The incorporation of polyhedral oligomeric silsesquioxanes (POSS) molecules as nanoparticles into polymers can provide improved physico-chemical properties. The enhancement depends on the extent of dispersion of the nanofiller, which is determined by the compatibility with the polymer that is by the POSS type, and the processing method. In this study, poly(ε-caprolactone)/POSS derivatives nanocomposites (PCL/POSS) were obtained via solution-casting and melt compounding. Two amino-derivatives containing different alkyl substituents, and ditelechelic POSS-containing hybrid PCL masterbatch were used as nanofillers. The effect of preparation method, POSS content and type on the morphology, thermal, mechanical, and surface properties of nanocomposites were studied. Morphological analysis evidenced the formation of POSS crystalline aggregates, self-assembled POSS molecules of submicrometer size dispersed in the polymer matrix. The best dispersion was achieved using the ditelechelic POSS-containing hybrid PCL masterbatch, and comparing the two amino-POSS derivatives, the one with longer alkyl chain of substituents exhibited better degree of dispersion independent of preparation method. DSC analysis showed the role of POSS derivatives as nucleating agents for PCL. The incorporation of POSS derivatives into the PCL matrix improved thermal stability. The preparation method, POSS type and content had influence on mechanical properties of nanocomposites. POSS nanoparticles enhanced the surface hydrophobicity of PCL. In recent years, the growing problem of waste disposal has sparked a great interest in biodegradable polymers ,2,3,4. PAmong the variety of nanoscale fillers, polyhedral oligomeric silsesquioxanes (POSS) nanoparticles are considered as one of the most interesting nanofillers that have been used in the preparation of nanocomposites. POSS are a new class of organic/inorganic hybrid materials exhibiting a specific three dimensional cage structure made up of Si–O, with size from 1.5 to 3 nm in diameter. The tetravalent Si atoms of POSS are bound to organic groups, one or more of which may contain reactive functional groups. POSS additives can be incorporated into organic polymers via copolymerization, grafting, or blending ,15,16,17g-PCL nanohybrid by melt blending into PCL. Individualized POSS nanoparticles dispersed in the nanocomposites were only found when POSS-g-PCL nanohybrid was used as a masterbatch. Nanocomposites with enhanced crystallinity and thermo-mechanical properties were obtained. Miltner et al. [In previous works, different POSS derivatives have been incorporated into PCL ,23,24,25r et al.  reportedr et al.  studied g-PCL-g-propyl-heptaisooctyl-POSS (PIOPOSS–PCL–PIOPOSS), were used as fillers to prepare PCL/POSS nanocomposites. X-ray diffraction (XRD) and transmission electron microscopy (TEM) were used to examine the state of dispersion of POSS nanoparticles in the nanocomposites. Thermal properties were determined using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The mechanical properties were investigated through tensile tests. Surface properties of nanocomposites were studied by contact angle measurements.The purpose of the present study is to investigate the effects of POSS type, POSS concentration, and preparation method (solution-casting and melt compounding) on the morphology, thermal, mechanical, and surface properties of the PCL/POSS nanocomposites. Two amino-derivative POSS containing different alkyl group, aminopropylheptaisobutyl-POSS (APIBPOSS) and aminopropylheptaisooctyl-POSS (APIOPOSS), and ditelechelic POSS-containing hybrid poly(ε-caprolactone) masterbatch, propyl-heptaisooctyl-POSS-Aminopropyl-heptaisobutyl-POSS is the only amino-POSS derivative used in the so far reported studies focused on PCL/POSS nanocomposites, and neither the effect of preparation method (solution casting and melt mixing), nor the effect of POSS substituent group have been studied ,23,24,2531H71NO12Si8, Fw = 874.58), a white crystalline powder, and APIOPOSS , a pale yellow viscous liquid, were purchased from Hybrid plastics . PIOPOSS-PCL-PIOPOSS hybrid was synthesized by grafting APIOPOSS to PCL chains using “click chemistry” as described elsewhere [N-(3-(heptaisooctyl POSS) propyl) propiolamide) and bis-azide end-functionalized PCL were used for the click chemistry approach. 3) was obtained from Scharlau .Poly(ε-caprolactone) (PCL) , was supplied by Sigma-Aldrich . APIBPOSS  . For characterization purposes, the extruded mixture was compression-molded at 60 °C and 300 bars of pressure for 5 min. The nanocomposites were named PCL/APIBPOSS-x-M and PCL/APIOPOSS-x-M where x denotes the weight percentage of POSS derivative.XRD patterns were recorded on a Bruker D8 Advance X-ray diffractometer  with a graphite monochromator, Cu Kα generator (λ = 0.154 nm), and operating at 40 kV/30 mA.TEM micrographs were obtained using a Philips Tecnai G2 20 TWIN TEM  at 200 kV accelerated voltage. The samples were cryo-ultramicrotomed using a Leica EM UC6 ultramicrotome apparatus and placed onto Cu grids.−1.Molecular weight of the PCL matrix (before and after nanocomposites preparation) was determined by gel permeation chromatography (GPC) analysis, using a Waters 2410 HPLC instrument  equipped with Styragel columns calibrated with polystyrene standards, with tetrahydrofuran as eluent with the flow rate of 1 mL min−1. The samples, about 6 mg, were heated from −100 to 100 °C and held in the molten state for 5 min , then cooled to −60 °C at 10 °C min−1 and held 5 min, and again heated to 100 °C at 10 °C min−1.DSC analyses were carried out using a TA instruments TA-DSC Q2000  under nitrogen atmosphere at a heating rate of 10 °C min−1. The thermal degradation temperature was taken as the onset temperature at which 5% of weight loss occurs.Thermogravimetric analyses were performed on a TA instruments His Res TG-Q-500 instrument  under nitrogen or air atmosphere from 50 to 800 °C at a heating rate of 10 °C min−1. Testing was carried out on at least five identical samples of each composition and the average values were reported.Tensile tests were carried out with a Universal mechanical testing machine Instron model 5569  according to ASTM D 638, at room temperature, gauge length of 35 mm and speed of 5 mm minStatic contact angles were measured by using the sessile drop technique with a digital goniometer  equipped with a dispensing needle (Dataphysics Contact Angle System OCA), using deionized water as liquid. At least 10 measurements were taken at different locations of the each sample surface and average values of static contact angles were reported.The morphology and the state of the POSS dispersion in the PCL matrix were observed with the complementary techniques of XRD and TEM. θ = 21.34°, 21.96°, and 23.56°, corresponding to the (110), (111), and (200) planes, respectively [θ range of 5–14° of PCL/APIBPOSS containing 2 and 5% of nanofiller  was also detected 1/2 [3)1/2 [3)1/2 [3)1/2, versus 2.2 (J/cm3)1/2 for APIBPOSS. Therefore, on the basis of this difference a higher solubility of PIOPOSS in the PCL matrix, that is greater compatibility, and less tendency to aggregate in comparison with APIBPOSS is expected. Considering the Flory–Huggins theory for polymer solutions and blends, the Flory–Huggins parameter χ12, included in the definition of the mixing enthalpy, can be related to the solubility parameters of two substances [δ1 and δ2 in our case are the solubility parameters of the PCL 1 and POSS 2, respectively, R and T are the gas constant and temperature, respectively, and VM is a reference volume which is the molar volume of the smallest repeat unit. It is expected that the interaction between PCL and APIOPOSS would be more thermodynamically favorable than the PCL/APIBPOSS, since the values for solubility parameter are closer than that of APIBPOSS. Solubility parameter value is not determined in the case of the ditelechelic hybrid, however, an enhancement in the dispersion state would be expected since the PCL chains covalently bonded to the POSS surface could improve the compatibility between PCL and the POSS nanoparticles. This enhancement of compatibility could be due to the solubility of low molecular weight PCL chains of the hybrid into the PCL matrix. The TEM observations are in agreement with the solubility parameters.Solubility parameters can be used for predicting the solubility of one material into another, in this case the POSS nanoparticles into the polymer matrix ,28,29,303)1/2 , 17.5  of the neat PCL and nanocomposites extruded at 90 °C and 50 rpm for 10 min. The Mw and Mn values show that PCL did not degrade under the melt mixing conditions of nanocomposites.In order to assess whether degradation of PCL took place at high temperature during melt extrusion by aminolysis reaction between the primary amine function present on POSS nanocages (APIBPOSS and APIOPOSS) and the polymer matrix, molecular weight of PCL was measured. Tg) of solution blended and melt processed PCL/POSS nanocomposites is roughly independent on the type and content of POSS.The determination of thermal transitions of the composites and the study of the effect of POSS type and preparation method on these transitions were conducted by DSC measurements. Tm) as pristine PCL, while the value of the nanocomposite with 10 wt.% APIBPOSS was slightly higher (2 °C) than that of PCL. No significant differences in Tm value of PCL/APIOPOSS and PCL/POSS nanohybrid masterbatch nanocomposites were observed as compared with neat PCL. PCL/POSS nanocomposites prepared by melt mixing exhibited a slightly lower melting temperature as compared with neat extruded PCL.Solution blended PCL nanocomposites containing 2 and 5 wt.