On July 1, 2011, the Chinese government launched a national Action Plan for antibiotic stewardship targeting antibiotic misuse in public hospitals. The aim of this study was to evaluate the impacts of the Action Plan in terms of frequency and intensity of antibiotic utilization and patients costs in public general hospitals.Administrative pharmacy data from July 2010 to June 2014 were sampled from 65 public general hospitals and divided into three segments: (1) July 2010 to June 2011 as the preparation period; (2) July 2011 to June 2012 as the intervention period; and (3) July 2012 to June 2014 as the assessment period. The outcome measures included (1) antibiotic prescribing rates; (2) intensity of antibiotic consumption; (3) patients costs; and (4) duration of peri-operative antibiotic treatment in clean surgeries of thyroidectomy, breast, hernia, and orthopedic procedures. Longitudinal and cross-sectional analyses were conducted.Longitudinal analyses showed significant trend changes in the frequency and intensity of antibiotic consumption, the patients’ costs on antibiotics, and the duration of antibiotic treatment received by surgical patients undergoing the 4 clean procedures during the intervention period. Cross-sectional analyses showed that the antibiotic prescribing rates were reduced to 35.3% and 12.9% in inpatient and outpatient settings, that the intensity of antibiotic consumption was reduced to 35.9 DDD/100 bed-days, that patients’ costs on antibiotics were reduced significantly, and that the duration of peri-operative antibiotic treatment received by surgical patients undergoing the 4 types of clean procedures decreased to less than 24 hour during the assessment period.The Action Plan, as a combination of managerial and professional strategies, was effective in reducing the frequency and intensity of antibiotic consumption, patients’ costs on antibiotics, and the duration of peri-operative antibiotic treatment in the 4 clean surgeries. Staphylococcus aureus (MRSA), extended-spectrum β-lactamase-producing Escherichia coli, imipenem-resistant Pseudomonas aeruginosa, and imipenem-resistant Acinetobacter baumannii accounted for 50% to 70% of nosocomial infections in China in 2010 [The increasing prevalence of antibiotic resistance has been recognized as a public health threat worldwide, especially in China . The pre in 2010 ,4. An epAccording to recommendations from the World Health Organization (WHO), healthcare authorities should put emphasis on four aspects to contain antibiotic resistance, including 1) establishment of a national system to address antibiotic resistance; (2) legislation followed by enforcement to prevent illegal sales or marketing of prescription drugs targeting microbial infections; (3) education and stewardship on rational antibiotic use; and (4) strict adherence to guidelines aiming to prevent infections in the entire healthcare facilities . Collect establisThe aim of this Research Article was to bridge the gap by examining the pharmacoeconomic impacts of the Action Plan. Administrative pharmacy data and electronic medical records were extracted from the hospital information systems in 65 public general hospitals across China. The impacts of the Action Plan on antibiotic consumption and economic costs were analyzed using segmented regression analysis of interrupted time series (ITS).Regulations on Prescription Management issued on February 10, 2010, which highlights pharmacy validation by clinical pharmacists on medication use, especially on antibiotic prescribing [Regulations on pharmacy administration in medical institutions issued on January 30, 2011, which underscores the key roles of Drug and Therapeutics Committees (DTCs) and clinical pharmacists in formulary control, concurrent prescribing monitoring, and pharmacy validation [Action Plan for Antibiotic Stewardship in Clinical Application issued on April 25, 2011, which outlines the key elements in developing and implementing a framework for antibiotic stewardship in public hospitals [The Action Plan for combating antibiotic resistance officially took into effect on July 1, 2011 . Since cospitals . In our The Action Plan dictated: (1) that the chief administrators (leaders groups) of the hospital should be responsible for patient outcomes and cost-effectiveness of antibiotic utilization; (2) that the prescription evaluation system should be enforced with manifested disciplinary actions against infringement ; (3) thaRegulations on Clinical Applications of Antibiotics [Apart from regular dissemination sessions through routine DTC meetings in respective hospitals, the Ministry of Health regularly held national education programs for physicians and managerial personnel. Supervision on the compliance with the Action Plan was conducted twice a year by the healthcare authorities. These measures are an ongoing process, so is the refinement of the guidelines for prescribing antibiotics. On May 8, 2012, the Chinese MoH issued a revised version of antibiotic guidelines entitled http://www.clinphar.cn/). The inclusion criteria required the completeness and availability of administrative pharmacy data and electronic medical records from all medical units, excluding the departments of pediatrics and hematology, over the past 4 years (July 2010 to June 2014). By stratified sampling based on classification  of public general hospitals, the research protocols were sent to the pharmacy departments of 300 public general hospitals. Among the 152 hospitals that responded, 65 hospitals  were selected depending on the inclusion criteria. The stratification of sampling was based on the ratio of the total number of medical encounters in tertiary hospitals to the number in secondary hospitals in 2011  [Conceived by the first author in May 2014, a research on the pharmacoeconomic impacts of the Action Plan was discussed by peers on a professional clinical pharmacist community  . This reSince 3 major policy changes mentioned above had occurred before the initiation of the Action Plan on July 1, 2011, we chose data points of 12 months prior to the initiation. The coauthors of our study agreed to identify this time period as a preparation period. Further, it was reasonable to postulate that there were lagged effects of the Action Plan as disseminating and implementing the Action Plan occurred during an extended period of time. After preliminary data analysis on the collected data, the study period was divided into 3 segments characteristic of the segmented regression analysis, including Segment 1: the preparation period (July 2010 to June 2011); Segment 2: the policy intervention period (July 2011 to June 2012); and Segment 3: the assessment period (July 2012 to June 2014).The outcome measures were the managerial goals set by the Action Plan, as described above. Antibiotic consumption data were collected from the administrative pharmacy data and electronic medical records in the 65 hospitals using a self-developed program, by which the consumed medication including antibiotics (ATC code: J01–J05) were converted into the ATC/DDD system  . Antibioy-intercept); and (2) trend, which is the rate of change of an outcome measure of interest . Segmented regression analysis of interrupted time series allows us to assess, in statistical terms, how much an intervention changed an outcome of interest, immediately and over time; instantly or with delay; transiently or long-term [0 estimates the level of the outcome during the preparation period; β1 estimates the trend during the preparation period; β2 estimates the level change during the policy intervention period; β3 estimates the trend change during the policy intervention period; β4 estimates the level change during the assessment period; β5 estimates the trend change during the assessment period. Yt is the average monthly value of the outcome measure of interest at month t; time is a continuous variable indicating time in months at time t starting from the preparation period (time 0); intervention is an indicator for time t occurring before (intervention = 0) or after (intervention = 1) the policy intervention which was implemented at month 13 ; time after intervention is a continuous variable counting the month after the policy intervention at time t, coded 0 before the policy intervention or 1–36 after the policy intervention; assessment is an indicator for time t occurring before (assessment = 0) or after the assessment (assessment = 1) which was implemented at month 25; time after assessment is a continuous variable counting the months after the assessment at time t, coded 0 before the assessment or 1–24 after the assessment. The last term in et, representing variation unexplained by the segmented regression model. The error term et is assumed to be comprised of a Gaussian random error (white noise) and an potential error term at time t that may be correlated to errors (the autoregressive component) or shocks (the moving-average component) at preceding or subsequent time points [et is reduced to a white noise by fitting an ARMA model to the error term et [Segmented regression analysis of ITS was conducted to analyze the aggregated monthly data of interest from indicated hospitals. The data points were then divided into 3 segments corresponding to the preparation period, policy intervention period, and assessment period. Two parameters define each segment of a time series: (1) level, which is the value of a time series at a beginning of a given times series . The effects of policy intervention are expressed as changes in level and trend and their corresponding standard errors. Segmented Regression analysis of ITS was conducted using PROC ARIMA of SAS. In addition, the impacts of the Action Plan were evaluated by whether the managerial goals on antibiotic consumption had been achieved during the assessment period; therefore, cross-sectional analyses were conducted on the average yearly values of outcome measures during the 3 periods using PROC MIXED of SAS. Bar charts were plotted for data visualization, with error bars representing standard deviations. Normality was checked by Shapiro-Wilk test, and homoscedasticity was checked using plots of residuals against the predicted values. The significance level was 0.05.se = 0.22; p < 0.001), by 1.07% , and by 1.31%  per month in the inpatient, outpatient and emergency settings during the intervention period, respectively  and emergency  settings during the assessment period compared with the preparation period  in the inpatient settings, and by 1.31 DDD/1000 outpatient-days  in the outpatient settings during the intervention period  during the intervention period, whereas the average costs on medication showed a significant decrease  at the start of the intervention period  per month during the intervention period for hospitalized patients  per month during the intervention period (p = 0.041), medication , antibiotics , and on the very-restricted antibiotics  for hospitalized patients during the assessment period compared with the preparation period , $0.81 , and $0.14  per month during the intervention period, respectively (p < 0.001), antibiotics , and on the very-restricted antibiotics  during the assessment period compared with the preparation period  per month during the intervention period; the duration of peri-operative antibiotic treatment received by the surgical patients decreased by 0.19 day  per month during the intervention period (p < 0.001) and the duration of peri-operative antibiotic treatment  during the assessment period compared with the preparation period  in the frequency and intensity of antibiotic consumption, the patients’ costs on antibiotics, and the duration of antibiotic treatment received by surgical patients undergoing the 4 clean procedures during the intervention period (Tables In summary, the impacts of a national action plan for antibiotic stewardship in China were evaluated with reference to the goals set by the Action Plan, including the frequency and intensity of antibiotic consumption as well as the duration of antibiotic prophylaxis in clean surgeries of thyroidectomy, breast, hernia, and orthopedic procedures. A total of 65 public general hospitals were included, and data were extracted from pharmacy modules of respective hospital information systems. Longitudinal analyses were conducted on the average monthly data by regression analysis of ITS; cross-sectional analyses were conducted on the average yearly data using the mixed model. Regression analyses of ITS revealed consistent and significant trend changes (d Tables , and 3. d Tables  in inpatd Tables  in inpatd Tables  during td Tables  and 62% d Tables  in inpatd Tables .The purpose of the Action Plan as a combination of professional and administrative strategies was to promote rational antibiotic utilization to contain the prevalence of antibiotic resistance and patients’ costs. The Action Plan focused on the managerial strategies. The effectiveness and efficiency of the managerial strategies can be attributed, at least partially, to the organizational structure in China’s public hospitals. The chief administrators are appointed jointly by higher healthcare administrations and cadre authorities, taking full responsibilities of day-to-day performance, including procurement of medicines and employment decisions . HealthcSince China’s private hospitals, which handled about 5% of total outpatient and inpatient services , are priAlong with the antibiotic stewardship program in public hospitals, the Chinese government began to strengthen antibiotic utilization policy specific to primary healthcare institutions in the community and in rural clinics, which will be evaluated in our future studies. We hope that the fundamental changes prompted by the Action Plan can gradually turn into institutionalized and standardized clinical practice in all healthcare institutions so as to effectively address the global threat—antibiotic resistance.In conclusion, the antibiotic stewardship in China was effective in reducing the frequency and intensity of antibiotic use in public hospitals. Furthermore, segmented regression analysis of ITS reveals how these changes in antibiotic prescriptions changed in different settings in various types of hospitals, which will provide evidence for healthcare policy makers when for future policy interventions on antibiotic stewardship.


