During the construction of concrete structures, it is often useful to know compressive strength at an early age. This is an amount of strength required for the safe removal of formwork, also known as stripping strength. It is certainly helpful to determine this strength non-destructively, i.e., without any invasive steps that would damage the structure. Second only to the ultrasonic pulse velocity test, the rebound hammer test is the most common NDT method currently used for this purpose. However, estimating compressive strength using general regression models can often yield inaccurate results. The experiment results show that the compressive strength of any concrete can be estimated using one’s own newly created regression model. A traditionally constructed regression model can predict the strength value with 50% reliability, or when two-sided confidence bands are used, with 95% reliability. However, civil engineers usually work with the so-called characteristic value defined as a 5% quantile. Therefore, it appears suitable to adjust conventional methods in order to achieve a regression model with 95% one-sided reliability. This paper describes a simple construction of such a characteristic curve. The results show that the characteristic curve created for the concrete in question could be a useful tool even outside of practical applications. Concrete structures have always been built for a long service life, safety, durability, load-bearing capacity, stability, and working and functional reliability. During construction or usage, however, there may arise a need to determine or verify the properties of the concrete. This is why accurate diagnostics of concrete elements or whole structures are essential. Non-destructive testing methods (NDT) are often used for this purpose . BesidesThe rebound hammer test is currently the most common method of testing the hardness of concrete and was first developed in Switzerland in the 1950s as the Schmidt rebound hammer (sometimes known as the Swiss hammer) . In 1950Its benefits notwithstanding, the rebound hammer test has some weak points, which should be kept in mind during testing and evaluation. Its primary purpose has always been to determine the quality of new concrete elements or structures. The general relationships between hardness and compressive strength were adjusted for this purpose, having been created by the manufacturers and then carried over to technical standards; they apply mostly to concrete of 14 to 56 days of age. The measurement range is then designed for structural concrete used during the second half of the 20th century; i.e., compressive strength of approximately 10 to 70 N/mm2 [2 . When te2 [2  concerne2 [2 , who say2 [2  presentsnnayopas  found thCorrect statistical analysis of the measured values is critical for evaluating Schmidt hammer tests. Alwash et al.  analysedi et al.  conductei et al.  speak agBesides assessing the quality of mature concrete or measuring its compressive strength, which, of course, carries certain associated problems, more modern types of impact hammers are capable of estimating the very early strength  of concrete of only a few hours or days of age. This paper focuses primarily on creating a conversion formula to assess this early compressive strength, which is closely related to e.g., determining a time when it is safe to remove formwork. In fact, this is close to the original purpose of Schmidt hammers–testing concrete which is only several months old.Many types of sclerometers have been developed over the past 70 years; however, the most common type used presently is the Schmidt type. There are several types available, differing from one another in the impact energy, shape and size of the plunger, or mechanical construction. In the past, and possibly even today, the most common Schmidt hammer is the Original Schmidt: a traditional rebound hammer, which became the basis for all the major rebound tests worldwide . The basor areas . Upon inor areas  consideror areas  rank it or areas .The experiment described below was performed with an Original Schmidt N, SilverSchmidt N, SilverSchmidt L, and SilverSchmidt L with a mushroom plunger (MP) accessory.This section discusses some models of dependence commonly used in contemporary civil engineering for estimating compressive strength based on rebound hammer tests. They will be further compared with models created using the experimental data.The standard  defines Line A:Line B:The document  presents00 N/mm2 .Based on the results obtained by the BAM institute, The Shaanxi Province Construction Science Research Institute, China, and Hunan University, China, the document  defines EN 13791 , ASTM C8EN 13791  and ACI EN 13791 . They stThe  also desMeasurements by the SilverSchmidt L can also be made with the mushroom attachment, which should enable measurements of young concrete with low compressive strength. The relationshipfined by  for a raDrawing a general relationship between the rebound number and compressive strength can be a complex task. The aim of this part of the article is to show a new approach to the evaluation of NDT test results by designing the so-called characteristic curve, which ensures 95% reliability.Several papers were published saying that formulating strength as a single parameter can be misleading . Single-x axis) change variation in compressive strength (y axis) as well. In other words, the higher the rebound number measured, the higher the variance in compressive strength. If the violation of homoscedasticity is ignored, the resulting model of relationship can underrepresent the value of compressive strength, especially in higher-strength concrete.The actual method of seeking the optimal model of relationship also requires attention. The most common method, known as regression analysis, or the least squares method, involves several assumptions, some of which may be violated during data evaluation. A determination of an optimal relationship between the rebound test and compressive strength often violates the assumption of homoscedasticity, i.e., homogeneity of variance . A violaHowever, the experimental data presented in this paper shows that under certain circumstances the above-mentioned issues can be legitimately dismissed. These are cases where the goal is not to find a general model for every concrete, but a specific model for only one. Moreover, such a model is not intended for measuring compressive strength across the whole spectrum, but for estimating the stripping rebound number, which should correspond to stripping compressive strength (see below). Most previously published models of the relationship between the rebound number and compressive strength are designed to estimate the median value of compressive strength. The model is therefore designed as a median curve plotted through the experimental data. In theory, a model thus designed is 50% reliable: the measured value of compressive strength is 50% likely to be higher or lower.In the civil engineering practice, however, most cases do not use 50% reliability, but 95%. Such a value of a material property is called a characteristic value. Concerning compressive strength, there is the term characteristic strength . It is ey is the conventional dependent variable (compressive strength), x is the independent variable (rebound number) and This is done using the above-mentioned method of least squares in its simplest form of a linear regression model :(7)y=b1+n is the number of measurements, i.e., value pairs. An important role in the least squares method is played by the matrixThe experimental data is essentially pairs The median values of regression coefficients can then be expressed using the following formulas:measured .At this point the model has a curve passing through the experimental data. It is generally recommended to supplement this curve with so-called confidence bands. This means a confidence band for the median curve, which is normally determined by 95 % interval estimates of e errors ,34(12)Sx, it is necessary to denote the value of Then, for any fixed t-distribution with The confidence band for the median value is then determined using the formula freedom ,34. Nextr. The aptitude of the model is most commonly denoted by the coefficient of determination Both regression bands are shown in Figure 5 through Figure 11. It is useful to expand this traditional regression analysis method with regression coefficient testing and assessing the overall aptitude of the model with the multiple correlation coefficient, which in our case equals the correlation coefficient y for every fixed x. This method of denotation works for most applications of regression analysis. However, seeing as civil engineering usually works with the characteristic value (5% quantile), this method is not quite ideal.It is important to remember that the confidence bands are constructed as two-sided interval estimates of x, and Student’s t-distribution. This quantile determines, among others, the aptitude of the confidence bands, i.e., the probability with which one could expect that the true y-value is indeed located within this band. Adjusting the We construct the characteristic curve using the relationship for determining the prediction band. The breadth of the band is determined by variance x, i.e., for every fixed result of a rebound test. It is, therefore, a half-planeThis curve essentially determines the value of compressive strength for every fixed The following sections show the use of this characteristic curve for determining the characteristic stripping hardness with real-world data.The goal of the measurements and their evaluation was to create a new conversion relationship for determining the compressive strength of concrete by rebound hammer tests. These relationships concern mainly early-age strength: the so-called stripping strength, i.e., in the range of 5 to 10 N/mmThe goal of the first stage was two-fold; to determine a conversion relationship for the rebound number to compressive strength for the selected concrete and to ascertain whether the Original Schmidt N and SilverSchmidt rebound hammers are suitable for this purpose: whether the statistical evaluation would confirm that the more advanced SilverSchmidt suffers from greater measurement variability .The experiment required making 18 cubic specimens of 150 mm in size. The specimens were cast on-site, during the construction of an arch bridge on Svitavská street in Brno, see The specimens were made from concrete taken from three concrete mixer trucks. Six cube specimens were made from each concrete sample, see R were taken using an Original Schmidt N and 5 readings of of the Q-value using a SilverSchmidt N, see Each cube was measured and weighed, and afterwards mounted in a testing press and compressed with a force of 50 kN. Two opposing sides were tested for hardness with a rebound hammer. A total of 5 readings of