Many studies have investigated the ways in which physicians decide whether to prescribe antibiotics, but very few studies have focused on the reasons for which general practitioners (GPs) choose to prescribe a particular antibiotic in a specific clinical situation. Improvements in our understanding of the rationale behind GPs’ decisions would provide insight into the reasons for which GPs do not always prescribe the antibiotic recommended in clinical practice guidelines and facilitate the development of appropriate interventions to improve antibiotic prescription.The objective of the study was to understand the rationale used by GPs to decide which antibiotic to prescribe in a specific clinical situation, and to propose a model representing this rationale.We used a three-step process. First, data were collected from interviews with 20 GPs, and analysed according to the grounded theory approach. Second, data were collected from publications exploring the factors used by GPs to choose an antibiotic. Third, data were used to develop a comprehensive model of the rationale used by GPs to decide which antibiotic to prescribe.The GPs considered various factors when choosing antibiotics: factors relating to microbiology , pharmacology , clinical conditions , and personal factors .Various interventions, targeting all the factors underlying antibiotic choice, are required to improve antibiotic prescription. GP-related factors could be improved through interventions aiming to improve the GPs’ knowledge of antibiotics . Factors relating to microbiology, pharmacology and clinical conditions could be targeted through the use of clinical decision support systems in everyday clinical practice. Antibiotic misuse is a major public health problem worldwide. One sort of misuse is the prescription of the wrong antibiotic molecule by the physician . Such erAntibiotic selection is a complex task in which many factors, such as clinical condition and tolerance in the patient, the microbiological and clinical efficacy of the antibiotic, ecological risk, and drug cost, must be taken into account .Antibiotic selection is mostly empirical, i.e. the antibiotic is selected without knowledge of the antimicrobial drug susceptibility profile of the causal pathogen , 6.Antibiotic selection is guided by bacterial resistance rates, which change frequently and rapidly, often without the awareness of physicians .Most antibiotics are prescribed by general practitioners (GPs) in primary care settings. GPs often experience difficulties deciding which antibiotic molecule to prescribe because:National health authorities release clinical practice guidelines , 8 to guHowever, despite the extensive diffusion of clinical practice guidelines, GPs still frequently prescribe the wrong antibiotic molecule –11. IndeMany studies have investigated physicians’ decision-making processes for antibiotic prescription. Various factors have been identified –16: (i) In this study, the rationale used by GPs in their choice of a particular antibiotic for a specific clinical situation was investigated, and a model representing this rationale is proposed.Semi-structured interviews of GPs were conducted. This provided an initial list of the reasons why GPs choose a particular antibiotic in a clinical situation.A literature review of publications exploring the rationale used by GPs to choose an antibiotic was then conducted. This added to the first list of reasons derived from interviews with GPs, leading to a final list of possible reasons.Finally, this list was used to build a model representing the rationale used by GPs to choose an antibiotic.We used a three-step process to explore the rationale used by GPs to choose a particular antibiotic for a specific clinical situation:Qualitative research methods were used, due to their suitability for exploring and understanding complex processes in detail . Data weSemi-structured interviews were conducted by a junior doctor in training (JK).The participants were GPs practicing in primary care. They were recruited by word of mouth, telephone calls, e-mails, and through the faculty of medicine. JK first contacted a few GPs met during medical training, and asked them both (i) if they would agree to be involved in the study, and (ii) if they could suggest other colleagues that we could contact. She then contacted these colleagues, and repeated the process until sufficient numbers of GPs had been recruited. We were careful to ensure that the panel of GPs had the greatest possible diversity of experience and opinions, by selecting GPs of both sexes, with a wide range of ages, and of durations and types of practice (public or private sector).The interview guide was developed for this study, and tested with five junior doctors before its use with the GPs. During the interview, seven simulated clinical cases were presented orally to the GPs ANDANDFocusing exclusively on GPs practicing in primary careExploring factors relating to the choice of antibiotic moleculeWritten in English or FrenchWe retrieved and reviewed 230 abstracts. Studies were considered eligible for inclusion if they satisfied the following criteria:The scientific publications selected from the literature review were analysed manually, and independently by JK and RT. For each publication, the factors involved in antibiotic choice were extracted. These factors were then incorporated into the list of codes derived from the interviews of GPs. This resulted in a final list of codes.The list resulting from step 2 was used to develop a comprehensive model of the rationale used by GPs to decide which antibiotic to prescribe. The hierarchical relationships between codes, identified in steps 1 and 2, but also the relationships of each code to one of the four main entities involved in antibiotic decision , were used to build the model.At each step of the method described, JK and RT compared their analyses and discussed inconsistencies until a consensus was obtained.The results of steps 1 and 2 are presented together in the results, whereas the model resulting from step 3 is presented separately.Interviews with 20 GPs and the data from three publications –23 were Three GPs were contacted, but refused to be involved in the study because they lacked time. The 20 GPs interviewed had a mean age of 47 years (range: 27 to 70 years). They had been practicing in the primary care setting for a mean of 18 years (range: 2 months to 37 years). Thirteen were salaried (public sector), and seven worked in private practice. Twelve were women. All but one of the GPs were interviewed with the same seven clinical cases . The remaining GP was interviewed with only five of the seven clinical cases because of a lack of time. Interviews lasted between 15 and 35 min.One of the publications studied  investigOur analysis of GP interviews and scientific publications (steps 1 and 2) revealed that antibiotic choice was guided by four main factors: the probable causal bacteria, the patient’s condition, antibiotic properties and general practitioner-related factors.(Ex1). Identification of the causal bacterium is not easy in primary care, because GPs cannot necessarily perform bacterial tests during consultations. They therefore have to use the patient’s symptoms and epidemiological data  to formulate hypotheses concerning the most likely causal bacterium (Ex2). The GPs then choose an antibiotic to which they presume the bacterium is susceptible. Ex1 (from publication [): “The likely infecting organism was also reported as a major influence on which antibiotic to prescribe”.lication ): “The lEx2: “For otitis… if there is also conjunctivitis, then I prescribe amoxicillin clavulanic-acid, because I suspect the pathogen to be Haemophilus influenzae”.Almost all the GPs reported that they chose the antibiotic to prescribe according to the bacterium causing the infection (Ex3).Ex3: “For uncomplicated pyelonephritis… I think I would prescribe a urine culture test, and then adjust the prescription according to the result of the test (…). I first prescribe ofloxacin, because of its broad-spectrum and then readjust after 48 hours, according to the results of the bacterial test. For example, if the bacterium is susceptible to amoxicillin, I would readjust and prescribe amoxicillin. But, without the result of the bacterial test, I would never prescribe amoxicillin because of the risk of resistance, unlike fluoroquinolones for which susceptibility is higher.”In some cases, GPs may decide to confirm their hypotheses, by prescribing bacteriological tests (e.g. urine culture). However, as the results of these tests may take some time to obtain, GPs are nevertheless obliged to prescribe antibiotics in accordance with their hypothesis, before subsequent readjustment, if necessary, on the basis of bacteriological tests (Ex4).Ex4: “I now prescribe fluoroquinolones as a first-line treatment, to avoid the emergence of extended-spectrum beta-lactamases”.A few GPs also reported a preference for prescribing antibiotics likely to do little collateral damage  .Ex5: “For pneumonia in young people I give amoxicillin (...). For elderly people, I prefer to give amoxicillin/clavulanic acid, which is more efficient, especially after flu-like conditions, which often leave patients frailer”.Ex6: “For acute cystitis, I usually give Monuril® (…). But today, I saw a patient who had an history of pyelonephritis. Because of this antecedent, I was worried about prescribing Monuril® as a single-dose… So, I decided to prescribe lomefloxacin for three days. So yes, because of her medical history, I wanted to be more effective than the usual treatment”.All GPs reported taking patient profile , medical history and comorbid conditions  into account. For example, for frail elderly patients or patients with comorbid conditions likely to worsen the infection (e.g. diabetes), the GPs preferred to prescribe antibiotics that were “powerful” or taken in long courses .Ex7: “For otitis… if symptoms are severe I prescribe Oflocet®, otherwise I give Augmentin®”.Ex8: “For childhood pharyngitis… Amoxicillin as the first-line treatment (…). But if the patient’s condition deteriorates, then I add clavulanic acid, because I want to be more effective and to cover more of the pathogens likely to cause upper