Prestressed monoblock railway sleepers are concrete elements with almost no reinforcement apart from the prestressing wires, which makes them very sensitive to any stress variation that can induce tensile stresses. In recent years, severe longitudinal cracking has been observed in a number of sleepers in hot regions of Spain, even before these elements were put in service. This work studies the problem while considering the thermal variation as the main factor affecting this cracking phenomenon. A non-linear static load-step analysis is applied on a non-linear finite element model to reproduce the problem and, after its experimental validation, the influence of three design parameters of the sleepers are studied: the nature of concrete aggregates, the dowel thickness, and the dowel material. The results show that all these three parameters may have significant influence on the problem, with the dowel material being the most important parameter. When the dowels are made of a material with a high elastic modulus and a high thermal expansion coefficient, the crack opening induced by a realistic thermal variation can reach significant values and result in longitudinal crack propagation. The changes of humidity are not considered in this study because they are beyond the scope of this work. Prestressed concrete monoblock railway sleepers are the most widespread type of sleepers in North America, Europe, Asia, and Australia . CompareNevertheless, this type of elements, unlike any usual prestressed concrete element, is manufactured without any or very low amount of steel reinforcement, which is required in order to install security measures in a railway line such as ATP (Automatic Train Protection) or CBTC (Communications-Based Train Control) . This isIn the last decades, major research efforts have been devoted to studying some of the most common problems that are related to railway sleepers. These studies are usually focused on quasistatic loads ,4, impacStudied problems usually deal with certain situations that take place during the service life of the sleeper, like the interaction of the sleeper and ballast or the dynamic effect of train loads. Nevertheless, in a study by Rezaie et al. , severe This problem has also been recently observed in Spain, even leading to full development of the longitudinal crack and breaking the sleepers in two halves see . It mustAs far as the authors know, there are not studies in the literature dealing with the effect of temperature on the development of this type of cracks. Since the sleepers have very low reinforcement, the effect of temperature could induce a stress field in concrete, which would add up to the effect of prestressing, which induces tension in the transverse direction, and the effect of the tightening torque applied at the dowels .In this study, a monoblock multipurpose sleeper  and the Standard track gauges, 1668 mm and 1435 mm, respectively) is analyzed under the effect of temperature before the sleeper is in service. Only positive variations of temperature were used that corresponded to the hot seasons for which the cracks firstly appear and showed their maximum opening. The lack of reinforcement makes this type of prestressed concrete elements particularly sensitive to small changes in their design that may seem irrelevant at first sight, such as modifying the material of the polymeric dowels where screws are introduced or modifying the type of aggregate used for manufacturing concrete.In the first part, a numerical model of the sleeper is described, introducing the prestressing load and carefully defining the material parameters for each component: concrete, dowels and prestressing wires. This model reproduces the fracture process and crack opening in concrete by using a smeared crack model  based onOnce the model was validated, the influence of three design aspects was assessed: the type of aggregates used for manufacturing concrete, the material of the dowels, and the geometry of the dowels, mainly focusing on their thickness.In this section, the numerical model used in this study is described and validated with experimental data. The experimental work is described first and the numerical model is presented later, finally comparing both results for validation.Metal moulds are cleaned.The steel wires and the polymeric dowels are placed.The steel wires are prestressed by means of hydraulic jacks.Concrete is poured and the mould is vibrated to guarantee a good filling of the mould.The moulds are introduced in a curing chamber that thoroughly controls and ensures specific conditions of humidity and temperature. These conditions may vary among manufacturers and usually comprise several stages, reaching maximum temperatures of around 50 °C.The strength of concrete is verified once the curing process is finished by testing cylindrical specimens.Prestressing force is transferred to concrete and moulds are removed.The tightening system is fixed at the sleeper by screwing it with a moderate torque.The sleepers can be piled up or transported for its later installation.Multipurpose precast concrete railway sleepers are industrially manufactured under controlled conditions. The process up to their piling up for its later installation may be summarized as follows:This study considers sleepers manufactured with polymeric dowels which are embedded in concrete. The loads and boundary conditions that have been considered in this study start when the prestressing force is transferred to hardened concrete, and finish when the sleeper is piled up next to the railway for its later installation, a situation that can be extended for several months, even more than a year. Therefore, three main actions are considered: the prestressing force, the presence of screws inside some dowels, and the effect of temperature on the sleeper.Regarding the screws inside the dowels, only their presence has been considered, but not the tightening torque applied when they are screwed inside the dowels. It must be noted that this tightening torque may induce compression stresses between the dowel and concrete, which could intensify the cracking problem under study. Therefore, not taking it into account leads to conservative values of the crack opening, which will be discussed later in this review.t = 5.1 mm by measuring the surface temperature of concrete and the screws using a thermal infrared sensor and the crack opening during thermal cycles.The experimental study that is used for validating the numerical model consisted of an accelerated test to study the evolution of the longitudinal cracking on sleepers employing glass-fibre reinforced polyamide dowels  with a tOnce the sleeper was manufactured, the tightening system was screwed with the same torque used on any sleeper that is piled up for later transportation, but at a much lower rate than the final torque applied to install the railway, ranging between 200 and 220 N·m. Then, a set of infrared heating lamps was placed over the sleeper, in line with the dowels, as shown in The sleeper was heated for 72 h and later cooled for another 72 h, registering a maximum thermal increment of 45 °C at the concrete surface, and 49 °C at the top surface of the screws. During this time, the sleepers were inspected every 12 h, measuring the crack opening by removing the screw for the inspection and screwing it again with the same torque by means of a torque wrench. The minimum temperature reached in the sleeper was 23 °C just after the prestressed load was applied during the manufacturing process.The numerical simulation has been carried out by means of the finite element method using the code VecTor2 . A non-lThe model reproduces the prestressing force by means of truss elements that follow the prestressing path and that are connected to the surrounding elements by their coincident nodes. The prestressing force corresponds to one half of the total one, obtained by an initial deformation of two steel wires of 10.5 mm of diameter to reach 225 kN. Two screws are considered inside two dowels see b, since cyf stands for the elastic limit under compression, tyf for the elastic limit under tension, E for the elastic modulus, ν for the Poisson ratio and α the thermal expansion coefficient. According to the Spanish standard for concrete structures [cyf and tyf of the dowel correspond to the maximum temperature of 68 °C reached at the concrete surface during the experimental test.ructures  in this For the numerical simulation, the dowels, the prestressing wire and the screws have been modelled using an elastic-plastic formulation, although none of them have reached the elastic limit, which agrees with what was experimentally observed. As for concrete, three models have been used in order to take several issues into account: the nonlinear stress-strain behaviuor of concrete before reaching its maximum load capacity, the effect of cracks on the material performance in compression and the softening behaviour under tensile stresses.T = 45 °C has been considered, as this is the maximum value experimentally measured in concrete, and has been introduced with 15 subsequent steps of small increments equal to 3 °C.Regarding the thermal increment, a value of Δεp stands for the strain at the peak stress, pf while parameters n and k adjust the pre-peak and post-peak behaviours, respectively, depending on the nominal strength of the concrete. The stress-strain diagram of concrete becomes nonlinear when the material is loaded close to its maximum bearing capacity. To model this phenomenon, the model proposed by Thorenfeldt et al. is used , which mβd factor expressed by Equation (2):dC depends on the relation of the maximum tensile stress and the maximum compression stress, thus considering the stress state of the material, and sC takes into account the possible shear slip along the crack.This phenomenon describes the reduction of the compressive strength and stiffness that concrete suffers when there are transverse cracking and tensile straining. The model used here corresponds to the formulation proposed by Vecchio and Collins  that cants,if stands