The aim of this study is to study the clinical features and diagnostic performance of IgG4 in Chinese populations with IgG4-related diseases (IgG4-RDs).The medical records of 2901 adult subjects who underwent serum IgG4 level tests conducted between December 2007 and May 2014 were reviewed.P < 0.001) participants. For IgG4 >135 mg/dL, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), likelihood ratio (LR)+, and LR− were 86%, 77%, 18%, 99%, 3.70, and 0.19, respectively. When the upper limit of normal was doubled for an IgG4 >270 mg/dL, the corresponding data were 75%, 94%, 43%, 98%, 12.79, and 0.26, respectively. For IgG4 >405 mg/dL , the corresponding data were 62%, 98%, 68%, 98%, 37.00, and 0.39, respectively. When calculated according to the manufacturer's package insert cutoff (>201 mg/dL) for the diagnosis of IgG4-RD, the corresponding sensitivity, specificity, PPV, NPV, LR+, and LR− were 80%, 89%, 29%, 99%, 7.00, and 0.23, respectively. For IgG4 >402 mg/dL , the corresponding data were 62%, 98%, 68%, 98%, 36.21, and 0.39, respectively. For IgG4 >603 mg/dL , the corresponding data were 50%, 99%, 84%, 97%, 90.77 and 0.51, respectively. The optimal cutoff value of serum IgG4 (measured by nephelometry using a Siemens BN ProSpec instrument and Siemens reagent) for the diagnosis of IgG4-RD was 248 mg/dL, the sensitivity and specificity were 77.6% and 92.8%, respectively.Serum concentrations of IgG4 were measured in 2901 cases, including 161 (5.6%) patients with IgG4-RD and 2740 (94.4%) patients without IgG4-RD (non-IgG4-RD group). The mean age of the IgG4-RD patients was 58.4 ± 16.1 years (range: 21–87), and 48 (29.8%) were women. The mean serum IgG4 level was significantly much higher in IgG4-RD patients than in non-IgG4-RD (1062.6 vs 104.3 mg/dL, The present study demonstrated that 2 or 3 times the upper limit of the manufacturer's reference range of the IgG4 level was a useful marker for the diagnosis of various types of IgG4-RD and the optimal cutoff level was 248 mg/dL. The purpose of this investigation was to evaluate the diagnostic performance of IgG4 test in a real-world setting by reviewing the final diagnoses of patients who were tested in a tertiary medical center to evaluate their IgG4 level. We aimed to assess the best cutoff of serum IgG4 levels for the diagnosis of IgG4-RD in patients with a wide variety of clinical features and organ/tissue involvement.IgG4-RD has been identified as an emerging disease entity, and the diagnosis of this disease has increased rapidly in recent years. A high serum IgG4 level and increased numbers of IgG4-positive plasma cells in tissues have been regarded as important clues to the diagnosis of IgG4-RD.29 or was 201 mg/dL in accordance with the manufacturer's package insert (reference range: 3–201 mg/dL).12All patients were treated at Chang Gung Memorial Hospital, a tertiary teaching medical center in Taiwan that has 3707 beds and admits over 150,000 patients each year. We identified patients with serum IgG4 levels measured between December 2007 and May 2014 and followed these patients up for at least 3 months. This study included 2901 adult subjects aged 18 years or older who underwent IgG4 testing at this institution. This study was approved by the Institutional Review Board of Chang Gung Memorial Hospital . Written informed consent was not necessary due to the retrospective nature of this study. All blood specimens were sent to the clinical laboratory at CGMH, which is certified by the College of American Pathologists. Serum levels of IgG4 were determined by immunonephelometry using a Siemens BN ProSpec instrument and Siemens reagent . The upper limit of normal for the serum IgG4 level was 135 mg/dL, which was in accordance with most previous studies32 Collected data included sex, age at onset, clinical features at presentation, laboratory test results from the first encounter, and mortality and morbidity. The data from the 161 IgG4-RD patients were used to compare the profiles of 2740 patients without IgG4-RD (non-IgG4-RD group).The medical records of 2901 subjects were reviewed from the time of diagnosis until death, loss to follow-up, or the end of December 2014. The diagnosis of IgG4-RD was made according to clinical diagnosis and international guideline.χ2 test or Fisher exact test, and 2-tailed Student t test was used for group comparisons of numerical data. We evaluated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratio (LR) of elevated serum IgG4 concentrations for the diagnosis of various IgG4-RDs. The best cutoff values for IgG4 were determined by receiver-operating characteristic (ROC) and area under curve (AUC) analyses. A P value <0.05 was considered statistically significant. All statistical analyses were performed using SPSS software version 17.0. .Continuous variables are expressed as means ± SD. Categorical variables are shown as percentages and were analyzed with a Serum IgG4 levels were measured in the 2901 adult patients. Table P < 0.001), men , mean serum IgG4 level , and the presence of an elevated IgG4 >135 mg/dL  or IgG4 >201 mg/dL  (Table Table P < 0.001) , we evaluated the test performances of a cutoff value for the upper limit of normal for the serum IgG4 by ROC curves analysis. The optimal cutoff value of serum IgG4 (measured by nephelometry using a Siemens BN ProSpec instrument and Siemens reagent) for the diagnosis of IgG4-RD was 248 mg/dL, the sensitivity and specificity were 77.6% and 92.8%, respectively. The area under the ROC curve (AUC) for IgG4 level was 0.903  of the IgG4-related diseases were non-AIP IgG4-RD. Moreover, in the present study, 26 of the 161 (16.1%) IgG4-RD patients had OOI outside of the hepatobiliary system, which is also similar to previous studies.35 Ghazale et al9 studied 510 patients with various pancreatic diseases, of whom only 45 had AIP (8.8%), which is similar to the present study's findings .IgG4-related disease is a systemic disorder that may involve multiple organs and tissues, including the pancreas, bile duct, salivary gland, eye, lymph node, skin, retroperitoneum, aorta, pituitary gland, lung, liver, kidney, thyroid, breast, prostate, spleen, and other organs/tissues.42 In the present study, we confirmed that autoimmune rheumatic diseases are likely under-recognized diseases associated with IgG4 elevation.29 However, in the setting of autoimmune rheumatic diseases, elevated serum IgG4 levels are not specific for IgG4-RD and are likely to be false-positives in the absence of clinical evidence of IgG4-RD. Of note, a long-term follow-up study of patients with autoimmune rheumatic disease demonstrated no increased risk of developing IgG4-RD compared with the general population.29 In a population with low pretest probability  of IgG4-RD, the serum IgG4 concentration has a poor PPV for the diagnosis of IgG4-RD and, therefore, the clinical significance of elevated serum IgG4 concentration alone must be interpreted with caution.Moreover, the present study revealed that patients with elevated serum IgG4 levels encountered in clinical practice manifest a wide range of diseases Table . Althoug29 whereas the specificity ranged from 60% to 97%.29 The use of IgG4 for the diagnosis of AIP was first suggested in 20013; Hamano et al found that elevated serum IgG4 levels were 95% sensitive and 97% specific in differentiating AIP from pancreatic cancer.9 Subsequent large cohorts of patients with a wide variety of pancreatic diseases showed that elevated serum IgG4 levels are characteristic but not diagnostic of AIP.21 Kamisawa et al28 reported that elevated serum IgG4 levels in 58% to 100% of AIP cases and the mean level ranged from 336.8 to 729.3 mg/dL. In the present study, the majority of IgG4-RD patients had elevated serum concentrations of IgG4 (80% >201 mg/dL and 86% >135 mg/dL). Among the 161 patients with diagnoses of IgG4-RD, only 23 (14.3%) had normal serum IgG4 concentrations (≤135 mg/dL). Moreover, the present study revealed that patients with elevated serum IgG4 levels