Nowadays, more efforts towards sustainability are required from the concrete industry. Replacing traditional aggregates by recycled bottom ash (BA) from municipal solid waste incineration can contribute to this goal. Until now, only partial replacement has been considered to keep the concrete workability, strength and durability under control. In this research, the feasibility of a full aggregate replacement was investigated for producing prefabricated Lego bricks. It was found that the required compressive strength class for this purpose (C20/25) could be achieved. Nevertheless, a thorough understanding of the BA properties is needed to overcome other issues. As BA is highly absorptive, the concrete’s water demand is high. This workability issue can be dealt with by subjecting the fine BA fraction to a crushing operation to eliminate the porous elements and by pre-wetting the fine and coarse BA fractions in a controlled manner. In addition, a reactive NaOH washing is needed to avoid formation of longitudinal voids and the resulting expansion due to the metallic aluminum present in the BA. Regarding the long-term behavior, heavy metal leaching and freeze-thaw exposure are not problematic, though there is susceptibility to acetic and lactic acid attack and maybe increased sensitivity to alkali-silica reaction. ED 2008/98/EC [et al. [et al. [Yearly, 3,331,000 tons of municipal solid waste are generated in Flanders. Around 880,000 tons are incinerated to gain energy and reduce the waste volume with 90% (Waste-to-Energy) . The inc08/98/EC , several08/98/EC . In this [et al. , Van Ger [et al. ).2O, CaO, CaCO3 and SiO2 [3vs. 2470 kg/m3). The water absorption is 4–10 times the value of gravel (4%–10%). Both characteristics are due to a high porosity [According to literature, BA from Belgium ,9, the Nand SiO2 ,10. Evidand SiO2 ,10. BA iporosity . BA is hporosity . BA concporosity .et al., a W/C ratio of 0.60–0.65 is ideal to achieve both an acceptable workability and a sufficient mechanical performance [In the fresh state, extensive aggregate replacement by BA may have a negative effect on the concrete workability. This is mainly due to the higher water absorption of the BA. However, when using rather high water-to-cement (W/C) ratios, workability may not be a real issue. According to Pera formance . Moreoveformance .etc.) provides little or no information on the performance of BA concrete.In hardened state, most damage phenomena are induced by the expansive reaction of metallic Al in an alkaline environment, which increases the porosity and reduces the strength. This effect exists for all hydroxide-forming elements present in the BA ,11. AlkaLiterature on the leaching behavior of concrete containing BA from MSWI is rather scarce. Since the material is immobilized within the cementitious matrix of the concrete, leaching values are normally lower than when the individual grains are in direct contact with the leaching solution. Regarding the leaching of (heavy) metals, Sorlini and Ginés found values that meet the national criteria  ,18.In the past, tests were mainly performed in view of a partial replacement of traditional aggregates by BA ,11,16,17In this research, the focus was on obtaining a qualitative concrete with replacement of traditional crushed limestone aggregates by BA for the production of prefabricated concrete products. The main novel character of the research lies in the fact that full instead of partial aggregate replacement is aimed for. The main benefit of such a practice is rather evident. If we are able to incorporate more BA from MSWI in concrete, less of the material will get landfilled, its valorization potential will increase significantly and the concrete industry will have to rely less on natural resources to ensure its production capacity. In other words, there will be considerable advantages from both an economic and environmental point of view. However, these benefits only exist if the production of this BA concrete is practically feasible in the casting stage and if the hardened concrete is sufficiently strong and durable for its intended field of application. Therefore, the following research approach was adopted. After careful characterization of the physical and chemical properties of the BA, several test mixtures with varying W/C ratios were made to find an optimal balance between workability and strength of the concrete. The effects of pre-treating the BA in various ways were carefully evaluated. A dedicated study of the expected long-term behavior for one potentially suitable mixture was done and a final optimized concrete mix design was proposed. Prefabricated Lego bricks were made using both mix designs and were compared with a Lego brick made of traditional concrete.etc.), amorphous slags and some ferrous  and non-ferrous  metals that cannot be removed in the treatment installation. The glass remains  normally represent the largest fraction. The proportioning with the other fractions is somewhat seasonally bound.The inert fraction of concrete traditionally consists of sand and aggregates. For the aggregates, it is often useful to use both a fine and a coarse fraction to achieve a better packing. In this research, the aim was a full replacement of the traditional fine and coarse aggregates by BA processed at the MSWI plant of Indaver nv. In terms of phase composition, this consisted of glass remains, a stony fraction  high sulfate resistant CEM I 52.5 N HES LA HSR. The total cement content for each concrete composition amounted to 350 kg/m3) was used for this purpose. Later on, a switch was made to polycarboxylic ether-based MasterGlenium ACE 30 con. 30% SPL  to reduce the delay in setting time.The mixing water consisted of tap water at a temperature of 20 °C. The amount of water used for the concrete varied with the applied W/C ratio: 0.65, 0.60 or 0.55. When lowering the water content substantially, the use of a SP was often imperative. Initially, polycarboxylic ether-based MasterGlenium 51 con. 35%  of all studied aggregates was measured in accordance with NBN EN 1097-6 using a calibrated pycnometer. The apparent mass density ρa (kg/m3) and the relative mass density after oven drying ρrd (kg/m3) were determined in accordance with the same standard.The water absorption over 24 h . Nevertheless, the static compressive strengths of the fine BA and limestone aggregates were determined in the same manner. Per type of sample, the test was repeated three times.The chemical properties of the BA were determined using Inductively Coupled Plasma (ICP), Ion Chromatography (IC) and Flow Injection Mercury System (FIMS) techniques available at the laboratories of Indaver nv.3) and the W/C ratio  were set for the concrete compositions under investigation, the required amounts of sand, fine and coarse aggregates were determined. This was done by approximating the optimal particle size distribution curve of Fuller using the least-of-squares method. This approach normally results in a minimal spacing between the different particles of the inert fraction.Once the total cement content  and the required amount of SP was determined. This amount was added while mixing for another 2 min. The SP dosing step was repeated until the proper slump and flow class were obtained. Finally, the test samples were cast and optimally cured in a climate chamber at 20 ± 2 °C and 95% ± 5% relative humidity (RH).n = 3) with a 150 mm side were subjected to the test. The characteristic value of the compressive strength fck at 28 days was obtained in correspondence with EN 1990 cf. Equation (1).2); kn is a factor equal to 3.37 for n = 3 and a variation coefficient VX unknown from prior knowledge; and s is the standard deviation on the individual values of the compressive strength of n samples. With the characteristic compressive strength known, the proper compressive strength class as specified in NBN EN 206-1 can be assigned.The compressive strength was determined in accordance with NBN EN 12390-2. This was done after seven days, 28 days and 56 days of optimal curing. Per testing age three cubic specimens  and relative to the their original height just after casting (=150 mm). Note that this is only a rudimentary assessment approach to get a first idea on the expansive behavior. The change in length of only one cube side reflects the total expansion only to a certain extent since the initial early age expansion in other directions is hindered by the cubic mold. Moreover, the duration of dihydrogen gas generation after reaction with the metallic Al and the setting time of the concrete also govern the amount of expansion as well. Further investigation on these influencing parameters is certainly still necessary in the future.cf. NBN B 05-201. Since the amount of water absorbed during the vacuum saturation is mainly limited to the pores in contact with the outer sample surface, the resulting porosity only reflects the open/permeable porosity. Per concrete mixture, the test was performed on nine cylindrical samples  taken from cubes (side: 150 mm). After 28 days of optimal curing, the samples were weighed and dried at a temperature of 40 ± 5 °C until constant mass (Δm after 24 h < 0.1%). Next, the samples were placed in a normalized vacuum tank. A vacuum with a residual pressure of 2.7 kPa was applied for 2.5 h. While keeping this vacuum condition, water was introduced at a rate of 50 mm/h until complete immersion of the samples. Subsequently, the air pressure was restored and the samples were kept under water for 24 h. Afterwards, they were weighed hydrostatically as well as above water. After the weighing, they were dried at 105 ± 5 °C until constant mass (Δm after 24 h < 0.1%) whereupon the whole procedure was repeated. Then, the open/permeable porosity φ was calculated for the two pre-drying temperatures (Equation (2)).d is the oven dry mass after pre-drying at 40 °C or 105 °C (g); ms is the water saturated mass after vacuum saturation (g); and ml is the mass under water after vacuum saturation (g).The porosity was determined using a vacuum saturation technique followed by hydrostatic weighing After 28 days of optimal curing, six cubes (side: 100 mm) were conserved in a closed tank filled with demineralized water. Conform CMA/2/II/A, the volume of the reagents should be two to five times the sample volume. Conform NEN 7345, this is four times the sample volume. In this research, the latter volume ratio was chosen. A water sample was taken after 30 days of immersion and examined using ICP, IC and FIMS.cf. the Walloon technical guideline STM D424 ST6. This method was chosen because, in contrast with the original Oberholster test or South-African NBRI  accelerated test method, it allows for a test directly on the concrete mixtures under investigation instead of on mortar bars containing the aggregates to be studied after an initial processing (crushing and sieving). Moreover, the modified Oberholster test holds the advantage of being a rather fast assessment technique (exposure period: 20 days) in comparison with some of the other methods designed for concrete . Per miSix cylinders  were drilled and cut from six cubes (side: 150 mm). After 28 days, the cylinders were exposed to 15 cycles involving intermittent exposure to acid. One cycle started by keeping the samples 24 h in a dry environment  and continued with 24 h of immersion in an acid solution (30 g acetic acid and 30 g lactic acid per liter), all taking place at a temperature of 20 ± 2 °C and 60% ± 5% RH. After each drying period, the mass of the samples was determined. After the last cycle, the mass was determined once again. The damage was evaluated based on the observed mass decrease and visual appearance.cf. NBN B 15-215. After saturation was observed, the samples were placed in a laboratory freezing chamber and were subjected to 14 freeze-thaw cycles which consisted of: (i) cooling down till 0 °C in 1–2 h; (ii) progressive freezing from 0 °C to −15 °C in 5 h ; (iii) maintaining a constant freezing temperature of −15 ± 2 °C for 10–11 h; (iv) defrosting in water; (v) keeping the samples in water until the end of the cycle at 24 h.Four cubes (side: 150 mm), optimally cured for 23 days, were subjected to a freeze-thaw test in compliance with NBN B15-231, which in turn refers to NBN B 05-203. The samples were submerged in demineralized water at a temperature of 20 ± 2 °C until constant mass (Δm 24 h < 0.05%) Two non-destructive test methods were used to evaluate the freeze-thaw resistance: a visual check-up and ultrasonic pulse velocity measurements using a commercial device. The visual damage assessment was done in accordance with NBN B 27-009/A1.3 prisms were cut from the concrete and 45 × 30 mm2 faces were glued onto glass slides