% APIBPOSS showed similar melting temperatures (Tc) for solution blended nanocomposites containing 2 and 5 wt.% of APIBPOSS were slightly higher than that of neat PCL. Moreover, Tc of PCL first increased and then decreased with increasing the POSS loading in the PCL/APIBPOSS nanocomposites. However, the onset crystallization temperature (data not shown) was almost unaffected by the incorporation of APIBPOSS irrespective of POSS loading. These results indicate that although in the presence of APIBPOSS the crystallization of PCL does not start earlier as compared with neat PCL, it runs much faster, and the degree of enhancement in Tc depends of POSS concentration. This indicates that APIBPOSS nanoparticles act as nucleating agent for the crystallization of PCL. On the other hand, an additional crystallization peak at 44 °C, attributed to APIBPOSS, was also observed. This result is in accordance with that obtained by XRD analysis. Tc value of PCL was unaffected by the addition of 2 wt.% of APIOPOSS, while decreased at higher POSS loading level  of PCL was calculated according to the following relation,mH is the enthalpy of fusion, Δ0mH is the enthalpy of fusion of a perfect PCL crystal (142 J g−1) [cX value increased as ditelechelic hybrid content increased, the composite containing 10 wt.% of POSS exhibited a slightly higher degree of crystallinity than PCL. The incorporation of APIBPOSS by melt compounding led to an increase in the degree of crystallinity of PCL that increased with the POSS content. For the APIOPOSS based nanocomposites the addition of 2 and 10 wt.% of POSS led to an increase in the crystallinity of PCL, while the incorporation of 5 wt.% of POSS had no effect.The percentage crystallinity (% 2 J g−1) , and wt.2) and oxidative (air) atmosphere to study the thermal and thermo-oxidative stability of PCL/POSS nanocomposites. T5%), the temperature of the maximum loss rate (maxT) and the fraction of solid residue at 750° C of the thermograms.Thermogravimetric analysis (TGA) was carried out in an inert  curves are shown in T5% value of PCL was higher than that of neat amino-POSS molecules and slightly lower than that of PIOPOSS-PCL-PIOPOSS hybrid. The solid residue amount at 750 °C was approximately 2.8% for APIBPOSS, 5.5% for APIOPOSS, and 6.4% for PIOPOSS-PCL-PIOPOSS. Thermal stability of neat POSS in nitrogen was observed to decrease in order: PIOPOSS-PCL-PIOPOSS > APIOPOSS > APIBPOSS . maxT value was independent of the POSS content. All solution blended PCL/APIOPOSS nanocomposite samples decomposed completely in a single step in the temperature range of 300–450 °C C. The iny of PCL D. A notiThe improvement in the thermal stability of the PCL/POSS nanocomposites can be explained by the formation of interactions between POSS and PCL matrix. The decline in thermal stability of PCL/amino-POSS nanocomposites as POSS concentration increases can be ascribed to the poorer dispersion level of nanoparticles in the polymer matrix, since larger aggregates were formed. The reduction of the thermal stability in the PCL/APIBPOSS-10-S can be associated to the poorer dispersion of the nanoparticles at this concentration level, as well as to the lower thermal stability of neat APIBPOSS as compared to PCL. The dependence of the thermal stability of POSS containing polymer nanocomposites on the type and content of POSS as well as on dispersion level of POSS nanoparticles in the polymer matrix has been reported in the literature .T5% value of the nanocomposites containing 2 and 10 wt.% APIBPOSS are slightly lower than that of neat polymer matrix. The TGA weight loss curves of the melt mixed PCL/APIOPOSS nanocomposites with 2 and 5 wt.% POSS exhibited a single decomposition step between 315 °C and 420 °C, while in the thermogram of the blend with 10% POSS two steps were observed in the 275–330 °C and 330–400 °C temperature range, respectively. The weight loss in the first step was about 8%, and can be attributed to APIOPOSS decomposition. The T5% value of the PCL/APIOPOSS nanocomposites was higher than that of neat PCL  and APIOPOSS (at content greater than 2 wt.%) by solution mixing, while it remained unchanged with the incorporation of APIBPOSS. However, the thermo-oxidative stability of PCL was enhanced by the incorporation amino-POSS derivatives by melt mixing. The ditelechelic hybrid masterbatch provided the greatest improvement both in thermal and thermo-oxidative stability of PCL for the entire filler content range studied, that can be explained by the better compatibility with PCL chains, which results in a better extent of dispersion . The enhancement in thermal stability of nanocomposite films can be ascribed to the thermal insulator and mass transport barrier effect of POSS nanoparticles.The Young´s modulus, tensile strength and strain at break were determined from experimental tensile stress-strain curves shown in The results obtained from the solution blended nanocomposites showed a decrease in elastic modulus of the nanocomposite samples as compared to the pure PCL A, and itThe difference between APIBPOSS and APIOPOSS is the length of the alkyl chains bounded to the Si atom, four and eight carbon atoms for APIBPOSS and APIOPOSS, respectively. An identical siliceous hard core is enveloped by alkyl chains that constitute a softer outer shell of variable thickness. APIBPOSS nanoparticles have the thinnest soft shell, whereas APIOPOSS has the thickest one. In the PIOPOSS-PCL-PIOPOSS nanohybrid in addition to eight alkyl chains there is a PCL chain grafted. The amount of inorganic material dispersed in the PCL/PIOPOSS-PCL-PIOPOSS blends is lower than that dispersed in the PCL/amino-POSS systems with the same POSS content. Our results confirm the observation of Baldi et al. .The solution blended nanocomposites containing 2 wt.% of APIBPOSS and APIOPOSS displayed an increase in tensile strength at break of about 28%, with respect to PCL B, whilstThe addition of APIBPOSS nanoparticles induced an increase in the elongation at break of PCL C, 100% wThe Young´s modulus of PCL was almost unaffected by the addition of amino-POSS by melt mixing. On the other hand, the tensile strength of all melt mixed PCL/APIBPOSS nanocomposites was lower than that of PCL, the reduction was between 20% and 30%. The tensile strength of PCL was almost unaffected by the addition of APIOPOSS. The addition of all APIBPOSS nanoparticles induced a reduction between 30 and 40% in the elongation at break of PCL, whilst the incorporation of APIOPOSS induced only a slight change.The type of POSS derivative and content, and the preparation method have effect on the mechanical properties of PCL/POSS based nanocomposites, due to differences in compatibility and dispersion state. However, the better dispersion state of POSS achieved in the melt mixed PCL/amino-POSS nanocomposites is not enough to achieve good reinforcement, as strong interfacial interaction between the matrix and the filler is also necessary.Studies reported in the literature indicated that hydrophobicity of polymer matrices increased on incorporation of POSS nanoparticles ,44. The For neat PCL the contact angle was 70.0°, and increased dramatically with loading of POSS derivatives, by 51%, 39%, and 37% for APIBPOSS, APIOPOSS, and ditelechelic hybrid, respectively . WCA werThree polyhedral oligomeric silsesquioxane  were incorporated into PCL matrix at different contents via solution casting and melt mixing. Morphology, thermal, and mechanical properties depended on the alkyl chain length of the nonreactive organic substituents attached to the corner silicon atoms, the presence of PCL chains covalently attached to POSS nanoparticles, POSS concentration, and preparation method.Spherical POSS aggregates of submicron size were observed within the PCL matrix, remaining the crystalline nature of APIBPOSS. Melt mixing led to a better dispersion state of amino-POSS nanoparticles than solution blending. The best dispersion in solution blended nanocomposites was achieved when using the masterbatch method. The difference in the dispersion level for different POSS derivative was attributed to their differences in solubility parameters.A nucleating effect was observed during crystallization process of the melt mixed nanocomposites due to the APIBPOSS and APIOPOSS nanoparticle presence, while only APIBPOSS and high levels of ditelechelic hybrid masterbatch behaved as nucleating agents in the solution blended composites. The nanocomposites obtained by solution blending were more thermally stable than neat PCL. The thermo-oxidative stability of PCL improved with loading of APIOPOSS and ditelechelic hybrid masterbatch by solution mixing, and amino-POSS derivatives by melt blending. The Young´s modulus of PCL decreased with the incorporation of the three types of POSS by solution-casting method, while remained almost constant for the melt mixed nanocomposites. The incorporation of POSS nanoparticles to PCL by solution blending led to a decrease in the material stiffness and brittleness. However, in the extruded blends the incorporation of APIBPOSS nanoparticles led to more brittle materials. The addition of POSS nanoparticles to PCL render the surface hydrophobic due to presence of filler on the surface.In this study, we have demonstrated that by controlling the POSS structure and content, and the processing method the properties of POSS/PCL nanocomposites may be tailored.


