The susceptibility of structural concrete to early-age cracking depends on material composition, methods of processing, structural boundary conditions, and a variety of environmental factors. Computational modeling offers a means for identifying primary factors and strategies for reducing cracking potential. Herein, lattice models are shown to be adept at simulating the thermal-hygral-mechanical phenomena that influence early-age cracking. In particular, this paper presents a lattice-based approach that utilizes a model of cementitious materials hydration to control the development of concrete properties, including stiffness, strength, and creep resistance. The approach is validated and used to simulate early-age cracking in concrete bridge decks. Structural configuration plays a key role in determining the magnitude and distribution of stresses caused by volume instabilities of the concrete material. Under restrained conditions, both thermal and hygral effects are found to be primary contributors to cracking potential. Early-age cracking is often a root cause of premature loss of safety and serviceability of concrete structures, including reinforced concrete bridge decks and slabs. Such cracking may occur due to plastic settlement and shrinkage, prior to concrete setting, or as a consequence of volumetric changes associated with thermal, hygral, or chemical phenomena that occur after setting ,2. The fMany of the parameters in Knowledge of early-age cracking has been gained primarily through laboratory testing, often using small-scale specimens, and through the monitoring of field performance. Laboratory testing allows for the examination of multiple specimens under controlled conditions, but it only approximates the circumstances of concrete bridge decks. In particular, laboratory testing might not adequately account for the restraint mechanisms and volumetric instabilities associated with actual structural and environmental boundary conditions. On the other hand, data from the monitoring of field performance are scarce and typically provide an incomplete picture of the reasons for good or poor performance. Furthermore, the consequences of variations in material composition, construction processes, and environmental conditions are difficult to anticipate without appropriate models.This research involves: (1) the development of a methodology for simulating the early-age behavior of structural concrete; and (2) application of the methodology to assessing early-age cracking of concrete bridge decks. The methodology relies on a simple form of lattice model , which hValidation exercises are conducted using measurements taken from small-scale laboratory tests and an instrumented bridge deck. The validated model is used to assess the various contributors to the early-age cracking potential of concrete bridge decks. Along with autogenous deformations and hygral gradients caused by the drying of exposed surfaces, thermal effects may be a prime contributor to deck cracking. The importance of restraint conditions on cracking potential is examined.The analyses of concrete early-age behavior are based on lattice models, which are composed of randomly positioned nodal points that are interconnected by lattice elements . The throf nodes . With reof nodes ,26 and aThe program is driven by a modeling of cementitious materials hydration, along with the influence of environmental boundary conditions that may vary with time. As described later, the hydration model also serves to determine mechanical properties, including tensile strength, elastic modulus, and creep behavior. After each time step of the thermal-hygral-structural analyses, the incremental changes in temperature and humidity are calculated. Corresponding thermal and hygral strain increments are determined and then introduced into the structural analysis.The lattice topology is defined by the Delaunay tessellation of a set of randomly placed nodes ; the VorThe use of irregularly spaced nodal points, connected by 1D elements, typically introduces spurious heterogeneity into the modeling effort. Such irregular lattices can be rendered homogenous through special techniques  or, as dDesirable features of the hydration model include the ability to simulate the hydration of blended cements, accounting for the chemical composition of the blend constituents. Herein, we use a versatile model of cementitious materials hydration ,32. ModeR is the universal gas constant (8.314 J/mol/K); The influence of temperature on the rate of hydration is represented by a maturity relationaterials .i multiplied by its weight fraction, The degree of cementitious materials hydration is assumed to beβ and τ are hydration parameters; and c is the cementitious materials content  and and5)α(α((5)α(teositions .T is temperature (K), Q is the rate of heat production (J/(kg · s)), λ is thermal conductivity (W/(m · K)), ρ is mass density , and Thermal radiation - Heat loss to the surroundings due to grey-body radiation is calculated usingnditions .The governing differential equation for heat conduction is∇·(λ∇T)+ρHeat exchange also occurs due to evaporation and condensation, but those mechanisms are considered to be of secondary importance for ordinary concrete structures. Some other relevant aspects of the thermal analyses are as follows.The heat capacity of the cement paste is estimated using an approach given by Bentz , in whicThermal conductivity of the concrete is estimated by taking the average of the Hashin-Shtrikman bounds for a two-phase composite formed of paste and aggregates .i and j, acts as a lineal conduit element. A semi-discrete form of Equation  until the For the lattice modeling of heat conduction, the material continuum is represented by a collection of 1D elements connected on a semi-random set of nodal points . Each edEquation  serves aquation  is showh as the field variable [s controls the rate of humidity drop and is thought to depend on The moisture field within the concrete varies with time due to both autogenous and external drying effects. Using relative humidity variable ,43, the ydration (16)hs=(d on w/c .h = 1), h = 0), and n controls the position of the diffusivity drop as the concrete dries from a saturated state Dh(ed state . The temented by (19)D0=DConvective transport of moisture across exposed surfaces is governed byThe lattice representation of the hygral field, and its solution procedure, are analogous to that of the thermal field . This approach was developed by Sadouki and van Mier  and lateAt this stage of model development, it is assumed that the diffusion process is uncoupled from the mechanical behavior of the material and any damage incurred during mechanical or hygral loading. Shrinkage strains in the elastic material arise from changes in relative humidity at the lattice nodes. A constant hygral shrinkage coefficient analysesΔεh=βhΔhCoupling of the thermal and hygral fields is not considered herein, but has been included in other studies ,51. Suchi and j, and their common Voronoi facet (C) of the Voronoi facet, and connected to the element nodes via rigid-arm constraints. The spring set consists of three axial springs, oriented normal and tangential to the facet, and three rotational springs about the same local (n-s-t) axes. The stiffness coefficients of the axial springs are:i and j; factor ξ relates the normal and shear spring stiffnesses, which can be adjusted to simulate macroscopic Poisson ratio of the material [ξ = 1, which is used herein, the lattice is elastically homogeneous under uniform modes of straining [ν = 0. Correct representation of the Poisson effect, both macroscopically and in an element-local sense, has recently been accomplished using an iterative procedure [s and t are aligned with the facet principal axes. The spring constants appear on the diagonal of the material matrix, ω is a scalar damage parameter used to model material fracture. Prior to fracture initiation, ω = 0. The element stiffness matrix  isA structural element is defined by two neighboring nodes, oi facet . The elematerial . In mostmaterial . For ξ =training ,56, althrocedure ,58. The acements . After ti and j, such that b is the element thickness. The dimension of After each equilibrium iteration within a load increment, the spring set forces of each element quations  and 23)ij are upnd width .α, residual tensile strength w =f springs of the rigid-body-spring network have been replaced with the series construct shown in m solidifying Kelvin units representing viscoelastic creep, s- and t-component) springs of the rigid-body-spring network are replaced by the same construct, but without the thermal and hygral unit. Superposition of the individual strain units, and differentiating their values with respect to time, produces the total strain rate:The stiffness and creep of concrete are modeled using solidification and microprestress theory ,73,74. IThe relationship between instantaneous strain rate and uniaxial stress rate, According to solidification theory, viscoelastic strains arise from creep of the solidified hydration products  whose properties do not change with age. Viscoelastic microstrain has the following formulation:arameter .