with a thickness of 2.9 mm. Then, the samples were cut and polished until the height of the concrete specimens and the glass equaled 10.1 mm. In a next step, the samples were impregnated under vacuum with a fluorescent epoxy. After impregnation, the excess epoxy was ground away and an object glass was glued onto the polished surface. In a final step, the glass slides were cut off and the concrete samples on the object glasses were polished until thin sections with a 25 µm thickness were obtained. A cover glass was glued onto them for protection. All thin sections were examined with a Leica DM LP polarizing microscope. Images were taken with a Leica DFC295 camera in fluorescent light mode.To explain the porosity, a microscopic investigation on thin sections was necessary. These thin sections were prepared as follows: 45 × 30 × 15 mmTo limit the high water absorption during concrete mixing and the resulting workability issues, the BA could be pre-wetted. In total, three pre-wetting techniques were examined. All of them were based on their expected water absorption as a function of time . The fir2. The mixture was stirred from time to time to ensure an optimal interaction between the BA and the solution and to guarantee a proper release of H2.The applied reactive washing procedure was based upon literature findings  and exis2 being released was captured in a second flask initially full of water. Since a portion of the water is displaced by the H2, the amount of metallic Al can be calculated from Equation (3) after measuring the initial and final water weight.H2 is the volume of entrapped H2 (L); MAl is the molar mass of Al (27 g/mol); v0 is the molar volume (22.4 L/mol); and mAl is the mass of reactive Al (g). Before applying the BA after the reactive washing in concrete, they were first rinsed with water until the pH had decreased sufficiently. For the fine and coarse BA fractions, the pH decreased from 12.8 to 9.0–10.0 and from 12.8 to 8.0, respectively.To evaluate the effectiveness of this reactive washing, the amount of reactive Al before and after the treatment was determined. Therefore, the BA samples were subjected to a test described in CUR recommendation 116 . Per sam3 Lego bricks were cast: one made of traditional concrete, one made of the initial BA concrete with full replacement of both the fine and coarse aggregate fractions and one made of the optimized BA concrete, also with full aggregate replacement. The mold for the Lego brick was provided by CB Recycling BV. The concrete was manufactured in a concrete mixer with a total volume capacity of only 200 L. As a consequence, the Lego bricks had to be cast in three subsequent stages. Each layer of concrete was carefully compacted using a vibration needle.Three 1600 × 800 × 400 mmThe particle size distributions of crushed limestone 2/6 and BA 0/6 are within the same range . Only thcf. NBN EN 12620, this BA fraction rather meets the requirements of an aggregate 2/14 instead of those of an aggregate 6/20. Comparison between the crushed and sieved and washed BA 6/20 reveals only very limited differences in particle size distribution.When looking at the particle size distributions of the coarse fractions, a clear shift to the left can be observed between limestone 6/20 and BA 6/20. In accordance with the proper definitions for minimum and maximum aggregate size Note that there are several factors with an influence on the difference in particle size distributions, e.g., the grading and strength of the original untreated material that is subjected to the processing as well as the effectiveness of the equipment used for crushing, sieving and washing.When making the comparison between the recorded aggregate crushing values or static compressive strengths for the sieved and washed and crushed BA and the limestone aggregates, it is immediately clear that the BA clearly shows a lower mechanical performance .This statement holds true for both the fine and coarse aggregates. The difference ranges between 13.6% and 21.6%, depending on the aggregate type and fraction. It is worth mentioning that the crushed BA fractions are all characterized by a significantly higher static compressive strength than the sieved and washed fractions. It is likely that the crushing operations performed in the processing installations of Indaver nv reduced the weaker particles in size, to values lower than the particle sizes considered during the static compressive strength tests. Thus, only the stronger aggregates remain. In the case of the sieved and washed BA there was no elimination of the weaker elements as such.rd and the apparent mass density ρa gives an indication of the material’s porosity. As such, the third column of the table clearly shows that the BA is more porous than the reference material. In case of the fine fraction, the crushed BA has a significantly lower porosity than the sieved and washed BA. On the other hand, the porosities of the crushed and sieved and washed coarse fractions are not significantly different from each other.From the apparent mass densities recorded , it is c24). This parameter is to a high extent correlated to the ratio of apparent and surface dry mass density. It is immediately clear that the BA has a higher inherent water absorption than the corresponding reference limestone aggregates. The value is about eight times the value of crushed limestone. Fine BA obtained by crushing has a substantially lower water absorption than the sieved and washed fine BA. Its value is comparable to the ones of the coarse BA. As indicated by the static compressive strength values  metals is of relevance in view of the concrete performance  quite dramatically.Lowering the W/C ratio normally results in the application of a higher SP dosage to achieve a sufficient workability (slump class S3–S4). For the reference concrete , which iFor the reference concrete (REF1–REF4), adequate strength results (>33 N/mm²) are already obtained after only seven days of curing , includiIn case only the fine aggregate fraction has been replaced with BA : C16/20 2 after only seven days of optimal curing. Their 28-day strength class was at least C25/30 and can reach C30/37 for W/C ratios of 0.60 and 0.55. As such, a more or less similar strength performance to the reference concrete can be assumed. Only the strength gain between 28 days and 56 days of optimal curing is more pronounced for the BA concrete.The replacement of only the coarse limestone by BA 6/20  and strength performance. Compressive strength testing revealed that even with a W/C ratio of 0.65, the minimum required strength class for prefabricated Lego bricks (C20/25) could still be met . KnowingFrom the vacuum saturation experiments, it can be concluded that the BA concrete is clearly more porous than the reference concrete . The proi.e., the longitudinal expansion voids at the surface and the pores in the aggregates, if capillary pores reach these aggregates. The expansion voids will not directly attract water as their size (around 100 μm in width) does not really accommodate capillary suction. Still, these voids enlarge the possible water penetration surface from which more capillary pores can be reached. If a porous aggregate is in contact with them, an extra amount of water would be stored in the concrete as well.In literature, the porosity obtained after pre-drying at 40 °C is said to correspond with the capillary porosity (pore diameter: 1–10 µm), while the difference in porosity obtained after pre-drying at 105 °C and 40 °C should represent the gel porosity (pore diameter: 10 nm) . The capNote that the capillary pores and the longitudinal expansion voids are influencing the strength and permeability of the concrete. The higher porosity after pre-drying at 40 ± 5 °C is a measure for the extra voids at the surface, but not of the inner structure. However, one could state that if these voids could be minimized, permeability will be diminished and strength will increase.For a better insight on the inner porosity, a microscopic analysis was performed as well .24) of the concrete’s inert fraction. The calculation revealed that when aiming at a theoretical W/C ratio of 0.65, the effective W/C ratio due to the high water absorption of the BA would only be 0.56. It also means that the higher open/permeable porosity for the BA mixture after pre-drying at 40 °C cannot be assigned to the presence of more capillary pores. Hence, it must indeed be caused by the presence of the longitudinal expansion voids and the highly absorptive aggregates.When analyzing the thin sections in fluorescent light mode, it can be seen that the cement matrix of the BA concrete has a darker green color than the one of the reference concrete. This normally indicates that the effective W/C ratio of the BA concrete is lower. The concrete’s effective water content was also calculated. In accordance with NBN EN 206-1, this is the reduced amount of mixing water available given the water absorption (WAvs. <6 µg/L). Still, the measured concentration was acceptable (<80 µg/L). There is a two-fold explanation for the adequate leaching behavior. First of all, the BA itself already meets the VLAREMA criteria. Leaching components usually come from the bottle glass and metal fragments present in the BA, but in this study these fractions apparently had no problematic effects. Secondly, once in concrete they are immobilized in the cement matrix which reduces the leaching even more. Leaching data published by Vandecasteele et al. on the original non-processed BA 6/50 further confirm both effects [Leaching values stayed below the limiting values imposed by the Flemish VLAREMA standards for the normalized elements, except for bromine . Copper vs. 0.18% ± 0.05%). Especially for the BA mixture, the recorded length increase exceeded 0.1% by far. This normally indicates a serious sensitivity to ASR. Surprisingly, this criterion was also not met for the reference limestone concrete. Note that the length change of the BA concrete is also characterized by a much larger standard deviation on the individual values. It demonstrates that the ASR reactivity of the BA depends on its specific composition and its often high heterogeneity.After the modified Oberholster test, substantial expansion and cracking were observed for the BA concrete. The length increase was around twice the value of the reference concrete , it evidently contains much less of the vulnerable CaCO3 in comparison with the limestone aggregates of the reference concrete. In other words, just the cement matrix of the BA concrete is susceptible to the acid attack. As this cement matrix is also more porous due to the presence of more longitudinal expansion voids  is more or less equal to the one after 14 freeze-thaw cycles (3994 ± 88 m/s). The ultrasonic pulse velocities recorded for the reference mixture did not change either . The difference in ultrasonic pulse velocity between the BA mixture and the reference mixture is due to the higher porosity and lower strength of the former concrete type. Note that the influence of de-icing salts on the freeze-thaw resistance was not investigated.Initially, it seemed that the large amount of fines was causing the high water absorption of the BA. Therefore, its water absorption with exclusion of the fraction <2 mm was determined and compared to the value of the non-sieved BA. Surprisingly, it was found that the water absorption was not really affected by this sieving operation . Also, wThe high water absorption was believed to be caused by the high porosity of the BA rather than by the amount of fines. Attempts were made to separate the porous from the non-porous elements. However, this turned out rather difficult. The porous elements could also not be detected visually. For instance, quite some metal parts within the BA looked porous because they were covered by with porous-looking layers due to the sintering process during incineration. Floating tests based on the difference in density between the non-porous and porous elements were also unsuccessful. However, it could be demonstrated that crushing the aggregates in a laboratory ball mill had a positive effect on the water absorption. As can be seen in Also pre-wetting of the BA had a distinct positive influence. However, a lot depends on the method applied. The first technique described in The second and third pre-wetting methods were more promising in terms of gaining a sufficient workability without losing too much strength performance  instead of the sieved and washed BA 0/6. For BA 6/20, there was no difference in water absorption between the sieved and washed and the crushed aggregates, so the former was used again. Both the BA 0/6 and 6/20 were sieved afterwards to exclude the fractions