for the stress that corresponds to a specific strain value εc,i, εcr for the strain at the maximum strength, crf, and εch for the strain at which the material completely loses its bearing capacity. crf, which has been considered equal to 4.05 N/mm2, and the fracture energy, FG, with a value of 125 N/m, obtained from experimental tests carried out for high strength concretes [When concrete is fractured as a result of tensile stresses, the bearing capacity is not lost abruptly and a progressive load decrease is commonly accepted; this is known as tension softening and can be modelled by defining a softening function relating stresses and crack openings. In this case, a smeared crack model, as classified by Jirásek , has beeoncretes .The maximum temperature increment measured experimentally in concrete was 45 °C. The numerical model predicts a longitudinal cracking that connects the four dowels, as shown in w, obtained experimentally, expw, and numerically, numw, for the maximum temperature variation of 45 °C measured in the laboratory for which the sleeper experienced the maximum crack opening. With these results, the model can be considered to be validated.The analysis of the influence of different factors in the mechanical behaviour of the sleeper after transporting and piling up and prior to the installation on the rail track is carried out in this section. To this end, different types of aggregates and dowels usually employed in the sleeper industry are taken into account. Regarding the aggregates, two types are considered: (i) carbonate (C) and (ii) siliceous (S). As for the dowels, two different properties are considered: the geometry and the type of material. Two geometries are studied: (i) a thinner geometry (G1) and (ii) that of the aforementioned dowel used in the i ranging from 1 up to 5.Furthermore, the stripe of the sleeper along its longitudinal axis where the dowels are located is divided in five zones see c, which Sixteen numerical models are set up from the benchmark numerical model by varying the type of aggregate (C and S), the geometry of the dowel (G1 and G2) and the material of the dowel . Non-linear analyses are carried out on each one, taking into account the same combination of loads than those used in the benchmark numerical model, that is, the load introduced by the prestressing steel wire at the first stage and the variation of the temperature from 0 (first stage) up to 60 °C (21st stage), with increments of 3 °C among them. It can be observed that the maximum thermal variation is 60 °C but not the used in the experimental test (45 °C) in order to take into account possible extreme values reached in hot regions such as the south-west of Spain, for instance. Only the concrete materials suffered plastic deformations in the tension domain, which caused cracks.Overall, sleepers designed with a specific dowel geometry and any type of aggregate but a different dowel material show higher crack opening for temperature increments over 21 °C when D4 dowels are used . The D1 There are two different zones in the evolution of the crack opening when D3 and D4 sleepers are analysed, regardless of the dowel geometry or type of aggregate. In the case of D3 sleepers, the first zone can be identified between 24 and 41 °C, while in the case of D4 sleepers this first zone can be observed between 21 and 39 °C, with similar slopes in both cases. The second zone can be identified between temperature increments of 33 and 60 °C for D3 sleepers and between 30 and 50 °C for D4 sleepers, with a similar slope in both cases but one lower than that observed in the first zone. D4 sleepers show a third zone (not observed in D3 sleepers) for which the slope grows again from a temperature increment of 51 °C. Therefore, a delay of 3 °C is observed between the curves of D3 sleepers and the counterpart of D4 sleepers, which leads to a higher crack opening observed in all cases for D4 sleepers because of the similar values of the slopes. The relative differences of the crack openings between those obtained with D4 sleepers (designed for specific dowel geometries and type of aggregates) and the counterpart D3 sleepers are expressed by the ratios reported in Owing to the referred delay, the differences observed in the crack opening for temperature increments ranging between 21 and 39 °C are important, about 7–9 times (at most) higher in D4 than in D3 sleepers. In the case of the temperature increment range between 39 and 51 °C, the differences are stabilized by achieving values ranging between 1.06 and 1.10. Eventually, the differences start again to grow from a temperature increment of 51 °C as a consequence of the third zone observed in D4 sleepers which cannot be observed in D3 sleepers. It is worth noting that the maximum differences are observed in a range of temperature increments that is not unusual for sleepers piled up outdoors in hot regions. Moreover, the aforementioned differences observed for the crack opening spring up as a consequence of the value of the elastic modulus because the higher this is the higher the capacity of the dowel to compress the concrete in which are embedded for the same temperature increment. This explains the highest crack opening shown by D4 sleepers over the rest of them. Therefore, it could be important to take this into account when designing sleepers using glass-fibre reinforced polyamide dowels with high elastic modulus placed in locations where important temperature variations are expected, especially when the sleepers are manufactured with carbonate aggregates.i ranging between 1 and 15 depending on the value of the elastic modulus . Eventually, a non-linear simulation is carried out on each numerical model using the same load combination than that in the benchmark numerical model. E is equal to 5000 and 4000 MPa, for G1 and G2 dowels, respectively. Nonetheless, when siliceous aggregate is used (It has been shown that there is a large difference in the crack opening evolution between the sleepers designed with lower elastic modulus dowels (D1 and D2) and those designed with higher elastic modulus dowels (D3 and D4). Trying to shed light on the influence of the elastic modulus to the crack opening evolution, a parametric study is now carried out varying the elastic modulus of the sleepers designed with glass-fibre reinforced polyamide dowels between 1000 and 15,000 MPa with increments of 1000 MPa between them. The two different dowel geometries (G1 and G2) and the two types of aggregate (C and S) used before are also considered. Therefore, sixty numerical models are set-up obtained by the combination of the different dowel geometries, type of aggregates and the fifteen values for the elastic modulus established before. The sleepers are denoted with the suffix EMi with  is used b,d the cFirst of all, it is important to note that the physical properties of the concrete rely on the type of aggregate used in its mix composition . An overT equal to 30 and 33 °C in sleepers with G2 dowels and 0.02 mm at ΔT equal to 36 °C in sleepers with G1 dowels. As for D4 sleepers, the maximum differences are 0.01 mm reached at ΔT equal to 27 °C and 30 °C with G1 and G2 dowels, respectively.The sleepers designed using carbonate aggregates show higher crack openings than those with siliceous aggregates, due to the lower expansion thermal coefficient in concretes manufactured with the first type of aggregate than those manufactured with the second one. In fact, concretes with a higher thermal expansion coefficient show higher strain values for the same temperature increment which, in turn, leads to lower levels of stress (compression and tension) at the joint with the dowels. This trend is clearly observed in D3 and D4 sleepers c,d. In tThe crack propagation is an issue of high concern for in concrete elements without proper reinforcement, such as monoblock railway sleepers, since it can lead to a complete failure of an element, making it useless, as observed in 2  with medium and high elastic moduli, respectively, induce an important cracking, as The geometry of the dowel, namely its thickness, can also have a certain influence on this problem, increasing the crack opening up to 0.015 mm for glass-fibre reinforced polyamide dowels.Using aggregates of different nature for manufacturing concrete can also have a relevant influence on the crack opening induced by thermal increments. Differences up to 0.02 mm are observed in sleepers made of carbonate aggregate concrete if compared with those made of siliceous aggregate concrete when glass-fibre reinforced polyamide dowels are used.E greater than 4000 MPa.A high elastic modulus dowel leads to triggering crack opening development at moderate temperature increments as low as 20 °C. This effect is observed when glass-fibre reinforced polyamide dowels are used with The crack propagation to areas beyond the dowels is observed when high elastic modulus dowels are employed, no matter the type of aggregate and dowel geometry used, such as the glass-fibre reinforced polyamide dowel analysed in this study.In this work, the possible longitudinal cracking connecting dowels, found in some real railway prestressed precast sleepers even before being installed, has been analysed while considering temperature as the main factor of study. The results show that some apparently not significant changes in the design of the sleeper and the tightening system, especially regarding the dowels, may be of critical importance and induce stresses that can be responsible for longitudinal cracking. The main conclusions can be summarized as follows:In addition to the conclusions presented, it is worth noting that these results only account for loads and thermal increments before the sleeper is put in service. It is to be expected that once it is in service, the train loads will add up stresses that will intensify the problem. It is also important to bear in mind that freezing-thawing cycles may affect greatly this crack opening, since once a crack is initiated, water can penetrate and freeze, leading to its expansion and helping the crack to propagate.


