This paper briefly presents the conditions within the sewer that lead to the development of concrete corrosion in that environment. The review focuses on the acidophilic microorganisms detected in sewer corrosion environments, and then summarizes their proposed functions and physiology, especially in relation to the corrosion process. To our knowledge, this is the first review of acidophilic corrosion microbial communities, in which, the ecology and the environmental conditions (when available) are considered. Ecological studies of sewer corrosion are limited, however, where possible, we summarize the important metabolic functions of the different acidophilic species detected in sewer concrete corrosion layers. It is evident that microbial functions in the acidic sewer corrosion environment can be linked to those occurring in the analogous acidic environments of acid mine drainage and bioleaching.Concrete corrosion is one of the most significant problems affecting valuable sewer infrastructure on a global scale. This problem occurs in the aerobic zone of the sewer, where a layer of surface corrosion develops on the exposed concrete and the surface pH is typically lowered from around 11–10 (pristine concrete) to pH 2–4. Acidophilic microorganisms become established as biofilms within the concrete corrosion layer and enhance the loss of concrete mass. Until recently, the acidophilic community was considered to comprise relatively few species of microorganisms, however, the biodiversity of the corrosion community is now recognized as being extensive and varying from different sewer environmental conditions. The diversity of acidophiles in the corrosion communities includes chemolithoautotrophs, chemolithoheterotrophs, and chemoorganoheterotrophs. The activity of these microorganisms is strongly affected by H Figure 1). These piping systems are extensive and are typically constructed of concrete. The total length of sewer in Australian is almost 117,000 km, and approximately 40% of this network is constructed from concrete. Through the piped connections from houses, drains, manholes, pump stations, and storm overflows, the collection system can be further divided into rising mains and gravity flow regions . The rising main sections are designed and operated to pump the sewage to a higher altitude and have no gas phase present within the pipes. In the gravity flow regions, the sewage flows due to gravity and these are always partially filled with sewage and thus have a gas phase . The broad range of pollutants and the high microbial presence within sewage is such that sewers function as ‘microbial reactors’ where substances are transformed and degraded based on their chemical and biological reactivity  that occurs in the headspace gas of the sewer . After generation, the H2S is partitioned from the liquid into the gas phase in the gravity sewer pipes. The gaseous H2S can then partition into condensation layers on the gas-phase exposed walls of the concrete pipe . In those surface layers it is oxidized into sulfuric acid through the activity of aerobic sulfide-oxidizing microorganisms . The tidal regions are frequently wetted by wastewater, while the crown region is exposed to the headspace sewer gas and only very occasionally  contacts the wastewater .Since those discoveries of Parker, the process has been termed microbially induced concrete corrosion (MICC) where microorganisms are involved in oxidation of hydrogen sulfide  will be active in the extremely acidic conditions of the surface biofilms (around pH 2–4)  and resu-1 . Underst-1 . This, t2) and H2S acidification reduce the surface pH of concrete from ∼13 to ∼9  have been detected in the headspace in various sewer field locations  in sewer air. The sewer RH typically ranges between 60 and 100% . In addiFigure 3). However, because of the minimal contact with wastewater and the paucity of nutrients innately present in concrete, the corrosion layer is likely very low in nutrients and organic carbon, especially on the concrete surface moving away from the tidal region. At the crown region, the main source of water is condensation, gas diffusion will provide volatile substrates and nutrients, and degrading microorganisms will also provide nutrient for growth. Although the corrosion is often reported to occur in the crown region, it is observed that more severe corrosion can occur in the tidal region where more frequent replenishment of nutrients, microbial inoculum, and moisture will occur in comparison to parts of the wall further away from that region  moist layer forms comprising largely of crystalline gypsum and other sulfur species (discussed more below), within which microbial biofilms will exist  , suggesting in this instance that because of the gas diffusion limitations (O2 and/or H2S), the microbes