smaller than 1 mm and 4 mm, respectively. This enabled a better approximation of the particle size distribution of the reference limestone 2/6 and 6/20 aggregates. Since the BA 0/6 was the most reactive due to its higher metallic Al content, this fine aggregate was subjected to the reactive washing with 1 M NaOH for two to three weeks. Prior to concrete mixing, the aggregates were pre-wetted with 2.9 l water per 180 L of concrete (1 m% of BA 6/20 and 2.5 m% of BA 0/6). A LA cement CEM I 52.5 N HES LA HSR was used as binder. The predefined W/C ratio amounted to 0.65. The compositions of all Lego bricks were included in cf. BA20) that was used for Lego brick 1 was characterized by a poor workability. Even the addition of 10 mL SP per kg cement could not overcome the problem. This behavior can be explained by the fact that another delivery of coarse BA was used for this concrete which was characterized by a higher water absorption. Nevertheless, with some extra compaction efforts, it was possible to cast the Lego brick. All protrusions were filled in a proper manner and no difficulties were encountered during demolding. However, in hardened state, surface laitance, clear traces of the vibration needle, longitudinal expansion voids and compaction voids could be seen. The expansion itself was comparable to what was observed earlier for mixture BA20 on small concrete cubes. Despite the larger dimensions of the Lego brick, the expansion was not excessive. This can be explained by the fact that the ratio of the troweled surface over the total concrete surface available (troweled and cast surfaces) was lower for the Lego brick than for the cubes with a 150 mm side. The mechanical performance of the concrete used for Lego brick 1 was inadequate since its strength class was only C16/20. This was mainly due to the difficult compaction of the poorly workable concrete which resulted in more voids.The unadjusted BA concrete mixture .Once Lego brick 3 was produced, the influence of the different optimization techniques could be evaluated. The use of crushed BA 2/6 and pre-wetting the aggregates solved the workability problem. No SP was needed anymore. The reactive washing of the fine BA 2/6 again appeared to be very effective in eliminating expansion and the longitudinal voids. The use of LA cement probably also helped to achieve this. The sieving operations performed on the BA to eliminate the excess in fine material and to approximate the particle size distributions of the traditional limestone aggregates resulted in a more evenly distributed use of sand and BA in accordance with the Fuller approach. This contributed to the better strength (C20/25) and workability (It is possible to produce a proper concrete in which both the fine and coarse aggregates have been replaced with BA resulting from MSWI. The concrete seems suitable for casting prefabricated Lego bricks. The minimum required strength class (=C20/25) can be assured even with W/C ratios of no less than 0.65 and without using an expensive SP.However, a dedicated processing of the BA prior to concrete manufacturing is imperative. Excluding the excess of fines to approximate the particle size distributions of the traditional limestone aggregates is advised. This results in a better packing and a higher strength of the concrete. A crushing operation before the sieving eliminates porous elements in the BA which absorb a lot of water. As such, a better workability of the concrete can be obtained. A controlled pre-wetting of the BA just before concrete mixing in relation to the time-dependent water absorption curve also helps to improve the concrete workability. Given these techniques, it will probably be possible to manufacture a sufficiently workable BA concrete with a design W/C ratio of only 0.60 in the future.The significant presence of metallic Al in the BA makes the concrete susceptible to the formation of longitudinal voids and expansion. The use of a LA cement can somewhat reduce this problem. A reactive washing of the BA with 1 M NaOH eliminates the problem completely. Still, the latter procedure is not ideal from both an economic and an environmental point of view. Further research on more appropriate reactive washing techniques is still needed.No problems regarding leaching and freeze-thaw were observed for the BA concrete. On the other hand, the concrete shows a pronounced surface roughening after acetic and lactic acid exposure and does not pass the modified Oberholster test for concrete. The expansion (>0.1%) after the latter test indicates ASR sensitivity. However, further microscopic analysis is needed to see whether ASR is indeed causing the problem. Moreover, the tested BA concrete was not fully optimized yet . Additional tests on the finally optimized mixture used for Lego brick 3 are, for the moment, still ongoing.


The proportion of the rate of response with respect to acceleration exhibits a linear relationship with increasing displacement in the vicinity of the catastrophic point. This allows for the prediction of catastrophic failure immediately prior to failure by extrapolating the trajectory of this relationship as it asymptotes to zero. Monte Carlo simulations are completed and these two critical scaling laws are confirmed.This paper presents a spring-fiber bundle model used to describe the failure process induced by energy release in heterogeneous materials. The conditions that induce catastrophic failure are determined by geometric conditions and energy equilibrium. It is revealed that the relative rates of deformation of, and damage to the fiber bundle with respect to the boundary controlling displacement  Material damage and fracture has attracted a large amount of theoretical and experimental interest owing to their relationship to many failure phenomena occurring in naval, aeronautics, and space industries , as wellLocalization is a common phenomenon appearing in the evolution of strain (or damage) that ultimately induces material failure and it is a significant factor in the complexity of fracture. After localization, a sample will bifurcate into a two-part continuum consisting of a less-deformed zone plus a highly-deformed (damage) band called a localized zone ,6,7,8. TAnalyzing the precursors to failure has been a long-standing problem and has been widely accepted as a significant way to predict material failure ,14,15,16In materials science and engineering, the well-known fiber bundle models (FBM), which is a class of simple models, has been widely used ,19,20,21In this paper, a model composed of an elastic spring and a fiber bundle oriented in series is developed to describe the catastrophic failure of a material induced by the energy release from the system. The conditions for catastrophic failure are derived based on energy equilibrium. An asymptotic analysis is used to derive the critical scaling laws near the catastrophic point. Monte Carlo simulations are performed to verify two critical scaling laws describing the failure.U and u, respectively. The spring of stiffness ks can be analogous to an elastic environment . The damageable part consists of N parallel fibers with a linearly elastic constitutive behavior. A global load-sharing criterion , where D(ε) = Nd/N represents the damage fraction of damageable part and Nd is the number of broken fibers. It is clear that the damage fraction, D, ranges from zero to unity. The force-deformation relation of the damageable part can then be written as:The resulting force acting on the spring can also be expressed as For the system to be in the equilibrium, Equations (3) and (4) must be equal, such that:m is the Weibull index.The damage fraction is widely described by a Weibull distribution of the form )=1−e−εm ,17,18,19Wc) can be fully provided by the energy release of the spring (ΔWs) without any external work, thus allowing for breaking (or deformation) to continue spontaneously and uncontrollably. In other words, the equilibrium is stable if:The equilibrium of the spring-fiber bundle system becomes unstable when the work needed for further deformation of the damageable part  by an increment of Δε on the damageable part is:The energy required to impose a similar deformation (ΔSubstituting Equations (7) and (8) into Equation (6) gives: εs implies that the elastic spring undergoes a deformation recovery process. Expression (9) leads to k > −df0/dε. Therefore, the critical condition that induces catastrophic failure is:The negative value of ΔFrom Equations (4), (5) and (10), the critical condition can also be expressed as:k > kc = −(df0/dε)min, where (df0/dε)min represents the minimum value of the tangent slope of the f0-ε curve of the fiber bundle. The deformation can be analytically derived as f0/dε)min, resulting in Thus, no macroscopic failure occurs when 0) for k < kc and k > kc. In these two cases, the Weibull index m equals 2, resulting in a kc value of about 0.446. It can be seen that when k = 0.2 , the catastrophic failure occurs following the peak force , the stress decreases continuously to zero and the failure is not catastrophic but gradual, as shown in As examples, ak force a. In conε0 can be expressed as a function of the deformation ε such that ε0 = [1 − D(ε)]ε/k + ε. The expansion of ε0 as a function of ε in the vicinity of the catastrophic point ε0f is then performed. That is:An asymptotic analysis of the area in the vicinity of the catastrophic point to demonstrate the critical scaling law is not presented. The geometric Equation (5) implies that the boundary displacement Substituting Equation (11) into Equation (12), we get:ε0, the following relation is obtained:By performing the first differentiation on Expression (13) with respect to Therefore, the deformation rate of the damageable part increases under a power law behavior with an exponent of −1/2 near the catastrophic point.ε0 and rearranging, the following relation is obtained:Furthermore, by performing the first and second differentiation on Expression (13) with respect to D by noting that the deformation can be expressed as a function of D. For example, An analogous procedure may be applied to calibrate in terms of damage D and strain ε are calculated with respect to the controlling variable m = 2. Based on the observed linear dependence (the left part of the curves in ε/dε0(d2ε/dε02)−1 (or dD/dε0(d2D/dε02)−1) against ε0 to zero.To examine Relations (14), (15), (16), and (17), the first and second derivatives of damage N fibers monotonically increased, (1) fiber breaking thresholds were randomly chosen according to the Weibull probability distribution with the thresholds then arranged in increasing order; (2) The load process was performed quasi-statically with a displacement of ε0 applied at each step as the minimum required to break the next fiber. After the breakage of a single fiber, the nominal force f0 on the system and consequently the deformation ε of the fiber bundle were recalculated. This process was repeated until the load on all surviving fibers was less than that of their individual thresholds; (3) The system is then loaded again and the process is repeated until the material fails in its entirety. During step 2, the break of an element may induce secondary failures which may in turn trigger more failures, and so on. If this occurs, this process will lead to a catastrophic failure.To further examine the critical behaviors near the catastrophic failure point, Monte Carlo simulations of the failure process were performed. Simulations of the failure process proceeded as follows: as the displacement on the system with a fiber bundle of k values. As shown in ε/dε0 ~ (ε0f − ε0)−1/2 and dD/dε0 ~ (ε0f − ε0)−1/2 with a critical exponent of −1/2. In all simulations, ∆ε/∆ε0(∆2ε/∆ε02)−1 and ∆D/∆ε0(∆2D/∆ε02)−1 exhibit a common linear relationship under a displacement of ε0 near the catastrophic failure point  is obtained mainly based on empirical analyses of creep deformation under constant load. However, in practical engineering, materials are usually subject to different loading conditions besides creep deformation. In considering that creep is not the dominant factor of material failure, Kilburn  proposedThe empirical Equation (18) is usually restricted to describe stress-rate-dependent material failure resulting in precursory rates being measured with respect to time. For a “stress-rate independent” material, which is defined as the case where stress in the material is independent of the strain rate, the conditions for material failure are not immediately evident from using time variations alone. The deformation and damage primarily depend on the controlling variable such as, for example, the boundary displacement shown in the present model in this paper. For these