This study developed a patient-level audit tool to assess the appropriateness of antibiotic prescribing in acute National Health Service (NHS) hospitals in the UK. A modified Delphi process was used to evaluate variables identified from published literature that could be used to support an assessment of appropriateness of antibiotic use. At a national workshop, 22 infection experts reached a consensus to define appropriate prescribing and agree upon an initial draft audit tool. Following this, a national multidisciplinary panel of 19 infection experts, of whom only one was part of the workshop, was convened to evaluate and validate variables using questionnaires to confirm the relevance of each variable in assessing appropriate prescribing. The initial evidence synthesis of published literature identified 25 variables that could be used to support an assessment of appropriateness of antibiotic use. All the panel members reviewed the variables for the first round of the Delphi; the panel accepted 23 out of 25 variables. Following review by the project team, one of the two rejected variables was rephrased, and the second neutral variable was re-scored. The panel accepted both these variables in round two with a 68% response rate. Accepted variables were used to develop an audit tool to determine the extent of appropriateness of antibiotic prescribing at the individual patient level in acute NHS hospitals through infection expert consensus based on the results of a Delphi process. Antimicrobial resistance (AMR) is a global threat to health affecting all healthcare systems and growing at an alarming pace ,2. In thIt is not currently possible to estimate with any certainty the proportion of antimicrobial prescribing in English hospitals that is inappropriate, as electronic prescribing data directly linking hospital prescriptions to clinical data are still not widely available. A key study aim was to develop and validate a patient-level audit tool that could support estimation of the number of days of antibiotic therapy that auditors considered non-essential and therefore potentially avoidable. The proportion of inappropriate antibiotic prescribing can be represented as non-essential days of therapy (DOTs) expressed as a percentage of total days of therapy. The goal of the audit tool was to collate variables that would support assessment of those aspects of prescribing most relevant for selection pressure and resistance. If successful, this would allow the UK to potentially set goals for reduction of antibiotic consumption in hospitals that are safe and achievable. A secondary aim included creating an audit tool that helped minimise subjectivity in order to standardise the assessment of appropriateness by prompting auditors to consider certain critical information in order to support their decision.Defining the gold standard for appropriate antibiotic prescribing is challenging due to the inherently subjective nature of evaluating quality in prescribing. An initial list was compiled to incorporate elements of high-quality prescribing identified by opinion leaders in the field, the UK Government Scientific Advisory Committee on Antimicrobial Prescribing, Resistance and Healthcare Associated Infection (APRHAI) and a workshop including 22 infection experts convened to define appropriate antibiotic prescribing. The collated list  sets outPrescribing an antibiotic for a patient in the absence of (documented) evidence of bacterial infection.Prescribing a critical broad-spectrum antibiotic to patients in the absence of a (documented) rationale.Continuing an antibiotic prescription beyond the course length recommended in local or national guidelines, in the absence of a (documented) rationale.It could reasonably be argued that each of these elements is relevant to efficacy, safety, and improving patient outcomes, and critical to the assessment of appropriateness of prescribing. However, the APRHAI committee took a view that improvement in performance against certain elements would be less likely to impact upon the overall consumption of antibiotics and, consequently, would be less likely to impact upon antibiotic resistance. Three aspects were therefore given ultimate priority as most relevant to identifying avoidable selection of resistance within the UK hospital setting:A consensus emerged from the one-day workshop that existing antibiotic prescribing guidelines for acute hospitals often do not suggest clinical thresholds for initiating or stopping antibiotics. This means there is a lack of consistency between hospitals in assessing whether antibiotics are indicated and for how long. There was also general agreement that antibiotic consumption data alone were not sufficient to determine the proportion of prescribing that is inappropriate. This was further complicated by the failure of hospital-level antibiotic consumption data to account for patient acuity and hospital case mix. The workshop group arrived at the conclusion that an individual patient audit by an infection specialist was required to establish with greater certainty the current proportion of prescribing that is inappropriate. This process was anticipated to be less vulnerable to case mix or speciality bias. It was agreed that a patient-level audit tool would be sent for expert elicitation via a Delphi process. The response rate to the initial survey was 100% (19/19), taking on average 32 minutes to complete. Of the first-round responders, 42% (8/19) were specialist antimicrobial pharmacists, 21% (4/19) were infectious disease doctors or medical microbiologists, 16% (3/19) were general medical doctors, and the remaining 21% (4/19) were antimicrobial stewardship nurses. The majority (14/19) of participants in round one had over five years’ experience and practice in antimicrobial stewardship and infection. When asked what proportion of inpatients prescribed antibiotics should be audited to provide reasonable confidence of the overall assessment of the appropriateness of antibiotic prescribing in secondary care, 79% (15/19) expressed the view that either 5–10% or 10–25% of inpatients on antibiotics would be an adequate sample size to represent the entire hospital patient population. The panel members were also asked at what frequency would it be necessary and reasonable to repeat an audit assessing appropriate antibiotic prescribing; 89% (17/19) indicated annually and 11% (2/19) stated every three years would be sufficient. Twenty-three of the 25 variables were scored as relevant or highly relevant for assessing appropriateness for one or more of the main decision points  and wereOut of the nineteen respondents (from Round 1) who were invited to participate in Round 2 the response rate was 68% (13/19). The same distribution of healthcare professionals participated in Round 2 with 69% (9/13) having over 5 years’ experience and practice in antimicrobial stewardship and infection. The neutral variable “presenting complaint” was rescored, with 85% (11/13) of respondents indicating this was considered relevant to assessing appropriate prescribing. A consensus was reached when the expert panel members were asked to score the renamed variable “review of antibiotic prescription within 72 h” with this being accepted by the panel .The majority (9/13) of respondents reported that there were local guidance or supportive tools available to help clinicians stop antibiotic therapy safely. Where not available, three of the four respondents agreed that such guidance would be helpful. Eight of the 19 original panel members agreed that the audit tool was fit for purpose, 32% (6/19) expressed a neutral view, and 5 panel members disagreed (5/19) including one panel member stating they were unable to assess this question. The participants were asked if the time taken to complete the audit tool is a worthwhile investment of NHS resources for the benefit of patient safety and public health, with 43% (8/19) agreeing that it is, 21% (4/19) having a neutral view, 26% (5/19) disagreeing, and 10% (2/19) being unable to assess this.An audit tool consisting of 25 variables to support assessment of the appropriateness of antibiotic prescribing in secondary care has been developed. The prototype audit tool was reviewed by 19 multi-disciplinary infection specialist health professionals through a two stage modified Delphi process and all 25 variables were accepted by specialists as relevant or very relevant to the aim of the audit following rewording of just one variable.The response rate of participants within the Delphi process was seen to reduce between rounds one and two. A systematic review of 31 studies indicated that the median response rate of a Delphi process does reduce by 2% from the first to the last round of Delphi processes , howeverThe inclusion of acuity scores within the audit tool was to help support the auditor in assessing appropriateness of antibiotics by highlighting the severity of the acute health status which could be as a result of a likely infection. The supportive use is important as a low acuity score does not rule out infection, but merely indicates no severe or deteriorating condition or a lesser probability of organ failure. Evidence from a multi-centre study of adult emergency departments in the UK reported a positive predictive value for National Early Warning Score (NEWS) ≥3 of 20% for mortality or ICU admission . It was During the second round of the Delphi process the panel did not accept that formal documentation of a pre-72-hour review was relevant. The panel did however accept that whether a pre-72-hour review took place was relevant, irrespective of documentation  for the purposes of assessing appropriateness of antibiotic prescribing. In the absence of a pre-72-hour review, it is likely that patients for whom diagnostic tests support an alternative diagnosis to infection are likely to continue antibiotics longer than necessary. This variable is also important due to the potential value it brings to predicting unnecessarily prolonged treatment courses, and it is part of ongoing quality improvement work within English hospitals, so the indicator was reworded for Round 2. Secondary healthcare quality improvement work within England has focussed on reducing total antibiotic consumption as well as obtaining evidence of antibiotic review within 72 h of commencing an antibiotic . The addition of separate questions to explore individual views on inappropriate prescribing within secondary care was used as it was not possible to estimate a sample size, because the proportion of non-essential DOTs was unknown. Delphi participants were asked what proportion of patients on antibiotics required auditing to give them assurance on appropriateness of antibiotic prescribing for their hospital. The expert panel members were invited to estimate the feasibility and likely value of the audit tool; this saw 26% of the expert panel disagreeing with statements that the audit tool was fit for purpose or a worthwhile investment of NHS resources. This finding was surprising given the high degree of consensus over the relevance of individual variables for supporting the assessment of appropriateness and was not explored in more detail. It may reflect a perception of futility that a simple audit tool could not sufficiently capture the complexity of an episode of infection to enable a reproducible assessment of appropriateness. A pilot study of the audit tool to test the reliability of the instrument is clearly a prerequisite before more widespread adoption.Strengths of this project include the development of an audit tool through a consensus of a multi-disciplinary team of experienced infection specialists working in hospital clinical practice. The authors believe the developed audit tool is the first of its kind internationally that can specifically quantify the scale of inappropriate prescribing directly resulting from unnecessary doses being administered. The audit tool was designed to minimise the burden of data collection by limiting the items of data collected to only those considered relevant or highly relevant to the specific aim of evaluation of appropriateness of prescribing at three critical prescribing decision time points. The audit tool also narrows the focus of the audit to evaluate only those elements of prescribing associated with unnecessary antibiotic doses and therefore likely to be most relevant to the selection of resistant microorganisms: whether an antibiotic is indicated at the start of treatment, whether treatment beyond 72 h is justified, and whether treatment beyond a standard course length is appropriate. The potential to collect more detailed clinical information to explore the subjective decision that the auditors would take was advantageous. Standardisation of the assessment process may be aided by the inclusion of objective variables to capture evidence of infection or sepsis, along with markers of severity including qSOFA score, NEWS, C-reactive protein (CRP), and white blood cell count. The potential limitations of the audit tool include the time needed to collect data and risk of subjectivity in assessment which are inherent limitations of this approach, however a balance is struck between the value of detailed patient-level data to robustly answer the important question of appropriateness set against the use of a standardised data collection tool to minimise variability in assessment. There was also limited opportunity for experts to consider variables not included in the tool, such as medical imaging and urine dipstick tests. Presenting an increased number of potentially relevant variables such as antibiotic dose and route of administration may have provided greater opportunity to discriminate between the perceived