index, shape index, unit weight, void content, and packing density—are also investigated on pre-processed CCA.Concrete with mechanically pre-processed CCA is investigated for 100% (CCA100) and 53% (CCA50) replacements in the reference concrete recipe. The CCA replacement percentages aim to address practical issues such as the availability of waste and environmental issues such as exploitation of natural resources. CCA100 fits for a continuous supply of concrete waste, substitutes coarse and fine natural aggregates, thus preventing further waste. The replacement of fine aggregate fraction with CCA, as in CCA50, substitutes natural sand, which is critical for ecological preservation and a concern for Swedish concrete producers, who have already transitioned towards substituting coarse natural aggregates with crushed stone. From a logistics perspective, CCA50 alternative fits scarce concrete waste supply to make possible replacements on a continuous basis.The mechanical preprocessing of CCA is combined with pre-processing of CCA by presoaking based on the water absorption of the CCA. The mechanical pre-processing improves the density of the CCA by removal of adhered mortar resulting in a lower water absorption, which consequently reduces the amount of pre-soaking water. The CCA properties jointly influence the aggregate packing density, which in turn influences the compressive strength and workability of the concrete. Packing density concludes the collaborative effect of several aggregate properties.The experimental program, see All fine aggregates corresponding to 53% of total aggregate content (CCA50)100% of coarse and fine aggregates (CCA100)The CCA investigated in this study originates from the prefabricated rejects of an industrially active concrete recipe of grade C40/50, also the reference concrete recipe in this study. In the reference concrete recipe, the CCA replaces:The reference aggregates are crushed stone of size 8/11.2 mm and naturally graded aggregate 0/8 mm. The CCA fractions are 8/11.2, 0.5/4, and 0/4 mm; fine CCA fractions are differently sized from reference aggregates as after crushing the particle grading has been modified to fit reference concrete grading . The 8/1The mechanical pre-processing is based on autogenous cleaning method carried out in a metal drum rotating at 50 rpm, tilted horizontally at an angle of 18° and is lined with vertical ribs to facilitate material lift and cause abrasion by free fall. The coarse and fine aggregates are individually pre-processed and the aggregate quantity in a single batch corresponds to a third of the drum volume, the drum having a height of 30 cm and diameter 27 cm. The aggregate quantity is weighed before pre-processing to determine the loss by pre-processing.Two mechanical pre-processing alternatives with durations of 10 and 15 min denoted as MP10 and MP15 respectively are investigated. In addition, un-preprocessed aggregates, denoted by MP0, are also investigated. After pre-processing the aggregates are washed on sieves to remove the displaced material or adhered mortar. The sieve mesh size used for washing depends on aggregate fraction size, shown in initial) is soaked in water for a duration of 2 h and subsequently heated at a temperature of 500 °C for 2 h followed by immediate immersion in 20 °C water. The aggregates are finally oven-dried and their weight is measured as mfinal. The adhered mortar loss is calculated according to Equation (1).The loss of adhered mortar caused by mechanical pre-processing is assessed from the change in adhered mortar content before and after pre-processing. The adhered mortar content on an aggregate fraction is experimentally determined by a thermal shock resulting in the displacement of adhered mortar from the aggregate surface ,31. The The losses from the mechanical pre-processing alternatives MP10 and MP15 are analyzed for reference and CCA concrete aggregates. After mechanical pre-processing, the water absorption of the combined CCA fraction is tested by the modified pycnometer method  to deterThe CCA and reference aggregates are characterized by properties shown in The flakiness index of fine aggregates is investigated down to 1 mm by a Swedish method developed to characterize crushed rock aggregates .The packing density is derived for all concrete mixes—reference concrete, CCA50 and CCA100 in this study.The cement used in this study is CEM II/A-LL 42.5 R, and the superplasticizer is polycarboxylate-based with a dry content of 24 ± 1 weight %. The reference concrete has a water–cement ratio of 0.5 and is constant for CCA100 and CCA50 concrete mixes.Before mixing the CCA are pre-processed by momentarily pre-soaking with water based on the 15 min water absorption value of the combined CCA fraction determined by the modified pycnometer method . Since tFollowing the mixing process, the workability of the fresh concrete is determined by measuring the slump and flow diameter, once per batch, according to SS-EN 12350-5. Three cylinder specimens of size 100 mm × 200 mm are cast, demolded after 24 h and cured for 28 days submerged in a curing tank with water at 20 ± 2 °C according to SS-EN 12390-2. Compressive strength is tested according to SS EN 12390-3 at 28 days.Assessment of adhered mortar loss is a way to measure the effectiveness of the pre-processing alternatives of 10 and 15 min. Mechanical pre-processing is pursued separately for each CCA and reference aggregate fraction and is followed up by related operations washing and sieving. CCA may undergo both loss of material and adhered mortar, whereas reference aggregates undergo a loss of material. Therefore, the actual amount of adhered mortar removed from CCA by mechanical pre-processing is the material loss in reference aggregates deducted from the CCA loss as shown in Equation (2).Thermal shock before pre-processing on each fraction to assess the potential loss of material and adhered mortar.Losses by mechanical pre-processing to assess the actual material and/or adhered mortar lossThermal shock after pre-processing to determine the remaining material and adhered mortar left on the aggregate. The sum of the loss from mechanical pre-processing and thermal shock from stage 3 should only exceed by small margins the losses from thermal shock before pre-processing. The small margins validate mechanical pre-processing and related processes to give reliable results on the adhered mortar loss.Mass balance is made to control the losses occurring in the washing and sieving. Especially when both coarse and fines are mechanically pre-processed it is of importance to ascertain that adhered mortar loss is coming up just marginally from the processes of washing and sieving but more from actual mechanical pre-processing. Mass balance is made individually for each CCA and reference aggregate fraction in three stages:Mass balance for a coarse aggregate fraction 8/11.2 mm show that the potential adhered mortar loss given by thermal shock before pre-processing is 2.36%, In stage 2 mechanical pre-processing MP15, The effectiveness of alternative MP15 is assessed to at least 22% in all fractions by relating losses in mechanical pre-processing in stage 2 to losses in thermal shock at stage 1. The adhered mortar loss for 0/4 mm fraction is 22%, 0.5/4 mm is 26%, and 8/11.2 mm is 22% which makes MP15 the alternative with most uniform eroding effect for each fraction compared to MP10 where removed mortar amount shows higher variability.Grading curves are aggregate quality indicators, such that when CCA grading matches with reference concrete aggregates results in good concrete workability and compressive strength . The mecThe coarse CCA grading curve, To assess the closeness of grading curves across fine and coarse CCA fractions, combined grading curves are prepared for each CCA concrete as shown in The CCA grading curve investigated directly after crushing is improved by mechanical pre-processing to come closer to the reference concrete grading curve. However, there is still some gap between the grading curve directly after pre-processing (MP15 primary grading) and the reference concrete curve. Therefore, the grading curve is modified to get closer to the reference concrete grading by re-adjusting the share of CCA fractions in the concrete recipe, CCA proportions seen in The closeness of the modified CCA grading and reference aggregate grading is validated by the fineness modulus, seen in The packing density is derived from the weighed unit weight of the aggregate fractions in the concrete mix. The packing density is also influenced collectively by aggregate density, flakiness index, shape index, particle grading, unit weight, and void content. Therefore, the changes arising in these properties from mechanical pre-processing affects the packing density. The property majorly affecting packing density is the change in the unit weight and particle grading of mechanically pre-processed aggregates, seen in Improvements in packing density for CCA100 arises for all pre-processing alternatives and particle grading within  but for CCA50 arises only at MP15. Increased packing density for CCA50, with solely fines pre-processed, gives a particle grading closer to reference aggregates and leading to a better fit to reference concrete workability, In the case of reference aggregates, the packing density is seen to progressively reduce with pre-processing duration due to the material loss in the 0/8 mm fractions arising from the washing and sieving process following mechanical pre-processing.The CCA water absorption is expected to reduce with the removal of adhered mortar by mechanical pre-processing techniques, the water absorption results in this study are in agreement with this rule. The water absorption is seen to decrease after mechanical pre-processing for both CCA50 and CCA100 independent of pre-processing duration for primary graded CCA, see As the water absorption value remains unchanged for CCA100 at 5.7% with 10 min of pre-processing, the pre-soaking water amount is maintained constant in the MP0 and MP10 concrete mixes, see Similar to earlier findings, the flakiness index and shape index reduce with mechanical pre-processing. Flakiness index is tested on sample, shape index on individual particles and the correlation in between them being that aggregates having a high flakiness index also have a high shape index . This isThis study investigates unit weight and void content tests in an un-compacted state in order to address the influence of shape—flakiness, shape index on unit weight ,35. The With improved flakiness index of 8/11.2 CCA it is seen that unit weight increases gradually with each pre-processing duration. With increasing unit weight a decreasing void content is expected and this is seen for 8/11.2 CCA independent of pre-processing duration. Similarly, there is a visible reduction in the void content of fine CCA fraction 0.5/4 mm with MP10 and MP15. It is seen that this increase in unit weight for both coarse and fines is leading to an increase in the packing density and thus an improved compressive strength.Previous research indicates that the CCA density increases with the removal of adhered mortar by mechanical pre-processing, distinctly for lower density aggregates . For higThe influence of the packing density on the compressive strength of concrete is initiated by a comparison of packing density with the concrete density, measured at 28 days just before the compression strength is carried out, shown in The workability of the concrete produced with mechanically pre-processed CCA for 10 and 15 min durations are measured by the flow diameter, seen in Previous research relates the increase in concrete compressive strength for mechanically pre-processed CCA to the improvements in CCA density occurring with adhered mortar removal. In this study, the