This study evaluated whether serious bacterial infections are more frequent at family practices with lower antibiotic prescribing rates.Cohort study.706 UK family practices in the Clinical Practice Research Datalink from 2002 to 2017.10.1 million registered patients with 69.3 million patient-years’ follow-up.All antibiotic prescriptions, subgroups of acute and repeat antibiotic prescriptions, and proportion of antibiotic prescriptions associated with specific-coded indications.First episodes of serious bacterial infections. Poisson models were fitted adjusting for age group, gender, comorbidity, deprivation, region and calendar year, with random intercepts representing family practice-specific estimates.The age-standardised antibiotic prescribing rate per 1000 patient-years increased from 2002  to 2012  before declining to 2017 . The median family practice had an antibiotic prescribing rate of 648 per 1000 patient-years with 95% range for different practices of 430–1038 antibiotic prescriptions per 1000 patient-years. Specific coded indications were recorded for 58% of antibiotic prescriptions at the median family practice, the 95% range at different family practices was from 10% to 75%. There were 139 759 first episodes of serious bacterial infection. After adjusting for covariates and the proportion of coded consultations, there was no evidence that serious bacterial infections were lower at family practices with higher total antibiotic prescribing. The adjusted rate ratio for 20% higher total antibiotic prescribing was 1.03, .We did not find population-level evidence that family practices with lower total antibiotic prescribing might have more frequent occurrence of serious bacterial infections overall. Improving the recording of infection episodes has potential to inform better antimicrobial stewardship in primary care. This cohort study included 10.1 million patients with 69.3 million patient-years of follow-up at 706 UK family practices from 2002 to 2017.The study included all antibiotic prescriptions and classified them according to the medical conditions recorded on the same date.The study relied on medical conditions recorded by healthcare professionals in primary care.Missing and misclassified information might result in bias, which might generally be towards a null finding.The study aimed to evaluate associations at the general practice level and the results do not exclude the possibility of association at the individual patient level.Antimicrobial resistance is a growing concern for health systems. The G20 health ministers noted that ‘drug-resistant (organisms) are to blame for 700 000 deaths worldwide each year, and this figure is predicted to rise to 10 million by 2050 if urgent action is not taken.’et alet alIt is possible that reducing antibiotic prescribing might be associated with greater risk of serious bacterial infections. Previous research investigated infection risk and antibiotic prescribing for respiratory illnesses.It is important to extend these investigations to include antibiotic prescribing for all indications because the reasons for antibiotic prescribing may not always be well documented, with up to half of antibiotic prescriptions in UK primary care not associated with any record of specific diagnostic medical codes.We carried out a population-based cohort study in the UK Clinical Practice Research Datalink (CPRD) employing data for 2002–2017. The CPRD is one of the world’s largest databases of primary care electronic health records, with participation of about 7% of UK family practices and with ongoing collection of anonymised data from 1990.In order to analyse antibiotic prescribing, a sample was drawn from the CPRD denominator file for the October 2018 release of CPRD. A random sample of registered patients was drawn, stratifying by year between 2002 and 2017 and by family practice. In each year of study, a sample of 10 participants was taken for each gender and age group using 5-year age groups up to a maximum of 104 years. Each sampled participant contributed data in multiple years of follow-up. There was a total sample of 671 830 individual participants, registered at a total of 706 family practices, who contributed person time between 2002 and 2017. The sampling design enabled estimation of all age-specific rates with similar precision, while age-standardisation provided weightings across age groups.For each participant in the antibiotic prescribing sample, we calculated the person-time at risk between the start and end of the patient’s record. Person time was grouped by gender, age group and comorbidity. Age groups were from 0 to 4, 5 to 9 and 10 to 14 and then 10 years age groups up to 85 years and over. Comorbidity was evaluated as either present or absent in each person-year using the ‘seasonal influenza at risk codes’ which are used to identify individuals at higher risk of infection who may benefit from influenza vaccination,Antibiotic prescriptions were evaluated using product codes for antibiotics listed in section 5.1 of the British National Formulary, excluding methenamine and drugs for tuberculosis, and leprosy. Different antibiotic classes and antibiotic doses were not considered further in this analysis. Multiple antibiotic prescription records on the same day were considered as a single antibiotic prescription. Medical codes recorded on the same date as the antibiotic prescription were used to classify the indication for prescription using categories of ‘respiratory’, ‘genitourinary’, ‘skin’ and ‘other specific’ indications. All other codes were classified as ‘non-specific’ codes.Clostridium difficile; sepsis and septic arthritis. Incident events were first records for each type of serious bacterial infection in a patient more than 12 months after the start of the patient record. However, a single patient might have first episodes of more than one type of bacterial infection. Possible recurrent events in the same patient were not evaluated further because, in electronic health records, it may not be possible to distinguish new occurrences from reference to ongoing or previous problems.Incident cases of serious bacterial infection were evaluated in the January 2019 release of CPRD for the years 2002–2017 with the CPRD denominator providing the person time at risk. CPRD records include details of consultations by general practice staff, as well as coded records of referrals to hospital or discharge letters from hospitals. The mean duration of follow-up was 6.9 years. Serious bacterial infections were selected for study from review of the International Classification of Diseases 10th revision,The analysis was in two stages. First, we estimated family practice-specific estimates for antibiotic prescribing; second, we evaluated whether these estimates were associated with the risk of serious bacterial infection. In the first stage of the analysis, we analysed antibiotic prescribing in primary care between 2002 and 2017 : model 110.1136/bmjopen-2020-036975.supp1Supplementary dataIn the second stage of analysis, serious bacterial infections were analysed as the outcome : model 2The protocol and results of the study were discussed at meetings with patients. Patients commented on the recent declining trend in antibiotic prescribing. They noted that avoiding antibiotics requires trade-offs between the limited benefits from antibiotic treatment, the side effects of antibiotic use, and the potential from longer-term problems from the increase in antimicrobial resistance. Patients considered that risks of serious bacterial infections were generally low at the present time. There is a need to communicate these results to patients and prescribers so that both groups can be aware of the wider contextual issue of antimicrobial resistance to inform antibiotic prescribing decisions.There were 706 family practices included in the analysis, with 10.1 million registered patients and 69.3 million patient-years of follow-up. In the subsample analysed for antibiotic prescribing, there were 706 family practices with 6 541 195 person-years of follow-up . There wC. difficile infections, kidney infections and osteomyelitis. The remaining conditions showed either stable incidence or slight declines. There were 139 759 first episodes of serious bacterial infections . Figure We conducted a sensitivity analysis by excluding repeat prescriptions that might not have been for acute infection episodes. There was no evidence that higher acute (non-repeat) antibiotic prescribing was associated with serious bacterial infections overall  . There wThis study found that antibiotic prescribing increased from 2002 to 2012 but declined subsequently with changes over time being of larger magnitude for women than men. The incidence of serious bacterial infections in men and women rose steadily between 2002 and 2017, particularly for sepsis (men and women), osteomyelitis (mainly in men) and kidney infections (mainly in women). The research aimed to test the hypothesis that family practices with lower utilisation of antibiotics might have greater risk of serious bacterial infections. We evaluated the incidence of serious bacterial infections including 10 groups of infections that affect different systems of the body as well as sepsis (including septicaemia). We did not find evidence that family practices that prescribe antibiotics less frequently might have a higher incidence of serious bacterial infections. We found evidence that each type of serious bacterial infection was recorded more frequently at family practices that record diagnostic codes for a high proportion of antibiotic prescriptions suggesting that variation in the incidence of serious bacterial infection among family practices may be partly an artefact of data recording. Measures are needed to improve the recording of infection episodes in primary care both when antibiotics are prescribed and when they are not. Repeat prescriptions account for a significant proportion of uncoded prescriptionsThe study drew on data for a large population comprising data for about 7% of the UK general population. In view of sample size constraints, antibiotic utilisation was estimated through analysis of data for a sample of patients, using hierarchical (multilevel) regression models to obtain family practice-specific antibiotic prescribing estimates. This contrasts with our previous study in which age-standardised and sex-standardised rates were calculated from the data for each practice.et alet alThe trends in total antibiotic utilisation reported here are consistent with national trends based on aggregate data.Family practices that reduce the amount of antibiotics prescribed do not risk any increase in serious bacterial infections overall. This finding does not exclude the possibility that serious bacterial infection may be associated with antibiotic prescribing patterns at individual patient level. Consequently, reducing antibiotic utilisation in primary care will require a detailed understanding of when antibiotics prescriptions are required and when they are not and increasing the quality of data recording with respect to antibiotic use should be a high priority. This study focused on population-level associations at the level of family practice. Future research should evaluate the associations at the level of the individual patient and the individual family practice consultation. This might provide primary care professionals and patients with objective evidence concerning levels risk that can inform decisions to prescribe or not prescribe antibiotics.