value of different variables for estimating non-essential doses. Whilst a relatively small sample of experts participated in the Delphi process, an important limitation, it is worth noting that 22 experts participated in the workshop to define appropriate antibiotic prescribing and develop the initial audit tool cascaded for the Delphi consensus. Subsequent piloting of the audit tool will need to include ongoing evaluation of the strengths and weakness of the tool and inform iterative improvements. The minor changes to the audit tool as a result of this Delphi process provide reassurance that extensive revision of the tool was not required, however a higher number of experts participating would have provided greater assurance of a reliable rating for each of the variables assessed. Since admission and discharge dates were not included in the tool it was not possible to determine at which point during their admission a patient receives antibiotics and therefore whether a patient is receiving treatment for a healthcare-associated infection or community-acquired infection unless this is stated explicitly by the auditor. This was identified by the project team as a priority to capture in future versions of the audit tool. The use of a web-based Delphi process limited opportunity for qualitative feedback from a face-to-face discussion and may have contributed to the lower response rate for Round 2. The selection of expert panel members was via national infection networks and only one healthcare professional also participated in the previous workshop that convened to define appropriate prescribing. To help reduce potential bias, all participants were blinded to who participated in the expert panel with individual correspondence being sent. The use of the developed audit tool is for active treatment and does not assess long-term and peri-operative surgical prophylaxis antibiotics. An adaptation could be made to the audit tool in order to assess these groups of patients. Finally, the developed audit tool was prioritised for antibacterial agents only but could also be adapted for antifungal and antiviral agents. Piloting the audit tool within NHS hospitals to assess usability and operability is the next step. This would also provide additional insight and development of the tool and mitigate against the limitations of the small consensus panel. The resource burden of data collection and whether there is variation between hospitals that use electronic systems or paper-based processes needs to be quantified. Although it is anticipated that the use of electronic systems should be faster than paper-based prescribing, ease of access to information for each variable may vary. Piloting the audit tool within 5 to 10 hospitals could provide a preliminary assessment of non-essential days of antibiotic therapy prescribed to inform the sample size calculation for a definitive study. Recruiting a mixture of hospital types  will be important to assess the practicality of the developed audit tool. The balance between the amount of information being collected with the time taken to collect the data in a busy operational hospital will be crucial. Evidence synthesis of published literature and international guidance contributed to the development of the initial prototype audit tool to try and quantify and identify inappropriate antimicrobial prescribing. The initial prototype audit tool then underwent preliminary feasibility testing at one acute teaching hospital in Southampton, England. This was conducted by a specialist pharmacist supported by a medical microbiologist, with a focus on evaluating the operability of the audit tool. After a subgroup of the UK government APRHAI scientific advisory committee drafted standards to define appropriate prescribing in secondary care a finalised prototype audit tool was created . The subTo elicit further expert opinion, a one-day workshop was held on 6 March 2017 with infection experts including secondary care clinicians (10/22), pharmacists (9/22), a nurse, an academic, and a medical director to explore views on the appropriateness of prescribing within hospitals. The project team including two pharmacists of the antimicrobial resistance programme at Public Health England and three national antimicrobial pharmacists met to discuss the workshop findings and updated the audit tool accordingly. Elements of the audit tool that were intended to support the assessment of appropriateness of antimicrobial prescribing were termed “variables” for the purposes of the validation process. The selection of variables to include in the audit tool was based on discussions within the antibiotic prescribing quality subgroup of APRHAI, iterative e-mail feedback from co-authors, and prototype audit tool testing in Southampton.To support the auditor in their assessment of the severity of infection and deterioration as a result of a likely infection the National Early Warning Score (NEWS) and quick sequential organ failure assessment (qSOFA) score were incorporated into the audit tool ,35. A thInitiation (was the antibiotic indicated and necessary at the start date?);Early post prescription review (was the antibiotic continued after infection was ruled out?);End of therapy (was the antibiotic continued beyond the standard duration?).Between October and December 2017, a RAND-modified Delphi process was conducted to validate each individual variable within the audit tool. A multi-disciplinary expert panel of infection and public health specialists was recruited via e-mail through national infection and microbiology networks and asked to assess the relevance of each variable against a five-point Likert Scale . The relNon-essential days of antibiotic therapy were included with potential reasons as follows: (1) antibiotic not indicated/unnecessary at start date; (2) unexplained continuation of antibiotic after infection ruled out; and (3) unexplained continuation of antibiotic beyond standard duration. The standard duration was defined by individual hospitals as identified in local antibiotic guidelines. A separate questionnaire was sent to the Delphi participants to explore individual views on inappropriate prescribing within secondary care. The expert panel participated in two rounds. Invitation via e-mail was sent to 19 participants before the first round. The online survey SelectSurvey.net was used in each Delphi round with participant reminder e-mails sent periodically. The results were discussed within the project team after the first round and the aggregated scores were shared with the participants prior to the second round. Each of the 25 variables was assessed for its relevance against the three main decision time points. Qualitative feedback was reviewed by one project team member and common themes reported for discussion with the full project team. The threshold for accepting a variable was met if the median score was “relevant” or “very relevant” for assessing appropriateness at any one of the three decision time points. A variable was rejected if the median score for all three of the critical decision points was “irrelevant” or “very irrelevant” with a neutral score being rescored in the second round to provide a definitive response. The rewording of questions between each round occurred by the project team and was presented to the participants from Round 1 for Round 2. After completing both rounds of the Delphi process the accepted variables were incorporated into a finalised audit tool .Data were summarised using non-parametric descriptive statistics which are considered suitable to measure consensus and stability in Delphi studies  and due In summary, the RAND-modified Delphi process has provided face validity of this audit tool and selection of critical variables that can be used to support the assessment of inappropriate antibiotic prescribing. The feedback from expert panel members helped shape development of the audit tool and provides an important endorsement from practising healthcare professionals within and outside the NHS. This audit methodology will help hospitals identify the location, extent, and nature of inappropriate antibiotic prescribing and provide evidence to drive local antimicrobial stewardship and focus targeted training to specific areas of improvement.


Examination performed by scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS) provided both qualitative and quantitative information on the penetration of the rust layer in the surrounding concrete porous network. Strain gauges were used to measure corrosion-induced deformations between steel and concrete matrices, as well as the formation of corrosion-induced cracks. A good correlation between the rate of penetration of the rust products in the surrounding pores and the delay of the cracking pressure in concrete was observed from the experimental results. This phenomenon is incorporated into the analytical model by using a reduction factor, which mainly depends on the pore size of the concrete. The crack width obtained exhibited a significant dependency on electric current density at the beginning of the test, depending mainly on the pore size of the concrete later. Research on early stages of corrosion of steel bars caused by chloride penetration is relevant in improving the durability of reinforced concrete structures. Similarly, the formation and development of cracks induced in the surrounding concrete is also of great importance. This paper uses integration of the analytical models examined in the published literature, combined with experimental research in corrosion induced at the concrete/steel interface, in estimating the time-to-crack initiation of reinforced concrete subjected to corrosion. This work studies the influence of the porous network and electric current density on the cracking process at early ages. The experimental program was performed by using an accelerated corrosion test. Two types of concrete were performed: A conventional concrete (CC) and a concrete with silica fume (SFC). A current density of 50 μA/cm Durability of reinforced concrete is a significant research line, given the high costs associated with the maintenance and repair of structures. Corrosion of steel-rebar reinforcement is one of the most serious and frequent deterioration mechanisms identified in reinforced concrete structures. This deterioration process frequently causes significant structural problems that eventually lead to collapse ,2. SteelOnce the passive film is broken, corrosion starts, and rust products are produced by an electrochemical reaction of the iron. The rust produced occupies a larger volume than the original material. At an early stage, this extra volume can be accommodated by a region of the porous network of the concrete that surrounds the rebar, delaying the tensile stress development in the concrete/steel interface ,4. ThereThe CAR thickness depends on several factors, in particular the volume and connectivity of the pores in the concrete/steel interface and the corrosion current density. The microstructural characteristics of the concrete/steel interface, in turn, depend on the surface area of reinforcement, w/c ratio, degree of hydration, degree of consolidation and, among others, type of cement. Thus, accurate prediction of the CAR size and crack initiation time is highly complex. Several published authors have proposed a fixed value for the CAR thickness, which due to expansive pressure must be filled with corrosion products before tension stress development ,7. RecenOnce the CAR is filled, the corrosion products cause expansive pressure on the surrounding concrete, with tensile stresses emerging on the concrete/steel interface . EventuaThe formation of cracks provides a path through which the aggressive agents from the environment can easily penetrate and reach the reinforcement, accelerating the corrosion process. In this stage, the corrosion products begin to fill the cracks, which then cause crack opening and propagation, spalling and delamination of the cover ,10. Figu2 and 100 μA/cm2, usually used for accelerated corrosion studies [To improve knowledge about durability of reinforced structures in chloride environments is necessary to obtain a thorough understanding of the corrosion process from its beginning. Particularly important is a detailed study of the CAR formation in order to predict time-to-crack initiation, the propagation period and ultimate service life. Many of the experimental studies on corrosion-induced crack initiation and propagation conducted previously have used high corrosion rates to accelerate the process on concrete with embedded rebar specimens being monitored with strain gauges on the surface ,12. Tech studies ,19,20. T studies . In this2 by weight of cement was added to each concrete [Two concrete mixtures were designed trying to obtain similar properties and approximately the same percentage of total porosity though different pore microstructure. As a result, two concretes with quite similar overall porosity, but different pore size distributions were obtained. Portland cement CEM I 52.5 R and Portland cement CEM I 42.5 R, in accordance with the standard EN 197-1:2011, were used for the preparation of the two concrete mixtures. The first cement type was used to elaborate a conventional concrete (CC) without admixtures and the second one to elaborate a silica fume concrete mixture (SFC) by using SF, with 91% of silica dioxide in its composition, as mineral admixture. The second mixture uses SF with 10% of replacement percentage weight of cement and two as an efficiency factor . The watconcrete ,23,24. F3. Rebars of diameter of 20 mm were treated with the aim of protecting the steel from corrosion initiators, propagating points and preferential attacks. First, rebars were coated entirely with epoxy resin. Later, the rebars were machined and the diameter reduced by up to 12 mm along 100 mm, beginning at a point located 30 mm from the extreme of the specimen, as shown in In order to study the evolution of the corrosion products at different ages from early stages and with two current densities, 16 specimens of reinforced concrete were cast for each concrete type with the following dimensions: 15 × 15 × 15 cmWith the objective of monitoring the tangential displacement of the surrounding concrete induced by the corrosion, strain gauges were embedded in three specimens per concrete type and current density. For such a purpose, these specimens were cast in two times, casting one half of the volumes in each of them. When the first half was set, four strain gauges were placed perpendicularly to each other at the concrete surface around the steel rebar as closely as possible . A resinFour experimental tests were carried out in order to study the mechanical properties of the concrete. The compressive strength, the elastic modulus and the tensile strength were measured at 28 days on cylindrical φ150 mm × 300 mm specimens. Compression strength tests were performed according to EN 12390-3. Three specimens were tested for each type of concrete. The elastic modulus was estimated in accordance with standard EN 12390-13. The indirect tensile strength was obtained according to standard EN 12390-6 by a tensile splitting test on three specimens.3 with a notch at the centre of 1/3 of the height of the beam. The mechanical properties of the two concretes studied are showed in Lastly, fracture energy was assessed according to the recommendation RILEM TC-187 SOC. Three specimens of each concrete type were tested under three-point bending testing procedure. The dimensions of the specimens were 100 × 100 × 430 mm2 by weight of cement was added to the mix [The experimental set-up used is shown in  the mix . 