respiratory tract infections”.All GPs also said that they took the patient’s symptoms and the course of the infection into account when prescribing antibiotics. For example, they reported a preference for broad-spectrum antibiotics (e.g. fluoroquinolones) for serious, intense, risky, persistent, repeated or complicated infections (Ex9).Ex9: “For prostatitis … I avoid fluoroquinolones (…) if the patient has taken fluoroquinolones in the last three months”.Some GPs also said that they took the patient’s history of antibiotic treatment into account. They avoid prescribing antibiotics that had not proved effective in the patient in the past, and antibiotics already prescribed to the patients in the last few months, so as to prevent the occurrence of bacterial resistance .Ex10: (from publication [): “Many GPs explained how fluoroquinolones were popular with a range of patients due to the low incidence of side-effects and the twice daily dose”.lication ): “Many Ex11: “I listen a little to what the patient says… if the patient repeatedly had sinusitis and tells me that one particular antibiotic is efficient, then I prescribe this antibiotic if it is appropriate. So, yes, sometimes, the patient’s wishes may play a role in antibiotic choice”.Patient preferences were also taken into account. GPs said that they sometimes adjusted their prescriptions according to the patient’s preference in terms of the type of molecule, galenic formulation or mode of administration .Ex12: “For sinusitis… I prescribe Orelox®, because it has always been effective”.Ex13: “For prostatitis …. I give ofloxacin… This antibiotic reaches high concentrations in the urinary tract, and this is important because prostatitis is a deep infection”.Most GPs reported that they considered the efficacy of the antibiotic when making their choice. They reported a preference for antibiotics with marketing authorisation for the infection, good pharmacokinetic parameters (e.g. rapid action), and antibiotics known to treat the type of infection concerned effectively (Ex14). They avoided prescribing antibiotics known to have adverse effects .Ex14: “For pharyngitis… I prescribe amoxicillin (...). It is very effective, and it has the least side effects”.Many GPs also said that they took the adverse effects of antibiotics into account (Ex15). Administration route, galenic formulation and the flavour of the preparation may also be adjusted to patient profile, to encourage patients to take their treatment (Ex16). For example, if the patient has trouble swallowing tablets, antibiotics may be prescribed as syrups or suspensions, or for intramuscular injection.Ex15: “For cystitis… I prescribe Monuril® as a single dose (…). It is very convenient for patients”.Ex16: “Josacin® is highly suitable for use in children because of its strawberry taste”.The administration protocol was often taken into account. Antibiotics with a convenient administration protocol  were preferred, to maximise patient observance .Ex17 (from publication [) “They needed to keep broad-spectrum antibiotics in reserve for severely ill patients”.lication ) “They nEx18: “For pharyngitis, I avoid third-generation cephalosporins. We have to preserve them.”Some GPs also explained that they avoided prescribing antibiotics from classes considered to be precious, such as fluoroquinolones, and third-generation cephalosporins. They reserved these antibiotics for very serious cases and for cases of infection with highly resistant bacteria (Ex19), but also the costs relating to hospital admission that antibiotic administration might prevent.Ex19: “I won’t prescribe pristinamycin as a first-line treatment because it is expensive for our national health insurance”.Very few GPs reported taking cost into account in their choice of antibiotic. Those that did considered the cost of the drug itself (Ex20), habits, experience (Ex21), and preferences (Ex22). These preferences seem to differ between GPs.Ex20: “For pyelonephritis… I used to prescribe quinolones because that was what we prescribed during my medical training, but I think things are changing…”.Ex21: “For cystitis… Monuril® (…). This is the antibiotic recommended for first-line treatment, and I have also had good experiences with this drug in terms of side effects and efficacy.”Ex22: “I know we can prescribe other antibiotics in this situation, but I prefer Orelox®.”Antibiotic choice is also guided by the GPs’ antibiotic knowledge (Ex23). GPs were also found to be influenced by the practices of colleagues, and of specialists in hospitals (Ex24). One GP reported being influenced by sales representatives from the pharmaceutical industry.Ex23: “I follow the recommendations in clinical practice guidelines (...) I also update my knowledge with the antibiotic website”.Ex24 (from publication [): “GPs’ prescribing choices were also influenced by discussions with other GPs at practice meetings”.lication ): “GPs’ All GPs said that they used external resources to guide their choice of antibiotic. Clinical practice guidelines were the most frequently mentioned resource, followed by antibiotic websites, personal memos, and scientific publications (Ex25), and one even admitted that antibiotic choice was influenced by his/her mood at the time of prescription (Ex26).Ex25: “For cystitis… instinctively, I prescribe Monuril®”.Ex26: “For sinusitis… I give Augmentin® or Zinnat®, depending on my mood”.Half the GPs also reported that they followed their own instincts when choosing antibiotics (Ex27) and by feelings of responsibility for their patients (Ex28). They explained that they sometimes prescribed very powerful antibiotics not recommended in guidelines because they were concerned about the possibility of complications occurring in the patient and because they wanted to do their best for their patients.Ex27: “For pneumonia… I should give amoxicillin, but this is the only situation in which I prescribe amoxicillin-clavulanic acid. I prefer to be more effective. Pneumonia is a source of anxiety for doctors, and for this reason, doctors may deliberately decide to prescribe outside of the guidelines”.Ex28 (from publication [): “Most of them justified their current liberal prescribing of fluoroquinolones on the basis of their duty to do the best for “the patient in front of them””.lication ): “Most Some GPs also said that they were guided by their fears The model resulting from our analysis, including all the factors involved in antibiotic choice, is presented in Fig. We conducted a qualitative research study, to explore the rationale used by GPs in their choice of an antibiotic in a specific clinical situation. We showed that GPs considered various factors when selecting the antibiotic to prescribe: factors relating to microbiological aspects , pharmacology (e.g. antibiotic properties), clinical conditions (e.g. symptoms), and personal factors .A model representing the rationale underlying the choice of antibiotics by GPs is proposed here. The exactness and exhaustiveness of the model were optimised by: (i) using open-ended questions, to encourage GPs to discuss their reasons for choosing a particular antibiotic more freely, (ii) conducting interviews until data saturation was achieved (obtained after the 17th interview), (iii) having two individuals with a medical background analyse the data separately, and then together, until a consensus was reached, (iv) complementing the model with the results of relevant published studies.This work had several limitations. First, the interviewer was a junior doctor in training, not used to conducting interviews. We tried to overcome this limitation by training the junior doctor before the interviews were conducted (e.g. through the testing of the interview guide with five junior doctors). Each interview was also discussed, providing the junior doctor with feedback. The number of GPs interviewed may also seem not enough, but data saturation was achieved after the 17th interview. This may be explained by the large number of clinical cases that GPs were asked to consider. A “social desirability bias”  may alsomedical speciality”, “patient origin” , “drug actions” , “enviroironment , pressurironment  and healironment ). “Medic(i)An intuitive element corresponding to GP-related factors, such as knowledge, experience, and memory. This intuitive element makes it possible for the GP to come up with a quick “automatic” response on the basis of experience with similar situations .(ii)An analytical element based on factors relating to the patient, antibiotic and bacteria. This analytical element provides a slower, more rational answer based on the checking of a series of hypotheses .We found that GPs did not limit antibiotic prescription to the molecules recommended in clinical practice guidelines. They used a rationale based on factors relating to the causal bacteria, the patient, the antibiotic and personal factors. This rationale can be broken down into two components :(i)An iif uncomplicated cystitis in women, then fosfomycin), which is then checked by the analytical system (e.g. is fosfomycin contraindicated in this patient?). An incorrect balance between these two elements may lead to incorrect decisions, such as the prescription of an antibiotic that is not recommended.GPs initially use the intuitive element to find an immediate answer , but also on improving the quality of prescriptions in terms of antibiotic choice (e.g. avoiding broad-spectrum antibiotics). Our findings suggest that interventions for improving antibiotic choice should target both the intuitive and analytical systems. The intuitive elements, corresponding to the knowledge and experience of GPs, could be targeted through interventions to improve GPs’ knowledge about antibiotics , 32, thrWhen GPs decide which antibiotic to prescribe, they do not limit themselves to those recommended in clinical practice guidelines. They use their knowledge and experience to guide their choice of antibiotic, but they also take into account factors relating to microbiology, pharmacology, and clinical conditions. All these factors should be considered when establishing interventions to improve antibiotic prescription.Additional file 1. Tsopra_ Interview guide, Clinical cases and the questions the GPs were asked during interviews.


