The increase of antimicrobial resistance, mainly due to increased antibiotic use, is worrying. Preliminary evidence suggests that antibiotic use differs across ethnic groups in the Netherlands, with higher use in people of non-Dutch origin. We aimed to determine whether appropriate knowledge and use of antibiotics differ by ethnicity and whether knowledge on antibiotics is associated with antibiotic use.We performed a cross-sectional study analyzing baseline data (2011–2015) from a population-based cohort (HELIUS study), which were linked to data from a health insurance register. We included 21,617 HELIUS participants of South-Asian Surinamese, African-Surinamese, Turkish, Moroccan, Ghanaian, and Dutch origin. Fifteen thousand seven participants had available prescription data from the Achmea Health Data-base (AHD) in the year prior to their HELIUS study visit. Participants were asked five questions on antibiotic treatment during influenza-like illness, pneumonia, fever, sore throat and bronchitis, from which higher versus lower antibiotic knowledge level was determined. Number of antibiotic prescriptions in the year prior to the HELIUS study visit was used to determine antibiotic use.The percentage of individuals with a higher level of antibiotic knowledge was lower among all ethnic minority groups (range 57 to 70%) compared to Dutch (80%). After correcting for baseline characteristics, including medical conditions, first-generation African Surinamese and Turkish migrants received a significantly lower number of antibiotic prescriptions compared to individuals of Dutch origin. Only second-generation Ghanaian participants received more prescriptions compared to Dutch participants . Higher level of antibiotic knowledge was not significantly associated with the number of prescriptions .Levels of antibiotic knowledge varied between ethnic groups, but a lower level of antibiotic knowledge did not correspond with a higher number of antibiotic prescriptions. The emergence of antimicrobial resistance, along with the steady decline in antibiotic development, has been identified as a major health threat for the coming decade by the World Health Organization (WHO). Increase in antibiotic use is the main reason for this development  and as sA recent meta-analysis showed a higher prevalence of antimicrobial resistance among migrants in Europe . There iThe HELIUS  study is a large-scale, population-based cohort study among different ethnic groups, which was established with the aim to investigate mechanisms underlying the impact of ethnicity on communicable and non-communicable diseases , 9. In 2This study then provides a unique opportunity to determine whether knowledge about and use of antibiotics vary between ethnic groups, and if so, whether differences in antibiotic use can be attributed to differences in knowledge about antibiotics. We hypothesized that antibiotic use differs among ethnic groups as a result of differences in knowledge.The HEalthy LIfe in an Urban Setting (HELIUS) study is a multiethnic cohort study conducted in Amsterdam, which focuses on cardiovascular disease (e.g. diabetes), mental health (e.g. depressive disorders), and infectious diseases , 9. In bEthnicity was defined according to the country of birth of the participant as well as that of their parents . SpecifiPermission to link participants’ individual data to outside health registries was asked in the written informed consent form . Of the Of the 22,165 participants, we excluded those of Javanese Surinamese or other/unknown Surinamese origin and those with another/unknown ethnic origin because of small participant numbers. For analyses on antibiotic use, we included those who gave permission for data linkage and could be linked to the AHD. To reduce bias for individuals with short-term insurance, we excluded those who were insured with Achmea for less than 365 days in the year preceding their HELIUS study visit.The primary outcomes were level of antibiotic knowledge and antibiotic use during the year prior to the HELIUS visit. Level of antibiotic knowledge was based on five questions, used in other studies , 6, 14, Antibiotic use was obtained from linked AHD data and was based on the total number of reimbursed antibiotics  dispensed by community pharmacies from 2010 until 2015. We evaluated antibiotic use (yes/no) in the year prior to the HELIUS study visit, as well as the number of antibiotic prescriptions over the past year and during the entire insured period.2)). Variables on antibiotic-related behavior were: not having finished antibiotic treatment; having saved antibiotics for later; and ever having asked the general practitioner (GP) for antibiotics. Definitions and grouping of variables are extensively described elsewhere [Independent variables were obtained from the HELIUS study questionnaire  and physical examination  comparing levels of antibiotic knowledge across determinants and their 95% confidence intervals (CI) were estimated using logistic regression. All variables with an associated Analysis on antibiotic use in the year prior to HELIUS study visit included all HELIUS participants who were linked to the AHD and were insured for at least 365 days with Achmea in the year prior to their HELIUS study visit. Determinants for having received ≥1 antibiotic prescription were assessed using logistic regression. The same multivariable approach as above was used for this outcome. We also compared antibiotic use during the entire period insured at Achmea versus the year prior to HELIUS study visit to assess differences when considering longer time periods.p-value < 0.2 in univariable analyses and variables above this p-value were removed in backwards-stepwise fashion. Incidence risk ratios (IRR) comparing the number of antibiotics prescribed over the past year across levels of determinants were estimated from this model.Determinants for the total number of antibiotic prescriptions were then evaluated. As this outcome contained a high proportion of zero values and was over-dispersed, we used a zero-inflated negative binomial regression model. This model contains two parts: one accounting for zero values in the count distribution (zero-inflated) and another accounting for the over-dispersed count distribution . Covariates for the zero-inflated part were determined a priori from the risk-factor analysis on ≥1 antibiotic prescription. Covariates for the negative binomial part were selected from covariates with a Multicollinearity was verified using variance inflation factors, while any variable with an inflation factor of ≥4 was considered multicollinear and excluded from the model. To understand whether the association between ethnicity and outcome was modified by demographic variables, interaction between ethnicity and other demographic variables was also assessed in all multivariable models.The three variables involving antibiotic-related behavior were not initially considered in the final multivariable models. To assess whether ethnic differences in antibiotic use could be explained by patterns of antibiotic-related behavior, additional multivariable models including these variables were constructed for the endpoints (i) having received ≥1 antibiotic prescription and (ii) total number of antibiotic prescriptions.p-value < 0.05. All analyses were conducted with Stata 13.1 .Figure Of the 22,165 HELIUS participants with available data, 21,617 were eligible after applying exclusion criteria. Their baseline characteristics, stratified by ethnicity, are shown in Table In several ethnic groups, there were substantial proportions of individuals reporting the need to be treated with antibiotics for illnesses without indication, as shown in Table p < 0.001) (Table As shown in Table 1) Table . Across p < 0.001), although the effect for second-generation Ghanaian participants was not statistically significant. The odds for higher level of antibiotic knowledge were higher in all age groups > 25 years of age (except for those ≥65) when compared to ≤25 years of age. Furthermore, women had a significantly higher odds of having a higher level of antibiotic knowledge compared to males. Lower odds for a higher level of antibiotic knowledge were found for the following medical conditions: myocardial Infarction (MI), severe or chronic fatigue, respiratory diseases and having a BMI ≥25. Lower odds for higher level of antibiotic knowledge were also seen among individuals who regularly or occasionally requested antibiotics from their GP or who regularly or occasionally did not finish treatment.In multivariable analysis, all ethnic minority groups had lower odds for higher level of antibiotic knowledge compared to Dutch . Of these 15,461 participants, 15,007 (97%) were insured for ≥365 days in the year prior to their HELIUS study visit. Additional file Table When considering the entire period during which participants were insured at Achmea prior to the HELIUS study visit , the proportion of participants receiving ≥1 antibiotic prescription was highest among first generation Turkish participants (69%) and lowest in second-generation Ghanaian participants (49%). The mean number of prescriptions during the entire insured period was comparable to the mean number of prescriptions in the year prior to HELIUS study visit for all ethnic groups Table .p < 0.001) and multivariable analysis (p < 0.001). In multivariable analysis, compared to Dutch individuals, first and second generation Ghanaian individuals and first-generation Moroccan individuals had significantly higher odds of receiving ≥1 antibiotic prescription. Adding variables on antibiotic-related behavior and level of antibiotic use knowledge to the multivariable model did not change these associations.Table p = 0.004). First-generation African Surinamese and Turkish migrants had a significantly lower number of antibiotic prescriptions compared to individuals of Dutch origin. Only second-generation Ghanaian participants has more prescriptions compared to Dutch participants. Furthermore, female sex, diabetes mellitus, MI, malignant disorder, respiratory disease, eczema and worse perceived health were significantly associated with a higher number of antibiotic prescriptions.Table p = 0.446). No significant interactions between ethnicity and sex or education were observed. Finally, adjusting the association between ethnicity and antibiotic use for antibiotic-related behaviors did not change these associations.Having a higher level of antibiotic knowledge was not significantly associated with the number of prescriptions when included in multivariable analysis  of the study population.Our study has also limitations. First, although HELIUS participants were recruited via an ethnicity-stratified random selection of the municipal registry of Amsterdam, the response rate for HELIUS study was 28% and there may be selection bias , 16–18, To our knowledge, this study is the first to examine ethnic disparities in level of antibiotic knowledge and use in a large population-based sample among adults with different ethnic backgrounds. Health policy makers and healthcare professionals are increasingly developing interventions to improve the quality of antibiotic use, which is needed to help contain antimicrobial resistance. Targeted campaigns can be considered, for instance, during the annual European Antibiotic Awareness Day, since this event addresses improvement in the quality of antibiotic use to the general public . Still, Additional file 1. Supplementary Methods.Additional file 2:Table S1. Characteristics of participants not linked versus linked to the Achmea Health Database.