Pseudomonas aeruginosa bacteria are present. To quantify the antibiotic diffusion dynamics we employ a phenomenological model using a subdiffusion-absorption equation with a fractional time derivative. This effective equation describes molecular diffusion in a medium structured akin Thompson’s plumpudding model; here the ‘pudding’ background represents the ASM and the ‘plums’ represent the bacterial biofilm. The pudding is a subdiffusion barrier for antibiotic molecules that can affect bacteria found in plums. For the experimental study we use an interferometric method to determine the time evolution of the amount of antibiotic that has diffused through the biofilm. The theoretical model shows that this function is qualitatively different depending on whether or not absorption of the antibiotic in the biofilm occurs. We show that the process can be divided into three successive stages: (1) only antibiotic subdiffusion with constant biofilm parameters, (2) subdiffusion and absorption of antibiotic molecules with variable biofilm transport parameters, (3) subdiffusion and absorption in the medium but the biofilm parameters are constant again. Stage 2 is interpreted as the appearance of an intensive defence build–up of bacteria against the action of the antibiotic, and in the stage 3 it is likely that the bacteria have been inactivated. Times at which stages change are determined from the experimentally obtained temporal evolution of the amount of antibiotic that has diffused through the ASM with bacteria. Our analysis shows good agreement between experimental and theoretical results and is consistent with the biologically expected biofilm response. We show that an experimental method to study the temporal evolution of the amount of a substance that has diffused through a biofilm is useful in studying the processes occurring in a biofilm. We also show that the complicated biological process of antibiotic diffusion in a biofilm can be described by a fractional subdiffusion-absorption equation with subdiffusion and absorption parameters that change over time.We study the experimentally measured ciprofloxacin antibiotic diffusion through a gel-like artificial sputum medium (ASM) mimicking physiological conditions typical for a cystic fibrosis layer, in which regions occupied by  Biological processes are very complex, so mathematical modelling of these processes is a quite difficult task. On the one hand, mathematical models are still being developed, even for relatively simple geometries, for instance, for molecular chemical reactions involved in gene regulation in bacteria cells –4. On thThe process of transporting an antibiotic into a bacterial biofilm is such a complicated process. A biofilm has a complex structure that changes over time. Special biofilm defence mechanisms, not fully understood, that affect the diffusion of antibiotic molecules in the biofilm can be activated –8. ModelNowadays, a variety of laboratory techniques are used to evaluate antibacterial properties of drugs, mainly, disk-diffusion methods as a standard in microbiological laboratories, antimicrobial gradient methods (E-tests) which allow to determine the minimum inhibitory concentration (MIC) of chemical agents, of ATP bioluminescence assay based on the measurement of adenosine triphosphate (ATP) produced by bacteria and antibiofilm screening assays . The antP. aeruginosa infections during cystic fibrosis. We present a model of the antibiotic diffusion in a biofilm that can be described as a ‘plumpudding’. Antibiotic particles can interact with bacteria located in ‘plums’, pocked in the ‘pudding’ background while the pudding is a diffusion barrier for the antibiotic. In the experimental system the ‘pudding’ represents the artificial sputum medium (ASM) which mimics cystic fibrosis patient sputum. The bacteria plums correspond to bacterial cells making up microcolonies, i.e. biofilms, such as Pseudomonas aeruginosa. In gel–like media subdiffusion is likely to occur  = length2/timeα and [κ] = 1/length, respectively. α /2κ2DM Γ(1 − α), and d = x2 − x1. In the above equations, we took into account that the biofilm coefficients may be different for the cases described by Eqs =C1-α),κ=0,WκB(t)=Cκtα),κ≠0,where a0ρ(t) is to be determined from empirical data. For the case considered in this paper, the function ρ(t) = a − b/t gives a good agreement of the WB function and experimental results in the time interval 〈t1, t2〉. The times t1 and t2 separating the subsequent stages are defined by the equations WB0(t1) = WκB(t1) and κ ≠ const. ≠ 0, WB takes the formWhen absorption occurs and the biofilm parameters change over time, the following function has been proposed Wκ˜(t)Baκ, bκ, aα in Eqs , 9) and andaκ, bκ, and the biofilm thickness d are small, κd ≪ 1 [D and α are constant, by swapping the other parameters in We suppose that the absorption probability of antibiotic molecules per unit length of biofilm, which is controlled by the parameter , κd ≪ 1 . If the WB, the amount of substance that has diffused into part B. The experimental results are shown in α = 0.96 is the same. This parameter has been determined as one of the fitting parameters when analyzing Stage 1. Unfortunately, the statistic is too poor to determine the error for α. Because the consistency of ASM is very similar to the consistency of 1% aqueous agarose solution for which α = 0.95 [α is realistic. We note that anomalous diffusion exponents as about of 0.9 are not exceptional and physically meaningful, see e.g. [a0 and b0 provide the best fit of the function WB0aκ, bκ, and cκ provide the best fit of the function WκBa and b here.As already mentioned, the setup of our experiment following Figs α = 0.95 , we suppsee e.g. , 41, 42.Stage 1 described by Stage 2 described by Stage 3 described by ρ(t) is increasing over time. Due to κ is a function decreasing over time and the parameter DM increases over time in Stage 2. The interpretation of the process is that at Stage 1 there is a sub-inhibitory concentration of the antibiotic near the bacteria located in the biofilm plums. The bacterial defence mechanisms are then not fully activated. We mention that WB0 in A to the regions M and B. We therefore assume that the concentration of the antibiotic in ASM increases with time. Thus, in Stage 2 the defence mechanisms is activated due to the increasing of antibiotic concentration near the plums. The antibiotic effect weakens the bacteria to such a level that the influence of factors causing absorption of antibiotic molecules and slowing down of diffusion decreases, which causes changes in the biofilm parameters. At the moment t2 these parameters stop changing, which can be interpreted as the inability of bacteria to continue their active defence.The observed order of the stages in Pseudomonas aeruginosa bacteria. However, when studying other processes it may be possible to observe the fourth stage in which there is no absorption and the parameters of the biofilm change over time; this stage is not observed in our date in We have shown a method to experimentally check whether a biofilm in a plumpudding scenario absorbs antibiotic particles and whether the biofilm parameters change over time. The presented three-stage model describes subdiffusion of ciprofloxacin through ASM with M of the system. In [ρ(t) is decreasing, so the absorption coefficient increases while the subdiffusion coefficient decreases over time. The reason that the course of antibiotic diffusion in a dense biofim and in the plumpudding scenario is qualitatively different is as follows. In a dense biofilm, antibiotic molecules can ‘feel the action’ of the bacterial defence mechanisms the whole time inside the biofilm. In a plumpudding case, an antibiotic molecule feels the defence mechanism after reaching a plum occupied by bacteria. This plum can be attacked intensively, from all sides, by an antibiotic which concentration at the surface may increase over time due to diffusion process. This leads to a weakening of the bacterial defences faster than in a dense biofilm. We hypothesize that the order of states, which may be checked experimentally, is indicative of the structure of the biofilm, namely whether or not it can be treated as a dense biofilm. However, since there are a lot of mechanisms for the defence of bacteria against the effects of an antibiotic, whether the order of stages in both cases is universal should receive further study along with improved experiments.A different course of the process has been observed when a ‘dense biofilm’ attacked by bacteria fills the entire space of the central part stem. In  it is shS1 File(PDF)Click here for additional data file.