CCA density is not showing a uniform response across the mechanical pre-processing alternatives despite the adhered mortar loss. However, the concrete density is uniformly increasing with pre-processing duration for both CCA50 and CCA100, The packing density summarizes improvements in different aggregate properties arising from mechanical pre-processing and maybe seen as a property assessing CCA quality. Packing density is a good way to assemble the influences of different aggregate properties on the compressive strength and workability of the concrete. It may be interpreted as a bridging property between aggregate and concrete properties. This is ascertained for CCA50 and CCA100, which show the same tendencies for compressive strength and workability at different packing densities, see The stability of the relationship between packing density, workability, and compressive strength can be investigated for different concrete recipes. This relationship can be useful to pre-determine concrete properties arising from CCA of given quality shown by packing density.Reduces the most adhered mortar content in all CCA fractions and improves the grading of fine CCA by bringing it closer to the reference aggregate.Significant improvements in flakiness index and shape index of coarse CCA.The pre-soaking technique is compatible with mechanical pre-processing in optimizing pre-soaking water amount resulting from the reduction in adhered mortar content by abrasion.Both compressive strength and workability of CCA50 and CCA100 are reaching compressive strength of reference concrete.The aggregate properties collectively influence the packing density, which increases with increasing pre-processing duration for both CCA replacements.Packing density is the property concluding the collaborative effect of several properties such as density, particle grading, flakiness index, shape index, unit weight, and void content.The packing density has similar influences for compressive strength and workability for both CCA concrete, the packing density maybe used to indicate CCA quality along with water absorption and other properties confirmed by further investigations.For further research, the stability of the observed relationship between packing density, workability, and compressive strength may be investigated for different concrete recipes.Two mechanical pre-processing durations are investigated on concrete mixes with two aggregate replacement percentages. Between the two pre-processing durations, 15 min pre-processing is noticed to be optimum since:


The possibility of using recycled aggregates from construction and demolition waste (CDW) in concrete is rather widely agreed upon when it comes to the use of coarse recycled aggregates. However, this is not the case when fine recycled aggregates (FRA) are considered, as it is deemed that these seriously impair the behaviour of concrete. Hence, this work presents a technical specification proposal for the use of FRA from CDW in concrete, to attempt to fill this gap in legislation. The specification is based on a wide collection of experimental results, from which it is shown that for low incorporation ratios (up to 25%), the properties of concrete with FRA from CDW are comparable to those of a reference concrete. The intended international scope of the specification is ensured by the fact that FRA from CDW are typified by composition  rather than by geographical origin or construction type. It is shown that, after typifying the FRA and assuming, as per design, the acceptable percentage losses (relative to a reference concrete) of mechanical, durability-related and long-term physical properties, if the maximum incorporation ratios proposed of each type of FRA are used, the variation of properties remains within the limits established. The construction sector is amongst the most environmental impacting in Europe, consuming high amounts of raw materials and energy. Naturally, this contributes to a high generation of construction and demolition waste (CDW), which is the largest fraction of waste produced in the European Union: about 900 million tonnes of the total 3000 million tonnes of waste generated yearly . RecycliThe mechanical properties (compressive and tensile strengths and Young’s modulus) of concrete with RA from mixed CDW ,8,9,10, Although the properties of concrete with RA from CDW generally decrease, the decreases are higher with the use of fine aggregates than with that of coarse aggregates ,20,23,30-A brief description of the experimental campaign conducted and of the results obtained;-A detailed presentation of the technical specification;-Validation of the specification considering the FRA used in the experimental campaign.Given the absences of legislation on the use of fine RA from CDW, this work aims at contributing to an increment of the use of these aggregates in concrete applications by the construction industry. This is made by presenting a proposal of specification that is in part inspired by LNEC E471 (for coarse RA), but founded on the development of an extensive experimental campaign on the study of concrete mixes with the use of fine RA from CDW. The specification proposal intends to have an international scope, this being ensured by the typifying of FRA from CDW by composition  rather than by geographical origin or construction type. The main novelty of this work, aiming at advancing the in-depth understanding between the properties of RA from CDW and the resulting concrete produced, is two-fold: (i) presentation of a specification for the use of fine RA from CDW in concrete (still absent) and (ii) the development of rules accounting for RA composition (rather than origin) and based on an assumed decrease in properties (rather than on the imposition of minimum concrete strength classes). To this end, the main objectives of the work, which also coincide with the following sections, are:In this section, a brief description of the experimental campaign that was used to support the development of the proposed technical specification is made. A detailed description of the experimental procedures and results can be found in ,23.A total of 13 concrete mixes were studied, including one reference concrete (RC) mix and 12 recycled aggregate concrete (RAC) mixes comprising RA from CDW from three recycling plants in Portugal  and the target strength class of the RC was C30/37. The mixing procedure was as follows: the RA were introduced into the mixer with 2/3 of the mixing water, to allow water absorption (4 min), the NA were added afterwards (2 min) and finally, the cement and remaining 1/3 of mixing water were introduced (4 min).Concrete mixes were produced with 350 kg/mRecycled aggregates used were both physically and chemically characterized. The following tests were performed: particles’ density , water absorption , water soluble sulphate content , acid soluble sulphate content  and total sulphur content . The obtained results are shown ahead in Regarding the characterization of concrete in the hardened state, the following properties were tested: (i) compressive strength in cubes and (ii) in cylinders at 28 days , (iii) splitting tensile strength at 28 days , (iv) Young’s modulus , (v) water absorption by immersion  and (vi) by capillarity , (vii) resistance to carbonation at 28 days , (viii) resistance to chloride-ion penetration at 28 days , (ix) shrinkage at 91 days  b and (x)cm,cubes), compressive strength in cylinders , splitting tensile strength (fctm) and Young’s modulus (E). Moreover, im), water absorption by capillarity after 72 h (ΔWcap), carbonation depth (Z), chloride-ion diffusivity coefficient (D), extension due to shrinkage (εsh) and extension due to creep (εcr). In both tables, the following labelling of the concrete mixes is adopted: “RC” stands for the reference concrete (with no FRA), as usual, and for the RAC mixes, taking “V10” as an example, the first letter stands for the FRA origin, “V” for Vimajas, “E” for Europontal and “A” for Ambilei, and the number after it for the percentage replacement of fine NA with fine RA from CDW .In general, it can be seen that the incorporation of fine RA leads to a decrease in the concrete properties and this decrease is generally higher as the replacement percentage increases, although for the lowest contents studied (10% and 25%) the properties’ variations are generally low and, at times, even some minor improvements in the properties can be achieved .This specification proposal follows the existing specification (E 471), which establishes the conditions for the use of coarse RA in the production of hydraulic binder concrete, and intends to overcome the lack of regulation on the use of fine RA in concrete.CDW were identified by the European Commission as a waste stream whose treatment and recycling are a priority, given the high quantity generated and its high potential for reuse as a raw material. Proper management and recycling of this type of waste leads to a reduction (i) in the consumption of natural resources and (ii) in the amount of landfilled waste, both measures with beneficial effects on the environment.In view of this objective, Community Directive 2008/98/EC establishes that the European Union member states must take the required measures to achieve a minimum of 70% reuse of the CDW produced by 2020 .In order to fulfil this objective, the Portuguese Government published Decree No. 46/2008 of March 12, which establishes the regime for CDW management operations, covering their prevention and reuse and their collection operations, transport, storage, sorting, treatment and recovery. This document encourages the separation by type of CDW in the construction site and its local subsequent reuse, thus mitigating the use of energy for transportation to a different location. It is mandatory to separate non-inert materials which should be made “by streams and rows of materials, for recycling or other forms of recovery”. The separation of all these constituents, when not carried out immediately on site, must be done at a CDW recycling plant. This decree is also intended to mitigate the disposal of waste in illegal landfills.Recycled CDW is essentially divided into three parts: the inert or mineral part, such as concrete, brick, mortar, sand and stone; the non-inert part, such as metals, plastics, glass, cardboard and paper; and the hazardous waste, which must be recycled through specifically prepared means.Since 2004, the European List of Waste (ELW) has been applied in Portugal, published in Diário da República through Decree-Law No. 209/2004. The ELW ensures the harmonization of existing regulations regarding the identification and classification of waste, allowing separation, transport, and recovery operations to be carried out in a more appropriate manner. Using a six-digit code in the list, it is possible to identify the origin of the waste, as well as the specific type of waste. CDW are identified with code 17—Construction and demolition waste (including soil excavated from contaminated sites). The remaining four digits of the code identify the type of waste such as concrete  or wood , amongst others. The recycling plants sort the separated material, which may or not be inert, identifying it with the respective code, and send the data to the Portuguese Environment Agency, which is in charge of establishing statistical data.With respect to the use of aggregates from CDW in concrete, it is agreed that the replacement of part of the coarse NA with coarse RA does not significantly affect the properties of concrete. However, this is not the case when fine NA are replaced with fine RA. Therefore, the fine RA, having an expected worse behaviour compared to their coarse counterparts, were therefore initially discarded from experimental investigations. This led to a near-absence of legislation