Switching of the inclusion of guest molecules was realized by the crystallization induced self-assembly of a benzothiadiazole-type macrocyclic boronic ester. Selective inclusion of each of bicyclic and tricyclic aromatic guest molecules was realized utilizing the self-assembly of a crystalline benzothiadiazole-type macrocyclic boronic ester. The complete switching of the guest selectivity was achieved simply by changing the cosolvent used in the formation of the crystalline host–guest complexes. Both the association free energy of host–guest complexes and the stability of packing structure were found to play important roles for the determination of the guest selectivity in this system, and the critical role of solvent molecules in the crystalline state for the switching phenomena was clarified. Crystalline host materials are often capable of separating a single guest molecule from a mixture of analogous compounds, which is practically useful for isolation or removal of a specific molecule.et al.K) is generally utilized as an effective index to evaluate the relative affinity of different guest molecules for a host compound in the solution state. Although one can expect the selective inclusion of a guest molecule with a high K value into a crystalline host material, the relationship between the order of K values in solution and the solid-state separation of guest mixtures is not well documented as conventional crystalline host materials are often insoluble or dissociate into their components in solution. Herein, we demonstrate the selective guest separation by a self-assembled, crystalline macrocyclic boronic ester based on the K values of the discrete host boronic ester with guest molecules, and more importantly, a facile switching of guest selectivity in the crystalline state was achieved simply by changing the cosolvent used in the formation of the crystalline host–guest complexes  was chosen as a component for the construction of such a macrocyclic boronic ester since 2,1,3-benzothiadiazole unit is known as an efficient electron-accepting unit, which was expected to recognize the electronic state of guest molecules.3 composed of two molecules each of diboronic acid 1 and racemic bis 2 was obtained as a precipitate in 96% yield by the self-assembly of 1 with 2 in methanol/THF (NA) was added to a deuterated chloroform solution of 3, chemical shift values of 3 changed in 1H NMR spectrum of the mixture  in the solution state as expected. The binding stoichiometry of 3 with NA was estimated to be 1 : 1 by Job plot analysis  of NA with 3 was determined to be 104 M–1 by the 1H NMR experiment aromatic compounds were also evaluated by 1H NMR analyses . It should be noted that association constants of 3 for tricyclic compounds were higher than those for the corresponding bicyclic analogues .We already reported the self-assembly of macrocyclic boronic esters simply by mixing a di- or tri-boronic acid with the indacene-type bis anol/THF . When nae Fig. S2, indicats Fig. S1, and theperiment . Associa3 was carried out in the presence of naphthalene and anthracene aiming at the selective inclusion of one guest compound in 3 (K) of 3 with anthracene (218 M–1) than with naphthalene (104 M–1), anthracene was expected to be included in 3 preferentially. In fact, anthracene-included 3 (3·ANT·CH2Cl2) selectively precipitated out in 92% yield as dichloromethane solvate when equimolar amounts of 1, rac-2, naphthalene, and anthracene were mixed in methanol/dichloromethane (1 : 1) at room temperature for 24 h (ANT/NA ≥ 20 : 1 by 1H NMR). Powder X-ray diffraction (PXRD) analysis of the precipitate showed that the precipitate was an aggregate of microcrystals  were also applicable instead of dichloromethane for the selective inclusion of anthracene, suggesting the importance of the difference of the association constants of the two guest compounds rather than cosolvent used in the self-assembly of the host–guest complex (Table S323 (3·NA·4CHCl3) was selectively obtained as a crystalline precipitate in 96% yield when chloroform was used as cosolvent (NA/ANT ≥ 20 : 1 by 1H NMR).Next, the self-assembly of und in 3 . Conside Fig. S25, and rec Fig. S28.13 OtherTable S32. Interes3·NA·4CHCl3 suitable for X-ray analysis was prepared by vapor diffusion of hexane into a chloroform solution of 3·NA. As shown in 3·NA·4CHCl3 forms hydrogen bonds with two chloroform molecules by the oxygen atom of the boronic ester moiety and the nitrogen atom of the benzothiadiazole moiety, and thus each 3·NA is surrounded by four chloroform molecules . That is, two chloroform molecules, forming hydrogen bonds with neighboring 3·NA·4CHCl3, are additionally located just before and after the included naphthalene molecule  was obtained where each 3·ANT also formed hydrogen bonds with four chloroform molecules  than those of the corresponding bicyclic ones , tricyclic heterocyclic compounds are considered to be included in 3 when dichloromethane is used as cosolvent. When the self-assembly of 3 was carried out using dichloromethane, 3·DBT·CH2Cl2, 3·DBF·CH2Cl2, and 3·ACR·CH2Cl2 were selectively precipitated out in high yields in the presence of the corresponding bicyclic guest molecules, respectively (tricyclic/bicyclic ≥ 20 : 1 by 1H NMR). On the other hand, when the same experiments were carried out using chloroform as cosolvent, the reversal of the selectivity occurred and bicyclic compounds were selectively included in 3 as 3·BT·4CHCl3, 3·BF·4CHCl3, and 3·QU·4CHCl3, respectively (bicyclic/tricyclic ≥ 20 : 1 by 1H NMR). Single crystal X-ray diffraction analyses of 3·guest·4CHCl3 including these bicyclic heteroaromatic compounds revealed that the packing structures were identical to that of 3·NA·4CHCl3 (P21/c), indicating that the selective inclusion of the bicyclic compounds is attributed to the formation of the stable packing structure possessing the confined cavity created by 3 and chloroform molecules (Fig. S27 and S32–S3413We envisaged that the selective inclusion of each of the two guest compounds should also be applicable to several other combinations of bicyclic and tricyclic heteroaromatic compounds . Accordi3 containing benzothiadiazole moiety. The use of discrete self-assembled structure as crystalline host compound was found to have an advantage over extended porous frameworks such as MOFs in terms of the alteration of the guest selectivity. Although the crystalline-state guest selectivity generally coincided with the order of solution-state association energies of host–guest complexes when common organic solvents such as dichloromethane were used as the cosolvent, the guest selectivity was altered by using chloroform as the cosolvent, which could bind with host 3 by hydrogen bonding, thus forming the stable crystal structure with restricted space for guest inclusion. It should be noted that the solution-state association constant of a discrete self-assembled structure has not been utilized as an aid to understand the guest selectivity in crystalline-state to date. Moreover, the effective use of solvent effect for the switching of crystalline-state guest selectivity was demonstrated for the first time.In conclusion, the selective inclusion of each of two kinds of guest molecules was achieved by using the crystalline macrocyclic boronic ester Supplementary informationClick here for additional data file.Crystal structure dataClick here for additional data file.


Seeing one's practice as a high antibiotic prescriber compared to general practices with similar patient populations can be one of the best motivators for change. Current comparisons are based on age-sex weighting of the practice population for expected prescribing rates (STAR-PU). Here, we investigate whether there is a need to additionally account for further potentially legitimate medical reasons for higher antibiotic prescribing.Publicly available data from 7376 general practices in England between April 2014 and March 2015 were used. We built two different negative binomial regression models to compare observed versus expected antibiotic dispensing levels per practice: one including comorbidities as covariates and another with the addition of smoking prevalence and deprivation. We compared the ranking of practices in terms of items prescribed per STAR-PU according to i) conventional STAR-PU methodology, ii) observed vs expected prescribing levels using the comorbidity model, and iii) observed vs expected prescribing levels using the full model.The median number of antibiotic items prescribed per practice per STAR-PU was 1.09 . 1133 practices (76.8% of 1476) were consistently identified as being in the top 20% of high antibiotic prescribers. However, some practices that would be classified as high prescribers using the current STAR-PU methodology would not be classified as high prescribers if comorbidity was accounted for  and if additionally smoking prevalence and deprivation were accounted for .Current age-sex weighted comparisons of antibiotic prescribing rates in England are fair for many, but not all practices. This new metric that accounts for legitimate medical reasons for higher antibiotic prescribing may have more credibility among general practitioners and, thus, more likely to be acted upon.Findings of this study indicate that the antibiotic prescribing metric by which practices are measured (and need to implement interventions determined) may be inadequate, and therefore raises the question of how they should be measured. Substantial variation between practices remains after accounting for comorbidities, deprivation and smoking. There is a need for a better understanding of why such variation remains and, more importantly, what can be done to reduce it. While antibiotics are more frequently indicated in patients with comorbidities, it is unclear to what extent antibiotic prescribing can be lowered among that patient population and how this could be achieved. •Antibiotic prescribing rates vary substantially between general practices in England•Some practices that are identified as high antibiotic prescribers would not be identified as such if legitimate reasons for variation, such as comorbidities, were taken into account.•Substantial variation remains after accounting for comorbidities, smoking and deprivation. We searched PubMed for studies evaluating variation in antibiotic prescribing in primary care. The papers included in the review were original research studies of any design in which the criteria for inclusion were: written in English; set in high-income countries; evaluating variation in antibiotic prescribing between general practices or benchmarking these practices based on their antibiotic prescribing rates. We used the following MeSH terms: “benchmarking” or “practice patterns physicians” or “small-area analysis” and “antibacterial agents” and any of “primary health care” or “general practice”. The overall picture was that non-medical reasons were explaining a substantial part of the variation in antibiotic prescribing. Identified factors included experience of physicians, the patient volume per physician, physicians being trained abroad, lack of access to diagnostic tests, patient expectations, time pressure and poor doctor-patient communication. Evidence related to what extent potential legitimate medical reasons explain the variation in antibiotic prescribing between practices was limited. In England, comparisons between practices were based on prescriptions per practice population or using Specific Therapeutic group Age-sex weight Related Prescribing Units (STAR-PUs) to account for differing age-sex distributions of patient populations.This study found that current STAR-PU based comparisons of antibiotic prescribing rates in England are fair for many, but not all practices. Some practices can legitimately claim that they have a frailer patient population  and prescribe, in line with guidelines in England, more antibiotics than other practices. Our estimates allow for comparing one's individual practice with other practices with similar patient populations in terms of comorbidity prevalences, or also in terms of smoking prevalence and deprivation.Antibiotic prescribing rates vary substantially between general practices in England, even after taking into account potential legitimate medical reasons for higher prescribing. Our newly developed metric that accounts for legitimate medical reasons for higher antibiotic prescribing rates may have higher credibility among general practitioners and, thus, potentially more likely to be acted upon, helping endeavours to reduce inappropriate antimicrobial use in English primary care.Alt-text: Unlabelled Box1Antibiotic resistance (ABR) is increasingly recognised as an important threat to modern healthcare Implementation of interventions designed to lower unnecessary antibiotic prescribing in primary care are often prioritised in general practices that prescribe above the norm However, STAR-PU weighting does not account for several other legitimate reasons for variation in antibiotic prescribing. It has previously been shown that variation in prescribing for respiratory tract infections (RTIs) is the main driver of differences in antibiotic prescribing rates Ideally, one would be able to identify high prescribing practices after accounting for all legitimate reasons for variation in antibiotic