The persistent development and spread of resistance to antibiotics remain an important public health concern in the UK and globally. About 74% of antibiotics prescribed in England in 2016 was in primary care. The Quality Premium (QP) initiative that rewards Clinical Commissioning Groups (CCGs) financially based on the quality of specific health services commissioned is one of the National Health Service (NHS) England interventions to reduce antimicrobial resistance through reduced prescribing. Emerging evidence suggests a reduction in antibiotic prescribing in primary care practices in the UK following QP initiative. This study aims to investigate the mechanism of impact of this high-cost health-system level intervention on antibiotic prescribing in primary care practices in England.The study will constitute secondary analyses of antibiotic prescribing data for almost all primary care practices in England from the NHS England Antibiotic Quality Premium Monitoring Dashboard and OpenPrescribing covering the period 2013 to 2018. The primary outcome is the number of antibiotic items per Specific Therapeutic group Age-sex Related Prescribing Unit (STAR-PU) prescribed monthly in each practice or CCG. We will first conduct an interrupted time series using ordinary least square regression method to examine whether antibiotic prescribing rate in England has changed over time, and how such changes, if any, are associated with QP implementation. Single and sequential multiple-mediator models using a unified approach for the natural direct and indirect effects will be conducted to investigate the relationship between QP initiative, the potential mediators and antibiotic prescribing rate with adjustment for practice and CCG characteristics.This study will use secondary data that are anonymised and obtained from studies that have either undergone ethical review or generated data from routine collection systems. Multiple channels will be used in disseminating the findings from this study to academic and non-academic audiences. This study will be the first to evaluate the mechanism of the impact of a financial incentive initiative involving Clinical Commissioning Groups (CCGs) to improve antibiotic prescribing in primary care practices in England.The investigation of multiple mediators in this study will help to identify the contributions of multiple strategies in translating the effects of Quality Premium (QP) while unpacking the extent of the effect of specific mediators.Due to the limited data on practice-level interventions or strategies that might potentially mediate the effect of the QP on antibiotic prescribing, we will not be able to extensively investigate the mechanism of QP impact at the practice level.Nevertheless, extensive investigations will be conducted at CCG level where the QP initiative is implemented and rewards paid out.The persistent development and spread of resistance to antimicrobials, especially antibiotics, remain an important public health concern in the UKAbout 74% of the antibiotics prescribed in England in 2016 was in primary care.Interventions such as antibiotic stewardship programmes, education and training initiatives targeted at prescribers and patients, financial incentives, among others have been implemented in England to reduce AMR through reduced prescribing. In particular, the Quality Premium (QP) is a National Health Service (NHS) England initiative established in 2013 to reward Clinical Commissioning Groups (CCGs) financially based on the quality of specific health services considered to be of national or local priority and commissioned over a specific period.Emerging evidence suggests a reduction in antibiotic prescribing in primary care practices in the UK following the QP initiative.The impact of interventions on specific outcomes is sometimes explained by a series of events. Potential mediators are important in assessing causal relationships like that between QP and antibiotic prescribing in primary care practices in England, where a potential mediator is a variable that hypothetically mediates the effect of QP on the outcome. The conceptual model shown in Our conceptual model suggests that in addition to its direct impact, the QP initiative acts by stimulating and enhancing the adoption of existing strategies to reduce and optimise antibiotic prescribing. In investigating the potential pathways connecting QP to reductions in antibiotic prescribing, we will be examining the hypothesis that factors like the Chief Medical Officer’s (CMO) letter, Treat Antibiotics Responsibly, Guidance, Education, Tools (TARGET) toolkit, antibiotic auditing, benchmarking, local incentives at CCG level, prescribers and patients’ antimicrobial stewardship (AMS) education/training can transmit part of the influence of the QP initiative to antibiotic prescribing.First implemented in September 2014, the CMO letter, which provided social norm feedback to primary care practitioners in England whose antibiotic prescribing rate was in the top 20%, reduced antibiotic prescribing by 3.3% in 6 months in a randomised trial.Another important mediator hypothesised in our conceptual model is AMS education/training of prescribers and patients. Educating and training prescribers on the importance of antibiotic stewardship and ways to promote prudence can help prescribers make better decisions on when an antibiotic is indicated and can also improve patients’ knowledge on the appropriate use of antibiotics. AMS interventions targeted at patients can improve their knowledge of when antibiotics are not needed and increase confidence and skills on how to self-care, which can result in reduced consultations for self-limiting illness and thus reduced antibiotic prescriptions.TARGET is a toolkit developed by the Public Health England (PHE), the Royal College of General Practitioners and other professional societies to promote prudent antibiotic use among prescribers and patients in primary care.We hypothesise that the implementation of the QP initiative informed the initiation or wider use of these strategies indicated in the conceptual model as mediators, which will subsequently influence antibiotic prescribing at primary care practices.The implementation of the QP initiative in NHS England constitutes a natural experiment and offers an opportunity to investigate the preintervention and postintervention periods to understand the mechanism of impact of the QP intervention in reducing antibiotic prescribing rates in primary care practices.Using routinely collected population-level data on antibiotic prescribing in England, this study aims to address the research question: What are the mechanisms and mediators of the impact of a high-cost health-system level intervention, the ‘antibiotic prescribing quality premium’? We will investigate the difference in antibiotic prescribing rate pre-QP and post-QP initiative to establish its direct, indirect (through mediators) and total effects in reducing antibiotic prescribing in primary care practices in England.Contemporary evaluations of the effectiveness of health policies go beyond estimating their total effect on outcomes. Mediation analysis decomposes the total effect of an intervention into separate causal pathways,The study will constitute secondary analyses of antibiotic prescribing data from NHS England covering the period 2013 to 2018. CCGs were established in England in April 2013 following the Health and Social Care Act 2012.Practice-level antibiotic prescribing data will be sourced from OpenPrescribing, an Evidence-Based Medicine DataLab project by the University of Oxford. OpenPrescribing publishes monthly antibiotics prescribing data from August 2013, with data for October 2018 the latest at the time of this protocol. Practice-level antibiotic prescribing data from OpenPrescribing is not STAR-PU weighted, so the extracted data will be STAR-PU weighted using figures from the 2013 Item-based age–sex weighting for oral antibacterialsOverall, the dataset offers coverage of at least 3 years postintervention given that antibiotic prescribing became a QP priority in March 2015. This will be important in investigating the immediate direct and indirect effects of the QP initiative while giving an insight into the sustainability of the identified effects (if any) in the long-term.The predictor will be a binary variable indicating the implementation of the QP intervention. The intervention will include all periods after March 2015 when the 2015/2016 QP guidance in England was published, while the control will be periods prior to this. The primary outcome of interest is the rates of antibiotic prescribing at CCG level in England, which will be a continuous variable indicating the number of items (per STAR-PU) prescribed per month.To account for differences in practice and CCG characteristics that can contribute to variance in antibiotic prescribing, we will be adjusting for the number of general practitioners in each practice (from the NHS Workforce data),Mediator variables will be derived from the questionnaire data from a PHE survey,Over the period covered by this study (2013–2018), there have been changes in the number of practices and CCGs in England. Some practices have closed, new practices opened and some CCGs merged over the period; as such, we will have missing values for some observations. To maximise the use of existing observations, we will retain all observed values in the main analysis and impute the missing values using multiple approaches.ITSA function on Stata, with post-trend specification to show a postintervention trend. The Cumby-Huizinga general test for autocorrelation will be used for general specification test of serial correlation in the time series data.Our first analysis will be an interrupted time series to investigate whether antibiotic prescribing rate in England has changed over time, and how such changes, if any, are associated with the QP implementation in March 2015. This will be conducted using the ordinary least square regression methodA new QP guideline was implemented each financial year with changes in the prescribing rate target and the proportion that improved prescribing constituted in the QP award for each year. Our mediation analyses will investigate the effects of the QP by comparing antibiotic prescribing rate in the financial year before its implementation to each subsequent year postimplementation; as such, our dataset for the mediation analyses will have the control group as the financial year before QP and the intervention group as a specific post-QP implementation year. Three analyses will be conducted for each of the three financial years since QP establishment. This will enable us to compare the effects of the different target levels that have been set over the years and the proportions of the QP award attributed to improvement in antibiotic prescribing.Using a unified model for the natural direct and indirect effects,medeff function in Stata.We will first fit single-mediator models with each mediator separately modelled using the A sequential multiple-mediator analysis is preferred to merely summing the effects of the single mediators because the