encountered in clinical practice manifest a wide range of diseases, and only 18% (138/773) of them have IgG4-RD, which is similar to the findings of previous studies in whites13 and Japanese.16 Studies have highlighted the spectrum of disorders associated with elevated serum IgG4 levels and concluded that a majority of patients with serum IgG4 elevations do not have IgG4-RD. In this study, >82.1% (635/773) of subjects with elevated IgG4 levels (>135 mg/dL) showed no evidence of an IgG4-RD. The corresponding value for a cutoff point of IgG4 >201 mg/dL based upon the manufacturer's package insert was 70.8% (311/439). Despite these shortcomings, the large proportion of patients with elevated IgG4 levels without evidence of the features of an IgG4-RD is an important observation.16IgG4-RD is a chronic fibroinflammatory condition frequently associated with elevations in serum IgG4 levels and tissue infiltration with abundant IgG4 + plasma cells. Accumulating evidence has confirmed that the IgG4 level is useful in the diagnosis of IgG4-RD. In previous studies and meta-analyses, the reported sensitivity of IgG4 for the diagnosis of IgG4-RD ranged from 52% to 97%,43 and 135 mg/dL based upon the Comprehensive Diagnostic Criteria,29 revised clinical diagnostic criteria for type 1 AIP (JPS-2011),45 and clinical diagnostic criteria for IgG4-SC (IgG4-SC-2012),46 whereas some use a cutoff of 130 mg/dL20 or even 119 mg/dL.16 The HISORt criteria from the Mayo Clinic43 and the Japanese consensus criteria43 were mainly produced to facilitate the diagnosis of Type I AIP. Chari et al8 introduced the HISORt criteria based on a prospective study of 29 consecutive patients at the Mayo Clinic who met the histological criteria for AIP. The Mayo Clinic reported a sensitivity, specificity, and positive predictive value of 76%, 93%, and 36%, respectively, using a cutoff value for IgG4 of 140 mg/dL.9 A serum IgG4 level >2 times the upper limit of normal greatly increased the specificity (99%) for AIP,9 which is a similar finding as that of the present study. It is noteworthy that the revised HISTOR criteria43 and the International Consensus Diagnostic Criteria for AIP47 consider an IgG4 level more than twice the upper limit of normal to be highly suggestive. Moreover, an elevation of the serum IgG4 over 2 or 3 times the upper limit of normal is generally considered to be specific and highly suggestive (or diagnostic) for AIP and IgG4-RD.48In previous studies, the upper limit of normal (ULN) for serum IgG4 is considered to be 140 mg/dL according to the Mayo Clinic criteria11 In previous studies,29 important differences were seen in the characteristics of patients evaluated as well as the cutoff value used to define a positive test. Previous studies on serum IgG4 measured in targeted populations with a high probability of having one or another manifestation of IgG4-RD have reported a high sensitivity and specificity.29 High serum IgG4 levels are reported to have a moderate-to-good sensitivity and specificity for the diagnosis of IgG4-RD but because of the low prevalence of the condition, the PPV of the serum IgG4 test is reported to be between 10% to 36% depending on the study populations.19 Consistent with previous studies, the findings of this study confirm that the PPV for the diagnosis of IgG4-RD is low at 17.9% with a cutoff of 135 mg/dL, which is similar to a previous study of 15% with a cutoff of 130 mg/dL14; however, the prevalence of IgG-RD in that study was very low 12 in contrast to the prevalence of IgG4-RD in the present study . Similarly, another 2 studies from the Mayo Clinic showed the PPV for IgG4-RD was 18.4% (29/158)5 and 10.0% (39/390),13 but the prevalence  of IgG4-RD was less than 1% . In contrast, the prevalence of AIP in the study by Ghazale et al9 was 8.8% (45/510), the PPV was 36% (>140 mg/dL), and the PPV could be improved to 75% if a serum IgG4 level of 280 mg/dL (2 times the upper limit of the reference range) was used, which is similar to the present study . Another study from Japan has also come to similar conclusions.16 These studies16 have a higher proportion of patients with IgG4-RD (5.6%–12.1%) and subsequently can offer a much higher positive predictive value. However, in another 2 previous studies,14 the pretest probability  was low (0.7%–0.9%); thus, the PPV is much lower. These differences might explain the wide range of sensitivity, specificity, and PPV results reported.19 The present study demonstrated that serum IgG4 concentration has valuable diagnostic utility when the pretest probability of the disease is more than several percent; therefore, indiscriminate testing of serum IgG4 levels should be discouraged as it does not add diagnostic value in the absence of consistent clinical findings. Moreover, a serum IgG4 >135 mg/dL has been widely accepted as the cutoff value for the diagnosis of IgG4-RD. However, there is no agreed-upon international standard for IgG4 quantification or the IgG4 cutoff level.48 The best IgG4 cutoff in the present study (measured by nephelometry using a Siemens BN ProSpec instrument and Siemens reagent) was 248 mg/dL for IgG4-RD. It was noted that the method and reagent used for IgG4 testing requires special concern as there was a 2-fold difference in the IgG4 levels obtained by different methods and reagents used for IgG4 testing.48 The differences in calibration reflected in the stated adult reference ranges for the 2 companies should be noted when interpreting the IgG4 data: for the Binding Site, 3.9–86.4 mg/dL, and for Siemens, 3.0–201 mg/dL.31The diagnostic performance of IgG4 in a Chinese population in the present study is similar to a previous meta-analysis, which evaluated the usefulness of serum IgG4 in diagnosing AIP and showed variations in sensitivity and specificity ranging from 67% to 94% and 89% to 100%, respectively.There are limitations of the present study that warrant discussion. First, it is still possible that some cases of IgG4-RD may have been missed and misclassified, especially in patients who did not have a classic IgG4-RD presentation. However, this problem is common to all studies that did not use tissue pathology-proven cases as the criterion standard of IgG4-RD. Second, problems might occur due to the fact that for the definitive diagnosis, histology is required, which often is difficult to obtain . Thus, the probability of misclassification is possible. However, the present study investigated a large number of unselected patients that had been enriched for patients with multiorgan as opposed to single-organ disease and included AIP and non-AIP IgG4-RD. One strength of this study was that we investigated the clinical utility of an IgG4 test performed not only outside gastroenterology setting but that covered all ranges of IgG4-RD. Moreover, this study investigated the clinical utility of different cutoff IgG4 levels in a real-world setting of serum IgG4 levels in 2901 Chinese patients.In conclusion, the serum IgG4 concentration has a moderate-to-good positive predictive value in the diagnosis of IgG4-related sclerosing disease when it is more than 2 or 3 times the ULN of the manufacturer's reference. Furthermore, a number of conditions may also result in high IgG4 concentrations and should be kept in mind when interpreting the IgG4 level. Failure to understand the test characteristics of serum assays for IgG4 and to employ them effectively in clinical practice can lead to either over diagnosis or delays in diagnosis. Characteristic histology and response to steroids can further establish the diagnosis of IgG4-RD in patients either with or without elevation of serum IgG4 levels. When reporting results, it would be helpful for laboratories to include their in-house data on the background rate of IgG4 positivity because many practicing clinicians are not aware of the high background rate of IgG4 positivity in the general population and the normal value of IgG4 levels varies by different methods and reagents used for IgG4 testing.