prescribing. In this study we evaluate which practices in England prescribe above the norm using models that do and do not account for legitimate medical reasons for variation in antibiotic prescribing. This may help in reducing antibiotic prescribing, as communicating performance metrics  can be one of the best motivators for change 2http://content.digital.nhs.uk). For each practice in England, antibiotics that are prescribed and subsequently dispensed in the community are included in this dataset. Other publicly available data that were obtained from NHS Digital included: the number of patients registered at each practice split into gender and five year age bands, comorbidity prevalences, and oral antibacterials items-based STAR-PU weights Publicly available systemic antibiotic  item-based dispensing data were obtained from NHS Digital for the financial year April 2014 – March 2015  data and included: asthma (excluding patients who have not been prescribed asthma-related drugs in the preceding 12 months), chronic obstructive pulmonary disease (COPD), coronary heart disease, heart failure, cancer (excluding patients with non-melanotic skin cancers), chronic kidney disease (excluding patients with chronic kidney disease stage < 3), and diabetes. These comorbidities were selected as potential legitimate reasons for variation in antibiotic prescribing, because they are considered as factors that are associated with worse infection-related outcomes Another legitimate cause of variation in antibiotic prescribing is the smoking prevalence of the patient population. Both active and passive smoking are associated with an increased risk of infection and worse outcomes The Index of Multiple Deprivation (IMD) was included, because there is evidence that living conditions are associated with the risk of respiratory tract infections 2.1For the primary analysis, we created a dataset including only practices with no missing data for any of the predictors. In line with a previous study The ranking of practices based on their antibiotic prescribing rate per STAR-PU is straightforward. This can be accomplished by dividing the number of antibiotic items by the amount of STAR-PU for each practice and subsequently sorting the practices based on the obtained values. To additionally take into account other legitimate medical reasons for variation in antibiotic prescribing, we build two negative binomial regression models in order to evaluate the association between included predictors and antibiotic prescribing rates per STAR-PU at the practice level. The natural logarithm of the amount of STAR-PU per practice was included as on offset to take into account differences in practice sizes and age- and gender distributions of the practices. We built two different models: i) a model with only comorbidity prevalences as potential predictors, ii) a model with comorbidities, deprivation score, and smoking prevalence as potential predictors. We did not consider non-linearity for comorbidities and the smoking prevalence, because we assumed that the medical legitimacy of an antibiotic prescription for an individual is independent of the total number of smokers or patients with comorbidities registered with a practice. The IMD was categorised based on the quintiles of its distribution.For both negative binomial regression models, variables were selected for inclusion in the model using stepwise backward selection based on the Akaike Information Criterion (AIC). Subsequently, we removed variables that had a negative association with the antibiotic prescribing rate from the model, because to make the comparison between practices more fair we wanted to only take into account factors that both in theory and in practice are associated with higher (legitimate) antibiotic prescribing rates.To evaluate to what extent the models could explain the differences in antibiotic prescribing, we estimated the amount of deviance explained by each model. To enable a fair comparison of the deviance explained by each model, we fixed the dispersion parameter at the estimate derived for the model which considered all variables as potential predictors.We subsequently evaluated whether the same practices would be identified as being among the top 20% regarding their antibiotic prescribing rate when ranking them according to the current methodology using antibiotic items per STAR-PU versus to what extent a practice prescribes above or below their predicted antibiotic prescribing rate per STAR-PU. The latter was calculated by taking the observed prescribing rate per STAR-PU minus the predicted prescribing rate per STAR-PU. The predicted prescribing rate per STAR-PU was obtained using the model with comorbidity only and the model considering all factors listed above. An area-proportional Venn diagram was used to visualise to what extent different practices were among the top 20% of antibiotic prescribers using the current methodology and the new model-based methodologies. All analyses were performed using R, version 3.3.2.2.2For the primary analysis, we excluded practices that had fewer than 750 registered patients. However, after excluding those practices, a few practices remained with questionable high/low antibiotic prescribing rates per STAR-PU (e.g. 0.05 or 17.14 antibiotics per STAR-PU). As we could not exclude the possibility that some of these practices were genuinely prescribing much more or less than most other practices, we kept them in the primary analyses. For sensitivity analyses, we further restricted the data used in the primary analyses by only using data from practices that had a prescribing rate between 1/3 and 3 antibiotics per STAR-PU. Values outside this range are less likely to be correct. Such implausible antibiotic prescribing rates may be due to data entry errors or due to the fact that a practice serves relatively many patients that are not registered at the practice, which increases the numerator but not the denominator.Because one may argue whether the prevalence of some of the included comorbidities could be considered legitimate reasons for higher antibiotic prescribing rates, we added a sensitivity analysis with a much more restricted model only taking into account the COPD and diabetes prevalence.3The characteristics of patients registered at the 7376 included practices are summarised in The negative binomial regression model, which only allowed comorbidities to be selected as predictors, included the asthma , COPD  and diabetes prevalence  as predictors of higher antibiotic use per STAR-PU . This moThe Venn diagram in The difference in ranking of all included practices, including those never identified as being among the top 20% antibiotic prescribers, based on the different methodologies is shown in Table S1. The same identifiable practice code as used in the publicly available data is included in this table, to enable practices to identify their own practice.3.1When only taking into account the prevalence of diabetes and COPD, results were very similar to the model that also allowed for other comorbidities. These two methods agreed on 1368 (92.7% of 1476) being high antibiotic prescribers.In a subsequent sensitivity analysis, 7311 practices remained after excluding practices with antibiotic prescribing rates per STAR-PU below 1/3 or above 3. Besides the comorbidities selected in the main analysis, the coronary heart disease prevalence  was also included in the final comorbidity only model . This moSimilar to the main analysis, there is substantial overlap between the different methodologies to identify the top 20% of antibiotic prescribers. In 1104 out of 1463 (75.5%) the STAR-PU based method and the model-based methods agree on which practices are among the top 20% highest antibiotic prescribers . Table S4This study found that current comparisons of antibiotic prescribing rates of general practices based on STAR-PU weighting only may be unfair for some practices. Although STAR-PU weighting does account for differences in the age and gender distribution of patient populations, using STAR-PU weighting alone results in practices being identified as high antibiotic prescribers which would not be ranked so highly when also taking into account other legitimate reasons for variation, such as comorbidities. Similarly, some practices with relatively healthy populations are missed as high prescribers when using only STAR-PU weightings.4.1This study used publicly available data, covering all patients registered with a general NHS practice in England. There are several studies that tried to find reasons why some practices prescribe substantially more antibiotics than other practices Although comorbidity prevalences were available at the practice level, other predictors could only be linked to a practice based on the local authorities the practice served. This could result in biased estimates if, for example, a practice in a relatively deprived area attracted patients with a higher socioeconomic status while all other patients attend other practices in the area. Potential legitimate reasons for higher prescribing in certain practices not available for this study include, for example, the prevalence of immunosuppressive diseases, consultation rates, and markers of the severity of infections Beyond the issue of potentially not having included all medically legitimate reasons for variations in antibiotic prescribing, the model-based approaches require a valid model to obtain predicted antibiotic prescribing rates per STAR-PU for every practice given the characteristics of their patient population. A model additionally including comorbidities that had a negative association with the antibiotic prescribing rate and non-linear functions for continuous variables would be better at explaining the variation between practices Although guidelines indicate that practices with more patients with comorbidities could legitimately prescribe more antibiotics for RTIs, the relationship between comorbidities and antibiotic prescribing for suspected UTI is complex. Asymptomatic bacteriuria is associated with comorbidity and frequently inappropriately treated with antibiotics in nursing homes It is important to note that this study does not address the issues of what constitutes ‘safe’ levels of prescribing or what proportion of antibiotics is inappropriate. In other words, this study seeks to rank practices' antibiotic prescribing in a fair manner, but it provides no insight into appropriate absolute levels of prescribing. If the majority of practices were overprescribing, the expected antibiotic prescribing rate from the model would still include a substantial proportion of inappropriate antibiotic prescriptions. Other recent work has attempted to quantify inappropriate prescribing in English primary care 4.2Several countries, including England, currently aim to reduce inappropriate antibiotic prescribing in order to tackle the problem of increasing levels of antibiotic resistance. The findings presented here can be used to identify practices that prescribe above the norm, even when taking into account age and sex distributions, the prevalence of comorbidities, smoking and deprivation of the patient population. These results can also be used to better identify high prescribing practices and target interventions designed to reduce antibiotic prescribing in those practices which might have a much greater potential to lower antibiotic prescribing rates. By identifying factors that are both in theory and in practice associated with higher antibiotic prescribing rates, this work may create a rational basis for incentivising stewardship with relation to different population groups. Although these factors can be considered as legitimate medical reasons for higher antibiotic prescribing rates, they include factors that can either be directly modified, such as smoking prevalence Given that the model is based on publicly available data which is regularly updated, the model can be updated on a regular basis to reflect changes in prescribing and underlying patient populations.5Current age- and sex-weighted comparisons of antibiotic prescribing rates in England are fair for most, but not all practices. Some practices can legitimately claim that they have a more frail patient population and prescribe, in line with guidelines in England, more antibiotics than other practices. After additionally accounting for prevalences in comorbidity such practices would no longer be identified as being among the top 20% of high prescribers . Similarly, other, currently missed, practices would move into the ‘high prescriber’ category if more inclusive methods were adopted. Our study produced a tool that can be regularly updated and fine-tuned using publicly available data in order to facilitate more fair and up-to-date comparisons of antibiotic prescribing rates of general practices in England.EH cleaned and analysed the data and drafted the manuscript. REC contributed statistical analysis code and revised the manuscript. TDH and TS designed the study and revised the manuscript. JVR conceptualised the study and revised the manuscript. KBP conceptualised and designed the work, analysed the data, and revised the manuscript. All authors contributed to critical review of manuscript drafts and reviewed and approved the final manuscript.We declare no competing interests.