2 in order to examine the influence of velocity of corrosion in the CAR formation. These values allow a sufficiently short experiment but keep induced corrosion within values which might be found in practice [2) with respect to Faraday’s law, otherwise a significant increase of in the tension–strain response and, consequently, in the cracking process might occur. Theoretically, intensity densities could reach 500μA/cm2, but non-negligible variations might appear, and the accuracy of the experiment could not be guaranteed [In this study, specimens were subjected to current densities of 50 and 100 µA/cmpractice . With suaranteed .2 was imposed, the total current in each circuit could be computed. Results of the surface rebar electricity density and total electricity current in each circuit are shown in Two independent circuits were assembled: The first one comprised only the specimen with strain gauges, and the second one the rest of the specimens by using a parallel system. Specimens from the second circuit were disconnected and extracted at different ages in order to provide study by means of SEM. Since a constant current density of 50 and 100 μA/cm2 were cut. Then, thin slices of approximately 10 mm thickness were obtained for SEM observation. All the cuts were made with the precision diamond cut-off machine STRUERS SECOTOM-10, with a 0.8 mm thick disc running across the prismatic sample. In order to avoid a washing of the corrosion products, liquid petroleum jelly was used to cool the cutting disc. Subsequently, these slices were prepared for SEM observation (see The study of the development of the corrosion process and progress of the rust corrosion layer (CL) were observed and analysed by means of SEM and EDS . The specimens were disconnected and cut at the following ages: One, two, five, eight, 14, 21, 26 and 35 days. First, prismatic samples containing the rebar with a square base of 50 × 50 mmtion see b. To thiA field-emission scanning electron microscope  and operated in backscattered electron (BSE) mode was used to create the element maps of the steel/concrete interface at different ages. On this basis the time-dependent corrosion product development, the CAR and subsequent formation and propagation of cracks were studied. Four chemical elements were analysed to examine rust development on the concrete/steel interface: Calcium, iron, oxygen and silicon. The results are represented in one general image. Different colour intensities, ranging from black over green to purple, make observation of layers in each element map possible. Steel rebars and the corrosion layer are brighter in the images due to the oxygen content. In the case of concrete, Ca and Si are found. An analytical line was selected across the steel/concrete interface on each image. The size of the reference region of each image depended on the age. Boundary conditions are shown in This work sought the influence of the pore size by maintaining the rest of the properties relatively constant. As The strain gauges were placed as closely as possible to the steel rebar in order to measure the strain as the rust products were growing. The data were checked daily and recorded. 2 show a linear pattern from the very beginning. In the case of the radial stresses with 50 μA/cm2, a bilinear pattern may be approached. Therefore, in this case, the strain gauges did not measure strain over a period of time, corresponding with the formation of the CAR. The time needed to accommodate the rust products  is quite similar, around 120 h, in each specimen. Once the CAR was completely filled with rust products, expansive pressure started with a linear increment. During the formation of cracks, it is worth noting than the circumferential strain measured by the gauges might have an additional component due to micro-cracking before the formation of the macroscopic cracking. This process is likely to occur together with a possible injection of corrosion gel into the micro-cracks during the process. After the initiation of cracking, part of the circumferential stress is released.Based on the circumferential strain shown in 2 by using the colour code. In the graphs below, the distributions of Fe and O are shown. The horizontal axis represents the distance from the starting point of the analytical line and the vertical axis the counts of photoelectrons per second.Mapping was adopted to observe the development of corrosion products at the steel/concrete interface. The areas with high levels of Fe are shown in purple and the rust layer represented in green. In order to complement the study, the distributions of corrosion products were analysed by EDS/WDS along an analytical line. Four chemical elements were chosen for this analysis: Fe, O, Si and Ca. Depending on the availability of these elements, the three main layers involved in the corrosion process could be distinguished: Steel, mill scale (CL + CAR) and concrete. As an example, The starting point of the analytical line and the vertical axis represent the counts of photoelectrons per second.2 and 50 µA/cm2. As In the image corresponding to 35 days, the end of the filling of the ΔR can be distinguished. This specimen had a rust layer (CL) of 18 μm and a layer where corrosion products were diffusely distributed (CAR). Some authors refer to this as the ‘corrosion filled paste’ ,28 when 2. Afterwards, a linear growth could be appreciated.Although examination of the concretes studied has not shown significant change in total porosity, a considerable pore refinement has been obtained by adding silica fume. SFC presented a reduction of 15.2% in the percentage of macropores, increasing the percentage of micropores with regard to CC. This might explain the differences obtained in the corrosion layer development, even though the variation exhibited between different concretes and intensities was relatively small.2  curves. 0r is the initial radius of the rebar; 1r is the radius of the non-corroded rebar; and 2r is the total radius of the corroded rebar, value that includes CL and CAR. Once the corrosion process has started, it is possible to differentiate three radii: Furthermore, Equation (3) establishes the equivalence of CAR + CL in this approach: With the aim of comparing the experimental circumferential strain provided by the experimental strain gauges measurements, placed as closely as possible to the rebar with the analytical approach, it is necessary to consider the geometrical dimensions of the strain gauges. Therefore, another radius is defined by adding the radius of the rebar with the half of the width of a strain gauge (Equation (4)), due to it being in contact to the surface of the steel . r* being the radius of the strain gauge measurement  and e tf is proposed [f in the elastic regime (n = 0). It should be noted that in order to evaluate the circumferential hoop strain, the entire corrosion layer thickness indicated in the WDS images, proposed  with theεsg), can be expressed as: f is the reduction factor, w is the width of crack, n is the number of cracks, ε is the circumferential strain that includes the opening of the cracks. Subsequently, the circumferential strain (Equation (1)), which before the opening of the crack or cracks is the measurement assessed by the strain gauges (in gauge ), ΔR* isThe reduction factor can be obtained from Equation (6). With a view to study the evolution of the crack width with time once the cracks initiate, the average reduction factor obtained from Equation (7) can be used at the ages studied. 3 containing the rebar at the centre were cut with the aim of observing the number and the trajectories of cracks. The amount of cracks observed was from one to three. The experimental tensile strength was 4.98 MPa for CC and 4.03 MPa for SFC, so the crack width will appear when the theoretical tensile stress (σ∗) exceeds this value. After completion of the test, prisms of 28 × 28 × 5 mm2 and eight days for 100 μA/cm2 in each concrete, though with a different tensile (σ∗) due to the microstructure of the network.From the results shown in 2, caused the smallest crack widths in both concrete types, with them being even smaller for SFC50 in comparison with CC50. Above 1000 C, the crack opening evolution obtained exhibited an increasing dependency on the pore refinement, with the crack widths obtained for the concrete with silica fume, SFC, being significantly lower in comparison with the plain concrete, CC. Additionally, it is worth noting that there is a value of the electric charge, around 1200 C for CC and 1800 for SFC, from which the use of the lowest current density caused a higher crack width in comparison with the specimens subjected to the highest current density, 100 μA/cm2. As This paper has studied the influence of the porous microstructure and current density in the initiation stage of rebar corrosion process and the crack formation caused by chlorides in reinforced concrete.It is shown that the increase in the current density has produced a more rapid development of the corrosion process. Furthermore, it should be noted that the smaller average pore diameter size of the porous microstructure causes a lower capability to accommodate the corrosion products of the concrete, leading to greater circumferential deformations than other cases from very early ages.The combination of an SEM analysis and strain gauges has shown a good performance when studying corrosion development at early ages. The use of wavelength dispersive X-ray spectroscopy enables data acquisition of the rust products evolution. The experimental work showed the formation of a rust layer at the interface steel/concrete at the beginning of the corrosion process, which later penetrated through the porous microstructure of the concrete around the steel bar. From the experimental results, an approximately linear relation of steel corrosion product thickness with time is deducted. An analytical model based on the thick-walled cylinder approach was used to reproduce the experimental results. A good level of agreement was found among the SEM observations, EDS analysis and the strain gauge measurements when a reduction factor f was included in the model for the prediction of the crack width. On the basis of calculations, it could be said that a pore refinement might influence the decrease of the reduction factor, consistent with a lesser capability to accommodate corrosion product.The results obtained show that embedding the strain gauges in the concrete, placed as closely as possible to the steel rebar, might allow more detailed information of the circumferential strain in the concrete at local level to be available than the use of strain gauges on the concrete surface. This procedure shows improvement in the cracking models. Therefore, the crack initiation time could be estimated through conversion of the retrieved strain data into stresses, when these last ones reach the tensile strength.In addition, from the results obtained, it could be said that the pore refinement and current intensity might have a significant influence on the crack width obtained as a function of the electric charge applied. At very early ages, up to approximately 750 C, the lowest current density applied caused the smallest crack widths in each concrete type. Later, the crack opening evolution obtained exhibited an increasing dependency on the pore refinement, with the crack widths obtained for the concrete with silica fume in comparison with the concrete without additions being significantly lower. Lastly, a value of the electric charge of around 1200 C for the plain concrete and 1800 C for the concrete with silica fume is shown, from which use of the lowest current density causes a higher crack width in comparison with the specimens subjected to the highest current density.