AIDS‐related deaths in people living with HIV/AIDS have been decreasing in number since the introduction of combination antiretroviral treatment (cART). However, data on recent causes of death in the Asia‐Pacific region are limited. Hence, we analysed and compared AIDS‐related and non‐AIDS–related mortality in high‐ and low‐income settings in the region.Patients from the TREAT Asia HIV Observational Database (TAHOD) and Australian HIV Observational Database (AHOD) receiving cART between 1999 and 2017 were included. Causes of death verification were based on review of the standardized Cause of Death (CoDe) form designed by the D:A:D group. Cohorts were grouped as AHOD , TAHOD‐high (high/upper‐middle income countries) and TAHOD‐low (lower‐middle income countries). TAHOD sites were split into high/upper‐middle income and lower‐middle income country settings based on World Bank classifications. Competing risk regression was used to analyse factors associated with AIDS and non‐AIDS–related mortality.p < 0.001). Similarly, incidence rates of AIDS‐related deaths decreased from 0.51/100 PYS to 0.09/100 PYS from year groups 2003 to 2007 to 2013 to 2017 (p < 0.001). More recent years of follow‐up were associated with reduced hazard for non‐AIDS mortality (2008 to 2012: aSHR (adjusted sub‐hazard ratio) 0.72, 95% confidence interval (CI) 0.54 to 0.96, p = 0.027; 2013 to 2017: aSHR 0.64, 95% CI 0.47 to 0.87, p = 0.004) compared to years 2003 to 2007. The AHOD cohort had almost twice the hazard of non‐AIDS mortality compared to TAHOD‐low (lower‐middle income sites) ; there were no differences between cohorts for AIDS‐related mortality (p = 0.834).Of 10,386 patients, 522 died; 187 from AIDS‐related and 335 from non‐AIDS–related causes. The overall incidence rate of deaths during follow‐up was 0.28 per 100 person‐years (/100 PYS) for AIDS and 0.51/100 PYS for non‐AIDS. Analysis indicated that the incidence rate of non‐AIDS mortality decreased from 0.78/100 PYS to 0.37/100 PYS from year groups 2003 to 2007 to 2013 to 2017 (AIDS and non‐AIDS–related mortality rates have decreased over the past years in the Asia‐Pacific region. There is a greater risk for non‐AIDS–associated deaths in the AHOD cohort compared to lower‐middle income settings in TAHOD. The objective of this study was to investigate the incidence rates of AIDS‐related and non‐AIDS–related deaths, and identify factors associated with different causes of death (COD) across country income levels in the Asia‐Pacific region during the cART era.22.1This analysis includes both Australian HIV Observational Database  and the TREAT Asia HIV Observational Database (TAHOD) enrolled patients who started cART and attended at least one subsequent follow‐up visit. The AHOD and TAHOD are observational clinical cohort studies of patients with HIV infection in Australia and New Zealand (AHOD) and 12 countries  in Asia and the Pacific region (TAHOD), whose methods have previously been described The start date (baseline) for cART was defined as the date patients started their first triple regimen. Those who used mono/dual therapy prior to starting cART were excluded. Cohorts were grouped as AHOD , TAHOD‐high (high/upper‐middle income countries) and TAHOD‐low (lower‐middle income countries). TAHOD sites were split into high/upper‐middle income and lower‐middle income settings (there are no low‐income sites in TAHOD) based on World Bank classifications 2.22.2.1Proportions of AIDS‐related and non‐AIDS–related mortality were analysed descriptively. Calendar years were categorized into ≤2007, 2008 to 2012 and 2013 to 2017. The denominator used to calculate each proportion was the total number of deaths in each year group. Mortality rates for different causes of deaths were also examined. The proportions and mortality rates were plotted across calendar years of follow‐up. Unknown causes of death were plotted as a separate group to allow for visual inspection of the reported cases of non‐AIDS causes of death.2.2.2Fine and Grays’ competing risk regression model was used to analyse factors associated with AIDS‐related and non‐AIDS–related mortality. The resulting sub‐hazard ratio (SHR) can be interpreted in a similar way to the hazard ratio. Follow‐up time began from cART initiation and left truncated at cohort entry for those who entered the cohort after starting cART. Left truncation minimizes survival bias by taking into account survival time prior to cohort entry in those who had initiated cART before enrolment into the cohort. The earliest year of follow‐up started in 1999 for AHOD and 2002 for TAHOD. While follow‐up time ended at date of death for patients who experienced mortality, all other patients were censored on their date of last follow‐up. Both AHOD and TAHOD cohorts had their last follow‐up date in year 2017. Other causes of death and loss to follow‐up (LTFU) p < 0.10 were fitted in the multivariate model using backward stepwise selection process. Covariates with p < 0.05 in the multivariate model were considered significant. A sensitivity analysis was performed by including age as a time‐updated covariate, and adjusting for age, sex and CD4 cell count in the final multivariate model.With the exception of cohort groups, covariates in the univariate analysis with Ethics approvals for TAHOD were obtained from the respective local ethics committees of all participating sites, the data management and biostatistical centre at the Kirby Institute  Human Research Ethics Committee), and the coordinating centre at TREAT Asia/amfAR. Written informed consent was sought in TAHOD if required by a site's local institutional review board. All TAHOD data transfers are anonymized prior to submission to the Kirby Institute. Ethics approval for AHOD was obtained from the respective local ethics committees of all participating sites and the UNSW Human Research Ethics Committee; written informed consent was obtained from all participants. All data management and statistical analyses were performed using SAS software version 9.4  and Stata software version 14.2 .3A total of 10,386 patients who had initiated cART and were in follow‐up between years 1999 and 2017 were included in the study. With a median follow‐up time of 6.0 years, 522 patients  experienced AIDS or non‐AIDS mortality: 187 died from AIDS‐related (incidence rate of 0.28 per 100 person‐years (PYS)) and 335 died from non‐AIDS–related causes (0.51/100 PYS)  29 to 40], 41 years [IQR 34 to 51] in the TAHOD‐high group and 42 years [IQR 35 to 53] in AHOD. Ninety‐five per cent of patients in AHOD were men compared with 81% and 75% in TAHOD‐high and TAHOD‐low income groups respectively. Heterosexual contact was the primary route of HIV exposure in TAHOD‐high and TAHOD‐low income sites (67%), whereas men who have sex with men (MSM) was the most common HIV exposure in the AHOD sites (70%). Median baseline CD4 cell counts were 61 cells/μL [IQR 20 to 154] in the TAHOD‐low group, 59 cells/μL [IQR 19 to 164] in the TAHOD‐high group and 210 cells/μL [IQR 87 to 350] in AHOD. Baseline HIV RNA were 190,000 copies/mL  in the TAHOD‐low group, 140,000 copies/mL  in the TAHOD‐high group and 110,000 copies/mL  in AHOD. (Table p = 0.196). In contrast, the TAHOD‐high and AHOD cohorts demonstrated a significant difference in the proportions of AIDS, non‐AIDS and unknown causes of deaths over all year groups . Figure p = 0.001; AHOD: p < 0.001), the decrease across all year groups in TAHOD‐high cohort was not significant (TAHOD‐high: p = 0.169). Non‐AIDS mortality decreased with statistical significance across all year groups in all cohorts . Non‐AIDS mortality decreased at a slower rate compared to AIDS‐related deaths in TAHOD‐high (p = 0.039) and AHOD (p = 0.035) cohorts. In the TAHOD‐low cohort, the rate of decrease between the incidence of AIDS mortality and non‐AIDS mortality was not significant (p = 0.071). A greater decrease in the incidence of non‐AIDS mortality was shown in AHOD compared to TAHOD‐high (p = 0.009) and TAHOD‐low (p = 0.026) cohorts.Figure p < 0.001), HCV co‐infection (p = 0.027), cohort group (p < 0.001), diabetes (p = 0.014), BMI, CD4, RNA and calendar year  were associated with AIDS‐related mortality. In multivariate analysis adjusting for cohort groups, factors associated with AIDS‐related mortality were higher viral load  compared to HIV RNA ≤400 copies/mL ; and high blood glucose . Factors showing protective effects were CD4 count >200 cells/μL  compared to CD4 ≤ 100 cells/μL; and higher BMI (overweight) patients  compared to patients who were in the normal BMI range of 18.5 to 24.9. Calendar year was not statistically significant in the multivariate model; however, incidence rates of AIDS‐related deaths decreased from 0.51/100 PYS to 0.09/100 PYS in year groups from 2003 to 2017.The incidence rate of AIDS‐related mortality during follow‐up was 0.28/100 PYS Table . Univarip = 0.039; 41 to 50 years: aSHR = 1.58, 95% CI 1.10 to 2.27, p = 0.013; and >50 years: aSHR = 4.43, 95% CI 3.15 to 6.25, p < 0.001) compared to age ≤30 years; HBV co‐infection ; HCV co‐infection ; high blood glucose ; and AHOD cohort  compared to TAHOD‐low. Non‐AIDS mortality was less likely in females ; higher BMI  compared to normal weight range (BMI of 18.5 to 24.9); and later calendar years of follow‐up  compared to year group 2003 to 2007. Higher CD4 count  compared to CD4 ≤ 100 cells/μL was also associated with lower non‐AIDS mortality. However, since the multivariable models were adjusted for time‐updated CD4 count and viral load, changes over time in the rate of non‐AIDS mortality are not entirely explained by CD4 count and viral load.The incidence rate of non‐AIDs–related mortality during follow‐up was 0.51 per 100 PYS Table . FactorsTables 4In our cross‐regional observational cohorts who received cART, the overall incidence rate of mortality over a median follow‐up time of 6.0 years was 0.28/100 PYS from AIDS‐related and 0.51/100 PYS from non‐AIDS–related causes. Moreover, incidence rates for AIDS‐related and non‐AIDS–related mortality have decreased over the years with the AHOD cohort showing higher hazard for non‐AIDS deaths compared to TAHOD‐low sites.With the introduction of cART, AIDS‐related death has decreased followed by an increase in non‐AIDS death In a Swiss HIV cohort study, AIDS‐related death was highest in 1992  and decreased to 0.211/100 PYS (95% CI 0.122 to 0.363) in 2010 HIV‐infected patients are prone to increased risk of cancer, and an estimated 30% to 40% of patients will develop cancer during their lifetime Cardiovascular events associated with lower CD4 cell counts were suggested in both the Strategies for Management of Antiretroviral Therapy (SMART) and D:A:D studies There are several limitations to our study. Information on patient adherence data is not collected in AHOD and it is possible that poor patient compliance or adherence may have been a reason for AIDS death. The delay in reporting in the causes of death in AHOD may lead to incomplete COD ascertainment and underestimation of the AIDS and non‐AIDS causes of death. However, the majority of the unknown causes of death would be traced at a later date. While TAHOD represents a primarily urban referral patient population, crossing from low to high country income categories, it is less representative of national‐level data. There is also the risk of unascertained mortality among those with LTFU.5We observed that the rates of AIDS‐related and non‐AIDS‐related mortality in our Asia‐Pacific cohorts have decreased over the past years. Factors associated with increased risk of AIDS‐related mortality were higher viral load, high blood glucose, low CD4 cell count and low BMI. Older age, hepatitis B and C co‐infection, high blood glucose, low CD4 cell count and BMI were associated with increased non‐AIDS death. Blood glucose levels, CD4 cell count and being underweight were risk factors for both categories of deaths. The higher risk for non‐AIDS–associated deaths in the AHOD cohort compared to the lower‐middle income setting in TAHOD may be related to older age and higher per cent of reporting number of deaths. The slower rate in the decline of non‐AIDS deaths and the higher proportions of non‐AIDS deaths still persisting over AIDS‐related deaths demonstrate that longer lifespans contribute to increased risk of developing cancers and other conditions more common with older age, resulting in more deaths from non‐AIDS causes.None of the authors have competing interests to declare.JYC contributed to conceptualization and design of the study; IYJ wrote the first draft of the manuscript and interpreted the results; DR contributed to acquisition of data, data analysis and interpretation; IW, CO, MG and IA contributed to editing of the article; all authors have read and approved the final manuscript.Table S1. Factors associated with AIDS mortality in the TREAT Asia HIV Observational Database and Australian HIV Observational Database cohorts with age as a time‐dependent covariate including age, sex and CD4 in the multivariate modelaTable S2. Factors associated with non‐AIDS mortality in the TREAT Asia HIV Observational Database and Australian HIV Observational Database cohorts with age as a time‐dependent covariate including age, sex and CD4 in the multivariate modelaClick here for additional data file.