The morphological image of the PDPA/Fe3O4 particles was characterized by scanning electron microscope and transmission electron microscope. The crystalline structure was scrutinized by X-ray diffraction. The rheological characteristics of the suspension composed of PDPA/Fe3O4 particles suspended in silicone oil were investigated by a rotation rheometer, demonstrating standard electrorheological (ER) characteristics with a dramatic increase in shear stress and dynamic moduli under the application of an electrical field strength. The shear stress curves under an electrical field could be described using the Bingham model and the yield stress showed a power-law relationship with the electric field strength with an exponent of 1.5, following the conduction model. Furthermore, the frequency-dependent dielectric behaviors of the PDPA/Fe3O4 ER suspension was tested using an inductance (L)-capacitance (C)-resistance (R) (LCR) meter. The dielectric properties were well described using the Cole–Cole equation and were consistent with the results of the ER experiments.Electro-responsive poly(diphenylamine)(PDPA)/Fe Electrorheological (ER) fluids belong to a class of “smart” materials, which are generally suspension systems consisted of semiconducting or polarizable particles suspended in a continuous phase medium, primarily for anhydrous insulating liquids, such as silicone oils, mineral oils, etc. . Their rA range of materials, such as cellulose, starch, clay, oxide mineral, carbon-based materials , conducting polymers, poly(ionic liquid) (PIL), etc. have been studied for the development of ER materials ,17,18,192 (PEDOT/SiO2) [3O4-polypyrrole (Fe3O4–PPy) [2/PPy [2O3/PANI [2/PANI [3O4@PANI [3O4 is often used as an inorganic component and is also used widely in chemistry, food, and medicine [As a type of conducting polymer, poly(diphenylamine) (PDPA) has also drawn attention owing to its electrochemistry, optical property, and higher solubility in organic solvents compared to PANI, and other conducting polymeric materials . MoreoveOT/SiO2) , core–sh3O4–PPy) , SiO2/PP) [2/PPy , Fe2O3/P2O3/PANI , TiO2/PA [2/PANI ,37, and 3O4@PANI . These mmedicine ,40,41 bemedicine .3O4 composite particles were synthesized by loading nano-sized Fe3O4 nanoparticles on a conducting PDPA matrix using a simple chemical co- precipitation method and adopted in an ER suspension. The behaviors of the PDPA/Fe3O4 composite particles were characterized and then their ER properties when suspended in silicone were investigated.In this study, organic–inorganic PDPA/Fe3O4 on PDPA, ferric chloride hexahydrate (FeCl3·6H2O) , ferrous sulfate heptahydrate (FeSO4·7H2O) , and ammonia solution   were used. Ethanol  and distilled water were adopted as solvents. The continuous phase of the ER suspension was silicone oil .Diphenylamine (DPA) , ammonium persulfate (APS)  and hydrochloric acid (HCl)  were used for the synthesis of PDPA first. In the process of loading FeAt first, PDPA particles were fabricated through a chemical oxidative polymerization process, as proposed in the previous study . DPA  was suspended in a 50% aqueous solution of ethanol and mixed with 40 mL of an aqueous solution (0.5 M FeCl3 and 0.25 M of FeSO4). After heating the mixed solution to 60 °C, 10 mL of aqueous NH3 solution was added, and the reaction was continued for 2 h. The precipitated product was collected by magnetic separation and then cleaned several times with ethanol and dried completely at 60 °C for 12 h. 3O4 composite.The PDPA/Fe3O4 particles tested via a gas pycnometer  was 2.44 g/cm3, while the electrical conductivity was obtained to be 5.9 × 10−8 S/cm via a low resistivity meter  and a square probe (electrode distance: 1.5 mm) . For the measurement, the PDPA powder was pressed into a disk with a diameter of 13 mm. The PDPA/Fe3O4 ER suspension was prepared by suspending PDPA/Fe3O4 (particle concentration of 10 vol%) in silicone oil.The density of the PDPA/Fe3O4 were investigated via a scanning electron microscope (SEM)  by adhering the powder to the sample holder with a double-sided carbon tape. As shown in 3O4 composite, respectively. The surface of PDPA/Fe3O4 was rougher than PDPA and spherical nanoparticles can be observed clearly. In order to further determine the morphology and structure of the materials, both PDPA and PDPA/Fe3O4 powders were dispersed in water by sonication, and then their dispersions were added dropwise on a copper mesh, sufficiently dried, and observed by a transmission electron microscope (TEM) . 3O4 composites, respectively, and the insets show the partial enlargements. Many spherical particles with diameters between 10 and 20 nm in enlargement of the PDPA/Fe3O4 can be seen clearly. The Fe3O4 granules on the surface of PDPA can increase the roughness and specific surface area, which is believed to contribute to an enhanced ER effect.Morphological images of PDPA and PDPA/Fe3O4 composite was performed from 5° to 90° 2θ using Cu-Kα. 3O4 composite. Two distinct XRD peaks at approximately 18° and 21° 2θ for PDPA, and there was no XRD peak in the range of 40° to 90° 2θ. The pattern of the PDPA/Fe3O4 composite showed corresponding peaks for the (220), (311), (400), (422), (511), and (440) planes, which match with the cubic spinel crystal structure for Fe3O4 (JCPDS Card. No. 88-0315). The crystallite size (D) of Fe3O4 was determined from the following Scherrer equation [k is a constant value of 0.89; λ is the radiation wavelength (1.54184 Å for Cu-Kα); β is the full width at half maximum (FWHM) of the XRD peak in radian, which is equal to 0.5° (π/360 radians) at the highest intense peak at (311); θ is the Bragg diffraction angle, and the value at the highest intense peak was 17.77 ° (17.77 π/180 radians). Therefore, the crystallite size was calculated to be 16.51 nm. XRD of the composite revealed not only the characteristic peaks of the Fe3O4, but also the peaks of PDPA at approximately 20°.Powder X-ray diffraction (XRD)  test of the PDPA and PDPA/Fe11), and 0 planes,3O4 nanoparticles in silicone oil under an electrical field. 3O4 nanoparticles dispersed without an electrical field, in which the nanoparticles were dispersed freely in the oil. When an electrical field was applied  was used to observe the transition of the suspension state for PDPA/Fe applied b, howeveBecause of the formation of chain-like structures, the ER fluid can transform to a solid-like state from an initial fluid-like state by applying an external electrical field. Therefore, with an input electrical field, the ER suspension can exhibit obvious yield stress at a low shear rate range and shear-thinning behaviors of shear viscosity under a shear flow with a direction perpendicular to the electrical field, which can be corroborated in the following ER tests.3O4 composite ER suspension were investigated by a rotational rheometer  with a cylindrical Couette-type geometry (CC17/E) of 0.71 mm gap distance. To investigate the ER properties in the presence of electrical field, a DC voltage generator was attached to the rheometer. Steady shear tests were measured using a controlled shear rate (CSR) mode with a shear rate ranging from 10−1 to 103 1/s at room temperature. The ER characteristics for the PDPA/Fe3O4 ER fluid. Note that pure PDPA was also reported to be an ER material [3O4-based ER suspension showed a more stable shear stress in the low shear rate range (<10 1/s), whereas the former showed reduced shear stress as the shear rate increased. Meanwhile, the electric field limit of PDPA/Fe3O4-based ER fluid that can be applied is 2.0 kV/mm, which is lower than that of the PDPA-based ER suspension (2.5 kV/mm). This is because the electrical conductivity of PDPA/Fe3O4 (5.9 × 10−8 S/cm) was higher than that of PDPA (8.913 × 10−11 S/cm), and its particle concentration prepared at 10 vol% was larger than that of the PDPA ER fluid (5 vol%).Furthermore, as presented in material , and come) was calculated using the shear viscosity at a specific electric field using the following equation:E and zero-field, respectively. As given in 6% at an electrical field strength of 2.0 kV/mm, which indicates that the PDPA/Fe3O4 particles formed strong chain structures with an input electrical field. Meanwhile, as the shear rate increased, the chain structures were gradually destroyed and the ER efficiency was reduced continuously.Furthermore, to evaluate its ER effect, the ER efficiency (G′) and loss (G″) moduli of the PDPA/Fe3O4 ER suspension. In the low strain range, G′ showed a plateau region, called the LVE region, where the chain-like forms were strong enough not to be destroyed by the applied strain. When the strain exceeded the critical value, structures that had formed began to be destroyed, showing a sharp decline in G′. Therefore, to avoid excessive strain causing chain damage and affecting the frequency-dependent changes in the chain structures, a strain value of 0.007% in the LVE region was selected as constant strain in the following frequency sweep tests.Oscillation tests were also carried out in a controlled shear deformation mode. Initially, the strain amplitude sweep tests were measured with a constant angular frequency (6.28 rad/s) to search the linear viscoelastic (LVE) region . Figure The elastic stress  generally follows a power-law expression:m, varies typically between 1.0 and 2.0, depending on the concentration of the ER fluids, morphology, size, dielectric, and conductivity of the different ER materials [3O4 ER suspension in this work, the slope was observed to be m = 1.5 for all three different yield stresses, conforming to the conduction model proposed by Davis and Ginder [aterials . For thed Ginder , where tG′ and G″ increased with an increased angular frequency, but with an input electrical field, they exhibited a relatively stable value over a whole frequency region and increased with increasing electric field strength. This indicated that under an input electric field, the interactions between the particles became stronger and the chain structures were not easily broken. Furthermore, a time-dependent relaxation modulus G(t) can be estimated from the frequency sweep test using the following Schwarzl equation [The frequency sweep measurement was tested with an angular frequency, varying from 0.1 and 200 rad/s at a constant strain (0.007%). As given in equation :(7)G(t) G(t) decreased significantly in a very short period of time, indicating that the ER suspension exhibited liquid-like properties. Meanwhile, with an electrical field, the relaxation modulus exhibited a stable value, showing that the ER fluid became a solid-like state.3O4-based ER fluid changes from a fluid-like state to a solid-like state under the stimulation of an electric field based on the results of the static shear tests and the dynamic oscillation tests. Moreover, under the electric field, with the increase of the shear rate, the ER fluid exhibited a very stable shear stress curve, such that the yield stress was up to 100 Pa, and the ER efficiency was also very high. The relatively high and stable behaviors of PDPA/Fe3O4-based ER fluid may increase the possibility of its practical application in engineering.In summary, it is not difficult to confirm that the PDPA/Fe3O4-based ER suspension over the wide frequency region (from 20 to 106 Hz) were tested using a LCR meter. Note that dielectric relaxation of materials can be described simply using the following Cole–Cole equation [In addition, the frequency-dependent dielectric behaviors of the ER suspension are important for predicting its ER effects. To further study the relationship among them, the dielectric constant  , the ∆ε 3O4 is a soft magnetic material, it has also been studied as an MR