The impact of an aircraft is widely known to be one of the worst events that can occur during the operation of a plant (classified for this reason as beyond design). This can become much more catastrophic and lead to the loss of strength of/collapse of the structures when it occurs in the presence of ageing  materials. Therefore, since the performance of all plant components may be affected by ageing, there is a need to evaluate the effect that aged components have on system performance and plant safety. This study addresses the numerical simulation of an aged Nuclear Power Plant (NPP) subjected to a military aircraft impact. The effects of impact velocity, direction, and location were investigated together with the more unfavorable conditions to be expected for the plant. The modelling method was also validated based on the results obtained from the experiments of Sugano et al., 1993. Non-linear analyses by means of finite element (FE) MARC code allowed us to simulate the performance of the reinforced concrete containment building and its impact on plant availability and reliability. The results showed that ageing increases a plant’s propensity to suffer damage. The damage at the impact area was confirmed to be dependent on the type of aircraft involved and the target wall thickness. The greater the degradation of the materials, the lower the residual resistance capacity, and the greater the risk of wall perforation. The need to investigate the effects caused by an aircraft impact on nuclear installation ,2,3) is Ageing could therefore become an Achilles’ heel for the resistance capacity of structures in such severe accident conditions. As components age, the plant ages too; this means that the cumulative effects of ageing and obsolescence on the safety of nuclear power plants must be re-evaluated periodically to verify that the performances of the single components and the whole plant are within acceptable limits. Therefore, a proper analysis has to be performed to ensure that the effects of ageing will not prevent structures, systems, and components (SSCs) from being able to accomplish their required safety functions. In doing that, according to the International Atomic Energy Agency (IAEA) recommendations  the effeAt present, current practice for Nuclear Power Plant (NPP) design against external events provides sufficient safety margin and robustness, allowing the plant to withstand scenarios such as aircraft impact. Nevertheless, an assessment of the plant reliability—in whole or in part—that accounts for ageing degradation is necessary to determine the point in time where profitable operation is no longer possible . This will help defining the optimum preconditions for achieving safe long-term operation (LTO) and maintaining the plant performance level (availability and reliability). A quantification of these combined effects may be evaluated .A lot of studies on aircraft impact are available currently in the literature ,5,6,7,8;The Nuclear Energy Institute (NEI) report  providesLi et al.  revisiteZhang et al.  numericaThe review study of Jiang and Chorzepa  summarizAs quoted in , the impIn this framework, further concerns are due to the concrete containment (CC) ageing over time: the greater the ageing, the lesser the load-bearing capacity. Therefore, the important open question is if the actual CC wall thickness is capable of withstanding an aircraft impact.the qualification of the numerical FEM code used for the numerical investigation ;the description of the implemented model and assumptions made;the obtained results. The method to approach aircraft impact is described at length in .The following section provides: The study of the penetration and perforation of a thick wall (plate) covers a wide range of problems, interests, and applications. In most problems, the main point of interest is either the damage behind the thickened or reinforced wall or the damage confined to the wall itself. According to Backman and Goldsmith , the walThe impact phenomenon is difficult to characterize from a physical point of view because it depends on several factors, such as the type of impact  , missileAn analytical model must incorporate erosion and breakup into its solutions. In the third regime, the hypervelocity regime, the impact pressures are much greater than both the involved projectile and the target strength, so erosion dominates the penetration process.In the present paper, we deal with a soft impact, whose interest resides in the possibility to simulate the interacting structures, such as deformable . A soft impact has no rebound and the two mass points stick together. The interacting structures become one single body after the crushing and the kinetic energy (depending on the “missile’s” velocity and mass) can be dissipated . This as2. The qualification of the FEM code  was perfIn the qualification analyses by MARC© code using the same initial and boundary conditions, the same geometrical dimensions and material properties have been adopted. The impact duration was 2.1 ms. The striking was simulated by assuming a contact method (touching type); the contact detection between all contact pairs was based on a double-sided method. Moreover, a piecewise linear approximation which was based on the relative displacement between the bodies in contact was also implemented.Since the target wall was penetrated, the reinforcing rebars resulted uncovered . The global effects include overall axial, bending, and shear effects in the structural elements between the impact area and support locations.The global damage identifies the collapse of large portions of the building walls, load carrying members, etc., apart from vibration, that can potentially shake the whole building structure. The extent of such a “global failure” will depend primarily on the dynamic characteristics of the CC and missile, and the relative damage is, in general, associated with the excessive deformation of the entire structural system, assuming that local perforation does not occur. The behavior of concrete in compression and its compressive strength become very important in assessing the local behavior, whereas the tensile strength properties and the stress–strain response of reinforcement steel, in many cases, dominate the deflection and vibration behavior of the reinforced concrete structural members.As for the local effects concerned, according to  these arIn the light of the aforementioned points, the containment structure must have a minimum wall thickness to prevent perforation, even in the presence of penetration and scabbing , and firFor the purposes of this study, a deterministic method which uses dynamic simulations to verify “the acceptance criteria” are respected, as required by the applicants, has been adopted.The numerical simulation of a reinforced concrete structure is a challenging task due to the inhomogeneity of the material (non-linear behavior) which is also dependent on the strain rate. In order to correctly consider the dynamic characteristics of an impacted structure, a missile–target interaction method with explicit integration techniques has been adopted.The reinforced concrete containment of this study is that of a typical pressurized water reactor  resting on a rock soil (“rigid foundation”), represented by means of clamped restraints. To comply with the ASCE rules and ACI standards, the CC reinforcement is made of #8 reinforcing steel bars in the dome, distributed about 30 mm from the center of each direction and each face, #18 vertical bars in the cylindrical part at about 30 mm spacing for each face, and #18 horizontal bars on both sides of the vertical reinforcing grid. The basement has instead steel plates of 13 mm thickness . The matTo achieve sufficient accuracy of the dynamic analysis results, sensitivity studies were performed to identify the allowable maximum element size. In determining this, the frequency of the highest mode and the longitudinal propagation velocity of the concrete material were considered. The mesh size was chosen to be uniform in each 15° angular sector of CC discretization, with 20 elements through the thickness  and about 72 elements across the airplane cross-section.The connection of the reinforcement and concrete may be a crucial issue. All the models presented in this paper utilize a perfect bond with fully kinematic coupling, therefore the effects of bond slipping cannot be taken into account.Adequate initial and boundary conditions (continuum mechanics) have been assumed so as to preserve energy and momentum.The mathematical model is able to describe the characteristic of contact deformation during crushing. The contact force is automatically calculated by a code based on the conservation of the impulse. Moreover, assuming a continuous material, contact theory and structure mechanics allowed us to describe the CC mechanical behavior through its mechanical properties such as Young’s modulus, yielding stress value, and contact type, etc. A proper contact table describing the interaction between the two bodies—i.e., missile and target—was also defined. The contact detection method was described by a stress-based contact algorithm .In simulations dealing with impact loading, pronounced material nonlinearities occur. The constitutive laws, especially for concrete, must be able to reproduce the relevant phenomena.The behavior of concrete is assumed to be linear elastic within an elastic limit surface and up to the limit stress. With the onset of plastic strain and its further increase, material damage will rise until failure occurs. This is considered by damage parameters representing the progressive cracking and crushing of concrete caused by the abrupt stiffness changes (due to the propagation of the aircraft missile’s kinetic energy), which scale the failure surface down to a residual strength surface.The main challenge in non-linear analyses of concrete structures is due to the relatively low tensile strength. The tensile stress causing cracking in concrete is about one tenth of its crushing strength; in reinforced concrete structures, this “weakness” is compensated by the use of reinforcement. In addition, it should be considered that the concrete material strength may increase at elevated strain rates. To account for this effect, which for concrete is particularly due to the inertial effects, a dynamic increase factor (DIF) equal to 1 is considered for steel and concrete, as the dynamic load factor associated with the impactive or impulsive loading is less than 1.2 .td and tcd are the tensile and compression damage parameters, respectively. E0 is the undamaged modulus of elasticity. tε and cε are the tensile and compression strains, whereas The implemented concrete ‘plasticity’ model accounts for material degradation in compression and in tension as impact progresses. Damage effect types are associated with cracking properties, such as critical stress, softening modulus, crushing strain, etc. It is necessary to remark that in the analyses, the compressive stiffness was recovered upon crack closure as the load changed from tension to compression, but the tensile stiffness was not recovered when the load changed from compression to tension. Equations (1) and (2) provide the stress–strain relationships for uniaxial tension and compression:The airplane and reinforcement steel non-linear material behavior can be modelled using an elastic-plastic material model with the von Mises yield criteria and the Cowper–Symonds strain rate method. To simulate extreme loading conditions, such as impact phenomena, material models should be strain rate-dependent. Moreover, the dynamic yield strength is considered in the Cowper–Symonds formula:yσ and ysσ are the static and the dynamic yield stress, respectively; terature . FurtherIn preliminarily analyzing the ultimate structural capacity, varying material properties with age  are taken into account. Such a variation/degradation is considered in the assessment assuming that the values of the mechanical and physical properties of both the concrete and steel—e.g., yielding strength and Young’s modulus—are equal to 80% of the nominal value.For the purposes of the simulation, a horizontal impact onto the CC dome is assumed in order to consider the worst accident scenario .The aircraft crashing was simulated by performing a nonlinear transient analysis and assuming the updated Lagrangian procedure with follower force/stiffness command. For the current analysis, the large strain plasticity procedure is activated. The “large displacement” model option, which causes distributed loads to be based on the current deformed geometry, contributes to a stiffness effect on the tangential stiffness matrix. Erosion is not thus implemented because the model procedure allows us to account for the failure process and handle the large distortion problem (large deformation), such that the actual strength of the structure is calculated by the code by immediately deactivating the damaged elements.−5 s to properly capture the damage of the material as the impact progresses.The time step size was set to be equal to 10Because of the strike against the target, a part of the aircraft is crushed while the remaining portion undergoes elastic deformation. The kinetic energy transferred during the impact is, thus, partially dissipated by the crushing and buckling of the plane and partially through the deformation of the walls. The impact force at the time of the crushing of the fuselage (30 ms) is about 89 MN; this value is in good agreement with the Riera impact load  is reached in less time for an aged containment than for an unaged one due to the reduced strength of the materials. 3int and A2int trends.If the inner and outer structures are separated, the travelling shock waves are attenuated significantly and filtered during propagation all the way down to the foundation and, from there, to the supporting point of the equipment in the inner structure, as shown by the AAs for vibration, the calculated acceleration of about 40 g is not sufficient to damage the internal structures, and particularly the containment vessel.Finally, it is possible to say that, despite the 20% reduction in the materials’ properties, the strength capacity/integrity of the CC seemed not to be compromised. In fact, the phenomena of instability induced by overturning moments do not appear, nor does the strain exceed the limit value of 0.005, which is the acceptance criteria suggested by the IAEA for the compressive strain of concrete.Prior to investigating the effects of aircraft impact in an existing Gen II PWR containment, the qualification of FEM code, which was used for the simulations, was conducted on the basis of the experimental results available in the literature (a very good agreement was found).The results showed that ageing increases a plant’s propensity to suffer extensive or localized penetration that was about 5.8 and 7.7 cm for unaged and aged structures, respectively. Moreover, despite a partial wall penetration (a narrow cone was clearly observed), no wall perforation occurred.The greater the materials’ degradation, the lower the residual resistance capacity and the greater the risk of wall perforation. By assuming the same impact force, the strength capacity of the aged containment is reduced by about 30%.Generally, the local effects  do not pose a threat to the safety-related systems necessary to shut down a nuclear plant. Global stability seems to be guaranteed, as overturning moments do not appear, nor do the strains of concrete exceed 0.005 .