the rebound number The goal of the second part of the experiment was to determine the relationship between the rebound number and compressive strength for concrete C 50/60, which is used in precast prestressed girders. Effort was made to capture low (stripping) strength. The formula used for making the V03 girders is detailed in While the girders were being made, concrete C 50/60 was sampled and made into 18 cube-shaped specimens with the size of 150 mm. While still freshly poured in steel moulds, they were covered with a PE sheet and left near the girders in the manufacturing hall, where the ambient temperature did not exceed 15 The testing was conducted similarly to the first stage of the experiment with the sole difference that besides the Original Schmidt N and SilverSchmidt N, the SilverSchmidt L both with and without the mushroom attachment was used. The SilverSchmidt L with the attachment is primarily used to test very young concrete, which is why it was used only during the first 2 days , but not beyond. While the previous parts of the experiment were carried out with only one kind of concrete, the third involved making cube specimens from six different concrete mixtures. They only differed in the amount of cement, water, and admixtures; in essence, the The basic fresh-state properties determined in compliance with ,38,39 arQ-value ten times using a SilverSchmidt PC L with the mushroom accessory attached; five measurements on two opposing sides. Finally, the compressive strength test was performed according to [Each concrete was used to make 6 cube specimens sized 150 mm. This made a total of 36 test specimens. While still in polyurethane moulds, the specimens were covered with a PE sheet and stored at standard laboratory conditions  do not require a regression model more complex than a simple line. Moreover, this simplest shape of regression model enables a relatively simple formulation of the characteristic curve.We certainly do not question the validity of relationships described elsewhere , or theiOur regression models and rebound numbers representing stripping strength always apply to the one specific concrete they were designed for and do not work with others. The goal of the paper was to show how such regression models may be created for any concrete.The experiments indicate the following:


Family screening of a 48‐year‐old male with recently diagnosed IgG4‐related disease (IgG4‐RD) revealed unanticipated elevations in plasma IgG4 in his two healthy teenaged sons.We performed gene sequencing, immune cell studies, HLA typing, and analyses of circulating cytotoxic CD4+ T lymphocytes and plasmablasts to seek clues to pathogenesis. DNA from a separate cohort of 99 patients with known IgG4‐RD was also sequenced for the presence of genetic variants in a specific gene, FGFBP2.The three share a previously unreported heterozygous single base deletion in fibroblast growth factor binding protein type 2 (FGFBP2), which causes a frameshift in the coding sequence. The FGFBP2 protein is secreted by cytotoxic T‐lymphocytes and binds fibroblast growth factor. The variant sequence in the FGFBP2 protein is predicted to form a disordered random coil rather than a helical‐turn‐helix structure, unable to adopt a stable conformation. The proband and the two sons had 5–10‐fold higher numbers of circulating cytotoxic CD4 + T cells and plasmablasts compared to matched controls. The three members also share a homozygous missense common variant in FGFBP2 found in heterozygous form in ~40% of the population. This common variant was found in 73% of an independent, well characterized IgG4‐RD cohort, showing enrichment in idiopathic IgG4‐RD.The presence of a shared deleterious variant and homozygous common variant in FGFBP2 in the proband and sons strongly implicates this cytotoxic T cell product in the pathophysiology of IgG4‐RD. The high prevalence of a common FGFBP2 variant in sporadic IgG4‐RD supports the likelihood of participation in disease. Heritable IgG4‐RD has been inferred in prior reports, but no information exists on genetic features that may predispose to disease  stenosis. This was dilated by balloon angioplasty but subsequently recurred. Extensive evaluation for immune vascular disease was negative as was a survey of known causes of hypercoagulability. The patient did not have hypercholesterolemia or systemic hypertension and had no family history of cerebral vascular disease. A second MCA stenosis occurred and the patient had watershed ischemic zones in the cerebral hemisphere noted on magnetic resonance imaging (MRI). The cerebral circulation developed collaterals and a moyamoya appearance was identified on angiography  for further evaluation. Family history was negative for any unusual diseases or of familial illness. The proband's father had resected prostate cancer and his mother had died of lymphoma. The proband had no unusual hobbies or occupational exposures and did not smoke. His childhood and adolescence had been without unusual diseases. The brother and wife had none of the proband's disease features. The proband's two children were healthy teenage boys who had normal school advancement and participation in sports. Plasma IgG4 levels were obtained on all family members and were normal except for the two sons having elevated levels at 125 mg/dl (nl < 89) and 184 mg/dl (nl < 143 for age).2.1Review of the proband's prior submandibular biopsy tissue showed a dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. Immunostains of the tissue revealed a predominant IgG4‐positive plasma cell infiltrate (>100 per high power field), with an IgG4:total IgG ratio of > 40%, thereby satisfying the histopathologic criteria for a diagnosis of IgG4‐RD  was performed at the UDN sequencing core on the proband, his wife, father, brother, and two teenage sons. No clinically actionable genes were found. WGS revealed two candidate variants that were shared by the proband and his two sons. These variants were also shared with the proband's normal father, but not the brother or wife.FGFBP2), chromosome 4, OMIM:614768. FGFBP2 is expressed in cytotoxic lymphocytes whose function is unclear. Given the fact that CD+CTLS have been implicated by us in this disease, we speculate that an alteration in FGFBP2 protein might enhance cytotoxic CD4 + T cell function. We have no information on FGFBP2 protein and IgG4 class switch.The first is a previously unreported frameshift variant, NM_031950.3:c.602delA p.Lys201ArgfsTer26, in fibroblast growth factor binding protein type 2 (FGFBP2 c.268C>Tp.Pro90Ser (rs758329) OMIM: 607713 that has an allele population frequency of 0.40 in the ExAC database. This common missense variant was homozygous in the proband, two sons and father, and heterozygous in the proband's wife.A second variant was found in FGFBP2 variants in a large repository of 99 known IgG4‐RD patients at the Massachusetts General Hospital (MGH). Complete sequencing of the FGFBP2 gene was done in 51 subjects with IgG4‐RD and in a validation cohort of 48 patients. Although the rare missense variant found in our family was not detected in any of the MGH subjects, the common FGFBP2 variant, rs758329 was enriched in the MGH test IgG4‐RD cohort . The validation cohort of 48 IgG4‐RD subjects also revealed enrichment of rs758329 (70.8%). All other SNPs remained at close to population frequencies for large numbers of non‐Finnish European populations. Thus, the common variant was not only enriched in nonfamilial IgG4‐RD but also homozygous in our affected patients.We searched for A variant in a gene associated with Moyamoya disease was found in the heterozygous state in the proband, his father and two sons but not in the brother or wife. Variants in this gene, RNF 213, chr 17 are associated with disease in about 15% of the Moyamoya cases in Japan and Korea  and variant (MUT) protein sequences, Figure 2.4Structural modeling by similar techniques as above was used to determine the effects of the missense variant on the RNF protein. The protein is a ubiquitin‐protein ligase that may play a role in angiogenesis, involved in Wnt signaling. The mutation in our family falls within a structured region that alternates helix and loop. A nearby mutation is known to increase the risk of Moyamoya disease  and two sons .2.6p < 0.001), suggesting an antigen‐driven expansion. This dominant TCR was four times more frequent than the next most frequent CDR3. The overwhelming majority of TCRs was unique minority species and contributed less than T cells each. A similar Next Gen sequencing approach has revealed that patients with IgG4‐related disease have clonal expansions in the blood of CD4 + CTLs . Fluorescence labeling was then performed for 30 minutes on ice using monoclonal antibodies from Biolegend unless otherwise specified. Plasmablast identification was undertaken using the following antibodies: FITC anti‐human CD3 (clone UCHT1), APC/Cy7 anti‐human CD19 (clone SJ25C1), APC anti‐human CD79b (Igβ) (clone CB3‐1), PerCP/Cy5.5 anti‐human CD20 (clone 2H7), Brilliant Violet 510™ anti‐human CD27 (clone M‐T271), and PE/Cy7 anti‐human CD38 (clone HIT2).Antigen‐experienced/effector CD4 + T cells and CD4 + CTLs were identified using the following antibodies: Alexa Fluor® 488 anti‐human CD4 (clone OKT4), Brilliant Violet 510™ anti‐human CD27 (clone M‐T271), APC/Cy7 anti‐human CD45RO (clone UCHL1), and PE anti‐human CD319 (SLAMF7) (clone 162.1). All cells were counter stained using blue viability dye to exclude apoptotic cells (Thermofisher) and analyzed on a BD LSR II cytometer (BD Biosciences). Subsequent analyses were carried out using FlowJo V10.3.Flow cytometric enumeration of activated B and T cells was undertaken as previously described  than the unaffected brother of the proband (8 per million PBMCs).3CD4 + T cells with a cytolytic phenotype (CD4 + CTLs) that secrete pro‐fibrotic cytokines including IL‐1beta, TGF‐beta, and interferon‐gamma are viewed as essential to the pathophysiology of IgG4‐RD (Maehara et al., In summary, we have analyzed the family of a patient with IgG4‐RD. His teenage sons, though healthy, have abnormal IgG4 levels and high levels of circulating IgG4 plasmablasts and CD4 + CTLs. The proband and sons share a rare missense variant in a protein that binds fibroblast growth factor and is predicted to reduce function. This variant was not found in a cohort of 99 cases of idiopathic IgG4‐RD, but another common FGFBP2 variant was found to be highly enriched in these known cases and was found in homozygous form in the affected members of our family. The possibility of familial IgG4‐RD seems strong, although the likelihood that the sons will develop IgG4‐RD is unknown. Further work on the functional properties and the possible contribution of the abnormal FGFBP2 protein to IgG4‐RD is needed. This is an unusual case of familial IgG4‐RD with possible involvement of a dysfunctional T cell protein.None declared.