We reconstructed the equivalent dose throughout the patient’s body from therapeutic and stray radiation and applied SMN incidence and mortality risk models for each modality. Excluding skin cancer, the risk of incidence after proton CSI was a third of that of photon CSI. The predicted absolute SMN risks were high. For photon CSI, the SMN incidence rates greater than 10% were for thyroid, non-melanoma skin, lung, colon, stomach, and other solid cancers, and for proton CSI they were non-melanoma skin, lung, and other solid cancers. In each setting, lung cancer accounted for half the risk of mortality. In conclusion, the predicted SMN risk for a 13-year-old girl undergoing proton CSI was reduced vs. photon CSI. This study demonstrates the feasibility of inter-institutional whole-body dose and risk assessments and also serves as a model for including risk estimation in personalized cancer care.Children receiving radiotherapy face the probability of a subsequent malignant neoplasm (SMN). In some cases, the predicted SMN risk can be reduced by proton therapy. The purpose of this study was to apply the most comprehensive dose assessment methods to estimate the reduction in SMN risk after proton therapy  Some studies have estimated the risk of SMN for children receiving radiotherapy for tumors of the central nervous system ,12,13,14 effects ,17,18,19 effects . Over thThe purpose of this study was to estimate for a single patient the reduction in SMN risk that may be achieved by applying proton beams rather than photon beams in craniospinal irradiation (CSI). We did this by estimating the predicted risks of radiogenic SMN incidence and mortality for a 13-year-old girl in two separate clinical environments. These estimates included dosimetric contributions from both therapeutic and stray radiation calculated in this study and widely-accepted SMN risk models from the literature. As a result, we were able to determine the SMN sites of greatest concern for each modality. In addition, in this multi-institutional study, we expanded, tested, and improved our methods for estimating out-of-field dose in photon radiotherapy, which will be applied in future studies.RxD, of 23.4 Gy-RBE to the entire craniospinal axis (1.8 Gy-RBE/fraction in 13 fractions). The patient was a 13-year-old girl, with a height of 147 cm and a mass of 42.6 kg, who had been treated with proton CSI at MD Anderson. As part of the patient’s care, computed tomography (CT) images in the supine position had been acquired for treatment planning purposes; the images extended from the patient’s mid-thigh to beyond the top of the head (71.5 cm), with a reconstructed slice thickness of 2.5 mm (pixel size 0.98 mm × 0.98 mm). Target and avoidance structures were contoured as well as organs and tissues that corresponded to possible SMN sites, which included the “whole body” , bladder, breasts, colon, liver, lungs, ovaries, skin, stomach, thyroid, uterus, rectum, red bone marrow, and a “remainder” that was created as a Boolean subtraction of the union of all specific SMN-site organs and tissues from the whole body. This remainder volume included the central nervous system. SMN risks from intracranial boost fields targeting the tumor resection bed or posterior fossa were not considered in this study because boost fields are small and bear much less importance for SMN risk than the CSI fields [To test a typical scenario for a pediatric cancer patient with prospects for long-term survival of a primary cancer, we created separate CSI treatments for a patient diagnosed with medulloblastoma according to the standards of care of two leading academic cancer treatment facilities in their respective regions—The University of Texas MD Anderson Cancer Center (“MD Anderson”) using protons  and the I fields . This stRxD was 21.3 Gy. A treatment couch model had been added to the CT images to account for attenuation through the couch. The proton CSI treatment plan was created using a commercial treatment planning system  [The MD Anderson standard proton treatment technique for pediatric CSI is administered with the patient positioned in the supine position . The RBECA, USA) . The treCA, USA) ,24,25. T3He tracking. The system was validated by comparing its results to the results of previous studies and measured data. These changes resulted in more accurate dosimetric calculations, faster simulation times, and reduced variance. The treatment-plan Digital Imaging and Communications in Medicine-Radiation Therapy (DICOM-RT) objects [The TPS was used to calculate the in-field dose throughout the virtual geometry, including the patient and the treatment couch, with a treatment planning calculation grid of 2.5 mm. Equivalent dose from secondary neutrons was calculated in each voxel using the Monte Carlo Proton Radiotherapy Treatment Planning (MCPRTP) system ,23,26,27 objects —RT Image objects ,26, and  objects ,27.RxD of 23.4 Gy-RBE in common with the proton plan. At AUBMC, photon CSI is performed typically with a patient in the prone position, with the chin rotated out of the path of the upper spinal field. Because the CT image set had been collected at MD Anderson with the patient in the supine position, adjustments were made in the photon plan to remove the treatment couch and the patient’s chin from the TPS calculations to resemble the scenario in which the CT image set had been collected with the patient in the prone position. Field characteristics are listed in The RT Image and RT Structure Set files from MD Anderson containing the containing the CT images and contoured volumes were de-identified ,34, sentvD(pri), in Gy was calculated throughout the extent of the CT image set. The equivalent dose in each voxel from primary fields, vH(pri), in Sv was the product of the mean radiation weighting factor,vD(pri), or:TH(pri) was calculated as the mass-weighted average of the equivalent dose in all voxels from primary fields within a particular organ or tissue, T, using the following equation:ρv was the mass density of the tissue within a voxel. Finally, because the captured CT image set did not extend from the thighs to the feet, the low-dose regions inferior to the CT image set were not included in the red bone marrow, skin, remainder, and whole body volumes. To account for the effect of the lessening of TH(pri) values by the weights of missing voxels in these regions, mean doses for these volumes were reduced by multiplying them by the ratio of the mass of the patient in the CT image set to the mass of the patient’s entire body recorded in her clinical chart, or 0.726. Effectively, this approximation assumed that the dose in tissues inferior to the CT image set was negligible compared to the dose within the CT image set.Mean organ doses were determined from voxelized dose distributions calculated by each TPS. The absorbed dose in each voxel from primary fields, ation 92 . For priy factor ,37 at anvD(n), was calculated throughout the patient’s body—both in-field and out-of-field—using the MCPRTP system. The neutron component of the in-field absorbed dose was calculated separately because of the highervD(n) was calculated for external neutrons, vD(next), and internal neutrons, vD(nint), in separate simulations for each treatment field, and the values were then summed for all fields. The values forvH(next) and vH(nint), Equation (2) was used to calculate TH(next) and TH(nint), and these values were reduced as described in TH(n), was the sum of the external and internal neutron contributions, or:For proton CSI, absorbed dose from secondary neutrons in each voxel, oton CSI , so thatation 92 . EquatiovH/sp in (Sv·sp−1). Therefore, it was necessary to normalize the secondary neutron TH values to the therapeutic dose in the following manner. A beam normalization volume (BNV) was contoured for each field encompassing voxels in the central region of the proton CSI target volume of each field and receiving approximately uniform absorbed dose. Additional separate MCPRTP simulations were performed in which vD(pri)/sp (in Gy·sp−1) was determined and carried through the methods above to calculate vH(pri)/sp and HBNV(pri)/sp. Finally, TH was calculated as the product of TH/sp and the number of source particles required for HBNV(pri)/sp from MCPRTP to match the HBNV(pri) from the TPS, or:The equivalent dose results for neutrons calculated by MCPRTP were reported per source particle, Dose calculation algorithms of TPSs for photon radiotherapy are accurate in the in-field region but inaccurate in the out-of-field region ,39,40,41TH values, we exported the dose distribution calculated by the AUBMC TPS to DICOM RT Dose files, imported them into the MD Anderson TPS, and used the MD Anderson TPS to calculate TH, as described in In the first approach, we calculated the mean equivalent dose in organs and tissues for in-field, partially in-field, and out-of-field organs based only on the TPS calculation. To maintain consistency between the methods of calculating mean et al. [et al., a sensitivity analysis was performed to determine if the DVH data were sufficiently accurate for calculating the mean organ dose. Specifically, if adjusting vD in the voxels outside the 5% isodose surface by ±60% resulted in a greater than ±5% difference in TH, then TH for that organ was estimated based on a volume-weighted average that combined the TPS estimate of the in-field component of dose with a measured out-of-field component of dose. If not, TH for that organ was determined based on the vD values from the TPS.In the second approach, we applied the volume-weighted averaging technique developed by Howell et al. . Dose voet al. . The meavs. distance from the CSI field edge . Because the treatment unit for this study was the same as that in the previous study, the model and its fitted parameters were applied directly. For each voxel that was more than 1 cm outside of the field edge, the vD values were replaced by those calculated by the following equation:1 = 224.8 cm-cGy/Gy, μ1 = −2.16 cm, σ1 = 1.57 cm, α2 = 224.3 cm-cGy/Gy, μ2 = −7.43 cm, and σ2 = 10.28 cm from the previous study.In the third approach, we applied an analytical model developed in our previous study  of absorvH with the model-based estimate from Equation (5). The resulting position and dose data were converted back into a DICOM RT Dose file, and TH values were calculated as described in To replace the TPS-calculated values with those calculated by the model, we used the following computational methods. The 50% isodose surface was converted to a contoured structure using the TPS. Then the DICOM-RT objects for the dose distributions and contoured structures were exported from the TPS to separate RT Dose and RT Structure Set formatted files, respectively. The coordinates and doses of each voxel in the RT Dose file and the coordinates of each vertex of the 50% isodose surface in the RT Structure Set file were read into an in-house code and processed using commercial software . For each voxel that was both outside the 50% isodose surface and at a distance greater than 1 cm from the nearest vertex of the 50% isodose surface, the code replaced TI, and mortality, TM, were estimated for specific cancer sites that correspond to T using linear-no-threshold models:TI/TH and TM/TH were risk coefficients derived from the age-, sex-, and organ-specific risk models of the BEIR VII Report of the National Research Council of The National Academies [TI/TH and TM/TH coefficients for each T were interpolated linearly between values for a 10-year-old girl and a 15-year-old girl from Tables 12D-1 and 12D-2 in the BEIR VII Report. Hremainder was used to estimate the risk of other solid cancers, and Hred bone marrow was used to estimate the risk of leukemia. This risk model was used for all cancers with the following exceptions in which recommended risk coefficients were not provided in the BEIR