α. Following di Luzio and Cusatis [Aging of the cement paste matrix is attributed to accumulation of the solidified hydration products. The viscoelastic micro- and macro-strain rates are related as follows: Cusatis , the agiγ, using the history integral formulation of Equation . The radial surface of the concrete exchanges heat with the environment  was used to cover the bridge deck for the time interval urements , placeme to 0.48 , such thThe coefficient of convective heat transfer, nd speed . Based ond speed , a modifχ = 3.5 based on measurements of Kada et al. [Measurements of the CTE of the hardened deck concrete provided a et al.  on varioa et al. .Hygral analysis inputs: The ultimate value of relative humidity, associated with self-desiccation, was assumed to be s = 3 governing the rate of self-desiccation according to Equation (n = 5.Equation . The parEquation  and 19)Hygral anz = 0).The concrete surfaces bounded by plywood formwork are assumed to be sealed  While the curing sheeting is in place , along with a single support along that plane to prevent rigid-body motion in the vertical direction.All stresses originate from thermal and hygral strains. Externally applied loads  were not considered at this stage of the analysis. Elements spanning the cast deck and the mature concrete substrate were given properties of the substrate concrete. This is a reasonable approximation given the small element size and our relative lack of interest in behavior at that bi-material interface. A zero-displacement condition was enforced across the plane of symmetry  the use of curing media; and (2) restraint to deck movement. Cracking of the concrete is not simulated, except for the analysis results presented near the end of z-component of the stress tensor has been evaluated at the TC1 and TC3 thermocouple locations. These As noted above, curing compound and polymer/fabric sheets were applied on the concrete deck as part of the curing protocol. Concrete stresses at the mid-deck location, normalized by the 28-day tensile strength, are plotted in y-direction , is indWhile in place, the curing sheets act to significantly reduce both the hygral and thermal stresses, as shown in f is the current tensile strength value at that location) over the computational domain. t = 11.42 days, which is near the time of maximum Knowing the stress state and tensile strength at each nodal location, we can plot maps of cracking potential strength . Based oFurthermore, if a curing compound has been applied, the cracking potential is further reduced. For the simulation results presented in The structural configuration used for the previous analyses is representative of in-plane conditions away from supports or diaphragms placed along the span length. As a rough approximation of the conditions local to such stiffening elements, the cell volumes have been filled with concrete . The conStress values due to the thermal component are plotted in The deck stresses due to hygral effects are plotted in Total stresses at the mid-span location, which include the thermal, autogenous, and drying shrinkage components, are plotted in By allowing fracture to occur, according to the procedure outlined in The surface cracking due to hygral and thermal gradients is more extensive than shown in Whereas these results indicate deck cracking would occur, the restraint condition associated with the internal diaphragm is an extreme case. Three-dimensional analysis of the deck is necessary to more accurately assess the effects of structural configuration on deck stresses. Furthermore, the effects of restraint and thermal straining in the longitudinal direction of the bridge are not captured by these planar analyses, even though such effects might contribute significantly to cracking potential.This form of discrete model is capable of simulating the multi-field quantities associated with early-age concrete behavior, despite its discontinuous representation of the problem domain. There are no major disadvantages of this discrete approach with respect to continuum approaches, such as the finite element method. Advantages of this form of discrete model include its simplicity and adeptness at simulating the transition from diffuse damage to localized cracking.Stress-to-strength ratio is lacking as a practical measure of cracking potential. Sharp hygral or thermal gradients near exposed surfaces typically cause high stresses, which is indicative of cracking. However, the cracking may only be superficial. Knowledge of the stress conditions through the structural cross-section is also necessary for evaluating the severity and potential consequences of cracking. In this sense, numerical modeling nicely complements knowledge gained by laboratory testing and field observations.Structural configuration plays a key role in determining the magnitude and distribution of stresses caused by volume instabilities of the concrete material. Under largely restrained conditions, both thermal and hygral effects were found to be primary contributors to cracking potential, leading to crack propagation through the depth of the deck. Three-dimensional simulations are needed to assess the influence of longitudinal restraints, thermal flexing of the mature concrete girders, and the effects of reinforcing bars.Realistic simulations of the early-age behavior of structural concrete require a wealth of information regarding the material constituents, production/curing processes, and structural and environmental boundary conditions. As shown by the parametric studies conducted herein, cracking potential is sensitive to input quantities that are typically not well defined, especially in field applications. Ultimately, the assessment of cracking potential needs to be cast in a probabilistic framework that accounts for uncertainties in the various inputs to the modeling effort.This research pertains to modeling the early-age behavior of concrete materials with realistic structural and environmental boundary conditions. The discrete modeling approach, presented herein, is a novel assemblage of works of the authors and many other researchers. The relevant field quantities  are represented by lattice models, which are defined by Delaunay/Voronoi tessellations of the computational domain. The simulations begin when the concrete materials are mixed. Based on a modeling of cementitious materials hydration, the simulations provide a spatial description of property  and stress development. This information can be used to assess the potential for early-age cracking. The following conclusions were deduced from this study:


There are limited published data on the types and appropriateness of oral and intravenous (IV) antibiotics prescribed to patients receiving haemodialysis. This information is critical to optimise antibiotic prescribing. Therefore this study aims to describe the patterns of use and the appropriateness of oral and IV antibiotics prescribed to patients receiving haemodialysis.This was a prospective, observational study across four community and two hospital inpatient haemodialysis units in Melbourne, Australia. Data were collected from July 2014 to January 2015 from participants. Antibiotic regimens prescribed were compared with nationally available antibiotic guidelines and then classified as being either appropriate, inappropriate or not assessable by an expert multidisciplinary team using the National Antimicrobial Prescribing Survey tool.Overall, 114 participants consented to this study where 55.3% (63/114) received antibiotics and 235 antibiotic regimens were prescribed at a rate of 69.1 antibiotic regimens/100 patient-months. The most common oral antibiotics prescribed were amoxycillin/clavulanic acid and cephalexin. The most common IV antibiotics prescribed were vancomycin, piperacillin/tazobactam, cephazolin and ceftriaxone. The percentage of inappropriate antibiotic regimens prescribed were 34.9% (15/43) in the community setting and 22.1% (40/181) in the hospital setting. Furthermore, 29.4% (30/102) of oral and 20.5% (25/122) of IV antibiotic regimens were inappropriate with incorrect dosing as the primary reason.Although this study is limited by the sample size, it describes the high antibiotic exposure that patients receiving haemodialysis experience. Of concern is inappropriate dose and frequency being a major issue. This requires interventions focused on the quality use of medicines and antimicrobial stewardship aspects of prescribing in this population. Infection contributes greatly to mortality and hospitalisation in patients receiving haemodialysis worldwide –3. TheseIn Australia, patients receive maintenance haemodialysis in community satellite dialysis units, outpatient or inpatient hospital dialysis units or at home. Currently, many patients receive maintenance haemodialysis in community satellite or hospital outpatient units in Australia . As suchTo date, studies have focused on investigating intravenous (IV) antibiotic prescribing and appropriateness in this population in the hospital and outpatient setting , 9. HoweThis prospective, observational study was approved by Melbourne Health (QA2014012), Western Health (QA2014.049) and Monash University  ethics committees.Four community haemodialysis units (CHU), two community satellite and two hospital outpatient haemodialysis units, participated in this study. These CHUs were affiliated with two participating hospitals, each of which had a tertiary teaching hospital inpatient haemodialysis unit (HIHU). All CHUs and HIHUs were located in Melbourne, Australia.Eligible participants were invited to participate and written consent obtained. Eligibility criteria were: adults (≥18 years old), receiving intermittent haemodialysis and able to provide written consent. The duration of the study at each unit was four months, with a two to three week lag period between commencing the study from one participating unit to another, in order to optimise study management and participant recruitment. The overall study duration was six months (July 2014 to January 2015). All consenting participants were followed until the end of the four month study period for each unit regardless of when enrollment occurred.In the CHU, eligible participants were approached to participate at the start of the study period by one of the investigators. For the HIHU, eligible participants were approached during their hospital stay by investigators. Any CHU participants admitted to a participating HIHU were followed up during their inpatient stay. Any HIHU participants transferred to a participating CHU were also followed up at the CHU. Participants transferred to a non-participating CHU or HIHU were not followed up.Baseline demographic, medical, medication and haemodialysis-related data were collected for all participants. For each participant receiving antibiotics, the documented indication, antibiotic strength, dosage regimen, duration of treatment and specialty of the prescriber; and if available, microscopy, culture, antibiotic susceptibility (M/C/S) and therapeutic drug monitoring (TDM) results were collected. The documented indication was defined as the indication stated in the medical records, by the participant or the prescriber, irrespective of the clinical definition of the infection.For CHU participants, data were obtained from the participant or carer and their medical histories. Participants receiving antibiotics were asked to bring their antibiotics to their haemodialysis session at the CHU. The prescriber was also contacted where possible during the study to confirm the documented indication and antibiotic regimen(s) prescribed, plus results from M/C/S tests. In the HIHU all data were obtained from the participant’s hospital medical records.The documented indications for antibiotic prescribing were classified as prophylactic therapy; respiratory tract (RTI), skin and soft tissue (SSTI), vascular access (VAI), bloodstream (BSI), urinary tract (UTI), gastrointestinal tract (GITI) and other infections; infection source not known; and infection not documented when no indication was specified . HospitaOnly administered antibiotic regimens were evaluated in this study. Antibiotic regimens included single doses and antibiotic courses where more than a single dose was administered. A single dose is often prescribed for prophylaxis (e.g. pre-transplant prophylaxis) or empirical therapy for a suspected infection. Antibiotic regimens prescribed in the community setting were prescribed in a primary healthcare or outpatient setting. The duration of treatment in this setting was either the prescribed duration or the number of days to complete the prescribed quantity.Antibiotic regimens prescribed in the hospital setting were those prescribed in an inpatient setting. In the hospital setting, the duration of treatment was taken as the date the antibiotic commenced to the date it was ceased on the medication chart. If the antibiotic dose, dosing interval or route of administration was altered in the medication chart, it was classified as a new antibiotic regimen.Oral and IV antibiotic regimens prescribed were compared to the recommendations from the Australian national Therapeutic Guidelines (TG): Antibiotic Version 14 and 15, , 13 unleThe TG: Antibiotic provides recommendations from an antibiotic expert group, all of whom are working in Australia, on the types of antibiotics, dose, frequency and duration of treatment, for a wide variety of infections seen in both the community and hospital setting. The evidence to support the recommendations are drawn from published literature (where available) and the experts’ collective experiences. Antibiotic dosing guidelines in renal impairment and dialysis setting are provided as a table in an appendix in the TG: Antibiotic for all antibiotics available in Australia . This taThe Renal Drug Handbook Third Edition was referred to in order to confirm the ideal dosing of the antibiotic regimen when it was not available in the TG: Antibiotic or hospital guidelines . Only doEach antibiotic regimen prescribed was then reviewed by an expert multidisciplinary team to determine whether they were appropriate, inappropriate or not assessable based on the classifications utilised in the publically available National Antimicrobial Prescribing Survey (NAPS) (see Table The expert multi-disciplinary team consisted of a pharmacist with community pharmacy experience (KH), renal pharmacist (MN) and infectious diseases consultant (KB) who independently assigned appropriateness to all antibiotic regimens prescribed. The team then compared their assessments and any discrepancies were discussed until consensus was reached.2 test, Fishers exact test and Mann-Whitney U test were used where appropriate. A p-value of 0.05 or less was considered statistically significant. The rate of antibiotic use is reported as the number of antibiotic regimens prescribed per 100 patient follow up months (100 PM). The patient follow up months is the sum of the months that participants were followed up.Statistical analysis was performed using IBM SPSS Statistics version 22 and χIn total, 239 patients were approached to participate in the study. Of these, 63 were excluded as they could not provide consent due to medical reasons or language barriers. Overall, 114/176 participants consented to participate with 81 from the CHU and 33 from the HIHU. Nineteen CHU participants were admitted into a participating HIHU and four HIHU participants were transferred into a participating CHU during the study period. Eight participants were considered withdrawals from the study due to death (two CHU and three HIHU participants) or kidney transplantation (one CHU and two HIHU participants). There were 340 patient-months (PM) of follow up overall, with 308 for the CHUs and 32 for the HIHUs.The participant’s demographic data are shown in Table Pneumocystis jiroveci pneumonia prophylaxis. Infection was not documented for three episodes and two had unknown indications due to missing medical inpatient records.There were 114 documented indications for antibiotic therapy. Of the suspected and documented infections, 76 were community-acquired (rate of 22.4 episodes of infection/100 PM) and 17 hospital-acquired (5.0 episodes/100 PM). The most common infections were RTI (27/114), SSTI (19/114), BSI (14/114), UTI (11/114) and VAI (7/114). Five episodes of BSI involved participants who had catheters as their vascular access. Additionally, 16 indications were for prophylactic therapy of which, five were for surgical prophylaxis and five for Staphylococcus (23/35) and Enterococcus (7/35) species. Three were methicillin-resistant Staphylococcus aureus (MRSA) and one was vancomycin-resistant enterococcus. The most common gram-negative bacteria isolated was Escherichia coli (4/17). No multi-drug resistant gram-negative bacteria were isolated.There were 190 microbiological cultures requested with blood (97/190), wound (28/190) and urine cultures (24/190) the most common. Most were requested from the hospital setting, with three from the community setting. Seventy micro-organisms were isolated from 54 cultures; 35/70 were gram-positive and 17/70 were gram-negative bacteria. The most common gram-positive bacteria isolated were Overall, 55.3% (63/114) of participants received antibiotics; 43.2% (35/81) CHU participants and 84.8% (28/33) HIHU participants. A total of 235 antibiotic regimens were prescribed . The rate of antibiotic use overall was 69.1 antibiotic regimens/100 PM, with 32.4 regimens/100 PM for oral and 36.8 regimens/100 PM for IV antibiotics. The rate of antibiotic regimens prescribed in the community setting was 15.5 regimens/100 PM (48 antibiotic regimens in 308 PM) and in the hospital setting the rate was 584.4 regimens/100 PM (187 antibiotic regimens in 32 PM). Only four regimens in the community setting and 29 in the hospital setting were prescribed as directed therapy after a pathogen had been reported in clinical specimens. Twenty-one antibiotic regimens were prescribed for prophylactic therapy, eight of which were trimethoprim/sulfamethoxazole.The most common oral antibiotics prescribed were amoxycillin/clavulanic acid for RTI and SSTIs and cephalexin for SSTI and UTIs Table . The mosOverall, 95.3% 224/235) of the antibiotic regimens could be assessed for appropriateness of prescribing. Of these, 75.4% 169/224) were appropriate and 24.6% (55/224) were inappropriate (Table /235 of t69/224 weThe most common inappropriately prescribed oral antibiotics were amoxycillin/clavulanic acid and cephalexin Table . For amoBoth cephazolin and meropenem were the most common inappropriately prescribed IV antibiotics Table  often duTo the best of our knowledge, this study is the first to evaluate the types and appropriateness of antibiotic regimens prescribed to patients receiving haemodialysis in Australia, and more specifically, for oral antibiotics, worldwide. In this study, 55% of the participants received at least one antibiotic in comparison to the Australian general population where 45% were supplied with at least one antibiotic in a twelve month period . The ratClassifying an antibiotic as inappropriate was often related to the dose and dosing interval selected. This has also been reported in patients with chronic kidney disease not requiring dialysis . ConsequTo date, very few studies have explored antibiotic use and appropriateness in patients receiving haemodialysis. A hospital outpatient based study from the United States of America evaluated the appropriateness of IV antibiotics prescribed . They foOral antibiotics are commonly prescribed in the primary care and hospital setting, yet are less well explored compared to IV antibiotics. Of concern is that almost a third of oral antibiotic regimens prescribed in this study were inappropriate, highlighting the need for more research to further explore the use and appropriateness of oral antibiotics prescribed to this patient population in other countries.Interestingly, vancomycin was prescribed appropriately in most cases in our study. Vancomycin was prescribed empirically for most cases in the study, which was deemed an appropriate indication due to the risk of MRSA infections in this patient group. Other studies where vancomycin is prescribed empirically before culture and sensitivities are available have also reported that 80–88% of vancomycin doses or courses are appropriate , 19. YetThere are unique challenges associated with prescribing antibiotics in the haemodialysis setting such as the need to take into account the effect of haemodialysis on antibiotic clearance. It is vital that prescribers have readily accessible user-friendly resources to aid antibiotic prescribing to those receiving haemodialysis. Examples include decision support programs or incorporation of guidelines or tools into clinical and health pathways. Dissemination of knowledge from specialists in this area to other prescribers, particularly in primary healthcare could also be explored.Establishing antimicrobial stewardship in dialysis centres has been discussed by D’Agata . The majWhilst the study was conducted in Australia, it is acknowledged that there may be differences with regards to guideline recommendations for antibiotic dosing in the dialysis setting in other countries. In Australia, the main national antibiotic guideline is the TG: Antibiotics which provides recommendations for dose adjustments to be made in renal impairment. Other international guidelines available to guide the dosing of antibiotics in the dialysis setting include the Renal Drug Handbook, published in the United Kingdom,  and the Despite sample size limitations and a shorter follow up period compared to previous studies, , 9 the cThe current study has provided important insight into the types and appropriateness of antibiotics prescribed to patients receiving haemodialysis in an environment where data are scant. Indeed, for the first time, the appropriateness of orally administered antibiotics prescribed to this cohort was investigated. Our data indicates that there is a high burden of antibiotic exposure and considerable inappropriate prescribing of antibiotics to those receiving haemodialysis. Our study suggests that antimicrobial stewardship or continuing education related interventions are needed to optimise the use of antibiotics in patients receiving haemodialysis to minimise the emergence of resistant organisms and importantly, to optimise patient safety and outcomes.