Elevated levels of oxido-nitrosative stress, hydroxyproline, and myeloperoxidase levels in BALF and lung were significantly decreased by hesperidin on day 14. Hesperidin significantly inhibited BLM-induced down-regulated lung Nrf2 and HO-1 as well as up-regulated TNF-α, IL-1β, IL-6, collagen-1, TGF-β, and Smad-3 mRNA expressions. Western blot analysis showed that alteration in lung NF-κB, IκBα, AMPK, and PP2C-α protein expressions were ameliorated by hesperidin on day 28. Furthermore, BLM induced histological and ultrastructural aberrations in the lung which were attenuated by hesperidin treatment. Hesperidin alleviates BLM-induced IPF via inhibition of TGF-β1/Smad3/AMPK and IκBα/NF-κB pathways which in turn ameliorate the modulation of oxido-inflammatory markers (Nrf2 and HO-1) and pro-inflammatory markers  to reduce collagen deposition during pulmonary fibrosis. See also Figure 1Bleomycin (BLM) is a chemotherapeutic agent which is associated with Idiopathic pulmonary fibrosis (IPF) due to its chronic administration. Hesperidin, a bioflavonoid has been reported to possess antioxidant, anti-inflammatory, wound healing, and antiapoptotic potential. To evaluate the therapeutic potential of hesperidin against BLM-induced pulmonary fibrosis and decipher its possible mechanism of action. Intraperitoneal administration of BLM (6 IU/kg) caused induction of IPF in Sprague-Dawley rats. Rats were treated with hesperidin  for 28 days, followed by estimation of various parameters in bronchoalveolar lavage fluid (BALF) and lung. Hesperidin (50 and 100 mg/kg) administration significantly ameliorated ( Adenosine monophosphate-activated protein kinase (AMPK), Alkaline Phosphatase (ALP), Bleomycin (BLM), Bronchoalveolar Lavage Fluid (BALF), Enhanced Pause (Penh), Expired Volume (EV), Frequency of breathing (f), Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), Glutathione (GSH), Heme oxygenase 1 (HO-1), Hydroxyproline (HP), Idiopathic pulmonary fibrosis (IPF), Interleukins (IL's), Lactate Dehydrogenase (LDH), Malondialdehyde (MDA), Mothers against decapentaplegic homolog-3 (Smad-3), Myeloperoxidase (MPO), Nitric Oxide (NO), Non-phosphorylated AMPK (PP2C-α), Nuclear factor E2-related factor 2 (Nrf2), Nuclear factor-Kappa B (NF-κB), Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha (IκBα), Transforming Growth Factor-β (TGF-β), Transmission Electron Microscopy (TEM), Tumor Necrosis Factor-alpha (TNF-α).Idiopathic Pulmonary fibrosis (IPF) is a multifactorial, chronic disease featured by progressive formation of a scar in the lung parenchyma. The prognosis and diagnosis of IPF are poor with 3-5 years of median survival rate after its diagnosis, which leads to high mortality and morbidity . It is Accumulated evidence suggested that elevated influx of reactive oxygen species (ROS) due to pulmonary insults resulted in the release of pro-inflammatory cytokines (such as tumor necrosis factor-α (TNF-α) and interleukins (IL's)) during initial stage . These The current treatment regimens for the management of IPF include various agents such as cytokine antagonists, immunosuppressant (methotrexate), anti-inflammatory agents (corticosteroid), and colchicines which mainly focus on suppressing the inflammatory response . AdditiBleomycin, a chemotherapeutic agent of glycopeptide group of antibiotics, is used clinically for the management of an array of human malignancies such as cervical cancer, testicular cancer, Hodgkin's disease, and squamous cell carcinomas of the head and neck . Howevein vivo  is a bioflavonoid glycoside widely present in citrus fruits. Hesperidin has been documented to possess a wide range of pharmacological properties including antioxidant, antidiabetic, anti-inflammatory, wound healing, neuroprotective, antihypertensive, antiarthritic, cardioprotective, hepatoprotective, anticancer and antiapoptotic potential . It hasal., 2008). Furtheal., 2008). Previoal., 2008). Howevead libitum). A time of 09:00 to 17:00 h were consider to carry out all the experiments protocol which was approved by the Institutional Animal Ethics Committee . A guidelines mentioned by Committee for Control and Supervision of Experimentation on Animals (CPCSEA), Government of India were followed to perform all experimentsSprague-Dawley rats  were procured from the National Institute of Biosciences, Pune (India). The housing conditions for rats throughout the experimental protocol were: temparature: 24 ± 1 °C, relative humidity: 45-55 %, dark/light cycle: 12:12 h, food: standard pellet chow, water: filtered , BLM , Total RNA Extraction kit  and One-step RT-PCR kit , TNF-α, IL's  ELISA kits , primary antibodies of Thr-172 (phosphorylated AMPK), PP2C-α (non-phosphorylated AMPK), p-NF-κB and p-IκBα .BLM hydrochloride (6 IU/kg in 0.9 % NaCl) was used to induce PF in overnight fasted rats according to method report elsewhere , then tA previous report used to determine the treatment doses of hesperidin   according to method described elsewhere  whereas al., 2015). On day 28, blood was withdrawn by a retro-orbital puncture and the levels of serum Alanine transaminase (ALT), Aspartate Aminotransferase (AST), Alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were measured by using reagent assay kits .BALF total cell counts and levels of total protein, SOD, GSH, MDA, NO, hydroxyproline (HP), myeloperoxidase (MPO) in BALF and lung were estimated according to earlier reported methods . PartThe mRNA expressions of TNF-α, IL-1β, IL-6, Nrf2, HO-1, TGF-β, Collagen-1, Smad-3, and β-actin were analyzed in lung tissue using RT-PCR according to method described elsewhere . WhereaHistopathological analysis of lung tissue was carried out using hematoxylin and eosin (H&E) stain (on day 14) and Masson's trichrome (MT) and Picro-Sirius red (PSR) stains (on day 28) as described previously . Whereap < 0.05 was considered to be statistically significant.GraphPad Prism 5.0 software  was used to perform data analysis. Data are expressed as mean ± standard error mean (SEM) and analyzed by using One-Way ANOVA followed by Tukey's multiple range post hoc analysis (for parametric tests) as well as Kruskal-Wallis test for post hoc analysis (non-parametric tests). A value of p < 0.05) and lung index increased significantly (p < 0.05) when compared with normal and sham rats. Administration of MP (10 mg/kg) significantly (p < 0.05) attenuated BLM-induced decrease in body weight and increase in lung index as compared to BLM controlled rats. When compared with BLM controlled rats, hesperidin  treatment significantly (p < 0.05) inhibited alterations in lung index and body weight. However, when compared with hesperidin treatment, MP (10 mg/kg) treatment more significantly (p < 0.05) inhibited BLM-induced alterations in body weight and lung index  in percent oxygen saturation in BLM controlled rats after intratracheal instillation of BLM. MP (10 mg/kg) administration significantly (p < 0.05) increased percent oxygen saturation level as compared to BLM controlled rats. Administration of hesperidin  also significantly increased (p < 0.05) the level of percent oxygen saturation as compared to BLM controlled rats. However, inhibition of BLM-induced decrease in percent oxygen saturation level was more significant (p < 0.05) in MP (10 mg/kg) as compared to hesperidin treatment  when compared with normal and sham rats. MP (10 mg/kg) administration significantly attenuated (p < 0.05) BLM-induced increase in serum ALP and LDH as compared to BLM controlled rats. Hesperidin (50 and 100 mg/kg) significantly reduced (p < 0.05) BLM-induced increase in serum ALP and LDH when compared with BLM controlled rats. BLM-induced increase in serum ALP and LDH was more significantly (p < 0.05) decreased by MP (10 mg/kg) as compared to hesperidin treatment  in lung function test in BLM controlled rats. However, MP (10 mg/kg) treatment significantly inhibited (p < 0.05) lung function test alterations induced by BLM when compared with BLM controlled rats. Hesperidin (50 and 100 mg/kg) also significantly attenuated (p < 0.05) BLM-induced alterations in lung function test as compared to BLM controlled rats. BLM-induced alterations in PIF and enhanced paused were more significantly (p < 0.05) decreased by treatment with hesperidin (100 mg/kg) when compared with MP (10 mg/kg) treatment. There was no any significant difference in the lung function test between sham, per se and normal rats  in the BALF total cell count, lymphocyte and eosinophil counts whereas neutrophil and monocyte count decreased significantly (p < 0.05) in BLM controlled rats when compared with normal and sham rats. MP (10 mg/kg) treatment