sum may differ from the joint mediated effect, particularly as our potential mediators may influence one another.Sensitivity analyses using dummy implementation dates of 1 to 3 months before and after the actual month each of the QP guidance were published will be conducted to assess the difference between the time the guidance is published and the dissemination of information and development of local arrangements by the CCGs. These analyses will further help to investigate the anticipatory effect of the policy and whether lag in implementation attenuates the effect of the intervention.Also, we will conduct separate analysis with the outcome variable (antibiotic prescribing rate) as a binary variable (indicating whether each CCG achieved the required rate of reduction in antibiotic prescribing as stated in the QP guidance for each year) to examine whether the classification of the outcome variable based on achievement of QP target influences the results.Subgroup analyses will be conducted on clusters of primary care practices based on their antibiotic prescribing behaviour (high and low prescribers) and indices of deprivation to examine whether any effect of the QP initiative seen in the overall population is different in subgroups of practices. The top and bottom 20% antibiotic prescribers as of March 2015 will be categorised as high and low prescribers. To address the issue of regression to mean in subgroup analyses, we will build a separate model with categorisation into high and low prescribers based on the mean of the prescribing rate of practices in the last 3 months to March 2015. The use of mean of multiple measures will offer a better estimate of each practice’s true mean before the 2015/2016 QP initiative.This study has some limitations. The survey that provided data on mediator variables included 187 of the 209 CCGs existing at the time of the study. However, this sample size is large enough for strong statistical power, and multiple imputation will be used to address issues on missingness. Furthermore, due to the limited data on practice-level interventions or strategies that might potentially mediate the effect of the QP on antibiotic prescribing, we will not be able to extensively investigate the mechanism of QP impact at the practice level. Nevertheless, extensive investigations will be conducted at CCG level where we have more data on potential mediators.In 2013, the Primary Care Trusts in England, which were responsible for planning and commissioning healthcare services at the primary care level, were transformed to CCGs.We recognise that the causal interpretation of any effect from our mediation analysis rests on assumptions such as sequential ignorability and exchangeability. Causal inference from this analysis will be limited given that our data are observational with the absence of random assignment of cases to treatment and mediator levels, as well as the likelihood of unmeasured confounders. The rate of consultation for conditions where antibiotics might be prescribed is one of the unmeasured confounders in our study. This has not been accounted for in our analyses as these data are not available nationally at the practice level.Although the QP intervention has been reported to have been effective in reducing antibiotic prescribing,Evidence on the mechanism of impact of strategies like QP will be important in improving its uptake and sustainability while maximising its potential in reducing antibiotic prescribing in primary care settings.Finally, financially incentivised strategies for clinical compliance have been criticised for their ability to result in unintended consequences.This study will use secondary data mostly from routine collection system and will not directly involve patients or the public. The dissemination of the results will include communication channels and public engagement events that will involve primary care practitioners and CCG representatives.Prescribing data from NHS BSA and NHS Digital are generated from routinely collected prescribing data on items that have been dispensed in primary care practices in England. The survey that produced the data on mediator variables was registered with the PHE Research Support and Governance Office (RSGO) and approved by PHE Research Ethics and Governance Group (REGG) and Health Research Association (HRA).Multiple channels will be used in disseminating the findings from this study to academic and non-academic audiences, which will include an engagement workshop with our stakeholder network, presentations in scientific conferences, publication in peer-reviewed journals and press conference coinciding with paper publications.


Objective. This report explains how to remove broken files using ultrasonic instruments and endodontic micro forceps. Case Report. A 25-year-old female patient had incomplete root canal treatment at the lower right first molar 1 week ago. There were radiolucency in the bifurcation and apical root and the presence of broken files in the 1/3 coronal mesiolingual root. The retrieval started by making a staging platform with an ET20 ultrasonic tip. Endodontic micro forceps were used including a screw wedge that works by clamping the file fragments through a mechanical lock and pulling them to the coronal. Conclusion. It is possible to successfully remove broken files from the root canal using ultrasonic instruments and endodontic micro forceps.Broken files affect cleaning, shaping, and filling processes of the root canal, thereby causing maintenance failure.  The success of root canal treatment depends on the results of the cleaning and shaping process. However, there is a risk of broken files because its presence inhibits the process of cleaning, shaping, and filling, thereby leading to treatment failure . A brokeThere are several alternative treatments for this occurrence, and they include taking the broken file fragment and bypassing it while inside the root canal . HoweverTechnological advancement has made it possible to have several tools for file retrieval, including ultrasonic, microtube, and plier devices, with the assistance of a microscope to facilitate visibility and minimize the extraction of root canal dentine . TherefoA 25-year-old female patient complained that her lower right back teeth are not comfortable with chewing; therefore, root canal treatment was conducted one week ago after one year of spontaneous pain. On intraoral examination, caries reached the pulp in the lower right first molars, with negative vitality and positive percussion. Radiographic examination showed radiolucent images in the bifurcation area and apical mesial and distal roots and a broken file from the orifice to the middle of the mesiolingual root Figures .Based on the subjective, objective, and radiographic examination, the diagnosis of the right mandibular first molar is symptomatic apical periodontitis, accompanied by a broken file on the mesiolingual root. The treatment conducted was for the nonvital root canals with Ceramage  onlay restoration.The tooth was prepared to obtain adequate coronal access with 2.5% NaOCl as an irrigant to remove debris. The working length was measured through the use of an electronic apex locator . The root canal was prepared in the mesiobuccal and distal roots through the use of ProTaper Next  until the master apical file was obtained at X3/16.5 mm mesiobuccal root and X3/17.5 mm distal root. Irrigation was conducted, and the orifices of both root canals were closed with a paper point and cotton to prevent the entry of file fragments. In the mesial root canal, the retrieval started by making a staging platform with a Satelec ET20  ultrasonic tip until 2 to 3 mm of the broken file was exposed. This was aimed at loosening the file from the root canal wall of the dentin and providing a space for the device. The staging platform is the space between the tip of the exposed file and the root canal wall which was further circulated around the file in an anticlockwise direction to give the effect of unscrewing force. This helps in retrieving files with a clockwise cutting action. The energy applied can help loosen the file and provide a space between it and the root canal wall. The Satelec ET25  ultrasonic tip could then be used to loosen those on the part of the wall.Irrigation was conducted by using 2.5% NaOCl and 17% EDTA, and activation was done through an EndoActivator . Since the direct application of ultrasonic devices does not have the ability required to remove the file, endodontic micro forceps  were used including a screw wedge that works by clamping the file fragments through a mechanical lock and pulling them to the coronal . After tThe mesiolingual root canal was prepared through the ProTaper Next  up to X3/16.5 mm and the master gutta-percha cone confirmed by radiographic photographs.It was medicated with calcium hydroxide paste  and restored temporarily.® Gutta Percha, Dentsply Tulsa Dental, Switzerland) with an MTA Fillapex sealer and closed with RMGIC  and temporary restoration .Two weeks after the first visit, the root canal was filled with continuous wave compaction through gutta-percha . Two weeks after onlay preparation, onlay was cemented using resin cement . The evaThe use of an ultrasonic instrument assisted by a microscope is a conservative method of handling a broken file compared to other alternatives , 5. It cRemoval of broken files can be conducted in dry or wet conditions . Dry con™ Retreatment Kit , made from titanium niobium alloy and coated with diamond, making them abrasive. The ET20 was moved counterclockwise in 1/3 coronal and ET25 in the middle 1/3 of the root canal to give the file an unscrewing force effect [The tips used were ET20 and ET25 from the Endo SuccessThe root canal was filled with a continuous wave compaction technique and through the use of an MTA Fillapex  sealer which is good for dentin because of its ability to harden. They also possess good density, thus preventing leakage in the periapical region and closing communication between pulp and periodontal tissue. The MTA content in the sealer supports healing and hard tissue formation in the lesion.M. luteus, S. aureus, E. coli, P. aeruginosa, C. albicans, and E. faecalis because of its alkaline pH [MTA Fillapex has several advantages such as the stimulation of new tissue formation, rapid tissue repair without causing inflammatory reactions, high radio-opacity, provision of good visualization on the radiograph, release of calcium ions to induce rapid tissue regeneration in areas with periapical lesions and microbial activity, making insertion and handling easier, having adequate working time, and being easy to remove  , 7. It caline pH .In this case, the mandibular right first molars with symptomatic apical periodontitis with a broken file on the orifice to the middle of the mesiolingual root canal were retrieved with a combination of ultrasonic tips and endodontic micro forceps, accompanied by a microscope to increase visibility. The treatment was successful because a broken instrument was completely removed followed by loss of subjective complaints. The radiograph also revealed diminished apical radiolucency.