occurred mainly on the concrete surface where the biofilm was denser nearer the surface of the corrosion layer  . It was on layer .Figure 5). Gypsum (CaSO4) is formed preferentially in acidic conditions (at pH lower than 3), hence it is usually more prevalent nearer the surface of the corrosion layer  and iron species, either from within the concrete or from iron rebar become dissolved and could transfer in the concrete pores and micro-cracks. Additional cracking of the concrete can also be caused by the rust precipitation in iron salt rich areas near the intact concrete  . The microbial biofilm is denser near the surface of the corrosion layer where the oxygen and H2S levels are highest (The activity of the biofilms in the top regions of the corrosion layer will produce acid  which dion layer . The gypon layer  and in son layer . Unlike on layer . The forigure 5) . Based o highest . Sulfuri highest . With thThiothrix spp., Thiobacillus plumbophilus   and acidophilic sulfur-oxidizing microorganisms (ASOM) both of which use reduced forms of sulfur as energy sources, but respectively, have a preference for growth at a neutral or acidic pH . After tophilus) , Thiomonolitanus . Thiothr by ASOM .Acidithiobacillus thiooxidans (formerly Thiobacillus thiooxidans) as a main biological component of sewer corrosion. Sulfur oxidation, as performed by these bacteria is undoubtedly a key metabolic activity, however, as revealed below, recent investigations of sewer corrosion ecology using culture independent detection techniques indicate that a diverse range of microorganisms is present. Recent studies performing microbial community profiling by NGS have advanced and are providing incredible new insight, even though molecular studies of the acidic concrete corrosion environment are still in their infancy.As mentioned above, there is a succession of microbial types involved in the concrete corrosion from the time of initial exposure, when the concrete surface is alkaline (pH 9–13), to when an established corroding concrete has developed and this is lowered to around pH 2–4. This review focuses on the acidophilic microorganisms of the established corrosion layer when the surface pH is acidic. Currently much importance is placed on the readily cultured bacterium Conventionally, research of the acidophilic communities involved in MICC has been mainly based on culture-dependent methods, where microorganisms are grown from corrosion samples using various culture media . AlthougAcidithiobacillus .On one occasion y low pH . Ferroplize iron , althougize iron . This watolerant . In addithomonas , Ochrobastridium . In a ststridium . While c7 cells/g of dry corrosion product and 4.5 × 108 cells/g of dry corrosion product, respectively. Acidithiobacillus were detected at 9 and 13% of the total cells in the manhole and crown samples, respectively . While this approach is likely to provide the most real quantitative estimations of cells in samples, unfortunately it is only very rarely applied to study concrete corrosion. FISH of concrete samples is conceivably a difficult procedure due to combination of relatively meager cell densities, variable cell activity, and interfering autofluorescence from mineral particles. Nonetheless, a successful FISH approach has been applied by performing the hybridisation in solution (rather than directly on samples dried onto microscope slides) and filtering portions of the solution onto black filters for microscopy . Total cectively . In anotectively . SequencAcidiphilium, Xanthomonas, and even photosynthetic organisms of the Cyanobacteria, however, no hyper-acidophilic SOMs sequence was found  and sulfide (S2-) ions. At pH 2–3 most will be in the form of H2S which will undergo chemical and biological oxidations, through a number of electron transfer steps to produce sulfuric acid, see below (Iron Oxidation). The oxidation of reduced sulfur compounds would be the major energy source in the oxidative corrosion layers of the dark sewer, an environment that is low in other inorganic or organic electron donating molecules. Reduced iron is another electron source that may be present mainly due to the reinforcing bar used in the concrete pipe. However, very little energy is gained from the oxidation of both reduced sulfur and reduced iron compounds and these organisms may utilize much energy for carbon fixation for growth . Publications that focus on the detailed roles of acidophiles in the MICC layer are limited. Some functions can be inferred from the rare metagenomic studies of sewer corrosion. Often the microbial functions (presented in Table 1) are inferred from pure culture studies of related microorganisms obtained from other similar acidic environments, such as acid mine drainage and bioleaching (Table 1).In relation to the limited types of