significantly inhibited (p < 0.05) BLM-induced BALF differential cell count alterations as compared to BLM controlled rats. There was significant increase (p < 0.05) in BALF neutrophil and monocyte counts, and significant decrease (p < 0.05) in BALF total cell count, lymphocyte and eosinophil counts in hesperidin (50 and 100 mg/kg) treated rats as compared to BLM controlled rats. The attenuation of BLM-induced increased lymphocytes and eosinophils, whereas decreased monocytes counts in BALF was more significant (p < 0.05) in MP (10 mg/kg) treated rats when compared with hesperidin treated rats (Table 3There was a significant increase (s Table 3.p < 0.05) decrease in SOD and GSH levels in BALF as well as significant increase (p < 0.05) in MDA, NO and HP levels in BALF of BLM controlled rats when compared with normal and sham rats. Whereas, MP (10 mg/kg) administration significantly (p < 0.05) decreased the levels of MDA, NO, and HP in BALF and significantly increased (p < 0.05) BALF SOD and GSH levels as compared to BLM controlled rats. The BLM-induced decrease in SOD and GSH levels increased significantly (p < 0.05) in hesperidin (50 and 100 mg/kg) treatment whereas the levels of BALF MDA, NO and HP decreased significantly (p < 0.05) in hesperidin  treatment as compared to BLM controlled rats. Hesperidin (100 mg/kg) treatment more significantly (p < 0.05) elevated BALF SOD and GSH levels as compared to MP (10 mg/kg) treatment. However, there was no significant difference in the BALF SOD, GSH, MDA, NO, and HP in normal, sham, and per se treated rats  whereas levels of MDA, NO, HP and MPO increased significantly (p < 0.05) in the lungs of BLM controlled rats after intratracheal instillation of BLM. MP (10 mg/kg) treatment showed significant (p < 0.05) inhibition in BLM-induced alterations in SOD, GSH, MDA, NO, and HP in the lung as compared to BLM controlled rats. However, it failed to produce any significant reduction in elevated MPO levels compared to BLM controlled rats. Treatment with hesperidin (50 and 100 mg/kg) also significantly increased (p < 0.05) SOD and GSH levels whereas significantly decreased (p < 0.05) levels of MDA, NO, HP and MPO in the lungs as compared to BLM controlled rats. BLM-induced alterations in SOD, GSH, MDA, NO, and HP was more significantly (p < 0.05) attenuated by MP (10 mg/kg) as compared to hesperidin treatment  whereas TNF-α, IL-1β, and IL-6 mRNA expressions significantly up-regulated (p < 0.05) in BLM-controlled rats when compared with sham and normal rats. When compared with BLM controlled rats, treatment with MP (10 mg/kg) significantly (p < 0.05) down-regulated lung TNF-α, IL-1β, and IL-6 mRNA expressions whereas it significantly (p < 0.05) up-regulated lung Nrf2 and HO-1 mRNA expressions. BLM-induced alterations in lung Nrf2, HO-1, TNF-α, IL-1β, and IL-6 mRNA expressions were significantly attenuated (p < 0.05) when rats treated with hesperidin (50 and 100 mg/kg) as compared to BLM controlled rats. The attenuation of alteration in mRNA expressions of lung TNF-α, IL-1β, IL-6, Nrf2 and HO-1 were more significant (p < 0.05) in rats treated with MP (10 mg/kg) when compared with treatment with hesperidin  in lung collagen-1, TGF-β, and Smad-3 mRNA expressions in BLM controlled rats compared to sham and normal rats. Whereas, treatment with MP (10 mg/kg) significantly (p < 0.05) inhibited BLM-induced up-regulated lung collagen-1, TGF-β, and Smad-3 mRNA expressions as compared to BLM controlled rats. Hesperidin (50 and 100 mg/kg) treatment also significantly down-regulated (p < 0.05) mRNA expressions of collagen-1, TGF-β and Smad-3 in lungs when compared with BLM controlled rats. Administration of MP (10 mg/kg) showed more significant inhibition (p < 0.05) in BLM-induced up-regulated lung collagen-1, TGF-β, and Smad-3 mRNA expressions as compared to hesperidin treatment  in lung NF-κB and IκBα protein expressions in BLM controlled rats after intratracheal instillation of BLM when compared with sham and normal rats. Administration of MP (10 mg/kg) significantly inhibited (p < 0.05) BLM-induced up-regulated lung NF-κB and IκBα protein expressions as compared to BLM controlled rats. Hesperidin (50 and 100 mg/kg) treatment also significantly down-regulated (p < 0.05) lung NF-κB and IκBα protein expressions as compared to BLM controlled rats. However, BLM-induced up-regulated lung NF-κB, and IκBα protein expressions were more significantly (p < 0.05) down-regulated by MP (10 mg/kg) as compared to hesperidin treatment. There was no significant difference in the lung NF-κB and IκBα protein expressions in normal, sham, and per se treated rats  whereas lung PP2C-α protein expression was significantly up-regulated (p < 0.05) after BLM administration in BLM controlled rats. Treatment with hesperidin (50 and 100 mg/kg) significantly attenuated (p < 0.05) BLM-induced down-regulated (p < 0.05) lung AMPK and up-regulated (p < 0.05) lung PP2C-α protein expressions when compared with BLM controlled rats. However, administration of MP (10 mg/kg) did not produce any significant inhibition in BLM-induced altered lung AMPK and PP2C-α protein expressions as compared to BLM controlled rats. The lung AMPK and PP2C-α protein expressions did not differ significantly in the normal, sham, and per se treated rats  in inflammatory influx in the peribronchial and perivascular region, interstitial fibrosis, and Ashcroft score in BLM controlled rats as compared to normal and sham rats  BLM-induced inflammatory infiltration, interstitial fibrosis, and Ashcroft score as compared to BLM controlled rats  peribronchial and perivascular inflammatory influx, interstitial fibrosis, and Ashcroft score as compared to BLM controlled rats  is a chronic, progressive interstitial lung disease resulting from the accumulation of excessive collagen, epithelial cell injury, matrix remodeling, and disruption of alveolar architecture leading to declining pulmonary function. Bleomycin (BLM), which is an effective antineoplastic agent, selectively induces pulmonary fibrosis. Thus, BLM is a well-established and widely used animal model to induce lung fibrosis, which resembles with the clinical characteristics of human IPF. In the present investigation also intratracheal instillation of BLM produced inflammatory infiltration in Bronchoalveolar lavage fluid (BALF) and lung, alteration in gas exchange and pulmonary function, elevated levels of ROS, and activation of TGF-B/Smad3 pathway which resulted in pulmonary fibrosis. However, administration of hesperidin significantly attenuated BLM-induced pulmonary fibrosis via inhibition of elevated oxido-nitrosative stress, the release of pro-inflammatory cytokines  and IκBα/NF-κB as well as modulation of TGF-B/smad3 pathway to reduce collagen deposition.It has been well documented that animal models play a vital role in the evaluation of disease progression during BLM-induced PF . IntrNumerous evidence suggested that insult to pulmonary tissue induced by various toxicants resulted in an alteration in the respiratory patterns  is a stress-inducible protein that plays a crucial role in the protection against oxidative stress and regulation of lung inflammation . Researin vitro  in the pathogenesis of BLM-induced pulmonary fibrosis . Cytokial., 2017). Pulmonal., 2017). This ial., 2017). Researal., 2017). It hasal., 2017). The real., 2017; Yeh et al., 2017).It has been well accepted that BLM-induced IPF associates with biphasic events where a “switch” appears between inflammatory and fibrotic phase at around day 14 after intratracheal instillation of bleomycin . The eaSmad3, a member of mothers against decapentaplegic homolog 3 has been implicated as a central player in the formation of the transcriptional activation complex that induces lung fibrosis  is one of the key elements in the pathogenesis of fibrosis in various organs, including pulmonary fibrosis . ActivaIntratracheal instillation of BLM induces significant aberrations in histologic and cellular architecture of pulmonary tissue revealed by visualizing histological and transmission electron microscopic analysis of lung tissue from BLM control mice . These Currently, corticosteroids as potent anti-inflammatory reagents have been widely used for the management of pulmonary fibrosis. However, their certain side effects and relief in the fraction of patient limit their implications in IPF treatment. Remedies of herbal origin are gaining more attention for the treatment of pulmonary fibrosis  and pro-inflammatory markers  to reduce collagen deposition during pulmonary fibrosis Figure 1.The authors declare no conflict of interest.