This paper investigates the properties of steam cured recycled aggregate concrete (RAC), in an attempt to determine the optimum conditions of the steam-curing cycle for RAC, and incorporating high early strength cement (HESC). Varying conditions of steam curing were employed. The steam-curing cycle was set based on the peak temperature, and the duration for which the peak temperature was maintained. Three peak temperatures were used for steam curing, 50 °C, 60 °C, and 70 °C, maintained for up to two hours. The compressive strength results indicated that the steam-curing cycle employing the peak temperature of 50 °C maintained for one hour with a total duration of four hours was the optimum for strength development, both at the early and late stages of hydration. Determining the optimum steam-curing temperature and duration will help reduce the associated curing cost, thus further economizing the production cost of recycled aggregate concrete. The use of recycled aggregates (RA) in concrete has gained much attention over the previous several decades, due to continuously declining natural resources leading to increasing interest in sustainable development ,2,3,4. TIn order to address the aforementioned issue, various methods have been employed to date to improve the strength of the resulting concretes. These include incorporating nanomaterials within the concrete under consideration ,17,18, uDue to the faster hydration rate and higher strength gain, steam curing has gained wide acceptability. Various research findings have been reported in the past, demonstrating its usefulness in precast concrete manufacturing. Turkel and Alabas  conducteAmong various research findings published in the past, the work of Ramezanianpour et al. ,27 is ofCompressive strength measurements indicated that in a constant total time, increase in pre-curing period leads to lower immediate compressive strength. On the other hand, increase in treatment temperature and total cycle time (which means higher energy and time consumption) led to higher immediate compressive strength .The durability results established that the peak temperature of 70 °C imposes a negative effect on durability properties. However, it was seen that they employed very long curing cycles (from 16 h to 20 h), which makes the resulting concrete energy intensive, rather than energy efficient. In the same way, Ba et al.  investigAlthough the useful effects of steam curing on the mechanical properties have been explored in the past, there has been little work conducted evaluating the optimum parameters for steam curing. Moreover, there are no research findings that report the optimum steam-curing parameters for recycled aggregate concrete (RAC). This parametric study fills these research gaps by investigating the effects of various temperatures and exposure durations on the mechanical strength of steam-cured recycled aggregate concrete. The determination of the optimum temperature and exposure duration will lead to reduced costs and embodied energy, thus contributing to sustainable development.A number of published studies have comprehensively evaluated the suitability of steam curing in normal concrete, but these were only focused on concrete produced with ordinary Portland cement (OPC) as the binder, and merely followed the steam-curing cycle as recommended by . With thThis experimental study fills the current research gap by exploring various properties of steam-cured, high early-strength RAC. The steam-curing conditions were also varied, so that the steam-curing conditions for optimum concrete properties could be ascertained. The novelty of this study lies in the determination of the optimum steam-curing parameters for recycled aggregate concrete, incorporating high early strength cement.The primary binders used in this study included ordinary Portland cement (OPC) and moderately high early strength cement (HESC).2/g and 4490 cm2/g, and a loss on ignition of 2.26% and 1.05%, respectively. Their other properties conformed to the Korean Standards KSL5201-1989. Coarse and fine aggregates  was 25 mm, whereas well-graded fine aggregates under 5 mm particle size were used in the experimental study. The aggregates recycled by the Insun recycling plant  were used after treatment/bonded mortar removal. This was achieved using several methods, involving “mechanical processes (involving grinding/churning/sieving), thermal processes  and chemical methods . Up to 95% of the bonded mortar could be successfully removed. Admixtures (high rate water reducing admixture and air-entraining admixtures) were utilized for maintaining the uniformity, consistency, and cohesiveness of the fresh concrete mix while stabilizing the air bubbles in the mix and improving its workability. Ordinary potable tap water  was used for mixing the ingredients” .The basic properties of the raw materials are reported in The mix design procedure and concrete mixing, casting, and curing were done according to American Concrete Institute (ACI) standards ,35,36, aThe concrete was mixed in a rotating drum type mixer. First, all of the required coarse aggregate was put in the mixer along with 50% of the cement. These were mixed for one minute while progressively adding 50% of the required water. After one minute, the fine aggregate, remaining water, and cement were added while the mixer continued to rotate for three more minutes. Admixtures were added simultaneously with the water. The whole mixing procedure took around four minutes. Subsequently, the specimens were cast in molds of various sizes. Cylindrical specimens with a diameter of 100 mm and a length of 200 mm were cast, for compressive strength testing . Specimens from all four aforementioned series were subjected to steam curing under varying conditions , e.g., tThe properties of the developed concretes (both in fresh and hardened states) were evaluated by various ASTM testing standards ,44,45,46The fresh state properties of the concretes are shown in The air content results were rather different to those obtained for the slump, as a general trend could not be ascertained. The air content tended to increase in the concretes that contained recycled aggregates. This can be explained by the poor packing of the somewhat rounded aggregate shape (of recycled aggregates), in contrast to the angular grains . The greater air content also signified an anticipated decline in compressive strength, due to a greater void ratio and lower gel/space ratio. As the present study primarily focused on the effect of varying steam-curing conditions, the positive (or negative) effects will be reflected in the hardened concrete (as can be seen from the compressive strength results). It should also be pointed out that these properties were also affected by the dosages of admixtures, if used in the mix . It is, The compressive strength results are shown in It was observed that the compressive strength of the specimens decreased as the maximum temperature of the steam-curing cycle increased. A great disparity in strength was observed when compared to the control mix (O-N-60-4). This is consistent with the maturity theory of concrete ,53. The Another steam-curing parameter evaluated in this study was the duration for which the maximum temperature was maintained. The experimental study demonstrated that a one-hour holding duration of the maximum temperature was optimum. Previously, Ramezanianpour et al. ,27 had sTypically, the increased temperature is thought to increase the early strength of concrete due to an escalated hydration reaction. However, this generalization cannot be guaranteed for a different cement type that has a moderately high early strength (as used in this study). Both the physical properties (fineness and surface area), and chemical composition, play a vital role in the rate of the hydration reaction. The fact that the tested concrete had a high compressive strength despite the recycled aggregate, low temperature steam curing, and short duration, may be due to the characteristics of the moderately high early strength cement. Conventionally-produced high early strength cement has a higher C3S content than ordinary Portland cement. Therefore, the early strength is high, and the hydration heat and drying shrinkage are increased, while the long-term strength is lower than that of ordinary Portland cement . It is sIn this experimental study, the properties of steam-cured concrete were evaluated in an attempt to determine the optimum conditions of a steam-curing cycle for recycled aggregate concrete, incorporating high early strength cement (HESC). Concrete specimens containing ordinary Portland cement (OPC) and HESC were formulated. After specimen casting, varying conditions of steam curing were employed. The steam-curing cycle was set based on the peak temperature, and the duration for which the peak temperature was maintained. Three peak temperatures were used for steam curing, 50 °C, 60 °C, and 70 °C, maintained for up to two hours. The compressive strength results indicated that the steam-curing cycle employing the peak temperature of 50 °C and maintained for one hour with a total duration of six hours, was the optimum method for strength development, both at the early and late stages of hydration.Steam curing significantly increases the hydration rate of recycled aggregate concrete, thus helping to attain the target (design strength) within three days of casting.Utilizing moderately high early strength cement leads to a higher rate of strength gain of recycled aggregate concrete when steam curing is employed. This leads to increased early-age strength, without compromising the ultimate strength owing to the higher C2S content.The optimum conditions for steam curing based on the strength criterion were a heating/cooling rate of 20 °C/h and a peak temperature of 50 °C, maintained for one hour.Determining the optimum steam-curing temperature and duration will help reduce the associated curing costs, thus further economizing the production of recycled aggregate concrete.The following meaningful conclusions were drawn from this experimental study:The research findings point towards a useful and economical application for steam-cured recycled aggregate concrete in precast concrete construction, where the goal is speedy construction with superior mechanical properties. The use of recycled aggregates can slow the depletion of natural resources and help promote sustainable development. It is, however, clarified that the accelerated hydration for faster strength gain might lead to shrinkage and cracking, which must be evaluated prior to critical structural elements, particularly for structures with a higher ratio of surface area to depth, such as slabs and pavements. Nevertheless, the use of shrinkage-reducing admixtures or expansive cement can reduce the likelihood of such cracking.Although the use of steam-cured RAC with optimum duration and temperature conditions ought to maximize the resulting mechanical attributes, the cost of achieving this and the associated carbon dioxide emissions must also be evaluated to determine the overall impact.