VII Report. For non-melanoma skin cancer (NMSC), we applied values of Iskin/Hskin and Mskin/Hskin that we derived from ICRP Publication 60 [Mthyroid/Hthyroid, we multiplied the interpolated value for Ithyroid/Hthyroid by the proposed lethality fraction for thyroid cancer of 0.1 from ICRP Publication 60. Thus, we took into account all known radiogenic cancer risks.The excess absolute lifetime risks of radiogenic cancer incidence, cademies . IT/HT aation 60 , adjustiTI/TH and TM/TH by a factor of 1.5 for all cancers except leukemia. Similarly, we excluded DDREF for Iskin/Hskin and Mskin/Hskin. The final values of TI/TH and TM/TH, after adjustment for DDREF, for a 13-year-old girl are listed in The risk coefficients for all cancers except leukemia had been reduced by a dose and dose rate effectiveness factor (DDREF) of 1.5 that corrected the risk models for low dose (<100 mGy) or low dose rate (<0.01 mGy/min) exposures. Because the organ doses in this study were moderate to high, we removed the DDREF by increasing vD of the therapeutic fields as calculated by the TPSs. In the axial plane shown, the proton CSI plan had a narrower (left to right) but deeper 100% isodose line than the photon CSI plan. These effects resulted from differences in standards of care at the two clinics, with AUBMC having wider lateral margins for photon CSI and MD Anderson including the distal portion of the vertebral body in the proton CSI target volume, both of which are to avoid a steep dose gradient in the vertebrae for patients that are still maturing and subsequently to reduce the risk of asymmetric bone growth [e growth .TH for proton CSI at MD Anderson are listed in TH in the red bone marrow, remainder, whole body, skin, and lungs. These were also the organs and tissues that received the largest TH. The liver, thyroid, and colon received comparable contributions from proton fields and secondary neutrons, and secondary neutrons predominated TH in the stomach, breasts, uterus, bladder, and ovaries. In each organ and tissue, both external and internal neutrons were contributors to TH, and TH from external neutrons was between 1.4 and 4.4 times that from internal neutrons. Apart from the whole body volume, the organs and tissues receiving the highest TH in proton CSI were the red bone marrow, remainder, skin, and lungs.Values of TH for photon CSI at AUBMC are listed in TH values. This was true even for the breast, in which only 12% of the volume was within the 5% isodose surface. Therefore, in the volume-weighted average approach, TH was modified only for the uterus, ovaries, and bladder, as shown in TH values. Those increases in TH were slight in the whole body, stomach, remainder, red bone marrow, and skin (percent difference ≤10%); moderate in the colon, liver, and lungs (10% < percent difference ≤ 50%), and large in the bladder, uterus, breasts, and ovaries (percent difference >50%). Compared to the model-based approach, the TPS calculation underestimated Hbreasts by more than a factor of 2. The volume-weighted approach resulted in higher Huterus, Hovaries, and Hbladder values that were higher than those of the TPS calculations but lower than those of the model-based approach. Because it was entirely in-field, the choice of methods had no effect on the reported thyroid dose. The organs and tissues receiving the highest TH in photon CSI at AUBMC were the thyroid, stomach, colon, red bone marrow, and lungs.Values of TH values were higher for photon CSI at AUBMC than for proton CSI at MD Anderson in all organs and tissues except the skin, which had approximately equal TH. The red bone marrow, remainder, and whole body organs also had TH values for photon CSI that were within a factor of 2 of those of proton CSI. Other radiosensitive organs and tissues had TH values for photon CSI that were factors of 2.3 to 20.1 higher than those of proton CSI.After accounting for out-of-field dose, TI values from photon CSI at AUBMC and proton CSI at MD Anderson are shown in TI for proton CSI to TI for photon CSI. The SMN with the highest TI values for photon CSI were thyroid cancer, NMSC, lung cancer, and other solid cancers. Those with highest TI values for proton CSI were NMSC, other solid cancers, and lung cancer. Differences in TI of 5% or more between the two treatments were found for thyroid, lung, colon, breast, stomach, and other solid cancers; and differences in TI for the other cancers were less than 2%. Ratios of TI were less than 1 for all cancers except NMSC and were smallest for stomach, colon, and thyroid cancers. The ratio of the sums of TI for all cancers was 0.46 when including NMSC and 0.30 when excluding NMSC. NMSC accounted for one-quarter and one-half of the sums of TI in photon CSI and proton CSI, respectively. In photon CSI, only one-tenth of the total risk of SMN incidence was from out-of-field dose, but in proton CSI, one-quarter of the total risk of SMN incidence was from stray radiation.TM values from photon CSI at AUBMC or proton CSI at MD Anderson are shown in TM for proton CSI to TM for photon CSI. The SMN sites of greatest concern for a radiation-related fatality were lung cancer and other solid cancers in both cases. The ratios of risk for each SMN site were identical to those for incidence. Differences in TM of 5% or more were found for lung, colon, stomach, thyroid, and other solid cancers. The ratio of risk of SMN mortality for all cancer sites was 0.39, and the risk of fatality from NMSC was negligible. In photon CSI, one-eighth of the total risk of SMN mortality was from out-of-field dose, and in proton CSI, one-quarter of the total risk of SMN mortality was attributable to stray radiation.We performed an inter-institution comparison study on the predicted lifetime attributable risks of SMN incidence and mortality for a 13-year-old girl receiving photon CSI at an academic cancer center in the Middle East with those for the same patient receiving proton CSI at an academic cancer center in the U.S., taking into account both primary and stray radiation and all known radiogenic cancers. We found that the risks of incidence or mortality for proton CSI were approximately half those for photon CSI. With proton CSI, the absolute risks of SMN incidence were especially reduced for thyroid, lung, colon, breast, stomach, and other solid cancers compared to photon CSI. The specific SMN of greatest concern for a radiation-related fatality was lung cancer, accounting for half the risk in each case. It was also lung cancer for which proton therapy yielded the greatest reduction in absolute SMN mortality risk. Stray radiation contributed to the incidence and mortality risks in both treatment modalities and was especially important in proton CSI, even though the total risk remained lower in all cancer sites. This study demonstrated the feasibility of comparative inter-institutional whole-body dose and risk assessment capabilities.et al. found that the probability of NMSC incidence was high. As time after exposure increases, the treatment-related incidence and mortality rates for their cohort likely will increase. In a study involving 10 pediatric patients, Brodin et al. [et al. agree with our high predicted risk of SMN incidence our patient and decreased risk of SMN incidence by using proton instead of photon CSI. In a previous study for a cohort of 17 patients receiving proton CSI or photon CSI within MD Anderson, we found the ratios of SMN risks from proton CSI versus photon CSI to range between 0.10 to 0.22 for incidence and between 0.20 and 0.53 for mortality [The predicted lifetime absolute attributable risks of SMN incidence and mortality in this study were high. This was true even for SMNs that originate outside the craniospinal axis. In a previous study for a 4-year-old boy undergoing proton CSI or photon CSI at MD Anderson , we founn et al.  also preortality . Our ratet al. [For the patient and treatment tested here, one-sixth of the risks of SMN incidence and mortality in proton CSI were due to external neutrons. This finding confirms a similar previous result for a 3-year-old boy . By neglet al.  to incluet al. [We estimated the predicted risks of incidence of NMSC and found them to be approximately equal between proton and photon CSI. NMSC is the most common treatment-related subsequent neoplasm in childhood cancer survivors  and has et al.  that NMSChildren are particularly susceptible to SMN and some other late effects because of the radiation sensitivity of their organs and tissues, the proximity of non-target organs and tissues to the treatment fields, and the ongoing development of their organs ,49,50. TThe main limitations of our study are associated with the risk models. The uncertainties in risk are large and difficult to estimate, owing in part to the imprecise understanding of the applicability of DDREF in fractionated radiotherapy. The risk model has other inherent limitations. The models were derived from data from a general population, mainly atomic bomb survivors, and the application of these risk models to cancer patients receiving therapeutic doses introduces uncertainty in the risk predictions that is difficult to quantify ,43,52,53vs. photon therapy. Specifically, when considering all radiogenic cancers, we found that a 13-year-old girl receiving proton CSI incurred much lower predicted risks of SMN incidence and mortality than she would if receiving photon CSI. The SMN of greatest concern for mortality was lung cancer. The results of our study suggest that the risk of radiogenic cancer may be reduced and quality of life improved for children needing CSI in countries in which proton therapy is not available if proton therapy is accessible to them; however, more research is needed to confirm these findings in patients of various ages and both sexes.In summary, this case study demonstrated the feasibility of inter-institutional whole-body dose and risk assessments and provided further evidence that proton radiotherapy reduces the risk of late effects for children with brain cancer


We investigated whether beliefs about addiction being a ‘disease’ or ‘brain disease’, and holding certain beliefs about addiction aetiology, are associated with public views about addicted persons and support for different types of treatment, coerced treatment and punishment for addiction.Data were collected as part of the 2012 Queensland Social Survey, a computer assisted telephone interview of 1263 residents of Queensland, Australia. Participants were presented with scenarios of two addicted males, one who was addicted to heroin and the other addicted to alcohol. Participants were then asked a series of questions for both characters.2 = 273.90, p < 0.001). Being 35 years of age or older , heroin: OR = 0.49 (0.28-0.85)) and having 15 or more years of education , heroin: 0.55 (0.40-0.75)) predicted less support for coerced treatment. 