The authors regret that the above mentioned paper contained a serious error relating to The authors apologize for using the figure without permission and not acknowledging the source of the figure, which was taken from the article by Yamasue et al. (2002). The figure was not linked to its proper source due to an unfortunate chain of events. It was originally included as an exemplar as part of the training given on the procedure for extracting the CSI data. Dr Virginia Ng, who had finalised the region-of-interest positioning for this study and conducted the training program, unfortunately passed away suddenly towards the end of the study in January 2008. Later, it was erroneously taken as implicit that the training image used to delineate the region of interest was derived from a participant in our own study, as opposed to having been taken from an earlier publication.To correct the error in our publication, we have supplied an image of an SPGR scan depicting the axial slice from which the anterior cingulate cortex was measured using a control participant in our study . The detThe same SPGR that was used to prescribe the CSI was segmented into grey matter, white matter and CSF fractions using SPM-2. The fractions of the different tissue types were determined for each CSI voxel using automated routines in SAGE/IDL . The positions of the CSI voxels and PRESS-localised volume relative to the SPGR were extracted automatically from the CSI and SPGR file headers. This assumes that the subject does not move between the SPGR and the MRSI acquisitions; therefore the time between the two scans was kept to a minimum. A similar routine in SAGE/IDL was also used to extract the raw data for each MRSI voxel to pass to LC model for analysis. The routine allows large 2D-MRSI datasets to be analysed and production of quantitative metabolite maps using the frequency-domain fitting method LCModel .NeuroReport, and its publisher .The authors greatly regret the error, and are grateful for the understanding of Professor H. Yamasue and colleagues, the Editor of


We examined this claim in animal models.S-MCYS was less accumulated in some non-tumor tissues than [11C]MET, but showed lower tumor-to-brain contrast.[The online version of this article (10.1007/s11307-017-1137-z) contains supplementary material, which is available to authorized users. However, [11C]MET is taken up not only by tumors but also by various other lesions [11C]MET. A successful alternative is the amino acid analog O-2-[18F]fluoroethyl-L-tyrosine ([18F]FET) [S-[11C]methyl-L-cysteine ([11C]MCYS) [11C]MCYS in Hepa1–6 tumors compared to [11C]MET, but a lower uptake in turpentine-induced sterile inflammations [11C]MCYS was claimed to offer superior differentiation of tumor from inflammation and to have considerable potential as an oncologic PET tracer.The radiolabeled amino acid L-methyl-1Cmethion lesions . For thi18F]FET) . Another1C]MCYS) , 6. MCYS1C]MCYS) , 8. Biodmmations . Thus, [11C]MCYS and [11C]MET in various animal models: immune-competent rats with orthotopically implanted gliomas  than [11C]MET, but shows a higher uptake in the healthy brain, resulting in lower tumor-to-brain contrast of [11C]MCYS scans. Moreover, irradiation of gliomas results in an acute, 5- to 6-fold increase of the volume with significant [11C]MCYS uptake which does not reflect the presence of viable tumor cells. Based on these results, [11C]MCYS and [11C]MET appear to reflect different aspects of in vivo biology.In order to examine this claim, we performed longitudinal PET studies with methionine was prepared by methylation of L-homocysteine thiolactone with [11C]methyl iodide. The radiochemical yield was 60 %, and specific activities were greater than 2 TBq/mmol [11C]methyl-L-cysteine was synthesized by [11C]methylation of L-cysteine [11C]methyl triflate rather than [11C]methyl iodide. 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) was produced by the Hamacher method MCYS and [11C]MET scans were made after 8 days and a [18F]FDG scan after 15 days; 2 : C6 glioma cells were injected as in group 1, but [11C]MCYS and [11C]MET scans were made after 6, 9, and 12 days; 3 : As group 2, but the lesion-containing hemisphere was irradiated after 8 days; 4 : 2 μl of physiological saline was stereotactically injected into the right striatum and [11C]MCYS and [11C]MET scans were made after 3 days; 5 (LPS-injected): As group 4, but 2 μl of a solution of LPS in saline was stereotactically injected into the right striatum in order to induce neuroinflammation.All actions with experimental animals were performed by licensed investigators. The study protocol was approved by the Institutional Animal Care and Use Committee of the University of Groningen (protocol 6561A). Male Wistar rats were acquired from Harlan. They were housed at 21 ± 2 °C under a fixed 12-h light–dark regime. Standard laboratory chow and water were available 2 and heart rate were continuously monitored. A longitudinal incision was made along the medial line of the skull, the skin and fascia were pushed aside, and the skull was exposed. A hole was drilled at the coordinates of the striatum , until the dura became visible and could be opened MCYS scan and a [11C]MET scan were made of each animal on each scanning day, with an interval of at least 2 h. The list mode data of the emission scans were reframed into a dynamic sequence: 6 × 10 s, 4 × 30 s, 2 × 60 s, 1 × 120 s, 1 × 180 s, 4 × 300 s, 3 × 600 s frames. Images were reconstructed employing ordered subset expectation maximization . The final datasets consisted of 95 slices with a thickness of 0.8 mm and an in-plane image matrix of 128 × 128 pixels. Voxel size was 0.5 × 0.5 × 0.8 mm. The linear resolution at the center of the field-of-view was 1.5 mm. Data sets were corrected for decay, random coincidences, scatter, and attenuation.On each scanning day, rats were anesthetized with isoflurane . [11C]MET, the maximum had to be set to SUV 1.4 (± 10 %). Care was taken to include in the ROIs only planes that were located within the brain, since wound tissue on top of the skull could strongly take up [11C]MET, particularly at short intervals (3–6 days) after surgery.Three-dimensional regions of interest (ROIs) were manually drawn in PET images, representing the tumor, LPS- or saline-injected striatum, contralateral healthy brain, and the wound on top of the skull. ROI volumes and levels of radioactivity (mean and maximum within the ROI) were calculated, using AsiPro® (Siemens). Tracer accumulation was expressed as a standardized uptake value (SUV): [tissue activity concentration (MBq/g) × body weight (g)/injected dose (MBq)], assuming a specific tissue gravity of 1 g/ml. Images were smoothed with a Gaussian filter (1.5 mm in both directions). The color scale of the images was set from SUV 0 to 2 (± 10 %), in order to clearly delineate the lesion. However, for visualization of LPS- or saline-injected striatum with FDG scan made in the same rats after 15 days indicated the presence of tumors with a volume of 451 ± 81 μl, filling almost an entire cerebral hemisphere and starting to invade the rest of the brain . An [he brain . Because11C]MCYS and [11C]MET showed a similar uptake in untreated tumors at 6, 8, or 9 days post inoculation , but [11C]MCYS showed only minor accumulation in these tissues , uptake of radioactivity in tumor and wound tissue was about equal .Mean tumor sizes estimated from [11C]MET was already significantly reduced , in contrast to the uptake of [11C]MCYS .At 1 day after irradiation, the tumor uptake of [11C]MET and [11C]MCYS scans in untreated animals were closely correlated  tumor volume between 9 and 12 days , whereas [11C]MET did not show any significant change in tumor volume during this period. At 12 days p.i., a therapy-related suppression of tumor growth was detected with both tracers, whereas untreated gliomas continued to grow exponentially  than in [11C]MET scans . This difference between saline and LPS was not visualized by [11C]MET  accumulates in healing wounds.The PET studies indicated a similar uptake of the two tracers in untreated gliomas at 6, 8, and 9 days and a slightly higher uptake of 1CMCYS athylation . The labPET scan . This di11C]MCYS indicated 47 % larger tumor volumes than [11C]MET  larger than the tumor volume observed with the same tracer in untreated rats  rather than the presence of viable tumor cells.We also examined the impact of radiotherapy on tracer uptake in gliomas. Tumor-bearing rats were scanned 1 and 4 days after the application of a single X-ray fraction of 25 Gy on day 8 after inoculation. The uptake of both tracers showed a significant decline after radiotherapy Table  which reMET Fig. , but the11C]MET and [11C]MCYS in a neuroinflammation model. The LPS model which we employed is associated with activated microglia and infiltration of leukocytes after 3 days [11C]MCYS showed a higher uptake than [11C]MET both in LPS-injected and saline-injected striatum, but the uptake of [11C]MCYS in healthy brain tissue was also higher. The lesioned-to-intact striatum ratios of the two tracers were therefore identical  the tumor-to-brain contrast in [11C]MCYS scans was 19 to 26 % lower than the tumor-to-brain contrast of [11C]MET. This difference in image contrast was due to a higher uptake of [11C]MCYS in brain tissue; (2) an acute, 2-fold increase of the apparent tumor volume was observed in [11C]MCYS scans after irradiation which appeared to be related to a treatment-induced artifact; (3) the decrease of tumor metabolism induced by radiotherapy was detected earlier in [11C]MET than in [11C]MCYS scans; and (4) both [11C]MET and [11C]MCYS showed negligible accumulation in LPS-injected striatum, i.e., in activated microglia. For these reasons, [11C]MCYS and [11C]MET appear to reflect different aspects of in vivo biology. [11C]MCYS may offer the advantage of lower background accumulation in extracranial tissue whereas [11C]MET may exhibit a lower normophysiological signal in the brain. Since the current data were acquired in anesthetized animals, tracer distribution may be different in the absence of anesthesia. Future studies should be aimed at elucidating the processes affecting the uptake of both amino acids and identifying the advantage of one compound over another in various circumstances.[ESM 1(PDF 101 kb)