Pseudomonas aeruginosa  and extended spectrum β-lactamase (ESBL)-producing bacteria  had the highest risk of inadequate treatment. Previous exposure with third generation cephalosporin was identified as the only independent risk factor . Empirically inadequately treated bacteremias were significantly more likely to have worse outcomes than those with adequate therapy, including a higher risk of major organ damage  and infectious complications , and overall mortality . Conclusions: Inadequate empirical antibiotic therapy occurs in one-fifth of Gram-negative bacteremias in the NICU, and is associated with worse outcomes. Additional prospective studies are needed to elucidate the optimal timing and aggressive antibiotic regimen for neonates who are at risk of antibiotic-resistant Gram-negative bacteremia.Background: Timely appropriate empirical antibiotic plays an important role in critically ill patients with gram-negative bacteremia. However, the relevant data and significant impacts have not been well studied in the neonatal intensive care unit (NICU). Methods: An 8-year (1 January 2007–31 December 2014) cohort study of all NICU patients with gram-negative bacteremia (GNB) in a tertiary-care medical center was performed. Inadequate empirical antibiotic therapy was defined when a patient did not receive any antimicrobial agent to which the causative microorganisms were susceptible within 24 h of blood culture sampling. Neonates with GNB treated with inadequate antibiotics were compared with those who received initial adequate antibiotics. Results: Among 376 episodes of Gram-negative bacteremia, 75 (19.9%) received inadequate empirical antibiotic therapy. The cause of inadequate treatment was mostly due to the pathogen resistance to prescribed antibiotics (88.0%). Bacteremia caused by  Bloodstream infection is the major cause of mortality in the neonatal intensive care unit (NICU), after more advanced perinatal care and improved delivery room resuscitation have been achieved in the recent years ,2. AlthoAppropriate initial antibiotic therapy has been demonstrated as the key independent factor of treatment outcomes in patients with Gram-negative bacteremia in previous studies from the adult ICUs or wards ,12,13,14This study was conducted in the NICUs of Chang Gung Memorial Hospital (CGMH), and all neonates hospitalized in the NICUs of Linkou CGMH were enrolled. These NICUs contains a total of three units and has a total capacity of 47 beds equipped with mechanical ventilator, and 48 beds with special care nurseries. Since 2003, all neonates admitted to our NICUs were included in a database and followed up until death or hospital discharge. This database contained basic demographics, comorbidities of prematurity, all nosocomial infections, and discharge diagnosis. We conducted a retrospective cohort study using this prospectively collected database. Written consent for this study was not required by the Ethics Committee of CGMH, which approved this research. All patients between January 2007 and December 2014 with microbiologically documented GNB were enrolled for analysis. Polymicrobial infections were also included if one of the pathogens was a Gram-negative organism. Subsequent episodes of bacteremia in study patients within one month from the first episode of Gram-negative bacteremia were excluded due to better outcome analysis. We reviewed the medical records of the neonates with initial inadequate antibiotics and compared them with those who received appropriate initial antimicrobial therapy. The main outcome measures included the infectious complications, early mortality (death within 7 days of bacteremia onset), and overall mortality (death due to any reason within 30 days of bacteremia onset).In addition to all basic demographics and complications of prematurity retrieved from our neonatal database, chart and electronic medical records of patients who met the inclusion criteria were reviewed for the presence of the following features: details of clinical features, laboratory data and treatment courses of bacteremias, initial antimicrobial therapy regimen, use of central venous catheter (CVC), total parenteral nutrition (TPN) and/or intrafat, mechanical ventilators, underlying comorbidities, surgical interventions, and receipt of corticosteroid or antibiotics within 30 days prior to bacteremia. Severity of illness was calculated by two investigators (Dr. S.-M.C. and Dr. J.-F.H.) based on the Neonatal Therapeutic Intervention Scoring System (NTISS) .Gram-negative bacteremia was defined as the identification of gram-negative bacilli in a blood culture specimen. Only clinically significant bacteremias were enrolled, which was defined as at least one positive blood culture, together with clinical features compatible with systemic inflammatory response syndrome ,7,12. ThIn our institution, blood cultures were incubated in the Bactec 9240 system, and antibiotic susceptibility testing was performed by using the disk diffusion method according to the recommendations of the Clinical Laboratory Standards Institute . MultidrEarly-onset sepsis and late-onset sepsis were defined as clinical sepsis combined with bacterial growth on a blood culture obtained within the first 72 h of life and > 72 h of life, respectively ,8. A bact test or Mann–Whitney U–test were used to compare continuous variables depending on values distribution, and χ2 or Fisher’s exact test was used to compare categorical variables. A two-sided P value of < 0.05 was considered significant. In identifying the independent risk factors for mortality, a backward stepwise logistic regression analysis was used to control for the effects of confounding factors. Variables with a P value of < 0.05 in the univariate analysis were candidates for multivariate analysis as well as the main variable of interest . Kaplan–Meier analysis was used to compare the survival situation of neonates with GNB treated with appropriate versus inappropriate antibiotics. Statistical analyses were performed using SPSS version 15.0 .The student’s The datasets used/or analyzed during the current study are available from the corresponding author on reasonable request.This study was approved by the institutional review board of Chang Gung Memorial Hospital, (the IRB certificate number: 103-3236B) with a waiver of informed consent because all patient records and information were anonymized and de-identified prior to analysis.During the study period, a total of 333 neonates with 395 episodes of Gram-negative bacteremia were identified; 19 of them were the recurrent episodes which occurred within one month after the first episode and were excluded, leaving a total of 333 neonates with 376 episodes of Gram-negative bacteremia for analysis .Klebsiella spp. , Escherichia coli , Enterobactor spp. , and Acinetobacter baumannii . Thirty-three episodes of bacteremias were polymicrobial (8.8%). There were 70 (18.6%) multidrug-resistant organisms among the isolates, including 47 extended-spectrum β-lactamase (ESBL) producers.Most of our cases were nosocomial infections , and only 5 episodes (1.3%) were community-acquired. There were 354 episodes of late-onset sepsis and 22 episodes of early-onset sepsis. The predominant organisms for monomicrobial bacteremias were The antibiotics with Gram-negative activity that were most frequently prescribed during the first 24 h of bacteremias onset were cefotaxime , gentamicin , meropenem , ceftazidime , and aztreonam . In 9 (2.4%) episodes, only monotherapy with vancomycin was prescribed initially. In 348 cases (92.6%), more than one antibiotic were used during this time period.Seventy-five (19.9%) episodes of Gram-negative bacteremia were treated with inadequate empirical antibiotics. In 66 (88.0%) of these cases, subsequently identified pathogens resistant to the prescribed antibiotics were responsible for the inadequate treatment, including multidrug resistant strains for 51 (68.0%) isolates. For the other 9 (12.0%) cases, the clinicians failed to administer in-vitro susceptible antibiotics within 24 h after the initial positive blood culture was drawn. The median time from bacteremia onset to receive adequate antibiotic treatment in those without initially adequate treatment was 47 h (range: 29–94 h). Within 24 h after notification of antibiotic susceptibility, all patients received adequate antibiotic treatment.Klebsiella pneumoniae  was the most common pathogen treated with initially inadequate antibiotic, followed by E. coli  and Pseudomonas aeruginosa . However, ESBL-producing bacteria  and Pseudomonas aeruginosa  had the highest rate of receiving inadequate antibiotics initially , and significantly more likely to have antibiotic exposure with a third generation cephalosporin (P < 0.001) and vancomycin (P = 0.004) within one month before bacteremia onset than adequately treated bacteremias. In terms of clinical manifestations and laboratory data at onset of bacteremia, there were no significant differences between the two groups, except higher serum C-reactive protein concentration in the bacteremias without adequate treatment . With multivariate logistic regression analysis, only previous antibiotic exposure to a third generation cephalosporin within one month was identified as the independent risk factor . Between patients receiving initially inadequate and adequate empirical treatment, there were no significant differences in terms of demographics, age at onset of bacteremia, use of CVC, TPN and/or intrafat, mechanical ventilation, and underlying chronic conditions . InitialP = 0.002) and infectious complications (p < 0.001). P = 0.013). This can also be confirmed by log rank test (p = 0.051) [For bacteremias without initial adequate therapy, a total of nine patients died within 7 days, including 5 patients who died within 48 h after bacteremia onset without receiving any effective antimicrobial therapy. Infants without initially adequate antibiotic therapy did not have a significantly higher early mortality rate than those with adequately therapy, and the risk of recurrent bacteremia within one month was also comparable . However= 0.051) .P. aeruginosa and ESBL-producing bacteria. Previous antibiotic exposure to a third generation cephalosporin was identified as the independent risk factor for initially inadequately treated bacteremias before blood culture results and antibiotic susceptibilities were available. The possible explanation could be that broad-spectrum cephalosporin exposure caused selection of drug-resistant bacteria, which further resulted in inadequately treated bacteremias, if alternatively more effective antibiotics were not prescribed. The adverse outcomes were in patients with the significantly higher rates of infectious complications and overall mortality (within 30 days) compared with adequately treated patients.Results from this study indicated