Respondents who answered correctly regarding the need to adhere to antibiotics were more likely to have completed their antibiotic course (p < 0.001). Future educational initiatives should provide key information on the role of antibiotics and the importance of complying with antibiotics in this population.Antibiotics are commonly prescribed among older adults, and inappropriate use of antibiotics has been noted. However, there is limited information about their knowledge and expectations for antibiotics. This study aimed to assess older adults’ knowledge of antibiotic use and resistance, their expectations for antibiotics and the relationship between knowledge, expectation and inappropriate practices related to antibiotic use. A cross-sectional survey involving respondents aged 60 years and above was conducted, using a validated questionnaire. A lack of knowledge about the role of antibiotics was observed, whereby more than half of the respondents incorrectly believed that antibiotics can treat viral infections (53.5%) and colds and coughs (53.7%). Also, 67.9% of respondents incorrectly believed that antibiotic resistance occurs when the body becomes resistant to antibiotics. Almost half of the respondents would expect antibiotics for symptoms of self-limiting viral infections. Respondents who answered correctly for the role of antibiotics in viral infections were more likely not to expect antibiotics for cold, flu and cough ( The devastating threat of antimicrobial resistance (AMR) to global human health is unquestionable . AntimicAntibiotic consumption by the elderly population was found to be between 11% to 45%, with a significant rise over the past decade ,8,9. As The reported incidence of infections was higher in the older adult population because of the presence of chronic comorbidities, deteriorating organ functions and reduced host defence system ,16. OldeA lack of knowledge on antibiotic use in the general public has been reported, with more than half of them who thought that antibiotics are useful in treating viral infections, and about one half of them would stop taking antibiotics when they felt better . Those wPatients who were unaware of the consequences of antibiotic overuse to the community were found to expect antibiotics from their prescriber . StudiesTo our knowledge, many studies have been done to assess the knowledge of antibiotic use and resistance; however, there has been limited research targeting vulnerable population groups, including older adults. Due to the paucity of information in this area, we conducted a study among the older adult population in Malaysia to assess their knowledge on antibiotic use and resistance and their expectations towards the need for antibiotics. This study also aimed to assess the relationship between knowledge, expectations and practices related to antibiotic use among older adults.2 = the table value of chi-square for 1 degree of freedom at the desired confidence level (3.841); N = the population size ; P = the population proportion (assumed to be 0.05 since this would provide the maximum sample size); d = the degree of accuracy expressed as a proportion (0.05).A cross-sectional study was conducted at a tertiary hospital in Kuala Lumpur from March 2019 to May 2019. Malaysian citizens aged 60 years and above were included in this study. Inpatients and those with cognitive impairment were excluded from the study. Respondents were recruited via convenience sampling. A minimum sample size of 382 was calculated using the below formula, based on a response distribution of 50%, confidence level of 95% and a margin of 5% error .n = χ2NA questionnaire was developed based on literature review of other validated questionnaires from several studies ,36,37,38The questionnaire was available in English and the national language . It was first reviewed for content validity by an expert panel consisting of senior consultant specialists and pharmacists with expertise in infectious disease. A pilot study among 30 respondents was conducted to assess the clarity of the questions before finalizing the questionnaire. Internal consistency of the questionnaire using Cronbach’s α for the sections on knowledge and expectation were 0.686 and 0.829 respectively.Adults who were available in the hospital area were screened via inclusion and exclusion criteria. Potential elderly respondents were identified and approached by the researchers, and the purpose of the study was explained before their participation. After obtaining written consent, the questionnaire was given to the participants for completion. Assistance was provided for those who requested for it by the researcher. No personal identifiers were included in the form. Respondent participation was voluntary, and their responses were dealt with a high level of confidentiality and anonymity. Ethical approval was obtained from the hospital ethics committee (reference number: UKM PPI/111/8/JEP-2018-717), before proceeding to the data collection phase.t-test was used to address the difference in total knowledge scores regarding respondent expectation for antibiotics. The chi-squared test was used to assess the association between respondents’ knowledge on antibiotic effect with their expectation to be prescribed with an antibiotic for colds, flu and cough.Data analyses were performed using IBM SPSS version 18. Descriptive statistics were used to summarize the data. The independent t-test was also used to assess the difference in total knowledge scores between those who reported having had at least one inappropriate practice and those with no inappropriate practice. The chi-squared test was used to assess the association between two subitems of the knowledge section  with the practice of completing the antibiotic course. Chi-squared tests were also used to assess the association between demographic characteristics  and knowledge of antibiotics. For this analysis, adequate and inadequate knowledge were defined as total knowledge scores of >10 and <10, respectively. A p-value of <0.05 with confidence interval of 95% was considered statistically significant for all tests.In addition, independent A total of 402 participants were recruited. Demographic characteristics of respondents are shown in Respondents’ prior experiences and practices related to antibiotic use are presented in Low rates of inappropriate practices in antibiotic use were observed, whereby only 3.5% of respondents had ever obtained antibiotics without a prescription, 3.5% used own/others’ leftover antibiotics without advice from healthcare professionals and 2.5% shared own leftover antibiotics with friends or family or neighbours. The most common inappropriate practice was not completing antibiotics according to the duration prescribed, which was reported by 17.2% of the respondents .The respondents scored an average of 6.6 (± 2.4) out of a total score of 12 in knowledge on antibiotic use and 3.6 (± 1.8) out of a total score of 8 in knowledge on antibiotic resistance, with the total score on both sections 10.2 (± 3.5) out of a total score of 20. A high proportion of respondents (70.4%) answered correctly that antibiotics are medicines that can be used to kill bacteria . HoweverIn terms of knowledge on antibiotic resistance, 67.9% of respondents incorrectly believed that antibiotic resistance occurs when the body becomes resistant to antibiotics, and 62.4% of them thought that antibiotic resistance is only a problem for people who take antibiotics regularly. About half of the respondents either did not believe (30.8%) or were not sure (20.6%) that antibiotic resistance could affect them or their family .The respondents’ expectations to be prescribed with antibiotics for common symptoms were shown in Only a small proportion of respondents agreed or strongly agreed that they would be less satisfied with the physician visit if they do not receive an antibiotic (12.44%) or that they will visit another physician if the physician does not prescribe an antibiotic (18.66%). A total of 83.4% agreed or strongly agreed that they expect the physician to discuss with them regarding the need for an antibiotic for their symptoms, rather than just giving them a prescription .p = 0.030 (p < 0.001)  compared to those with other responses (10.05 ± 3.522), with  = 0.030 . However< 0.001) .p = 0.577). However, respondents who answered correctly for the statements  were more likely to have completed their antibiotic course (p < 0.001)  .p = 0.007). In addition, there was a significant association between educational level and knowledge, whereby respondents with higher educational level tended to have adequate knowledge (p < 0.001). There were no significant associations between gender, ethnicity and prior receipt of antibiotics with knowledge.As shown in The findings in this study point to a lack of knowledge about the role of antibiotics and awareness about the impact of antibiotic resistance among the older adult population in Malaysia. Moreover, this study revealed inappropriate expectations for antibiotic prescriptions for symptoms related to self-limiting viral infections in some of the respondents.A substantial proportion of older adults in this study reported using antibiotics within the past 12 months 42.8%). However, the percentage of respondents using antibiotics within the past month (13.9%) was lower compared to previous studies conducted among the general public in Malaysia and among the elderly in a multi-country survey by WHO ,38,39,40.8%. HoweInappropriate practices related to antibiotic use were relatively low compared to other studies. Only 3.5% of the respondents in this study had obtained antibiotics without prescription, which was comparable to another Malaysian study in Putrajaya (4.5%) , but lowIn terms of knowledge regarding antibiotic use, respondents in this study were found to be confused with the role and identification of antibiotics, a finding that is in line with other Malaysian studies ,40,41,56Respondents were aware of the problem of antibiotic resistance and were able to make connection between antibiotic use and resistance. However, misinterpretations were noted, whereby a majority of them (67.9%) as compared to 76% of the general public in WHO multi-country survey , viewed Commonly, antibiotics were incorrectly believed by the public to be useful for symptoms in viral infections such as fever, cough, sore throat, colds or flu ,58. ThisIn addition, responses in this study also suggested that majority of older adults trusted the physicians’ decisions regardless if antibiotics were prescribed to them, which was in line to that reported in a local study . ElderlyThis study did not find a significant difference in total knowledge scores between respondents with at least one inappropriate practice and those with no inappropriate practice. In their study, McNulty et al. also concluded that there was no simple relationship between knowledge, attitude and practice on the prudent use of antibiotics . HoweverIn this study, age and educational level were found to have significant associations with respondents’ knowledge on antibiotic use and resistance. Respondents who were older and with fewer educational qualifications were less knowledgeable about antibiotics. These findings were in line with some studies conducted in Malaysia and other countries ,37. In aThe strength of this study was that it was conducted in an under-represented population in this research area. However, there were a few limitations in this study. First, this study was conducted in a single centre, and therefore the results may not be generalizable to the whole elderly population in Malaysia. Future research can be conducted in community or nursing home settings to enable comparison of findings among different settings, so as to aid in the local tailoring of planned actions. Secondly, the use of convenience sampling method may have resulted in the possibility of selection bias during the recruitment of respondents. Furthermore, as with all self-reported data, there was also the potential for recall and response bias.Although low rates of inappropriate antibiotic use practices were reported in this study, this study identified several gaps in important areas of knowledge on antibiotic use, particularly on the role and identification of antibiotics. In addition, incorrect beliefs about antibiotic resistance were observed among older adults. Provision of key information on indication of antibiotics may influence respondents’ expectations toward antibiotics, and information on the importance of complying with antibiotic regime may influence their correct use of antibiotics. These findings should be considered when designing suitable educational interventions or local campaigns which are older adult-specific, to correct the misunderstandings in antibiotic use and resistance for this group of population.