China has a high rate of antibiotic use. The Chinese Ministry of Health (MOH) established the Center for Antibacterial Surveillance (CAS) to monitor the use of antibacterial agents in hospitals in 2005. The purpose of this study was to identify trends, pattern changes and regional differences in antibiotic consumption in 151 public general tertiary hospitals across China from 2011–2014.Valid data for antibiotic use were collected quarterly, and the antibiotic consumption data were expressed as the defined daily dose (DDD) per 100 inpatient days (ID). We compared the patterns of antibiotic use in different classes and geographical clusters.Total antibiotic use significantly decreased (P = 0.018) from 75.86 DDD/100 ID in 2011 to 47.03 DDD/100 ID in 2014. The total consumption of flomoxef sodium and cefminox increased from 1.31 DDD/100 BD in 2011 to 8.6 DDD/100 BD in 2014. Cephalosporins were the most frequently used antibiotics in all regions. Third-generation cephalosporins accounted for more than 45% of the cephalosporins used. Carbapenem use substantially increased (P = 0.043). Penicillin combinations with inhibitors accounted for 50% of the penicillin used, and prescribed meropenem accounted for most of the carbapenems used in all regions in 2014. The subclasses in each antibiotic group were used differently between the seven regions, and the total hospital antibiotic use in 2014 differed significantly by region (P = 0.014).Although the volume and intensity of total antibiotic use decreased, the antibiotic use patterns were not optimal, and broad-spectrum antibiotics were still the main classes. The aggregate data obtained during the study period reveal similar antibiotic consumption patterns in different regions. These findings provide useful information for improving the rational use of antibiotics. More detailed data on antibiotics linked to inpatient diseases need to be collected in future studies. Enterobacteriaceae, methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Acinetobacter baumannii, represent more than 50% of microbial isolates in China[Antibiotic consumption is one of the main causes of bacterial resistance to antibiotics and is a major global public health problem, particu in China.Several factors contribute to the misuse of antibiotics in China. First, physicians might overprescribe antibiotics because of a lack of knowledge about rational use or because they want to prevent potential infections. Second, antibiotics are regarded as a panacea or cure-all by patients, so they demand them even when they are not indicated, and they may also ask for newer antibiotics because they think these will be more effective. Third, To change this situation, promote the rational use of antimicrobial agents, contain antimicrobial resistance, support the global governance endeavours of the World Health Organization (WHO) and complIn 2005, the Chinese Ministry of Health (MOH) established the Center for Antibacterial Surveillance (CAS) to monitor the use of antibacterial agents in hospitals in China . The CASSome countries use national surveillance data to monitor antibiotic use. In Europe, retrospective data collected by the European Surveillance of Antibiotic Consumption (ESAC) project revealed a rather constant antibiotic consumption pattern with high variation across countries. Data coThese studies in China focused on a small number of hospitals or cities, did not analyse overall or subgroup comparisons of antibiotic use between different years and did not assess the effects of the interventions on changes in the use of different drugs in different regions. Studies investigating the differences in antibiotic use must be conducted in different regions of China, which has a population approaching 1.4 billion and a vast area. Therefore, in this study, we attempted to complete the following goals: first, we aimed to investigate the trends in antibiotic consumption by inpatients in public tertiary hospitals in China after the 3-year national campaign; second, we aimed to explore the variations in the consumption and patterns of antibiotic use in different regions; and third, we aimed to analyse the evolution of frequently used antibiotics and hospital-specific antibiotics (mainly the carbapenems and glycopeptides) in 151 hospitals between 2011 and 2014. In contrast to previous studies, our study is based on the national surveillance database, which contains reliable and valid data with more extensive coverage. Hence, this study is complementary and supplementary to previous studies and provides baseline information to improve future antimicrobial stewardship programmes.The CAS currently has 192 core member institutions, which are public tertiary hospitals  in 31 provinces, autonomous regions and municipalities in mainland China[This study was a retrospective analysis. The data regarding antibiotic consumption by inpatients were collected quarterly from 2011–2014 from the CAS and did not include discharge medication. The data contained information for the following variables: region ; hospital name; quarter; drug specification; unit; generic name; quantity of consumption; and inpatient days. The data on inpatient days were calculated by multiplying the quarterly total number of hospital discharges with the mean number of days of hospitalization.http://www.whocc.no/atc_ddd_index/). The antibiotic consumption data were divided into six main antibiotic groups, including the penicillins and beta-lactamase inhibitors (J01C), cephalosporins+carbapenems+monobactams (J01D), macrolides and lincosamides (J01F), quinolones (J01M), glycopeptides+polymyxins+steroid antibacterial+imidazole derivatives+nitrofuran derivatives (J01X) and other antibiotics . The glycopeptides (J01XA) and carbapenems (J01DH) are regarded as the last resort against serious bacterial resistance[The validated data were managed in Microsoft Excel 2016 . Aggregated surveillance data for antibiotic consumption were limited to systemic antibacterial agents and classified according to the Anatomical Therapeutic Chemical (ATC) classification . The data were collected at the level of the active ingredient (level 5 of ATC class J01) and the defined daily dose (DDD) measurement unit. The number of DDDs (defined daily doses) was calculated according to the WHO Collaborating Centre for Drug Statistics Methodology (available at esistance are and The penicillins (J01C) were further divided into the following four subclasses: narrow-spectrum penicillins (J01CE); broad-spectrum penicillins (J01CA); beta-lactamase-resistant penicillins (J01CF); and combinations with beta-lactamase inhibitors (J01CR). The cephalosporins were further divided into the following five subclasses: the four generations and other cephalosporins . The glycopeptides (J01XA) were further divided into the following two subclasses: vancomycin (J01XA01) and teicoplanin (J01XA02). The carbapenems (J01DH) were further divided into the following five subclasses: imipenem and cilastatin (J01DH51); panipenem and betamipron (J01DH55); meropenem (J01DH02); faropenem (J01DH03); and biapenem (J01DH05).The participating hospitals in the different provinces, autonomous regions and municipalities were geographically clustered into the following seven regions: north China (NC); east China (EC); south China (SC); central China (CC); northeast China (NEC); northwest China (NWC); and southwest China (SWC). The distribution of the 151 hospitals in the different regions is shown in ® SPSS® Statistics 20.The inpatient antibiotic consumption was measured using DDDs per 100 inpatient days (DDD/100 ID). The overall and subclass comparisons of antibiotic consumption between 2011 and 2014 were performed using the non-parametric Wilcoxon signed-rank test. The significance threshold was set at 5% (P<0.05). Antibiotic consumption in hospitals in the different regions was compared using the non-parametric Kruskal-Wallis test with a two-sided P-value <0.05 as the significance level. The percentages of the subclasses for each of the main antibiotic classes were compared among the seven regions. The data were analysed using the statistical package IBMBetween 2011 and 2014, antibiotic consumption in the participating hospitals expressed as the total number of DDDs decreased