The frequency of patients with decreased best corrected visual acuity (BCVA) was significantly higher in group D (p = 0.002). Receiver operating characteristic (ROC) curves for the prediction of extraocular muscle enlargement and worsened BCVA using a panel consisting of important blood test data identified by machine learning yielded areas under the curve of 0.78 and 0.86, respectively. Clinical features were compared between patients divided into two groups by the cutoff serum IgE or IgG4 level obtained from ROC curves. Patients with serum IgE above 425 IU/mL had a higher frequency of extraocular muscle enlargement . Patients with serum IgG4 above 712 mg/dL had a higher frequency of decreased BCVA . Conclusion: Unsupervised hierarchical clustering analysis using routine blood test data differentiates four distinct clinical phenotypes of IgG4-ROD, which suggest differences in pathophysiologic mechanisms. High serum IgG4 is a potential predictor of worsened BCVA, and high serum IgE is a potential predictor of extraocular muscle enlargement in IgG4-ROD patients.Purpose: To describe the clinical features of patients with immunoglobulin G4 (IgG4)-related ophthalmic disease (IgG4-ROD) grouped by unbiased cluster analysis using peripheral blood test data and to find novel biomarkers for predicting clinical features. Methods: One hundred and seven patients diagnosed with IgG4-ROD were divided into four groups by unsupervised hierarchical cluster analysis using peripheral blood test data. The clinical features of the four groups were compared and novel markers for prediction of clinical course were explored. Results: Unbiased cluster analysis divided patients into four groups. Group B had a significantly higher frequency of extraocular muscle enlargement ( Immunoglobulin G4-related disease (IgG4-RD) is a disease entity of unknown cause. The disease is characterized by the formation of mass lesions resembling tumor, thickening of various tissues, infiltration of immunoglobulin G4 (IgG4)-positive cells, and high serum IgG4 ,2. AlthoCluster analysis refers to statistical methods that attempt to discriminate relatively homogeneous groups of individuals based on selected characteristics. Recently, cluster analysis has been used to identify phenotypic groups within a disease for various diseases ,16,17. TAs IgG4-ROD is a heterogeneous disease with diverse clinical symptoms, the goal of IgG4-ROD classification is to improve prediction of the phenotype of an individual patient, so as to aid ophthalmologists in making a decision on treatment strategy (such as whether to prescribe systemic steroid therapy), ultimately achieving personalized or stratified care for IgG4-ROD.We conducted a retrospective, non-interventional, single-institutional observational study. This research was conducted in compliance with the Helsinki principles. Ethical approval was obtained from the Medical Ethical Research Committee in Tokyo Medical University Hospital (Ethic code: 2016-150). All patients signed an informed consent form before participation.We reviewed the medical records at the Department of Ophthalmology, Tokyo Medical University Hospital between July 2008 and March 2020, and identified 152 patients with IgG4-ROD. Among these patients, 45 were excluded because of no peripheral blood test data for soluble IL-2 receptor (sIL-2R) and beta2-microglobulin (β2MG) (25 patients), prednisolone (PSL) treatment initiated before presentation to our hospital (17 patients), and no data of gene rearrangement (3 patients). The remaining 107 patients with IgG4-ROD were included in this analysis. The subjects  were all Asian adults with an average onset age of 57.3 ± 14.5 years. All patients underwent magnetic resonance imaging (MRI) or computer tomography (CT) to evaluate the location of lesion. Lesion sites were evaluated by two ophthalmology specialists using MRI or CT images. Peripheral blood tests were performed at the first visit to our hospital. Biopsy was performed on all patients who had a palpable mass and gave informed consent to undergo biopsy. Gene rearrangement and flow cytometry were performed in all patients who underwent biopsy. The diagnosis of IgG4-ROD was determined based on the diagnostic criteria for IgG4-ROD . The folUnsupervised hierarchical clustering analysis was performed using the following continuous variables: peripheral white blood cell (WBC) count, percent lymphocyte (Lym), percent eosinocyte (Eo), peripheral platelet (PLT) count, serum total protein (TP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (γ-GTP), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), total bilirubin (T-BIL), blood urea nitrogen (BUN), creatinine (Cre), C-reactive protein (CRP), immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin E (IgE), β2MG, sIL-2R, and serum IgG4. Analysis was performed using statistical software . We divided the patients into four groups by unbiased clustering analysis using Ward’s method ,19. We tROC curves were generated to predict extraocular muscle enlargement, worsened BCVA, and lesion above neck excluding LG and SG, using peripheral blood tests identified as significantly discriminating the three clinical features. ROC curves were also generated using multiple important factors selected by machine learning to evaluate the change in the area under the ROC curve (AUC). Clinical features were compared between patients divided into two groups by cutoff values obtained from ROC curves.https://notabug.org/mbq/Boruta/). The Boruta feature selection was based on the package “Boruta” in R .Machine learning using random forest was performed by Boruta multivariate analysis .Kruskal–Wallis test and Steel–Dwass test were used to compare clinical features and peripheral blood test data among four groups divided by unbiased clustering analysis and condensed unbiased clustering analysis. Mann–Whitney U test and chi-squared test were used to compare clinical features and peripheral blood test data between two groups divided by the presence or absence of each of the following clinical features: worsened BCVA, enlargement of extraocular muscles, and lesion above neck excluding LG and SG. Mann–Whitney U test and chi-squared test were also used to compare clinical features and peripheral blood test data between two groups divided by the cutoff value obtained from ROC curve. A Patient demographics are shown in n = 53; 50% of subjects), consisting of patients who had a low WBC count. Group B was the smallest cluster , consisting of patients with high serum IgA and high serum IgE. Group C consisted of 41 subjects (38%) with high platelet count. Group D consisted of 8 subjects (7%) with older onset, high serum IgG, high β2MG, high serum sIL-2R, and high serum IgG4.As the first step in the analysis, we applied unbiased clustering analysis to obtain a global overview of laboratory test data . Using up < 0.001, p < 0.001, and p = 0.002, respectively). Group B had significantly higher frequency of extraocular muscle enlargement than the other groups (p < 0.001). Groups B and D had significantly higher frequency of lesion above neck excluding LG and SG than the other groups (p = 0.03). No significant differences were observed among the four groups in other clinical features. These results indicated that peripheral blood test data may be useful for the prediction of the clinical course of IgG4-ROD. However, there were several issues of using 20 peripheral blood tests for such analysis, including cost and whether all the tests are necessary for all patients with IgG4-ROD. Therefore, we performed another clustering analysis to examine whether similar results can be obtained even when the peripheral blood test data were reduced to the minimum.We then compared the clinical features between groups A, B, C, and D. The clinical features in the four groups are shown in n = 41; 38% of subjects), consisting of patients who had a high percent of Eo, high serum IgE, and high serum sIL-2R. Group F was the smallest cluster , consisting of patients who had a high percent of Eo, high serum IgG, high serum IgE, and high serum IgG4. Group G  consisted of patients who had a low WBC count. Group H  consisted of patients who had a low percent of Eo. Clinical features in the four groups divided by the condensed unbiased clustering analysis are shown in We performed a condensed unbiased clustering analysis using a smaller number of selected peripheral blood test data. We excluded tests that were deemed unnecessary, costly, or had problems of complexity and reproducibility in clinical use. Peripheral blood tests that showed high frequencies of abnormality in patients with IgG4-ROD were selected for the condensed clustering analysis, as shown in p = 0.04, p < 0.001, and p = 0.001, respectively). Group F tended to have higher frequencies of orbital mass, orbital diffuse lesion, optic neuropathy, and visual field defect compared with the other groups . On the other hand, the Steel–Dwass test showed that group F had significantly high frequencies of orbital mass, orbital diffuse lesion, optic neuropathy, and visual field defect compared with group G . Group E had a significantly higher frequency of extraocular muscle enlargement (p = 0.02). Other parameters were not significantly different.Group F had a significantly longer follow-up period, higher serum IgG4, and higher frequency of worsened BCVA than the other groups . Other clinical features and laboratory findings were not significantly difference between the two groups. These results showed that patients with extraocular muscle enlargement had abnormal peripheral blood findings of elevated WBC count, Eo count, CRP, and serum IgE.First, we compared the clinical features and laboratory findings between subjects divided into two groups based on extraocular muscle enlargement . Patientp = 0.01, p < 0.001, p = 0.003, p = 0.004, p = 0.004, p = 0.02, p = 0.03, p = 0.04, p = 0.002, p = 0.02, p = 0.01, p < 0.001, p = 0.006, p = 0.006, p < 0.001, and p < 0.001, respectively).We then compared the clinical features and laboratory findings between subjects divided into two groups based on worsened BCVA . PatientOther clinical features and laboratory findings were not significantly different between the group with and that without worsened BCVA. These results showed that patients with worsened BCVA had abnormal peripheral blood findings of increased serum IgG4, WBC count, serum TP, CRP, serum IgG, serum IgA, serum IgE, and β2MG.p = 0.01, p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001, p = 0.001, p = 0.001, p < 0.001, p < 0.001, and p < 0.001, respectively).Next, we compared the clinical features and laboratory findings between subjects divided into two groups based on lesion above the neck excluding LG and SG . PatientOther clinical features and laboratory findings were not significantly different between the two groups. These results showed that patients with lesion above neck excluding LG and SG had abnormal peripheral blood finding of an elevated WBC count.The results of this analysis indicate that routine laboratory findings may be useful for predicting extraocular muscle enlargement, worsened BCVA, and lesion above neck excluding LG and SG in IgG4-ROD.Having identified the peripheral blood findings that were significantly different between patients divided based on extraocular muscle enlargement, worsened BCVA, or lesion above the neck excluding LG and SG, we plotted ROC curves to investigate which of the laboratory test findings is most suitable for predicting each of the three clinical features . ROC curThese results indicate that serum IgE is most suitable for the prediction of extraocular muscle enlargement and serum IgG4 is most suitable for the prediction of worsened BCVA, while prediction of lesion above the neck excluding LG and SG using peripheral blood tests may be difficult.We