electron donors, this would seemingly limit the range of metabolic guilds of microorganisms that proliferate in sewer corrosion layers. However, the diversity of microorganisms of corrosion communities can include chemolithoautotrophs, chemolithoheterotrophs, and chemoorganoheterotrophs (the later often referred to as heterotrophs). We have summarized the important metabolic functions of different acidophilic species found in the sewer corrosion layer of concrete , carbon-fixation, production of extracellular polymeric substances (EPS) and the generation of sulfuric acid. The production of EPS would be an important activity that enables the biofilms in the corrosion layer to exist. As a major component of the biofilm matrix it would provide favorable habitat for the EPS producers and for other non-EPS producing microorganisms (Table 1). It is estimated that Acidithiobacillus spp. excrete as much as 20% of the CO2 they fix as small organic substances . These activities would maintain favorable conditions for the growth of the chemolithoautotrophs, and enable their activities to continue and enhance the sewer corrosion. Some heterotrophs in this environment are also found to have the ability to oxidize H2S or iron. Acidiphilium spp. are sulfur oxidizing heterotrophs that are often detected in corrosion layer communities. Additionally, Acidiphilium are known to reduce ferric iron in anaerobic conditions , trithionate (S3O62-), and sulfite (SO32-)  would be the major energy conserving reaction in aerobic sewer corrosion environments. As mentioned above, this environment is comparatively low in other energy rich substrates. The oxidation pathways have been studied in only a few ASOM that are relevant to sewer concrete corrosion. Autotrophic acidophiles of  (SO32-) . The hetc carbon . The curc carbon .42- have been detected in sulfur oxidisers in general, and for ASOM, the pathways vary , such as S-sulfanylglutathione (GSSH) (2S which is oxidized to S0 and to sulfite by sulfide:quinone oxidoreductase (Sqr) and persulfide dioxygenase (Pdo), respectively. These oxidation steps pass electrons onto the cytoplasmic membrane quinone pool and then to various terminal oxidases to reduce oxygen and produce a membrane proton motive force  . In addition, an alternate tetrathionate intermediate (S4I) pathway occurs in Acidithiobacillus  or the tetrathionate intermediate (S4I) pathway. In the S4I pathway thiosulfate is firstly oxidized into tetrathionate through thiosulfate:quinol oxidoreductase and then tetrathionate is hydrolysed by tetrathionate hydrolase to thiosulfate and other products  (Oxidation pathways of acidophiles in sulfur-rich environments have been reviewed recently . Variousays vary . It is te (GSSH) . The perve force . In A. fbacillus . As a ceigure 7) .A. caldus indicates it has some components of ISC metabolism similar to A. ferrooxidans, such as Sqr, truncated Sox, S4I and terminal oxidases   . The acidophiles, A. thiooxidans and Acidiphilium spp. may be similar to A. caldus, as genome analysis indicates they may also use the Sox pathway for oxidation of ISCs to sulfate  . Another sulfate . In addi. caldus .Mycobacterium are primarily assumed a heterotrophic role in MICC. However, recently an acidophilic Mycobacterium sp. has been observed to oxidize sulfur and produce acid, although, there is no knowledge yet of the pathway involved (Ferroplasma spp. are not known for sulfur oxidizing activity (Ferroplasma genomes such as sulfur oxygenase reductase (Sor) homologs  cycle  cycle . Genes c. caldus . As well. caldus . In oblinditions . Carboxylus spp.  and geneooxidans . For A. s of CO2 . This maIn relation to carbon fixation, NAD(P)H, is an important cofactor in that process . In the Acidiphilium spp., Mycobacterium spp. and fungi, are described as heterotrophic microorganisms that are scavenging organic compounds . Additionally, it is well known that small organic molecules excreted by ASOM can be toxic and inhibit the growth and activity of those bacteria H, which are important reductants in various anabolic reactions of these organisms, including the role of carbon fixation in Leptospirillum spp. and A. ferrooxidans. Consequently, to produce these reducing equivalents, these iron oxidisers are forced to use energy and drive electrons in “uphill” reactions driven by the proton motive force . EPS would aid the attachment of the bacteria to the concrete surface and is the major component in microbial biofilms. Heterotrophic bacteria are an essential part of the sewer corrosion communities, as they degrade the extracellular organic molecules to support their growth, which also removes the presence of small organic molecules that may be toxic to ASOM.Sewer corrosion is universally accepted as a microbial corrosion process. The primary and direct cause is