Antibiotic prescriptions for lower respiratory tract infections occur commonly in primary care but there is uncertainty about the most effective initial treatment strategy. Both increasing antimicrobial resistance and awareness of preventable harm from medicines make resolving this uncertainty a priority. Pragmatic, real-life epidemiological investigations are needed to inform future interventional studies.In this cross-sectional database study we analysed antibiotic prescriptions for non-pneumonic, lower respiratory tract infections (LRTI) in primary care as captured in the Optimum Care Database from 1984 to 2017. The primary outcome was a second antibiotic prescription for a LRTI code within 14 days of index prescription, the secondary outcome further antibiotic prescription for any indication. Only individuals without chronic respiratory diseases were included. We conducted univariable analysis to identify factors associated with repeat prescriptions and generate hypotheses for forthcoming projects.p < 0.001). This would support current prescribing practice for amoxicillin as index drug in those without respiratory disease. Prospective studies are needed to explore the observed differences.We analysed 367,188 index prescriptions for LRTI. Amoxicillin was the commonest used index drug (65.1%). In 6% a second antibiotic course coded for a further LRTI was prescribed (11.2% without this coding restriction). Further antibiotic prescriptions for LRTI were significantly associated with older age, previous smoking, seven day index courses and not using amoxicillin initially. The largest effect size was seen when amoxicillin was not used as index drug (odds ratio (OR) 1.15,  Lower respiratory tract infections (LRTI) are the commonest reason for antibiotic prescriptions in primary care across Europe and the probability of antibiotic prescription for coughs and colds by general practitioners in the United Kingdom (UK) increased by 40 % between 1999 and 2011 [Primary care is an ideal target for optimising antibiotic therapy since 74% of all UK antibiotics are prescribed here . The risSince real-life experiences should inform real-life decision making, we undertook this retrospective observational investigation of antibiotic prescriptions in non-pneumonic LRTI and their outcomes from 1984 to 2017. We described prescribing practice and investigated factors associated with repeat prescriptions with the aim to identify areas for further investigations.We carried out a cross-sectional database study drawing on retrospective, electronic medical records from the Optimum Patient Care Research Database (OPCRD). We included all subjects older than 15 years who received at least one antibiotic prescription for LRTI from 27 April 1984 to 5 January 2017. Primary outcome was a new antibiotic prescription for a LRTI READ code within 14 days of initial prescription. Secondary outcome was an antibiotic prescription for any indication within 14 days of index prescription. We excluded cases with coded diagnoses of pneumonia, chronic respiratory conditions ) and those whose index antibiotic course was longer than 28 days.http://optimumpatientcare.org/opcrd/). The OPCRD is a research-quality primary care database with a focus on respiratory diseases. It contained anonymised, routinely recorded patient data from over 525 UK general practices. The OPCRD was approved by the Trent Multi-Centre Research Ethics Committee for clinical research use. The study protocol was approved by the OPCRD’s Anonymised Data Ethics Protocols and Transparency Committee.The OPCRD comprised data extracted through the Optimum Patient Care (OPC) Clinical Service Evaluation . Univariable analysis was carried out for gender, age, body mass index (BMI), smoking status, index antibiotic drug and index duration. Statistically significant results were defined as There were 1,549,402 antibiotic prescriptions in the OPCRD from 1984 to 2017; of these 753,885 were for ‘simple’ LRTI  in patients over 15 years. ‘Chest infection not otherwise specified’, ‘bronchitis’ and ‘lower respiratory tract infections’ were the commonest codes for LRTI . We analysed the 367,188 cases (51%) for which an index duration was clearly documented (see supplementary figure).Of the total eligible 367,188 index prescriptions, 58.9% occurred in female patients. Mean age was 55.4 years, range 16–106 years. Mean BMI was 28.1 ± 6.1 . 35.4% were non-smokers, 27% current smokers and 28.9% were ex-smokers (missing smoking status in 8.7%). Most prescriptions occurred from 2006 to 2010 (35.3%). Most patients received only one index prescription (59.3%), with 20.4% having two and 20.3% three or more separate index prescriptions. The commonest index duration was 7 days (74.1%), followed by 5 or 6 days (22.7%). Amoxicillin was the index antibiotic prescribed most frequently (65.1%), clarithromycin and erythromycin were the next most frequent (9.1% and 7.4% respectively). About 548 cases received 2 further antibiotic courses within 14 days of the index prescription – these were excluded from further analysis.41,227 cases had a second antibiotic prescription within 14 days of the index prescription (11.2%). More than half of the additional antibiotic prescriptions were coded for another LRTI . Most of the 22,176 s prescriptions for another LRTI code were for 7 days (75.2%). Clarithromycin, amoxicillin and doxycyline were the most commonly used second line antibiotics .p < 0.001) than those not receiving antibiotics (see p < 0.001). Ex-smokers were more likely to receive repeat antibiotics than non-smokers . Ex-smokers were at significantly higher risk of repeat antibiotic prescription compared to current smokers . Not using amoxicillin as index antibiotic was associated with more repeat antibiotic prescriptions . Seven day index courses were associated with more repeat prescriptions than both shorter and longer courses . Higher BMI was associated with further prescriptions . There was no difference gender (p = 0.08).Those receiving further antibiotics for LRTI were significantly older , 95% CI −3.6 – −3.1, tics see . CurrentAbout 89,694 cases were included in this period. The most commonly prescribed index duration was again 7 days (83.7%).The most frequently used index antibiotics were amoxicillin (70.3%), clarithromycin (14.7%) and co-amoxiclav (4.8%).p = 0.01, see Supplementary Table 2). Those receiving antibiotics were significantly older  with a higher BMI . Current smokers were less likely to receive antibiotics  than non-smokers, ex-smokers more likely than non-smokers  and significantly more likely than current smokers . Not using amoxicillin as index antibiotic retained a higher risk of repeat prescription . In contrast to the overall study findings shorter durations were now associated with a higher risk of repeat prescription than 7 day courses . Longer durations maintained their lower risk of repeat antibiotics .Men were less likely to receive further antibiotics  clarithromycin, amoxicillin and doxycycline were used most commonly as second line agents .p < 0.001) with a significantly higher BMI . Men were significantly less likely to receive antibiotics than women . Current smokers were less likely, ex-smokers more likely to receive antibiotics than non-smokers . Ex-smokers were significantly more likely to receive further antibiotics than current smokers . Not using amoxicillin as index drug was associated with higher risk of repeat antibiotics . There was no significant difference between longer and 7 day courses .Those receiving further courses were significantly older . Doctors may attribute cough in a current smoker to the smoking and hence not prescribe antibiotics. This is in contrast to retrospective European data where current smoking was an independent risk factor for antibiotic prescription in primary care patients presenting with cough and the increased risk of community acquired pneumonia and death of pneumococcal disease in smokers ,15. Yet We analysed electronic health records. There is a drive to use more routinely collected data, particularly in primary care research, for example from the National Institute of Health Research, and highlighted by recent successes such as the Salford Lung Study, to reduce burden on patients, bias and approximate real-world practice ,18. HoweOther limitations include lack of information on other healthcare contacts or signs of infection and on other confounders, for example non-respiratory co-morbidities, allergies, prior antibiotic use, unattainability of total number of LRTI in the study period and inability to distinguish appropriate from inappropriate prescribing. Yet treatment decisions are often made independent of these, for example initial clinical severity scores and clinical response to therapy were not related to duration of antibiotic therapy in adults admitted with community acquired pneumonia . VariatiNevertheless, we present a hypothesis-generating real-world picture of the prescribing patterns of antibiotics for LRTI over 33 years in 7% of all UK primary care practices, analysing over 365,000 cases. With evidence on effective antibiotic treatment currently lacking it is paramount to have a historical, pragmatic perspective as a basis to design safe interventional studies in the future.Antibiotics were prescribed for LRTI in people without chronic chest conditions. There was variation in practice and apparent deviation from guidelines. Amoxicillin as index drug seemed more successful in avoiding repeat antibiotic prescriptions than other agents, supporting the demonstrated current prescribing practice. The results for optimal antibiotic duration were less clear, but suggested that shorter index durations may be appropriate for LRTI. This pragmatic study has implications for further work around guideline implementation, antimicrobial resistance strategies, and interventional studies of antibiotic duration.