performed machine learning using Boruta to analyze which peripheral blood findings are more important for predicting clinical features such as extraocular muscle enlargement, worsened BCVA, and lesion above the neck excluding LG and SG. The rank plot of feature importance is shown in We then generated ROC curves using combinations of the important findings obtained from the Boruta analysis. ROC curves using panels of important findings for extraocular muscle enlargement  and worsened BCVA  are shown in p = 0.01 and p = 0.004, respectively). Patients with IgG4 above 713 mg/dL had a high male ratio; older onset; and high frequencies of bilateral LG swelling, lesion excluding LG and SG, lesion above the neck excluding LG and SG, trigeminal nerve enlargement, worsened BCVA, optic neuropathy, visual field defect, and dry eye symptoms .Finally, we compared clinical features in patients divided by the cut-off serum IgE concentration of 425 IU/mL or cutoff serum IgG4 concentration of 713 mg/dL obtained from ROC analysis . PatientThese results indicate that patients with serum IgE above 425 mg/dL are more likely to have extraocular muscle enlargement, while patients with serum IgG4 above 713 mg/dL have a higher probability of lesions involving ocular adnexal tissues and other tissues above the neck, higher frequency of worsened BCVA due to optic neuropathy, and higher frequency of dry eye symptoms.The Japanese study group of IgG4-ROD reported that the prevalence of IgG4-ROD ranked second among ocular adnexal lymphoproliferative disorders . In that5 These results show that IgG4-RD patients with lesion above the neck have higher serum IgG4 than those without above the neck lesion. Moreover, we found that patients with serum IgG4 above 713 mg/dL had higher frequencies of bilateral LG enlargement and dry eye symptoms than patients with serum IgG4 below 713 mg/dL. These findings thus suggest that high serum IgG4 may be a risk factor of multi-organ lesion, particularly lesion above the neck, and dry eye symptoms. On the other hand, patients with lesion above the neck excluding LG and SG had a significantly lower frequency of lesion below the neck in this study. However, Boruta analysis found that none of the peripheral blood test findings including serum IgG4 were important for lesion above neck excluding LG and SG. Even when ROC analysis was conducted for WBC count, the only abnormal laboratory data found in lesion above the neck, the AUC was low (0.63). These results indicate that peripheral blood tests including serum IgG4 are not useful for predicting above the neck lesions excluding LG and SG.In the first unbiased clustering analysis, groups B and D had a significantly higher frequency of lesion above the neck excluding LG and SG than other groups. Patients with serum IgG4 above 713 mg/dL also had a higher frequency of lesion excluding LG and SG, especially lesion above the neck, than patients with serum IgG4 below 713 mg/dL. In another study of 493 patients with IgG4-RD divided by phenotype, serum IgG4 levels were 316 and 178 mg/dL in pancreato-hepato-biliary disease and aortitis, respectively, while the levels were 445 and 1170 mg/dL in head and neck-limited disease and classic Mikulicz syndrome, respectively.p < 0.001 versus AUC 0.71; p = 0.01).Interestingly, patients with serum IgG4 above 713 mg/dL had a significantly higher frequency of enlargement of trigeminal nerve, but not enlargement of extraocular muscles. Moreover, patients with a high frequency of enlargement of extraocular muscles were not classified into group D or F with high serum IgG4 (above 1000 mg/dL), but into groups B and E with moderate elevation of serum IgG4. Groups B and E consisted of patients who had a high percentage of Eo and high serum IgE. A previous report also indicated that eosinophilia and relatively elevated serum IgG4 were associated with enlargement of extraocular muscles . MoreoveThe mechanisms behind the diverse inflammatory markers such as eosinophilia and serum IgE are likely to be complex, but may signify a Th2-driven autoimmune mechanism ,30. TherAlthough a case of IgG4-ROD with optic neuropathy was reported , optic nIn this study, WBC, CRP, TP, and β2MG were significantly higher in patients with worsened BCVA than in those with preserved BCVA. One previous study reported higher serum CRP in IgG4-related aortic aneurysms and periaortitis compared with IgG4-related retroperitoneal fibrosis . CRP is This study has several strengths and weaknesses. This is the first study to use unsupervised hierarchical cluster analysis to identify a panel of biomarkers in a relatively large sample of patients with IgG4-ROD, despite the rarity of the disease. This study demonstrates the potential of using a panel of commonly available laboratory test data in predicting the prognosis of IgG4-ROD, which will have wide applicability once validated. On the other hand, there are several limitations. First, the retrospective nature of the study may cause selection bias and confounding bias. Thus, the results should be considered exploratory. Second, because all cases were collected from a single tertiary care hospital, there is potential referral bias. Future studies should prospectively validate these laboratory data in independent cohorts and evaluate whether the addition of other markers improves the accuracy of predicting the clinical course such as enlargement of extraocular muscles, worsening of BCVA, and development of extraocular lesions. Future studies are needed to assess the feasibility of using this unbiased cluster analysis in a prospective manner to predict the visual outcome and development of extraocular lesions.In conclusion, using unbiased clustering analysis, we were able to identify four groups among IgG4-ROD patients, which are associated with different clinical courses, and discover the biomarkers for predicting enlargement of extraocular muscles and worsened BCVA in IgG4-ROD. These phenotypes within IgG4-ROD may in part explain the heterogeneity of this disease. Unbiased clustering analysis reveals that patients with high serum IgE have a high frequency of extraocular muscle enlargement and patients with high serum IgG4 have a high frequency of multi-organ lesion especially lesion above the neck, dry eye symptoms, and worsened BCVA. Surprisingly, although high serum IgG4 alone predicts worsened BCVA among IgG4-ROD patients, using a panel of tests comprising IgG4, IgG, IgA, WBC count, T-BIL, and β2MG improves the accuracy of predicting high risk of worsened BCVA, suggesting that a panel approach may be more effective than serum IgG4 alone, and provides additional evidence for the prevention and management of worsened BCVA in IgG4-ROD. We also noted that these parameters were highly variable among patients. Indeed, for IgG4-ROD patients, data based on serum IgG4 and other markers that can be tested routinely in the hospital laboratory may impact clinical decisions and potentially contribute to the understanding of the mechanisms behind why some patient with IgG4-ROD develop visual disturbance, whereas others do not, and why some patients have extraocular lesions, whereas others do not. A better understanding of this heterogeneity and the link to visual function and extraocular lesions may provide opportunities to conduct personalized or stratified care for IgG4-ROD.


Materials and Methods. This study was conducted on independent practice dentists working in the region of Tunis. A questionnaire was made on “Google forms” and sent to all of them via personal emails. The questionnaire included demographic data and 13 questions about anti-inflammatory medicines: indications and contraindications, the side effects, and their prescription in dental practice. Data analysis was performed on SPSS software version 20.0 , using the χ2 test for statistical analysis. Results. Two hundred dentists participated to the survey. The female gender was predominant (70%). More than half of the responders were recently graduated and working in their own dental offices. The present study showed that 60% of dentists rarely prescribe anti-inflammatory drugs. Ibuprofen was prescribed by 82% of the dentists. Next came dexamethasone acetate (68.2%). The most frequent indication was postoperative pain (65%). Gastric problem was found to be the most mentioned adverse effect (69%). Thus, 72% of the dentists prescribed proton pump inhibitors with AI. Conclusion. According to this study, dentists have a lack of knowledge and awareness about some contraindications, side effects, and drugs interactions. Thus, knowledge updating, practices assessment, and continuous education are always required to avoid drug iatrogenesis.Dentists prescribe several types of drugs such as anti-inflammatory medicines in their practice in order to manage pain. An adequate knowledge of anti-inflammatory drugs' characteristics is mandatory for a reasonable prescription to ensure patients safety. The study aimed to describe dentists' anti-inflammatory drugs prescription in dental practice.  Anti-inflammatory drugs are a widely used therapeutic class due to their antipyretic, analgesic, and anti-inflammatory activities.The most prescribed classes of drugs in the dental practice are antibiotics, analgesics, antiseptics, and anti-inflammatory drugs (AIDs).Dentists prescribe both steroids and nonsteroidal anti-inflammatory drugs (NSAIDs) for many reasons: dental or orofacial pain, postoperative pain after endodontic procedures, oral and implant surgery, or oral dermatologic diseases.Each drug has its own characteristics, and each disease has its own medical treatment which influences drug indications and contraindications. Prescription of anti-inflammatory drugs (AIDs) must correspond to a standardized national or international prescription pattern. It should also be personalized for each patient according to his medical history to avoid possible interactions and undesirable effects.AIDs have undeniable beneficial anti-inflammatory and analgesic properties. Nonetheless, the use of nonsteroidal AIDs can be associated with the higher risk of gastrointestinal, renal, and cardiovascular complications , 2. AlsoAs for all the drugs, any error in AIDs prescription may introduce adverse effects and potential drug-drug interaction .There are many studies assessing the prescription of antibiotics in the dental practice. This is probably in order to monitor the risk of the bacterial resistance emergence .However, few studies assessing practices of dentists toward prescription of AIDs in Tunisia or elsewhere were published. Dentists must have the adequate knowledge for indications of AIDs, their pharmacologic characteristics, and their side effects and potential interactions. Thus, surveys concerning prescribing are needed for dentists to have an overview of their knowledge and their awareness in order to improve rational drug therapy and patients' safety.In this context, this study aimed on describing dentists' anti-inflammatory prescription in dental practice.This cross-sectional pilot study was performed on independent practice dentists practicing in the region of Tunis, capital of Tunisia, during the period between May and July 2019.As Tunisian university courses are presented in French, the questionnaire was formulated in French, with reference to the relevant literature. It included 13 questions (Appendix) about dentists' knowledge of anti-inflammatory drugs and its use in dental practice: the prescribed molecules, the frequency of prescription, contraindications and their awareness about AIDs side effects, drugs interactions, and self-medication among patients. The internal consistency of the questionnaire was assessed, and Cronbach alpha coefficient was equal to 0.72.The self-administrated questionnaire was entered on “Google forms” and randomly sent to the dentists