L. intracellularis on a Canadian farrow-to-finish pig farm. This is done by modeling the production and economic impact of different antibiotics and vaccines available for managing this disease, listed in the Canadian Compendium of Veterinary Products. The economic impacts (in Canadian dollars) of the disease are estimated and the net benefits of alternative prevention and treatment options are compared to determine the relative cost-effectiveness of each strategy. Of the 12 options analyzed, four were preventative (antibiotic and vaccine) and eight were antibiotic treatments. Prophylactic chlortetracycline (an antibiotic) is the most cost-effective option for managing L. intracellularis, while Porcilis Ileitis (a vaccine) is the least cost-effective strategy. This result remains robust considering sensitivity analysis of the production parameters, which indicates that preventative antibiotics are more cost-effective than vaccines. This implies that banning preventative antibiotic treatments harms the bottom line of farmers under current market conditions.Increasing awareness of antibiotic resistance has correspondingly increased efforts to identify and reduce the causal behaviors that led to this severe public health threat. The consequences of these efforts are regulatory and market pressures limiting antibiotic use by livestock farmers which may lead to significant financial and welfare challenges on the farm, even if antibiotics can be substituted by vaccines. The purpose of this study is to measure the relative cost-effectiveness of antibiotics vs. vaccines for controlling  Antibiotic resistance is one of the most significant threats facing human and animal healthcare systems today . Less thGiven the significant volume of antibiotics administered to livestock, many consider reducing animal antibiotics as one way to reduce antibiotic resistance in humans . In an eAntibiotics provide economic benefits to farmers by promoting growth, preventing diseases, and treating the diseases that do arise in their livestock. Economic research on antibiotic use has tended to focus on measuring the value of antibiotic growth promoters (AGPs) , 5. SimiMycoplasma hyopneumoniae  in pigs at the farm level, with and without intervention from vaccine and antibiotic options…Antibiotics and vaccines are the focus of this study because these are the products that are used for disease intervention. While management options such as improved biosecurity will reduce the occurrence of disease (thus reducing the need for both products), biosecurity is for disease prevention and not disease intervention or management. An empirical model of a representative farrow-to-finish pig farm in Canada is developed and the costs of the disease without intervention are initially established. The reduction in these costs from alternative antibiotic and vaccine strategies are then estimated. The identification of the cost-effective management options to deal with L. intracellularis can help farmers, veterinarians, and government representatives to reduce antibiotic use while maintaining the financial viability of the farm. Similar adapted modeling frameworks can also be used to evaluate the net financial benefits that preventive and treatment antibiotics and vaccines provide to farms with other livestock and other diseases and can also be extended to consider the economic impacts beyond the farm gate.Given that the impact of reduced antibiotic use on livestock farms is not known, the purpose of this study is to demonstrate how the relative cost-effectiveness of antibiotics and vaccines can be measured for managing diseases in livestock. A bioeconomic farm enterprise modeling framework was created to measure these differences. This article uses this framework to model the production and financial impacts of L. intracellularis on a typical Canadian farrow-to-finish swine farm. To do this, the production and profitability (in Canadian dollars) of a pig farm were calculated under 40 different farm scenarios . The cost of L. intracellularis can be estimated by comparing the profits with and without the disease and the cost-effective management options can be determined by comparing profitability across the treatments under a given disease scenario.This study develops a bioeconomic modeling framework that can be used to measure the financial impacts of antibiotics and vaccines for managing disease in livestock. Specifically, this is done by estimating and comparing the relative cost-effectiveness of 12 antibiotic and vaccine options for managing cenarios . The firOne of the advantages of this bioeconomic simulation model is that it can adapt to limited representative data availability, as is the case in some of the 12 different treatments examined on swine farms, by focussing on the relative ranking of the treatments, not necessarily their absolute values. Variability in production and economic information can also be addressed by checking the robustness of the rankings using sensitivity analysis. Combined with the thorough accounting of the modeling parameters presented in this article, the model outputs can be compared and contrasted to any farm situation, although they are not intended to represent any particular farm.The first part of the following section outlines the methods used to build the baseline empirical model. The second part provides the assumptions on the productivity and mortality impacts of the disease scenarios while the third part discusses the efficacy of the management options within each disease scenario.L. intracellularis in pig herds.A static and deterministic empirical model was created in Excel® to represent the operations of a typical farrow-to-finish operation in Canada. This type of model was deemed appropriate for this research given the endemic nature of In Canada, pig farms are generally separated into three different production stages: the sow barn, the nursery barn and the finishing barn. The sow barn is where the breeding animals are housed, and piglets are nursed. In this model, the breeding cycle involves 2 days of breeding, a 115-day gestation period, 21 days of nursing and then a 5-day break before beginning the cycle again. At 21 days, piglets are weaned and sent to the nursery barn. They spend 8 weeks in this barn before being moved to a finishing barn. Here, they will spend 16 weeks growing before they leave the farm and are shipped to a processing plant. Cull sows are assumed to be sold and replacement gilts are assumed to be purchased in.In the sow barn, mature female pigs are housed to raise their piglets. Assuming 21 days for weaning, a 5-day weaning to breeding interval, 2 days of breeding and a 115-day gestation length, a sow can produce 2.55 litters per year. For a 1,000 head sow-herd that batch-farrows weekly, this results in 20 groups of sows with 50 sows per group. Assuming the farmer sells his sows as culls after the sixth parity and there is 0.8% sow herd mortality per parity, the replacement rate for sows is 17.5% per parity or 44.62%, annually.Therefore, in each group, 41 of the females are sows and 9 of the females are gilts. If sows wean 11.31 piglets and gilts wean 9.35 piglets per breeding, then, annually, this combines to 27.96 pigs/sow/year. Assuming an 85% farrowing rate, this amounts to ~24,239 pigs per year being shipped to the nursery barn, or 466 pigs per week. Pigs are then kept in the nursery for 8 weeks and, with typical mortality around 3%, there are ~452 pigs being shipped from the nursery to the finishing barn per week for a loss of about 14 pigs per group. Provided there is 2% mortality in the finishing barn over a 16-week period, this amounts to 443 pigs being shipped per week to the processing plant, or about 23,042 pigs per year. The production parameters in this model are created from the parameters used by Weng et al.  in their Swine Enterprise Budgets since 2014 (OMAFRA various)  for the first 7 weeks and a finisher ration ($264.29/ton) for the final 9 weeks. Over the 16 weeks in the finishing barn, pigs are assumed to eat a total of 285.96 kg of feed for a cost of $85.42 per pig shipped. In the finishing barn, other variable costs are $14.19 per marketed pig and fixed costs are $12.18 per marketed pig.The net result per marketed pig for the baseline is revenue of $183.82 and total costs of $178.83 for a profit of $4.99, which is typical of industry average conditions for Ontario and consequently serves as one means of validating the model.L. intracellularis, which is the typical approach to categorize disease impacts . Therefore, treatment begins in the last week in the nursery barn and may continue into the finishing barn.The remaining management options for L. intracellularis outbreak. The improvements in average daily gain, decrease in feed efficiency and decrease in mortality for each option under each of the three disease scenarios are summarized in The 12 disease management options can improve the production performance of a sick pig with the extent of the improvement depending on the option and the severity of the with L. intracellularis and its management strategies. Sources for L. intracellularis and their production performance measured over a set period of time. Because all pigs were inoculated with L. intracellularis, the results of these studies are assumed to show the benefits of vaccines/antibiotics for managing a worst-case incidence. This data was then used to make assumptions about the impact of the vaccine/antibiotic for managing an expected L. intracellularis incidence  and a best-case L. intracellularis incidence . Citations in L. intracellularis rather than inoculating them. The results of these studies are assumed to show the benefits of vaccines/antibiotics for managing an expected incidence. Data from these studies were used to make assumptions about the worst-case scenario  and the best-case scenario . For any missing data, assumptions were made by comparing between management strategies to fill in the gaps.The values given in The values in this table reflect the change in the pig's performance compared to when the disease is not being managed. For example, the average daily gain for a 10-week-old pig in a worst-case disease scenario is 0.53 kg. If preventative chlortetracycline had been used, we multiply 0.53 kg by 1.83 to get an average daily gain 0.97 kg. However, a 10-week-old pig that is healthy only has an average daily gain of 0.66 kg. In this model, a pig's production improvement from management is limited to the production of the healthy pig so its average daily gain would improve from 