The lack of ductility is the greatest concern in the applications of carbon fiber reinforced polymer (CFRP) materials, when used as pre-stressing reinforcements. To improve the ductility, a partially bonded FRP system which is intentionally unbonded in the middle part of the beam and bonded in both end parts of the beam has been developed and applied to prestressed concrete beams. While, many researchers investigated the instantaneous performance of partially bonded CFRP prestressed concrete beams, this study intended to evaluate the fatigue performance, the static load-carrying capacity after fatigue loading and ductility. Based on the fatigue loading tests followed by static loading tests, over-reinforced and web-confined partially bonded CFRP prestressed concrete beams exhibited satisfactory fatigue performance without cracks and stiffness degradation during fatigue loading. In addition, no degradation of load-carrying capacity was observed in static loading tests after the fatigue tests. The ductility index of concrete beams, prestressed with partially bonded CFRP bars, is combined with over-reinforcements and web-confinements, similar to that of beams prestressed with steel bars. Conventional steel tendons in prestressed concrete structures are naturally vulnerable to corrosion, which is exacerbated over time and may result in a decrease in structural stiffness, strength, and service life. The best solution to the corrosion problem is to use non-metallic reinforcements, such as fiber reinforced polymer (FRP) composites, which have high tensile strength and are non-corrosive, non-magnetic, and lightweight ,2,3,4. TTo avoid failure due to brittleness, the prestressing reinforcement ratio should be designed to be greater than the balanced ratio, at which the rupture of FRP tendons and concrete crushing failures take place simultaneously . HoweverHowever, the anchorage in a fully unbonded FRP system is a critical issue as it ensures reliable force transfer and interaction with the rest of the structure. There are no efficient and competitive prestressing systems for FRP tendons despite research over the last two decades ,15. AlthThe majority of investigations relating to partially bonded systems have focused on the analysis of short-term performance and ductility ,21,22,23In this current study, a partially bonded system was applied to prestressed concrete beams with FRP tendons to investigate fatigue behavior and capacity, as well as ductility enhancement in terms of ductility index (DI). An experimental program was carried out, and the test results were also discussed. Six simply supported, 3000 mm long concrete beams were fabricated with various bonding lengths of CFRP bars, the reinforcement ratio of prestressing bars, and web-confinement. Three beams were tested under fatigue loading (completing one million cycles); then, the beams were statically loaded up to failure, in order to evaluate the effect of fatigue loadings on the remaining load-carrying capacity. The other three beams were tested in static conditions up to failure for comparison purposes.Since FRP bars and concrete are both brittle materials, the fracture characteristics of concrete beams, prestressed with FRP bars, are of interest because of its brittle failure. Therefore, a partially bonded system was developed to overcome brittle problems based on many investigations. The results showed that ductility of the partially bonded system had improved. In spite of the considerable amounts of results on the ductility of the concrete beam, prestressed with partially bonded FRP bars, most investigations were focused on the analysis of short-term performance and ductility. This paper generates important experimental data to address fatigue performance as well as ductility.3. Experimental programs,minA = 0.004tA, where tA is a part of the cross section between the flexural tension face and the center of gravity of the gross section. As non-prestressed steel bars of 6.0 mm diameter were placed below CFRP bars and in the top compressive zone with 25 mm cover. These bars also facilitate easy assembly of a reinforcement cage. The experimental program includes three sets of beams. Six simply supported concrete beams prestressed by CFRP bars with different bonding conditions: Fully unbonded, partially bonded and fully unbonded. The main variables were the reinforcement ratio of prestressing bars, and web-confinement, including bonding conditions. The specimen identification scheme in bρ, where bρ is the balanced ratio, the reinforcement ratio that led to simultaneous achievement of the ultimate strain of FRP bar and the ultimate compressive strain of concrete [1β = 0.85 for concrete strengths up to 27.5 MPa, after which it is reduced at a rate of 0.05 for each 6.9 MPa of strength in excess of 27.5 MPa to a minimum value of 0.65; cf’ is compressive strength of concrete, puf is the ultimate tensile strength of the CFRP bar, cuε is the ultimate strain in concrete in compression (= 0.003), puε is the ultimate tensile strain of the CFRP bar, and peε is the effective strain in prestressed CFRP bar, sA is total sectional area of non-prestressed reinforcement, b is beam width, d is depth to the CFRP bar (distance from extreme compression fiber to centroid of CFRP bars), buf is the ultimate tensile strength of non-prestressed reinforcementThe F1FU/S1FU specimen was post-tensioned with a fully unbonded CFRP bar and no transverse confinement. A thin plastic tube was used to create the unbonded region, as shown in concrete . The balconcrete ,(1)ρb=0bρ.The F1PU/S1PU specimen has the same layout of reinforcement as the F1FU/S1FU specimen. However, unlike F1FU/S1FU, a CFRP bar was partially bonded to concrete. For the partially bonded beams, a thin plastic tube was used to make the unbonded region, whose length is 1400 mm in the mid-span as shown in bρ. Web-confinement was also provided with closed steel stirrups at every 50 mm as shown in The F2PC/S2PC specimen has two CFRP bars partially bonded to concrete. The F2PC/S2PC specimen was over-reinforced with a prestressing reinforcement ratio of 3.2The prestressing system consisted of a 200 kN hydraulic jack , a pressure dial gage , and a prestressing steel chair see . The jacThe beam specimens were cast in one batch. The CFRP bar has a rough surface pattern with double helical rib geometry for mechanical interlock see b. The avmaxP, was selected to be equivalent to 60% of the cracking load for each specimen. The minimum load is equal to 1.0 kN equivalent to 10% of selected maximum load in order to avoid impact loads during cycling. The fatigue loading was periodically stopped at 1, 103, 104, 105, 3 × 105, 5 × 105, and 106 cycles, in order to conduct intermediate static tests to monitor the damage accumulation and its effect on the stiffness of beams. The maximum load of intermediate static tests was limited to the peak magnitude of the fatigue load. After completing one million cycles, the beams were tested monotonically, up to the failure to evaluate the fatigue capacity of the prestressed concrete beams. During the fatigue and static tests, crack propagation patterns were monitored and marked on the beam surface.Three-point bending fatigue tests were carried out. Three beams with span 2700 mm were loaded, as shown in This section presents test results of each beam, considered in the experimental program, and summarizes the relevant research findings. In the first phase, three beams were tested under fatigue loadings at different load ranges, based on a percentage of the cracking load. Three beams in the second phase were tested under monotonic loading conditions up to a failure for the reference. An overall summary of the tests results is given in Load-deflection diagrams of the F1FU specimen are presented in After the initial cracks were observed in the F1FU specimen, the beam stiffness that was evaluated by the slope of the load-deflection relationship was reduced with the increasing number of cycles, as shown in The F1FU specimen survived one million cycles and was subsequently loaded monotonically to failure. New cracks during monotonic loading appeared at the end of the pre-existing crack, located 100 mm from the mid-span at the load of 24.5 kN, as shown in sA/s,minA = 1.13 where sA is the area of non-prestressed reinforcement). Unbonded FRP bars can improve ductility by relieving the strain from critical sections or averaging strains along unbonded length of bars [The non-prestressing reinforcement rupture was observed on both specimens (F1FU/S1FU) under monotonic loading despite exceeding the minimum non-prestressing reinforcements  and transverse confinement in the compression zone. No flexural cracks occurred during one million fatigue loadings. The bond failure of CFRP bars at the end of the beam were not observed after one million fatigue loadings. A perfect elastic response, corresponding to the initial stiffness, was observed after one million cycles, as shown in Over-reinforcement and transverse confinement have been proposed as methods to improve the ductility of FRP systems. The absence of plasticity in FRP materials points to the under-reinforced flexural sections undergoing a sudden tensile rupture. Thus, the concrete crushing failure mode of an over-reinforced member is more desirable, due to enhanced energy absorption and greater ductility, leading to a more gradual failure mode . For oveThe static load test of the F2PC specimen followed by the fatigue test was performed to identify the remaining strength after the fatigue loading and the results were compared to a S2PC beam, as presented in ρ/bρ = 3.2 for F2PC/ S2PC specimens and ρ/bρ = 1.6 for others) will shift the location of the neutral axis in the direction of the tension area, so that the extent of concrete used becomes bigger. In other words, when concrete strength increases, the degree of crushing decreases. When it comes to ductility, the neutral axis’ depth of the beam in failure can determine its ductility. Therefore, further study of the practical rule in limiting the neutral axis’ depth seems to be required on high-performance concrete beams to assure adequate ductility levels.Compared to the extent of concrete crushing of the F2PC/ S2PC specimens to other specimens, a larger concrete compressive destruction zone of the F2PC/ S2PC specimens are observed (See detail photographs in The load-deflection curves of S2PC (no fatigue loading) and F2PC specimens are presented in totalE is the total energy, calculated as the area under the load-deflection curve up to the peak load, and elasticE is the elastic energy, which is illustrated in elasticE) can be estimated from unloading tests. If unloading data are not available, it can be evaluated using the area of the triangle formed at failure load by the weighted average slope of the two initial straight lines of the load-deflection diagram, as shown in The