31.7% of respondents agreed heroin use should be punished by imprisonment and being 35 years of age or older (OR = 0.51 (0.33-0.80)) predicted lack of support. The sample agreed that an alcohol or heroin dependent person would suffer career damage , marriage breakdown  and get in trouble with the law . Respondents expressed more comfort with encountering alcohol rather than heroin addicted persons in the workplace or at a dinner party. Beliefs that addiction was a ‘brain disease’ or a ‘disease’ did not predict any of these attitudes. Beliefs about addiction aetiology were inconsistent predictors of outcomes measured.There was widespread support for all treatment modalities . There was less support for coerced treatment for alcohol than heroin addiction (alcohol: 41%, heroin: 71%, χAge and educational attainment were the most consistent predictors of stigmatising beliefs and beliefs about coercion and punishment. Beliefs that addiction is a ‘disease’ or a ‘brain disease’ were not associated with an overall reduction in beliefs about stigma, coercion or punishment. Beliefs in different causes of addiction were not consistent predictors of beliefs about stigma, coercion or punishment. Neuroscience research on the effects of chronic addictive drug use on brain function has been used to argue that addiction is a chronic relapsing ‘brain disease’ ,2. In paThe implications of this model for how addicted individuals are viewed and treated are hotly contested. Advocates argue that acceptance of the brain disease view will reduce the stigmatisation that many people with an addiction experience by showing that an inability to refrain from using drugs arises not from personal qualities such as moral ‘weakness’ but as a result of drugs ‘hijacking’ the brain’s reward system . The hopCritics of the brain disease model of addiction argue that it will fail to deliver these benefits or perhaps produce more negative consequences for addicted persons. Some argue that placing responsibility for addiction on the individual’s ‘brain’ neglects the role of the social environment – ranging from family to workplace, to broader structural and cultural dynamics – as a contributor to addiction. They argue that the brain disease model individualises responsibility and may increase funding for health programs that focus on ‘medical’ aspects of addiction at the expense of social ones . Some deincrease stigmatisation  and calculating the mean score  . PositivFollowing exploratory data analysis, the demographic variables included as predictors of attitudes in the logistic regressions we conducted were: gender ; age ; and education . The binary variable ‘familiarity’ was based on answers to questions about personal experience with addiction. Those who had or knew someone who had had a problem with alcohol/heroin use were classed as having familiarity with addiction . 62% of respondents had themselves experienced or had someone close to them experience problematic alcohol use. 19% of respondents reported having familiarity with problematic heroin use. In both cases, it was mostly someone close to the participant rather than the participant who had experienced problematic substance use .‘Biological’: indicating participants’ agreement that addiction is caused by i) chemistry in the brain; or is ii) genetic/inherited;‘Socio-environmental’: including i) the way he was raised; or ii) stress;‘Personal qualities’: including i) psychological problems; ii) addictive personality; or iii) ‘bad character’.As described previously , we creaResponses to the four and five-point scales for agreement, likelihood and helpfulness were re-coded into binary variables  as follows: disagree/strongly disagree = negative = 0, agree/strongly agree = affirmative = 1; unlikely/very unlikely = negative = 0, very likely/quite likely = affirmative = 1; not helpful = negative = 0, very helpful/somewhat helpful = affirmative = 1.Don’t know/unsure responses to these questions  were discarded from analysis. Overall high rates of agreement relating to treatment made logistic regression analysis infeasible for these questions. The two questions from the AMIQ pertaining to ‘comfort’ were combined, by adding the dichotomized variables together, to create a comfort scale .There was strong support for all treatment modalities for both the heroin and alcohol addicted characters Table . Partici2 = 273.90, p < 0.001). Beliefs about whether addiction was a disease or a brain disease were not associated with support for coerced treatment (Table There was significantly greater support for forcing Peter into treatment for his heroin addiction (71%) than for forcing John into treatment for his alcohol addiction 41%)  to agree that John should be forced into treatment. In the case of heroin addiction, those 35 years of age and older were 0.49 times as likely as those aged 18–34  to agree that Peter should be forced into treatment. Having 15 or more years of education was associated with lower support for coerced treatment in the case of both alcohol  and heroin addiction  compared to those with 1–12 years of education.People who had experienced their own, or another’s alcohol addiction were 0.72 times less likely than those with no familiarity with alcohol addiction to agree that John should be coerced into treatment . No association was evident between familiarity with heroin addiction and views on coerced treatment. Females were 0.73 times less likely than males to agree that Peter should be forced into treatment for his heroin addiction (OR = 0.54-0.99). We observed no association between gender and beliefs about coerced alcohol addiction treatment.Approximately one-third (31.7%) of the sample agreed that Peter should go to prison for his heroin addiction. Table t-test, p < 0.001).Table Low variation in ratings on the AMIQ items mean that it was not possible to assess associations between demographic factors and stigmatising beliefs about addiction. Answers to questions about the extent to which people felt comfortable interacting with addicted persons in the workplace or at a dinner party showed more variation than answers to questions about the possible negative consequences of addiction. We therefore modelled these separately Table .Table 7Persons with more familiarity with alcohol addiction were more comfortable with an alcohol addicted person . The same was the case for people who agreed that alcohol addiction had biological causes . People who were neutral or did not know if alcohol addiction had social-environmental causes were more likely to be comfortable than those who disagreed . People who agreed that alcohol addiction was caused by personal qualities were less likely to feel comfortable with an alcohol addicted person than those who disagreed .Different factors predicted the level of comfort people felt with a heroin addicted person. Females were less likely to report feeling comfortable with a heroin addicted person  and those with 15 or more years of education were marginally more likely to feel comfortable with someone who had a heroin addiction . People who were neutral or did not know whether heroin addiction had social-environmental causes were more likely to feel comfortable with a heroin addicted person than those who disagreed . Those who agreed that heroin addiction had social-environmental causes were also more likely to feel comfortable with a heroin addicted person than those who disagreed .Our findings show that public acceptance of the brain disease model of addiction did not reliably predict, either positively or negatively, the attitudinal outcomes we measured. This corroborates our previous qualitative research, which suggested that neuroscientific understandings of addiction were added to, and incorporated into, older ideas about addictions, making it unlikely that new ideas about addiction will produce dramatic shifts in the public’s beliefs about addiction and its treatment ,16. It aAll forms of treatment except medication were endorsed on average by more than 90% of participants. Medication was supported by more than 80% of participants. Participants were highly supportive of all treatment options for both alcohol and heroin addiction, suggesting that the public favours a ‘try anything and everything’ approach.Predictions that understanding addiction as a brain disease would be associated with greater or lesser support for the use of coerced medical treatment of addicted individuals were not supported by our findings ,6. InsteSupport for the belief that addiction is a brain disease did not predict agreement with imprisoning someone addicted to heroin. Support for the belief that addiction is a disease was on the borderline of significance in predicting beliefs about imprisonment for heroin addiction. Support for addiction as a disease or a brain disease was not associated with attitudes towards coerced addiction treatment. Age and education level were more consistent predictors of support for coerced treatment across alcohol and heroin, and age also predicted agreement with imprisonment. This suggests that, overall, life experience (i.e. being 35 years of age or older) and one’s broader knowledge shaped less punitive attitudes towards addicted persons. Women were less likely than men to support coerced treatment of heroin addiction but not alcohol addiction. There was no gender difference in beliefs about imprisonment for heroin use.Methodological differences between this and previous studies of stigma in addiction limit the ability to make exact quantitative comparisons. However, our pattern of results were consistent with previous studies using the AMIQ , where tFamiliarity with alcohol addiction was associated with increased comfort with someone addicted to alcohol. This pattern did not hold for heroin. This fits with mixed evidence shown in the literature: familiarity can, but does not necessarily, increase comfort levels ,27. BeinHaving 15 of more years of education was barely significant in predicting comfort with someone addicted to heroin. Educational attainment is not a factor that has received much attention in the literature to date. The lack of a clear pattern in the roles of familiarity, gender and educational level in predicting comfort suggest that more research needs to be done in order to understand these factors and their implications.extent to which addiction is considered voluntary, by comparison to mental illnesses like schizophrenia. They advocate for a more detailed understanding of the factors underpinning ‘social’ versus ‘biological’ causal beliefs [Our findings have implications for the communication of information about addiction. The variability in our findings across the drugs alcohol and heroin raises questions about the benefits of formulating messages about the nature of addiction in general. Our findings suggest that we may need to reduce negative views of heroin users and the challenge the public’s tendency to believe that coerced treatment of this group of drug users is justifiable and/or effective . Our fin beliefs . It coul beliefs . Examini beliefs .per se. Three of the questions are quite similar to the symptoms of substance use disorders specified in the DSM-5 [Methodological differences limit our ability to directly compare our findings on stigma with the previous literature . Our quehe DSM-5 . Thus, rThe primary purpose of this study was to provide a snapshot of the Australian public’s views on the treatment and stigma of addiction, and to do so in a way that yielded results of policy relevance. Latent Class Analysis could be used to achieve a more nuanced understanding of, and address theoretical questions about, the relationships between causal beliefs and stigma ,34. In pThe overall high level of agreement among respondents in the use of all treatment modalities restricted our ability to undertake statistical analyses to compare beliefs about addiction aetiology and beliefs about treatment. Additionally, we did not ask questions about the public’s belief in the effectiveness of treatments. Further research exploring the public’s beliefs about treatment efficacy is needed.As we have reported elsewhere, the low response rate and bias in the sample towards older and more educated individuals limits the generalisability of our findings . A low rOur study does not support the more extreme predictions made about either the benefits or the harms of public acceptance of ‘brain disease’ explanations of addiction. The findings suggest a need to communicate messages that destigmatise drug dependent persons, particularly those addicted to heroin. On our data, communication of information about biological causes and understandings of heroin addiction may not yield the large benefits predicted by proponents of this view, although our data suggest a possible benefit from communicating messages about the biology of alcohol addiction.