that initially inadequate antimicrobial treatment was significantly associated with antibiotic resistant Gram-negative bacteria, mainly Several factors have been found for inadequate treatment in other settings, e.g., hospital admission in the 90 days prior to the current admission, admission to surgery, nosocomial infection, and polymicrobial infection ,24,25. AS. marcescens and A. baumannii causing bacteremias were multidrug resistant and associated with high mortality or morbidity in the NICU [S. marcescens and most of the A. baumannii isolates in our cohort were susceptible to aminoglycoside or cefotaxime, and thus, they were not difficult to treat. The significantly higher mortality of inadequately treated Gram-negative bacteremias may partially be explained by the pathogens themselves, and P. aeruginosa and ESBL-producing bacteria, the major causative organisms of this study, have been found to be more likely to cause fulminant illness or early mortality [The appropriateness of initial antibiotics depends on the empirical antibiotic prescribed and the local antibiotic susceptibility patterns. It seemed reasonable that the lower the rate of drug resistant organisms in the NICU, the lower the rate of initially inadequate antimicrobial therapy. Therefore, the issue of how to reduce antimicrobial resistance in the ICU ,32 is imthe NICU ,34, all ortality ,36. In this study, the result in neonates with GNB is comparable with that documented in the literature of studies which were conducted in adults ,24,25. GThis study highlighted the importance of further efforts to elucidate the optimal timing and aggressive antibiotic regimen for neonates who are at risk of antibiotic-resistant Gram-negative bacteremia. Antimicrobial stewardship interventions have been well studied to prompt appropriate antibiotics prescription in the NICU ,38,39. IBecause colonization of the newborns with MDR Gram-negative pathogens makes them the potential source of nosocomial outbreaks ,40, furtThere are some limitations in this study. This study was observational and not randomized; therefore, the choices of initial empirical antibiotic depended on attending physicians, instead of the researchers. We failed to account for some important confounders that might influence the decision of attending physician in modifying antibiotics, such as the clinical progression on the first day of bacteremia. Besides this, the data were derived from a single center; therefore our conclusions are necessarily limited in generalizability to other settings and institutions. Pseudomonas spp, may reduce the rate of inadequate antibiotic treatment, which can potentially improve the treatment outcomes. In conclusion, initial inappropriate antibiotic therapy in neonates with gram-negative bacteremia is associated with a significant higher risk of overall mortality and infectious complications. Early identification of neonatal sepsis caused by antibiotic resistant pathogens, such as ESBL producing gram-negative bacilli or


Dietary interventions, including a low-protein diet (LPD) and methionine (Met) restriction, have shown longevity, anti-aging and metabolic health effects. We previously reported that the LPD has a renoprotective effect against diabetic kidney disease (DKD) in rats with type 2 diabetes and obesity. However, it is unclear whether the beneficial effect of the LPD is mediated by low-Met intake or how Met is related to the pathogenesis for DKD. We herein show that the addition of Met with the LPD abrogates the beneficial effects induced by the LPD such as anti-oxidative stress, anti-inflammation and anti-fibrosis, in diabetic kidney. Additionally, the increased levels of S-adenosylmethionine (SAM) in renal tubular cells, which are associated with the reduced expression of glycine N-methyltransferase (Gnmt) and non-restricted Met intake, contributes to the activation of mechanistic target of rapamycin complex 1 (mTORC1) and impaired autophagy, in diabetic kidney. Moreover, starvation-induced autophagy was suppressed in renal cortex of Gnmt null mice and amino acid free-induced autophagy was also suppressed by administration of SAM in cultured HK-2 cells. A LPD could exert a renoprotective effect through the suppression of mTORC1 and restoration of autophagy, which is associated with reduced levels of SAM due to low-Met intake, in diabetic kidney. Diabetic kidney disease (DKD) is recognized as the leading cause of end-stage renal disease (ESRD). The degree of tubulointerstitial damage rather than glomerular damage is predictive of a decline in renal function in patients with chronic kidney disease (CKD), including DKD , 2. TherDietary interventions have been recognized as one of the experimental methods for lifespan extension and the suppression of age-related diseases. Numerous reports have shown that calorie restriction (CR) or dietary restriction (DR) without malnutrition extends the lifespan and improves metabolic health in organisms . HoweverThe overall body weight (BW) changes of rats are presented in The diabetes + LPD group exhibited lower blood glucose levels under ad libitum feeding than those of the diabetes + STD group. However, the diabetes + LPD + Met group showed high levels of blood glucose under ad libitum feeding, which were similar to those of the diabetes + STD group . The LPDThe levels of urinary albumin and liver-type fatty acid binding protein (L-FABP) excretion in diabetes + STD rats were markedly increased compared to those of the control rats at the end of the study  and 2I. Col3), Kim-1, Cd68 and tumor necrosis factor-α (Tnf-α) in the renal cortex was significantly increased compared to that in the control (Representative photomicrographs of Masson’s trichrome (MT) staining, Periodic Acid Schiff (PAS) staining and kidney injury molecule-1 (Kim-1) immunohistochemically stained kidney sections from each rat group are shown in  control  to 3H. R control  to 3H.Gnmt expression in the renal cortex was evaluated by western blotting and real time-polymerase chain reaction (PCR) –4C. BothDiabetes + STD showed an increased intensity of immunohistochemical staining for phospho-S6 ribosomal protein (p-S6RP) (a downstream effector molecule of mTORC1) in tubular lesions compared to that in the control rats, and LPD decreased the intensity of its staining to levels similar to those observed in the controls  and 5B. Diabetes + STD exhibited alterations in mitochondrial morphology in PTCs, such as fragmented mitochondria and increased numbers of PTCs without elongated mitochondria  and 6B. To clarify whether SAM itself suppresses autophagy, we analyzed microtubule associated protein light chain 3-II (LC3-II) turnover through preventing lysosomal degradation by using chloroquine (CQ), in cultured HK-2 cells  and renal cortex of Gnmt KO mice. Administration of SAM suppressed amino acid-free-induced autophagy in cultured HK-2 cells  and 7B. Recent reports have shown that a LPD could exert beneficial effects on longevity and metabolic health . PreviouDrosophila [. Compared with young flies, older flies have increased SAM levels, even though Gnmt is transcriptionally induced with aging [. However, overexpression of Gnmt suppresses the age-dependent SAM increase and extends the lifespan. A previous report showed that Gnmt is distributed in the liver, kidney, pancreas and jejunum of rats, and in the kidney, Gnmt expression was observed primarily in the PTCs [As the mechanism by which additional Met intake cancelled the benefit of a LPD on DKD, we focused on Met metabolism in the kidney. Met is converted to SAM in a reaction catalyzed by the enzyme Met adenosyl transferase (MAT), and SAM is converted to S-adenosylhomocysteine (SAH) by Gnmt, a key enzyme for SAM metabolism that maintains the intracellular SAM levels . SAM is osophila . Compareth aging . Howeverthe PTCs . In thisthe PTCs . Furtherthe PTCs . Moreovethe PTCs , while othe PTCs . Anotherthe PTCs . Thus, aGnmt mRNA levels were suppressed in patients with advanced nonalcoholic fatty liver disease (NAFLD) [Gnmt deficiency and/or hypermethioninemia, and elevated SAM levels could play a role in the pathogenesis of NAFLD by inhibiting lipophagy through PP2A methylation in an mTORC1-independent mechanism [Impairment of autophagy is closely related to aging and age-related diseases, including kidney disease . We also (NAFLD)  and Gnmtechanism .Previous studies have shown that dietary protein restriction may show metabolic benefits, such as reduced body fat gain, improved glucose tolerance, and increased energy expenditure, which are mediated by FGF21 –40. AddiIn conclusions, in this study, we found that the addition of Met to a LPD abrogated the renoprotective effects on diabetes-induced renal injuries in rats with T2DM and obesity, indicating that a LPD could exert beneficial effects on renoprotection through low Met intake. Met might lead to renal injuries in diabetic rats through the accumulation of SAM, which is related to reduced Gnmt expression, possibly contributing to the modulation of mTORC1 activation and autophagy. Thus, activation of Gnmt may be a therapeutic target for DKD through a decrease in SAM levels. Furthermore, Met exacerbates the diabetic state in LPD-fed diabetic rats, which may be associated with the cancellation of LPD-induced plasma FGF21 levels. However, further study is necessary to elucidate whether a low-Met or MetR diet can suppress diabetic renal injuries as well as a LPD.In a clinical setting, a LPD is considered the dietary therapy for the suppression of CKD, including DKD. However, an inappropriate LPD has the risk of malnutrition, such as protein energy wasting and sarcopenia, in patients. Therefore, a low-Met diet, such as lowering Met intake to levels characteristic of vegan diets, which have naturally low Met levels , or avoifa/+) rats (WLRs) were provided by the Takeda Pharmaceutical Company Biological Institute  and maintained at Kanazawa Medical University [fa/fa) rats (WFRs), and age-matched nondiabetic WLRs were used. At 24 weeks of age, the rats were divided into four groups: (1) WLRs fed a STD includes 0.64% Met (control); (2) WFRs fed a STD (0.64% Met) (diabetes + STD); (3) WFRs fed a LPD (0.15% Met) (diabetes + LPD); and (4) WFRs fed a LPD + Met (0.64% Met) (diabetes + LPD + Met). Food for the STD, LPD and LP + Met diet was purchased from CLEA . The STD contained 23.84 kcal% protein, 16.80 kcal% fat, 59.36 kcal% carbohydrates and 3.55 kcal/g energy , as shown in Male and female Wistar lean  at the end of the experiment . UrinaryThe kidney sections were stained with MT/PAS reagent . For theMitochondrial morphology and fragmented mitochondria in the PTCs were observed using TEM, as previously described . In detaCol3, Cd68, Tnf-α, and Kim-1 were purchased from Thermo Fisher Scientific . The analytical data were adjusted to the level of 18S mRNA expression as an