material. The detailed contents can be found in previous work [3O4-based MR fluid provided a largely increased shear stress, shear viscosity, and dynamic moduli with the application of a magnetic field.In addition, magnetorheological (MR) fluids have similar properties to ER suspensions, which are usually composed of soft-magnetic particles dispersed in a carrier liquid, and its viscoelastic properties change significantly with the employment and withdrawal of the magnetic field. Because the as-fabricated PDPA/Feous work , where t3O4) particles were fabricated by synthesizing PDPA using an oxidation polymerization method and loading nano-sized Fe3O4 particles onto it using chemical co-precipitation. The morphology and crystal structure of the fabricated PDPA/Fe3O4 was studied by SEM, TEM, and XRD. The formation of chain-like structures of PDPA/Fe3O4 particles with an external electrical field was characterized by optical microscopy. The rheological characteristics of the PDPA/Fe3O4 ER suspension under various electrical field strengths were investigated by a rotation rheometer. In the static shear tests, the PDPA/Fe3O4–based ER fluid demonstrated a Newtonian fluid property, while under an electrical field, the ER suspension demonstrated Bingham plastic behavior and was fitted well by the Bingham model. In the dynamic oscillation tests, with an input electrical field, the dynamic moduli showed a dramatic increase and provided proof of the transition of the ER suspension from a liquid-like to solid-like state. The relationship between yield stresses and electrical field strength showed that it conforms to the conduction model. The dielectric characteristics of the PDPA/Fe3O4 ER suspension also were tested via a LCR meter, corresponding to the ER characteristics. Furthermore, along with its MR characteristics previously reported, the PDPA/Fe3O4–based ER fluid can contribute to more stable ER performance than a PDPA–based ER fluid. Compared with the other previously reported organic–inorganic ER materials, the most significant advantage of the PDPA/Fe3O4 was that it had suitable conductivity, so that no de-doping step was needed, which undoubtedly improved the economic efficiency while simplifying the operation. All in all, the synthesis process of the PDPA itself was simple, the flow behavior of the PDPA/Fe3O4 ER fluid was stable, the ER efficiency was high, and the economic benefit was good; these advantages of the PDPA/Fe3O4 ER fluid are beneficial to its application in engineering.Electro-responsive composite (PDPA/Fe


The paper describes a new model of concrete production, which contains a glass cullet. A worn-out car side window have been used for the production of recycled glass aggregate (RGA) and its properties were examined. The RGA was used in concrete as a 50% and 100% mass substitute of the traditional aggregate. Basic tests of fresh concrete mix and hardened concrete were carried out. The consistency, the air content in the concrete mix, the density of hardened concrete, water absorption, water resistance, frost resistance, and the compressive strength  were evaluated. Composite samples were also subjected to microscopic analysis. The results showed that the RGA can be recommended as an aggregate for concretes, and the features of the RGA concrete are more favorable than those of traditional concrete. The microscopic analyses allowed us to identify the reasons for improving the properties of the RGA composites. Almost all branches of industry significantly interfere with the natural environment, often degrading it. In connection with this, the scientific discussions more and more often draw attention to the issue of the so-called ecological security. The priority here is proper waste management, and in particular, taking actions so that the largest possible quantities of wastes can be re-used ,2. This The solution proposed in this situation is an attempt to use wastes in other branches of industry, which would not require special technological measures to be included in a production process. An example of such industrial activity is the production of concretes. The concrete plants are located in almost all urban agglomerations, which is an asset that eliminates the costs of transporting the wastes. The introduction of glass wastes into the concrete production would, therefore, require only their crushing, which in the case of car side windows is an uncomplicated procedure. Such action would have double environmental benefits: it would reduce the amount of wastes, and at the same time it would reduce the extraction of natural aggregates.The issue of using glass as an additive to concrete was analyzed by many researchers. Many of the results of these studies were the reason for the introduction of new technologies into industrial applications. One of them is the technology for the production and dosing of glass fibers to cementitious composites ,10,11,12Another glass additive used for the concrete production is glass powder ,23,24,25A relatively new trend is the use of recycled glass ,31,32,33The main purpose of this work was to design a new cementitious composite that would contain in its volume a glass waste obtained from worn-out side windows (vehicle origin) and to examine its basic features. The material for the tests was obtained from the car junkyard and a recycled aggregate was produced. The recycled glass aggregate (RGA) has been subjected to basic tests that are carried out for traditional aggregates. Cement composites were prepared in which the RGA was used as a 50% and 100% mass substitute of the traditional gravel aggregate (4–8 mm fraction). As a comparative composite, concrete with the same composition was prepared, but containing 100% of the traditional, i.e., sand–gravel aggregate. Basic tests of both fresh concrete mix and hardened concrete were carried out for all composites. The consistency of the fresh concrete mix, the air content in the concrete mix, the density of a hardened concrete, water absorption, water resistance, and frost resistance were tested. The compressive strength after 9, 28, and 90 days of maturation was also determined. The microscopic examination was also carried out. The novelty of the paper is the assessment of the possibility of using a waste product, such as worn-out side car windows, for the production of the recycled glass aggregate with the intention of its use in concrete.The Ordinary Portland Cement CEM I 42.5N-SR3/NA  was used as a binder for the concretes. The cement is characterized by stable physico–chemical parameters, proper setting time, high early and final strength, low alkali content, and high resistance to aggressive chemical agents. Those are the reasons which is why it is popularly used in the production of ready-mixed concretes. The detailed values of the physico–chemical parameters of the cement are summarized in 3, pH = 4.0–6.0, dry matter content—24 ± 1.2%, chloride content—≤0.1%, and alkali content ≤0.5%.As a plasticizing admixture, the Stachement 1266  superplasticizer was used. The purpose of its use was to optimize the properties of the mixture in the aspect of the amount of water used in relation to the mix consistency. It is an admixture based on polycarboxylates and lignosulphonates with a high fluidizing effect, which is preserved for a longer period than with the usual superplasticizers. The Stachement 1266 is used for the production of ready-mixed concretes, from which it is required to maintain consistency over a long period of time. It is used for the production of high-strength concretes, monolithic concrete constructions, and industrial floors. The superplasticizer is a homogeneous liquid with a dark brown color. Its density is about 1065 kg/m3. During the crushing, a certain amount of a glass powder was also created; probably from the crushing of individual glass grains in the jaws of the crusher. The raw material used to make a substitute for the mineral aggregate was car side windows coming from worn-out vehicles. The windows were taken from the scrap yard and transported to the laboratory. The material fragmentation was carried out in a jaw crusher. The windows in the first stage of crushing was broken into many small elements, which then was separated from each other. The recyclate had an irregular shape and sharp edges. Most grains had approximate dimensions of 5 × 5 × 5 mmThe traditional aggregate was a sand-gravel aggregate (SGA) consisting of three fractions: 0–4 mm, 4–8 mm, and 8–16 mm. The proportions of individual fractions were determined in a computational way assuming a sand point at the level of 28%.For the RGA and SGA, the grain size composition was assessed according to EN 933-1:2012 . The parThe theoretical-experimental method was used to determine the recipe of the concrete mix . Designiw/c) was equal to 0.39. Finally, the recipes for all concrete mixes are listed in The design of the concrete mixture began with determining the qualitative features of components and determining their basic properties. On the basis of the products’ technical data sheets and own research, the bulk densities of concrete constituents, natural moisture of aggregates, and their sand points were determined. The sand point of the aggregate mixture was set at 28%. On the basis of general formulas, the proportions of aggregates were selected, followed by the amount of individual concrete components. The water/cement mass ratio  was examined. The test was performed on an Epsilon 3 Panalytical spectrometer .All concrete mixes were subjected to the consistency test according to the EN 12350-2 . During For all concrete mixes, the measurement of air content by the Boyle–Mariotte method was also carried out . The TES3. Six samples of each concrete were prepared. The study was conducted in accordance with the EN 12390-7 [The hardened concrete has been subjected to the bulk density measurement. The test was performed on cubic samples of 100 × 100 × 100 mm 12390-7 .The water absorption of concretes was also tested. The measurements were taken on identical samples as the bulk density test. Six samples of each concrete were tested. The samples were immersed in water and remained in it until their weight was constant. The water absorption was calculated in accordance with  as the p3 were tested. The samples, after being molded, were subjected to the moisture care in a closed container partially filled with water. After the third day, the samples were removed from the molds, and then for the following days, they were kept in the above-described environment. The tests were carried out in accordance with the EN 12390-3 [The compressive strength of hardened concrete was also determined. Samples of dimensions equal to 150 × 150 × 150 mm 12390-3 . The tes3 cubic samples. The results obtained are the arithmetic mean of six measurements.Another test that was carried out was the assessment of the concretes’ water resistance. It was performed in accordance with the EN 12390-8:2011 . This stThe frost resistance of concretes was also examined. This study was carried out in accordance with . It consThe microscopic analyses were carried out using two microscopes, i.e., an optical microscope and scanning electron microscope (SEM). Samples for the SEM analysis were dried to a constant mass in a laboratory dryer. Then, they were glued to a special holder using double-sided carbon tape. In order to obtain an electro-conductive layer, the samples were subjected to the preparation consisting in the spraying of a thin layer of carbon on their surface. Observations were carried out in a high vacuum mode.Both SGA and RGA have very similar values, while RGA is characterized by the bulk density higher by approx. 