ductility is defined by the ability to sustain inelastic deformation without loss in the load carrying capacity prior to failure. Conventional ductility is defined as the ratio of deflection at the ultimate load to deflection at yield. This definition cannot be used to evaluate the ductility of concrete members prestressed with CFRP bars, since CFRP bars exhibit linearly elastic behavior until failure. Instead, the ductility of prestressed beams, using CFRP bars, can be calculated by the ratio between elastic and inelastic energies, consumed under the load-deflection curve ,38,39. IThe DI of five beams was evaluated using Equation 2, and the results are presented in It was found that DI values vary according to bonding conditions - ranging between 0.54 and 0.85 - and it was shown that concrete beams prestressed with fully unbonded/partially bonded CFRP bars have a higher DI than those of specimens prestressed with fully bonded CFRP bars. In general, DI values range from 0.1 to 0.5 for the concrete beams prestressed with fully bonded CFRP tendons ,38. The The F1FU specimen post-tensioned with a fully unbonded bar exhibited good fatigue performance and high ductility. No considerable reduction in beam stiffness or slippage in anchorage was observed during one million cycles. In a static test, conducted after completing one million cycles, the F1FU specimen, despite beam failure by non-prestressing reinforcement rupture, had the highest ductility index.It was observed that S1FU and F1FU specimens experienced failure by non-prestressed reinforcement during static tests. From a design point view, an adequate amount of non-prestressing reinforcement should be considered to prevent abrupt failure due to the unexpected rupture of non-prestressed steel bars.The F1FU/S1FU specimens prestressed with fully unbonded bars failed by non-prestressing reinforcement rupture during monotonic loading. Fully unbonded bars can improve the ductility of prestressed concrete beams, despite the prestressing reinforcement ratio being less than the balanced prestressing reinforcement ratio. However, from a design point, an adequate amount of non-prestressing reinforcement is essential for preventing the unexpected rupture of non-prestressing reinforcement, and to ensure the inelastic behavior of prestressed concrete beams with fully unbonded bars.The over-reinforced and web-confined concrete beams, prestressed by partially bonded bars, i.e., the F2PC specimen, exhibited good fatigue performance with no cracks and no reduction in beam stiffness during one million cycles. In addition, it was found that no reduction in the load-carrying capacity and beam stiffness occurred in a static test, conducted after the conclusion of one million cycles.Improved ductility was observed for beams prestressed with fully partially bonded CFRP bars, when compared with prestressed beams that have fully bonded CFRP bars. Over-reinforced and web-confined concrete beams, prestressed with partially bonded CFRP bars, were proposed, and evaluated to possess good fatigue capacity and durability based on the experimental results.Six simply supported beams were tested to study the fatigue behavior and failure character of concrete beams, prestressed with fully unbonded/partially bonded CFRP bars. The experimental program was conducted utilizing fully unbonded/partially bonded bars, web confinement, and over-reinforcement as experimental parameters. Ductility indices of specimens were also evaluated. Based on the experimental program, the following conclusions can be drawn:


MET amplification is rare in treatment-naïve metastatic colorectal cancer (CRC) tumors, but can emerge as a mechanism of resistance to anti-EGFR therapies. Preclinical and clinical data suggest that patients with MET amplified tumors benefit from MET-targeted therapy. Cabozantinib is an inhibitor of multiple tyrosine kinases, included c-MET. Panitumumab is an inhibitor of EGFR. This report describes a patient with KRAS, NRAS, and BRAF wild-type metastatic CRC who experienced disease progression on all standard chemotherapy and anti-EGFR antibody therapy. The patient was enrolled in a clinical trial evaluating the combination of cabozantinib plus panitumumab. After only 6 weeks of treatment, the patient experienced a significant anti-tumor response. Although tumor tissue was negative for MET amplification, molecular profiling of cell-free DNA (cfDNA) revealed MET amplification. This case represents the first report showing the activity of cabozantinib in combination with panitumumab in a patient with metastatic CRC, and suggests that MET amplification in cfDNA may be a biomarker of response. A clinical trial targeting MET amplified metastatic CRC is currently underway. MET proto-oncogene, c-MET is a disulfide-linked glycoprotein consisting of an extracellular α-subunit and a membrane spanning β-subunit , is implicated in tumorigenesis, proliferation, invasiveness, metastasis, and resistance to cancer treatment . Encoded-subunit . Hepatoc-subunit . HGF/c-M-subunit . Aberranfication .MET gene amplification has been observed in multiple tumor types, including colorectal cancer (CRC) (MET amplification is one of the key mechanisms mediating both primary (MET amplification leads to acquired resistance to EGFR tyrosine kinase inhibitors (TKI)s by persistent activation of ERBB3 signaling (MET amplification can be detected with or without the presence of the EGFR T790M “gatekeeper” mutation (MET amplification is low (~3 %) in patients with untreated NSCLC, but increases to 5–22% in patients who develop acquired resistance to EGFR TKI therapy (MET amplification under the selective pressure of anti-EGFR therapy supports the notion that MET amplification is a driver of acquired treatment resistance (er (CRC) , 6, gaster (CRC) , 8, genier (CRC) , head aner (CRC) , non-smaer (CRC) , 12, neuer (CRC) , and ovaer (CRC) , 15. MET primary  and acqu primary  to epideignaling  and MET mutation . The pre therapy , 19, 20.sistance .MET amplification is associated with resistance to anti-EGFR antibodies, including cetuximab and panitumumab. In mice engrafted with MET amplified CRC tumors, treatment with cetuximab is ineffective, suggesting that MET amplification may be responsible for intrinsic resistance to anti-EGFR antibodies  of the tumor tissue biopsies identified MET amplification as one of the most common genomic alterations  of patients with RAS wild-type tumors after exposure to anti-EGFR antibody therapy, but not found at an elevated frequency in anti-EGFR antibody-naïve patients  also supports  therapy . In anotpatients . In addipatients . These fMET amplified patient-derived colorectal cancer xenograft models, MET tyrosine kinase inhibitors (TKIs) reversed resistance to EGFR blockade  for use as monotherapy for metastatic medullary thyroid cancerA 57-year-old male was initially diagnosed with locally advanced rectal cancer T3N1M0) and treated with neoadjuvant chemoradiation followed by surgical resection  biopsy revealed metastatic adenocarcinoma consistent with CRC primary. He received first-line treatment with FOLFIRI plus bevacizumab, but eventually experienced disease progression. He then progressed on a clinical trial combining capecitabine with an investigational therapy, followed by progression on regorafenib.KRAS and NRAS wild-type, he was then treated with anti-EGFR antibody therapy (panitumumab). After 7 months of disease control, imaging revealed a new hypermetabolic LN at the right common iliac chain, and irinotecan was added to panitumumab. This treatment was eventually discontinued due to disease progression. A new biopsy of a mediastinal LN was performed and next generation sequencing (NGS) revealed that the tumor was still KRAS, NRAS, and BRAF wild-type, and there was no evidence of MET amplification  or between different lesions throughout the body , as described previously  in Guardant Health. RN has ownership interest (including patents) in Guardant Health. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In this paper, the authors present a stress wave-based active sensing method to detect the crack in FRP-reinforced concrete beams. The embedded smart aggregates (SAs), which utilize Lead Zirconate Titanate (PZT) as transducers, are employed in this research to generate and sense the stress wave. Three specimens are involved in the experimental program and each is made of concrete, longitudinal distributed reinforcement, steel stirrups, main bar (FRP bar or steel bar), and four SAs. A pair of SAs installed on the lower part of the main bar and the other pair of SAs mounted on the upper part of main bar are utilized to monitor the crack occurrence and development in the three test specimens. The signals received by the SA sensors are analyzed in both time domain and frequency domain. The wavelet packet energy is used to extract damage features. The applied load–vertical displacement curves of mid-span in the specimen are obtained. Experimental results show the test specimens experience crushing failure when the concrete compression exceeds its compressive strength. Increasing the contact area between FRP bar and concrete can effectively improve the cracking load of the FRP-reinforced concrete beam and reduce the cracking speed and depth of FRP-reinforced concrete beam; on the other hand, increasing the elastic modulus of the main bar can slow down the crack development of concrete on the upper side of the main bar and decrease the displacement of reinforced concrete beam during the loading test process. The research results show that the developed piezoceramic-based active sensing method, though low-cost, can monitor the crack-induced damage and estimate the process of damage degree in real-time, and has potentials to provide an early warning of crack occurrence and development for FRP-reinforced concrete beams. Traditional steel reinforced concrete structures often suffer from corrosion ,2,3. On Crack detection and monitoring in reinforced concrete structures has received much attention in the literature ,14. The In recent years, due to their advantages, such as low-cost , wide baIn this paper, an active sensing technique based on wave propagation using SAs is developed to detect the occurrence and development of cracks in FRP-reinforced concrete beam. The test involves the three specimens with two pairs of SAs in each specimen. A pair of SAs are placed on the lower part of the main bar to monitor the cracking of the bottom of reinforced concrete beam. The other pair of SAs are installed on the upper part of the main bar to monitor the development of cracks after cracks pass through the main bar. The dial indicators are installed at the mid-span and both ends of the test specimens. A screw jack is used to apply the load to the test specimens through a distribution beam, and a load cell is used to measure the force. In the three test specimens, the