internal control.The isolation of total RNA from the renal cortex, cDNA synthesis and quantitative real-time PCR were performed as previously described . TaqMan Western blotting of the renal cortex was performed using antibodies against Gnmt (1:1000), p62 (1:1000), β-actin (1:1000), p-S6RP (1:1000), S6RP (1:1000), Methyl-PP2A, PP2A and LCMT1 as previously described. The anti-rabbit polyclonal p62 antibody (PM045) was obtained from Medical and Biological Laboratories . Anti-rabbit monoclonal PP2A (#2259), mouse monoclonal LCMT1 (#5691), rabbit polyclonal p-S6RP (Ser235/236) (#2211), and rabbit monoclonal S6RP (#2217) antibodies were obtained from Cell Signaling Technology . Anti-mouse monoclonal methylated-PP2A (sc-81603) and mouse monoclonal Gnmt (sc-166834) antibodies were purchased from Santa Cruz Biotechnology . Anti-mouse monoclonal β-actin antibodies were obtained from Sigma-Aldrich .The contents of SAM in the renal cortex were measured by liquid chromatography/mass spectrometry using LC/MS/MS 8040  at the laboratory of Euglena Co., Ltd. .HK-2 cells, which are human kidney proximal tubular cells, were obtained from the American Type Culture Collection (ATCC) . HK-2 cells were maintained in Keratinocyte-SFM (1×) medium (Life Technologies Green Island NY).Autophagic flux was determined by analyzing LC3-II turnover by preventing lysosomal degradation using CQ . LC3-II expression was evaluated by western blotting using anti-LC3 antibodies  , 46. LC3tm1Cwa/J  male and female mice were purchased from Jackson Laboratory  [Gnmt and C57BL/6J mice as wild type littermates were provided free access to food and water. Mice were housed in a temperature- and humidity-controlled room on a 12 h:12 h light-dark cycle. All mice were studied at 8 weeks of age. To assess the autophagic flux by the autophagy-lysosome pathway, mice were injected intraperitoneally with CQ (50 μg/g body weight) and were killed 6 hours after the injection [B6.129-Gnmtia, USA) . These mnjection . To studSAM (4 mM) was administered to cultured HK-2 cells under HBSS, and samples for western blotting were collected at 0, 15, 30 and 60 min. The expression of methyl-PP2A and p-S6RP was evaluated by western blotting.The data are expressed as the mean ± standard deviation (SD). A one-way ANOVA or a repeated measures one-way ANOVA followed by Tukey’s multiple comparison test was used to determine the significance of pairwise differences among the four groups. A p value of <0.05 was considered significant.


In 2017, approximately 73% of antibiotics in England were prescribed from primary care practices. It has been estimated that 9%–23% of antibiotic prescriptions between 2013 and 2015 were inappropriate. Reducing antibiotic prescribing in primary care was included as one of the national priorities in a financial incentive scheme in 2015–2016.To investigate whether the effects of the Quality Premium (QP), which provided performance-related financial incentives to clinical commissioning groups (CCGs), could be explained by practice characteristics that contribute to variations in antibiotic prescribing.Longitudinal monthly prescribing data were analysed for 6251 primary care practices in England from April 2014 to March 2016.Linear generalised estimating equations models were fitted, examining the effect of the 2015–2016 QP on the number of antibiotic items per specific therapeutic group age–sex related prescribing unit (STAR-PU) prescribed, adjusting for seasonality and months since implementation. Consistency of effects after further adjustment for variations in practice characteristics were also examined, including practice workforce, comorbidities prevalence, prescribing rates of non-antibiotic drugs, and deprivation.p<0.001). Practices with low workforce and those with higher diabetes prevalence had greater reductions in prescribing following 2015–2016 QP compared with other practices (interaction p<0.001).Antibiotics prescribed in primary care practices in England reduced by -0.172 items per STAR-PU  after 2015–2016 QP implementation, with slight increases in the months following April 2015 . Adjusting the model for practice characteristics, the immediate and month-on-month effects following implementation remained consistent, with slight attenuation in immediate reduction from -0.172 to -0.166 items per STAR-PU. In subgroup analysis, the QP effect was significantly greater among the top 20% prescribing practices (interaction In high-prescribing practices, those with low workforce and high diabetes prevalence had more reduction following the QP compared with other practices, highlighting the need for targeted support of these practices and appropriate resourcing of primary care. The QP has previously been associated with reductions in antibiotic prescribing in primary care practices in England. To the authors’ knowledge, this study is the first to investigate the other possible explanations of the effect of the QP on antibiotic prescribing in primary care practices, strengthening the evidence on the effectiveness of this financial incentive scheme. The results show a consistent effect of QP after accounting for differences in practice characteristics, indicating its inclusiveness in reaching diverse populations. The study provides novel evidence on the differential effect of QP, emphasising the role of CCGs in identifying and supporting higher-prescribing practices, understaffed practices, and those dealing with a high prevalence of comorbidities.3 Primary care is the main contributor to antibiotic usage in England, constituting approximately 73% of antibiotics prescribed in 2017.4 It is estimated that 9%–23% of antibiotic prescriptions in primary care practices in England between 2013 and 2015 were inappropriate, which is based on prescribing guidelines.5The overuse of antibiotics drives resistance through the selection of antibiotic-resistant strains of organisms.6 The prevalence of comorbidities such as diabetes varies over time and geographical area, contributing to the disparities in the antibiotic prescribing pattern within and between primary care practices.8Antibiotic prescribing is recommended in the management of respiratory tract infections (RTIs) in some patients, including older patients with diabetes or heart failure, who are considered at particular risk of developing complications.10 The QP is an NHS England performance-related incentive scheme established in 2013 to reward CCGs financially, based on the quality of specific health services considered to be national or local priorities and commissioned over a specific period.9 Individual GP practices did not receive financial remuneration in relation to this award. Reducing antibiotic prescribing in primary care was included as one of the national priorities in the 2015–2016 QP guidance, targeting a reduction of 1% of the mean value in England in 2013–2014 (1.161 antibiotic items per STAR-PU) for a CCG to obtain the financial incentive .Several approaches have been adopted to reduce primary care antibiotic prescribing in England including: increased surveillance and prescribing feedback; the provision of C-reactive protein point-of-care testing; education and training interventions targeted at prescribers and patients; public antimicrobial stewardship (AMS) campaigns; and financial incentives.13 specifically a reduction of about 2.7 million antibiotic items between 2014–2015 and 2016–2017 financial years (1 April to 31 March).4 Such reductions in antibiotic prescribing would be expected to contribute to reductions in the development of resistance.14The QP intervention has been associated with substantial reductions in antibiotic prescribing in primary care practices in England,However, it is not clear whether these reported reductions can be entirely attributed to the QP as current evaluations have not accounted for other possible explanations, such as variations in practice characteristics over time. The main aim of this study was, therefore, to investigate whether differences in primary care practice characteristics, which can contribute to variance in antibiotic prescribing , explained any of the effects of the QP scheme on the prescribing rates in primary care practices. Furthermore, the study investigated whether the QP had a differential effect on high-prescribing practices and other subgroups of practices.New QP guidance was implemented at the start of each financial year in England with changes in the targeted reductions in antibiotic prescribing and its associated award. This study adopted a natural experiment approach in investigating the mechanism of impact of the 2015–2016 QP target on antibiotic prescribing in primary care practices in England, with the preceding financial year as the control, by conducting analyses of longitudinal (monthly) prescribing data for 6251 primary care practices in England from April 2014 to March 2016. While there are more recent antibiotic prescribing data, including data beyond March 2016would have meant exceeding the period covered by the 2015–2016 QP guidance, as prescribing in subsequent periods are covered by different QP guidance and targets.15 The frequency of prescribing of these drugs has been reported as an indicator of antibiotic prescribing rates.16 Adjusting for the prescribing behaviour of opioids and benzodiazepines was important to account for the overall medicine prescribing behaviour of practices that might not be specific to antibiotics.Like antibiotics, the prescription of opioids and benzodiazepines is monitored in the UK with prescribers encouraged to reduce their prescription.17 and the number of registered patients in each age–sex category in a practice for each specific month.18The primary outcome was a continuous variable indicating the number of antibiotic items per STAR-PU prescribed by a practice in England per month. Practice-level antibiotic prescribing data were sourced from OpenPrescribing (an Evidence-Based Medicine DataLab project at the University of Oxford) and STAR-PU weighted using figures from the 2013 item-based age–sex weighting for oral antibacterials,The main predictor was a binary variable indicating the implementation of the 2015–2016 QP. The intervention period included April 2015 to March 2016 with the control period as the prior 12 months . A continuous variable representing the number of months since 2015–2016 QP implementation was used to examine changes in trend in the months following the intervention.Confounder and effect modifiers in this study included:19the number of GPs per 10 000 patients in each practice for each financial year (sourced from the NHS workforce data);21 (this only accounts for the site of practice and not patient-level data);the Index of Multiple Deprivation (IMD), computed based on the lower super output area for each practice's postcode22 These comorbidities have been chosen as their prevalence is relevant to the antibiotic prescribing rate of a practice given that antibiotic prescribing is recommended in the management of some patients with RTI with these comorbidities;25 and,yearly prevalence of specific comorbidities per 100 patients, namely asthma, chronic obstructive pulmonary disease (COPD), diabetes mellitus (for type 1 and 2), cancer, and chronic kidney disease, from the NHS Quality and Outcomes Framework (QOF) database (QOF data do not distinguish between type 1 and type 2 diabetes mellitus).26the monthly prescribing rate of opioids and benzodiazepines (per 100 patients) from practice level prescribing data published by NHS Digital.Data from the different sources were linked using practice code, which is a unique identifier for practices in England. Data from OpenPrescribing and NHS Digital are from the same source: NHS Business Services Authority prescribing and dispensing information systems.27As the analysis is at a monthly level, all models were adjusted for seasonality  to account for the seasonal differences in antibiotic prescribing, with increased incidence of RTIs during the winter months associated with higher antibiotic prescribing.The dataset covered 7549 practices existing over the study period. 