kinds of materials, the relative change of measurable responses such as damage and strain, with respect to the controlling variable, are most useful in its application. Hao et al.  proposedε0 is increased at a constant rate with respect to time such that dε/dε0 (dD/dε0) ∝ dε/dt (dD/dt). This result may suggest that the time-derivatives given in Relation (18) might be a subset of a more general expression connecting the controlling variable derivatives.Equation (1) is of widespread interest as a forecasting tool and has been extensively applied to material failure phenomena. Equations (14) and (16) are equivalent to the relation given in (18) if the boundary displacement R represents a corresponding response variable (such as the strain and damage discussed in this paper). The failure point can then be determined by linearly extrapolating the curve of (dR/dε0)–1/β against ε0 to zero. In comparison, the prediction made by using Relations (15) or (17) does not have the benefit of knowing in advance the value of the exponent β. The failure time can be estimated by linearly extrapolating the curve of the proportion of the signal rate on the acceleration against the controlling variable, the boundary displacement ε0, to zero. In the application of these two methods, it is both feasible and preferable that the two methods are used together in order for each one to verify the trend given by the other.In application, Equations (14) and (16) would be rewritten into a linear form, given as:It should be mentioned that for the present method (Equations (15) and (17)), the signal has to be differentiated with respect to the boundary displacement and then inverted. These calculations will inevitably induce large fluctuations and thus pose an important limitation in terms of real-time operational usage. Two methods for point data and continuous deformation data, respectively, were suggested by Bell et al. ,36 to dif0/dε)min of the minimum slope of the force-deformation curve of the damageable part.A model of a spring-fiber bundle oriented in series is proposed to describe material failure. Two failure processes are observed. The first process is the gradual failure characterized by a continuous force that decreases to zero. The second is a catastrophic failure characterized by a violent avalanche of fibers. A critical condition inducing the catastrophic failure is reached when the stiffness of the elastic spring is equal to the negative tangent slope of the force-deformation curve of the fiber bundle. Thus, the catastrophic failure will not occur at any point during the loading process if the stiffness of the spring is larger than the −(dTwo critical scaling laws work as the precursors of catastrophic failure. The deformation rate of the damageable part increases according to the power law behavior


Uptake was evaluated using the maximum standardized uptake value (SUVmax). Regions of interest (ROIs) were placed within the tumors and target organs of brain, thyroid, submandibular gland, lung, liver, esophagus, stomach pancreas, spleen, muscle, and bone marrow.Seven patients who had at least one histologically confirmed head and neck tumor were included in this study. They underwent both whole-body 11C-Met showed strong correlation . Although 18F-BPA and 11C-Met showed markedly different uptake in some organs , the uptake of 11C-Met was consistently higher than that of 18F-BPA in these cases.The tumor SUVmax of FBPA and 11C-Met PET/CT might be used instead of 18F-BPA PET/CT to predict the accumulation of 10B in tumors and to select candidates for BNCT. However, it would not be suitable for evaluating accumulation in some normal organs. Therefore, the 18F-BPA-PET study remains a prerequisite for BNCT. This is the first report of the correlation between 18F-BPA and 11C-Met accumulation. After the injection of a 10B carrier, it accumulates in target tumor cells. The region to be treated is then exposed to thermal neutrons, and the nuclear reaction of these neutrons with 10B produces alpha particles and 7Li at very short range (<10 μm), causing lethal damage to tumor cells. The success of BNCT is dependent on the sufficient accumulation of 10B in tumor cells and the minimization of such accumulation in normal cells [10B accumulation is not consistent across cases, and is reported to depend upon tumor type. However, even tumors of the same grade may differ in terms of their biochemical properties. Therefore, it is necessary to assess 10B accumulation in each case prior to performing BNCT [Boron neutron capture therapy (BNCT) has recently attracted attention and has been used for brain tumors, head and neck cancers, and melanoma –4. It isal cells , 5. 10B ing BNCT .10B-borono-L-phenylalanine (BPA) is the most frequently used 10B carrier, and 18F-BPA, an 18F-labelled analog of BPA, has been developed to predict 10B accumulation in tumors and normal tissues by positron emission tomography (PET) [18F-BPA-PET study is carried out to evaluate the tumor-to–normal tissue accumulation ratio (TNR). The TNR strongly influences the success of BNCT, and the ideal TNR has been reported to be greater than 2.5 to 5 [18F-BPA, a radiolabeled amino acid, is limited due to low radio yield, low synthetic yield, and high cost. Therefore few hospitals or institutions can synthesize 18F-BPA in practice [hy (PET) , 8. Befopractice .11C -labelled Methionine (11C-Met) is the most popular radiolabeled amino acid. Methionine is an essential amino acid and plays an important role in protein synthesis as it is coded for by the initiation codon. Radiolabeled methionine is a convenient radiochemical product because it can be obtained by rapid synthesis with high radiochemical yield [11C-Met is a highly sensitive tool capable of yielding considerable information on protein synthesis, and has been used widely in the assessment of various cancers [18F-fluorodeoxyglucose, 11C-Met shows low uptake in the brain, so 11C-Met PET can evaluate head and neck tumors without interference from physiological accumulation in the brain [al yield . 11C-Met cancers . Comparehe brain , 14.18F-BPA and 11C-Met, in patients with head and neck tumors, in order to evaluate whether 11C-Met PET can be used instead of 18F-BPA PET for screening potential candidates for BNCT.In this study, we evaluated the distribution of these two radiolabeled amino acids, All chemical reagents were obtained from commercial sources. This study was conducted according to a protocol approved by the institutional review board/independent ethics committee of the National Cancer Center Hospital . All patients signed a written informed consent form before the initiation of the study.18F-BPA was synthesized by direct electrophilic radiofluorination of BPA  using 18F-acetyl hypofluorite as described previously [18F-BPA was performed by high performance liquid chromatography (HPLC) using a YMC-Pack ODS-A column  eluted with 0.1% acetic acid at a flow rate of 10 ml/minute. The radiochemical purity of 18F-BPA as determined by HPLC was > 99.5%, while its specific activity was 25 MBq/μmol.eviously . Purific11C-Met was synthesized in the radiochemical laboratory of this institute by methylation with L-homocysteine thiolactone followed by isolation of the final product by solid phase extraction using L-homocysteine thiolactone  [11C-Met ranged from 95 to 98%.MO, USA) . The rad18F-BPA-PET/computed tomography (CT) and 11C-Met-PET/CT at least 24 h apart, but within 6 months of each other, between January 2014 and July 2016. Of the 116 patients who underwent 18F-BPA PET/CT, seven also underwent 11C-Met-PET/CT. These seven patients were retrospectively selected for this study. They had histologically confirmed head and neck tumors, Eastern Cooperative Oncology Group performance status (PS) of 0–1, adequate organ function  and alanine aminotransferase (ALT) ≤ 100 IU/L, serum creatinine ≤ 1.5 mg/dL, baseline left ventricular ejection fraction (LVEF) > 60%), and were older than age 20. For evaluating the distribution of 11C-Met and 18F-BPA in normal organs, we excluded patients with congestive heart failure, uncontrolled angina pectoris, arrhythmia, symptomatic infectious disease, severe bleeding, pulmonary fibrosis, obstructive bowel disease or severe diarrhea, and symptomatic peripheral or cardiac effusion.The seven patients included in this study underwent both Patients fasted for at least 4 h before examination.18F-BPA PET/CT imaging was carried out at 1 h after the injection of 18F-BPA (ca. 4 MBq/kg). The scan timing for 18F-BPA PET/CT was determined as in our previous work [11C-Met PET/CT was carried out 10 min after the injection of 11C-Met (ca. 4 MBq/kg). The scan timing for11C-Met PET/CT was determined by a previous report [PET/CT images were acquired with a Discovery 600 scanner . Whole-body s report . A scout18F-BPA uptake was evaluated using the maximum SUV (SUVmax) 1 h after injection, while 11C-Met uptake was evaluated 10 min after injection. ROIs were placed within the tumor and target organs of brain (white matter), thyroid, submandibular gland, lung, liver, esophagus , stomach, pancreas, spleen, muscle (latissimus dorsi), and bone marrow (12th thoracic vertebra). Tumor ROIs were defined as the areas of highest activity. ROIs were also placed onto normal tissue surrounding the tumor to calculate the TNR of 18F-BPA. Clinically, dose planning is performed based on the TNR prior to the initiation of BNCT to avoid severe damage to normal tissues.PET image evaluation and quantification of the standardized uptake value (SUV) were performed using AW Volume Share 4.5 software . Regions of interest (ROIs) were delineated on the axial 2-D image. SUV was defined as regional radioactivity divided by injected radioactivity normalized to body weight. P < 0.05 were considered significant. Since patients in previous studies were determined to be eligible for BNCT when the TNR of 18F-BPA was more than 2.5 [18F-BPA TNR of more than 2.5 as a cut-off to distinguish positive from negative.For statistical analysis of the data, JMP software  was used. A linear regression analysis was performed for the correlation study. Fisher’s exact test was used to estimate the concordance of the cut-off values of the two tracers. Probability values of than 2.5 , 8, 16, 18F-BPA-PET/CT and 11C-Met-PET/CT during the study period and were enrolled in this study .Seven patients with head and neck tumors underwent both 18F-BPA-PET/CT was performed prior to 11C-Met-PET/CT. In the remaining three cases, 18F-BPA-PET/CT was performed after 11C-Met-PET/CT. The interval between studies was less than 3 weeks in six cases, and more than 3 months in one case (No. 1). The interval ranged from 2 to 123 days .Patient and tumor characteristics are summarized in Table 18F-BPA and 11C-Met is shown in Fig. 18F-BPA and 11C-Met in tumor tissue are summarized in Table 18F-BPA and 11C-Met varied widely among tumor cases, even in those with the same pathology. The tumor SUVmax of 18F-BPA ranged from 1.6 to 5.6 , while that of 11C-Met ranged from 1.5 to 5.8 . The TNRs of both 18F-BPA and 11C-Met also varied widely. The TNR of 18F-BPA ranged from 1.3 to 3.9 , while that of 11C-Met ranged from 1.1 to 5.1 .Representative PET/CT imaging of 18F-BPA and 11C-Met were weakly correlated (r2 = 0.51), though statistical significance was not observed (P = 0.07). However, the SUVmax of 18F-BPA and 11C-Met within each tumor exhibited strong correlation .The TNRs of elated r = 0.51, 11C-Met and 18F-BPA in normal organs are summarized in Table 18F-BPA in normal organs showed smaller differences between patients than accumulations in tumors.Accumulations of 18F-BPA and 11C-Met differed widely in the submandibular gland, liver, heart, stomach, pancreas, spleen, and bone marrow. In these organs, the uptake of 11C-Met was consistently higher than that of 18F-BPA. In all other organs, no significant difference was observed.Across all patients, the uptake of 18F-BPA-PET/CT and 11C-Met-PET/CT was more than 3 months; palliative surgery was performed during the interscan interval, although the target tumor was almost unresectable. The long interval and palliative operation may have affected the results in this case. However, excluding the single long-interval case, the TNRs of 18F-BPA and 11C-Met showed a weak correlation (r2 = 0.57 P = 0.08), and the SUVmax of 18F-BPA and 11C-Met within each tumor were strongly correlated . As a result, we do not believe that the interscan interval or the palliative operation particularly influenced the results of this study. On the other hand, five patients underwent surgery and received radiotherapy and chemotherapy within 1 year before the PET scans, and it is unclear whether this treatment influenced our results.It is well-known that