Staphylococcus aureus (CA-MRSA) in North America, ED attendances and hospital admissions secondary to ABSSSIs have increased significantly. First-line antibiotic drug therapies for ABSSSIs have therefore changed to take account of CA-MRSA and the threat of evolving antibiotic resistance. Prior to 2010, randomized controlled trials (RCTs) of antibiotic therapy for ABSSSI used broad trial inclusion criteria and utilized investigator-determined clinical resolution, 7 to 14 days after the end of therapy, as the primary outcome measure. In order to produce more objective, reproducible, and quantifiable primary outcome measures, the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research and a multidisciplinary consortium convened by the Foundation for the National Institutes of Health (FNIH) issued significantly changed trial guidance criteria. The currently recommended primary outcome measure is an assessment of greater than 20% reduction in the area of erythema, edema, or induration from baseline, measured at 48 to 72 h after randomization and initiation of drug treatment. In contrast, the European Medicines Agency (EMA) still recommends measurement of clinical resolution at a later time period. We discuss the evolution of changes to trial guidance criteria issued by the FDA since 1998 and the potential difficulties of implementing the recommended primary outcome measured at an earlier time point in RCTs of outpatient antibiotic treatment performed in the ED setting.Acute bacterial skin and skin structure infections (ABSSSIs), which include cellulitis, abscesses, and wound infections, are among the most commonly encountered conditions in emergency departments (EDs) internationally. Primarily, as a result of the recent epidemic of community-associated methicillin resistant  Cellulitis, abscesses, and wound infections, most recently renamed as acute bacterial skin and skin structure infections (ABSSSIs) , represeStaphylococcus aureus (CA-MRSA) is the most common identifiable cause of purulent skin infections in EDs [S. aureus as a primary cause of ABSSSI, the advent of CA-MRSA was associated with increased ED attendances [In the USA, community-associated methicillin-resistant s in EDs . Data frs in EDs . Rather endances  and hospendances  secondarendances ,12. CA-Mendances .In addition to antibiotic stewardship and infection control policies, it follows that the identification of new drug therapies for ABSSSI is clinically important . EquallyThe need for more objective, reproducible, and reliable outcome measurements in RCTs of antibiotic treatment for ABSSSI prompted revision of clinical trial guidance criteria issued by the US Food and Drug Administration (FDA) . Over thThis review describes recommendations relevant to the ED setting, from regulatory authorities in the United States (US) and Europe concerning the measurement of treatment outcomes and inclusion criteria for RCTs of antibiotic therapy for ABSSSIs. Not only have there been changes to disease nomenclature, but also a complete revision of clinical trial entry criteria and the timing and method of measurement of the primary outcome.Nomenclature for this group of infections is confusing for two major reasons. Firstly, phenomenological descriptions of different types of infection , predisposing conditions (diabetic foot ulcer), eponymous diseases , and microbiological causes of infection ,21 have US regulations concerning the conduct of RCTs of antibiotic therapy for ABSSSI are issued in the form of ‘Guidance for Industry’ documents by the FDA Center for Drug Evaluation and Research (CDER). In the 1998 guidance document, infections were classified as complicated or uncomplicated   Biomarkers Consortium. This consortium analyzed both historical data and data from recently published trials which examined this new efficacy endpoint in conjunction with the older endpoint of ‘clinical cure’.2 measured by the area of redness, edema, or induration [ABSSSIs are defined as cellulitis or erysipelas, wound infections, and abscesses of at least 75 cmduration . Measureduration , but othduration . It is sduration . In addiA mixture of the different ABSSSI disease entities should be included with a cap of 30% on the number of major abscesses enrolled . The 201Limiting the number of patients with abscess to less than 30% of trial participants will minimize the bias that surgical treatment of abscesses may introduce to the RCT, and prevent overrepresentation of abscesses from regions where purulent cellulitis is more commonly encountered . The rolPatients should ideally not have received any antibiotic therapy prior to trial enrollment unless there is objective evidence of the ABSSSI deteriorating while on treatment . HoweverThe primary outcome measure should assess for 20% or greater reduction in lesion size when measured at 48 to 72 h compared to baseline . The timAccording to the most recent FDA guidance, the secondary outcome measure should be investigator-determined clinical resolution measured between 7 and 14 days after the completion of therapy .Measurement of reduction in the area of erythema represents a more objective, quantifiable, and reproducible primary outcome assessment than clinical cure at the end of therapy. However, there is still controversy regarding what constitutes a clinically meaningful trial outcome measure for RCTs of ABSSSI treatment ,19,31. AIt is worth noting that although the FDA issues guidelines pertaining to clinical trial design, the guidelines are not binding but represent ‘current thinking’ on issues related to trial design Table . SeveralThe primary outcome measure recommended by the EMA is an investigator-determined clinical outcome  measured at 7 to 14 days after the end of therapy. The EMA primary outcome measure is the same as the FDA-recommended secondary outcome measure . It is lThe feasibility of employing the recent FDA-recommended primary efficacy outcome measure (reduction in lesion size 48 to 72 h after randomization to treatment) may be challenging in ED-based RCTs of antibiotic treatment for ABSSSIs. ED-specific challenges to patient recruitment such as overcrowding and loss to follow-up of recruited patients who may not live in the ED’s catchment region are well recognized . In an EOther trials of outpatient antibiotic therapy for ABSSSIs performed in the ED-setting have used investigator-determined clinical resolution of disease at the test-of-cure visit ,46-49. AIn the context of the recently updated 2013 FDA guidance regarding the conduct of RCTs of antibiotic treatment for ABSSSIs, it is timely for emergency medicine professional organizations, such as the Society for Academic Emergency Medicine (SAEM) in the US and the European Society for Emergency Medicine (EuSEM), to develop consensus recommendations to guide emergency medicine researchers on which outcome measures to use for ED-based RCTs of antibiotic therapy for ABSSSIs. In the meantime, emergency medicine researchers should use the primary outcome measure of reduction in lesion size between 2 and 3 days after randomization and clinical cure 7 to 14 days post end of therapy for ED-based RCTs of antibiotic treatment for ABSSSIs.


In order to improve the durability of fly ash concrete, a series of experimental studies are carried out, where durability improving admixture is used to reduce drying shrinkage and improve freezing-thawing resistance. The effects of durability improving admixture, air content, water-binder ratio, and fly ash replacement ratio on the performance of fly ash concrete are discussed in this paper. The results show that by using durability improving admixture in nonair-entraining fly ash concrete, the compressive strength of fly ash concrete can be improved by 10%–20%, and the drying shrinkage is reduced by 60%. Carbonation resistance of concrete is roughly proportional to water-cement ratio regardless of water-binder ratio and fly ash replacement ratio. For the specimens cured in air for 2 weeks, the freezing-thawing resistance is improved. In addition, by making use of durability improving admixture, it is easier to control the air content and make fly ash concrete into nonair-entraining one. The quality of fly ash concrete is thereby optimized. Coal is widely used in China as fuel for power plants because of its dependability and economy. In 2009, more than 375 million tons of fly ash was generated from coal-fired power plants in China. How to effectively use fly ash is still a major social problem. In order to construct recycling society, researchers have found many ways to make efficient use of fly ash in civil engineering field –10, but On the basis of the above mentioned background, this paper focused on the nonair-entraining concrete. The effects of durability improving admixture, air content, water-binder ratio, and fly ash replacement ratio on strength development, drying shrinkage, carbonation, and freezing-thawing resistance of fly ash concrete are to be investigated.The characteristics of materials used and the properties of fly ash used are shown in Tables 3 of durability improving admixture was added to the final mixture. Air-entraining water reducing admixture was added to all the concrete, accounting for 1% of the weight of binder. In order to regulate fixed air content (4.5%), the standard air-entraining concrete (hereinafter referred to as “ST”) used special air-entraining water reducing admixture. The concrete using durability improving admixture (hereinafter referred to as “D”) became nonair-entraining type concrete, because of strong antifoam reaction in the admixture itself. The nonair-entraining concrete (hereinafter referred to as “PL”) obtained fixed 1% air content by antifoam admixture. The target slump of concrete was 18 cm, and the target air content was 4.5% (ST) and 1.0% .In this experiment, fly ash (FA) was used to replace the internal mass of cement, and 10 kg/mCylindrical specimens, 100 mm in diameter and 200 mm in height, for compression tests were encased in light gauge molds in 3 layers and stripped molds after 24 hours. Then, specimens were cured in water at 20°C until testing ages. Prism specimens were used for drying shrinkage tests, accelerating carbonation tests, and freezing and thawing tests, the dimension of which was 100 mm × 100 mm × 400 mm. The specimens were cast in 2 layers and stripped molds after 24 hours. Then, the specimens for drying shrinkage tests were cured in water at 20°C for 7 days; the specimens for accelerating carbonation tests were cured in water at 20°C until 28 days and stored at air dried condition at 20°C for 28 days; the specimens for freezing-thawing tests were cured in water at 20°C until 28 days.The specimens were tested at the age of 7 days, 28 days, and 91 days in wet condition according to JIS A 1108-2006. Modulus of elasticity tests were measured at the same time of compressive strength tests according to JIS A 1149-2010.The specimens were taken from water at 7 days and then stored at 20°C and 60% R.H. in air, and were measured their length change and weight loss for 13 weeks according to JIS A 1129-1-2010.2 concentration according to JIS A 1153-2012. Carbonation depth was determined by phenolphthalein test on sprinkled surface.After being moist-cured for 28 days and air-dried for 28 days, the specimens were stored in accelerating carbonation chamber at 20°C, 60% R.H., and 5% COThe specimens were subjected to freezing-thawing cycles at the age of 28 days according to ASTM C666/C666M-2003(2008) or JIS A 1148-2010.W/B = 50%, cured in water at 20°C). The compressive strength of concrete reduces with the increase of fly ash replacement ratio. This result is not related to water-binder ratio and the presence or absence of durability improving admixture and air content. However, compressive strength growth of concrete is found to be increased with the increase of fly ash replacement ratio after 28 days. The relationship of cement-water ratio and compressive strength and the relationship of binder-water ratio and compressive strength are shown in W/B = 50% or W/B = 43%).4 N/mm2 at 28 days. Modulus of elasticity showed the same tendency as tensile strength.Upon Figures C: carbonation depth, mm, t: elapsed time, week, and A: carbonation rate, mm/By means of conventional carbonation rate method, the carbonation depth is expressed by  given bex: carbonation velocity coefficient; A: carbonation rate, mm/B: carbonation depth at the start of carbonation acceleration, mm.After 4 weeks of curing in water and 4 weeks of curing in air, because the self-carbonation caused by pozzolanic reaction of fly ash is negligible, it is considered that carbonation velocity coefficient is roughly equal in the same water-cement ratio regardless of fly ash replacement ratio. The ratio of carbonation velocity coefficient of fly ash concrete is ST : PL : D = 18.2 : 13.3 : 11.6 = 1.0 : 0.7 : 0.6. It indicates that nonair-entraining mode can significantly reduce the carbonation rate.The carbonation acceleration experiment is an experiment in raising the carbon dioxide concentration in the surrounding atmosphere, which accelerated carbonation of the concrete and evaluated anticarbonation ability by measuring carbonation depth. In this experiment, 4 different types of precuring carbonation acceleration experiment were applied for water-binder ratio of 50%. Among them, there are initial curing methods I: after 28 days of curing in water then curing in air for 28 days, initial curing methods II: after 28 days of curing in water then curing in seal for 63 days, and finally curing in air for 28 days; initial curing methods III: after 28 days of curing in water then curing in air for 91 days; and initial curing methods IV: after 7 days of curing in water then curing in air for 91 days. In this experiment, 3 different types of precuring freezing-thawing experiments were applied. Among them, there are initial curing methods A: curing in air for 28 days; initial curing methods B: after 28 days of curing in water then curing in air for 14 days; and initial curing methods C: after 28 days of curing in water then curing in air for 28 days.μm of antifreeze damage index as shown in μm. The air content of fresh concrete is the same in PL and D concrete, but the content of air in D concrete becomes 0.5~1.0% greater. This is considered that the glycol ether derivative of the durability improving admixture exists in hardened concrete in the form of tiny droplets under 150 μm. Here, the mechanism of durability improvement is discussed in the perspective of air bubble system. By 2-week drying process in precuring, resistance to freeze damage is improved significantly. When void water dried, a part of glycol ether derivative in the concrete is taken into capillary and gel air cavities, and the original oil specks perform the same function as air bubbles, easing water freeze expansion. It is thought that this improves the resistance to freeze damage.μm or less of oil specks into the hardened concrete. Furthermore, accompanying the drying of void water, by injecting a portion into capillary cavities, shrinkage is lowered. The same reaction occurs in gel cavities, which are the lamellar cavities formed in lamellar crystal while C-S-H hydrate is produced. It is believed that hardened concrete is formed and durability is improved through these processes. Concerning the effect of durability improving admixture in preventing freeze damage, a significant improvement is noted by 2-week drying process in precuring. Considering cavity distribution in concrete, when durability improvement admixture is used, as shown in By using durability improving admixture in nonair-entraining fly ash concrete, the compressive strength of fly ash concrete can be improved by 10%–20%, and its initial compressive strength improved also.Irrespective of the presence of air, durability improving admixture, or fly ash replacement ratio, both tensile strength and modulus of elasticity are dependent on compressive strength.By using durability improving admixture in fly ash concrete, the drying shrinkage is reduced by 60%.Carbonation resistance of concrete is roughly proportional to water-cement ratio regardless of water-binder ratio and fly ash replacement ratio. The ratio of carbonation velocity coefficient of fly ash concrete is ST : PL : D = 1.0 : 0.7 : 0.6. Also, carbonation acceleration experiment of concrete with more than 15% fly ash replacement ratio depends on the carbonation depth at the start.By using durability improving admixture for 2 weeks of curing in air (drying process), the freezing-thawing resistance can be improved even in nonair-entraining concrete.The following conclusions were drawn from the work presented above on the effects of durability improving admixture, air content, water-binder ratio, and fly ash replacement ratio on fly ash concrete properties.By making use of durability improving admixture, it is easier to control the air content and make fly ash concrete into nonair-entraining one. The quality of fly ash concrete is thereby optimized. In the field of application fly ash concrete, the use of nonair-entraining mode and durability improving admixture is a valuable option.