876 practices were dropped due to incomplete observation for all variables  and then 422 practices (5.6%) that were outliers were dropped using the interquartile range rule; therefore, the final analyses included 6251 (82.8%) practices.28 to investigate the effect of the 2015–2016 QP on antibiotic prescribing. The first model included variables reflecting the 2015–2016 QP and the number of months since its implementation as the predictors, adjusting for seasonality.Generalised estimating equations models were fitted with an autoregressive ‘AR(1)’ covariance structureTo examine whether this estimated effect of the 2015–2016 QP on antibiotic prescribing was explained by differences in practice characteristics that can contribute to variance in antibiotic prescribing, variables were intoduced reflecting practice characteristics  to investigate whether the effect of the QP was retained, declined, or intensified.In the multivariable model, variables causing multicollinearity were excluded (defined by opposite effects in univariable and multivariable models and high Spearman correlation >0.5). To address non-linearity, the association was modelled between the outcome and workforce using linear spline terms with knots equally spaced over the range of the workforce data . A principal component analysis (PCA) was used to compute a summary score reflecting respiratory diseases comorbidity . The PCA produced two components with eigenvalues of 1.41 and 0.59. The first component was retained , which explained 71% of the variation in the data on respiratory diseases prevalence.Subgroup analyses were also conducted using interaction terms to examine whether the 2015–2016 QP had a differential effect on antibiotic prescribing among: high-prescribing practices (the top 20% prescribing practices based on the mean antibiotic items per STAR-PU prescribed in 2014–2015); practices with a higher prevalence of comorbidities; low workforce; and in deprived areas. For more detailed analysis of the differential effect of QP based on levels of comorbidity prevalence, the study used linear spline functions with knots equally spaced over the range of the variables on diabetes prevalence  and the PCA summary score for respiratory diseases .All analyses were conducted using Stata (version 15.1). Results for all models are presented as coefficients with 95% CIs.The data constituted 150 024 observations for 6251 practices; each practice contributed data for 24 months. The mean number of antibiotic items prescribed in 2014–2015 QP was 1.106 items per STAR-PU (95% CI = 1.103 to 1.108); this was 0.097 items higher than the mean in the post-intervention period . The topUnivariable models showed the predictors and covariates (apart from the last spline term for workforce) were all significantly associated with the antibiotic prescribing rate in primary care practices in England (see Supplementary Table S1).Antibiotic prescribing in general practices in England reduced by -0.172 items per STAR-PU (95% CI = -0.176 to -0.168) after 2015–2016 QP implementation in April 2015 compared with the 12 months before . There wAfter extending the model to adjust for practice characteristics , the immediate and month-on-month effects seen after 2015–2016 QP implementation remained consistent, with only a slight attenuation in mean reduction in items prescribed immediately following the QP from -0.172 to -0.166 items per STAR-PU, a 3.5% relative reduction in effect size .With the subgroup analyses, the study examined whether the effect of the QP on antibiotic prescribing was greater within specific subgroups of practices, such as those that are among the top 20% prescribers, with a more complex patient population in relation to the prevalence of comorbidities, size of workforce, and deprivation index using interaction terms.p<0.001)  compared with other practices  .p<0.001).For the interaction between QP and diabetes prevalence, a significant variation in prescribing behaviour before versus after QP was seen only in practices with diabetes prevalence of between 7.60% and 11.28% . Before p<0.001) (p>0.23).The study also found a significant interaction in practices where GP headcount was fewer than 4.91 and those between 4.91 and 9.81 per 10 000 patients. Following the implementation of QP, the understaffed practices (with fewer than 4.91 GPs per 10 000 patients) experienced a decrease in the pre-QP increasing trend in antibiotic prescribing  (interaction p<0.001) . This wap>0.13) or respiratory diseases prevalence .The reduction in antibiotic prescribing after the implementation of the QP was similar for all subgroups of practices based on deprivation . The reduction reported in practices with higher diabetes prevalence indicates their ability to work towards reducing prescribing rate, while coping with other needs arising from the complexity of their patient population. This finding is important considering the increasing trend in diabetes prevalence in the UK,To the authors’ knowledge, the study is the first to account for other possible explanations of the effect of the QP on antibiotic prescribing in primary care practices , strengthening the evidence on the effectiveness of this financial incentive scheme. A large dataset was used including most (82.8%) practices in England over the observation period, with 12 months observations before as well as after the implementation to capture the temporal trend in antibiotic prescribing.32 and severity of illness, have not been accounted for in the analyses as these data are not available nationally at practice level.One of the limitations of the study is that some practice characteristics that could be associated with antibiotic prescribing behaviours, such as consultation rates33 this limits the causal interpretation of the observed effect of the 2015–2016 QP. However, the QP is the most relevant difference in antibiotic stewardship between 2014–2015 and 2015–2016 financial years, as most of the national interventions, such as the TARGET toolkit (introduced in 2012),36 and the chief medical officer’s letter to high prescribers (introduced in 2014),37 were implemented in both periods.Also, it is recognised that the QP is not the only antibiotic stewardship intervention in England in the period covered by this study;42 Evaluation studies have reported mixed effects from such incentive schemes. While the finding on the immediate effect of the 2015–2016 QP on antibiotic prescribing confirms those of other UK studies on this incentive scheme,12 some studies have shown a limited effect of similar schemes as seen in the month-on-month increase post-QP reported in the study. A study in the Netherlands showed a limited, temporary effect of a one-off behaviour independent financial bonus on the volume of drug prescriptions and the quality of prescribing behaviour in general practice.40 Similar results were reported in a UK study that demonstrated reduction in some measures of quality of care following the removal of a financial incentive scheme to improve clinical performance.43 However, unlike the QOF evaluated in the study by Minchin et al.,43 QP is paid at CCG level only , and CCGs need to meet other core criteria to receive the reward.Financial incentives have been used to improve performance and quality of care in different clinical areas and settings.37 However, a similar randomised clinical trial in Switzerland demonstrated that personalised prescription feedback to physicians to reduce antibiotic prescribing in primary care made no significant difference in overall antibiotic prescribing.44 These studies have mostly focused on interventions that are specifically designed to target high prescribers alone.Furthermore, evaluations of other antibiotic stewardship interventions on high prescribers have also shown mixed effects. A behaviour change intervention that provided social norm feedback to high-prescribing primary care practices in England on their prescribing behaviour showed an overall significant impact in reducing antibiotic prescribing.The study provides novel evidence on the differential effect of the 2015–2016 QP. Highlighting the ability of high-prescribing practices, understaffed practices, and those dealing with a higher prevalence of comorbidities to make substantial improvements when adequately supported; this study emphasises the role of CCGs in identifying and working with these practices.45 CCGs have an important responsibility to identify and work with understaffed practices in the implementation of antimicrobial stewardship interventions to facilitate performance improvements.The substantial scope for change in high-antibiotic prescribing practices illustrated by this study should prompt these practices to take action on this issue, and to actively seek support from CCGs in addressing overprescribing. Also, policymakers and antibiotic stewardship programmes should target these practices specifically in the design and targeted implementation of antibiotic stewardship interventions. The shortage of GPs in NHS primary care is of increasing concern, and the greater effect on understaffed practices underlines the need for appropriate resourcing. The current government’s promises regarding increased GP numbers notwithstanding,The gradual increase in antibiotic prescribing in the months following the 2015–2016 QP (countering some of the immediate effects of the intervention) demonstrates the need for more efforts towards the sustainability of the effects of AMS interventions. Approaches to maintain or improve the immediate effects of such interventions should be considered at the design stage.