via personal emails. The principal investigator explained that this study was undertaken by the third author in fulfillment of the requirements for the degree of Doctor in Dental Medicine in the Faculty of Dental Medicine of Monastir.All the dentists practicing in the region of Tunis, the capital of Tunisia, were included in this study. They were 800 in 2019, according to the Regional Council of the Order of Dentists.We considered that participants gave an informed consent to the participation since they responded to the survey.X2 test was used to analyze qualitative data. The significance level was set at 95%, and the maximum acceptable difference was 5%.Data obtained from the questionnaire were also transferred to SPSS software 20.0 , where descriptive statistics were analyzed. The A random sample of 200 dentists practicing in Tunis participated to the survey. The response rate was then 25%. The mean age was 35±9 years. The female gender represented 70% of them. More than half of the responders were recently graduated and working in their own dental offices. The present study showed that 60% of dentists rarely prescribe AI drugs. Ibuprofen was prescribed by 82% of the dentists. Dexamethasone acetate was prescribed by 68% of them.Sixty-five percent of the participants prescribed AIDs to treat postoperative pain. Half of them prescribed those medicines for oral infections with dental origins such as cellulitis and abscess. Some of them prescribed AIDs to treat temporomandibular joint pain (33%).Most of the dentists (61%) prescribed AIDs for a short-term period . According to them, the most cited contraindications were severe gastric disease (98%) followed by pregnancy (30%). Only few dentists cited allergic background, kidney failure, hepatic failure, heart failure, and HTA and respiratory impairment with, respectively, 13%, 16%, 7%, 9%, and 6%.Regarding side effects, dentists cited mainly gastric irritation, kidney failure, allergic reactions, and hepatic failure in, respectively, 69%, 16%, 10%, and 6.5%.p < 0.05).According to this study, 82% of the participants declared that they were aware of gastric irritation related to AIDs and 72% of them prescribed proton pump inhibitors with AIDs with statistically significant association . About 70% of them avoided the association with antiplatelet agents and anticoagulants. Sixty percent avoided the association with methotrexate. About half of them avoided the association with phenytoin, diuretics, and lithium, and 33% did not associate AIDs with antidiabetics. The other dentists collaborated with the treating doctor of the patient in order to adjust the dosage according to the doctor's recommendations.p < 0.05).Most of the dentists declared that they were aware that patients may practice self-medication before doctor's visiting (97%). Most of them asked the patients if he/she took an AI drug before prescription, discussed AI drugs' adverse effects and contraindications, and explained the inherent risks in taking medication without a doctor or pharmacist advice (95%), AIDs with statistically significant association  recognized gastric irritation as a side effect.Minor side effects of AID are related to gastric toxicity and irritation. Gastrointestinal adverse events mentioned by the participants were nausea, vomiting, dyspepsia, abdominal pain, peptic ulcer disease, gastrointestinal bleeding, diarrhoea, constipation, and gastric reflux. Seventy-four percent of them prescribed proton pomp inhibitors in association with AID to minimize this effect. Prescription of gastroprotective agents, such as histamine type-2 (H2) blockers and proton pump inhibitors, is common in the world .Serious side effects include renal impairment, hepatic failure, cardiovascular events, neurologic effects, respiratory dysfunction, hematological abnormalities, and allergic reactions.It seemed that there was a lack of knowledge about systemic side effects. In fact, only few study participants cited allergic reactions, kidney failure, hepatic failure, respiratory impairment, osteoporosis, salt and water retention, oedema, hyperglycemia, cardiovascular risks, immunosuppression, and infection exacerbation.In this study, the majority of the participants declared that they prescribed AID for short time therapy. Corticosteroids' short-term treatment is generally safe . NeverthIt should be emphasized that even short time treatment with NSAID can be associated with an increased risk of cardiovascular events, leading to death according to Hoxha et al., 2020 . Thus, dDentists must have the adequate knowledge for clinical indications of AID. Thus, educational programs concerning prescribing guidelines are needed for dentists to improve rational drug therapy and patients' safety.Most of the participants were aware about drugs interactions with AIDs. They referred to the treating doctor of their patients to ask about the safety of the association between antiplatelet agents, anticoagulants, methotrexate, and AIDs. Most of them avoided some associations. However, avoiding such prescription may not be the best solution to manage the pain. Therefore, it is important to measure the benefits and the risk of such associations. Drug interactions lead to toxicity or therapeutic failure .One of the methods to minimize drugs interactions is to get informed about the associated medication. Such information is necessary to adapt or to avoid some prescriptions.Dentists must ask patient about his medical history and current medication in order to reduce drug interactions. They may use alternative drugs where indicated or reduce the dose of the AIDs if possible. Patients and treating doctors should provide updated information, and a thorough AIDs intake should also be recorded and clearly documented by the dentist.Tunisia is a developing country where patients are not adequately aware about self-medication risks. Data about self-medication are not available, but overall, people and even medical and dental students practice self-medication. They buy drugs directly from pharmacies, which may increase the risk of health hazards. This can be due to restricted financial resources, unwillingness to visit the dentist, poor sociocultural background ignoring self-medication risks, considering pain as a minor illness, and sometimes busy time.Patients should be routinely asked and warned about the hazards of receiving AIDs from pharmacists or even from other physicians because inappropriate or excessive drug prescription not only leads to financial loss for patients but also causes adverse effects and serious complications. Health decision makers should work cooperatively with pharmacists and doctors to adopt the necessary measures allowing control AIDs sales with a view to minimizing self-medication.This study gave an overview of dentists' practices. However, it had some limits.It was a pilot study where the sample size was small. This study merits to be reconducted with larger sample. As with any self-administered survey, the answers given by participants may not reflect real actual practices and attitudes.Moreover, our study analyzed the prescription of AIDs in general. We suggest that questions should be organized in two categories: questions about nonsteroidal AI drugs and corticosteroid AI drugs separately.Also, we included in our study both general dentists and specialist dentists . Thus, this may affect the prescription type, prevalence, and indications; so, we suggest that prescription practices of both groups of dentists should be evaluated separately in future studies.It would have been helpful if our data assessed knowledge with precise scores including, for example, patients' main diagnosis and complications for which drugs were prescribed.To the best of our knowledge, this is the only study in Tunisia that focus on dentists' AI medicines prescription. Further studies with prescription patterns are needed to assess knowledge, awareness, and practices of Tunisian dentists.According to this study, dentists prescribed AIDs when indicated for temporomandibular pain and postoperative pain especially after endodontic procedures or wisdom teeth removal. They were aware of certain side effects such as gastric irritation and iatrogenesis for pregnancy. They were also aware of self-medication among patients and tried to prevent it. However, pitfalls were observed in areas of systemic complications.Based on our findings, we suggest that continuous education programs are mandatory to insist on the risks of AIDs, their contraindications, and assist dentists to choose the appropriate molecule with respect to the national or/and international guidelines for AID prescription. Moreover, it is necessary to raise public awareness of self-medication risks in order to avoid health hazards and risk of legal actions.


Chloride-induced steel corrosion is the most concerning issue for the durability of concrete structures. Concrete and steel samples were obtained from a 30-year-old reinforced concrete bridge. The chloride content was measured by a potentiometric titration method and the microstructure of concrete was obtained by scanning electron microscopy and mercury intrusion porosimetry. The rust phases of the steel were detected by X-ray diffraction and Raman analysis. It was found that the convection depth for chloride transport in cracked concrete was significantly larger than that in uncracked concrete. The concrete in a pier column facing upstream had greater porosity due to the water impact and calcium leaching. The coefficients of variability of chloride diffusivity of concrete for the bridge deck and the pier column were significantly different. Rust phases including lepidocrocite, goethite, akaganeite, magnetite, and maghemite were detected using Raman spectroscopy and X-ray diffraction. The major phases of steel rust in the atmospheric zone were lepidocrocite and goethite, while they were lepidocrocite and maghemite in the tidal zone. The results of this study would provide information concerning the chloride-induced steel corrosion under a marine environment in order to predict long-term behaviors of a reinforced concrete structure. The degradation of reinforced concrete (RC) structures in a marine environment is related to physical and chemical processes including chloride penetration, sulfate attack, and carbonation. Among these factors, chloride penetration is the most concerning for the durability of concrete structures ,2. CostaChloride ions move into concrete by the mechanisms of diffusion and convection. Diffusion is caused by differences in chloride ion concentrations in pore water while convection is due to water transport carrying chloride ions. During the chloride transport process, some chloride is dissolved in pore water and the rest is bound by cement hydrates, i.e., free chloride and bound chloride, respectively. The free chloride is responsible for destroying the passive layer of steel and initiating steel corrosion .In a tidal zone, concrete is subject to periodic drying and wetting processes during the ebb and rise of the tide. During wetting periods, chloride ions are brought into concrete along with seawater absorption. During drying periods, chloride diffuses from the exposed surface to the deeper areas that have a lower chloride concentration. Cyclic wetting and drying conditions can significantly accelerate chloride penetration in concrete. Field tests for a concrete harbor deck in the tidal zone were carried out at different altitudes by Zhang and Jin . The pro−]/[OH−] was used as an indicator for the corrosion initiation by researchers [−]/[OH−] ratio ranges from 0.12 to 3.0 [2+, then reacts with hydroxide ion in the concrete pore solution, forming the transition product Fe(OH)2, which will be oxidized to Fe(OH)3. As corrosion time increases, dehydration of Fe(OH)2 occurs, leading to