P < 0.001), and by −41.50 DOT/1,000 patient-days per month in intensive care units (ICUs) . Similarly, glycopeptides usage decreased by −2.61 DOT/1,000 patient-days per month in GWs , and −27.41 DOT/1,000 patient-days per month in ICUs . Use of 3rd generation cephalosporins, beta-lactam/beta-lactamase inhibitors, and fluoroquinolones in GWs showed change comparable with that of carbapenems or glycopeptides use. Furthermore, trends of antimicrobial resistance rate of Staphylococcus aureus to gentamicin in GWs, Staphylococcus aureus to ciprofloxacin and oxacillin in ICUs, and Pseudomonas aeruginosa to imipenem in ICUs decreased in slope in the intervention period. The in-hospital mortality rate per 1,000 patient-days among ICU patients remained stable between the pre-intervention and intervention periods. In conclusion, an IDS-led ASPs could enact a meaningful reduction in antibiotic use, and a decrease in antibiotic resistance rate, without changing mortality rates in a large Korean hospital.The aim of this study was to evaluate the impact of an infectious diseases specialist (IDS)-led antimicrobial stewardship programmes (ASPs) in a large Korean hospital. An interrupted time series analysis assessing the trends in antibiotic use and antimicrobial resistance rate of major pathogens between September 2015 and August 2017 was performed in an 859-bed university-affiliated hospital in Korea. The restrictive measure for designated antibiotics led by an IDS reduced carbapenems usage by −4.57 days of therapy (DOT)/1,000 patient-days per month in general wards (GWs) (95% confidence interval [CI], −6.69 to −2.46;  Once a pathogen acquires resistance to antibiotics, it renders antimicrobial treatment ineffective, leading to increased mortality, prolonged hospitalization, and increased medical costs2. In spite of this, in the last decade, few pharmaceutical companies have actively retained antibiotic discovery programmes3. To curb the spreading of antimicrobial resistance, the World Health Organization (WHO) established a global action plan to tackle antimicrobial resistance, which was endorsed by the Group of 7 (G7) summit in 20154. Accordingly, the Korean Ministry of Health and Welfare established the Korean National Action Plan on Antimicrobial Resistance in 20165.Antimicrobial resistance is one of the greatest threats to public health and is an emerging crisis for humans5. ASPs comprise a set of multidisciplinary activities focusing on proper antibiotic use, including implementing interventions for antibiotic prescription, monitoring of antibiotic usage and resistance patterns, regular reporting information on antibiotic use and resistance to medical staff, and educating clinicians about resistance and optimal prescription6.Antimicrobial stewardship programmes (ASPs) are often a key strategy among action plans against antimicrobial resistance7. The main reason for this has been the lack of manpower in the ASPs in most hospitals: ASPs were operated mainly by one or two infectious diseases specialists (IDSs) in each hospital7. Therefore, in order to improve ASPs in Korea, it is necessary to reinforce the priority of, and increase manpower to the implementation of ASPs.While many large hospitals in Korea has been conducting ASPs since 2000s, they have been limited, and heavily dependent on modified preauthorization-of-antibiotic use programmes; in other words, restrictive measures for designated antibioticsThe aim of this study was to evaluate the impact of an IDS-led ASPs in a large Korean hospital. To this end, we conducted an interrupted time series analysis on the antibiotic use and the antimicrobial resistance rate of major pathogens before, and after interventions.Eulji University hospital is an 859-bed university-affiliated secondary care hospital with a 34-bed intensive care unit (ICU). In addition, there is a 20-bed trauma unit and a 30-bed neonatal ICU; but no burn, or bone marrow transplant units.There have been no actual ASPs implemented in the hospital except for occasional educational initiatives. There were no written internal guidelines regarding empirical antibiotic administration in common infectious diseases. Even though a computerized antibiotic control programme was developed in October 2005, it was not operational due to a lack of manpower: all requested antibiotics were approved without any restriction. Furthermore, frequent absence of the IDSs discouraged physicians from consulting on proper antibiotic use: there were no available IDSs on site during December 2010–March 2011, August 2011–September 2012, June 2014–July 2014, and January 2016–August 2016.Infection control measures remained largely unchanged until September 2016. The most prominent strategy for infection control was monitoring and feedback of hand hygiene; average annual compliance rate was 70.8% in 2014, 68.6% in 2015, and 74.6% in 2016.In September 2016, an IDS who had 1.5 years’ experience in running ASPs started his service at the hospital, and dedicated 2.5–3.5 hours per day to running the ASP.8. For the approved antibiotics, follow-up evaluation for the appropriateness was performed after the period of approval which was set by the IDS: usually 4–7 days. Regardless of antibiotic order outcome, a written suggestion of appropriate antibiotics was sent to the prescribing physicians.In September 2016, restrictive measures for designated antibiotics were initiated, using a computerized antibiotic control programme. Designated antibiotics included carbapenems , tigecycline, glycopeptides (vancomycin and teicoplanin), oxazolidinone (linezolid), and polymyxin (colistin). Physicians were instructed to fill out a special antibiotic order form when prescription of any of the above antibiotics was needed. The purpose for the antibiotic use was a mandatory field on the special antibiotic order form. Once the special antibiotic order was made, the IDS could assess the prescription through the computerized antibiotic control programme. The decision on whether to approve or reject the prescription of the designated antibiotics was made via the programme within 48 hours, after medical record review. Pending the decision of IDS, the designated antibiotics could be administered to avoid delay in initiating therapy. The appropriateness of antibiotic use was assessed in accordance with the antibiograms of isolated pathogens, and the Sanford guideline to antimicrobial therapyet al.9. If the combination prescription of anaerobic antibiotics was assessed as “inappropriate”, the pharmacist notified each attending physician about the result.In April 2017, a system for monitoring unnecessary double anaerobic coverage prescription was established. When combination antibiotic prescription with either metronidazole or clindamycin, and one of beta-lactam/beta-lactamase inhibitors (BL/BLIs) or carbapenems was detected via the computerized system, a pharmacist reviewed the medical records and sent the assessment of the appropriateness of each prescription to the IDS. The IDS confirmed the appropriateness as mentioned in a previous report by Song The trends in antibiotic use, antimicrobial resistance rate for major pathogens, and in-hospital mortality before, and after interventions were analysed.The primary outcome of the study was antibiotic use. The secondary outcomes consisted of the antimicrobial resistance rate for major pathogens, and in-hospital mortality. Patients in the general wards (GWs) and ICU were analysed separately, and the trauma unit, neonatal ICU, and paediatric ward were excluded from analysis. In-hospital mortality was analysed only for ICU patients.Data on the number of monthly antibiotic prescriptions, monthly patient-days, and monthly antimicrobial sensitivity tests of major bacterial pathogens among inpatients between September 2015 and August 2017 were acquired from the electronic database. In addition, monthly Acute Physiology and Chronic Health Evaluation (APACHE 2) score, and monthly in-hospital mortality rate among ICU patients between September 2015 and August 2017 were acquired from the hospital data processing department.The study protocol was approved by the Institutional Review Boards of the Eulji University Hospital (2017-12-001-001), and the requirement for written informed consent from patients was waived due to the retrospective nature of the study, and its impracticability.10. Systemic agents with per oral or parenteral administration routes were included, while topical agents were excluded. Each class of antibiotic was quantified via days of therapy (DOT), which was then standardized per 1,000 patient-days (PD)11.In this paper, Anatomical Therapeutic Chemical (ATC) classification system class J01 antibiotics, which does not include antifungal agents or anti-tuberculosis agents, were included for analysisst generation cephalosporins (1st CEPs), 2nd generation cephalosporins (2nd CEPs), 3rd generation cephalosporins (3rd CEPs), 4th generation cephalosporins (4th CEPs), aminoglycosides (AGs), BL/BLIs, carbapenems, fluoroquinolones (FQs), glycopeptides, lincosamides, macrolides, metronidazole, monobactam, oxazolidinone, penicillins, polymyxin, tetracyclines, tigecycline, and trimethoprim/sulfamethoxazole (SXT). Other antibiotics, such as amphenicol, fosfomycin, and streptogramin were excluded because they are rarely used.We classified antibiotic agents into 19 classes: 1rd CEPs, 4th CEPs, BL/BLIs, and FQs as broad-spectrum antibiotics. Carbapenems, tigecycline, glycopeptides, oxazolidinone, and polymyxin were defined as antibiotics against multidrug-resistant (MDR) pathogens. The remaining antibiotic classes were defined as non-broad-spectrum antibiotics.We defined 3We analysed the antimicrobial resistance rate for major bacterial pathogens isolated from any site of patients at least 48 hours after hospital admission. The first isolate of these pathogens for each admission per patient was included in the analysis. In addition, we performed subgroup analysis according to the type of specimens .Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecium. We defined the antimicrobial resistance rate as the proportion of resistant isolates among total isolates.In this paper, the major bacterial pathogens were: 12, and outcomes of R (resistance) or I (intermediate) were defined as resistance. Extended-spectrum beta-lactamase (ESBL)-producing isolates were defined as E. coli or K. pneumoniae proven to be positive by an ESBL test in the Vitek 2 system.All isolates and their antimicrobial susceptibilities were identified using a Vitek 2 automated bacterial identification system . The breakpoints of each compound were defined in reference to the Clinical and Laboratory Standards Institute (CLSI)13. We confirmed that Durbin-Watson test statistics for the overall antibiotic usage and resistance rate indicated no serious autocorrelation after the adjustment. The study period (September 2015–August 2017) was divided by interventions and analysed as follows:(i)In the analysis of the impact by major intervention, the study period was divided into pre-intervention (September 2015–August 2016) and major intervention (September 2016–August 2017).(ii)In the analysis of the impact by minor intervention, the study period was divided into pre-intervention (September 2015–August 2016), major intervention (September 2016–March 2017), and minor intervention (April 2017–August 2017).The impact of intervention on antibiotic use, antimicrobial resistance rate, and in-hospital mortality were evaluated through segmented regression analysis of an interrupted time series with adjustment for autocorrelationThe impact of minor intervention was tested against the whole previous period (September 2015–March 2017) because main target antibiotics of the minor intervention (lincosamides and metronidazole) were not included in designated antibiotics of the restrictive measures.P < 0.05.We defined “change in level” as the difference between the observed value at the beginning of the pre-intervention, and intervention periods, and “change in trend” as the difference between the change rates of the pre-intervention, and intervention periods. The segmented regression analysis was applied using the newey command (considering Newey-West standard errors) in STATA version 15 . Statistical significance was defined as P = 0.003) was observed after the intervention, the intervention resulted in a change in trend by −28.14 DOT/1,000 PD per month (P < 0.001). The total antibiotic use in ICUs were 3945.29, and 3313.13 DOT/1,000 PD in the pre-intervention, and intervention period, respectively; the secular trend did not change after the intervention.Table P = 0.001), while a significant decrease in trend by −14.34 DOT/1,000 PD per month was observed (P < 0.001). For the usage of broad-spectrum antibiotics in ICUs, there was a significant decrease in level , but no significant change in trend. The intervention did not affect the trend of non-broad-spectrum antibiotics for patients in both the GWs and ICUs  and a significant negative change in slope . As for broad-spectrum antibiotics in GWs, there was a significant increase in level of antibiotic usage after the intervention  and by −484.92 DOT/1,000 PD in ICUs (P < 0.001); the trend changed by −4.57 DOT/1,000 PD per month in GWs (P < 0.001) and by −41.50 DOT/1,000 PD per month in ICUs (P < 0.001). Similarly, glycopeptides usage was significantly affected by the intervention both in the GWs and ICUs: change in level were −20.23 DOT/1,000 PD in GWs (P = 0.014) and −331.62 DOT/1,000 PD in ICUs (P < 0.001); change in trend were −2.61 DOT/1,000 PD per month in GWs (P = 0.007) and −27.41 DOT/1,000 PD per month in ICUs (P = 0.009). Furthermore, the major intervention resulted in a significant decrease in both level and trend for the use of polymyxin among patients of ICUs.Among antibiotics against MDR pathogens, the impact of the major intervention on carbapenems and glycopeptides were particularly prominent. The restrictive measure for designated antibiotics immediately decreased the carbapenems usage by −39.11 DOT/1,000 PD in GWs  but not affected that in ICUs. Accordingly, there was a significant negative change in slope for the consumption of non-broad-spectrum antibiotics in GWs after the minor intervention . The usage of carbapenems, BL/BLIs, and lincosamides were not affected by the minor intervention in both the GWs and ICUs.Table S. aureus isolates: a decrease in trend was observed for gentamicin in GWs , ciprofloxacin in ICUs , and oxacillin in ICUs . In addition, a significant decrease in trend was observed for the resistance rate of P. aeruginosa to imipenem in ICUs  . Furthermore, as for K. pneumoniae isolated from sputum in ICUs, a significant decrease in trend was observed for the rate of ciprofloxacin resistance  and ESBL production   and trend  of APACHE 2 score after the intervention.The average APACHE 2 scores of the pre-intervention, and intervention period were 17.5, and 20.8 per patient, respectively; there was no significant change in the level  and trend .The average in-hospital mortality rates per 1,000 patient-days were 19.4 in the pre-intervention period, and 18.6 in the intervention period. In-hospital mortality among ICU patients remained stable between the two periods: there was no significant change in level  was superior to a restrictive measure such as preauthorization-of-antibiotic use24. Therefore, reinforcement of feedback measures should be considered for better ASPs in Korean hospitals.Interestingly, our study not only showed a significant reduction in the usage of designated antibiotics, but also a significant reduction in usage of other broad-spectrum antibiotics, such as 37. ASPs were operated only by one or two IDSs in 85.2% of large hospitals in Korea without appropriate reward for performing ASPs7. According to Infectious Disease Society of America (IDSA) guidelines, multidisciplinary antimicrobial stewardship teams, which include an IDS and a clinical pharmacist with infectious diseases training are essential for realizing ASPs, and individuals of the team should be compensated appropriately for their time6. Because ASPs are the most important and effective strategy for controlling MDR pathogens25, stakeholders and policy makers should consider a national level of support to implement appropriate ASPs in Korean hospitals.Unfortunately, ASPs in Korean hospitals heavily depended on restrictive measures for designated antibiotics due to limited manpower6.The strength of the present study is that the study setting well reflects the real-world situation in large Korean hospitals. Another strength is that antibiotic usage was measured by DOT. To the best of our knowledge, this is the first study in Korea to record antibiotic usage by DOT. According to a recent guideline for ASPs, using DOT is recommended to measure antibiotic consumptionDespite the above strengths, there are some limitations to the present study. Firstly, due to the nature of the ecological study, the effects of confounders such as other ASPs, infection control measures, behavioural changes of physicians, etc. could not be fully controlled. Secondly, the patient-level clinical outcomes to the interventions could not be evaluated. Thirdly, this study was conducted in a large university-affiliated secondary care hospital. Therefore, the results cannot be generalized to different settings. Finally, the study focused on one IDS. Although the training system of IDSs is similar across Korean hospitals, and the quality of IDSs is controlled by the Korean Association of Internal Medicine; replicating the findings with more IDSs is required before these findings can be generalized.An IDS-led ASPs could enact a meaningful reduction in antibiotic use, and a decrease in antibiotic resistance rate, without changing mortality rates in a large Korean hospital. Further researches are necessary to assess the impact of IDS-led ASPs, with different methods, in different settings.Supplementary tables


The optimal approach for treating outpatient male urinary tract infections (UTIs) is unclear. We studied the current management of male UTI in private outpatient clinics, and we evaluated antibiotic choice, treatment duration, and the outcome of recurrence of UTI.International Classification of Diseases, Ninth Revision, Clinical Modification codes for UTI or associated symptoms were extracted from the EPIC Clarity Database of 2 family medicine, 2 urology, and 1 internal medicine clinics. For eligible visits in which an antibiotic was prescribed, we extracted data on the antibiotic used, treatment duration, recurrent UTI episodes, and patient medical and surgical history.Visits for all male patients 18 years of age and older during 2011–2015 with A total of 637 visits were included for 573 unique patients (mean age 53.7 [±16.7 years]). Fluoroquinolones were the most commonly prescribed antibiotics (69.7%), followed by trimethoprim-sulfamethoxazole (21.2%), nitrofurantoin (5.3%), and beta-lactams (3.8%). Antibiotic choice was not associated with UTI recurrence. In the overall cohort, longer treatment duration was not significantly associated with UTI recurrence . Longer treatment was associated with increased recurrence after excluding men with urologic abnormalities, immunocompromising conditions, prostatitis, pyelonephritis, nephrolithiasis, and benign prostatic hyperplasia .Our study adds evidence that men with UTI without evidence of complicating conditions do not need to be treated for longer than 7 days. Shorter duration of treatment was not associated with increased risk of recurrence. Shorter treatment durations