by 9.31%  as the total number of inpatient days increased during this period by 18.98% . The total antibiotic consumption trends are shown in The consumption of the other cephalosporins increased by 6.56-fold from 1.31 DDD/100 ID in 2011 to 8.6 DDD/100 ID in 2014. Their proportions increased from 3.92% to 26.87%, whereas the consumption of the first-, second-, third- and fourth-generation cephalosporins was reduced by 26.13%, 36.53%, 20.23% and 35.96%, respectively (P = 0.05) .Between 2011 and 2014, the consumption of narrow-spectrum, broad-spectrum and combinations with beta-lactamase inhibitor penicillins was reduced by 49.32%, 41.23% and 11.90%, respectively. Compared to 2011, the 2014 consumption pattern showed a proportional increase in beta-lactamase-resistant penicillin and combinations with beta-lactamase inhibitors that was compensated by the decrease in broad-spectrum and narrow-spectrum penicillins (P = 0.10) .Although these drugs were used in 2011, pefloxacin, fleroxacin, rufloxacin and gemifloxacin were not used in the participating hospitals in 2014. The consumption of pipemidic acid showed a large (more than 100%) increase (222.03%) (P = 0.317). The proportion of pipemidic acid use accounted for 18.10% of the total quinolone consumption in 2014, whereas this drug accounted for only 5.11% of the total quinolone consumption in 2011 (P = 0.078). The most frequently used class of quinolones in 2011 and 2014 was levofloxacin, which accounted for more than 30% of the total quinolone consumption each year .Compared with 2011, the consumption of carbapenem (J01DH) antibiotics was significantly increased (P = 0.043) in 2014. A large (more than 100%) increase was observed in the use of panipenem/betamipron, biapenem and ertapenem, with the proportions of each drug accounting for more than 10% of the total carbapenem consumption . The conAs shown in Within the penicillins (J01C), the use of combinations of penicillins accounted for most (50% and more) of the penicillin consumption in all areas, and the most frequent use occurred in SWC. The proportion of broad-spectrum penicillins was high (20% and more) in NWC, with a range between 20% and 10% in five areas, and was low (less than 10%) in SC. The proportion of beta-lactam-resistant penicillins was high (20% and more) in four areas  and ranged from 7% to 17% in the remaining areas .Within the cephalosporins , the proportion of the third-generation cephalosporins accounted for more than 45%; SWC had the highest proportion (56.91%), and NC had the lowest proportion (45.81%). The proportion of the second-generation cephalosporins was 30% or greater in NC, EC and SC; ranged between 21% and 24% in NWC, SWC and CC; and was 13.37% in NEC. The lowest proportion of the first-generation cephalosporins occurred in NC (8.39%), and the remaining areas had a proportion ranging from 10.12% to 18.23%. The relative frequency of the consumption of the fourth-generation cephalosporins ranged from 0.81% in NWC to 6.19% in NEC. The proportion of carbapenems and aztreonam was greater than 10% in NEC and NWC but was low in SWC (1.09%) .Within the quinolones, the proportion of levofloxacin accounted for the majority in each area and was greater than 50% in CC (73.41%), NC (60.99%), SC (56.38%) and SWC (54.74%). The proportion of moxifloxacin was greater than 30% in SWC (35.39%), NWC (33.22%) and NC (30.96%) and less than 10% in CC (8.66%). The primary use of ofloxacin occurred in NWC, and the highest proportion of pipemidic acid use occurred in EC. Enoxacin was mainly used in NEC, CC and NWC .Within the carbapenems used in the participating hospitals, meropenem use accounted for the highest consumption in each area, with a high proportion (40% and more) in CC and a low proportion (less than 30%) in NEC. Panipenem and betamipron were used only in SWC (27.18%), NEC (19.90%), SC (13.025) and EC (9.34%). Ertapenem and faropenem were used only in NC (23.53%), NWC (18.55%) and NEC (8.07%) .Within the glycopeptides, the proportion of vancomycin use was high (75% or greater) in SWC and low (less than 25%) in CC. The use of teicoplanin was substantial (75% or greater) only in CC .Boxplots of the antibiotic consumption in 151 hospitals in the different areas in 2014 are provided in To the best of our knowledge, this study is the first to estimate regional differences and compare the evolution of antibiotic consumption in hospital care across China. We showed that antibiotic consumption by inpatients in public tertiary hospitals decreased substantially (37.93% decrease between quarter 1 of 2011 and quarter 4 of 2012). The trends were similar to previous studies in China–17. ThesA previous article showed that broad-spectrum antibiotics were preferred in China from 2005–2012, our stuWe found that the broad-spectrum penicillins  were used more frequently than the narrow-spectrum penicillins, which was similar to observations in EU countries and the E. coli ranged from 43.8%-67.2% in various provinces across China and was higher in the NE than in the SW region[The number of quinolones was reduced for five subclasses , and levofloxacin (J01M12) remained the frequently used drug among the quinolines in 2014. The probable reason was that quinolones were severely restricted by the MOH due to the increasing rate of bacterial resistance in 2008, and theSW region, which iKlebsiella pneumoniae from 2005–2014[Klebsiella pneumoniae needs to be analysed further.We also found that the consumption of carbapenems (27.03% increase between 2011 and 2014) and glycopeptides (18.48% increase between 2011 and 2014) substantially increased during the study period. Significantly increasing trends were observed for the carbapenems (increased by 64.58%) and glycopeptides (increased by 29.17%) in a nationwide descriptive epidemiological study in the Republic of Korea from 2008–2012. A secon2005–2014. The relThe aggregated data from the CAS during the study period revealed an antibiotic consumption pattern in different areas across China that was similar to the ATC-3 classification. Considering the different socio-economic conditions and bacterial resistance, the MOH required health authorities of different areas to develop antibacterial drug lists that met local conditions. In addiet al. [One of the targets of the 2011 intervention in hospital care was that total antibiotic use should be limited to less than 40 DDD/100 ID. We showet al. found a sCAS was the first surveillance project by the MOH to monitor antibiotic consumption online at the national level in China. The monitored data provided credible and systematic information regarding antibiotic consumption in hospitals and enabled health authorities at national and regional centres to make scientific decisions. The resThere are several limitations to the study. First, valid data concerning antibiotic use were collected from 2011–14 due to the restriction of data availability. Because we could not obtain data prior to 2011, we could not compare the data before and after the 3-year national action. Second, the original data were collected only from public tertiary hospitals because many information systems of secondary hospitals did not have access to the CAS, and the data were not updated in a timely manner. Third, some agencies were not covered by the surveillance system, such as village clinics and township health centres. Fourth, the CAS collected data only for inpatients; therefore, we could not analyse the relationships between antibiotic consumption in ambulatory and hospital care. According to a study in Europe, the basic characteristics of use (extent and nature) are strongly correlated between the two healthcare settings within each country. Fifth, Escherichia. coli and third-generation cephalosporin-resistant Klebsiella pneumoniae dropped from 51.8%, 71.8%, and 62.3% to 35.8%, 59.0% and 36.5%, respectively. The prevalence of carbapenem-resistant Pseudomonas aeruginosa has also declined, and the resistance of Enterococcus faecium to vancomycin remained relatively stable[According to the report of Chinese Antimicrobial Resistance Surveillance System (CARSS) from 2011–2015, the prevalence of MRSA, third-generation cephalosporin-resistant ly stable. To contWe revealed a significant reduction in antibiotic use in public tertiary hospitals in China after the national initiative that aimed to reduce the misuse and overuse of antibiotics. Although the volume and intensity of total antibiotic use decreased, the patterns of antibiotic use in 2014 were not optimal. We also found that the consumption patterns of antibiotics for systematic use (J01) in different regions across China were similar and that the most used antibiotics were the cephalosporins (J01D). The subclasses of each antibiotic group were used differently in the seven regions, and the intensities of the antibiotic use in hospitals in different regions were significantly different. These findings provide useful information for the improvement of the rational use of antibiotics. However, we did not analyse the specific reasons for these differences because we did not collect determinants of drug use . Thus, further studies about the factors that determine prescribing behaviour in hospitals are needed.S1 Table(DOCX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.