The segments of the database with a low and moderate safety level have been identified as i) NSC moderately and heavily confined by higher modulus glass fibers , ii) high strength concrete (HSC) moderately and heavily confined  by glass fibers, iii) HSC lightly confined  by carbon fibers, and iv) HSC lightly confined by aramid fibers. Additional experimental studies are required on these segments of the database before they can be used reliably for design and modeling purposes. In this paper compressive strength and ultimate strain results in the current database of fiber-reinforced polymer (FRP)-confined concrete are used to determine the reliability of their design space. The Lognormal, Normal, Frechet, Gumbel, and Weibull distributions are selected to evaluate the probabilistic characteristics of six FRP material categories. Following this, safety levels of the database are determined based on a probabilistic model. An iterative reliability method is developed with conjugate search direction for evaluating the reliability. The results show that Lognormal and Gumbel distributions provide best probability distribution for model errors of strength and strain enhancement ratios. The developed conjugate reliability method provides improved robustness over the existing reliability methods owing to its faster convergence to stable results. The results reveal that the part of the database containing normal strength concrete (NSC) heavily confined (i.e., actual confinement ratio ( Three reliability examples are considered as follows:In this section, the performance of the developed CFORM is compared with other algorithms including HL-RF, CC, FSL, CHL-RF, DSTM, conjugate FORM-based LFR, and CCC through the use of three nonlinear limit state functions. Example 1: A highly nonlinear reliability problem with non-normal limit state function of Equation (7) is considered .x1 presents the Lognormal distributed variable with the mean (μ) of 5 and standard deviation (σ) of l, and 2x presents the Gumbel distribution with μ of 10 and σ of 10. The converged β was robustly obtained by CFORM after 11 iterations as β = 3.259, while β obtained by MCS with 1.2×106 samples was 3.501. Therefore, CFORM was more robust and efficient in solving Equation (7) compared to MCS. β obtained from HL-RF, CC, FSL, CHL-RF, and the proposed CFORM. It is shown in the figure that HL-RF method yields to 4-periodic solutions as β = . CC and FSL robustly converged to the same β of 3.259, but they are less efficient than the DSTM, LFR, CCC, CHL-RF, and CFORM. Unlike the CC, DSTM, and FSL, the formulation of HL-RF is iterated without chaos feedback control factor. Therefore, as can be seen in Ac, As, Ec, Es, and l are cross-section area of reinforced concrete, cross-section area of steel bar, elastic modulus of concrete, elastic modulus of steel bar, and length of the truss member, respectively. This example included six normal independent random variables with statistical properties shown in Example 2: A composite roof truss with compression members made of reinforced concrete, and tension bars made of steel illustrated in β obtained by MCS with 1.06×106 samples was 2.350. The iterative histories of β obtained from different FORM algorithms are illustrated in β of 2.422 after 88 (5.23 s), 44 (3.36 s), 37 (3.17 s), 38 (3.18 s), and 27 (2.61 s) iterations, respectively. The nonlinearity map of DSTM, HL-RF, and CC algorithms provides the chaotic search direction at final iterations due to their formulations while the FSL method with small finite-step length improves this drawback of the FORM-based HL-RF, CC, and DSTM. It is worth noting that, once again, the CFORM converged faster than the other converged algorithms while conjugate algorithms of CCC and LFR are shown the similar efficiency for this problem. The CFORM with nonlinear descript conjugate map provided stable results like the other conjugate approaches of CCC, LFR, and CHL-RF for this problem.P1–P7 loads, E as Young’s modulus, and iA with i=1, 2, 3, …, 24 as cross-section of 1–24 bars components with statistical properties shown in Example 3: A dam truss structure presented in β for different FORM algorithms are presented in β using MCS is 1.76 after 106 samples with CPU-run time of 26,484 s while the proposed FORM-based CFORM and FSL algorithms are converged after 21 (49.4 s) and 88 (161.6 s) iterations to β of 1.735 and 1.944, respectively. As shown in The converged results of The results of the three examples indicate that HL-RF, CC, and DSTM algorithms provide unstable solutions, whereas the CFORM, CCC, LFR, and FSL robustly converge. The CFORM converges quicker compared to the other reliability algorithms-based conjugate search direction of LFR, CCC, and CHL-RF. These observations indicate that the proposed CFORM provided superior results compared to existing reliability methods in terms of efficiency and robustness; hence it is selected in this study for the reliability analysis of FRP-confined concrete.ccf′ and cuε of FRP-confined concrete as follows:ccf′, cof′, cuε, and coε denote ultimate compressive strength, unconfined concrete strength, ultimate axial strain, and axial strain corresponding to cof′, respectively. (ccf′/cof′)Mod and (cuε/coε)Mod represent the strength and strain enhancement ratio defined using mathematical models, respectively. fκ and ccf′ and cuε of FRP-confined concrete models, respectively. To express the uncertainties between the prediction and experimental ultimate condition of FRP-confined concrete, fκ and For reliability analysis of FRP-confined concrete, two major limit state functions can be defined based on h,rupε is the FRP hoop rupture strain; fε is the ultimate tensile strength, ft is the total thickness, and fE is the elastic modulus of fibers used in FRP jackets; and D is the diameter of specimens. coε is determined using Equation (19) [The models proposed by Ozbakkaloglu and Lim  (Equatioion (19) .H is the specimen height in millimeter.fκ and εκ. The probability distribution parameters of Frechet, Gumbel, Weibull, Lognormal, and Normal distribution functions for the model errors are estimated by the maximum likelihood method and the best distribution function is selected using the chi-squared statistic  are calculated to determine eference  for detaμ of 1.005 and coefficients of variation (COV) of 0.184 were obtained for the model uncertainty of strength enhancement ratio and μ of 1.195 and COV of 0.247 were obtained for strain enhancement ratio.The histogram of data, Gumbel distribution function for model error of strength enhancement ratio and Lognormal distribution function for model error of strain enhancement ratio are illustrated in fE and ft) on the probabilistic characteristics of the model error, six categories are considered for FRP confinement based on the fiber type and fE, including three categories for specimens confined by carbon FRP (CFRP), two categories for glass FRP (GFRP), and one category for aramid FRP (AFRP). A large experimental database containing 769 cylindrical concrete specimens confined by unidirectional fibers in hoop direction was used in the probabilistic analysis. A total of 607 data points were compiled from References [cof′ < 50 MPa) and HSC  specimens confined by i) low , normal , and high  modulus carbon fibers, ii) lower  and higher modulus  glass fibers, and iii) aramid fibers under light  ≤ 0.2), moderate , and heavy  confinement levels.To investigate the effect of FRP material properties  of other FRP properties . Therefore, it is suggested that COV of ft and fE can be taken to be 0.08 and 0.1, respectively. As can be seen in ft, whereas Gumbel or Lognormal distribution is better fitted for fE which is denoted to results extracted from Reference [cof′, H, and D follow the Normal distribution with COV of 0.18, 0.1, and 0.1, respectively [The Normal, Lognormal, Frechet, Gumbel, and Weibull distributions are used to determine the best PDF in evaluating the properties of FRP-confined concrete. The parameters of PDF are evaluated by the maximum likelihood estimator. The results of statistical analysis for each of the previously defined specimen categories are illustrated in ectively . The selectively ,57.ccf′ and cuε of FRP-confined concrete and then β is determined according to the probabilistic model for each FRP category.The reliability analysis is implemented on the experimental data points of six FRP categories. Based on the results from the probabilistic modeling, the reliability index is determined using the proposed CFORM method. Therefore, a probabilistic model is developed based on the reliability analysis of Various uncertainties in this type of structural reliability analysis are given using the probabilistic models. Generally, the safety level-based reliability analyses of FRP-confined concrete database can be estimated based on a mathematical relation, in which the safe domain is separated into failure domain with respect to various uncertainties using a probabilistic model. The reliability index is then determined based on the limit state functions presented in Equations (20) and (21) which are determined by rearranging empirical models in Equations (14) and (15) into Equations (10) and (11) for evaluation of the safety level of FRP-confined concrete database.ccf′ and cuε, respectively. Based on the limit state functions, the reliability index of concrete confined by FRP is evaluated by eight random variables of cof′, D, H, ft, fE, fε, fκ, and κε. The means, COVs, and PDFs for the two variables of fκ and κε are given based on the presented results in β is computed using the CFORM algorithm for different FRP categories based on the limit state functions given in Equations (20) and (21). β and lu,af/cof’ for different FRP categories, which are respectively computed using limit state functions of lu,af/cof’ of more than 1, owing to the translation of hoop stress between the concrete core and FRP sheet.For assessing the safety levels of different segments of the current database of FRP-confined concrete, β < 2.5), moderate (2.5 ≤ β ≤ 3.25), high (3.25 < β ≤ 4.5), and very high (4.5 < β) levels. Four safety levels are defined for the segments of the database based on the reliability analysis results, namely: low . However, the accuracy of the proposed probabilistic framework is dependent on the accuracy of the predictions of the performance function. Therefore, it is recommended that the future experimental studies on FRP-confined concrete target segments of the database with a low and moderate safety level to propose an accurate empirical model (performance function) for predicting the ultimate condition of FRP-confined concrete columns.Based on the results presented in ccf′ and cuε of concrete confined by FRP. ccf′ and cuε of FRP-confined concrete were determined based on a FORM with conjugate search direction, which is called CFORM. Three nonlinear reliability problems were utilized to validate the efficiency and accuracy of the CFORM compared with existing reliability methods. Reliability analysis results demonstrated that the CFORM is more robust and efficient in comparison with the existing methods. CFORM was then implemented for evaluating the safety levels of ccf′ and cuε results in the current database of FRP-confined concrete. Four safety levels were defined for six categories based on cof’ and lu,af/cof’. The following conclusions are drawn from the reliability analysis of FRP-confined concrete:(1)fκ and κε of FRP-confined concrete.Lognormal and Gumbel distributions provide the best fitness for (2)lu,af/cof’ > 0.5) by low and normal modulus carbon fibers , and (ii) NSC moderately confined  by aramid fibers represent a very high safety level.The segments of the database containing (i) NSC heavily confined lu,af/cof’ > 0.2) (i) NSC by high modulus carbon fibers , (ii) HSC by low and normal modulus carbon fibers , and iii) HSC by aramid fibers exhibit a high safety level.The segments of the database containing moderately and heavily confined lu,af/cof’ > 0.3) by higher modulus glass fibers , (ii) HSC lightly confined  by highly modulus carbon fibers , and (iii) HSC lightly confined  by aramid fibers exhibit a moderate safety level.The segments of the database containing (i) NSC moderately and heavily confined lu,af/cof’ ≤ 0.5) by glass fibers, and (ii) HSC lightly confined  by low and normal modulus carbon fibers  represent a low safety level.The segments containing (i) HSC lightly and moderately confined (i.e., In this paper, a probabilistic model was developed to evaluate the failure probability of Additional experimental studies targeting the segments of the database with a low and moderate safety level are recommended to improve these parts of the database, so that it can be used reliably for design and modeling purposes. It is also suggested to use the proposed CFORM in fuzzy reliability analysis to prevent any uncertainties in the statistical properties of FRP-confined concrete that may arise from the quality of the preparation process of the specimen, measurement error, and inherent uncertainties.