the biological sulfide oxidation by ASOM. While 2S, humidity, temperature, pH, and wastewater flooding play crucial roles on the corrosion process. It is essential that future molecular studies include more details of the environmental conditions that relate to corrosion. This is important so that valuable correlations can be made between the observed ecology and corrosion activity.Environmental factors such H2S concentration in the sewer and/or inhibit the activity of ASOM. To mitigate the generation and partition of H2S, liquid and gas-phase technologies using chemicals such as nitrates or iron salts are applied (The corrosion process and core members of the microorganism community is summarized in this review. There is much interest to limit the activity of MICC to abate the destructive sewer corrosion process. Current control measures either try to lower the H applied . Free ni applied  and has  applied . Other t applied . HoweverThe idea of this review paper was proposed by PB and GJ. The structure and whole paper was written by XL. PB made great contribution on the function of microorgansims. GJ helped with the process of concrete corrosion. UK helped with the details and language in this review paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Tyrosine-kinase inhibitors of the hepatocyte growth factor receptor MET are under investigation for the treatment of hormone-refractory prostate cancer (HRPC) metastasis. Analysis of MET protein expression and genetic alterations might contribute to therapeutic stratification of prostate cancer patients. Our objective was to investigate MET on protein, DNA and RNA level in clinical prostate cancer at various stages of progression.MET DNA copy numbers were determined by in situ hybridization.Expression of MET was analyzed in hormone-naive primary prostate cancers (N=481), lymph node (N=40) and bone (N=8) metastases, as well as HRPC (N=54) and bone metastases (N=15). MET protein expression was analyzed by immunohistochemistry . MET mRNA levels and in situ demonstrated cytoplasmic signals in 14/54 (26%) of the HRPC patients, and was associated with MET protein expression , in absence of MET amplification or polysomy. MET protein expression was present in 7/8 (88%) hormone-naive and 10/15 (67%) HRPC bone metastases, without association of HRPC , with MET polysomy in 8/13 (61%) evaluable cases.None of the hormone-naive primary prostate cancer or lymph node metastases demonstrated MET protein or mRNA expression. In contrast, MET protein was expressed in 12/52 (23%) evaluable HRPC resections. RNA MET amplification or polysomy. Evaluation of MET status could be relevant for therapeutic stratification of late stage prostate cancer.In conclusion, MET was almost exclusively expressed in HRPC and prostate cancer bone metastasis, but was not related to  The tyrosine-kinase receptor MET and its ligand hepatocyte growth factor (HGF) play important roles in stromal-epithelial interactions in a diversity of tissues. Upon secretion by mesenchymal cells HGF targets the MET receptor, contributing to embryogenesis, tissue development, proliferation and differentiation –3. Over-et al. have recently shown that clone D1C2 was highly specific for the C-terminus of the MET receptor, while the other antibodies demonstrated less sensitive or non-specific behavior [Hormone-deprivation is the first choice of therapy for metastasized prostate cancer. Most patients, however, suffer from hormone-refractory prostate cancer (HRPC) within a few years after initial treatment. Tyrosine-kinase inhibitor Cabozantinib, which targets both MET and VEGFR2, is currently under investigation for its effects on metastasized prostate cancer . A phasebehavior . The aimin situ hybridization signals were present in basal and atrophic luminal cells of normal glands serving as positive controls   HRPC patients and 4/50 (12%) hormone-naive prostate cancer cases. Although there was a trend of elevated RNA in HRPC, this association was not significant   positive samples out of 97 evaluable cores . FISH did not reveal MET amplification or polysomy in any of the cases  HRPC patients at palliative trans-urethral resection as compared to 1 of 49 (2%) hormone-naive controls  Figure . A total) Figure . Presencs Figure .MET did not reveal amplification or polysomy in any of the cases. In contrast, MET immunohistochemistry revealed expression in 20% up to 100% of tumor cells in 18/23 (78%) prostate cancer bone metastasis . RNA in situ hybridization was not feasible on bone metastasis due to RNA degradation during decalcification of bone tissue using formic acid. [MET was found in 8/13 (61%) evaluable cases, with an average of 2.6 copy numbers per nucleus (range 2.2-3.3), but was not associated with HRPC  .None of the 40 evaluable hormone-naive lymph node metastases demonstrated expression of MET protein or RNA Figure . FISH fos Figure . MET proic acid.  