experimental program consists of two different experiments parameters, such as the contact area between main bar and concrete, and the elastic modulus of main bar. The cracks attenuated the propagating stress wave energy which can be reflected by the received signal in time domain, frequency domain, and the wavelet packet-based energy index. The experimental research validates the feasibility of monitoring the cracking in FRP-reinforced concrete beam using SA sensors based on active sensing technique.A three-dimensional diagram of cracking detection in reinforced concrete beams is shown in The principle of the active sensing approach is illustrated in n-level wavelet packet decomposition into 2n frequency bands. The signal energy of each frequency band can be computed by the summation of the square of each sampling data in the frequency band. Furthermore, the total of the signal energy is obtained by the summation of the signal energies from all frequency bands. In this research, the wavelet packet-based energy analysis is used to quantify the energy of the signals received by the SA sensors. The energy index of the received signals can be established for the purpose of directly comparing the change of the received signal energy during the test loading process. In the wavelet packet-based analysis, the sensor signal X can be decomposed by a n-level wavelet packet decomposition into 2n frequency bands. jX can be expressed asm is the number of sampling data and j is the frequency band . Additionally, the total energy of the decomposed signal Ei,j can be defined asi represents the data measured in different time. The total signal energy at time i can be computed by the summation of the decomposed signal energy iEObviously, the development of cracks can be investigated through the variation of stress wave received by the smart aggregate sensors in the reinforced concrete beam. Cracking should be monitored and quantitatively evaluated throughout the test loading process. The wavelet packet-based energy analysis has been widely applied in structural health monitoring in recent years ,46,47, ahE) is measured, and the signal energy collected is recorded as iE at different times. During the loading test, cracks begin to appear at the bottom of the reinforced concrete beams. When the stress wave encounters a crack, there will be an obvious reflection wave and a weakened received wave. The cracks will continue to develop with the load increasing, the signal energy iE received by the SA sensor will continuously decrease. When the reinforced concrete beam is completely destroyed, it will make the crack width so large that the SA sensor can hardly receive any signal and the wavelet packet energy will be almost zero.In the initial state, the healthy signal energy  monitoring the cracking characteristics of FRP-reinforced concrete beams with the same main bar but different contact areas between main bar and concrete, such as Beam A and Beam B, and (2) monitoring the cracking characteristics of FRP-reinforced concrete beam and steel reinforced concrete beam with same concrete contact area but different elastic modulus of main bar, such as Beam A and Beam C.The experimental setup includes the reinforced concrete test specimen with four SAs, one reaction frame, one load cell, one screw jack for loading the specimen, one concrete pad, one load distribution beam, two fixed supports and two sliding supports, three dial indicators for measuring the vertical displacement of the test specimen, two concrete support piers, one multifunctional strain measuring instrument for reading the value of the force sensor, one data acquisition board NI-USB 6363 with the function of generating and collecting the signals, and one supported laptop, as shown in Detailed layout of the experimental loading is shown in Before the formal loading test, to eliminate the initial defect of the test specimen and to ensure that the components of the specimen will be in good condition and the loading equipment and test instruments will work normally, the preloading test is carried out. During the loading process, the load applied by the screw jack is continuously applied to the test specimen through the load distribution beam. And the load is measured by the load cell and read by connecting the multifunctional strain measuring instrument. The static loading test is applied from zero until the failure occurs. The increment of each load class in the test is 2 kN. The vertical displacements of the test specimen are measured by the dial indicators under the different load levels in the static loading. At the same time, a steady swept sine wave signal is utilized as the excitation signal of embedded SA1 and SA2 actuators controlled by NI-USB 6363. The frequency range of the swept sine wave signal is from 100 Hz to 150 kHz. The amplitude and the period of the swept sine wave are 10 V and 1 s, respectively. The predetermined input signal  is directly programmed and sent to the SA1 and SA2 transducers, as actuators, from the NI-USB 6363. Since the data acquisition board NI-USB 6363 has the function of transmitting and receiving the signals simultaneously, the output signals from SA3 and SA4 transducers, as sensors, can be recorded utilizing the NI-USB 6363 in the loading test. After the data processing and analysis, the structure stiffness, time-domain signal, frequency domain and the wavelet packet-based energy index of the three test specimens are obtained.Failure photos of the test specimens are shown in By comparing the test failure photos of Beam A with one FRP bar with a diameter of 10 mm and Beam B with four FRP bars with a diameter of 5 mm, it can be seen that the degree of concrete crushing failure of Beam A is more severe than that of Beam B, and the crack length of Beam A is larger than that of Beam B, as shown in Since the measuring points D1 and D2 are installed at the top of the supports, they are only used to measure the displacements of the supports under the applied load. And the measuring point D3 is mounted in the mid-span of the specimen to monitor the maximum displacement of the test specimen, thus it can be seen that the applied load–vertical displacement curves of the measuring point D3 shows the stiffness characteristics of the specimens. According to the relationship of the displacement of measuring points of the test specimen, the displacement of the measuring point D3 used in the following analysis should subtract the average displacement of the measuring point D1 and D2. The applied load–vertical displacement curves of the measuring point D3 of the test specimens are shown in At the beginning of the applied load, the test specimens work in the elastic stage without cracking, and the vertical displacements of the measuring point D3 increase linearly with the applied load increasing. When the corresponding applied load arrives at the cracking load, the cracks in the test specimens begin to appear in the mid-span of the specimen. This will lead to the decrease of the stiffness of the reinforced concrete beam specimens, and the increase of the vertical displacement of the specimens under the same applied load, that is, the applied load–vertical displacement curves appear an obvious change at this cracking load. In the For Beam A and Beam C, the curves of the mid-span applied load vs. the vertical displacement are similar. When the test specimens are applied with the same applied load, the vertical displacements of the Beam A (designed with one FRP bar with a diameter of 10 mm) are slightly larger than that of the Beam B (designed with one steel bar with a diameter of 10 mm). This is mainly because the FRP bar and steel bar have different elastic modulus, and the elastic modulus of FRP bar is lower than that of steel bar. Therefore, the stiffness of FRP-reinforced concrete beam is lower than that of reinforced concrete beams, which will lead to the greater displacement of FRP-reinforced concrete beam under the same applied load than that of steel reinforced concrete beam.The time domain signals received by SA3 and SA4 sensors of Beam A are shown in Compared to the time domain signals, the difference in the trend of the power spectra density (PSD) energy can be more easily observed from the frequency domain. The frequency domain signals received by SA3 and SA4 sensors of Beam A are shown in To quantify the energy of the stress wave signals detected during the applied load process, the signal energy is analyzed by using the wavelet packet energy. The results are shown in The wavelet packet energy analysis of the sensors of Beam B is shown in This paper presents an experimental investigation of detecting crack-induced damage using a stress wave technique with embedded smart aggregates through three reinforced concrete beam specimens. Experimental results show that the crack-induced damages in FRP-reinforced concrete beam are successfully monitored by using the stress wave-based active sensing approach during the static load test in real-time. Experimental results show that the time domain amplitudes, frequency domain amplitudes and wavelet packet energies of the signal received by SA sensors decrease when the crack-induced damage occurs. With the increase of the applied load, the crack-induced damage increases gradually, resulting in that the transmitting stress wave signals are attenuated, and the signal amplitude of the sensors installed on the lower side of the main bar decreases faster than that of the sensors installed on the upper side of the main bar. The analysis results show that increasing the contact area between FRP bar and concrete can effectively increase the cracking load of the FRP-reinforced concrete beam and reduce the cracking speed and depth of FRP-reinforced concrete beam; increasing the elastic modulus of the main bar can slow down the crack development of concrete on the upper side of the main bar and decrease the displacement of reinforced concrete beam during the loading test process. Therefore, the developed piezoceramic-based active sensing method can monitor the crack occurrence and development for FRP-reinforced concrete beams in real-time. Since the appearance of crack in the FRP reinforcement concrete beams is random and uncertain, the author’s future work will involve the method to locate and quantify the spatial attitude of the cracking of FRP-reinforced concrete beams, which can accurately evaluate the damage degree of FRP reinforcement concrete beams caused by cracks. The piezoceramic smart aggregates are economical with low manufacturing cost and they can be easily integrated with concrete structures for real-time structural health monitoring. In addition, the low sampling rate requirement for the data analysis reduces the cost of the data acquisition system. These factors will pave the way for field implementation of the proposed method to monitor cracks in FRP concrete structures.