regarding their use.This specification proposal begins with the definition of three types of aggregates from CDW. These three types of RA have different requirements for their composition .Subsequently, in this specification proposal, four classes of RA utilization are defined. Each class corresponds to different quantitative decreases in the different properties of concrete, compared to a reference concrete (standard concrete). This approach is distinct from that adopted by LNEC E471 Specification as it does not limit the strength classes on which fine RA can be used. For instance, in The allowed percentages of incorporation of each of the three types of fine RA in order to comply with the quantitative requirements imposed for each class are shown in The fine RA, within any of the three defined types, must comply with the requirements established in this specification, with respect to a given set of physical properties as shown in The use of the three types of fine RA defined in the production of hydraulic binder concrete is subjected to the conditions set out in this specification proposal. The use of fine RA of different composition requires further specific studies to assess their influence on the fundamental properties of concrete.As seen in The minimum conformity requirements for fine RA for all applications, shown in The use of fine RA with compositions other than those shown in As mentioned, the specification proposal presented in the previous sub-section stemmed from an in-depth assessment of the implications of the incorporation in concrete of fine RA from CDW from three recycling plants .In this section, the use of the specification proposal is exemplified and validated using the FRA from CDW studied. The main goals are to show (i) how the specification proposal should be used and (ii) that if the maximum percentage of incorporation of FRA from CDW defined in Hence, the first step is to determine the type of FRA from CDW , according to Ambilei’s FRA are classified as type I since they are constituted, at more than 80%, by “concrete, concrete products, mortar, non-bonded aggregates, natural stone and aggregates treated with hydraulic binders”. Both Europontal’s and Vimajas’ FRA have contents of the former lower than 80%, but the sum of that fraction and of masonry is higher than 80%. In particular, for Europontal’s RA, that sum is higher than 90% and the sum of remaining components is lower than 10%, thus making these aggregates of type II. Finally, since the sum of the remaining components of Vimajas’ RA is higher than 10% (though lower than 20%), these aggregates are of type III.After classing the RA, there are still minimum properties, e.g., density, water absorption and sulphur-related contents, that must be guaranteed, according to Taking into account the results obtained in the experimental campaign developed . This is due to the fact that FRA lead to concrete with lower properties than those where coarse recycled aggregates are used;-Decreases in (i) mechanical (strength and stiffness), (ii) durability-related  and (iii) long-term physical (shrinkage and creep) properties of concrete with FRA were generally obtained experimentally with the increase in the incorporation ratio of FRA from CDW in concrete. The decreases in properties are mainly due to the higher porosity and lower strength and stiffness of FRA compared to fine natural aggregates;-For low incorporation ratios of FRA from CDW, of up to 25%, concrete mixes exhibit properties that are comparable to those of the reference concrete. For incorporation ratios higher than 25%, decreases of between 2% and 5%, between 6% and 17% and between 4% and 19% per each 10% increase in FRA percentage were obtained, respectively, for mechanical, durability-related and long-term physical properties;-The proposed technical specification was successfully validated since, when the maximum percentages of each type of FRA proposed in the specification were considered, the variation of properties remained within the limits established for a given concrete class. For instance, the use of (i) 25% FRA with more than 80% concrete or mortar content, or (ii) 10% FRA with more than 90% concrete, mortar and masonry combined, or (iii) 5% FRA with more than 80% concrete, mortar and masonry combined, resulted in concretes with decreases in the mechanical and remaining  properties, respectively, lower than 15% and 35%;-The proposed technical specification is intended for an international scope due to the fact that the FRA are typified based on their composition rather than on their geographical origin or construction type. This may contribute to an increase in the acceptance by the construction industry of the use of FRA from CDW in concrete applications.In this work, a specification proposal for the use of fine recycled aggregates, FRA, from construction and demolition waste, CDW, in concrete was presented. The specification proposal was inspired on the philosophy of the existing one on the use of coarse recycled aggregates, CRA, in Portugal-LNEC E 471, but modified in order for FRA to be used. Firstly, a brief literature review on concrete with CDW and on the existing standards on the use of recycled aggregates was presented. Then, the experimental campaign on which the specification proposal was founded was described and its results presented. Finally, the specification proposal was presented and its validation was made with the use of the FRA employed in the experimental campaign. The following main conclusions can be drawn:


Rational antibiotic prescribing is crucial to combat antibiotic resistance. Optimal strategies to improve antibiotic use are not known. Strama, the Swedish strategic program against antibiotic resistance, has been successful in reducing antibiotic prescription rates. This study investigates whether two specific interventions directed toward healthcare centers, an informational visit and a self-evaluation meeting, played a role in observed reduction in rates of antibiotic prescriptions in primary healthcare.The study was a retrospective, observational, empirical analysis exploiting the variation in the timing of the interventions and considering past prescriptions through use of estimations from dynamic panel data models. Primary healthcare data from 2011 to 2014 were examined. Data were from public and private primary healthcare centers in western Sweden. The key variables were prescription of antibiotics and indicator variables for the two interventions.The first intervention, an educational information intervention, decreased the number of prescriptions among public healthcare centers, but this effect was only temporary. We found no proof that the second intervention, a self-evaluation meeting at the healthcare center, had an impact on the reduction of prescriptions.Single educational interventions aimed at influencing rates of antibiotic prescriptions have limited impact. A multifaceted approach is needed in efforts to reduce the use of antibiotics in primary health care. Antibiotic resistance is a global problem with important medical and economic implications. The more antibiotics used, the more likely development of resistant microorganisms –5. AntibConservation, decreasing the use of antibiotics through different means, slows down the development of resistance and provides more time to develop alternatives . Even ifThe level of antibiotic prescription is low in Sweden compared with many other European countries . HoweverThe Strama Västra Götaland, the Swedish strategic program against antibiotic resistance, performed two different interventions, among other initiatives, targeting physicians and nurses in nearly all primary health care centers (PHCCs) in Region Västra Götaland in western Sweden during 2012–2014. Intervention A consisted of a visit from a peer at each center informing about rational use of antibiotics and how the center prescribed compared with others. Intervention B was initiated by Strama but conducted by the center itself; physicians shared their prescribing rates and discussed how well they had succeeded in following the guidelines for antibiotic prescription.It was not clear from previous studies which one should have had more impact. For example, Laxminarayan et al.  argue thIn this study, we investigate whether the two interventions affected the prescription rate at PHCC and, if so, whether there were differences in terms of effects of the two interventions between public and private healthcare centers. We investigate both prescriptions of all antibiotics and of antibiotics related to respiratory tract infections. Our empirical strategy exploits the variation in the timing of the interventions.In the second quarter of 2012, Strama Västra Götaland initiated two interventions directed toward PHCCs in the Västra Götaland region. In intervention A, a Strama peer visited each healthcare center and informed physicians and nurses about appropriate antibiotic prescribing behavior and how the center prescribed compared with other PHCCs in the region. Intervention B was initiated by Strama but conducted by the healthcare centers themselves, where clinicians shared their prescribing rates for different indications and antibiotics. They also discussed how well they had succeeded in following the guidelines for antibiotic prescription and possible ways to improve. Each PHCC was asked to send a report on this self-evaluation to Strama. After doing so, the center received a reward of a fixed sum plus an adjusted amount based on the number of listed patients at the healthcare center.The initial selection of PHCCs that would get a visit by Strama was not random; instead, centers that expressed an interest and those with high prescription levels were more likely to be targeted first. Selection later was also not randomized. At the end of 2012, about 35% of the centers had been visited. At the beginning of 2013, two things happened: more PHCCs were targeted by intervention A, and intervention B was started. As of the second quarter of 2014, 97 and 92% of the PHCCs had been targeted by interventions A and B, respectively. The interventions where never done simultaneously. However, they could have happened during the same observed quarter.We have data on prescription of all types of antibiotics and those related to treatment of respiratory tract infection at 206 PHCCs between the first quarter of 2011 and the second quarter of 2014. From the second quarter of 2011 and onwards, we also have information about characteristics of the PHCCs The main analysis is based on the balanced panel-that is, we included only healthcare centers for which we have observations for the whole-time period from the third quarter of 2011  to the fourth quarter of 2013.We investigated whether there were statistically significant differences between characteristics between private and public PHCC and between the last quarters of 2011 and 2013, using a t-test for continuous variables and Wilcoxon rank-sum test for discrete variables (shares).Using an econometric analysis, we investigated the effects of the two interventions on prescriptions while controlling for the relationship between characteristics of the healthcare centers and prescription levels, in general, and the difference between private and public PHCCs.We began by investigating the effects of the two interventions on total antibiotics prescriptions per patient visits. In addition, we investigated the level of respiratory tract infection related antibiotic prescriptions per patient visits of an average PHCC in Region Västra Götaland. We focused on respiratory tract infection related antibiotic prescriptions per patient visits because there is evidence that the rate of inappropriate prescriptions is higher in respiratory tract infections than in other type of infections . We