To describe antibiotic prescriptions in out-of-hour (OOH) service in primary care setting in Iceland and to study the indications for prescriptions.A population based retrospective study, using electronic data from the OOH registration system.OOH primary care setting in Reykjavik capital area in Iceland.All patients that received a prescription for oral antibiotic drug at an OOH service in Reykjavik capital area over a one-year period.Number of oral antibiotic prescriptions and diagnosis connected to the prescriptions according to age and sex.There were 75,582 contacts with the OOH primary care of which 25,059 contacts resulted in prescription of an oral antibiotic (33%). The most common antibiotic prescribed in total, and for the diagnosis studied, was amoxicillin with clavulanic acid. It was most often prescribed for acute otitis media. Of those diagnosed with otitis media 50% were treated with amoxicillin with clavulanic acid and 40% of those diagnosed with pneumonia received that treatment. The second most prescribed antibiotic was amoxicillin. Most often it was prescribed for sinusitis, in 47% of cases with that diagnosis.Antibiotic prescription rate is high and broad-spectrum drugs often prescribed in OOH primary care service in Iceland.The results should encourage general practitioners in Iceland to review antibiotic prescriptions in OOH service.Antibiotics are often prescribed in OOH primary care in Iceland and a substantial number of the patients diagnosed in OOH primary care with acute otitis media or pneumonia are prescribed broad-spectrum antibiotics. Antibiotic resistance has been an increasing problem in the whole world during the last decades . Health Increased antibiotic prescriptions in out-of-hour (OOH) services in general practice has been observed over the last years and decades in several European countries ,11–13. CAcute Respiratory Tract infections (ARTIs) are common reasons for consulting the OOH services and are considered to account for up to 60% of all OOH consultations ,12,14,16To promote rational antibiotic prescriptions in Iceland, especially for OOH service, we firstly have to analyse and describe the antibiotic prescriptions in OOH service and see how they are compared to clinical guidelines from other countries and for OM in Iceland.The aim of this study is to describe antibiotic prescriptions in OOH primary care in Reykjavik capital area over a one-year period and analyse them by patient age, gender and diagnosis.st 2014 to December 31st 2014, and were prescribed an oral antibiotic (J01) formed the study group. The study period was chosen to ensure a coherent winter season with seasonal peaks, such as influenza.All individuals who contacted the OOH primary care service in Reykjavik capital area from January 1st 2015 was 329,100 [st 2015 (61.3%) [Total population in Iceland on January 1 329,100 . Reykjav (61.3%) . OOH serThis is a population based retrospective study. All the data was taken from the OOH electronic medical registration system. OOH registration system is fully electronical and each contact is registred through the civil registration number, assigned to every citizen in Iceland. Information was gathered about the patient age, gender and type of consultation. Furthermore, we could provide data from the electronic medical system, for the ATC coding system  for oral antibiotics (J01) and connect them with the disease diagnosis by the ICD-10 code . Antibiotic prescriptions for the following diagnosis, in alphabetical order, was specifically studied; bronchitis (ICD10 code J20 and J40), cystitis , otitis media , pneumonia (ICD10 code J12-J18) and sinusitis . Age was categorised into following age groups; 0–4 years (age group 1), 5–17 years (age group 2), 18–60 years (age group 3) and >60 years (age group 4).The data was collected in Excel 2010 and SPSS (version 24) was used to perform the statistical analysis. We used descriptive statistic to describe the data.The data was not personally identifiable. Authorization for this study was given by The National Bioethics Committee in Iceland, in December 2015 (VSN-15-162).During the study period, there were 75,582 contacts with the OOH primary care service in Reykjavik capital area. Office clinical consultations were 72,360 (95.7%) and home visits 3222 (4.3%). Of those, 25,059 contacts resulted in a prescription of an oral antibiotic (33.1%). The number of individuals who were prescribed an oral antibiotic was 19,641, therefore, 5418 individuals (7.2%) got more than one prescription of an oral antibiotic during the study period. Antibiotic prescriptions through office consultation were 24,286 (96.9%), and 766 (3.1%) through home visits. Seven antibiotic prescriptions were given after a telephone consultation through a nurse.Mean age of the participants was 32.4 year . Males were 10,346 (41.3%) and females 14,712 (58.7%). In all age groups, females were often prescribed an antibiotic, except for the youngest age group, where males were 52.7% of those prescribed an antibiotic.Of the diagnosis we selected in this study, there were in total 12.850 prescriptions of 17 different oral antibiotics , 51.3% oThe most common antibiotic prescribed in total was amoxicillin with clavulanic acid, 5695 prescriptions (22.7%). The second most prescribed antibiotic in total was amoxicillin, 4608 prescriptions (18.4%). The third most common antibiotic prescribed in total was phenoxymethypenicillin, total of 4227 prescriptions (16.9%). This is, to our best knowledge, the first study on antibiotic prescriptions in OOH service in Reykjavik capital area. The main findings are that antibiotics were prescribed in one out of three consultations and almost 30% were prescribed amoxicillin with clavulanic acid. Studies from Denmark, Norway and England have revealed an overall antibiotic prescription rate in OOH service around 15% ,13,15. OWe do not have comparative studies on antibiotic prescriptions for daytime services in primary care in Iceland, but studies from other countries have tried to illustrate the difference in antibiotic prescription rate for OOH and daytime hours in primary care ,8,11,14.In OOH primary care service in Reykjavik capital area there are no nurses that triage the consultations as in OOH service in some other countries. Therefore, people can go directly to see a GP and no one is denied access. People may find it convenient to avoid abstaining from work, as they can see a GP directly in OOH service, and this has also been suggested in other Scandinavian studies ,13. In tThis study is a retrospective data analysis. The main strength of this study is that there is one place for primary care OOH service for Reykjavik capital area with electronic data. The results reflect the current reality as registered in the electronic patient records. The GP´s involved were not aware of the plans of a research at the time of the consultations. Antibiotic prescriptions were not studied specifically for all possible diagnosis or indications for antibiotic treatment. We only studied explicitly common, rather well-defined diagnosis. Since the result showed that these diagnosis only accounted for 50% of all prescriptions, it is a certain limitation.This study is based on the diagnosis given at the consultation, which is a limitation, as there may be a lack of accuracy in making diagnosis. We have no possibility to differentiate between those who were at the OOH service due to first-line antibiotic treatment failure, follow up due to former started treatment or amongst those who had been told to wait and see. The assesment of guidelines often requires facts that are recorded in plain text, such as history, clinical signs, severity of infections, whether first-line antibiotic treatment has failed and utilisation of rapid tests.These results can give the OOH service in primary care an opportunity to reassess the prescriptions of antibiotics. Increased awareness of antibiotic resistance and guidance of reducing antibiotic prescriptions are among important steps neccessary to take. Further studies would benefit from differentiating between daytime hours and OOH antibiotic prescriptions in the capital area of Reykjavík, and whether quantity and quality of antibiotic prescription has improved in OOH service since 2014. Furthermore, clinical guidelines, reflecting the respective bacterial resistance, are required at least for the most common ARTIs.This study shows a high rate of antibiotic prescription´s in OOH primary care service in Reykjavik capital area and a high prescription rate of broad-spectrum antibiotics. Results that indicate an opportunity to improve the quality and to develop a more rational prescription of antibiotics in primary care in Iceland.