18% compared to SGA. Thus, the structure of the traditional aggregate is more porous, which is disadvantageous, for example in the context of frost resistance or water absorption of a cementitious composite. The RGA sealed structure has a number of advantages, e.g., such an aggregate is characterized by a lower water demand, which facilitates the design of a concrete mixture, or a much higher compressive strength in relation to SGA (up to 27 times higher). In addition, very low water absorption of RGA (0.1%) will result in less water absorption of the concrete using such aggregate. High values of the RGA mechanical parameters (compressive strength and modulus of elasticity) indicate that the aggregate will be brittle at the same time. This is confirmed by the value of the crushing index, which is 4.3% higher compared to SGA.The above-mentioned RGA features compared to SGA allow to state that the recycled glass aggregate can be successfully used for the production of concretes. In addition, glass and aggregate products obtained from it are characterized by a very high chemical resistance. Concrete made of RGA could be successfully used in an environment in which there is an increased risk of material exposure to aggressive chemical agents.iO2—79.6%, Al2O3—15.1%, K2O—3.0%, Na2O—1.3%, Fe2O3—0.6%, and MgO—0.4%. In the case of glass waste used no heavy metals were found.The determination of the RGA chemical composition indicated the occurrence of the following oxide equivalents: Sw/c ratio (which is a positive phenomenon). This translates directly to the improvement of all concrete properties, in particular, the mechanical strength.The results of the consistency test are presented in The obtained mean results of air content in a fresh concrete mix resulted in the lack of RGA influence in this aspect. The CONTR mix has an air content of 1.80%, CG50—1.85%, and CG100—1.80%. It also proves that there are no chemical reactions between the cement matrix and the RGA grains, which would result in gas evolution.The water absorption test confirmed the earlier assumptions regarding once less concrete absorbability with the increase of the RGA content. The reference concrete (CONTR) containing only SGA in its volume had a water absorption of 13% higher compared to the concrete with the highest content of RGA (CG100). The recycled glass aggregate is a non-absorbable and homogeneous aggregate. Gravel aggregate of the 4–8 mm fraction has an absorbability of 2.1% and it may vary depending on the content of different types of grains. The reduction in the water absorption of concrete due to the use of the RGA is another proof of the general improvement of the composite’s properties.The water resistance test indicated that this property is more beneficial with the increase of the RGA content in the composite. The depth of water penetration for CG50 and CG100 was 14% and 22% lower, respectively, than for the CONTR. As in the case of water absorption, this is probably due to the structure of the RGA, which itself is a nonporous and nonabsorbent aggregate. This translates directly to the increase in resistance which puts the concrete composite against the hydrostatic pressure.r| > 0.9) between these parameters. The correlation coefficient between bulk density and water absorption is equal to 0.93; bulk density and water resistance (represented by depth of water penetration) −0.91; water absorption and water resistance −0.93. R2—the coefficient of determination, eS—the standard error of estimation, and W—the coefficient of random variation [Analyzing the entire population of results of the physical properties of concrete made with RGA, a very strong correlation was found (|ariation .2 > 0.8). The strongest relationship is between the bulk density and water absorption, which is also confirmed by the highest value of the correlation coefficient. In addition, in this case, the risk of estimation error is very small (W = 2.06%). With this in mind, it is possible to calculate the water absorption of the RGA concrete based on the bulk density with very high accuracy, using the calculated linear regression equation. In the other two cases, the risk of estimation error is still low (4.06% and 3.62%), although it is almost twice as high as the relation between the bulk density and water absorption.The linear regression equations reflect the empirical data . This shape unquestionably increases the adhesion of the cement matrix to the aggregate grains, whereby one of the critical spots in the concrete, i.e., the interfacial transition zone (ITZ) between the aggregate grains and the matrix, is strengthened. In the case of RGA, there is also a smaller percentage of grains in the flat and longitudinal shape, which is much more common in the case of the sand–gravel aggregate.The material destruction due to cyclic freezing–thawing varied slightly depending on the type of aggregate used. It was noted that in many places the destruction zone ran through the coarse grains of the SGA. This is confirmed by the fact that some of the water was present in the structure of these grains during the freezing cycle. In contrast, in concretes which contained the RGA, the destruction zone ran entirely through the cement matrix. No cracking was observed in the RGA grains.In all the tests carried out, the coefficients of variation or standard deviations were characterized by very low values. This indicates high reliability and repeatability of the results obtained, which is of great practical importance in the context of the quality of concrete with the use of the RGA.Analysis of images obtained from the optical and scanning electron microscopes allowed us to assess the morphology and texture of the RGA grains as well as the concrete for which production of the RGA was used. Further analysis of the RGA surface morphology indicates that the individual grains consist of two types of surfaces, i.e., within one grain, a flat, smooth surface may occur on one edge, while the perpendicular surface is more uneven, sharp, and refracted. When analyzing the theoretical influence of such an aggregate grain shape on the compressive strength of the RGA concrete, it can be concluded that the strength value will depend on the direction of grain placement  with respect to the direction of the compressive stresses. This is due to the fact that on the side of the smooth, flat surface of grain aggregate, the ITZ will be characterized by reduced cohesion. In addition, the force of adhesion of such a surface to the cement matrix will be reduced due to the inability of mechanical binding . HoweveAnalysis of the SEM photos indicates that the basalt and RGA grains have a very similar surface structure. Both types are broken aggregates. The grain surface is sharp and ragged. Basalt grains also have a glassy surface, and cohesion between the grains and cement paste is guaranteed by adhesion forces and mechanical grip. The similarity of these features of the RGA and basalt aggregate is another proof that the glass cullet obtained from crushing car side windows is an aggregate with features more favorable than conventional mineral aggregates, i.e., sand and gravel.The paper shows the possibility of utilizing car side windows in cement composites. The solutions proposed have a beneficial effect on the technical properties of the cementitious composites. The RGA may be used in the concrete production in a local way, but not on a large scale. The aim of the production of concrete with the RGA would not be so much the production of composites with high technical values but the utilization of wastes, which are currently not effectively used.Glass obtained from car side windows, despite the technical possibilities of its secondary use, is often deposited on landfills. This occurs mainly due to the small amount of wastes and the fact that their collection, segregation and transportation to distant places are expensive. The authors suggest to deposit car side windows at points of selective waste collection. From these sites, local concrete plants could obtain the waste and use it periodically in the case of the need to produce the cementitious composites with specific technical parameters .car side windows are a suitable material for the production of recycled aggregates; the particle size distribution curve of the RGA indicates that the most appropriate is its use as a 4-8 mm fraction .RGA has more favorable features than those of traditional mineral aggregates, i.e., sand and gravel; the aggregate is much less absorbable, has a more favorable grain shape and definitely higher strength parameters than traditional aggregates,cementitious concretes, in which RGA was used as a mass substitute for traditional aggregate in the amount of 50 and 100% of the 4–8 mm fraction, were characterized by lower water absorption, higher compressive strength, higher water resistance, and higher frost resistance; using the RGA, a cementitious composite was obtained with a definitely higher usable quality compared to the traditional concrete,microscopic analysis of RGA and concretes produced with it indicated that the structure and texture of the surface of broken glass on the edges is crystalline, uneven, and has many breaks; thus, it is similar to the surface morphology of basalt grains, which may be the reason for the greater adherence of the RGA to the cement matrix than for sand–gravel aggregates,the ITZ between the cement matrix and the RGA grains is cohesive, full, and has no disadvantageous features such as delamination or cavities, which increases the final cohesion and strength characteristics of the cementitious composite.On the basis of the analyzed and interpreted research results, final conclusions were drawn:


IgG4-related hypophysitis (IgG4-RH) is a rare disease, and its prevalence remains unclear. In recent years, an increasing number of cases have been reported because of the increasing recognition of this disease. We aimed to summarize case reports of IgG4-RH and outline the clinical features and outcomes.  We performed PubMed search of articles using the search terms “hypophysitis [AND] IgG4.” Consequently, only 54 English articles (76 cases) met Leporati's diagnostic criteria. p=0.001) and male-prone  and had a susceptibility of multiple organ involvement  compared to those with normal serum IgG4 levels. Males were older at disease onset  and had a higher IgG4 concentration  and a greater number of involved organs , while isolated hypophysitis was more prominent in female .  