Enterobacter cloacae complex (ECC) includes common nosocomial pathogens capable of producing a wide variety of infections. Broad-spectrum antibiotic resistance, including the recent emergence of resistance to last-resort carbapenems, has led to increased interest in this group of organisms and carbapenem-resistant E. cloacae complex (CREC) in particular. Molecular typing methods based on heat-shock protein sequence, pulsed-field gel electrophoresis, comparative genomic hybridization, and, most recently, multilocus sequence typing have led to the identification of over 1069 ECC sequence types in 18 phylogenetic clusters across the globe. Whole-genome sequencing and comparative genomics, moreover, have facilitated global analyses of clonal composition of ECC and specifically of CREC. Epidemiological and genomic studies have revealed diverse multidrug-resistant ECC clones including several potential epidemic lineages. Together with intrinsic β-lactam resistance, members of the ECC exhibit a unique ability to acquire genes encoding resistance to multiple classes of antibiotics, including a variety of carbapenemase genes. In this review, we address recent advances in the molecular epidemiology of multidrug-resistant E. cloacae complex, focusing on the global expansion of CREC.The  Enterobacter spp., the second most common carbapenem-resistant Enterobacteriaceae (CRE) in the United States, increasingly contribute to the spread of carbapenem-resistant infections (Enterobacter cloacae complex (ECC) are common nosocomial pathogens capable of producing a wide variety of infections, such as pneumonia, urinary tract infections, and septicemia (fections . In partpticemia . The emehsp) typing have led to the re-definition of members within this complex  and heat-shock protein  genotyping, multilocus sequence analysis (MLSA), comparative genomic hybridization (CGH), pulsed-field gel electrophoresis (PFGE), and more recently, MLST and WGS. Based on hsp60 allelic variation, ECC was previously classified into thirteen genovars (clusters I-XIII). These encompass Enterobacter asburiae (cluster I), Enterobacter kobei (cluster II), Enterobacter ludwigii (cluster V), Enterobacter hormaechei subsp. oharae (cluster VI), subsp. hormaechei (cluster VII), and subsp. steigerwaltii (cluster VIII), Enterobacter nimipressuralis (cluster X), E. cloacae subsp. cloacae (cluster XI) and subsp. dissolvens (cluster XII), unnamed E. cloacae Hoffmann clusters III, IV, and IX, and an unstable E. cloacae sequence crowd (cluster XIII)  ,b,c. Howbspecies .rpoB, fusA, gyrB, leuS, pyrG, and rplB) suggested the emergence of two distinct ECC clades: a recent clade including the three E. hormaechei subspecies and a heterogeneous older clade including multiple ECC clusters. The observed recombination:mutation ratio of 1.04  across ancestral clades also indicates potential recombination events in the early evolution of ECC, likely accounting for discrepancies between single amplicon methods (Enterobacter mori (Enterobacter xiangfangensis (cluster VI), and Enterobacter cancerogenus were recently classified   . Thus, tampC genes encoding an inducible AmpC-type Bush group 1 (class C) cephalosporinase. Resistance to third-generation cephalosporins and aztreonam can result from mutations, usually in ampD, leading to constitutive hyperproduction (derepression) of AmpC  genes confer resistance to most β-lactam antibiotics, including extended spectrum  cephalosporins (ESCs) and monobactams . These genes are typically plasmid-encoded and were first identified in ECC in 1989 . Since tKlebsiella pneumoniae carbapenemase (KPC), a class A β-lactamase which predominates in the United States, and the New Delhi metallo-β-lactamase-1 (NDM-1) have been most frequently described in ECC  and metallo-β-lactamases  . The Kled in ECC , althougd in ECC . Rarely,d in ECC .In addition to β-lactam resistance, ECC harbor a variety of multi-class antibiotic resistance genes. This includes aminoglycoside resistance primarily due to the acquisition of plasmids or mobile genetic cassettes encoding aminoglycoside 6’-N-acetyltransferase type I [AAC(6’)-I] . Mutatioaac(6′)-Ib-cr, or the presence of plasmid-borne qnr or qep genes, can confer low-level quinolone resistance in ECC (gyrA and parC (Escherichia coli (K. pneumoniae (An AAC(6′)-I variant produced by e in ECC . In addiand parC , have behia coli  and K. peumoniae . This fieumoniae . QRDR mueumoniae . HoweverE. cloacae complex was one of the first KPC-producing organisms identified , ST93 and ST90 , and ST78 (E. cloacae cluster III) were widespread among global CREC isolates from 37 countries (E. xiangfangensis) and ST108 were also identified in multiple countries.Previous multinational surveillance studies employing MLST found substantial clonal diversity of both ESBL-producing ECC and CREC, with evidence for several potential high-risk clones. The most widespread ESBL-producing ECC were ST66, ST78, ST108, and ST114, each having at least 10 isolates from three to five countries . Severalountries , while SK. pneumoniae (CRKP) appears to be declining in high-prevalence areas such as the Northeastern United States, multiple sites across the United States have reported increasing prevalence of CREC   IncFIA plasmid pMNCRE44  (ST171 is primarily associated with pNR3024) . These pospitals . InterespMNCRE44 . The tru plasmid . A duodeeported) . Howevereported)  and carbeported) , harboriblaKPC-containing plasmids  on multiple different genetic backbones in ST78, although the carbapenemase-harboring plasmid could not be determined using short-read sequencing. In Japan, ST78 isolates harbored blaIMP-1 on class 1 integrons encoded on multiple different plasmids including IncHI2, IncW, and IncFIB (In contrast, ST78 was identified as a high-risk clone among both ESBL-producing ECC and CREC. CREC ST78 has largely been isolated in the Northeastern United States, with multiple sporadic uptake events of plasmids , and hasplasmids . Global d IncFIB .blaKPC carbapenemases. Notably, although region-specific associations between carbapenemase genes and specific genetic backbones have been reported, shuffling of these genetic structures among different ECC clones appears to occur commonly including in geographically diverse areas (Other CREC STs have been associated with diverse KPC subtypes on IncN, IncX7, IncL/M, IncA/C, pKpQIL, and pKPC_UVA01-like plasmids, and plasmids with unknown replicon types . Howeverse areas .blaKPC and the successful CRKP clone ST258 (blaKPC and plasmid backbones harboring these genes may have enabled uptake into diverse ECC. In contrast to CRKP, the spread of CREC can be attributed to not only stable blaKPC-clone associations, as in the case of ST171 and blaKPC-3-encoding IncFIA plasmids, but also the sporadic uptake of diverse plasmids by heterogeneous clones. This includes clones with epidemic potential capable of harboring diverse blaKPC-containing plasmid backbones, such as ST78.Since the mid-1990s, when KPC was first described, the spread of CRKP has largely been attributed to the stable association between ne ST258 . AlthougblaKPC genes, other genomic factors linked to carbapenem- or other MDR may have aided in the rapid proliferation of CREC. Several lineage-specific genomic islands in both ST171 and ST78, encode for toxin-antitoxin and cell stress response systems (In addition to the presence of  systems . Genes f systems . These fVirulence of CREC compared to carbapenem-susceptible ECC has not been extensively assessed. However, murine macrophage cytotoxicity assays did reveal significantly reduced cell killing of CREC vs. ESBL isolates and, more specifically, reduced toxicity of CREC ST171 vs. ESBL ST78 isolates . Of noteAnalogous to the pan-genome, the concept of a “pan-metabolome” has also been applied to ECC . Severalin vitro. Moreover, despite recent advancements potentiated by WGS and comparative genomics, transcriptomics and/or metabolomics approaches may be useful in future studies to define the metabolic activity of CREC under different conditions. Lastly, the underreporting of CREC remains a possibility, and may influence findings regarding both population-level diversity and genomic mechanisms of resistance.Several gaps remain in our understanding of CREC. The notable diversity of CREC clones, carbapenemase genes, and plasmid backbones harboring MDR genes have thus far led to uncertainty regarding a clear timeline and evolutionary history of these organisms. Virulence, fitness, or other genomic factors potentiating the spread of CREC have not been completely defined or assessed Regardless, the unique diversity of CREC, even compared to other CRE such as CRKP, necessitates a tailored approach to preventing its transmission and further diversification. The establishment of high-risk global CREC clones, coupled with the apparent high frequency of plasmid uptake into diverse ECC, suggests that vigilant tracking of both localized outbreaks and the potential for horizontal plasmid transfer is required.A-CU initiated the review. AG-S performed a literature search. MKA wrote the first draft. All authors edited and reviewed the manuscript draft.A-CU has received research funding from Merck, GSK and Allergan, unrelated to the current study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cultural and social determinants influence antibiotic decision-making in hospitals. We investigated and compared cultural determinants of antibiotic decision-making in acute medical and surgical specialties.An ethnographic observational study of antibiotic decision-making in acute medical and surgical teams at a London teaching hospital was conducted (August 2015–May 2017). Data collection included 500 hours of direct observations, and face-to-face interviews with 23 key informants. A grounded theory approach, aided by Nvivo 11 software, analyzed the emerging themes. An iterative and recursive process of analysis ensured saturation of the