0.53 to 0.66 kg. The values in L. intracellularis decreases farm profits by reducing the average daily gain, decreasing the feed efficiency and increasing the mortality on average for the entire growing herd  have greater net returns than non-intervention. Porcilis Ileitis is the least cost-effective management option, coming at a cost of $1.38 per pig and a net return per pig of $-0.58. If the producer administers Porcilis Ileitis, it results in $12,490.80 less profit per year for the farm than doing nothing. Therefore, with chlortetracycline providing a $22,153.51 increase in annual net returns and Porcilis Ileitis providing a –$12,490.80 loss, there is a spread of $34,644.30 in annual net returns between the different options for managing a best-case L. intracellularis disease scenario.In the best-case L. intracellularis scenario, using any of the 12 management options is more cost-effective for the farm than doing nothing. Again, chlortetracycline is the most cost-effective disease management option available. When compared to non-intervention, administering chlortetracycline increases the net return per pig by $4.90 and increases annual net returns from $-13,452.49 to $98,320.31. This is a net benefit of $111,772.80 and is only $16,770.09 less than annual net returns under the healthy, baseline scenario. Similar to the best-case scenario, Porcilis Ileitis is the least cost-effective management option. However, in the expected disease scenario, the net return remains positive at $0.46 per pig shipped. This amounts to annual farm net returns of $10,486.11 and a $23,938.60 improvement from annual net returns of $-13,4452.49 without intervention. Under the expected scenario, the range in annual net returns for different management options is $87,834.20, with chlortetracycline  being the highest and Porcilis Ileitis  being the lowest. One notable change in the rank of management options from the best-case to the expected disease scenario is tylvalosin administered in water. Under the best-case scenario, tylvalosin in water is the 9th ranked management option in terms of cost-effectiveness, but, in the expected scenario, it is ranked 5th. This is because administering tylvalosin in water is expensive, but under the more severe disease scenario, the significant productivity improvements can now be realized.In the expected In the worst-case scenario, without any intervention, the farmer loses $10.53 per pig or $230,209.99 per year. Employing any of the disease management options is more cost-effective than doing nothing, with chlortetracycline being the most  and Porcilis Ileitis being the least  cost-effective. Of the 12 management options, seven of them will keep net returns above zero under the worst-case disease scenario, while five of them result in an annual net loss in income. In addition to Porcilis Ileitis, these products include Enterisol Ileitis , tylvalosin in feed , tylosin in feed at 110 and 44 ppm  and tylosin in feed at 110 ppm . With net returns being $89,687.78 with chlortetracycline and $-140,327.04 for Porcilis Ileitis, the spread between management options is quite significant under the worst-case disease scenario at $230,014.82 per year.A sensitivity analysis was performed on the efficacy of each of the 12 management options in all three of the disease scenarios. This analysis compared the rankings of each management option when their efficacy in managing mortality, average daily gain and feed efficiency were either increased or decreased by 10%. In general, the results of this sensitivity analysis suggest that the results of this model are robust. The rankings of management options do not change significantly when their efficacy is either increased or decreased by 10% for each of the three productivity variables tested. Prophylactic antibiotics remain as two of the most cost-effective options, while tiamulin and tylvalosin are the more cost-effective metaphylactic options. Furthermore, the vaccines remain as two of the least cost-effective options in each of the scenarios run.L. intracellularis in pigs and, in the process, has also provided a framework for assessing the net value of alternative antibiotics for different livestock and different diseases.As livestock producers transition to reduced antibiotic use, there will be significant discussion between industry representatives and healthcare experts about the best way to execute this transition. An effective plan will consider the value that antibiotics provide to farmers while recognizing the significant impact of use on antibiotic resistance. While there has been significant research on the risks of resistance in humans and animals (the costs of antibiotic use), there is little information on the benefits that specific antibiotics provide for managing livestock diseases. This research examined the production and financial impacts of using alternative management strategies for treating L. intracellularis. Without any treatment, a L. intracellularis outbreak would reduce net farm income from $115,090 to $88,869 under the best-case scenario and to a loss of $230,210 under a worst-case scenario. The small changes in growth rate, feed efficiency, and mortality that are impacted by the disease can have a significant impact on the financial success of a farm and highlight the costs of a complete ban of antibiotic use.These scenarios show the net financial benefits of different antibiotics and vaccines for managing L. intracellularis outbreak. This was certainly true for the more severe disease scenarios, as the substantial productivity improvements warranted the added cost of the medication. However, for each of the three disease scenarios, there was a significant difference in net returns between the most beneficial and least beneficial options.For most of the 36 management scenarios, it was more cost-effective to intervene rather than do nothing when facing a L. intracellularis. Part of this can be explained by fact that these medications are provided to the pigs at a much younger age. Medicating younger piglets is much cheaper than medicating older pigs because the younger piglets are smaller and require less medication. Furthermore, when medication is provided prophylactically, it is able to act on the disease as soon as it appears. This contrasts with the treatment scenario, where a farmer or veterinarian must first notice the clinical signs before the pigs are medicated. This means that there is a period of time where the disease is able to exist, multiply, and impact the pigs before they finally receive the medication they need. In the best-case and expected disease scenario, the second most cost-effective management option was tiamulin. In the worst-case scenario, the second most cost-effective management option was tylvalosin in water. Despite being provided to older pigs, tiamulin is very affordable and provides modest improvements in productivity. This makes it a good candidate for managing less severe L. intracellularis incidences. Tylvalosin in water is much more expensive but provides significant improvements in average daily gain, feed efficiency and mortality. Therefore, in the worst-case disease scenario, the increased cost is justified to mitigate the more severe production problems.In all three of the disease scenarios, prophylactic medication of in-feed chlortetracycline was the most profitable option and prophylactic in-feed tylosin was the third most profitable option for managing With Canada's livestock industries transitioning to reduced antibiotic use, it is likely that farmers will be required to reduce or eliminate prophylactic antibiotic administration in favor of using antibiotics metaphylactically or for individual treatment. This prevention vs. treatment argument is significant with respect to reducing antibiotic use as this model shows that there are significant financial benefits to managing diseases prophylactically. Furthermore, prophylactic antibiotic administration is likely to improve animal welfare as the livestock's production problems are either avoided entirely or managed more quickly. However, increased antibiotic use as a result of prophylactic administration is seen as a significant contributor to antibiotic resistance for reasons explained previously. Policy on antibiotic use needs to balance the risks of resistance and corresponding threat to human health along with animal welfare implications of untreated diseased animals , which iThe modeling framework can be used to determine the minimum price required by farmers who raise livestock for niche markets, including “raised without antibiotics” (RWA). Based on this study, we can see from L. intracellularis in all three disease scenarios. Chlortetracycline is a Class 3 antibiotic and is therefore less important to human health than a Class 2 antibiotic or Class 1 antibiotic, like tylosin. Tiamulin, the second most cost-effective option for the best-case and expected disease scenarios, is a pleuromutilin and Class 4 antibiotic. Tylvalosin is the second most cost-effective management option for the worst-case scenario, but is a macrolide and a Class 1 antibiotic. Therefore, if prophylactic antibiotic administration were allowed, it would be best to manage L. intracellularis prophylactically with chlortetracycline. In addition to being the most cost-effective option, chlortetracycline is only a Class 3 antibiotic and presents a low risk to human health. If clinical signs appeared after using chlortetracycline, they would likely be less severe, and the farmer could handle them by administering tiamulin. Similar to chlortetracycline, tiamulin is a cost-effective strategy and, as a Class 4 antibiotic, it is the least important for human health. Taking this approach would leave tylvalosin, one of the most important antibiotics (Class 1), for emergency situations with very severe L. intracellularis-related production problems. Based on cost-effectiveness, if prophylactic antibiotics become banned, tiamulin is the only management option that the farmer can use to avoid a severe L. intracellularis incidence. Therefore, this policy would increase the chance of the farmer having to use a Class 1 antibiotic, like tylvalosin, which is more important to human health. This analysis highlights how farm production and financial data can be paired with information about human health risk to evaluate antibiotic usage and policy.In addition to the way that antibiotics are used, the type of antibiotic used is an important consideration for human health risk. As previously stated, the World Health Organization