the formation of lepidocrocite (γ-FeOOH), which is the main rust phase at the initial stage of corrosion. Under a chloride-contaminated environment, another rust, akageneite (β-FeOOH), forms through unstable phase green rust, (3Fe(OH)2∙Fe(OH)2Cl∙nH2O). It was found that the structure of β-FeOOH was looser than γ-FeOOH, and β-FeOOH favored pitting corrosion, which would accelerate the corrosion of reinforcement [3O4). Corrosion products are composed of different oxides and oxyhydroxides with higher volumes than iron. Expansion due to conversion of iron to corrosion products can lead to cracking of cover concrete. The expansion can be better understood if the rust composition is known. Criado et al. [3O4, and maghemite (γ-Fe2O3) as corrosion products. The formation of rust phases is dependent on both steel materials and exposure conditions.The steel bar embedded in concrete is initially covered by a thin passive film of iron oxides . Chloridearchers ,19,20. T2 to 3.0 . The widorcement ,23. Undeo et al.  studied o et al.  tested sMuch laboratory work ,27,28 haIn the previous study on the steel corrosion embedded in concrete, most of the work has been carried out in the laboratory under accelerated conditions, due to the slow processes of corrosion under a natural environment. On the other hand, several studies which conducted field investigations revealed that the corrosion rate and compositions of corrosion products are caused by different corrosion patterns. However, the influence of different zones in the marine environment on chloride-induced corrosion has not been understood thoroughly. Chloride penetration in concrete and steel corrosion behavior have seldom been studied simultaneously in a real structure. The purpose of this study is to investigate the degradation of concrete and steel subjected to different zones in a real marine environment. The chloride profiles and steel corrosion were studied in the atmospheric and tidal zones for a 30-year-old concrete bridge in a marine environment in Shenzhen, China. Concrete microstructures were investigated by SEM and mercury intrusion porosimetry (MIP). Corrosion products of steel in the atmospheric and tidal zones were identified by XRD and Raman analysis.The aim of the research is to clarify the behaviors of chloride penetration and steel corrosion in a real marine environment. The chloride distribution in concrete, rust compositions, and morphology of embedded steel in a bridge will be tested. The tested bridge spans the entrance of a river into the Daya Bay on the Dapeng peninsula in the city of Shenzhen, China. The geographic location of the bridge is shown in Before the test, a thorough inspection of the bridge was carried out. Significant steel corrosion in most pier columns was detected by visual inspection. The steel corrosion in the bridge decks was also detected by a half-cell potential method, but corrosion degrees were not determined. By using a rebound method, the measured concrete strengths in piers and decks were 39.4 and 55.3 MPa, respectively. Regular reinforcing steel for steel bars in the RC structures was used in the bridge. For bridge piers, the average thickness of concrete covers for transverse and longitudinal reinforcements was 51.6 and 74.2 mm, respectively. For bridge decks, the average cover thickness for transverse and longitudinal reinforcements was 21.2 and 32.6 mm, respectively. By using phenolphthalein as an indicator, the measured carbonation depths for the pier and deck were 1.0 and 2.5 mm, respectively, which were well within the range of the concrete covers.The bridge is exposed to a typical marine environment and detailed environmental conditions are shown in Concrete and steel samples were obtained from the bridge to investigate chloride-induced steel corrosion. Two different bridge zones were considered: the atmospheric zone and the tidal zone. The bridge deck was considered for the atmospheric zone. Pier columns within a range of altitudes were subjected to periodic wetting and drying and were considered to be in the tidal zone.Ten concrete samples were cored out, with a diameter of 70 mm and a height of 50 mm. As shown in Concrete samples A1–A5 and T1–T5 were used to investigate the chloride distribution within the concrete in the atmospheric and tidal zones. Cylindrical concrete samples were ground to powder from the exposed surface to a depth of 16 mm at 1 mm intervals. From 16 to 30 mm, the samples were ground at an interval of 2 mm. The powders were oven-dried at 80 ± 5 °C for 6–8 h and cooled to room temperature in a desiccator.3) solution. The consumed volume of AgNO3 solution was recorded by an automatic potentiometer titrator  and was used to calculate the chloride content. The chloride content was expressed as the mass percentage of chloride ion in concrete. The chloride profile was obtained by plotting the chloride content against the corresponding depth from the exposed surface.According to the AASHTO T260-297 standard , the fred in the materials are filled with mercury at an applied pressure P. The pore diameter d corresponding to the applied pressure P is given by [γ is surface tension (480 mN/m) and θ is the contact angle between mercury and the pore wall (130°).The microstructure of concrete in different environmental zones can be obtained by using MIP and SEM techniques . MIP wasgiven by (1)d=−4γTested specimens for MIP were crushed particles with sizes of 10–15 mm from the concrete samples T1, T4, T5, and A1. The specimens were oven-dried at 60 °C for 24 h and then placed into the MIP instrument , which had a minimum detectable pore diameter of 6 nm. The applied pressure was increased stepwise to the highest level and the intruded volume of mercury was recorded at each step.SEM was used to study the microstructural morphology of concrete in different marine environmental zones by a device, the microscope S-3400N . The cover concrete from the bridge deck and pier columns was crushed to obtain small samples. The sample surfaces were polished and they were then oven-dried at 60 °C for 24 h. Before the SEM test, the sample was coated with a thin layer of gold to prevent charging. The microstructure of the steel rust from the steel samples was also tested by SEM.θ range of 5–80°, with a step width of 0.02° and a counting time of 0.2 s/step.XRD was used to analyze the phase composition of concrete and steel rust by a device . The samples A1 and T1 at a depth of 5 mm and the rust layers of the steel samples were ground to powders of sizes between 0.1 and 10 µm before the analysis. Generator settings were 40 kV and 40 mA, and XRD data were collected over a 2Raman spectroscopy is a non-destructive technique for characterization of various oxides and oxyhydroxides in steel rust ,38. It w2 (denoted as CH) grains and needle-like ettringite crystals were found. Samples T1–T3 exhibited a looser and more porous structure. By contrast, samples T4, T5, and A1 had more compact structures with well-distributed hydration products. XRD spectra of concrete samples A1 and T1 are shown in 2. CH was detected in A1 but not in T1. This result could possibly be explained by the leaching of solid CH in concrete subjected to flowing river water. CH leaching resulted in more pores and produced more passages for calcium ion diffusion towards the external water, which further promoted leaching [SEM micrographs of the concrete samples from the atmospheric and tidal zones are shown in leaching . AdditioMIP results for concrete samples from the piers and deck of the bridge are shown in Distributions of chloride ions within the concrete in the atmospheric and tidal zones are shown in The depth for the convection zone of the chloride profile is related to the influencing depth for water adsorption. The convection depth was defined as the distance from the exposed surface to the peak of a chloride profile. The results in The comparison of chloride profiles in 3A, C4AF, and their hydration products to form Friedel’s salt [The rate of chloride transport in concrete was influenced by the concrete’s microstructure. Chloride transport in concrete could also in turn influence its microstructure. In l’s salt . Chloridl’s salt  demonstrC is the chloride concentration (% of concrete by weight), and Dc is the chloride diffusivity (m2/s).It is widely believed that the chloride diffusion in concrete follows Fick’s law. Therefore, the chloride diffusion in a one-dimensional form can be expressed by the following Equation :(2)∂C∂t=Csa. Given the initial and boundary conditions for chloride concentration in Equations (3) and (4), the closed-form solution for Equation (2) can be obtained under an assumption of a semi-infinite solid [C is the chloride concentration at distance x from the surface at time t, Csa is the surface chloride concentration, and erfc is the complementary error function.The initial chloride concentration in the concrete is 0, and the boundary chloride concentration is set as te solid :(3)Cx,0=Csa and Dc, determine the evolution of chloride distribution within the concrete. These two parameters were obtained by fitting the diffusion part of the measured chloride profiles at the inner region based on Equation (3), as shown in In Equation (5), two key parameters, Csa in Csa was dependent on the exposure condition for the concrete samples. The surface chloride concentration on the bridge deck was significantly larger than that on the column. This is because the surface chloride on the deck was accumulated gradually from the deposition of airborne chloride, while the pier column was exposed to seawater. It was also found that Csa for the upstream column close to the river side was smaller than that for the downstream column close to the sea side. The coefficient of variability of the measured Csa for the bridge deck was 19.5% and that for the pier column was 21.2%. On the other hand, the coefficient of variability of the measured diffusivity for the bridge deck was 47.2% and that for the pier column was 70.0%. The results implied that the quality of the concrete in the same bridge was not uniform. Additionally, the variability for different structural elements was significantly different, which was also revealed by the results by Salta et al. [The estimated surface chloride concentration Sa and St, respectively) were obtained from the bridge, as shown in Sa, while the sample St corroded more severely and its surface was much rougher. On the outer surface of Sa, mostly black areas were seen, with some ochre rust. By contrast, more orange or ochre areas were found on the outer surface of St. Differently colored areas possibly imply different rust phases.Chloride transports from the ambient environment into concrete and reaches a steel bar surface. When the chloride content on the steel surface exceeds a critical value, the passive film of the steel is damaged and steel corrosion occurs. The samples of steel bars in the atmospheric zone and the tidal zone  method. The results in d et al.  also indThe porosity of concrete in a pier column facing upstream was greater due to the water impact and CH leaching. Concrete with a higher chloride content had lower porosity and a larger proportion of small pores.The convection zone depths of the chloride profiles were all in the range of 6–7 mm, except that the convection depths for the cracked concrete were 22–24 mm.The coefficients of variability of evaluated concrete chloride diffusivity for the bridge deck and the pier column were significantly different.The rust phases were primarily lepidocrocite and goethite in the atmospheric zone and lepidocrocite and maghemite in the tidal zone. This may imply that transformation of magnetite to maghemite occurred for a greater degree of corrosion.In this paper, the chloride distribution within concrete covers and the chloride-induced steel corrosion in a 30-year-old RC bridge exposed to a marine environment were investigated. This study enhances the understanding of chloride-induced steel corrosion under a natural condition. Based on experimental results, the following conclusions can be drawn:


Crack healing has been studied extensively to protect reinforced concrete structures from the ingress of harmful ions. Research examining the regain in the mechanical properties of self-healing composites has focused mostly on the computation of the healing ratio based on the measurement of the tensile and compressive strengths but with poor regard for the flexural performance. However, the regain in the flexural performance should also be investigated for design purposes. The present study performs flexural testing on reinforced concrete members using crushed clinker binder and aggregates as well as crystalline admixtures as healing agents. Healing ratios of 100% for crack widths smaller than 200 μm and 85% to 90% for crack widths of 250 μm were observed according to the admixing of clinker binder and aggregates. Water flow test showed that the members replacing binder by 100% of clinker achieved the best crack healing performance. The crack healing property of concrete improved to some extent the rebar yield load, the members’ ultimate load and energy absorption capacity and ductility index. The crack distribution density from the observed crack patterns confirmed the crack healing effect provided by clinker powder. The fine grain size of clinker made it possible to replace fine aggregates and longer healing time increased the crack healing effect. Reinforced concrete can deteriorate due to a variety of reasons among which the corrosion of reinforcing steel is a leading cause. Reinforced steel corrodes due to the ingress of harmful ions like chlorides and sulfates. Once steel starts to corrode, the resulting rust occupies a larger volume, which creates tensile stresses in concrete and eventually leads to cracking, delamination and spalling of concrete. In turn, such cracking of concrete accelerates the penetration of harmful ions that worsens the degradation of the reinforced concrete structure . ImplemeThe restless search for durability and resilience of concrete structures has led some researchers to focus on self-healing concrete composites with the built-in ability of repairing narrow cracks without human or external intervention ,3,4,5. TMost studies assessing the self-healing performance of concrete have focused on the recovery of durability through the evaluation of the crack filling ratio and the reduction of penetration ,26. The 2 and unhydrated cement to improve the self-healing ability of concrete [Considering the lifespan of the concrete structure and to be free of the exhaustion of the healing agent, this study pays attention to the autogenous healing. A recent study showed that the autogenous healing could be enhanced using GGBFS and crystalline admixture rather than using fly ash . The resconcrete . Moreoveconcrete  and Allaconcrete  reportedAccordingly, this study examines the autogenous healing of concrete containing clinker binder and aggregates as well as crystalline admixtures as healing agents. Crack healing effect is investigated through crack closing and water flow tests. In addition, even if the flexural behavior depends to a large extent on the steel reinforcement, bending tests are conducted on full-scale test members to investigate any eventual recovery in the flexural mechanical performance brought by the autogenous healing. For the tests, three different concrete mixes and four different loading and curing conditions were chosen as test variables. Cracking was induced by pre-loading the specimens at 28 days. The concrete mixes differ by the maximum particle size of the clinker powder replacing the binder and the aggregates. The curing conditions are air-dry curing for 28 days and additional water curing for 90 days. The loading conditions consider pre-loading and loading at 28 days, pre-loading at 28 days and loading at 28 + 90 days.The first stage of the investigation started with material test on the mortar mixes to be used later in the fabrication of the concrete specimens. The self-healing performance of pre-cracked mortar specimens was assessed by constant head water flow test  on sets V_28D series for the members at 28 days loaded until the ultimate state;PLRL_28D series for the members pre-loaded up to 50% of the ultimate load at 28 days followed by loading until the ultimate state;RL_28 + 90D series for the members pre-loaded up to 50% of the ultimate load at 28 days, followed by 90 days of water curing prior to loading until the ultimate state;V_28 + 90D series for the members loaded up to the ultimate load after 28 days and after 28 + 90 days.The three different concrete mixes listed in The combination of these test variables gives a total of 12 test members. The members were fabricated with the mixes presented in Strain gages were installed on the tensile and shear reinforcing bars before placing the concrete. Four strain gages were disposed on the tensile reinforcement with two sensors at mid-span and two sensors at 1/3 positions, that is at 600 mm in both sides from mid-span. Four strain gages were attached to the shear reinforcement with one sensor in each fourth and fifth shear rebar on the left and right-hand sides of the critical section at mid-span. The layout of the reinforcement strain gages is shown in As explained in The material test results of mortar and concrete are presented. The water flow test results are plotted in ckf, was measured on prismatic specimens at 28 days and 90 days later in compliance with KS L ISO 679. Similar levels of compressive strength were developed in all the mixes. The elastic modulus, cE, was measured as the slope of the linear 10–40% region in the stress–strain diagram using triaxial concrete strain rosette gages attached to the ϕ100 × 200-mm mold. Results similar to those of the compressive strength were obtained. The 0.85-mix series with a relatively meaningful binder replacement ratio by 0.85 mm of clinker exhibited the best physical properties. The slump and air content measured on fresh concrete are also indicated in bf, measured using the third-point loading method in compliance with KS F 2048. In The basic physical properties of the concrete mixes are presented in All the test members exhibited negligible difference in the crack, yield and ultimate loads apart from some slight variability. Moreover, all the test members failed through flexure. The number of vertical cracks observed in the test members ran between 10 and 15 with 11 cracks for member V_28D-2.5, 15 for member PLRL_28D-2.5, 14 for member RL_28 + 90D-2.5, 10 for member V_28 + 90D-2.5, 13 for member V_28D-0.85, 14 for member PLRL_28D-0.85, 12 for member RL_28 + 90D-0.85, 15 for member V_28 + 90D-0.85, 13 for member P-PLRL_28D, 14 for member P-RL_28 + 90D, and 13 for member P-V_28 + 90D. The crack pattern after the flexural test of the test members is shown in The enlarged images of the cracks reveal that the 0.85-series members replacing binder by 100% of clinker achieved the best crack healing performance. The 2.5-series members replacing each binder and aggregates by 50% of clinker exhibited crack healing performance in-between that of the P-series members without clinker and that of the 0.85-series members.An attempt to objectively quantify the crack healing effect is achieved by measuring the crack distribution density from the observed crack patterns shown in A closer look reveals that, for the 0.85-series members, the RL-series members that suffered pre-damage exhibit relatively smaller crack density than the V-series members which did not experience pre-damage. Besides, the opposite occurs for the P-series and 2.5-series members. This situation can be credited to the fact that, compared to the 2.5-series members, the 0.85-series members exhibit a strong healing effect for cracks thinner than 200 μm, which reduces the number of cracks, but does not heal wider cracks, which experience crack opening under reloading. This phenomenon becomes more acute in older members. According to the studies by Sunayana and Barai  and SturThe crack healing effect was also examined by water flow test. The results of the water flow test are arranged in The results arranged in The present study examined the effect of self-healing on the flexural behavior of reinforced concrete members. The considered healing agents were clinker binder and aggregates as well as crystalline admixtures. A total of 12 test members were fabricated with respect to 3 different concrete mixes and 4 different loading and curing conditions. The following conclusions can be drawn from the experimental results.The utilization of mineral admixtures was seen to improve the self-healing performance of mortar. Especially, healing ratios of 100% for crack widths smaller than 200 μm and 85% to 90% for crack widths of 250 μm were observed according to the admixing of clinker binder and aggregates. All the considered mixes exhibited similar results in terms of the compressive strength, elastic modulus and flexural strength. The series with a relatively meaningful binder replacement ratio by 0.85-mm clinker exhibited the best physical properties.A negligible difference was observed in the crack, yield and ultimate loads. Failure occurred through flexure with a similar number of vertical cracks. All the test members showed linear load-deflection relationship until the initiation of cracks followed by a nonlinear increase in the deflection beyond the crack initiation and the load continued to increase until the ultimate load. For the test members cured additionally for 90 days after 28 days, the ultimate deflection reached more than 100% of that of the members loaded after 28 days of curing due to the plastic deformation caused by the yield of the rebar and the aging.Rebar strain practically did not occur prior to the initiation of cracks and grew linearly after cracking to experience a large increase after yielding. The ultimate concrete strain in the members loaded up to the ultimate load at 28 days reached 0.0030 but that in the members that were additionally cured for 90 days after 28 days reached 0.0040 due to the aging and the effect of residual deformation.The maximum crack width observed after 90 days of additional curing ranged between 0.019 and 0.053 mm. These values can be attributed to various factors like crack closure following the removal of loading as well as crack healing. The enlarged images of the cracks revealed that the 0.85-series members replacing binder by 100% of clinker achieved the best crack healing performance. The 2.5-series members replacing each binder and aggregates by 50% of clinker exhibited crack healing performance in-between that of the P-series members without clinker and that of the 0.85-series members. This observation was confirmed by the results of the water flow test performed on the test members.In terms of mechanical performance, the crack healing property of concrete increased, to some extent, the rebar yield load, the members’ ultimate load and energy absorption capacity and ductility index. However, this effect appeared to be minimal when considering the increase in the energy absorption capacity brought by the age and the larger displacement sustained during reloading caused by the plastic deformation induced by pre-damage.An attempt to objectively quantify the crack healing effect by measuring the crack distribution density from the observed crack patterns was performed and this confirmed the crack healing effect provided by clinker powder.Finally, the fine grain size of clinker made it possible to replace fine aggregates and the longer healing time increased the crack healing effect.