usedBecause the assignment of PHCCs in both interventions was to some extent based on their past levels of prescriptions, and given the panel structure of the data, we evaluated the effects of the interventions by means of linear dynamic panel-data models. These models include p lags of the dependent variable as covariates and contain unobserved panel-level effects to take account of the feedback from past prescriptions. The specification to be estimated is presented as follows:yit denotes PHCC, i’s total antibiotics prescriptions per patient visits/respiratory infection related antibiotic prescriptions per 100 visitst, yi,t–1 is the level of prescriptions of healthcare center i in quarter t–1; Ti1 and Ti2 are intervention status indicators that are equal to 1 if the healthcare center was targeted by intervention A or B, respectively, and 0 otherwise; and xit is a vector of characteristics at both the center and patient levels, which are intended to capture the observed time-varying selection criteria used by Strama to determine the treatment status of clinics. Similarly, μt denotes quarterly dummy variables accounting for seasonal effects of antibiotic prescriptions; vi are panel-level unobserved effects that are correlated with the lagged dependent variable and take into account unobserved characteristics of healthcare centers, such as the motivation of directors to participate in the interventions; and εit is the error term. The direct effects of the interventions are estimated by the parameters α1 and α2. Standard errors include the Windmeijer’s finite-sample correction, which are suitable in presence of both heteroskedasticity and autocorrelation [where relation .yit as instruments for equations in levels, as well as lagged levels of yit as instruments for equations in first differences. The use of the system GMM estimator has several advantages with respect to the standard first differences GMM, including substantial efficiency gains, which makes the level restrictions informative even in the presence of weak instruments [2This equation is estimated by means of the extended system generalized method of moments estimator (GMM) derived by Arellano and Bover ) and Blutruments .2We estimated eq.  for all,We then investigated the effects of the two interventions on PHCCs with similar characteristics. We were interested mainly in public and private centers, but also those that did not already have low levels of antibiotic prescription before the interventions started. We therefore also analyzed the prescribing behavior of centers when removing the centers with low levels of prescription, in our case the bottom quartile with the lowest levels. This gave us information on the effects of the interventions when the type of the PHCC matters.Phenoxymethylpenicillin (ATC J01CE02), doxycycline (ATC J01CE02), amoxicillin (ATC J01CA04), cephalosporines (J01DB-DE), macrolides (ATC J01FA), amoxicillin with beta-lactamase inhibitor (ATC J01CR02).Table The number of antibiotic prescriptions had decreased almost 32% for the whole sample, i.e. from an average of 9.55 in 2011 to 6.54 in 2013 per 100 visits (of any type). The decrease was larger at private (37%) than at public (26%) healthcare centers, which means that the difference in prescriptions between public and private healthcare centers was considerably smaller in 2013 than in 2011. If we instead focus on respiratory tract infection related prescriptions, the number of prescriptions has decreased from an average of 5.76 in 2011 to 3.17 in 2013 per 100 visits, a 45% decrease. Thus, the decrease in respiratory tract infection related prescriptions was larger than the overall decrease in prescriptions. Again, the decrease was larger at private (51%) than at public (28%) healthcare centers.The average number of respiratory tract infection related antibiotic prescriptions per 100 infection visits and quarter for both types of centers is plotted in Fig. We can see two important things from the graph: private centers had higher levels of antibiotic prescriptions than public centers, but the difference was decreasing over time, and there was an overall downward trend in the prescription of respiratory tract infection related antibiotics. A similar pattern was observed for all antibiotics per patient visits at these centers.Results are presented in Table First, the model results show that there is a positive and statistically significant effect of the previous quarter’s level of prescriptions on the current quarter’s prescription level both for total prescriptions and for respiratory tract related antibiotics. This result holds even after controlling for characteristics of the health centers, and the effect is clearly stronger, twice as large, among private healthcare centers than among public ones.Our main interest is on the potential effects of the two interventions. We first focus on the results for the whole sample and total antibiotics prescriptions. None of the six intervention coefficients are statistically significant in the first or the second model. Among the healthcare center characteristics, the coefficients for the adjusted clinical groups and the size of the PHCC are statistically significant and negative. This indicates that a center with more patients with comorbidities has a lower level of antibiotic prescriptions and that centers with a relatively smaller number of patients have higher level of prescriptions. The quarter-by-year dummies are all negative and highly statistically significant. Since the reference quarter is the third quarter of 2011, the negative signs reflect the downward trend of prescriptions that we saw when looking at the raw data. For the general model in the whole sample, we can thus draw the conclusion that the interventions do not seem to have any statistically significant effect on antibiotics prescriptions in general.As shown in Table Next, we present the results for antibiotics prescribed for respiratory tract related infections. For the whole sample we observe a statistically significant short-term decrease in prescriptions during the first quarter after intervention A, but the effect disappears when we add controls for PHCC characteristics. Again, the comorbidities are significantly and negatively correlated with the level of prescriptions. Finally, we confirm the previous results for interventions for public and private health care centers: Intervention A had a short-lasting negative effect on prescription rates in public centers while we did not find support for an effect of intervention B. The effect size is larger for respiratory tract related infections: prescriptions at public centers with the intervention were on average 10.5% lower during the first quarter after the intervention . Our results persist regardless if we look at antibiotics prescriptions in general or prescriptions targeted to only respiratory tract infections. The results are not either sensitive if we estimate antibiotics prescriptions per visit or per number of listed patients (see Table A1 in the 3Since the level of prescriptions in the previous quarter is an important factor for prescription in the current quarter, as shown for all models in Table The results of Table Our study shows that an intervention with an educational information at the PHCC, decreased the number of prescriptions among public healthcare centers, but this effect was only temporary. We found no evidence that the intervention with a self-evaluation meeting at the healthcare center, had an impact on the reduction of prescriptions. The number of respiratory tract infection related antibiotic prescriptions per 100 visits has decreased by almost 45% between 2011 and 2013 in the Region Västra Götaland in western Sweden. This must be viewed as a successful antibiotic stewardship initiative. The number of total antibiotic prescriptions per 100 visits decreased with 32%. Despite the substantial reduction in total antibiotic prescriptions and respiratory tract infection antibiotics, where the rate of inappropriate prescriptions is suspected to be higher than in other type of infections, we find little support that either of the specific targeted interventions by themselves, an informational visit and a self-evaluation meeting, played a long-lasting role in this downward trend in either public or private health centers. In public centers, an intervention with an informational visit had a transient impact: the number of prescriptions, especially the number of respiratory tract infection related antibiotic prescriptions, was lower after a Strama peer had visited a PHCC, a result that holds even when controlling for the downward time trend in prescriptions and for various healthcare center characteristics. The effect was only temporary and disappeared after about half a year, confirming the previous findings by Dellit et al.  that theThe level of prescriptions at health centers is instead mostly explained by previous prescription levels, showing that it is difficult to change prescription habits. When we exclude all centers that belonged to the quartile with the lowest levels of prescriptions before the interventions started, similar results were obtained. The results are also robust for both antibiotics prescriptions in general and for prescriptions targeted to respiratory tract related infections as well as whether we estimate antibiotics per number of patients visit or per number of listed patients.We did not find any significant effects for either of the two interventions for private centers. Private healthcare centers were on average smaller, had a different patient composition, and prescribed more antibiotics compared with public centers. This is line with findings by Maun et al. . Our stuWhich other reasons than the two interventions could explain the successful decrease in antibiotic prescriptions? Especially the decrease in inappropriate prescribing, as we showed a larger decrease in prescribing of respiratory tract infection related antibiotics. Moreover, can we find any explanations why the interventions seem not to have played a more significant role? The national Strama organization was established already in the 90-ties in Sweden. During the years before the interventions the discussion of antibiotic resistance and prescriptions of antibiotic among healthcare workers and the public was intensified. The number of prescriptions was also declining already in the years before the interventions took place . This de4More important is how many of the permanently employed physicians and nurses and temporary personnel at healthcare centers were targeted by the two interventions, which varied across different centers . It is pInformation on each healthcare center’s rate of antibiotic prescription compared with the other centers was regularly provided by mailings since the second quarter 2013. This information partly replaced intervention A. We conclude that the specific interventions investigated in this study are found to have only modest impact on prescription rates indicating difficulties to find properly operating interventions. Finally, because of the importance of taking account of the dynamics of prescriptions while addressing the potential confounders such as the effects of related initiatives, future studies could benefit from modelling the initial conditions problem and state dependence when analyzing antibiotics prescriptions.With this in-depth econometric analysis, we cannot discern a significant, sustainable effect on antibiotic prescribing from either of the two specific interventions, a single educational visit and a self-evaluation meeting. The concurrent successful reduction of inappropriate antibiotic prescribing is due to several factors. Our findings support a multifaceted approach in continuous efforts for prudent use of antibiotics in primary healthcare.