Polysomy) Figure . None ofMET polysomy or amplification.Recent phase II and III studies have demonstrated that treatment of metastasized HRPC patients with Cabozantinib led to reduced tumor load on bone scans and in soft tissues together with prolonged progression-free survival . To detein vitro and in vivo studies have shown the involvement of MET in development and metastasis of prostate cancer [et al. have recently investigated the reliability of five commercially available antibodies targeting MET and found that C-terminal clone D1C2 showed the highest sensitivity and membranous specificity for MET on formalin-fixed paraffin-embedded tissues [Various e cancer –22. Actie cancer , 10, 12.e cancer , 24. Whie cancer , 26. Res tissues . We were tissues . Stainin tissues .et al. in a set of 40 metastatic prostate cancers [et al. found that abrogation of RANK, c-MYC or MET strongly reduced bone metastasis in vivo [Albeit low to absent in hormone-naive prostate cancer, MET expression was found in HRPC specimens and bone metastases. These findings are in line with previous reports showing enhanced MET expression in HRPC bone metastases , 14. Thi cancers . The ind cancers , 31. Dur cancers . While M in vivo . Additio in vivo , 34.et al. performed functional studies on patient-derived xenografts and Cabozantinib-treated patients [Despite improvement on bone scans and secondary side effects such as progression-free survival, treatment with Cabozantinib did not lead to better overall survival of HRPC patients , 35. In patients . While Cpatients –38.The strong points of this study include the thorough preceding characterization of the D1C2 antibody and the use of a wide range of clinically relevant prostate cancer specimens at various stages of disease progression. Disadvantages of the current study are that MET immunohistochemistry was scored visually and not by automated image-analysis. In addition, MET protein expression levels were determined by chromogenic detection at paraffin-embedded tissues, which might reach insufficient sensitivity to detect very low levels of protein.In conclusion, we demonstrate that MET is highly expressed in HRPC at palliative transurethral resection specimens and bone metastases, while expression is low to absent in hormone-naive primary prostate cancer and lymph node metastases. Protein expression of MET was not related to genetic polysomy or amplification, but was putatively caused by modifications in micro-environmental and tumor signaling pathways. Evaluation of MET status could be relevant for therapeutic stratification of late stage prostate cancer.Four prostate cancer cohorts representing various disease stages were used in this study. The first cohort consisted of 481 hormone-naive prostate cancer patients who had undergone radical prostatectomy for their disease. All patients had been diagnosed with prostate cancer in the scope of the European Randomized Study of Screening for Prostate Cancer, Rotterdam section , 40. As 2O2 in PBS. Heat-induced antigen retrieval was done in TRIS-EDTA buffer  using a pressure cooker at 1.2 bar. MET antibody  diluted 1:100 in 0.2% PBS/ BSA was incubated overnight at 4°C. Antibody was visualized using Vectastain ABC  and Envision , followed by counterstaining with hematoxylin. Basal and luminal atrophic epithelial cells from normal prostate glands served as internal control [Briefly, 5 μm formalin-fixed, paraffin-embedded sections were dewaxed and rehydrated using xylene and ethanol, and endogenous peroxidase was blocked for 20 minutes in 0.3% H2O2 in PBS. Heat-induced antigen retrieval was done in citrate buffer  for 15 minutes. Mouse anti-N-cadherin was diluted 1:50  in 1% PBS/ BSA and incubated overnight at 4°C. Antibody was visualized using Envision (DAKO) followed by counterstaining with hematoxylin.N-cadherin staining was done on five selected paraffin-embedded sections, of which a consecutive section was stained for MET . Sectionin situ hybridization on formalin-fixed paraffin-embedded tissue was done using RNAscope . Fresh 5 μm sections were heated at 60°C for 30 minutes, deparaffinized and rehydrated. After blocking of endogenous peroxidase for 15 minutes, slides were heated at 102°C for 15 minutes and treated with protease  for 15 minutes. The Hs-cMET specific target probe provided by the manufacturer , targeting base pairs 1236-2257 of MET, was hybridized for 2 hours. Signal amplification on the probe was followed by visualization with fast-red according to manufacturer's protocol and counterstained with hematoxylin. Probes for housekeeping gene ubiquitin C and bacterial gene dapB served as positive and negative control respectively . Basal and luminal atrophic epithelial cells from normal