accumulation of radioisotopes is affected by nature of tumors , 18. In 18F-BPA is a System L–specific imaging agent [+-independent and is a major nutrient transport system responsible for the transport of neutral amino acids. System L includes four families, LAT1–LAT4.Radiolabeled amino acids are among the most important tracers for identifying and examining tumors, since cellular proliferation requires protein synthesis. Amino acids are the natural building blocks of proteins, and high uptake of these precursors is a normal feature of rapidly proliferating cells such as tumor cells. Tumor cells take up amino acids by amino acid transporters, thus the numbers of such transporters is increased in most tumor types as compared to healthy tissue . Studiesng agent . System 18F-BPA uptake correlates with total LAT expression, but more specifically with that of LAT1 and LAT4, which are overexpressed in many tumors [11C-Met is taken up not only by System L, but also by many other types of amino acid transporter such as System A, System ASC, and System B [18F-BPA and 11C-Met in this study, regardless of pathology. Despite the fact that 11C-Met and 18F-BPA are affected by different amino acid transporters, we found that 11C-Met uptake correlated closely with 18F-BPA uptake. One possible explanation is that the rates of amino acid transport and protein synthesis are so rapid that differences in the types of amino acid transporter may not be significant. Further studies with larger numbers of participants and comparison of particular histological features should be performed to resolve this question.y tumors , 21–23. System B , 24, 25.System B . This ma11C-Met and 18F-BPA in the submandibular gland, liver, heart, stomach, pancreas, spleen, and bone marrow, whereas it was similar in all other normal organs. Previous papers have also reported similar tendencies in 11C-Met distribution [11C-Met and 18F-BPA in normal organs showed smaller individual differences than in tumors. The variation in relative accumulation between tumors and healthy organs may be attributed to the histological heterogeneity of tumors. Similarly, there was no significant difference between accumulations in brain, thyroid, lung, esophagus, and muscle. These organs had insufficient accumulations of both 11C-Met and 18F-BPA to reveal any difference, perhaps because there is less protein synthesis and cell proliferation in these organs, making the uptake of the amino acids themselves very low.In normal organs, we found that accumulation differed between ribution  . The up11C-Met than of 18F-BPA. This difference was especially pronounced in organs with high levels of protein synthesis or cell proliferation, such as the submandibular gland, pancreas, liver, stomach, and bone marrow. The heart produces several hormones, such as brain natriuretic peptide. The spleen sometimes has extramedullary hematopoietic functions in cases where the bone marrow has been damaged. Thus both organs can be considered to be involved in protein synthesis. Although these organs all require amino acids to synthesize proteins, the pancreas, liver, stomach, heart, and submandibular gland do not express LAT1 or LAT4, while the bone marrow and spleen express LAT1 but not LAT4 [18F-BPA uptake because is transported mainly by LAT1 and LAT4 [11C-Met can be transported by many types of amino acid transporter [0,+), expressed by the salivary glands [11C-Met in these organs was higher than that of 18F-BPA, and it may be that variation in the distribution of amino acid transporters causes differences in uptake. In other words, the greater accumulation of 11C-Met may suggest that its uptake reflects protein synthesis more generally, whereas the uptake of 18F-BPA also reflects the expression of LAT1 and LAT4.On the other hand, some normal organs showed higher uptake of not LAT4 , 28. Theand LAT4 . As mentnsporter , 20, incnsporter , and Sysy glands . This co18F-BPA in normal organs. This may be of great advantage, not only in the evaluation of 10B accumulation, but in tumor detection. It could be especially useful when evaluating tumors in the liver, the pancreas, or stomach. In particular, a study on bile duct carcinoma, including pancreatic cancer, found that the expression of LAT 1 correlated positively with degree of malignancy [18F-BPA might predict the malignancy of these cancers.Our study also revealed a low physiological accumulation of lignancy , thus th11C-Met may predict the accumulation of 18F-BPA in tumors. Nevertheless, for success of BNCT, performance of the TNR is more important than evaluation of SUVmax [Our findings suggest that the accumulation of f SUVmax .11C-Met was positive, the tumor TNR of 18F-BPA was also positive. However, the correlation between the TNRs of 18F-BPA and 11C-Met was not statistically significant. It is inferred that the accumulation in normal tissues surrounding the tumor differed between 18F-BPA and 11C-Met. In this study, as the organs demonstrating high uptake of 11C-Met were located far from the tumors, or post resection, we were able to a certain extent to evaluate the TNR by 11C-Met PET/CT. However, if a tumor were near such organs, it would disturb the evaluation of the TNR.In all cases where the tumor TNR of 18F-BPA accumulation in tumors showed a strong correlation with 11C-Met accumulation. Thus, 11C-Met PET/CT might be useful to select candidates for 18F-BPA PET/CT. However, 11C-Met PET/CT would not be suitable for evaluating accumulation in some normal organs, such as the submandibular gland, liver, heart, stomach pancreas, spleen, and bone marrow. Therefore, the 18F-BPA-PET study remains a prerequisite for BNCT. However, further studies are called for, using larger numbers of participants and selection of particular histological diagnostic criteria.Despite variations in tumor pathology and a small patient population, As mentioned, some limitations should be acknowledged. First, the very small population and retrospective nature of this study may have led to selection bias. Second, the study included a variety of tumor pathologies.


P = 0.03) and overall survival . In conclusion, our meta-analysis indicates that c-Met overexpression is a significant adverse prognostic factor for recurrence and survival in patients who underwent surgical resection for HCC.The overexpression of c-Met protein has been detected in hepatocellular carcinoma (HCC). However, its prognostic impact remains uncertain. We performed this meta-analysis to evaluate the prognostic value of c-Met overexpression in patients who underwent curative surgical resection for HCC. A systematic computerized search of the electronic databases was carried out. From 5 studies, 1,408 patients who underwent surgical resection for HCC were included in the meta-analysis. Compared with patients with HCC having low c-Met expression, patients with c-Met-high tumor showed significantly worse relapse-free survival (hazard ratio = 1.26 ,  Despite disease .For patients with advanced HCC, systemic treatment with sorafenib or sunitinib  can be recommended , 8. HoweMET and the tyrosine kinase receptor for hepatocyte growth factor (HGF) [c-Met is the product of the proto-oncogene or (HGF) . HGF, alor (HGF) , 12. c-Mor (HGF) . The enhor (HGF) , lung caor (HGF) , gastricor (HGF) , colorecor (HGF) , cervix or (HGF) , or pancor (HGF) . Severalor (HGF) –18.The overexpression of c-Met has also been observed in HCC –28. HoweFigure Table low or c-Methigh). The criteria are briefly summarized in the Table There was a marked heterogeneity between the criteria used to dichotomize c-Met status (c-MetP = 0.03)  and the random-effect model was selected.From three studies –28, 1,35) Figure . There wP = 0.01) .From five studies –28, 1,40) Figure . The fixVisual inspection of the funnel plots for RFS and OS showed symmetry, indicating there were no substantial publication biases Figure  and 3B.In this meta-analysis, we evaluated the prognostic impact of c-Met overexpression in patients with surgically resected HCC. The results show that high c-Met expression is significantly associated with worse RFS and OS. Our findings suggest that c-Met overexpression represent a potential adverse prognostic marker in patients who received curative surgery for HCC.et al. assessed c-Met expression and amplification in 287 patients with HCC and reported that c-Met overexpression was not significantly associated with any clinicopathological variable including tumor grade and size, vascular invasion, stage, RFS, and OS [c-Met plays a critical role in the pathogenesis and progression of many tumor types –13. The , and OS . Because, and OS –28, howeP = 0.03) and OS , compared with those with c-Met-low HCC. Our results indicate that high c-Met expression is an independent negative prognostic marker for recurrence and survival in HCC patients who received curative surgical resection.In the current meta-analysis, we included studies comparing survival outcomes (RFS or OS) according to c-Met expression status (low vs. high). Patients with c-Met-high HCC showed significantly worse RFS  and OS , compared with those treated with placebo. Thus, patients with HCC overexpressing c-Met might be good candidates for treatment with c-Met inhibitors. In addition, in a recent randomized phase III trial of patients with advanced non-small-cell lung cancer, the efficacy of tivatinib in combination with erlotinib was also significantly associated with c-Met expression [Several meta-analyses in other cancers have also demonstrated that high expression of c-Met is an adverse prognostic marker –17. Thuspression . These rin situ hybridization, real-time quantitative PCR, or molecular invasion probe, etc) are used for assessing c-Met status, with no standardized criteria for overexpression. In addition, there are differences in the IHC criteria for high c-Met expression. The discrepancies in the prognostic impact of c-Met overexpression among studies might be attributable to the different methods and criteria for c-Met overexpression. Therefore, the definition of reliable criteria for Met-high status is essential to identify patients who will benefit most from MET-targeted therapies.However, the major limitation for development of c-Met inhibitors is that there is no consensus regarding the criteria for c-Met overexpression. Currently, a variety of methods  and criteria to assess and stratify c-Met status, which might lead to the wide variation in the rate of c-Met overexpression among studies. Finally, papers published only in English were included, which might bias the results.In conclusion, our meta-analysis demonstrates that c-Met overexpression is a significant adverse prognostic marker for recurrence and survival in patients who underwent surgical resection for HCC. However, larger prospective studies using standardized methods are still needed to verify the prognostic role of c-Met expression.We performed this study according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . A systeEligible studies should meet the following inclusion criteria: (i) patients had a diagnosis of HCC and underwent curative surgical resection; (ii) RFS and/or OS were analyzed according to the c-Met expression status (low vs. high); (iii) HRs with 95% CIs for RFS or OS were reported or could be estimated from the data provided; (iv) articles were written in English.Data extraction was carried out independently by two investigators (BJK and HSK). If these two authors did not agree, the principle investigator (JHK) was consulted to resolve the dispute.The following data were extracted from all eligible studies: first author's name, year of publication, country, number of patients, treatment, methodology for c-Met expression, the criteria used to dichotomize c-Met expression as ‘high’ or ‘low’, and HRs with their 95% CIs for RFS or OS.Q statistic and the I2 inconsistency test. The fixed-effect model (Mantel–Haenszel method) was selected for pooling homogeneous outcomes when P ≥ 0.1 and I2≤ 50%, and the random-effects model (DerSimonian–Laird method) was applied for pooling heterogeneous outcomes when P < 0.1 and I2 > 50%. The RevMan software version 5.2 was used to combine the data, and the final results were presented with HRs and their 95% CIs. All reported P-values were two-sided and P < 0.05 was considered statistically significant. Publication bias was assessed graphically by the funnel plot method [Statistical values were obtained directly from the original articles. When HR with its 95% CIs was not provided, the Engauge Digitizer version 9.1 was used to estimate the needed data from Kaplan-Meier curves. The effect size of RFS and OS was pooled through HR and its 95% CI. The heterogeneity across studies was examined by t method .