To utilise the 2019 International Working Group on the Diabetic Foot (IWGDF) - diabetic foot infection (DFI) guidelines as an audit tool for clinical practice in patients with diabetes attending a High-Risk Foot Service.Data from 93 consecutive patients were collected over a 19-month period in patients attending a High-Risk Foot Service. The diagnosis and management of each patient in the sample were compared against the 2019 IWGDF DFI guidelines, grouped into four categories: Diagnosis, Microbiology, Treatment of soft tissue infection, and Surgical treatment and osteomyelitis. Deficits in performance were recorded using the recommendations as a benchmark standard.There were 109 DFI events. Nineteen (63%) of the recommendations were met, 7 (24%) were partially met, and four (13%) recommendations were not met. Fourteen of the sample had no documented requests for full blood counts. Tissue was obtained for culture in 32 (29%) of the sample. No percutaneous bone biopsies were performed. Only 13 (28%) patients had intraoperative bone specimens sent for culture and sensitivities, with no bone specimens sent for histopathology. Modification of antibiotic therapy following available culture results was low, occurring in 12 out of 63 possible occasions (19%). The duration of antibiotic regimens in PEDIS 2 infections and osteomyelitis was greater than that recommended.Utilising the IWGDF DFI guidelines to benchmark clinical practice is a useful tool to identify gaps in clinical performance or service delivery and may help to improve patient care.The online version contains supplementary material available at 10.1186/s13047-021-00448-w. Foot infections in persons with diabetes mellitus (DM) are major contributors to increased morbidity, mortality, hospital expenditure and decreased quality of life. The majority of diabetic foot infections (DFIs) occur when the skin envelope is breached, exposing otherwise sterile structures. In persons with DM, this typically occurs in the form of a foot ulceration (DFUs). Reports on the prevalence of infection in DFUs ranges between 9 and 60%, with several risk factors increasing the likelihood of developing an infection. Risk factors for development of infection can include ulcers that penetrate to bone, ulcers of greater durations (> 30 days), recurrent ulcers, ulcers with a traumatic aetiology, and presence of peripheral vascular disease .DFIs are clinically challenging to manage and represent a major causal pathway to lower extremity amputation . The manTo aid clinicians in providing a systematic, evidence-based clinical approach, the International Working Group on the Diabetic Foot (IWGDF) since 1999 has published evidence-based guidelines on the diagnosis and treatment of foot infection in persons with DM. The IWGDF have further contributed to classifying foot disease states by creating the PEDIS classification. Perfusion, extent, depth, infection, and sensation was designed by the IWGDF for selection of participants for clinical research. This system includes five components: perfusion (PAD), extent (area), depth, infection, and sensation (neuropathy) .The latest iteration from 2019 presents 27 recommendations that cover various aspects of diagnosis of soft tissue and bone infection, including a classification scheme for DFI and its severity . In addiIn this paper, we use the approach outlined by Standards for Quality Improvement Reporting Excellence (SQUIRE 2.0)  to reporThe data used in this study was from an internal database established by a a major metropolitan tertiary referral hospital High-Risk Foot Service to capture clinical data on Diabetic Foot Infections. The data used was collected over a 19-month period (March 2018 to September 2019), and 93 consecutive eligible patients (109 DFI events) aged over 18 years who presented for multi-disciplinary management of their diabetic foot infection (DFI) were enrolled in the study. Individuals were eligible if they had DM and a new DFI. Individuals could be enrolled on more than one occasion if they presented with multiple DFIs during the study period, but only if the index DFI had completely resolved and treatment was complete. Individuals with foot infections who did not have DM were not eligible for the study.The High-Risk Foot Service provides a multi-disciplinary team approach, with care provided by podiatrists, endocrinologists, general medicine physicians, infectious diseases physicians and vascular surgeons. Demographic, clinical, laboratory and relevant operation report data were obtained from the electronic medical record, and all extracted data were recorded in a secure Microsoft Excel spreadsheet. Conventional culture data obtained from eMR was reported by a hospital pathology service (Sydney South West Pathology Service). Plates were streaked for isolation onto four quadrants of recommended agars and grown under appropriate atmospheres to isolate clinically relevant organisms (both aerobe and anaerobe) per standardized methods.The IWGDF DFI guidelines has 27 recommendations which were used as the defined standards for the benchmarking episode. The 27 recommendations fall under four categories: Diagnosis (7), Microbiology (2), Treatment of Soft Tissue Infection (10), and Surgical Treatment and Osteomyelitis (8). Recommendations for antibiotic use in tropical and subtropical regions were not used in the benchmarking process as they were not relevant to the geographical  context.The electronic medical record (eMR) used by the Hospital contains details of all pathology and imaging tests performed on a patient as an inpatient or outpatient, as well as all clinician notations. Antibiotic use was extracted from both the eMR clinical notations and paper medical administration charts used for inpatients. One researcher was tasked with searching the records for information corresponding to the detail required by the standards. Two additional researchers then independently compared actions described in the extracted data grouped in each of the four categories for each patient against the standard of the recommendations. The results were then compared, and a decision made as to whether there was full compliance for the case, partial compliance or no compliance. Disputes were to be resolved with input from a fourth researcher. None of the researchers were blind to the identity of participant data. One senior researcher was involved in data extraction and held managerial responsibility within the High-Risk Foot Service and also undertook a clinical role within the High-Risk Foot Service. The two other researchers involved also undertook a clinical role within the clinic.The study was approved on the 26th November 2020 by the local institutional human research ethics committee (Project ID: 2020/ETH02129) and conducted according to national standards governing clinical research.All data collected was transcribed into a study specific data collection form, then entered electronically into a secured database. Descriptive data was reported as mean and standard deviation (±). Unpaired students t-tests and one-way analysis of variance (ANOVA) was used for comparisons. Data were analysed using the Statistical Package for Social Sciences Version 25 .A total of 93 individuals with 109 DFIs were recruited over the 19-month study period. Sixteen patients included in the dataset had repeat infections of the index infected DFU. The majority of patients had type 2 DM . There were 62 (67%) men and 31 (33%) women. The mean age of all participants was 58.3 ± 12 years. All 109 DFIs were associated with a diabetic foot ulcer (DFU). The location of DFUs and subsequent DFIs were 47 plantar forefoot (43%), 43 digits (40%), 11 midfoot (10%), and 8 calcaneus (7%).A summary of the clinical results benchmarked against each recommendation is outlined in supplementary data The IWGDF DFI guidelines list 27 recommendations, and as some are divided into subsections, the total number of responses is 30. The recommendations were met for 19 (63%), partially met in 7 (24%) and were not met in 4 (13%). There were no disputes about interpretation of the data.Of eight possible affirmative responses, five recommendations were met, two were partially met and one was not met. The areas of partial compliance were in obtaining baseline blood tests and a serum biomarker of inflammation. The area not met was in obtaining either a percutaneous or surgical specimen of bone for culture in suspected diabetic foot osteomyelitis (DFO). In 95 of 109 (87%) episodes of DFI, full blood counts were obtained at initial presentation, which included white cell count (mean 10 ± 3 × 10^9/L) and C-reactive protein (mean 46.4 ± 62.8 mg/L). The erythrocyte sedimentation rate was requested and available for 49 of 109 (45%) episodes of DFI (including DFO) (mean 53.5 ± 20 mm/hr). Fourteen (13%) episodes of DFI had no blood tests. Procalcitonin could not be ordered for any DFI as it is not available in our institution’s routine pathology ordering sets.Forty-six of 109 (42%) episodes of DFI were suspected of having DFO. With regards to the microbiological sampling and histopathology for definitive diagnosis or determining the causative pathogen necessary for targeting treatment, no patient had a percutaneous bone biopsy through healthy skin. In 26 of 46 (57%) episodes of DFI with surgical intervention for management of DFO, 13 of 46 (28%) had intraoperative bone