Tensile creep is an important factor affecting the early cracking resistance of concrete. The tensile creep model can effectively predict the development of tensile creep. In order to establish an appropriate tensile creep model, a temperature–stress testing machine (TSTM) was employed to test the development of temperature, deformation and restraint stress of benchmark concrete and concrete mixed with the MgO under different temperature curing modes. The development law of early age stress, strain and creep was analyzed via the test data of the TSTM. The early age tensile creep of concrete was predicted with the existing Kelvin creep model. The effect of variable temperature on creep was considered in this study, and an improved Kelvin creep model was proposed. The prediction accuracy of the two models was compared and analyzed. The results indicate that MgO has little influence on the creep and specific creep of concrete. The early age cracking resistance of MgO concrete is better than benchmark concrete. The improved Kelvin model based on the microprestress-solidification (MPS) theory predicts the early tensile creep of concrete more accurately in variable temperature conditions. These are significantly helpful for the application of the MgO expansion agent in dam engineering. By adjusting the calcination temperature and holding time, the delayed expansion effect can be matched with the temperature shrinkage history of mass concrete, which can be used to compensate for the shrinkage deformation of mass concrete [2 growth and (ii) expansion pressure caused by very small Mg(OH)2 crystal water absorption. Chatterji [2+ and OH− would first form and then an Mg(OH)2 crystal would precipitate and grow in a confined region, resulting in crystal growth pressure, which leads to the expansion of the cement pastes. After more than 30 years of theoretical and practice research on MgO expansion agents in China, MgO expansion agents have been applied to more than 50 dam projects.The easy cracking property of concrete at an early age is always an issue in engineering. One of the effective methods to control the concrete cracking at early ages is to add an expansion agent ,2. Usingconcrete . At preshatterji  indicateCreep is an inherent property of concrete. The creep of restrained concrete members can relax the most tensile stress, which reduces the concrete’s early cracking risk ,9,10,11.Creep has a great influence on the deformation and mechanical properties of concrete. Based on creep testing, many scholars suggest various creep prediction models and improved models at early stages. At present, the most widely used tensile creep model is the B3 model ,14,15. TThe benchmark concrete was called BC concrete for short. The MgO expansive agent was added to the benchmark concrete to obtain the expansion-agent concrete (EC). Under the temperature matched curing (TMC) mode and the constant temperature curing (CTC) mode, a temperature–stress testing machine (TSTM) was used to test the early stress and strain development of the two concretes in the restraint state. Based on the TSTM method of evaluating creep strain suggested by Kovler, the rules of tensile creep and specific creep were calculated and analyzed . AccordiThe BC concrete refers to the construction mix proportion of the slab concrete of rockfill dam. The EC concrete is the benchmark concrete mixed with the expansion agent. The mix proportions are shown in Raw materials: The cement used in this study was P.O 42.5 ordinary Portland cement. The fly ash was Class F I fly ash. The chemical composition of cementitious materials is listed in 3, 1.70% and 44%, respectively. The mixture design used two coarse aggregate gradation. The small gravel with a 5–20 mm particle size accounted for 45% of the total coarse aggregate by mass. The medium gravel with a 20–40 mm particle size accounted for the other 55%. The apparent density and absorption of small gravel was 2620 kg/m3 and 0.61%, respectively. For medium gravel, the corresponding values were 2620 kg/m3 and 0.88%, respectively. The voids of mixed coarse aggregate totaled 38%.The fine and coarse aggregates were artificial gravel. Fine aggregate with a fineness modulus of 2.97 was employed. The apparent density, absorption and voids of sand was 2630 kg/mPolycarboxylate high-performance water-reducing agent and air-entraining agent produced by Changan Yucai were used in this study. A certain M-type MgO expansion agent was used in the test. The performance indicators of the M-type MgO expansion agent are shown in TSTM shown in  was emplThe temperature–stress test used two dog-bone-shaped specimens: one was a restrained specimen, and the other was a free specimen. The free and restrained specimens maintained the same temperature-curing histories, and both were enfolded with a plastic film, to prevent moisture exchange with the outside. Hence, the drying shrinkage of the concrete could be ignored . The TMCDuring the TST, the computer recorded the temperature histories, free deformation strain (free strain) of the free specimen and restraint stress of the restrained specimen . Figure As shown in In the cooling phase, because concrete specimens under two modes were not broken at the lowest temperature of the TSTM, both were manually pulled off by the motor. The cracking stress of the TMC mode and CTC mode of the BC was −2.00 and −1.71 MPa, respectively; the cracking stress of the EC was −2.29 and −1.99 MPa, respectively. Combined with εth, ∆εau, ∆εcr and ∆εce are thermal strain, autogenous strain, creep strain and elastic strain for each compensation cycle, respectively. εth(t), εau(t), εcr(t) and εce(t) are the evolution of thermal strain, autogenous strain, creep strain and cumulative elastic strain, respectively, namely the accumulation of ∆εth, ∆εau, ∆εcr and ∆εce for every compensation cycle. εf(t) is free strain and equal to the sum of εth(t) and εau(t) as the restrained specimen and free specimen experienced the same curing temperature history.The method of evaluating creep strain was suggested by Kovler . He propAs shown in As shown in In summary, the autogenous shrinkage of concrete mixed with MgO was compensated in the temperature stress test, which delayed the appearance of tensile stress and increased the cracking stress . CorrespCombined with the measured data of the TST, the theoretical formula of the Kelvin model  under coE(ξ) is the modulus of elasticity based on the degree of hydration; εe is the strain of the elastic unit; E∞ represents the final modulus of elasticity; ξ(t) is the degree of hydration of the concrete at time t; ξ0 is the permeability threshold, generally taken as 0.1 [ξ∞ represents the final degree of hydration; and <·>+ represents the absolute value.The elastic unit:n as 0.1 , and we σ is the stress; σik and σηi are the stress of the elastic unit and viscous unit of the i Kelvin unit; εik is the strain of the i Kelvin unit; and ki(ξ) and ηi(ξ) are the function of the stiffness coefficient and viscosity coefficient of the i Kelvin unit with the development of hydration, and the value can be taken as follows [τi is the delay time of the i Kelvin unit and should meet a certain relationship [τ1 = 0.1 d, τ2 = 1 d and τ3 = 10 d.The Kelvin units: follows :(6){ki(ξtionship . In thisηa(t) is the viscosity coefficient of the viscous unit, εa is the strain of the viscous unit, α is the coefficient of microcrack influence and ka is a constant.The viscous unit:The constitutive equation of units is as follows:Combining with the slab concrete strain development of the TST, we show the discretized strain increment in Formula (8):The elastic strain increment obtained from Equation (4) is as follows:i = 1, 2, 3; The strain increment of the Kelvin units is obtained from Equations (5) and (6), as follows, where From Equation (7), the strain increment of the viscous unit is as follows:For the improved Kelvin model, it is necessary to know the development history of stress and the degree of hydration and the calculation parameters of the model. We then obtain the tensile creep development of the slab concrete under restraint by iterative calculation of Formula (8).Creep models are generally established under the constant temperature history. However, for the TST, because of the variable temperature with age, the accuracy of the prediction was affected.εa is the strain of the viscous unit; η(S) is the viscosity coefficient of the viscous unit; and 1/η(S) = cbSb−1, with c as the regression coefficient and b as 2 [Cs is spring of stiffness; and According to the relationship between temperature and creep mentioned in Bazant’s microprestress-solidification (MPS) theory , we imprd b as 2 ; S(t) iss1 is a constant; C1 is a constant; R is the gas universal constant; M is the molecular weight of water; T is the absolute temperature; and h(t) is a function of humidity with time. The following formula is obtained by taking the derivative of Equation (13) with time.Since the distances of water diffusion between the adjacent micropores and capillary pore are very short, the adsorbed water can establish thermodynamic equilibrium with the capillary water fast. Thus, it is assumed that all water phases locally are in thermodynamic equilibrium. This assumption follows the principle that Kelvin’s capillary equation is equal to the chemical potential in thermodynamics . That isBy substituting Equation (14) into Equation (12), the microprestress formula for variable humidity and variable temperature is obtained as follows.In this study, the concrete specimens were wrapped with plastic film, to prevent moisture exchange with the outside world. The humidity remains unchanged, so From Equation (16), the strain increment of the viscous unit is as follows:For the calculation of the Kelvin model, it was necessary to gain the degree of hydration curves of cementitious concrete materials at an early age. The degree of hydration curves could be calculated from the hydration heat. Based on the China National Standard GB/T12959-2008 , we adopBased on the least square method, the parameters of the tensile creep model were determined by analyzing the smallest difference between the model calculations and the actual measurements under the TMC mode. The calculation parameters of the Kelvin tensile creep model and improved model parameters based on MPS are shown in In order to check the accuracy of the model, the measured free strain of the early age concrete under the CTC mode was compared with the corresponding free strain prediction of the tensile creep model determined by the above parameters, as In order to reflect the accuracy of the model prediction more objectively, the maximum absolute value of the difference between the measured value and the predicted value was compared with the maximum measured value to obtain the maximum deviation ratio. As shown in The accuracy of the improved model was tested with the method mentioned in As shown in Comparing the two models, we see the maximum deviation ratio of the BC is reduced from 12.3% to 8.8%, and the ratio of EC is reduced from 13.3% to 9.3%. This proves that the improved model based on MPS theory is more accurate in the prediction of tensile creep.In this study, the used expansive agent reduced shrinkage of slab concrete, delayed the appearance of the tensile stress and increased the cracking stress simultaneously, thus resulting in being beneficial to cracking resistance. The MgO expansion has little effect on creep and specific creep of concrete. In summary, the concrete mixed with MgO had better early age cracking resistance than the benchmark concrete.Two tensile creep models were proposed to predict the tensile creep development of slab concrete at early age accurately.Compared with the Kelvin creep model, the improved tensile creep model considering temperature variation has an obvious improvement in prediction accuracy. It preferably predicts the development of the early age tensile creep of slab concrete under variable temperature.