The increase in antibiotic resistance has frequently been linked to unrestrained antibiotic dispensing. This review was conducted to mainly assess the perception and attitudes of community pharmacists towards antibiotic dispensing. This scoping review was performed between June 2016 and September 2016 to identify published studies related to the perception and attitudes of community pharmacists towards antibiotic dispensing. The combination of terms such as ‘antibiotic dispensing’, ‘antimicrobial resistance’, ‘community pharmacy’, and ‘community pharmacists’ were searched in electronic databases such as PubMed, ProQuest, Google Scholar, and Science Direct. Only published articles within the last 12 years were included. A total of 13 studies were identified. In general, community pharmacists have good awareness and knowledge of antibiotic dispensing. However, the majority of them are still selling antibiotics to their customers and/or patients for unjustified reasons. The community pharmacists seem well aware of the antimicrobial resistance crisis and considered it a significant health issue. However, many embraced the concept that dispensing antibiotics without medical prescription (DAwMP) can be one of the key features in the dissemination of multidrug resistant bacteria. Escherichia coli (E. coli), Klebsiella pneumoniae, Streptococcus pneumonia, and methicillin-resistant Staphylococcus aureus (MRSA) [Increased prevalence of drug-resistant bacteria leads to an upsurge in morbidity and mortality from bacterial infections . Infectis (MRSA) .Globally, one of the key issues in tuberculosis (TB) treatment is drug resistance. The statistics on anti-TB drug resistance highlighted 123,000 patients with MDR-TB or rifampicin-resistant tuberculosis (RR-TB) and around three-fourths were located in India, South Africa, China, and European regions . The repDuring 2014 and 2015 it was reported that the incidence for MRSA was declined in United States (44%), Europe 18%) Canada 16%), and South Africa (28%) but it gained momentum in India (40%), Latin America 90%), Australia, and sub-Saharan Africa %, and So,8,9. % Canada 0%, AustrE. coli emerged as difficult-to-treat extended-spectrum betalactamase (ESBL) producers exhibiting resistance to newer third-generation cephalosporins. In 2013, 17 European countries reported the majority of E. coli isolates (85–100%) as ESBL-positive [E. coli family as ESBL-positive (UTIs) followed by resistance to both third- and fourth-generation cephalosporins [K. pneumoniae and 2% of E. coli were resistant to carbapenem [positive . In the lates 85–0% as ESBosporins , while iThe root cause of this problem is multifactorial and stems from the overuse of antibiotics, inappropriate antibiotic prescribing and dispensing, extensive use in agriculture and veterinary sectors, lack of new antibiotics, and weak regulatory barriers . There iAn amalgamation of program elements focused on attitude and behavior changes is vital to achieve optimal health outcomes in a population. Antimicrobial stewardship (AMS) is an intervention program directed to improve and sustain appropriate antibiotic use in the absence of antimicrobial resistance and strengthen patient safety in a cost-effective manner . The AmeThis scoping review focused on the perception and attitude of community pharmacists towards antibiotic dispensing without prescription and the related factors and facilitators with most sought-after antibiotics in different diseases. The review is also expected to highlight research gaps followed by recommendations of interventions and health education.A step-wise methodological framework by Arksey and O’Malley was the basis of this scoping review . The steThe framework steps taken were (1) research questions identification; (2) relevant literature identification; (3) screening and selection of relevant literature; (4) data charting; and (5) analyzing summarizing, and reporting the results.As this review mainly focused on the perceptions and attitudes towards antibiotics dispensing among community pharmacists, the research question was “What are the opinions and attitudes of community pharmacists on antibiotic sales and does it affect the antibiotic resistance?”(a)What are the perceptions of community pharmacists towards antibiotic dispensing?(b)What are the attitudes of community pharmacists towards antibiotic dispensing?(c)How frequently did community pharmacists sell antibiotics in community pharmacies? (d)How often did customers demand antibiotics in community pharmacies? (e)What is the suitability of antibiotics that were dispensed from community pharmacies?We identified five areas of interest based on the antibiotic sales:A literature search was done from June 2016 until September 2016 to find and classify published studies related to knowledge, perception, and attitudes of community pharmacists towards antimicrobial dispensing. The search was performed using Boolean operators for the following combination: “perceptions”, “attitudes”, “antibiotic”, “antibiotic resistance”, “antibiotic dispensing”, “community pharmacy”, and “community pharmacists”. The electronic databases used for searching include PubMed, ProQuest, Google Scholar, and Science Direct.The articles were reviewed by reading the titles and the abstracts. Studies that used qualitative or quantitative methods, or both, were included in the review, while research focusing on general practitioners and customers were excluded from the review. The search was also narrowed down to English language articles published in the last 12 years. After screening, the full-text articles were read, and information was abstracted by using a standardized data form in a table format.In this process, three researchers independently studied and reviewed the abstracts of the papers and met three times  face-to-face to discuss the vague aspects and chose to redefine their strategy. Two other researchers read the full text of the articles for final inclusion. On strong disagreement of any study inclusion, the remaining researchers decided its final inclusion. Based on Arksey and O’Malley’s framework, the studies were categorized based on the authors; publication year; type of study; study tool; study population; study location; aims and objectives of the study; and study findings and conclusion and limitations .A few stages were carried out in this step. After searching the studies using the databases, any unrelated literatures based on their titles and abstract were excluded. The full texts of the remaining studies were retrieved and read. The studies that did not fulfil the requirement for the review were excluded. The last 13 remaining studies were categorized based on their methodology, either using questionnaires or interviews, or using simulated patients/simulated clients.The purpose of including simulated patient/simulated client studies stems from the fact that they are simply a direct reflection of pharmacists’ attitudes towards antibiotic dispensing and facilitates the validation of their reported perception and attitude in cross-sectional studies.A total of 507 references were identified from the electronic searches of four databases after duplicates were removed. A total of 478 identified studies were excluded based on the titles and abstracts. From the 29 research articles retrieved for detailed examination 16 were excluded . A totalIn general, community pharmacists showed appropriate knowingness and perception towards antibiotic dispensing without prescription and all identified this as growing public health issue ,18,25,28The attitudes of the majority of the pharmacists did not parallel with their awareness and perception and, interestingly, dispensing without medical prescription (DAwMP) is an extensive phenomenon seen in many community settings ,26,27,28The community pharmacists put the onus on customers/patients for nonprescription dispensing irrespective of which strata of society they are from ,17. CommCommunity pharmacists are generally eager to boost their business turnover, and seek more revenue and higher profits. Studies from India ,24,26, EThere always exists a bond of mutual trust and confidence among patients and doctors. From research evidence from Tanzania, community pharmacists cited their inability to correct health facility prescriptions for nonpneumonia cough and nonbloody diarrhea because patients had intrinsic trust and confidence for their doctors and always want to adhere to doctors’ prescriptions . LikewisThis review also highlighted that specific antibiotics were commonly dispensed to each scenario accounting for sore throat, URTI, sinusitis, urinary tract infection, acute bronchitis, otitis media, acute gastroenteritis, and/or diarrhea. Penicillin only or combination with penicillinase inhibitor were the most common antimicrobial agents dispensed for URTI ,23,26,27The strategy of executing simulated patients in assessing the attitudes of community pharmacists is appropriate to quantify customer care. This concept is well-established in developing countries where it is considered pertinent and economical and helps in identifying areas of improvement for providing quality services in patient care . The curBased on the review undertaken, most of the community pharmacists presented appropriate awareness towards AMR ,21,22,23URTI, the most commonly reported case at primary care institutions, are mostly of viral origin. In the current review the URTI scenarios used viral cough as the presented problem and the community pharmacists always dispensed penicillin or penicillin plus penicillinase inhibitor as the treatment ,23,26,27Otitis media is one such condition in which antibiotic intervention is generally not recommended . NeverthThe current review reported a liberal attitude of community pharmacists towards antibiotic dispensing in all the simulated clinical scenarios. Especially in case of URTI, it was observed that antibiotics were given mostly without emphasizing the demand from the SPs ,22,23,26A recently published commentary pinned high hopes on community pharmacists and positioned them as antibiotic stewards in upper respiratory tract infections . LikewisUnlike the current scoping review, the systematic review by McCullough et al.  focused The majority of the community pharmacists reflected necessary knowledge and appropriate perceptions toward antibiotic dispensing and resistance. The majority acknowledged that antimicrobial resistance is the culmination of injudicious and excessive antibiotic dispensing and irrational usage. However, antibiotics are still dispensed freely in a community setting and, thus galvanizing widespread antibiotic resistance. The authorities should reflect intensified mindfulness towards this problem by strengthening the implementation of current regulations, followed by brainstorming new alternatives to curb this menace. Finally, community pharmacists can work as collaborators between the prescribers and patients, educating patients on ‘where’, ‘when’, and ‘how’ to use antibiotics effectively, as well as to remind prescribers to follow guidelines, and furnishing them with up-to-date information about different therapeutic categories. Mass media campaigns voiced over by community pharmacists on the disposal of unused antibiotics can be one such future strategy which needs to be implemented soon in lower- and middle-income countries.