specimens sent for microbiology, culture and sensitivities. No specimens were sent for histopathology.Of two recommendations, one was met, and one was partially met. The area of partial compliance was in collecting tissue specimens for culture. The most utilised sampling technique was a wound swab, obtained in 77 (71%) episodes of DFI. Tissue specimens were collected in 32 (29%) episodes of DFI, either by biopsy using a 3 mm biopsy needle or by curettage using a dermal curette.Staphylococcus aureus , which was identified as a mono-microbial infection in 22 DFIs. If methicillin resistant Staphylococcus aureus (9 [5%]) isolates are included with MSSA, these organisms account for 53 of 185 (29%) isolates. Streptococci were commonly isolated , Streptococcus milleri (4 [2%]), Streptococcus dysgalactiae (3 [1.6%]). Collectively, aerobic gram-positive cocci accounted for 72 (39%) cultured isolates.Of ten recommendations, eight were met, and two were partially met. The areas of partial compliance were in modification of empiric antibiotic therapy in view of available culture results, with the preference being to continue broad spectrum antibiotic therapy rather than changing to a narrower spectrum agent. Empiric treatment for DFI was initiated in all 63 (100%) episodes of soft tissue DFI. In 55 (87%) cases there was an initial prescription of oral antibiotic therapy and eight (13%) required parenteral antibiotic therapy. Conventional culture identified 185 isolates from 109 episodes of DFI . The mosOral amoxicillin-clavulanate was the most commonly prescribed empiric first-line antibiotic in 30 of 63 (48%) episodes of DFI. This was followed by in rank order: oral clindamycin (8), oral cephalexin (7), intravenous piperacillin and tazobactam (6), oral ciprofloxacin (4), oral dicloxacillin (4 intravenous cephazolin (2), oral trimethoprim/sulphamethoxazole (1), oral doxycycline (1). In 41 (66%) episodes of DFI no alterations to therapy were made despite culture results identifying an organism sensitive to a narrow spectrum agent.Of eight recommendations with 11 possible responses, four were met, two were partially met and three were not met. One of the partially met standards was based on the use of an oral agent, doxycycline, that has limited evidence of efficacy in DFO. The other partially met recommendation was sending proximal bone chips obtained at surgical resection for evidence of residual infection.The three areas of non-compliance were concerned with the duration of antibiotic therapy. Twenty of 46 (43%) episodes of DFI with DFO were managed with antibiotic therapy and did not undergo surgical intervention. The mean total duration of antibiotic therapy was 14.4 ± 9.1 weeks. The other 26 episodes required surgical intervention for resolution of infection/clinical cure. Of this number, 19 (73%) received a mean duration of (failed) oral antibiotic therapy of 5.8 ± 3.4 weeks prior to requiring surgical intervention. We define failed antibiotic therapy as a failure to achieve infection resolution or clinical cure of the index OM referencing no changes to, or a deterioration of clinical, laboratory and imaging modalities. When combining the total duration of antibiotic therapy to include baseline, surgical intervention and cessation of antibiotic therapy post-surgery, the mean duration of antibiotic therapy in this group was 11.7 ± 6.9 weeks. Seven episodes with DFO required acute admission to hospital for parenteral therapy at baseline due to the severity of infection. In all cases antibiotic therapy was commenced on presentation, and surgical intervention occurred within 7 days of admission. In this group, the mean duration from presentation to cessation of antibiotic therapy was 2 ± 0 weeks.The management of DFI is clinically challenging and a standardised approach to care requires frequent evaluation and auditing of clinical service delivery. Changing practice to conform to evidence should result in improved outcomes for patients. The reasons for partial and non-compliance are not simply a reflection of lack of knowledge of the evidence but reflect constraints on local resources and the influence of local interpretations of evidence and local policies.Recommendations 7 and 25 of the IWGDF DFI guidelines specifically relate to obtaining appropriate bone specimens for culture and histopathology. These samples are useful for making or confirming a definitive diagnosis and determining the causative pathogen in DFO. The audit identified that no percutaneous bone biopsies were undertaken, and no bone samples (percutaneous or intraoperative specimens) were sent for histopathology. The most likely explanations for this are: a lack of experience in performing percutaneous biopsy either in an out-patient setting or operating theatre, limited theatre time in a busy tertiary facility, and a failure within local protocols to ensure surgeons obtain intraoperative bone specimens to send for culture and histopathology.Recommendations 23 and 24 of the IWGDF DFI guidelines provide guidance for the duration and delivery of antibiotic therapy for DFI-associated osteomyelitis. The aim is to ensure that patients do not receive unduly long durations of therapy with the primary aim of reducing selective pressures for antibiotic resistance. With this in mind the recommended duration of antibiotic therapy for DFI-associated osteomyelitis is 6 weeks. The levels of evidence for this recommendation is based mostly on clinical experience –10, withTreatment for DFI-related osteomyelitis in patients who required initial parenteral treatment was also longer than the recommendations. The IWGDF guidelines recommend 5–7 days of parenteral treatment before de-escalating to oral therapy. Our mean total duration was 24 ± 9.8 days. This was not unexpected and reflected established practice regarding outpatient parenteral antimicrobial therapy in the High-Risk Foot Clinic . In JanuThe lack of tissue biopsy for culture is difficult to explain. There is evidence indicating that the sensitivity and specificity of tissue specimens for culture results are higher than for swabs –16. All Staphylococcus aureus and beta-haemolytic Streptococci [Empiric therapy was not often altered, even when available culture results subsequently identified key pathogens amenable to narrowing in the spectrum of antibiotic activity. Only 12 (19%) DFI episodes had alterations to specifically target aerobic Gram-positive cocci, despite these making up a large percentage (39%) of isolates. In all cases, the IWGDF DFI guidelines make recommendations that all mild to moderate (PEDIS 2 and 3) DFIs should be focused to a narrow spectrum of pathogen cover, ideally directed by culture results. In mild to moderate (PEDIS 2 and 3) DFIs this coverage is typically targeted towards the predominant pathogens of infection; aerobic Gram-positive cocci, including ptococci .In this study, once patients were commenced on empiric regimens, they frequently remained on the same antibiotic for the duration of their therapy. Anecdotal feedback from clinicians responsible for prescribing antibiotics in the High-Risk Foot Service was sought. These highlighted clinicians thought that targeting of regimens were not needed in patients who experienced clinical improvement or resolution of symptoms on empiric regimens, especially since empiric first-line therapies were based on recommendations by local Australian (eTG) guidelines.Cost and waiting lists restrict the use of some investigations in this study. No patient in the sample had an MRI during the study period. Procalcitonin is not a publicly funded pathology test in Australia and was therefore not utilised.As with any un-blinded audit there is a risk of bias in interpretation of the data. However, data extraction and comparison in this audit is simple, as absences are obvious and not open to dispute. For example, the lack of a pathology result, change in antibiotic or use of hyperbaric oxygen are recorded or not. The use of three researchers improves the accuracy of the findings, and there were no disputes about interpretation of the data. Any absence of expected data was interpreted as a non-performance against the relevant recommendation.The IWGDF DFI guidelines present an opportunity for clinicians and service providers to benchmark their current practice against defined expert and evidence-based recommendations. This process has identified several areas of local clinical practice that require change and improvement, commencing with the broader dissemination of the IWGDF guidelines to all relevant staff. The most pressing issue identified with this benchmark process is the lack of access to bone biopsy, either ensuring adequate specimens are obtained intra-operatively and sent for conventional culture or by means of percutaneous biopsy through unaffected skin. The latter in particular identifies a need for service development and upskilling of the workforce, this is a likely reflection of services across Australia.Additional file 1: Supplementary data 1. IWGDF recommendations and the benchmarking process undertaken by three researchers on the diagnosis and management of DFI events. Supplementary data 2. Raw data of 93 persons with DFI in 109 DFI events. Supplementary data 3. Sunburst diagram of microbiology results from 109 DFI events. A total of 185 microbial isolates were identified, 7 DFI events had no growth on culture.