groups antibiotics into four classes depending on their relative importance to human health. Class 4 is the least important and Class 1 is the most important. The results of this study suggest that chlortetracycline is the most cost-effective option for managing L. intracellularis, it can be easily modified to include multiple sub-groups within the herd. This would more accurately reflect a true disease scenario, where only some pigs are infected, and some have more severe production problems than others. However, the intricacies of these types of disease scenarios can become quite complicated, so a straightforward model limits the number of required assumptions. In addition, the model could be extended to include additional preventative strategies, such as biosecurity measures, to assess the cost-effective means for preventing, rather than managing a disease. For veterinarians or farmers that know their specific herd scenario, a more intricate model may be more useful as a decision-making tool for different disease management options. The framework of this model can be extended to reflect different business structures, such as a “loop” where different farmers specialize in raising pigs through specific life stages. Farmers focusing on one area of production have different incentives than a farmer who manages a farrow to finish operation and thus different reasons for changing reduce antibiotic use.To our knowledge this is the first study that takes a comprehensive bioeconomic approach to estimating the net financial benefit of each antibiotic and each vaccine labeled for managing a specific disease in pigs. By calculating the cost-effectiveness of these management strategies for different disease severity levels, it can be seen which intervention strategies provide the greatest benefit for producers who are facing this illness. This model uses meta-data from the literature to specify parameters to generate results. For the model to produce more accurate results, a clinical study should be conducted with the intent of providing the values for these parameters. This would allow for more opportunity to examine the range of effectiveness for each disease management option. While the model in this study used herd-level averages to measure the production impact of Irrespective of the assumptions made or the potential applications of this model, this research provides a framework that can perform a coordinated evaluation of the value that antibiotics provide to the swine industry and other livestock industries. If this type of study were repeated  for other diseases and other livestock, a representative assessment could be made as to which antibiotics provide the greatest benefit and which provide the least amount of benefit to each of the livestock industries. Then, through work with public health officials and other experts in antibiotic resistance, a strategic plan could be made for reducing antibiotic use. This plan would value the importance of antibiotics in maintaining the financial viability of farms, while considering the significant risk that the use of some antibiotics presents to human and animal healthcare systems.L. intracellularis, annual net returns without intervention were $86,869.01, –$13,452.49, and –$230,209.99, respectively. Prophylactic chlortetracycline was the most cost-effective management option in each of the three scenarios with an annual net return of $109,022.52, $98,320.31, and $89,687.78 in the best-case, expected and worst-case disease scenarios, respectively. The Porcilis Ileitis vaccine was the least cost-effective management strategy in each scenario. Although vaccines are emerging as viable alternatives to prophylactic antibiotic use, this study suggests that vaccines result in significant financial losses for the farmer. Ceasing prophylactic antibiotic use may, unintendedly, lead to an increase in the use of antibiotics that are more important for human health. If prophylactic chlortetracycline (Class 3 antibiotic), were to be banned in order to reduce total antibiotic use, there may be a greater chance of more severe L. intracellularis. In this case, farmers might need to use antibiotics that are more important to human health like tylosin or tylvalosin (both Class 1 antibiotics) to handle the disease. Although antibiotic resistance is complex, discussions about reducing antibiotic resistance should acknowledge the risk and the benefit that comes from specific livestock antibiotic use. A coordinated research program that pairs the framework in this study with field trials will help to inform this discussion which will lead to a more comprehensive plan for reducing antibiotic resistance caused by livestock antibiotic use.Antibiotics and vaccines play significant roles in helping farms remain profitable in the presence of a disease. In this model, the calculated net return of a farrow-to-finish operation with 1,000 sows was $115,090.39 annually. In the best-case, expected and worst-case disease scenarios for The datasets generated for this study are available on request to the corresponding author.TJ gathered the data, conducted the analysis, and wrote the initial draft. AW organized and supervised the research and did final editing. MM helped in the simulation model. ZP provided expertise on the disease modeling and cost estimates.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The Ccrit values were measured on samples taken from engineering structures. This approach allows to overcome the well-known limitations of testing laboratory samples. The data are available in a public data repository. Currently, 46 Ccrit are reported (measured on four different structures). The database will continuously be updated. The database includes information about the structure, material properties, and local condition of the steel-concrete interface. For possible applications of this database and discussion refer to the related research article in Corrosion Science.A living data collection providing critical chloride contents for steel corrosion in concrete (C This file will be continuously updated in order to make new data accessible to the community. The file in the repository indicates the date of publication.At present, this file contains CThe database contains the information summarized in 22.1crit  were drilled from reinforced concrete structures. Each core contained a centrally located reinforcing steel bar, which, at the time of sampling, was not yet corroding . The samples were transferred to the laboratory and subjected to a preparation protocol, which included establishing electrical connections to the rebar for measuring purposes as well as coating lateral faces of the concrete sample to ensure 1-dimensional chloride ingress during the laboratory test and to avoid undesired rebar end effects (corrosion testing artefacts). The corrosion state was monitored by means of electrochemical measurements. Upon corrosion initiation, the chloride content in the concrete at level of reinforcement was measured to determine the CStandard  or an eqcrit values reported here were determined with one single method. This permits to narrow the influence of the test method itself, which, due to the many different approaches used in the literature, is one of the main factors complicating the interpretation and comparability of literature results [We consider it a particular advantage that all the C results .2.2crit (from lowest to highest). The highest sample number within an element is equal to the number of samples tested within this element.Each tested sample received an identification number to permit unambiguous assignments. The samples were labeled and numbered as schematically described in 2.3As shown in The geographic location of the structure, type of structure, as well as the specific element of the structure are documented. Information related to the structure  as well as information related to the sampling area (size and height above ground) are also given in the data collection.2.4The cover depth of the reinforcement was measured directly after drilling the sample from the structure.Information about cement type and mix proportions were obtained either through microscopy analysis or according to documentation on the structure, in case the latter was available. This includes w/b-ratio, cement type, and aggregate details (type and size).The electrical concrete resistivity was quantified after splitting the samples, that is, at the end of the laboratory test when the concrete was in wet conditions (but below saturation). Concrete cubes with an approx. dimension of 50 mm × 50 mm x 50 mm were used for resistivity measurements. Resistivity was measured with two steel plate electrodes according to the recommendation from RILEM TC-154 .After splitting the sample, the carbonation depth was evaluated with help of the phenolphthalein spray test, namely by spraying on the freshly broken concrete surface in the cover depth . The ind2.5The diameter of the reinforcement in the drilling cores was measured. Moreover, the orientation of the reinforcement in the structure and with respect to the chloride exposure side is documented . ReinforInformation about the type of steel is given according to structure documentation. This includes the chemical composition of the steel , the existence of ribs (smooth or ribbed surface), and its microstructure. The steel microstructure of the used reinforcement is analyzed with polished and etched  sections under an optical microscope .sat-reference electrode [sat) are documented at the beginning of exposure, immediately before corrosion initiation and at the end of the corrosion test.The steel potentials were monitored with an automated data-logger and a Ag/AgCllectrode . In the 2.6crit) was measured at level of the reinforcement, referred to mass of concrete. To convert it to mass of cement, we used an image analysis method [e.g. according to Swiss Standards [3 concrete). Both values (viz. the Ccrit with an assumed cement content of 300 kg of cement per m3 concrete and the Ccrit with the measured cement content in each specific sample) are reported in the data collection.The acid-soluble chloride content corresponding to corrosion initiation , adjacent to a rib (aR) and between two ribs (bR). Here, aR means that the corroding spot was right at the very edge of the rib, whereas bR means that the corroding spot was further away from this edge, located somewhere on the “plain” surface of the rebar.For horizontally oriented reinforcement, the location of the corrosion spot is documented in relation to the structure.