Social media, defined as interactive Web applications, have been on the rise globally, particularly among adults. The objective of this study was to investigate the trend of the literature related to the most used social network worldwide  in the field of psychology. Specifically, this study will assess the growth in publications, citation analysis, international collaboration, author productivity, emerging topics and the mapping of frequent terms in publications pertaining to social media in the field of psychology.Publications related to social media in the field of psychology published between 2004 and 2014 were obtained from the Web of Science. The records extracted were analysed for bibliometric characteristics such as the growth in publications, citation analysis, international collaboration, emerging topics and the mapping of frequent terms in publications pertaining to social media in the field of psychology. VOSviewer v.1.6.5 was used to construct scientific maps.h-index (48).The most common document type was research articles . Over 99.06% of the publications were published in English. Computers in Human Behavior was the most prolific journal. The University of Wisconsin–Madison ranked first in terms of the total publications (n = 39). A visualisation analysis showed that personality psychology, experimental psychology, psychological risk factors, and developmental psychology were continual concerns of the research.Overall, 959 publications were retrieved during the period between 2004 and 2015. The number of research publications in social media in the field of psychology showed a steady upward growth. Publications from the USA accounted for 57.14% of the total publications and the highest This is the first study reporting the global trends in the research related to social media in the psychology field. Based on the raw data from the Web of Science, publication characteristics such as quality and quantity were assessed using bibliometric techniques over 12 years. The USA and its institutions play a dominant role in this topic. The most preferred topics related to social media in psychology are personality psychology, experimental psychology, psychological risk factors, and developmental psychology. Social media, defined as interactive Web applications , have beThe database used in this bibliometric study, the Web of Science (WoS) database: Core Collection , is one Step 1:The topic search query phrase “(Facebook OR Twitter OR LinkedIn OR Snapchat OR Instagram)” was applied to gather all the publications with those phrases in their titles, abstracts, or keywords. The documents published during the period from 2004 to 2015 were included in the study while the years 2016 and 2017 were excluded, as those years are still open for new issues.Step 2:We then limited our retrieved publications related to social media to all those indexed under research categories related to psychology in the WoS database, including “Psychology”, “Psychology Clinical”, “Psychology Developmental”, “Psychology Multidisciplinary”, “Psychology Experimental”, “Psychology Social”, and “Psychology Applied”.Step 3:The search queries from steps 1 and 2 were merged into one search query as the following: TS = (Facebook) OR TS = (Twitter) OR TS = (LinkedIn) OR TS = (Snapchat) OR TS = (Instagram). It was refined by the following Web of Science categories:.Step 4:h-index, the impact factor (IF), the collaboration, and the citations. The IF was used according to the 2015 Journal Citation Reports® published by Thomson Reuters, 2016 [All the collected data were analysed and plotted based on the following characteristics: publication year, the main journal in the field, the institutions, the country/territory, the document type and language, the rs, 2016 .Step 5:We then analysed the records to identify the relationship between the countries, the institutions, and the terms through visualisations the main clusters in each one by using VOSviewer v.1.6.5 software. The key terms were recognised in the titles and abstracts of the retrieved publications related to social media in psychology, and the co-occurrence frequencies of these terms were calculated. The term map was constructed based on the co-occurrence frequencies of these terms to cluster the main topics in this field.To retrieve the research related to social media in the field of psychology, we applied the following steps to conduct this bibliometric study:Microsoft Excel 2007 and VOSviewer v.1.6.5 software were used for the graphics. SPSS statistical software  was used for the statistical analyses. The Pearson correlation test was used to determine the correlation between the number of publication in the field of social media and the number of publication related to social media in psychology. P values < 0.05 were considered to be statistically significant. The descriptive statistics were presented as frequencies and percentages.The present study outlines the bibliometric indicators of the scientific research related to social media in psychology during the research timeframe from 2004 to 2015. We found a total of 10,843 publications related to social media published between 2004 and 2015. There were 959 scientific publications related to social media in psychology. Nine types of documents were found, and the most common was research articles (873 documents), which accounted for 91.03% of the total publications. The second most common document type was meeting abstracts . As expected, the majority of the publications were written in English (99.06%). Figure This increase in publications related to social media in psychology seems to be related to (1) social networking sites, which became very popular in previous decade , 26; (2)h-index values . The USA is followed by the UK , Canada , Germany , and Australia . The h-index for all retrieved publications was 59. The publications with the most international collaboration were those from the USA (n = 100). The UK and China ranked second and third, with 35 and 17 documents for each, respectively. The collaboration between countries based on co-authorship is shown in Fig. h-index [Table  h-index , 35–37.  h-index –41.TableComputers in Human Behavior (n = 375), Cyberpsychology Behavior and Social Networking (n = 134), the Journal of Adolescent Health (n = 30), Personality and Individual Differences (n = 25), and American Behavioral Scientist (n = 23).Table The scientific landscape of main research areas related to social media in psychology is presented in Fig. Journal of Applied Developmental Psychology in 2009 and has been cited 426 times [Table 26 times . The mos26 times .Table 3TUniversity of Wisconsin–Madison ranked first in terms of the total publications (n = 39). Ohio State University (n = 25) was second to the University of Wisconsin–Madison in the total number of publications, followed by Michigan State University (n = 23) and the University of Texas at Austin (n = 23). Figure Table This bibliometric study represents the first concise analysis of the global publications related to social media in psychology and shows the benefits of bibliometric analysis for evaluating research productivity in a standardised way. There are some limitations, most of which have already been mentioned in previous bibliometric studies –56. The Up to the authors’ best knowledge, this is the first ever bibliometric study to report worldwide activity in social media—related research in psychology field. Our study provides some novel insights useful for policy makers, researchers, and funders interested in advancing an evidence-based social media and psychology research agenda. International research collaborations and research networks should be encouraged to help prioritize social media—related psychology research particularly in countries with research capacities. Our findings provide baseline data for scholars and policy makers to recognize the bibliometric indicators in the current study as measures of research performance in social media for future policies and funding decisions. Finally, our study showed that bibliometric analysis is a good methodological tool to map published literature in a particular subject and to pin point research gaps in that subject.