Acute otitis media (AOM) is a common and most often self-limiting infection in childhood, usually managed in general practice. Even though antibiotics are only recommended when certain diagnostic and clinical criteria are met a high antibiotic prescription rate is observed.The study’s objective was to analyse associations between patient- and general practitioner (GP) characteristics and antibiotic prescribing for children with AOM in an effort to explain the high antibiotic prescribing rates.All general practices in the Northern, Southern and Central regions of Denmark were invited to record symptoms, examinations, findings and antibiotic treatment for all children ≤7 years of age diagnosed with AOM during a four-week winter period in 2017/2018. Associations were analysed by means of multivariate logistic regressions. The study design was cross-sectional.GPs from 60 general practices diagnosed 278 children with AOM of whom 207 (74%) were prescribed antibiotics, most often penicillin V (60%). About half of the children had tympanometry performed. Antibiotic prescribing rates varied considerably between practices (0–100%). Antibiotic prescribing was associated with fever (odds ratio (OR) 3.69 95% confidence interval (CI) 1.93–7.05), purulent ear secretion (OR 2.35 95% CI 1.01–5.50) and poor general condition (OR 3.12 95% CI 1.31–7.46), and the practice’s antibiotic prescribing rate to other patients with symptoms of an acute respiratory tract infection (OR 2.85 CI 95% 1.07–7.60) and specifically to other children with AOM (OR 4.15 CI 95% 1.82–9.47).GPs’ antibiotic prescribing rates for children with AOM vary considerably even considering the of signs, symptoms, request for antibiotics, and use of tympanometry. Interventions to reduce overprescribing should be targeted high-prescribing practices. Acute otitis media (AOM) is a common and most often self-limiting infection in childhood, usually managed in general practice. In Denmark, 60% of all children will have experienced at least one episode of AOM before their seventh birthday . AOM diaIn cases of AOM, antibiotics more often result in adverse events than analgesics, such as vomiting, diarrhoea or rash , 6. FurtThis study aimed to analyse associations between patient- and general practitioner (GP) characteristics and antibiotic prescribing for children with AOM in an effort to explain the high antibiotic prescribing rates.This study is based on cross-sectional data from two audits on management of patients with acute respiratory tract infections (RTI) conducted in the winters of year 2017 in the Northern and Southern region and year 2018 in the Central region of Denmark. All GP practices in the regions were invited. By use of the Audit Project Odense (APO) method, for 20 days, the participating GPs and staff consecutively registered all patient encounters with RTI including AOM. The recording method is well-known by Danish GPs and has been used in several other studies . Only fiVirtually all services in the Danish healthcare system are fully tax-funded. GPs act as primary care providers and gatekeepers to more extended services  . As an eFor each patient a questionnaire was filled in  included the patient’s age, gender, symptoms and signs. 2) included model 1 and added the GP’s age, gender and region of practice. In model 3 and 4 each child was further characterized by the general practice’s antibiotic prescribing rates, respectively, for patients with RTI in general and specifically for children with AOM. These were individually respectively computed as the proportion of the other recorded patients with RTI and children with AOM in the practice who had antibiotics prescribed. The rates were divided in lowest 25th percentile, 25th–75th percentile and highest 75th percentile. The practice’s rate of antibiotic prescription for children with AOM could not be assessed for 15 children in practices, as these practices only registered one child with AOM. These practices and children were excluded from the fourth model. The models were based on diagnostic criteria of AOM [In the analyses, it was assumed that GP trainee doctors and practice nurses acted in accordance with and under the supervision of the principal GP(s). Consequently, children managed by a nurse or GP trainee were classified according to the principal GP(s)‘s gender and age.Standard errors in the models are specified as robust. A test for variance inflation factor (VIF) was performed to ensure noncollinearity with standard threshold of VIF ≤ 10. Missing values were removed listwise. All analyses were performed using STATA 15.1 statistical software .N = 303), Southern (N = 785) and Central (N = 811) regions of Denmark were invited to participate in the study. In total 143 (7.5%) GPs participated, of whom 85 (59%) diagnosed at least one child with AOM. The number of children registered with AOM varied between GPs from 0 to 6 for the 5th and 95th percentile, respectively. The average age of the participating GPs was lower than the average in the Northern region, but equal to the regional average in the Southern and Central regions. The proportion of female GPs was higher compared to the background population of GPs in the Southern region [All 1899 GPs in the Northern (n region –22 (TablThe study included 278 children diagnosed with AOM without missing data (47 cases excluded due to missing data). Compared to children diagnosed with other RTIs, the AOM diagnosis was associated with purulent ear secretion, ear pain, abnormal tympanometry, and fever (Supplementary Table Slightly more boys than girls were diagnosed with AOM (56%). Mean age was 2.5 years. Tympanometry was performed in about half of the cases  to all patients with symptoms of RTI and specifically to children with AOM showed association Table .Table 3adj 2.85 : 1.07–7.60)) (Table adj 2.93 (CI: 1.45–5.94) and highest vs lowest rate ORadj 4.15 (CI: 1.82–9.47)) ) Table : Model 3Three out of four children diagnosed with AOM in Danish general practice were prescribed antibiotics. The inter-practice variation was considerable. Among patient characteristics, fever, poor general condition, and purulent ear secretion were associated with antibiotic prescribing. Furthermore, the practice’s rates of prescribing antibiotics for RTIs in general and specifically for AOM in children were closely associated with prescription of antibiotics to the individual child. Parent request for antibiotics was not significantly associated with antibiotic prescribing in any of the models.The clinical findings associated with the AOM diagnosis were similar to findings in other studies; purulent ear secretion, ear pain, abnormal tympanometry, and fever having the strongest associations (Supplementary Table We found an antibiotic prescribing rate of 74%, similar to a Danish study from year 2012 with a prescribing rate of 73% for AOM , and a SStreptococcus pneumoniae is low, and since penicillin V is a narrow-spectrum antibiotic and has relatively few side effects, compared to other antibiotics, it is recommended as the first-choice antibiotic for children with AOM [We found that penicillin V was prescribed for 60% of cases, and amoxicillin for 22%. In Denmark, the prevalence of penicillin-resistant with AOM , 26. In with AOM , 27.This study demonstrated large variations in Danish practices’ antibiotic prescribing rates for RTIs Fig.  and specIn this study fever, purulent ear secretion, and poor general condition were statistically significantly associated with antibiotic prescribing. Multiple studies suggest these findings to be indicative of an antibiotic prescription –4. In adIn our study, even though recommended indicative of antibiotic treatment neither symptom duration ≥3 days nor symptom worsening was statistically associated with antibiotic treatment –4. RegarThough likely to influence the GP, parent’s request for antibiotics was not associated with prescribing in this study. GPs may misinterpret parent’s expectations. An Australian study from 2019 found that 86% of parents disagreed that they expected antibiotics for their child, though the GP interpreted the parent as wanting a prescription .In this study, the most significant predictor of antibiotic prescribing was the practice’s antibiotic prescribing rate for RTIs and for children with AOM in particular. In line with this finding, a Danish study from 1997 showed that GPs with a high over-all prescription rate are also more likely to prescribe antibiotics . Some GPThe main strengths of the study are the consecutive in situ recording of all consulting children with AOM and the GP and staff’s familiarity with the recording method reducing selection and information bias . A partiA shortcoming is the cross-sectional study design, which impairs assessments of causality; i.e. some of the specific assessments of the children including the AOM diagnosis may in some cases have been done and certainly recorded after deciding to prescribe antibiotics and thus be influenced by the decision to treat and not the other way around.The study has a risk of selection bias. GPs’ choice to participate in the audit may depend on workload and degree of interest in RTIs, antibiotics, and quality improvement in general. A 2009 study done in Sweden showed that GPs who chose to enrol in medical audits had significantly lower antibiotic prescription patterns for RTIs compared to their non-participating colleagues , indicatA potential limitation is the exclusion of patients for whom it was not the first visit for the current disease. This hinders evaluation of the ‘Watchful waiting’ approach. It is however speculative whether this influences our results, considering the lack of association between antibiotic prescribing and ‘Symptom duration ≤ 3 days’ in the analyses.The study is restricted by reporting of age in whole years instead of in months. Children below 6 months of age diagnosed with AOM should always be treated with antibiotics according to national guidelines . This agOverprescribing of antibiotics for children diagnosed with AOM is evident and concerning. The inter-practice variation is large and independent of the patients’ signs, symptoms, and request for antibiotics. In order to support prudent prescribing of antibiotics for AOM, interventions should target to inform high-prescribing practices and further research should investigate more detailed practice-related factors associated with overprescribing of antibiotics to AOM.GPs’ antibiotic prescribing rates for children with AOM vary considerably even considering the of signs, symptoms, request for antibiotics, and use of tympanometry. Interventions to reduce overprescribing should be targeted high-prescribing practices.Additional file 1: Figure S1. Registration template.Additional file 2: Figure S2. Flowchart of the inclusion process of general practices and patients.Additional file 3: Table S1. Association of acute respiratory tract infection symptoms and being diagnosed with AOM.