Dietary restriction of methionine and cysteine is a well-described model that improves metabolic health in rodents. To investigate the translational potential in humans, we evaluated the effects of dietary methionine and cysteine restriction on cardiometabolic risk factors, plasma and urinary amino acid profile, serum fibroblast growth factor 21 (FGF21), and subcutaneous adipose tissue gene expression in women with overweight and obesity in a double-blind randomized controlled pilot study.-low, n = 7), medium  or high  in methionine and cysteine for 7 days. The diets differed only by methionine and cysteine content. Blood and urine were collected at day 0, 1, 3 and 7 and subcutaneous adipose tissue biopsies were taken at day 0 and 7.Twenty women with overweight or obesity were allocated to a diet low (Met/Cys-low vs. Met/Cys-high group. The Met/Cys-low group had increased mRNA expression of lipogenic genes in adipose tissue including DGAT1. When we excluded one participant with high fasting insulin at baseline, the Met/Cys-low group showed increased expression of ACAC, DGAT1, and tendencies for increased expression of FASN and SCD1 compared to the Met/Cys-high group. The participants reported satisfactory compliance and that the diets were moderately easy to follow.Plasma methionine and cystathionine and urinary total cysteine decreased, whereas FGF21 increased in the Met/CysOur data suggest that dietary methionine and cysteine restriction may have beneficial effects on circulating biomarkers, including FGF21, and influence subcutaneous adipose tissue gene expression. These results will aid in the design and implementation of future large-scale dietary interventions with methionine and cysteine restriction.Trial registration ClinicalTrials.gov Identifier: NCT03629392, registration date: 14/08/2018 https://clinicaltrials.gov/ct2/show/NCT03629392. Overweight and obesity are major risk factors for metabolic disruptions including dyslipidemia and insulin resistance that increase overall risk of morbidity and mortality , 2. DietMethionine is an essential amino acid that through a sequence of reactions can be converted to cysteine . CysteinDespite the clear benefits of methionine and cysteine restriction in animal experiments, and epidemiologic data suggesting that cysteine is obesogenic , there aThe primary aim of this pilot study was to evaluate the potential effects of a 7-day diet low, moderate or high in methionine and cysteine content on a wide selection of potential outcomes identified in preclinical and observational studies , 16, 18 2) aged 20–40 years. Participants were also included if body fat percentage corresponded to > 33% as measured by dual-energy X-ray absorptiometry , whereas the concentrations decreased in the Met/Cys-medium and Met/Cys-high groups by 30% [from 98  to 69 ] and 64% [from 75  to 27 ], respectively. The linear mixed regression analyses revealed a significant group × time interaction for the FGF21 response in the Met/Cys-low group compared with the Met/Cys-high group  and the control Met/Cys-high group , which is involved in synthesis of triacylglycerol, in the Met/Cys-low group, with a 0.43 log2-fold change vs. Met/Cys-high after 7 days (95% CI 0.00–0.86). Inconclusive results were observed for transcript levels of acetyl-CoA carboxylase [ACAC ], SCD1 , glutamate-cysteine ligase catalytic subunit [GCLC ], glutamate-cysteine ligase modifier subunit [GCLM ], carnitine palmitoyltransferase I [CPT1A (0.33: − 0.15–0.82)], and mammalian target of rapamycin [MTOR ].We compared changes in subcutaneous adipose tissue mRNA expression between baseline and day 7, for 16 candidate genes, between the intervention groups , and DGAT1 . Similar but inconclusive results were observed for fatty acid synthase [FASN ], SCD1 , and mammalian target of rapamycin [MTOR ]. In the Met/Cys-medium group, the response in mRNA expression generally followed the same pattern as the Met/Cys-high group.Exclusion of one participant with high baseline HOMA-IR influenced results for transcripts related to lipogenesis including -low  and Met/Cys-medium  groups compared to the Met/Cys-high group, but results were inconclusive as indicated by the wide CIs. When we excluded the subject with high HOMA-IR at baseline, results tended towards a greater reduction in the Met/Cys-low compared to the Met/Cys-high group was observed .As a proxy marker of hepatic SCD1 activity, we examined the plasma SCD-16 index (the ratio between 16:1n-7 and 16:0). The estimated mean changes for the plasma SCD-16 index were compatible with reductions in both the Met/CysDGAT1 , between tCys and SREBP , and between free reduced cysteine and PRDM16 . Other prominent correlations were for the glutathione synthesizing gene, GCLM, with tCys , protein-bound cysteine , and taurine .We examined whether changes in plasma sulfur amino acids were correlated with the changes in adipose tissue gene expression Fig. . Among tSelf-reported compliance with the diets was ~ 95% among the participants, and there were no differences in self-reported compliance between the groups (data not shown). Satisfaction with the diets was moderate , and the participants reported that the diets were moderately easy to follow (39 points). Side effects were light to moderate for gastrointestinal and other symptoms including headache, fatigue, dizziness, and sleep disturbances. There were no differences in side effects between groups (data not shown). No severe harmful effects were reported.-low group tended towards improvements in plasma apoB/A1 after 7 days of intervention, but the results were inconclusive. In addition, FGF21 increased in the Met/Cys-low group compared to the Met/Cys-high group and there were changes in plasma and urinary concentrations of several of the sulfur amino acids and in adipose tissue mRNA expression of particularly DGAT1 in the Met/Cys-low group. The Met/Cys-low and Met/Cys-medium groups tended towards reductions in plasma SCD1 activity index. The findings on adipose tissue mRNA expression of DGAT1 and ACAC as well as SCD1 activity indices in plasma became more pronounced when we excluded one outlier with high HOMA-IR at baseline.This double-blind randomized controlled pilot study describes for the first time the effects of dietary restriction of both methionine and cysteine content, with either severe or moderate restriction on plasma biomarkers and subcutaneous adipose tissue mRNA expression related to energy metabolism, in healthy overweight and obese women. Participants in the Met/Cys-low group is in line with preclinical studies showing upregulated hepatic gene expression and elevated circulating FGF21 in response to methionine restriction [The increases in serum FGF21 in the Met/Cystriction , 18, 39.triction . Many pl-low group as compared with the Met/Cys-high group. In our previous pilot study, normal-weight subjects exhibited a slight increase in the cysteine–cysteine disulphide, cystine [-low group compared with the Met/Cys-high group, which were in line with a previous 16-week study in obese participants [CDO, which is the rate-limiting enzyme in oxidation of cysteine to taurine [CDO in adipose tissue. This was not surprising as CDO is regulated at the protein level, and is mostly expressed in the liver [In line with our previously published 7-days pilot study in normal-weight individuals , we obse cystine . In the icipants . The conicipants  might be taurine . Althoughe liver . OverallGCLM, which is crucial in glutathione synthesis, tended to be enhanced in the Met/Cys-low compared to the Met/Cys-high group. The clear trend for an increased expression of GCLM mRNA during low dietary cysteine intakes may seem paradoxical. However, a previous study demonstrated similar findings in mice, suggesting that cysteine deprivation may enhance glutathione production to protect against cellular stress, at least in the short term [Glutathione can serve as a reservoir for cysteine during periods of deficient intakes . Howeverort term . We do nDGAT1 mRNA expression in the Met/Cys-low group, and a tendency towards induction of other genes involved in lipid metabolism . The effects became more pronounced for most lipid-related transcripts when we excluded a subject with high baseline HOMA-IR. Our findings are consistent with preclinical data, where dietary methionine restriction upregulates enzymes involved in lipogenesis, triglyceride synthesis and fatty acid oxidation [SCD1, DGAT1), promoting a shift from fatty acid synthesis to fatty acid oxidation in the liver [We observed effects on subcutaneous adipose tissue xidation , 42, 43.xidation , 16. Howhe liver , 17, 32.The present study included one participant with high HOMA-IR at baseline. Although initially included in the main analyses, the participant was excluded from analyses investigating the effect of the intervention on subcutaneous adipose tissue gene expression and the SCD-16 index (surrogate of hepatic SCD1 activity). When we excluded the participant from these analyses, several findings appeared stronger including expression of genes involved in lipogenesis as well as the plasma SCD-16 index. The responses in subcutaneous adipose tissue mRNA expression and the reduction in plasma SCD-16 index after exclusion appear to be consistent with preclinical studies , 17, 32.