themes. The multiple modes of enquiry enabled cross-validation and triangulation of the findings.In medicine, accepted norms of the decision-making process are characterized as collectivist , rationalized, and policy-informed, with emphasis on de-escalation of therapy. The gaps in antibiotic decision-making in acute medicine occur chiefly in the transition between the emergency department and inpatient teams, where ownership of the antibiotic prescription is lost. In surgery, team priorities are split between 3 settings: operating room, outpatient clinic, and ward. Senior surgeons are often absent from the ward, leaving junior staff to make complex medical decisions. This results in defensive antibiotic decision-making, leading to prolonged and inappropriate antibiotic use.In medicine, the legacy of infection diagnosis made in the emergency department determines antibiotic decision-making. In surgery, antibiotic decision-making is perceived as a nonsurgical intervention that can be delegated to junior staff or other specialties. Different, bespoke approaches to optimize antibiotic prescribing are therefore needed to address these specific challenges. Culture and team dynamics within specialties influence antibiotic decision-making. A collectivist culture in medicine supports rationalized and policy-driven decision-making. In surgery, antibiotic decision-making is delegated to juniors or other specialties. Addressing these specific challenges is critical to optimizing antibiotic prescribing. See the Editorial Commentary by Szymczak on pages 21–3.) are implemented in hospitals to optimize antibiotic use . These pASP studies emphasize quantitative methodologies, to answer “what works,” and “by how much” with an emergent body of research investigating “why” interventions do or do not work . StudiesEthical approval for this study was granted by the UK National Research Ethics Committee (application number 176038).The study was conducted in a central London teaching hospital with 1300 beds and an existing ASP . Wards wEthnography is the study of people within the context in which they exist, live, and work , 13. TheHealthcare professionals participating in the observations were invited to participate in a follow up face-to-face interview. The interviews were semistructured with an interview guide, developed through review of literature and drawing upon previous work of the research team . The intThe data were analyzed using classic grounded theory approach , using mThe results presented below are derived from the analysis of field notes, documents, and the interview data. The field notes and quotes in this article are representative of the key emerging themes. Between August 2015 and May 2017, 30 surgical and 22 medical WRs  were obsIn surgery, individualism is clear in the influence of consultant surgeons on the team , 28. TheHow time is viewed and managed is an important attribute of each specialty and determines the collective behavior of the teams. The sense of time in the medical team is less structured or pressurized. In contrast, the surgical team focus primarily on the “now,” requiring the team to plan and schedule, and have a sense of the time taken up by the WR, and the need to end it and move on to other tasks , Q2. ThiIn surgery, the diagnosis of infection is reliant on infection markers, including C-reactive protein, white cell count, and temperature. The decision-making is focused more on prevention and prophylaxis than on treatment of infections. In medicine, though infection markers are an important part of the process, the team members try to rationalize their decisions, making efforts to align them with local policy and readily involve other healthcare professionals.The need and expectation to intervene in surgery means that antibiotics are readily initiated for surgical patients. This process is rationalized by the surgeons as being an extension of their roles as “interventionists” . In the In medicine, junior members were concerned about managing risks in the context of making decisions on behalf of senior leaders. The junior doctors are more likely to start and escalate antibiotic therapy but are reliant on consultants deciding whether therapy needs to be de-escalated , Q15.In medicine, the critical decisions about whether a patient needs to be prescribed antibiotics occur in the first 24 hours of admission. There are multiple teams involved in the care of the patient, presenting challenges for assuming ownership of antibiotic decision-making. The participants identified problems arising from pressure to act and respond rapidly in the emergency department (ED) , Q18. ThThe patient care pathway in hospitals includes a multitude of medical and surgical specialties, pharmacists, nurses, and allied healthcare professionals, who may prioritize different policies, agendas, and interim goals. Different specialties have their own language, behaviors, social norms, and values. The cultural differences between specialties and healthcare professionals: (1) shape the shared knowledge within and across specialities in patient pathways, and (2) result in variation in care, thus impacting patient outcomes. Antibiotic decision-making is driven by different determinants in medicine vs surgery. There are different drivers of overuse that arise from cultural and contextual differences across these specialties. An understanding of these key differences is essential to the development of contextually fit and sustainable interventions to optimize antibiotic use.The interplay of collectivist vs individualistic approaches, together with fear of negative outcomes in surgery, leads to less tolerance to uncertainty. In medicine, uncertainty arises from the transition of care between ED and inpatient teams. The medical teams take a more collectivist approach than surgical teams. Though subject to communication flaws, the medical team addresses them by including other healthcare professionals, such as the pharmacist and infectious diseases consultant, in routine, daily decision-making. The presence of the pharmacist on the WR and the infectious diseases consultant on the ward means that they can have direct discussions with the consultants and decisions can be made there and then. The cultural norm of collectivism and the interdisciplinary approach to decision-making contribute to efforts to optimize antibiotic use. The gaps in care around antibiotic decision-making in medicine appear to be in the 24 hours after admission, when the patient moves from ED to medical wards. This transition of care between different teams is a challenge to antibiotic optimization. The Surviving Sepsis Campaigns have driven the culture of being “infection aware” and initiating antibiotics for patients upon admission , but canThe surgical team however, has its own unique challenges. Having the senior surgeons in theater and the junior doctors chasing medical jobs means that the skill mix of the team on the ward is sometimes imbalanced. Difficult decisions such as de-escalation of antibiotic therapy are often deferred. This may result in prolonged and unnecessary courses of antibiotics for surgical patients. The surgeons prioritize surgical and patient outcomes, and their fear of negative patient outcomes overrides the fear of the unintended consequences of inappropriate antibiotic use. Time is limited in the surgical team due to the demands from the clinics, operating room, and wards. The different professions do get involved in the surgical patient pathway, but they tend to work in silos, with few communication opportunities between them. Multidisciplinary teamwork is not easily practiced in such a context, and time constraints are part of the problem. The surgeons’ time on the ward is extremely limited, so they must prioritize their commitments, preferring to only communicate with their own team and expecting the junior members of the team to coordinate the multidisciplinary tasks and actions that are identified. Therefore, it may not be expedient to suggest replicating the acute medical model of including a pharmacist on surgical WRs. Equally it may be unrealistic to expect surgeons to include ASPs in their daily review of patients. We identified inconsistencies in the approach to antibiotic decision-making in surgery, often with the key identified variables not discussed as part of the WR. Some of this is due to the practicalities of the WRs in surgery and can be overcome through simple solutions . The surThis is a single-center study limited to acute medical and surgical teams in one hospital in England. While the findings may be broadly applicable to other settings, we are replicating the study in centers in India and South Africa investigating antibiotic decision-making across surgical pathways. The study methodology has also been replicated in a study in Australia.The observed variation in the social norms, values, and behaviors in medicine and surgery defines the approach to antibiotic decision-making. The medical team adopts a more policy-driven, interdisciplinary approach that includes pharmacist and infectious diseases input. The transition of care between the ED and inpatient care is a critical point for optimizing antibiotic prescription decisions in medicine. The surgical teams perceive themselves to be highly skilled interventionists, and see ASPs as having a low priority. Medical and surgical specialties represent different tribes, with different cultures and challenges. To optimize antibiotic use across these specialties, it is imperative that interventions are designed with these unique challenges in mind.Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Supplementary materials are available at ciy844_suppl_Supplementary_Material_Data_CollectionClick here for additional data file.ciy844_suppl_Supplementary_Material_ParticipantsClick here for additional data file.ciy844_suppl_Supplementary_MaterialClick here for additional data file.