To elicit the views of well‐informed community members on the acceptability of proposed policy interventions designed to improve community use of antibiotics in Australia.Two community juries held in 2016.NSW, Australia. Twenty‐nine participants of diverse social and cultural backgrounds, mixed genders and ages recruited via public advertising: one jury was drawn from a large metropolitan setting; the other from a regional/rural setting.Western Sydney and Dubbo communities in Jury verdict and rationale in response to a prioritization task and structured questions.Both juries concluded that potential policy interventions to curb antibiotic misuse in the community should be directed towards: (i) ensuring that the public and prescribers were better educated about the dangers of antibiotic resistance; (ii) making community‐based human and animal health‐care practitioners accountable for their prescribing decisions. Patient‐centred approaches such as delayed prescribing were seen as less acceptable than prescriber‐centred approaches; both juries completely rejected any proposal to decrease consumer demand by increasing antibiotic prices.These informed citizens acknowledged the importance of raising public awareness of the risks, impacts and costs of antibiotic resistance and placed a high priority on increasing social and professional accountability through restrictive measures. Their overarching aim was that policy interventions should be directed towards creating collective actions and broad social support for changing antibiotic use through establishing and explaining the need for mechanisms to control and support better prescribing by practitioners, while not transferring the burdens, costs and risks of interventions to consumers. While the measures introduced under the auspices of the Globally, the problem of AMR is increasingly conceptualized as one of supply and demand. Efforts to increase supply are focused on incentivizing therapeutic innovation.Responding to the need to curb antibiotic overuse and misuse, researchers around the world have been trialing more restrictive measures and clinician‐ and patient‐centred behavioural interventions. Policies aimed at postponing access to antibiotics for “low risk” or otherwise demanding patients include post‐dated or delayed prescribing.Clearly, most of the proposed policy remedies described above are not cost or effort neutral. Some are likely to be burdensome and contentious in that they will intentionally, and sometimes coercively, impose new costs on some for the benefit of others.We report on two community juries convened in 2016 to consider how to make antibiotic use in Australia more sustainable. A community jury (similar to the proprietary method Citizens' Juries) is a group of citizens brought together to receive detailed evidence about and deliberate on a specific issue. Community juries have been used in Australia and elsewhere to consider complex and contentious issues surrounding health resource prioritization and the introduction of new health technologies.National Antimicrobial Resistance Strategy,We consulted relevant policymakers  to design the questions juries would consider Box . All agrBox 11Educate prescribers and the public on appropriate antibiotic use.Make antibiotics significantly more expensive .Prohibit antibiotics from being dispensed on the day of prescription —this could apply to prescriptions written by GPs, veterinarians and/or dentists.Prohibit or severely restrict community‐based practitioners such as GPs, veterinarians and/or dentists from prescribing antibiotics of last resort.Ban the use of growth promoting antibiotics in food‐producing animals.Ask GPs, veterinarians and/or dentists to hang a signed poster in their consulting room pledging to only prescribe antibiotics when they are needed.Require GPs, veterinarians and/or dentists to write a justification on the patient's record each time they prescribe antibiotics.Antibiotics are often used when they are not needed. If this situation continues, antibiotics will no longer be effective when they are needed to treat a serious infection that could be fatal without effective treatment. The following measures have been proposed to help make sure that antibiotics continue to be effective when we really need them.Part A: Are there any other measures to promote sustainable antibiotic use that the jury thinks should be added to the list for consideration?In Part B, you will decide which of these seven measures is the best way to make antibiotic use more sustainable. Before you rank these seven measures, you may want to add more to the list.Part B: In this task, we are asking the jury to reorganize the list of measures. Put the best measure to make antibiotic use more sustainable at the top, and the worst measure at the bottom. Put all of the measures in order, from best to worst. Please carefully record the reasons for your decisions.2A group of citizens is convened for 1‐3 days;They are asked to consider a specific issue;They hear evidence from, and ask question of (often opposed) experts;They are given time for deliberation, and to come to a conclusion, which is documented.Community juries are a deliberative method, with these general characteristics:There are two main approaches to community juries. In the first, participants work as a group to draft open sets of recommendations on an issue; in the second, jury members vote on options presented by researchers.2.1We recruited two Community Juries, of both genders and a range of ages Table . We placOf 82 responders 32 could not commit or were not available. Six were ineligible because they or a close family member had prescribing authority or had recently worked for a pharmaceutical company. Of the remaining sample we recruited 30 jurors (15 from each area) based on their eligibility, socio‐demographic characteristics and availability. We sought socioeconomic and cultural diversity across juries. The jury in Western Sydney was more socio‐culturally diverse than the jury in Dubbo reflecting the composition of these communities; both juries broadly matched the average educational attainment in the Australian population  focused on interrogating the evidence and understanding the ethical, legal and practical issues. Jurors were first shown a documentary 30 minute) on the nature of antibiotic resistance, produced by the Science Unit of the Australian Broadcasting Corporation. minute oImmediately after each video, the expert was available by teleconference call or in person for jurors to question. These question and answer sessions, facilitated by a researcher, allowed jurors to clarify or question the arguments presented.For the first hour of Jury Day 2 (Sunday), jurors reflected on, discussed and debated the evidence, aided by a researcher acting as facilitator. Facilitation focused on promoting constructive dialogue and fair interaction amongst jurors. Juries then deliberated for an hour without researchers present to reach a verdict. After this hour, the researchers re‐entered the jury room. The verdict, underpinning reasoning and dissenting views, were reported to the research team in a final facilitated feedback session; the research team focused on recording these as accurately as possible, constantly checking with the jurors for clarification. The transcripts of the unfacilitated deliberation indicate that constructive dialogue and fair interaction continued during un‐facilitated periods. Our research and reporting processes for these Community juries were cross‐checked against the CJChecklist protocol.2.2The two deliberative groups (juries) are the unit of analysis in this study. All jury deliberations (facilitated and un‐facilitated) and expert question and answer sessions were audio‐recorded and then transcribed by an independent service. During the final session, a researcher recorded the verdict and reasons on a flipchart during the course of discussion. Each point was reviewed by the jury to ensure accuracy and altered at their direction. The transcripts of all sessions were subsequently qualitatively analysed by the first two authors to identify key reasons why jurors prioritized, supported and/or rejected the options they considered. Open coding was used to identify the range of arguments and reasons put forward by the jurors in their deliberations. Authors one and two then used framework analysis to systematically map how different arguments and reasons appeared in the two juries, respectively.3Part A: to identify 3 other measures to promote sustainable antibiotic use that they thought should be added to the list of seven policy interventions under consideration.Part B: to rank the resulting list of 10 policy interventions, from best to worst, and give reasons for their decisions.To recap, in their deliberations, the two juries were asked to address a two‐part question Box :Part A:3.1The juries in Western Sydney and Dubbo nominated similar additional policy interventions to form part of their deliberations. Both groups added that: (i) greater effort should be made to monitor imported foods for the presence of antibiotic residues and antibiotic resistant bacteriaBanning the use of antibacterial disinfectants in household cleaning products;Banning of sales promotion for antibiotics across human and animal health care;Mandatory warnings on antibiotic packaging; andIntroducing a yearly quota for each person of antibiotics sourced from primary care.Interventions considered but ultimately not supported by either jury included the following:3.2Most jurors did not actively differentiate between different groups of prescribers  during their deliberations or in their decision making, even though they were given several opportunities to do so. Rather than ranking each measure during the unfacilitated deliberation session, both juries independently chose to create priority categories  to which they then allocated each of the 10 interventions Table . These w3.3Both juries placed a relatively high priority on efforts to educate prescribers and consumers on appropriate antibiotic use, because they