-medium group may have been too high to achieve the same beneficial effects as the Met/Cys-low group as seen in moderate restriction in animal models [This is the first study reporting findings from a combined dietary methionine and cysteine restriction in humans. The main strength of this study is the randomized, controlled and double-blind design which is rare for dietary interventions, and that we were able to design diets that only differed by methionine and cysteine content and were otherwise identical. Another major strength is the translational approach and that the study provides valuable insight for future large-scale studies investigating whether the beneficial findings of methionine and cysteine restriction in animals also pertain to humans. In particular, we have collected and reported data on a wide range of outcomes that have previously been identified in preclinical as well as epidemiological studies, including plasma concentrations of amino acids , expressl models . We note-medium followed similar patterns as the Met/Cys-high group with respect to most outcomes, a diet low in methionine and cysteine should be utilized to maximize effects in future studies.Results from this pilot trial with diets that differed only by methionine and cysteine content indicate that such an intervention is feasible in humans and might have effects that are comparable to demonstrations in animals. Due to the small sample size and short duration these results must be interpreted with care, but merit future, long-term investigations into whether dietary methionine and cysteine restriction can confer sustainable and beneficial effects over time in overweight and obese populations. Because the Met/CysAdditional file 1. Mean nutrient content and composition in the 7-day diet, excluding SAA-powder.Additional file 2. A typical daily menu in the 7-day diet.Additional file 3. Mean daily sulfur amino acid intake in the low, moderate and high Met/Cys diets.Additional file 4. Primer sequences of gene expression measured by qPCR.Additional file 5. Spearman’s rank correlation coefficients and 95% confidence intervals between sulfur amino acids and related intermediates.Additional file 6. Estimated means linear predictions/responses in plasma sulfur amino acids. Values are derived from a linear mixed model regression. The p-values denote the p for interaction between group and time and indicate the difference in response over time between the Met/Cys-medium and Met/Cys-high groups. Abbreviations: Met/Cys, methionine and cysteine; SAM, S-adenosylmethionine, SAH, S-adenosylhomocysteine; GSH, glutathione; GSSG, oxidized glutathione.Additional file 7. Estimated means linear predictions/response in creatinine-adjusted urinary sulfur amino acid concentrations. Values are derived from a linear mixed model regression. The p-values denote the p for interaction between group and time and indicate the difference in response over time between the Met/Cys-low and Met/Cys-high groups. Abbreviations: Met/Cys, methionine and cysteine.Additional file 8. Estimated means linear predictions/response in creatinine-adjusted urinary sulfur amino acid concentrations. Values are derived from a linear mixed model regression. The p-values denote the p for interaction between group and time and indicate the difference in response over time between the Met/Cys-medium and Met/Cys-high groups. Abbreviations: Met/Cys, methionine and cysteine.Additional file 9. Estimated means linear predictions/response in serum Fibroblast growth Factor 21 to the diets. Values are derived from a linear mixed model regression. The p-values denote the p for interaction between group and time and indicate the difference in response over time between the Met/Cys-medium and Met/Cys-high groups. Abbreviations: FGF21, fibroblast growth factor 21; Met/Cys, methionine and cysteine.Additional file 10. Individual responses in mRNA expression in subcutaneous adipose tissue in the Met/Cys-low group. Abbreviations; Met/Cys, methionine and cysteine; MTR, methionine synthase reductase; CBS, cystathionine-β-synthase; CDO, cysteine dioxygenase; GCLC, glutamate-cysteine ligase catalytic subunit; GCLM, glutamate-cysteine ligase regulatory subunit; CPT1A, carnitine palmitoyl-transferase 1a; ACACA, acetyl-CoA carboxylase; FASN, fatty acid synthase; DGAT1, diacylglycerol O-acyltransferase 1; SCD1, stearoyl CoA-desaturase 1; SREBP, sterol regulatory element binding protein; PPARG, peroxisome-proliferator activated receptor γ; MTOR, mammalian target of rapamycin; LEP, leptin; PRDM16, PR domain containing 16.Additional file 11. Individual responses in mRNA expression in subcutaneous adipose tissue in the Met/Cys-medium group. Abbreviations; Met/Cys, methionine and cysteine; MTR, methionine synthase reductase; CBS, cystathionine-β-synthase; CDO, cysteine dioxygenase; GCLC, glutamate-cysteine ligase catalytic subunit; GCLM, glutamate-cysteine ligase regulatory subunit; CPT1A, carnitine palmitoyl-transferase 1a; ACACA, acetyl-CoA carboxylase; FASN, fatty acid synthase; DGAT1, diacylglycerol O-acyltransferase 1; SCD1, stearoyl CoA-desaturase 1; SREBP, sterol regulatory element binding protein; PPARG, peroxisome-proliferator activated receptor γ; MTOR, mammalian target of rapamycin; LEP, leptin; PRDM16, PR domain containing 16.Additional file 12. Individual responses in mRNA expression in subcutaneous adipose tissue in the Met/Cys-high group. Abbreviations; Met/Cys, methionine and cysteine; MTR, methionine synthase reductase; CBS, cystathionine-β-synthase; CDO, cysteine dioxygenase; GCLC, glutamate-cysteine ligase catalytic subunit; GCLM, glutamate-cysteine ligase regulatory subunit; CPT1A, carnitine palmitoyl-transferase 1a; ACACA, acetyl-CoA carboxylase; FASN, fatty acid synthase; DGAT1, diacylglycerol O-acyltransferase 1; SCD1, stearoyl CoA-desaturase 1; SREBP, sterol regulatory element binding protein; PPARG, peroxisome-proliferator activated receptor γ; MTOR, mammalian target of rapamycin; LEP, leptin; PRDM16, PR domain containing 16.Additional file 13. Correlation  between changes in plasma sulfur amino acids and gene expression.


Fig 1). In addition, the phenomenon of heteroresistance  has come into focus [Antibiotics have enabled the most important advances in healthcare and their clinical implementation ranks as one of the most significant medical achievements. Understandably, the often observed and increasingly prevalent failure to treat bacterial infections with antibiotics has emerged as a major public health concern. Treatment failure can be caused by 2 separate, distinct phenomena: antibiotic resistance , and anto focus . While ato focus ,4, antibAntibiotics induce various forms of cell damage. For example, fluoroquinolones convert topoisomerases into endonucleases causing DNA damage; β-lactams and other inhibitors of cell wall (peptidoglycan) synthesis destroy the essential bacterial cell wall; polymyxins damage membranes; and aminoglycosides corrupt the translation machinery . An impoVibrio cholerae, is induced by cell wall damage and upregulates peptidoglycan synthesis in response [The SOS DNA damage response senses and repairs damage induced by fluoroquinolones and is critical for survival after exposure to these agents , while cresponse . Additioresponse ,9, and wresponse , and resresponse . Antibioresponse .Importantly, tolerance has been shown to be a stepping stone toward the development of frank resistance –14. It iFig 1). Part of the reason for the varied nomenclature is that the ability of these cells to survive and grow in the presence of antibiotics depends greatly on the organism, culture medium and conditions, and how the switch to the cell wall–deficient state is induced.An important aspect of the tolerance phenomenon lies in the role of environmental conditions. The most striking example of this is the role of osmolarity on survival of cells treated with cell wall–damaging agents, particularly β-lactams. Under hypotonic conditions, peptidoglycan provides bacteria with the ability to withstand the higher turgor pressure that would otherwise result in explosive lysis but in iso-osmotic conditions, such as those present in tissue fluids and urine; the requirement for a cell wall is reduced, and the mechanical damage inflicted by cell wall–active antibiotics is mitigated. Indeed, many bacteria can adapt, to some extent, to loss of their cell wall. These peptidoglycan-deficient cells are derived, often reversibly, from wild-type bacterial cells and have been given a plethora of names, including L-forms, spheroplasts, and S-cells , althougBacillus subtilis has shown that the switch to a fully viable growing L-form state requires at least 3 steps. First, escape of the membrane-bound protoplast from the enveloping peptidoglycan sheath, usually dependent on external hydrolytic enzymes or β-lactam–induced autolysis [Detailed work on utolysis . Second,utolysis . Third, utolysis . Similarutolysis .Spheroplasts are formed by many gram-negative bacterial species after exposure to inhibitors of cell wall synthesis –22. SimiFig 1) [Borrelia burgdorferi, remain susceptible to cell wall–acting antibiotics [Persisters are defined as a small subpopulation of extremely tolerant, presumably dormant, cells observed in many bacterial populations. Persisters remain viable after a susceptible majority population is rapidly killed by a bactericidal antibiotic  ,25. As sFig 1) . Thus, pFig 1) . By slowFig 1) . TherefoFig 1) ,30. Howeibiotics , suggestEscherichia coli cells that persist in the presence of the β-lactam ampicillin (“ampicillin persisters”) during exponential phase show no signs of cellular damage following antibiotic exposure [E. coli persister cells [What appears to be dormancy may in fact represent a gradient of metabolic activity rather than complete metabolic shutdown, providing varying degrees of protection depending on the antibiotic class . Highly exposure . In conter cells . Thus, sDespite an obvious logical connection between tolerance and antibiotic treatment outcomes, studies addressing this issue remain scarce, and the clinical significance of tolerance is unclear. It is often challenging to distinguish the effects of tolerance from other factors: growth in a niche that limits antibiotic penetration, proximity to the producer of an enzyme that inactivates antibiotics, or niche-specific expression of resistance factors. While work in animal models has suggested an in vivo role for tolerance in treatment outcomes, clinical evidence is scarce ,35.Mycobacterium tuberculosis, where treatment of disease caused by susceptible isolates, as determined by in vitro antibiotic susceptibility testing, requires several months of antibiotic therapy. M. tuberculosis’ high tolerance is likely a consequence of its extremely slow growth rate in the lung [E. coli isolates from the patients converted to a cell wall–less form in the presence of a cell wall–acting antibiotic and transitioned to the walled state upon removal of the antibiotic. Thus, switching between walled (susceptible) and cell wall–deficient (tolerant) forms may contribute to recurrence in UTIs.The most notorious antibiotic tolerant bacterium is the lung . Antibiothe lung . NotablyWhile additional evidence is needed to firmly establish the significance of antibiotic tolerance on treatment outcomes, clinical isolates of significant bacterial pathogens exhibit high-level tolerance against many antibiotics ,22,38, aFuture research should thoroughly address the clinical significance of antibiotic tolerance. To do so, 2 important hurdles must be overcome. First, assays analogous to standard antibiotic susceptibility testing methods such as disk/gradient diffusion or broth microdilution that detect antibiotic tolerance in the clinical laboratory must be implemented. Such assays must be facile to perform and the resultant data readily interpreted by end users. The tolerance disk test (TDtest) and an associated variant ,45, whic