prostate glands served as internal control. Cells were defined positive when two or more ISH signals per cell were present.RNA MET copy number, fluorescence in situ hybridization (FISH) was done using a commercial probe targeting MET . An SE7 centromere probe served as copy number control. Tissue sections were dewaxed and rehydrated, followed by heating in citrate buffer  for 13 minutes. Tissue was treated with pepsine  for 20 minutes and dehydrated, followed by probe hybridising overnight at 37°C. Copy numbers were calculated as an average of probe hybridization in 20 nuclei of prostate cancer cells. A MET/SE7 ratio of 1 with more than 2 signals per nucleus was defined as MET polysomy, while a ratio of >1 with presence of more than 2.2 MET signals per nucleus was considered amplification.To establish 2) test. Two-sided p-values of <0.05 were considered statistically significant. Statistical analysis was done with the Statistical Package for Social Sciences .MET expression in both hormone-naive prostate cancer and HRPC was compared using Pearson's Chi-square (X


Rn gate with a standard set of universal gates. For this problem, a method exists that uses a single ancillary qubit to reduce the number of gates. In this work, we extend this method to three ends. First, we find a method that can decompose into fewer gates than the best known results in decomposition of controlled-Rn. We also confirm that the proposed method reduces the total number of gates of the quantum Fourier transform. Second, we propose another efficient decomposition that can be mapped to a nearest-neighbor architecture with only local CNOT gates. Finally, we find a method that can minimize the depth to 5 gate steps in a nearest-neighbor architecture with only local CNOT gates.We consider decomposition for a controlled- Therefore, for reliable quantum computation, all quantum operations of a quantum algorithm should be represented by a universal gate set that arises from a fault-tolerant protocol such as Clifford + T gates2.Due to the recent advances in quantum device technology, an arbitrary single-qubit gate or a Z-rotation gate can be implemented with fairly high accuracy, and a small quantum algorithm can be tested. However, even with the gate of a small error rate currently being realized, it is difficult to directly perform scalable quantum computation since it requires that arbitrarily large computations is implemented. In order to overcome this problem, fault-tolerable computation is still neededH), phase (S), π/8 (T), and controlled-NOT (CNOT) gates. Although it is known that quantum algorithms have much lower computational complexities than classical algorithms for problem such as factoring large integers3, when such quantum algorithm are decomposed into CNOT, H, S, and T gates, the result includes a huge number of gates. Thus, the advantages of quantum computing might be nullified. To enhance the benefits of quantum computation, it is important to use an efficient decomposition of quantum algorithms into universal gates. Here, we first consider the decomposition of single-qubit gates and two-qubit gates. Any single-qubit gate can be decomposed in terms of Hadamard gates and Z-rotation gates Rz(θ)5, and there are well-known methods to approximate Rz(θ) efficiently9. Next, we consider a controlled-Rn gate as the simplest 2-qubit gate to be decomposed into a universal set of gates. Controlled-Rn gates represent the fundamental part of the quantum Fourier transform (QFT) and many other quantum algorithms. Thus, controlled-Rn decomposition has a significant impact on the overall decomposition of a quantum algorithm. In this work, we propose efficient controlled-Rn decomposition methods as a technique to help enhance the benefits of quantum computation.We consider a standard set of universal gates consisting of Hadamard (denoted Rn gate is defined as follows:R2 gate is an S gate (or P gate), and the R3 gate is a T gate. The R2 and R3 gates are included in the universal set. However, Rn for n ≥ 4 cannot be exactly decomposed with only a standard set of universal gates8. Thus, we should approximate Rn for n ≥ 4 to express it with the standard set.An Rn gate, we use the gridsynth method9. Given a precision ε > 0, the approximation of an Rn gate is to find an operator U expressible as H, S, T and Pauli operators such thatTo approximate the 9 gives the result of the efficient approximation of an Rn gate in a probabilistic manner. Thus, we estimate the average number of gates for it. From Table Rn gate as 127, 253 and 379 with ε = 10−5, 10−10, and 10−15, respectively. Note that the average number of gates is independent of the rotation angle.The gridsynth algorithmRn gate is defined as follows:A controlled-Rn gate with 2 CNOTs, 2 Rn+1s and 1 Rn10. When we approximate the controlled-Rn