believed raising community awareness was an essential foundation for effective implementation of all other interventions. Acknowledging that efforts at communication around the issue of AMR had not previously made a substantive difference to levels of antibiotic consumption in Australia, jurors thought that targeted social and on‐product marketing campaigns could be used, in concert with more traditional forms of public health communication, to make people more mindful of the costs and risks of AMR. Food labelling, for example, could include information about the amounts of antibiotics used in production; antibacterial cleaning product labels could have a warning that they can promote resistance among bacteria in the environment. Jurors also noted that public messaging about antibiotic misuse should include alternative strategies for self‐management of minor illnesses—noting that unless people were equipped to respond to mild diseases appropriately, they would revert to established patterns of consumption Table .The introduction of surveillance systems and more robust restrictions to monitor and modify the prescribing behaviours of community‐based practitioners was also strongly supported by both groups. Jurors reasoned that, as trained professionals, human and animal health‐care providers should accept the external auditing of, and take responsibility for, their prescribing decisions. Most jurors did not think these types of measures placed an unwarranted burden on practitioners. In contrast, introducing a “practitioner's pledge” to waiting rooms or delayed prescribing was given a relatively low priority by both juries. Both groups saw the value of reminding everyone of the importance of changing their antibiotic use. Nevertheless, these interventions were not viewed favourably because jurors believed they would be largely unnecessary if the education campaign was effective and the new restrictions on prescribers were properly embedded and accepted by the public. They also thought that unless adopted universally, the “practitioner's pledge” and delayed prescribing would just encourage “doctor shopping” and punish health‐care practitioners who were doing the right thing by their patients and the community.The continued use of antibiotics for growth promotion in food production was not supported by either jury. Jurors reasoned that banning the non‐therapeutic use of antibiotics in agriculture was worth the extra cost to consumers. Both juries also thought that stricter monitoring of imported foods for the presence of resistant organisms and antibiotic residues, with trade suspensions for compliance failures, were necessary so that local producers were not unfairly disadvantaged. Both groups saw maintaining the capacity to treat infectious disease in animals as important. However, the Western Sydney jury gave a higher priority than the Dubbo jury to monitoring imported foods although, as a group representing a rural community, the latter were more likely to be adversely effected by any asymmetrical changes in these policies. Because the costs of banning growth promotants and increased monitoring of imported foodstuff would almost certainly be passed on to consumers, both groups thought that the public education campaign should explain the need for these measures.Finally, the juries were unanimous that introducing a tax or price disincentive to curb antibiotic use should not be considered, even if its application was limited to animal health and/or agriculture. They reasoned that increasing the cost of antibiotics would only deepen existing inequities of access to effective health care for those truly in need. In their reasoning jurors again noted that, if appropriate antibiotic prescribing was the norm, then increasing the price to reduce demand could not be considered a viable policy option. Jurors were also concerned that placing the burden on consumers in this manner would not facilitate a genuine culture shift, but rather encourage secondary unauthorized markets in antibiotics.4Antimicrobial Resistance Strategy means that many of these measures are being trialed,This study aimed to examine and compare the extent to which groups of informed citizens living in large metropolitan and regional/rural settings would support different policy approaches to curbing the misuse of antibiotics in the Australian community. A range of evidence‐based strategies have been shown to significantly reduce the unnecessary prescribing of antibiotics, and current evidence suggests that community‐based practitioners have a central role in maintaining the efficacy of antibiotics.After 2 days of information and deliberation, both juries placed a high priority on: (i) ensuring that the general public were better educated about AMR and their role in responding to the risks posed; and (ii) introducing coercive and restrictive measures that increase practitioner responsibility for their antibiotic prescribing decisions. The overarching policy aim of both juries was to increase accountability as a means to curb antibiotic misuse. Jurors recommended that health‐care providers be made much more accountable for their prescribing decisions through interventions that place restrictions on their clinical autonomy, systems for surveillance and active auditing of their practices, or both. This suggests that, when well‐informed about the drivers of AMR and risks it poses to Australia's agricultural and health‐care systems, members of public are open to imposing more intrusive or restrictive types of measures than those currently being implemented under the government‐led package of reforms.When given the opportunity to suggest interventions not included in the original list of seven, both juries recommended and strongly supported creating an antibiotic prescribing surveillance system to improve accountability through monitoring health‐care providers and giving them feedback on their prescribing behaviours. Indeed, both juries favoured introducing a suite of further measures and regulations that would act as a check on prescribers to direct them away from unwarranted antibiotic use. Evidence as to the effectiveness of prescriber‐focused interventions is limited, but growing rapidly,Introducing new restrictions on prescribers may meet with resistance from some professional groups in Australia, and different models would be required for different health‐care settings.Other less coercive interventions and nudging techniques such as the practitioner's pledge have been found to lower prescribing rates,In general, neither group favoured patient‐based interventions such as price increases and delayed prescribing. In human medicine at least, systematic reviews suggest that delayed prescribing is likely to be one of the most effective interventions, especially for upper respiratory tract infections.Any attempt to decrease consumer demand by imposing a tax or levy to increase antibiotic prices was completely rejected by both groups. However, the jurors' aversion to imposing costs on the public to curb antibiotic overuse was restricted to therapeutic use—for both human and animal patients. Jurors saw any price increase for consumers as being punitive because burdens would be imposed on those who truly needed antibiotics. Both groups were also averse to increasing costs for the therapeutic use of antibiotics for animals because of the risk that this would be a barrier to effective care for some that could result in poorer animal welfare outcomes. That said, both juries saw grounds for further restriction on the non‐therapeutic use of antibiotics in animals and the creation of mechanisms—such as monitoring imports for antibiotic residues and resistant bacteria—to ensure that poor practices elsewhere were not rewarded. Both groups were keen to make Australia a shining example in restricting the non‐therapeutic use of antibiotics in food production use while also ensuring that the cost of antibiotic‐free agriculture was shared across society.Despite similarities in the intervention rankings, there were some differences in how each of the juries justified their positions. The jury in metropolitan Western Sydney seemed keen to emphasize a non‐punitive form of accountability, which was closely integrated with efforts towards raising public awareness about AMR. In contrast, the jury in regional Dubbo were more comfortable introducing more coercive restrictions and punitive forms of accountability for providers who failed to do the right thing. When viewed in the light of the dilemma between the need for responsible and restrictive use of antibiotics on the one hand, and physicians' obligations to their patients on the other, both sets of jurors were very reluctant to shift the risks and burdens of effective antimicrobial stewardship onto patients. For jurors, it was important that any restrictive measures were implemented judiciously such that none acted as a barrier to timely and effective care.4.1A limitation to this study is that community juries are comprised of small groups of “engaged citizens” whose views may not represent those of the general public. However as two juries in different settings came to similar conclusions, it seems likely our findings are replicable.5With or without a second golden age of drug discovery, the sustainable use of antibiotics is essential; to achieve this a major sociocultural shift will be required that is both constitutive of and supported by new distribution systems that allocate this resource according to individual needs, population benefits, a shared conception of the common good, and values such as equity and fairness.The overarching aim of both juries, during their deliberations, was that policy interventions for this issue should be directed towards creating collective actions and broad social accountability for antibiotic use. The jury outcomes echo the basic but important observation that if we are to curb inappropriate antibiotic use while also ensuring access when antibiotics are required, then a variety of actions are needed to target different groups in each society.None to declare.