Gram-negative pneumonia in patients who are intubated and mechanically ventilated is associated with increased morbidity and mortality as well as higher healthcare costs compared with those who do not have the disease. Intravenous antibiotics are currently the standard of care for pneumonia; however, increasing rates of multidrug resistance and limited penetration of some classes of antimicrobials into the lungs reduce the effectiveness of this treatment option, and current clinical cure rates are variable, while recurrence rates remain high. Inhaled antibiotics may have the potential to improve outcomes in this patient population, but their use is currently restricted by a lack of specifically formulated solutions for inhalation and a limited number of devices designed for the nebulization of antibiotics. In this article, we review the challenges clinicians face in the treatment of pneumonia and discuss the characteristics that would constitute an ideal inhaled drug/device combination. We also review inhaled antibiotic options currently in development for the treatment of pneumonia in patients who are intubated and mechanically ventilated. Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) remain important causes of morbidity and mortality despite advances in antimicrobial therapy . PatientStaphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) add to the increasing difficulty of treating VAP. Unsurprisingly, MDR pathogens are associated with significant attributable mortality [Current treatments are typically given through the intravenous (IV) route; however, despite widespread implementation of current antibiotic guidelines for the treatment of pneumonia, clinical cure rates rarely exceed 60 %, and recurrence rates remain high . The higortality , and theortality , 13; cleortality .Effective treatment of bacterial pneumonia requires the concentration of the antibiotic in the lung to exceed the minimum inhibitory concentration (MIC) of the infecting pathogen. However, while some antimicrobial drugs such as fluoroquinolones penetrate well into lung tissue when administered intravenously , others In mechanically ventilated and intubated patients with pneumonia, targeting antibiotics to the lungs via aerosolization could offer a way to achieve high exposures of antibiotics directly at the site of infection, while minimizing systemic side effects , 25. IniPrevious approaches to nebulized antibiotic therapy have had several clinical and technical limitations, including sub-optimal delivery and lack of drugs specifically formulated for aerosolization , 27. WhiE. coli was greater after nebulization compared with intravenous administration [Perhaps the key advantage of administering antibiotics by inhalation rather than via IV infusion is the potential to deliver high concentrations of antibiotic directly to the site of lung infection , 29. Anistration . Furtherstration , 33. TheThe high lung concentrations achieved with inhaled antibiotics are paired with low systemic absorption ; indeed,K. pneumoniae, P. aeruginosa and AmpC-producing Enterobacteriaceae, among others [Aerosolized antibiotic therapy also provides the potential for a reduction in the overall use of systemic antibiotics , 41, witg others , 43; decg others .Improving outcomes for critically ill patients with pneumonia requires the optimization of clinical factors such as ventilator settings, device usability and patient safety. An ideal inhaled antibiotic therapy should have a suitable formulation for aerosolization and consistently deliver high antibiotic concentrations to the site of infection via an efficient device; the drug should also have limited systemic penetration to prevent unwanted side effects.Currently available IV drug formulations are not optimized for aerosolization and often have properties that may impede drug delivery . In addiP.aeruginosa and Acinetobacter spp. in North American ICUs [The choice of dose in early studies assessing aerosol delivery of antibiotics was sometimes based on the packaging of parenteral IV antibiotics, rather than on an a priori definition of the amount of drug that was needed in the lower airway . Since tcan ICUs .For optimal therapeutic effect, an appropriately formulated antibiotic should be used in combination with an efficient delivery device. A recent meta-analysis of inhaled treatments showed that while nebulized antibiotics (with or without IV antibiotic) may improve clinical cure rates compared with IV antibiotics alone, nebulizers themselves vary considerably in efficiency . Indeed,New drug–device combinations may hold promise in this area. The pulmonary drug delivery system (PDDS) device currently in development (NKTR-061) is an adaptive vibrating mesh nebulizer which has been combined with a specially formulated Amikacin Inhalation Solution BAY41-6551). With this combination, approximately 60 % of the inhaled dose is delivered to the lung , 54. The1. With tA key practical consideration for an ideal nebulizer is its ease of use in the hospital setting. For intubated and mechanically ventilated patients, the nebulizer should integrate directly into the ventilator circuit, with only minimal need to adjust ventilator settings or remove humidification , 52. HowSynchronizing aerosol generation with the inspiratory flow of the ventilator could also enhance drug delivery . An in vThe use of nebulized antibiotics has been increasing steadily since the 1970s, and inhaled antibiotic therapy is being revisited as a potential treatment option due to the surge in pneumonia caused by MDR bacteria . AerosolInhaled colistin has shown clinical utility in pneumonia, generating high lung concentrations and achieving efficient bacterial killing with a clinical cure rate of approximately 67 % , 51, 59.Indeed, despite some promising data, the overall number of well-designed trials examining the efficacy and tolerability of nebulized antibiotics remains low. Many studies have only involved a single center and are confounded by inadequate patient enrollment, poor methodology or failures in standardizing or reporting delivery methods and particle sizes . CurrentAerosolized adjunctive therapy with IV antimicrobials is suggested by the ATS/IDSA guidelines (2005) as appropriate for patients with pneumonia caused by MDR Gram-negative organisms who are not responding to systemic therapy alone; however, these guidelines are now a decade old and may no longer be an accurate reflection of the bacterial landscape currently confronting clinicians in the ICU. Other more recent guidelines, such as the Canadian HAP/VAP guideline (2008), recommend the use of aerosolized vancomycin in patients infected with MRSA; other guidelines currently make no recommendations for the use of inhaled antibiotics , 61.While there is now a more positive attitude toward nebulized antibiotics, clinician knowledge pertaining to the delivery of aerosolized therapy remains poor. Techniques to improve nebulizer output, such as reducing the inspiratory flow, are not regularly employed, and potentially dangerous practices  were reported in a recent survey into physicians’ practice, knowledge and beliefs regarding aerosol therapy .Aerosolized antibiotics have been used off-label for the treatment of pneumonia in mechanically ventilated, critically ill patients for around 40 years, but there is still no consensus, guideline or FDA-approved product available for such treatment . There a® [The PARI eFlow rapid nebuliser system®  is a mul®  to deliv® –66. When® –66. A Ph®) is approved by the FDA for use in patients with cystic fibrosis and is currently under investigation for use in patients with pneumonia. Early studies have suggested that TOBI® is well tolerated and effective for the treatment of VAP caused by P. aeruginosa or Acinetobacter spp., with reduced systemic side effects compared with IV tobramycin [Inhaled tobramycin  . The PDDS synchronizes aerosolization of the antibiotic with the first 75 % of the inspiratory flow, with the aim of enhancing deposition in the lung and reducing wastage. The system can also be used in on-vent and hand-held configurations in a number of orientations to allow therapy to continue after extubation, with no need for ventilator setting or dose adjustment , 68. In ery 12 h . MaximumNebulizer technology continues to evolve. Improvements in nebulizer capabilities may offer new treatment options that maximize the potential benefits of inhaled antibiotic therapy. Recent advances are promising to deliver nebulized therapy options with optimal particle sizes and to achieve improved drug delivery throughout the lung, while maintaining low systemic exposures. The combination of specifically designed drug formulations and modern, high efficiency delivery devices has the potential to overcome current challenges in the aerosolized treatment of pneumonia .Increasing resistance and limited efficacy of currently available IV antibiotics for the treatment of pneumonia in intubated and mechanically ventilated patients are a growing cause for concern, and the choice of effective treatments is limited. New therapy options are urgently needed; continued improvements in antibiotic formulations and nebulizer system designs provide an increasingly positive outlook for the future of inhaled antibiotics.