Background: Overprescribing antibiotics for common or inaccurately diagnosed childhood infections is a frequent problem in primary healthcare in most countries. Delayed antibiotic prescriptions have been shown to reduce the use of antibiotics in primary healthcare.Objective: The aim was to examine primary care physicians’ views on delayed antibiotic prescriptions to preschool children with symptoms of upper respiratory tract infections (URTIs).Methods: A questionnaire was sent to 1180 physicians working in general practice in the Capital Region of Denmark, between January and March 2015. The questions focused on physicians’ attitude and use of delayed antibiotic prescriptions to children with URTIs.Results: The response rate was 49% (n = 574). Seven per cent of the physicians often used delayed prescriptions to children with symptoms of URTI, but 46% believed that delayed prescription could reduce antibiotic use. The physicians’ views on delayed antibiotic prescription were significantly associated with their number of years working in general practice. Parents’ willingness to wait-and-see, need for reassurance, and knowledge about antibiotics influenced the physicians’ views. Also, clinical symptoms and signs, parents’ willingness to shoulder the responsibility, the capability of observation without antibiotic treatment, and structural factors like out-of-hour services were relevant factors in the decision.Conclusions: Most physicians, especially those with fewer years of practice, had a positive attitude towards delayed antibiotic prescription. Several factors influence the views of the physicians—from perceptions of parents to larger structural elements and years of experience. KEY MESSAGESDelayed antibiotic prescriptions reduce the use of antibiotics.Most responding physicians—especially those with fewer years of experience in primary care—were positive towards delayed antibiotic prescription.Antibiotic resistance is a growing public health concern and closely related to use of antibiotics . In DenmA substantial variation in antibiotic prescription among children across European countries suggests that antibiotics have been inappropriately used . The higDelayed prescription is one of the best strategies available to reduce the use of antibiotics, without influencing patient morbidity or mortality ,11. DelaDelayed antibiotic prescription was officially introduced in Denmark in 2014 through the Danish College of General Practitioners’ clinical guidelines on RTI. It has been recommended to consider delayed prescription in URTIs with a high degree of self-limitation . In 2008While the positive effects of delayed antibiotic prescription are well documented, little is known about the physicians’ views on delayed antibiotic prescription. Denmark is among the countries with the lowest prescription rates among children in Europe . To reduIn Denmark, general physicians are responsible for the primary care of the whole population, including children. This study sought to examine general physicians’ views on delayed antibiotic prescription in preschool children with symptoms of URTIs.A questionnaire was developed and distributed to 1105 general practitioners (GPs), including 75 physicians in training, in Denmark between January and March 2015.The addresses of the GPs were identified via MedCom.dk, while the names of the physicians were identified via Sundhed.dk. The physicians received the questionnaire by post. A stamped self-addressed envelope was enclosed for reply. About ten days after the questionnaires were sent; the physicians who did not respond received a reminder by post.How often do you use delayed antibiotic prescription in children with symptoms of URTIs?Do you believe delayed antibiotic prescription can reduce the use of antibiotics in children with URTIs?Why or why not? (Open text field.)The questionnaire sought to collect demographic details such as gender, practice location, type of physician (GP or trainee), and the number of years in general practice, and practice type (single or partnership). Questions regarding delayed antibiotic prescription were also included:The provision of an open text field made it possible for the physicians to elaborate their views on delayed antibiotic prescription. A definition of delayed antibiotic prescription preceded the questions: ‘A “wait and see” prescription is a time-limited antibiotic prescription. If symptoms continue, the patient can redeem the prescription.’ The questionnaire also included five questions about the GPs’ perceptions of parental knowledge and expectations, which are not reproduced in this article.To maximize its validity, the questionnaire was pretested on relevant respondents before distribution; two GPs filled the questionnaire as a pilot study, and in-depth cognitive interviews were carried out to examine how the physicians understood and responded to the questions . In addiLogistic regression analyses were performed with the dependent variable being whether the physicians believed delayed antibiotic prescription could reduce the number of antibiotics used to treat URTIs in preschool children. The respondents who replied ‘no’ or ‘don’t know’ were grouped together. Excluding those respondents who replied ‘don’t know’ from analyses did not affect the results of the survey. Analyses were performed using SPSS Statistics 22.We used an inductive approach to analyse the qualitative data. The comments from the open text field were coded to discover patterns in the comments and then categorized in main and subtopics. In this process, efforts have been made to eliminate the influence of the pre-understanding of the researcher, and the topics were defined by data allowing an open-minded analysis of the qualitative data.Out of a total of 1180 physicians, 574 responded (49%). Of these, 322 used the open text field to elaborate their views. Of the respondents, 21% never issued a delayed antibiotic prescription to children with symptoms of URTIs, 40% rarely did so while 32% did it sometimes, and 7% often used delayed prescriptions. A physician’s use of delayed prescription was not significantly related to gender or number of years in practice, the location of practice, or level of antibiotic use in the physician’s municipality.Almost half of the respondents (46%) were positive about the potential of delayed antibiotic prescription to reduce the use of antibiotics in preschool children with symptoms of URTIs. Nearly one-fourth of the respondents (23%) were not positive, while a third (30%) declared not having any opinion. The number of years in practice was significantly associated with the physician’s view on delayed antibiotic prescription. Physicians with more than 25 years of experience were less likely to be positive towards delayed antibiotic prescription compared to those with fewer years of experience . Other fWillingness to wait-and-see. Some physicians believe that most parents are willing to wait-and-see how the symptoms evolve and argue that a need to redeem the prescription is often prevented due to a remission of symptoms.Parents will experience that the infection disappears spontaneously without treatment. (Physician K)On the other hand, others argue that many parents would redeem the prescription and give antibiotics. They cite work pressure in parents and lack of babysitting possibilities as a possible explanation to this.I believe many will redeem the prescription right away, both in the hope of the child getting better sooner and because they are under pressure from their job due to the child’s sick days. (Physician A)Need for reassurance. Some physicians believe that delayed prescription with proper information is a reassurance to the parents because parents are given the responsibility to act if the symptoms persist or worsen.The delayed antibiotic prescription gives the parents reassurance, making them more willing to wait and see when they have antibiotics on hand. (Physician J)Knowledge about infections and antibiotics. Education and knowledge of parents were highlighted as the main factors for some parents supporting the use of delayed antibiotic prescriptions.Some physicians argue that a decision whether to give antibiotics can only be taken by a physician, not by the parents.Parents are not able to assess whether there is a need for antibiotics. Instead of self-medication, they should come for a new consultation. (Physician M)Other physicians argue that the strategy gives parents greater co-responsibility, making the parents more reflective about using antibiotics, and the strategy is referred to as a learning tool to educate the parents.The parents are involved in the decision-making process and feel co-responsible for it. [The delayed antibiotic prescription has] an educational value—they have to take a critical stance, and they learn to have fewer expectations or demands for antibiotics. (Physician C)Out-of-hours services. Physicians argue that before weekends and holidays they are more inclined to use delayed prescriptions so that the parents can avoid out-of-hours visits, especially after the introduction of a new organization of the Capital Region of Denmark’s emergency departments, where nurses primarily treat patients.Especially on Fridays, we experience that the threshold for giving antibiotics has dropped because we are not comfortable with the help our patients are offered by [the emergency department] ‘1813’ in the weekends. (Physician L)The physicians also emphasized a substantial workload as a reason for making them inclined to use delayed prescriptions, due to lack of time to follow up on the child.Most (61%) of the respondents never or rarely used delayed antibiotic prescriptions for preschool children with URTIs. Most of them were positive (46%) rather than negative (23%) about the potential of delayed prescriptions to reduce antibiotic use. Physicians having no belief in the strategy were often those with significant work experience. Physicians with many years of experience may have a more paternalistic approach compared to their younger colleagues, or they could be more certain in the assessment of the child and, therefore, find the strategy less relevant. The physicians’ perception is influenced by the parents’ willingness to wait-and-see if the child recovers without antibiotic treatment. How both the physicians and parents consider the responsibility and capability of observation without antibiotic treatment and structural factors like out-of-hours services influence the physicians’ views about the strategy.Although many physicians responded (574), the response rate was low (49%). However, low response rates among GPs is a recognized problem in survey research ,16. No eThe responding physicians might have been more positive towards delayed antibiotic prescription or more engaged in the field of research and hence have a lower antibiotic use. However, out of the responding physicians, there were not more physicians from low-use municipalities, compared to the group of non-respondents (57% versus 59%).Pretesting the questionnaire before distribution has reduced the risk of information bias in this study.No information about the individual physician’s antibiotic use or prescribing style was available for our analyses.To the best of our knowledge, this is the first study focusing on delayed antibiotic prescription to children with URTIs. We found that physicians are mostly positive towards the strategy. A previous Norwegian study also found that most GPs (69%) use delayed antibiotic prescription as a reasonable strategy for patients with sinusitis and otitis, which are more common in children . ConsistIn line with our study, a qualitative study from New Zealand found that delayed antibiotic prescription is a safety net that enables the patients to act when needed. The study also found that delayed prescription is a method to educate patients and empower them to be more involved in decision-making .We found a discrepancy between the number of physicians with a positive attitude to delayed antibiotic prescription and the number of physicians using it. Delayed prescription has been shown to decrease inappropriate use of antibiotics, and measures should be put in place to facilitate the use of delayed antibiotic prescription in children with URTIs.Some physicians stated that they became more positive towards the delayed prescription strategy since the introduction of a new organization of the emergency departments. This shows that the physician’s view of the quality of out-of-hours services is a significant factor, which should be considered when implementing the strategy.Future studies should focus on the experiences of patients who receive a delayed prescription. Educated and knowledgeable parents are a logical target group for a delayed prescription, but there is a need for formalized recommendations regarding which patients are suitable for this strategy.Only 7% of the physicians often used a delayed prescription for children with URTIs, but most of them believe that delayed prescription for preschool children with URTIs could reduce antibiotic use. Physicians with many years of experience in general practice were less likely to be positive towards delayed antibiotic prescription compared to physicians with fewer years of experience. Different factors might influence the views of the physicians—from perceptions of parents to larger structural factors—towards implementing the strategy. However, the physician must consider if delayed antibiotic prescription is an appropriate strategy case by case.