for many infections, including UTI, are becoming more attractive to reduce the risk of resistance, adverse events, and costs. Urinary tract infections (UTIs) are the most common bacterial infections in the United States and the most frequent cause of bacteremia in men . IncidenAntimicrobial stewardship strategies encourage using narrow-spectrum antibiotics for the shortest duration required for clinical recovery. However, in a recent review on management of UTI in older men, recommendations regarding the optimal duration of treatment were hampered due to the lack of clinical trials comparing the efficacy of different regimens . CurrentInternational Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes for UTI or lower urinary tract symptoms documented during an office visit between January 1, 2011 and September 30, 2015. These codes included 595.0 (acute cystitis), 595.9 (unspecified cystitis), 599.0 (UTI), 788.1 (dysuria), 788.63 (urgency of urination), and 788.41 (frequency of urination). In addition to a UTI-related diagnosis, patients must have also been prescribed a UTI-relevant antibiotic during the same visit. Urinary tract infection-relevant antibiotics included fluoroquinolones, nitrofurantoin, trimethoprim alone or in combination with sulfamethoxazole, beta-lactams, aminoglycosides, and macrolides. For each eligible visit, we extracted variables pertaining to the patient’s age, race, date of office visit, presence of fever, comorbidities, antibiotic prescribed, and duration prescribed, history of urogenital procedures or malignancy, anatomic abnormalities, as well as history of diabetes, benign prostatic hyperplasia (BPH), nephrolithiasis, and prostatitis. We also extracted data to determine a patient’s immune status, including whether the patient was being treated with biologics, undergoing chemotherapy, or prescribed steroids. For visits with recurrent UTI, we determined whether the uropathogen in the index visit was susceptible to the empiric therapy prescribed.This retrospective cohort study included patients from 3 different types of outpatient specialty clinics, including 2 family medicine, 1 general internal medicine, and 2 urology private practices. Deidentified records from an electronic health record (EHR) system (EPIC Clarity Database) were used to identify all men 18 years of age and older with any of 6 Our process for applying patient-level and visit-level exclusion criteria to select eligible outpatient visits for inclusion in our analysis is described in All UTI-related visits were classified as an index case, an early recurrence, or a late recurrence. Index cases were defined as the first visit with a defined UTI  during the study period. Early recurrence was defined as a subsequent visit between 6 and 29 days after the index case with an ICD-9 code for UTI or symptoms plus a new prescription for antibiotic course. Late recurrence was defined as a subsequent visit between 30 and 365 days after the index case with ICD-9 code for UTI or symptoms, plus a UTI-relevant antibiotic prescription. We excluded visits with a second prescription occurring within 5 days of the index visit because these likely represent treatment of index event resulting from an adverse effect, loss of initial prescription, or ineffectiveness of the original agent.The study’s primary exposure was treatment duration, dichotomized as short (≤7 days) or long (>7 days) based on expert recommendation for treatment of UTI . Visits 2, Fisher’s exact, and Mann-Whitney U tests to compare patient characteristics and treatment regimens between visits stratified by presence or absence of complicating factors. Crude (unadjusted) and logistic regression models were used to identify relevant predictors of antibiotic choice; we included in multivariable models those factors that had a P < .10 in univariate analyses. Multiple linear regression analysis was used to identify the predictors of treatment duration. Logistic regression analysis was also used to calculate odds ratios (OR) and 95% confidence intervals (CIs) representing the association between the treatment duration and UTI recurrence. Factors were considered significantly associated with recurrence using P < .05. Data were analyzed using SPSS  for Windows. This study was reviewed by the Baylor College of Medicine Institutional Review Board and was not considered to be human subjects research.We used χOur study included 637 visits among 573 unique men seen between January 1, 2011 and September 30, 2015 . PatientP = .01), but they were more likely to have been treated with nitrofurantoin . Patients with higher CCI were more likely to have been treated with a beta-lactam, irrespective of age . Patients seen in the urology department were also more likely to be treated with a beta-lactam  and were less likely to be treated with TMP-SMX . Complicating factors, race, diabetes, BPH, and fever were not associated with antibiotic choice.Age, CCI, and department were statistically significant predictors of antibiotic choice. Men 55 years and older were prescribed fluoroquinolones less frequently than younger men  after adjusting for antibiotic class and departmental specialty. Nitrofurantoin use was associated with longer treatment , whereas use of beta lactams was associated with shorter treatment duration . Visits in the urology department were more likely to be treated with longer courses of antibiotics .The presence of any complicating factor , antibiotic class, and the departmental specialty  were significant predictors of treatment duration in the multiple linear regression analysis. Visits with complicating factors were treated for longer duration than visits without complicating factors  had any recurrence with 7 patients having early recurrence, 25 patients having late recurrence, and 1 patient having both early and late recurrence. For all patients with recurrent UTI, we performed a detailed review of the index and recurrent visits and extracted all urine culture results and antibiotic susceptibilities. All subsequent visits represented acute symptomatic UTI with a new antibiotic prescribed for UTI recurrence. The uropathogen in the index visit was susceptible to the empiric therapy prescribed except in 2 cases of TMP/SMX resistance. Thus, resistance to initial therapy could not be evaluated as a factor for predicting recurrence. In the overall cohort, longer treatment duration was not significantly associated with UTI recurrence . Antibiotic duration is often driven by a desire to reduce the risk of recurrent infection. In this retrospective cohort study of outpatient men with UTI, we found that longer antibiotic treatment was associated with 2-fold increased odds of recurrent UTI after excluding men with urologic abnormalities, immunocompromising conditions, prostatitis, pyelonephritis, nephrolithiasis, and BPH. This lack of benefit in reducing recurrent UTI was independent of age, CCI index, presence of diabetes, department , patient race, presence of fever, and the type of antibiotic. Our findings are in agreement with the results of a recent observational study performed in the Veterans Affairs population showing that longer treatment (>7 days) for male UTI was not associated with a reduction in early or late recurrence . The curAn unexpected finding was the higher rate of recurrence with longer therapy in the subgroup with fewer complicating factors. Our findings are consistent with previous observational studies in other patient subgroups that demonstrated lack of clinical benefit with longer antibiotic duration. Longer course of antibiotics was associated with a higher recurrence within 30 days in a Dutch observational study including women with UTI and diabetes . TreatmeThe most frequently prescribed antibiotics in our study were fluoroquinolones, which continue to be used as a first-line treatment despite rising rates of resistance , 22, andThe results of our observational study must be interpreted with caution, particularly due to the possibility of confounding by indication. Longer courses of antibiotics could have been prescribed for sicker patients, thus confounding the relationship between treatment duration and recurrence. We tried to minimize this bias through rigorous eligibility criteria and by including a comorbidity burden indicator in our multivariable analyses. In addition, the data used in our study were collected for administrative and billing purposes and not for the purpose of research. As a result, visits analyzed may be subject to misclassification and not be indicative of a UTI, particularly visits identified by symptom codes rather than ICD codes. Our inclusion criteria required a UTI-relevant antibiotic to have been prescribed at the time of the visit, which we believe indicates provider suspicion of infection. To exclude visits in which antibiotics may have been prescribed for nonurinary infections, visits with any alternative indication of infection were excluded from our study population. To avoid sampling bias, we abstained from expanding our inclusion dates beyond September 30, 2015 to avoid any inconsistencies in diagnoses following the ICD-9 to ICD-10 transition  as others have reported . An addiIn conclusion, longer treatment duration in outpatient settings was associated with increased recurrence of UTI in men without additional complicating factors. Our study adds evidence that men with UTI and no additional complicating factor such as prostatitis can be treated with a 7-day antibiotic course. Shorter duration of antibiotic treatment for male UTI may lead to decreased risk of antibiotic resistance, fewer adverse effects, and lower costs. We are currently conducting a randomized, controlled trial of 7 versus 14 days of antibiotics for male UTI that will bring further evidence to guide clinical practice , 27.