Depending on the environmental conditions, cells adapt their metabolism and specific growth rate. Rearrangements occur on many different levels such as macromolecular composition, gene and protein expression, morphology and metabolic flux patterns. As the interplay of these processes also determines the output of a recombinant protein producing system, having control over specific growth rate of the culture is advantageous. Continuous culture methods were developed to grow cells in a constant environment and have been used for decades to study basic microbial physiology in a controlled and reproducible manner. Our review summarizes the uses of continuous cultures in cell physiology studies and process development, with a focus on recombinant protein-producing microorganisms.  Besides microbial physiology studies and process development, there is an interest in continuous cultures to manufacture recombinant proteins [Efficient strategies to produce recombinant proteins are gaining increasing importance, as more applications that require high amounts of high-quality proteins reach the market . Higher proteins ,7, as thproteins ,9.In this review, we summarize how continuous cultures have been used to understand basics of recombinant cell physiology, for process development and industrial production of recombinant proteins. As semi-continuous perfusion processes have been used for mammalian cell-based recombinant processes for a long time and reviewed elsewhere ,11,12, oHost cells can be considered as catalysts in the process of producing recombinant proteins. When a genetic element designed to produce a protein of interest is placed into host cells, its output depends strongly on the physiological state. One of the key characteristic of the physiological state of cells is their specific growth rate (µ) . Most chSalmonella typhimurium varies strongly according to how fast the cells are growing [Schaechter et al. first showed that the macromolecular composition (contents of ribonucleic acid (RNA), DNA, and protein) of  growing . This ha growing ,16,17. I growing , transcr growing , and tra growing ,21 are c growing ,23,24,25 growing ,26,27. W growing . Overflo growing ,30 that  growing . This isTherefore, if processes are carried out in continuous cultures where µ can be fixed, the interpretation and control of processes can be simplified as metabolic rearrangements due to changing µ can be avoided.p—in many different organisms. These process characteristics can be directly compared between different experimental setups as they are independent of process specific settings such as biomass density and reactor volume. We summarize continuous cultures studies reporting product formation kinetics in Chemostat cultures allow tight control over all growth conditions and the option to modify μ of host cells by limiting the feeding rate of an essential growth substrate. For this reason, chemostats have been widely used to determine the product formation kinetics—the relationship between µ and qp achieved in different μ-dependent studies, the highest qp values have been reached with Escherichia coli. With the strong inducible T7 promoter, as high as 75% of total protein production directed towards recombinant production has been reported [p has been observed [E. coli, bell-shaped kinetics with a maximum qp most frequently achieved at medium µ values have been reported [p above a threshold µ often co-occurred with high acetate production, which probably limits the ability to reach a higher qp with faster growth [When comparing the maximal qreported . Commonlobserved ,33. For reported ,35,36,37Pichia pastoris, recently summarized by Looser et al. [P. pastoris, most often two expression systems are used: (1) methanol inducible AOX1 ) and (2) constitutive glycolytic GAP promoter . For the methanol-inducible AOX expression system, bell-shaped protein formation kinetics with a maximum qp near low growth rates (µ < 0.1 h−1) have most commonly been observed [P. pastoris. Overall, a low µ range has been demonstrated to be optimal for AOX promoter-dependent protein expression. In S. cerevisiae, a galactose-dependent expression system that is induced by galactose and repressed by glucose is often used. With this promoter system used in galactose-based media, growth coupled qp has been observed [p kinetics, possibly because of increasing inhibiting glucose concentrations at higher µ [P. pastoris, a growth coupled increase of qp with increasing μ has been observed [p values are commonly reported at the maximum µ values above 0.15 h−1. Similar growth coupled product formation kinetics have been reported for other yeast processes utilizing glycolytic promoters [S. cerevisiae [P. pastoris [Probably the most thorough µ-dependent recombinant process analysis has been carried out using r et al. . In P. pobserved ,39,40, aobserved ,42,43. Pobserved . In conthigher µ ,46. For observed ,47,48,49romoters ,51,52. Tpastoris  was usedAspergillus niger has often been carried out using chromosomal expression instead of plasmid-based systems [p have been reached at µ > 0.1 h−1 [In contrast to most processes with yeast and bacteria, protein expression in  systems ,54,55,56 systems ,55. In m 0.1 h−1 ,54,55,56In summary, growth coupled product formation kinetics seems more common in continuous cultures. This is probably one of the reasons why often satisfactory yields are reached using simple batch cultures where µ is not restricted. Although empirical determination of optimal µ for each new recombinant process should be carried out, some general trends can be estimated beforehand depending on the host organism, promoter system and induction strategy.E. coli [E. coli [Applying chemostat cultivations for each new process development can be laborious and time consuming. Chemostat starts as a batch culture, after which the culture is typically stabilized for five bioreactor volume changes. This can take many days depending on the specified dilution rate . To incrE. coli . The minE. coli . Another[E. coli . These mHansenula polymorpha and demonstrated highest space-time-yield near maximum μ of the organism [S. cerevisiae. In the continuous culture, two optima were found, one at a lower μ below the critical specific growth rate for aerobic overflow metabolism of ethanol, and the other at a higher μ. Interestingly, in fed-batch cultivations, only the lower optimal μ was confirmed while the qp was low at higher μ. [Another improvement of the classical chemostat is the accelerostat cultivation method where the dilution rate of culture (defines μ in steady state) is changed slowly enough for the cells to remain in a state comparable with steady state . This syorganism . Recentligher μ. Besides μ-dependent product formation kinetics studies, continuous cultures have been used to optimize many other process parameters. We summarized selected examples that demonstrate the versatile uses of continuous cultures in recombinant process development in Bacillus stearothermophilus and identified a system that could be maintained for more than 300 generations without significant plasmid loss [Controlled and constant environment provided by continuous cultures is an advantage that can be effectively used to study the effect of growth conditions on plasmid stability. Brigidi et al. compared several plasmids for α-amylase production in mid loss . Others mid loss ,69,70. Pmid loss .Bacillus megaterium using 13C-labelled glucose and pyruvate [34S labelling procedure for the flux measurements of a recombinant protein producing P. pastoris [Metabolic flux analysis has been widely used for identification of major intracellular pathways and critical branch points in metabolic networks. Isotope incorporation analysis is considerably simplified in steady-state conditions and therefore is most often carried out in chemostats. Fürch et al. studied the metabolic link between glycolysis and the tricarboxylic acid (TCA) cycle in pyruvate . They shpyruvate . Pfefferpastoris . Using cpastoris .p and µ have been reported (P. pastoris [p was more correlated with cell cycle than µ, and based on the results, constructed strains with customized cell cycle phase distribution. Resulting strains had increased qp at low µ, and increased space-time-yield of the target proteins Fab and trypsinogen [With the use of GAP promoters, often a strong positive correlation between qreported . Buchetipastoris . They shpsinogen .Besides the more advanced specific cases described above, there are many other process parameters that have been optimized using steady-state continuous cultures: feed composition , temperaS. cerevisiae, but also in this case, process stability was problematic [Growing cells in continuous cultures results in a steady-state operation, which is easier to characterize and understand, but it can also have economic benefits. Many growing industries have at one point made a switch from batch to continuous manufacturing and this has had a tremendous effect on their efficiencies . Severalblematic .E. coli as inclusion bodies [Besides the cultivation side, a production facility must also consider downstream operations that need to be coupled with the upstream operations to maximize the benefits of a truly continuous bioprocess. There are many recent developments in the direction of fully end-to-end continuous recombinant protein production processes, which include downstream purification, cell lysis, and protein refolding ,86. Moren bodies . A recenn bodies .Within this contribution, we focus on the application of continuous cultures for different aspects of microbial recombinant protein production. Furthermore, we describe how methods of keeping cells in constant environment using continuous cultures have been used to advance basic understanding of recombinant cell physiology and for process development in microorganisms.