Of the 76 cases, the ratio of men to women was 1.5 : 1, and the age at diagnosis was 54.1 ± 17.8 years. The median IgG4 concentration was 405.0 mg/dl. Anterior hypopituitarism, isolated central diabetes insipidus, and panhypopituitarism were observed in 14 (18.4%), 12 (15.8%), and 44 (57.9%) cases, respectively. The sequence of anterior hormone deficiency was as follows: gonadotropin (68.4%), ACTH (63.2%), TSH (59.2%), GH (48.7%), and prolactin (42.1%). The median number of involved organs was 1.5, and the lung (18.4%), retroperitoneum (17.1%), kidney (15.8%), submandibular glands (14.5%), and pancreas (13.2%) were the common involved organs. Elevated IgG4 concentration and normal IgG4 level were in 42 (76.4%) and 13 (23.6%) cases, respectively. Patients with elevated serum IgG4 concentration were older (60.9 ± 14.3 vs 45.6 ± 17.4,  In this review, we found that there were different characteristics between different genders. Patients with elevated serum IgG4 level in terms of some clinical features were also different from those with normal serum IgG4 level. However, the data in this review were limited by bias and confounding. Further clinical studies with larger sample sizes are warranted. IgG4-related disease (IgG4-RD) is a rare, newly recognized, multiorgan involved disease, which was characterized by infiltration of IgG4-positive plasma cells into the organs and elevated serum IgG4 level. The incidence of IgG4-RD was estimated to be 0.28–1.08/100,000 patients in Japan . It accoThis systematic review of the literature was conducted based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines .We performed a PubMed database of the US National Library of Medicine search of articles using the search terms “hypophysitis [AND] IgG4” published up to March, 2019. A manual search of the literature was also performed. Articles were excluded if (1) cases were reported in languages other than English, (2) cases without individual data, and 3) cases not conformed with Leporati's diagnostic criteria . Two inv cases noAnterior hypopituitarism was defined as any anterior pituitary hormone deficiency. Secondary hypogonadism was diagnosed when FSH/LH concentration and estradiol or testosterone level was not elevated, respectively, for women or men. Secondary adrenal deficiency was defined as low morning serum cortisol and ACTH level. Secondary hypothyroidism was diagnosed when the serum FT4 level was below the normal range and serum TSH level was inappropriately low or normal. GH deficiency was defined as low age-adjusted IGF1 level. The diagnosis of diabetes insipidus was based on the clinical findings of polyuria and polydipsia, low levels of antidiuretic hormone (ADH), low urine osmolality in a water deprivation test, and an increase in urinary osmolality or a decrease in urine volumes in response to a desmopressin trial.t-test; all continuous, non-normally distributed data were analyzed by nonparametric testing (Mann–Whitney U test). Categorical variables were assessed by chi-square or Fisher's exact test, as appropriate. All statistical tests were performed by SPSS version 20. A p value <0.05 was considered statistically significant.All parameters were described in the standard summary statistics, including mean, standard deviation (SD), median, minimum, maximum, and composition ratio. Statistical differences for continuous, normally distributed data were analyzed by Student's n = 46/76) were men (the mean ± SD age at time of onset was 61.5 ± 12.6 years), 39.5% (n = 30/76) were women (the mean ± SD age at time of onset was 42.9 ± 18.8 years), and the ratio of men to women was 1.5 : 1. The minimum age was 14 years (ranged from 14 years to 87 years). Two patients were pregnant women. According to the data, the ages of onset were as follows: 7 (9.2%) patients were in their 40s, 19 (25.0%) in their 50s, 13 (17.1%) in their 60s, and 17 (22.4%) in their 70s  accounted for 18.4%. Central diabetic insipidus (polyuria and polydipsia) accounted for 39.5%. Anterior hypopituitarism  accounted for 10.5% and general symptoms  accounted for 40.8%. Certainly, headache (26.3%) was also caused by direct compression of pituitary mass.n = 52, 68.4%), followed by ACTH , TSH , GH , and prolactin . Of all cases, isolated ACTH deficiency (n = 1), isolated hypogonadism (n = 5), and isolated hypothyroidism (n = 1) were documented.Seven cases had no available data of anterior pituitary function, and 5 cases lacked description of posterior pituitary function in the 76 cases. Almost all cases of IgG4-RH showed central diabetes insipidus and/or hypopituitarism although three patients had no pituitary dysfunction. Various degrees of anterior hypopituitarism were observed in 14 (18.4%) cases. Isolated diabetes insipidus was diagnosed in 12 (15.8%) cases. Panhypopituitarism was recorded in 44 (57.9%) cases. Among patients with damaged anterior pituitary, gonadotropin was the most commonly deficient hormone (n = 62). Comparing men with women, IgG4 concentration in men was higher .In the 76 cases, 14 cases did not record the IgG4 level and 7 cases only showed normal without available data. Normal IgG4 level was defined as 140 mg/dl. Forty-two (76.4%) cases had elevated IgG4 concentration, when 13 (23.6%) cases showed normal IgG4 level (7 cases lack of detailed data). Among those patients who had available serum IgG4 level, the median IgG4 concentration was 405 mg/dl  cases presented with pituitary mass. Twenty (26.3%) cases presented with thickened pituitary stalk. Thirty-nine (51.3%) cases showed pituitary mass and thickened pituitary simultaneously. In cases involving central diabetes insipidus, the bright signal seen in the posterior pituitary of T1-weighing imaging was absent.n = 14, 18.4%), followed by the retroperitoneum , kidney , submandibular glands , and pancreas  . The lung was the most commonly involved organ  . We obseForty-three (56.3%) cases were diagnosed by pituitary biopsy via a transcranial approach or transsphenoidal approach. Twenty-three (30.3%) cases were diagnosed based on biopsy-proven IgG4-related disease in other organs when enlarged pituitary gland and/or pituitary stalk were presented.n = 55, 72.4%). Various kinds and doses of glucocorticoid were used to treat this disease. However, there were still some cases showing a relapse of the pituitary mass when the doses of glucocorticoid were tapered (n = 60/64) of cases showed improvement following treatment, at least initially.There was only one not receiving treatment; moreover, there was little change in the follow-up of 4 years. The use of glucocorticoid alone was the most common therapy for our patients . Another important difference between men and women was that the isolated IgG4-RH was almost exclusively present in women (p=0.001). However, they had no difference in efficiency of therapy .We analyzed the clinical features of patients according to elevated versus normal serum IgG4 concentration . It showThis review presented the largest number of IgG4-RH cases ever enumerated in English, with 76 cases meeting the inclusion criteria. We analyzed the characteristics of each parameter. In addition, we compared the differences of each parameter based on sex and serum IgG4 level aiming to understand the IgG4-RH precisely.p=0.001). Importantly, 9 cases had been diagnosed IgG4-RD prior to IgG4-RH. We learned that it is important to follow-up these cases by considering them potential IgG4-RH cases.Our analysis showed IgG4-RH presented at the 6th decade of life (mean age 54.1 ± 17.8 years) and was associated with a 1.5 : 1 male predominance, by contrast with the common lymphocytic hypophysitis, which was common in young females, particularly in association with late pregnancy or the postpartum period, and peaked in incidence in the 4th decade of life . Iseda eWith regard to features of MRI and pituitary function, the data characteristics were similar to Shikuma's review . The seqn = 60/64) cases showed shrinkage of pituitary size after treatment. However, 5 cases of IgG4-RH relapsed when glucocorticoid were tapered at a low dose in all patients. All of them were men aged from 43 to 75 years. Tabata et al. [Despite pituitary biopsy being an invasive examination and hard to operate, 43 (56.6%) cases were diagnosed by this method. We may reduce the necessity of pituitary biopsy by finding suspicious other organ damage with a careful examination. Currently, there was no clear standard for the treatment of IgG4-RH. Steroid therapy was the first-line treatment. The initial dose of prednisone was usually 0.6 mg/kg/day, and the dose could be regulated for rapid progression or higher body weight. It continued for 1-2 months. The dose was tapered to a maintenance dose (2.5–5 mg/day) over a period of 2-3 months, with a taper of 5 mg every 1-2 weeks. If disease relapsed, the physician might consider a maintenance dose for an extended period of time, up to three years, or a combination of immunosuppressants , 67. Fora et al.  detectedWhile the exact etiology of IgG4-RH still remains unclear, its potential association with autoimmune conditions has been frequently reported. This review showed 5 cases (6.1%) were associated with autoimmune diseases, such as hashimoto's thyroiditis , 54, sysThis review had certain limitations. On the one hand, this review was grounded on case reports and small case series, but case reports not published in the English language were excluded. In addition, some case reports described the clinical data and outcomes very briefly. Consequently, some of the variables were missing. These biases may have an influence on the conclusions of this review. On the other hand, reporting bias due to overreporting of severe cases may lead to an overestimation of the clinical disease. This bias could not be thoroughly ruled out. For rare diseases, such as IgG4-RH, we can establish an online disease registry system to facilitate systematic data collection furthermore.We described clinical features of IgG4-RH. In addition, we revealed that there were different characteristics between different serum IgG4 levels and sexes. However, further clinical studies with larger sample sizes are warranted due to bias and confounding in this review.


IgG4-related disease, described around the years 2000 as a form of autoimmune pancreatitis, is now increasingly accepted as a systemic syndrome. The diagnosis is based on both comprehensive and organ-specific criteria. For the kidney, Mayo clinic classification and the guidelines of the Japanese Nephrology Society are used. Ultimately, together with parameters that characterize every organ or apparatus involved, the key element is the confirmation of growing levels of IgG4 in blood or in tissues.We describe a male patient with chronic renal failure associated to hypertension without proteinuria. IgG4-related disease was diagnosed through renal biopsy. After an initial positive response to steroids, he presented tinnitus, and histological assessment showed cerebral and subsequently cardiac damage, both IgG4-related. This case appears unique for the type of histologically documented cardiac and neurological parenchymal involvement, and at the same time, exemplifies the subtle and pernicious course of the disease. Frequently, blurred and non-specific signs prevail. Here, kidney damage was associated with minimal urinary findings, slowly progressive renal dysfunction and other factors that can be equivocated in the differential diagnosis. Neurological involvement was represented by tinnitus alone, while cardiac alterations were completely asymptomatic.This report is representative of the neurological and cardiac changes described in the literature for IgG4-related disease, which may be correlated or not with the renal form and highlights the need, in some cases, of targeted therapeutic approaches. In addition to glucocorticoids, as in this case, rituximab may be necessary. IgG4-Related Disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory condition. Several well-known illnesses , once considered unrelated, are now unified under this systemic disorder . The epiThe pathogenesis of IgG4-RD can be highly variable. The presentation of an unknown antigen by B-cells and plasmablasts to CD4+ T-lymphocytes triggers the local production of fibrogenic cytokines, namely IL-1β, IFN-γ and TGF- β, which contribute to spread the fibrosis to different organs. For unknown reasons, the previous interaction, involving CD4+ Tfh2 (IL-4 and IL-10), induces a switch to IgG4 production within lymph node germinal centers. Different autoantigens, like proteins expressed in bile duct epithelia and in pancreatic acinar cells, have been proposed as targets/triggers in IgG4-RD patients, although they are not found in all the organs potentially involved .RTX seems to be the most effective second-line treatment, although randomized controlled trials are still lacking.