IgG subclass 4–related disease (IgG4-RD) is characterized by increased serum levels of IgG4 and infiltration of biliary, pancreatic, and other tissues by IgG4-positive plasma cells. We assessed the prevalence of allergy and/or atopy, serum, and tissue IgE antibodies, and blood and tissue eosinophils in patients with IgG4-RD. We investigated the association between serum IgE and diagnosis and relapse of this disease.We performed a prospective study of 48 patients with IgG4-RD, 42 patients with an increased serum level of IgG4 with other inflammatory and autoimmune conditions (disease control subjects), and 51 healthy individuals  recruited from Oxford, United Kingdom from March 2010 through March 2014, and followed for a median of 41 months . Serum levels of immunoglobulin were measured at diagnosis, during steroid treatment, and at disease relapse for patients with IgG4-RD; levels at diagnosis were compared with baseline levels of control subjects. Allergen-specific IgEs were measured using the IgE ImmunoCAP. Levels and distribution of IgG4 and IgE antibodies in lymphoid, biliary, and pancreatic tissues from patients with IgG4-RD and disease control subjects were measured by immunohistochemistry. We analyzed data using the Spearman rank correlation and receiver operating characteristic curves.P < .0001). Peripheral blood eosinophilia was detected in 38% of patients with IgG4-RD versus 9% of healthy control subjects (P = .004). Of patients with IgG4-RD, 63% had a history of allergy and 40% had a history of atopy with an IgE-specific response; these values were 60% and 53% in patients with increased serum levels of IgE (P < .05). Level of IgE at diagnosis >480 kIU/L distinguished patients with IgG4-RD from disease control subjects with 86% specificity, 36% sensitivity, and a likelihood ratio of 3.2. Level of IgE at diagnosis >380 kIU/L identified patients with disease relapse with 88% specificity, 64% sensitivity, and a likelihood ratio of 5.4. IgE-positive mast cells and eosinophilia were observed in lymphoid, biliary, and pancreatic tissue samples from 50% and 86% of patients with IgG4-RD, respectively.Serum levels of IgG4 increased to 1.4 g/L or more, and IgE increased to 125 kIU/L or more, in 81% and 54% of patients with IgG4-RD, respectively, compared with 6% and 16% of healthy control subjects (In a prospective study, we associated IgG4-RD with allergy, atopy, eosinophilia, increased serum levels of IgE, and IgE-positive mast cells in lymphoid, biliary, and pancreatic tissue. An IgE-mediated allergic response therefore seems to develop in most patients with IgG4-RD; levels of IgE might be used in diagnosis and predicting relapse. IgG subclass 4–related disease (IgG4-RD) is a systemic fibroinflammatory condition, of which IgG4-related sclerosing cholangitis and autoimmune pancreatitis (AIP) are the biliary and pancreatic manifestations. An elevated serum IgG4 and abundance of IgG4-positive plasma cells infiltrating the involved organs is well described.5Strong links between IgG4 and IgE are well established. IgG4 responses are often associated with IgE-mediated allergy, but these responses are distinct. Both IgG4 and IgE are induced by Th2 cytokines interleukin (IL) 4 and/or IL1312In this paper, we set out to establish the prevalence of allergy and atopy, blood and tissue eosinophilia, serum total and allergen-specific IgE responses, and tissue IgE antibodies in a prospective UK cohort of IgG4-RD patients. We sought to determine the utility of serum IgE in differentiating patients with IgG4-related sclerosing cholangitis/AIP from disease mimics with an elevated serum IgG4, such as primary sclerosing cholangitis, and its relationship with corticosteroid use and disease relapse.For this study, 48 IgG4-RD patients, 42 disease control subjects with an elevated serum IgG4 (DC), and 51 healthy control subjects (HC) were recruited from the John Radcliffe Hospital, Oxford, United Kingdom, between March 2010 and March 2014, and followed-up for a median of 41 months . Diagnostic criteria for each group are defined in the Serum immunoglobulins were measured at diagnosis, during steroid treatment, and at disease relapse within the IgG4-RD cohort. Comparisons among IgG4-RD patients, DC, and HC were made at diagnosis before steroid initiation. Total serum IgG and IgG4 were measured by nephelometry . Total IgE was measured by the automated Immunocap method . Elevated serum IgG (≥16 g/L), IgG4 (≥1.4 g/L), and IgE (≥125 kIU/L) were defined by institution range.An IgE ImmunoCAP method was used to determine and quantify allergen-specific IgE antibodies. IgE-specific allergen testing was performed using a set of allergen mixes: grass pollen, mold, tree pollen, and nut , as specified in the Peripheral blood eosinophil count was measured at diagnosis. An elevated eosinophil count was defined as >500 cells/μL (count >0.5). Tissue eosinophil number was graded as none (0), occasional (<10), moderate (10–25), or marked (>25) on hematoxylin-eosin specimens by the reporting pathologist.Tissues were assessed for morphology and immunostained with IgG and IgG4 monoclonal antibody and IgE polyclonal antibody, as described in the P < .05 was considered significant.Comparisons among groups were analyzed with a 2-tailed Mann-Whitney test; correlations quantified as Spearman rank correlation coefficient. Statistics and receiver operating characteristic curve analysis were performed using Graphpad Prism  version 6.0. A P < .0001), as shown in Supplementary Figure 1A and B). There was no difference in the IgE/IgG4 ratio between the 2 groups . Elevated IgG4 concentrations were demonstrated in 81% (39 of 48), and elevated IgE in 54% (26 of 48) of the cases, both more prevalent compared with HC (P < .0001) (P = .001) , and serum IgE and IgG  (A). However, there was no difference between serum IgE levels in IgG4-RD patients with a normal and high IgG level (P = .178) (B). Serum IgE levels were increased in the high IgG4 compared with normal IgG4 group (P = .017) . In the 9 IgG4-RD patients with a normal serum IgG4 at diagnosis, only 1 had an elevated IgE.The serum IgG, IgG1, IgG4, and IgE levels at diagnosis were higher in IgG4-RD patients than in HC (< .0001) . There w = .028) A. Howeve = .178) B. Serum P = .004) (P = .001) (C and D) and serum IgG4  (C). However, there was no difference between serum IgG4 levels in IgG4-RD patients with a normal and high eosinophil count (P = .298) (D).Peripheral blood eosinophilia was present in 38% of IgG4-RD  versus 8.6% of HC  ( = .004) . There w = .001) C and D a = .019) C. Howeve = .298) D.P < .001) (A), and national UK statistics of 20% . There was a higher serum IgE in IgG4-RD patients with an allergic history than those without (P = .031) (B). An elevated serum IgE level was present in 60% of IgG4-RD patients with allergy. No patient had a history or evidence of parasitic infection.A history of allergy was identified in 63% of patients with IgG4-RD compared with 17% of HC ( < .001) A, and na = .031) B. An eleP = .25).Atopy was defined by evidence of an IgE antibody response in addition to clinical symptoms. An allergen-specific IgE response was identified in 52% (25 of 48) of IgG4-RD patients and 40% (19 of 48) of IgG4-RD patients were defined as “atopic.” An elevated serum IgE level was present in 53% of IgG4-RD patients with atopy. In total, 62% (16 of 26) of IgG4-RD with an elevated total serum IgE had a positive allergen-specific IgE response and 41% (9 of 22) with a normal IgE had a positive IgE-allergen specific response (P = .005) . Three-quarters (75%) of those with an elevated IgE (12 of 16) were positive to at least 1 of these panels, whereas 24% of those with a normal IgE (4 of 17) were positive to a single grass allergen panel only ( = .005) .P = .21) and gender (P = 1.0). In those IgG4-RD patients with an elevated IgG4 (n = 39), serum IgE was higher  than in the non-IgG4-RD DCs (n = 42)  (P = .003) (A). The ability of serum IgE to distinguish IgG4-RD from DC is shown on the receiver operating characteristic curve; area under the curve was 0.69  (B).Serum IgE levels were measured in IgG4-RD patients with an elevated IgG4, and DC who had other autoimmune, inflammatory, and infective diseases and an elevated IgG4, to investigate if IgE levels may help to discriminate the 2 groups. The groups were well matched in age ( = .003) A. The ab57–0.81) B.Figure At a serum IgE cutoff of 125 kIU/L, sensitivity was 67%, specificity was 64%, negative predictive value was 68%, and positive predictive value was 63%, with a likelihood ratio of 1.8 to distinguish IgG4-RD from non-IgG4-RD DCs with an elevated IgG4. At a serum IgE of 480 kIU/L , the sensitivity fell to 36%, specificity increased to 86%, positive predictive value was 70%, and negative predictive value was 59%, with a likelihood ratio of 3.2.P < .001) (A). Over time, serum IgE levels plateaued or increased, corresponding to corticosteroid discontinuation and clinical remission (B).Of 48 IgG4-RD patients, 79% (38 of 48) received corticosteroid therapy, 15% (10 of 48) underwent surgical resection, and 6.2% (3 of 48) had conservative management because of severe diabetes (1), end-stage cirrhosis (1), and patient preference (1). In those who received corticosteroid therapy with available serum samples (n = 15), IgE levels were lower compared with pretreatment levels by 12 weeks ( < .001) A. Over temission B.P = .001) (A). Receiver operating characteristic curve analysis yielded an area under the curve of 0.76 . Using an IgE cutoff of 380 kIU/L, the sensitivity was 64%, specificity was 88%, with a likelihood ratio of 5.4, to predict relapse (B). An IgE of >125 kIU/L at diagnosis did not predict relapse.Of 48 IgG4-RD patients, 43 had sufficient follow-up (>6 months) to determine evidence of relapse. At least 1 episode of biochemical and/or radiologic relapse was recorded in 54% (23 of 43). Serum IgE at diagnosis was higher in those IgG4-RD patients who relapsed than those who did not ( = .001) A. Receiv relapse B. An IgEHistologic specimens were available from 77% (37 of 48) of IgG4-RD patients for morphologic review and immunostaining; 15 resection and 32 biopsies. Tissue eosinophils were present in 86% (32 of 37) of specimens. Eosinophil infiltration was graded as “moderate” (10–25 eosinophils/high power field [HPF]) or “marked” (>25 eosinophils/HPF) in 73% (27 of 37) of specimens.Tissue IgG4 immunohistochemistry was performed in all 37 IgG4-RD specimens; the IgG4-positive plasma cell count >10/HPF  in 95% (35 of 37). The 2 patients with biopsy IgG4 counts <10/HPF had resection specimens with morphologic characteristics and ratios “highly suggestive” of IgG4-RD.–10 cells/HPF) (P = .15) tissues. The IgE-positive cell count was >10/HPF in 50% of samples stained (4 of 8). In IgG4-RD tissues, IgE-positive cells were localized to the mantle zone of the germinal center, within lymphoid aggregates and also scattered throughout the inflammatory infiltrate (A). The IgE-positive cell staining was both nuclear and surface. Mast cells were also scattered throughout the inflammatory infiltrate (B). IgE-positive cells and mast cells had a similar distribution, and costaining demonstrated evidence of IgE-positive mast cells  in IgG4-RD tissue (C). IgE-positive cells stained separately to CD20-positive B cells (D) and CD138-positive plasma cells , which were within the normal range.Red flags, incorporating these findings, are shown in In the original landmark study of elevated serum IgG4 in patients with AIP in Japan, there was no difference reported in IgE levels between AIP and HC.Our results support the utility of serum IgE in diagnosis of IgG4-RD, with a level of >480 KU/L differentiating IgG4-RD from DC with an elevated serum IgG4 . This 2-dimensional diagnostic approach  was supported by the observation that patients with a normal serum IgG4 did not have an elevated IgE. There were no DCs with malignancy in this dataset; however, serum IgE levels may be used to distinguish organ-specific IgG4-RD from malignant lesions, potentially minimizing unnecessary surgical intervention. This approach requires further validation. An elevated IgE at diagnosis >380 KU/L was also a marker of disease relapse , defining a subgroup requiring careful follow-up. This is supported by findings in a recent retrospective cohort study of predictors of disease relapse in IgG4-RD after rituximab therapy; in 21 (37%) patients experiencing disease relapse, baseline serum IgG4, IgE, and circulating eosinophils predicted relapse.Interestingly, IgE levels decreased during the first 12 weeks of corticosteroid therapy, with a parallel fall in disease activity , important in allergic inflammation, is expressed on Th2 cells; innate cells, such as eosinophils; and responds to mast cell–derived factors.The discovery of IgE, eosinophilia, and mast cell infiltration in IgG4-RD highlights novel therapeutic options. The prostaglandin DIn summary, this prospective study provides new evidence for the relationship of serum and tissue IgE antibodies in patients with IgG4-RD. Firstly, it supports the measurement of serum IgE levels at diagnosis, to help differentiate IgG4-RD from non-IgG4-RD conditions, and to determine the risk of subsequent disease relapse in those with IgG4-RD. Secondly, it implicates an IgE-mediated allergic response in a subgroup of patients, supported by a history of allergy and atopy, peripheral and tissue eosinophilia and the presence of IgE+ mast cells in affected tissues, which enables novel therapeutic avenues to be explored.