The inappropriate use of antibiotics in hospitals increases resistance, morbidity, and mortality. Little is currently known about appropriate antibiotic use among hospitals in Lahore, the capital city of Pakistan.Longitudinal surveillance was conducted over a period of 2 months among hospitals in Lahore, Pakistan. Antibiotic treatment was considered inappropriate on the basis of a wrong dosage regimen, wrong indication, or both based on the British National Formulary.A total of 2022 antibiotics were given to 1185 patients. Out of the total prescribed, approximately two-thirds of the study population (70.3%) had at least one inappropriate antimicrobial. Overall, 27.2% of patients had respiratory tract infections, and out of these, 62.8% were considered as having inappropriate therapy. Cephalosporins were extensively prescribed among patients, and in many cases, this was inappropriate (67.2%). Penicillins were given to 283 patients, out of which 201 (71.0%) were prescribed for either the wrong indication or dosage or both. Significant variations were also observed regarding inappropriate prescribing for several antimicrobials including the carbapenems (70.9%), aminoglycosides (35.8%), fluoroquinolones (64.2%), macrolides (74.6%) and other antibacterials (73.1%).Educational interventions, institutional guidelines, and antimicrobial stewardship programs need to be developed to enhance future appropriate antimicrobial use in hospitals in Pakistan. Policies by healthcare and Government officials are also needed to minimize inappropriate antibiotic use. The role of antibiotics in successfully treating infectious diseases cannot be denied. However, inappropriate antibiotic use poses a major challenge to public health in terms of increasing antimicrobial resistance (AMR) with its associated impact on morbidity, mortality, and costs as well as increasing adverse effects . This haWhilst antibiotics are principally prescribed in ambulatory care , antibioEscherichia coli isolates, 82% were resistant to beta-lactam antibiotics with many resistant to fluoroquinolones and trimethoprim-sulfamethoxazole – attributable to antibiotic overuse [In LMICs, physicians are particularly challenged with antimicrobial prescribing due to a lack of diagnostic facilities and poor level of healthcare systems in a number of countries as well as a lack of antimicrobial stewardship programs , 14. As  overuse . However overuse , 17.However, the frequent and needless use of antibiotics has increased AMR rates in Pakistan . There hWe conducted a longitudinal observational study over 2 months between March and April 2017 among two private hospitals and two public sector hospitals in Lahore, Pakistan, the capital city of Pakistan. This reflects the availability of both private and public sector hospitals in Pakistan. We believed that if we saw major issues regarding antimicrobial prescribing among hospitals in the capital city, Lahore, this would be reflected in hospitals throughout Pakistan. The participation of hospitals was voluntary. Antibiotics were prescribed in each hospital by the physicians in charge of the patients’ care, based on their own decision, or based on recommendations of the consultant, with currently no hospital or national guidelines to guide prescribing. The diagnosis was based on clinical judgement as typically culture and sensitivity testing (CST) is not undertaken in hospitals in Pakistan unless patients are in a critical condition in view of financial constraints. Patients undergoing treatment with one or more antibiotics either for a perceived clinical infection or surgical prophylaxis were included in the study.We assessed the patients who were hospitalized in pulmonology, gastroenterology, nephrology, orthopedic, and general surgical/medical wards. We excluded those wards where antimicrobial prescribing patterns were seen as same in all patients, e.g., all patients were given ceftriaxone and metronidazole as prophylaxis in gynecological and obstetric wards. Patient receiving antimicrobials for medical prophylaxis were also not included because the indication was not clear. We also excluded all those wards where systemic antimicrobial use was perceived to be very low such as eye wards and Ear Nose and Throat (ENT) wards.Patients were categorized according to International Classification of Diseases (ICD) as being treated for a site-specific infection such as a respiratory tract infection, including lower respiratory tract infections such as pneumonia, tuberculosis, and exacerbations of chronic obstructive pulmonary disease; a urinary tract infection including cystitis and pyelonephritis; a skin and soft tissue infection including bursitis, wound infection and cellulitis; or a bloodstream infection.Experienced clinical research coordinators were trained to collect data prior to initiating the survey. Hospital pharmacists coordinated the data collection in each ward, while physicians and nurses also helped with data collection. Data were collected from progress notes, observation charts, pathology and microbiology results, and prescription sheets. The use of antibiotics was considered as surgical prophylaxis if mentioned in preoperative assessment documents and postoperative if prescribed after surgery. With regards to current antibiotic use, all antibiotics were documented using the ATC classification . Data coInstitutional guidelines on antibiotic use had not been developed in any surveyed hospital despite Lahore being the capital city. In addition, there are no national guidelines currently available in Pakistan. Furthermore, there is also no currently established mechanism to implement any guidelines once available within hospitals in Pakistan, such as a Drugs and Therapeutic Committee, antibiotic guideline groups, or antibiotic stewardship groups.Consequently, antibiotic prescribing guidelines from the British National Formulary were used as the standard to evaluate the appropriateness of prescribing antibiotics . The BriTo check antibiotic appropriateness, antibiotic selection, dosage form, dose, frequency, duration, contraindication, hypersensitivity, and antibiotic susceptibility reports were considered against BNF guidance. Antibiotic treatment was considered inappropriate on the basis of the wrong dosage regimen  or the wrong indication  or both.Data were analyzed using Statistical Program for Social Sciences (SPSS version 20). Simple descriptive statistics were applied to analyze patterns of infection, antibiotic use and the appropriateness of antibiotic prescribing among hospitalized patients. We did not break the figures down into public and private hospitals because we wanted a general picture across both sectors before looking further at specific hospital sites and categories.The study was approved and registered from the Ethics committee on human research, University College of Pharmacy, University of the Punjab, Lahore, Pakistan, under the registration number (HEC/1000/PUCP/1925I). Since the study did not contain any individual person’s data in any form , the ethics committee has granted an exemption from consent to be issued before accessing their files. The head of departments of various wards and their staff physicians and nurses were informed about the study and they allowed the principal investigators  to conduct the study in the respective wards.n = 595) and female (n = 590) patients. A total of 2022 antibiotics were given for 1185 patients. Patients receiving single antibiotic treatment (43.4%) or combination therapy (56.6%) were studied for the appropriateness of their antibiotic treatment. Data collectors gathered the data from a number of wards in the hospitals, including gastroenterology (25.8%), pulmonology (23.2%) and other specialized departments as listed in Table The demographic and clinical properties of the study population are summarized in Table Out of total of 1185 patients on antimicrobial therapy, only 29.7% received appropriate treatment according to the BNF  were prescribed inappropriately. However, this is similar to studies in South Africa where poor compliance to indications, administration, and current guidelines was seen for pre-operative prophylaxis in children , and in Despite the efforts of the WHO towards developing and implementing strategies to enhance appropriate antimicrobial use, good antimicrobial prescribing practices are still not followed in a number of LMICs , 32. TheHealthcare providers should also carefully evaluate medication appropriateness and should know about the benefits and risks before prescribing antibiotics to patients . PertineWe are aware of a number of limitations with this study. Firstly, the information collected was dependent on the knowledge and training of individual data collectors. Whilst each of these data collectors was provided with detailed information, variability between data collectors could not totally be excluded. Secondly, the appropriateness of antibiotic selection was based on the assumption that the diagnosis was accurate as CST reports are not in place in most of the hospitals. This is always a limitation of this type of study in the majority of LMICs. Thirdly, treatment outcomes were not checked as our primary focus was the appropriateness of the antibiotic used. Fourthly, the educational background of the doctors and other medical staff was not considered in this study, neither was disaggregating the findings from private from public hospitals, as we wanted to gain baseline data. Lastly, although this longitudinal survey gave a detailed view of the appropriateness of antibiotic prescribing in the four hospitals surveyed, which were representational of Lahore, we cannot be fully confident that our findings are replicated throughout Pakistan. However, despite these limitations, we believe our findings are robust, providing direction to key stakeholders in Pakistan in the future to improve antibiotic use in hospitals. This will be followed up.Inappropriate antimicrobial use was frequently observed among the studied hospitals in Lahore. More than half of the patients had inappropriate antimicrobial therapy, and cephalosporins were frequently prescribed to these patients. This inappropriate use can be minimized through educational interventions for healthcare practitioners, institutional guidelines for appropriate antimicrobial use, implementation of antimicrobial stewardship programs and development of strategies by healthcare professionals and Government officials to combat unnecessary and overuse of antimicrobials in hospitals. These are considerations for the future and will be followed up in future research.