with precision 10−10, the total number of gates is 761 on average from Table Rn requires an excessive number of gates.Figure Rn gate using a single ancillary qubit. The circuit consists of 1 Rn, 16 CNOTs, 4 Hs, 8 Ts and 6 T†s.Figure 8, one advantage of such a circuit is that it reduces the depth with only a small constant overhead. As mentioned earlier, Rn and Rn+1 require many gates according to the precision. In the case of the precision 10−10, Rn and Rn+1 both require approximately 253 gates. Therefore, the approach where a single ancillary qubit is employed appears to be beneficial.As noted in ref.11 offers an approach to implementing a controlled-U operation using an ancillary qubit containing an eigenstate of U. However, in this paper, we only focus on an approach using Rn gate in an approach of the ref.11. As future work, we will analyze the decomposition of a controlled-U operation.We note that the ref.T is shown in ref.12. We can observe that the middle T gate in ref.12 can be replaced with the Rn. In this case, controlled-Rn gate can be decomposed into 4 Hadamard gates, 2 Phase gates, 12 CNOT gates, 8 T gates, and 1 Rn gate. This result is the best known to date and is the same as in ref.13. If we use two ancillary qubits, T depth of decompsition of controlled-T can be reduced from 5 to 313. However, if we consider only one ancillary qubit, T-depth 5 and T-count 9 are the best results in decomposition of controlled-T gate.The previously known efficient decomposition of a controlled-In this work, we improve the previous method to three ends: to reduce the total number of gates, achieve an efficient layout and achieve a smaller depth.Rn consists of a lower total number of gates keeping one Rn gate.We propose an improvement whereby the controlled-The controlled-Rngate can be decomposed with at most one ancillary stateRn, eight CNOTs, four Hs, four Ts and four T†s.The proof is given in Section Proofs. The corresponding decomposition is shown in Fig. 14. In particular, in the case of a controlled-T, using ancillary qubits results in an exact decomposition of the controlled-Rn and not an approximation. Thus, the gap between Method 1 and Improvement 1 is more larger. The Method 3 is more efficient than the Method 2 in decomposition of controlled-T. However, it consist of 12 CNOTs, 4 Hs, 1 P, 1 P†, 5 Ts and 4 T†s. The decomposition includes 27 gates, whereas our decomposition includes only 21 gates. In more detail, T-count is the same for ref.12 and our method. However, the advantage of our method is reduction by 4 CNOT gates and 2 Phase gates. The reduction of CNOT gates is important since implementation of CNOT gates is physically not easy and controlled-Rn is not the final algorithm16. Thus, its impact in quantum algorithms will be large. For example, according to module count analysis of ScaffCC Program14 for Shor’s algorithm, the controlled-T gate is used 641,990,656 times in total. This means that reducing 6 gates in decomposition of the controlled-T gate reduces 3,851,943,936 gates in computing of Shor’s algorithm.The advantage of the proposed method is shown in Table Rn gate without using nonlocal CNOT gates.For practical quantum computing, we should consider the layout of quantum circuits. Since nonlocal two-qubit-gate operation is not allowed in general, a long-range CNOT gate is implemented with several adjacent SWAP gates. In the following theorem, we present an efficient decomposition of a controlled-A controlled-Rngate can be implemented under the nearest-neighbor-interaction-only architecture with at most one ancillary stateRn, twelve adjacent CNOTs, four Hs, four Ts and four T †s.17. Thus, Method 2 consists of 1 Rn, 28 adjacent CNOTs, 4 Hs, 8 Ts and 6 T †s, while Improvement 2 consists of 1 Rn, 12 adjacent CNOTs, 4 Hs, 4 Ts and 4 T †. Therefore, using our method, we use 16 fewer CNOT gates, 4 fewer T gates and 2 fewer T † gates.The proof is given in Section Proofs. The corresponding circuit is shown in Fig. Rn.The depth of a circuit means the length of the critical path of the circuit. To ensure an efficient run time of a practical quantum computer, the depth of a circuit should be minimized. For this purpose, we propose a circuit with a smaller depth for a controlled-While maintaining the Rn-type gate depth 1, the controlled-Rn can be implemented with at most one ancillary state Rn has a depth of 25, while this circuit only has a depth of 5. Although Method 1 only has a depth of 4, the depth after the approximation of the Rn-type gates is nearly twice that of Improvement 3.The proof is given in Section Proofs. The corresponding circuit is shown in Fig. 12, controlled-S gate can be decomposed in a depth of 5. However, in the decomposition, two long-range CNOTs is used. Thus, in order to represent controlled-S gate only with adjacent CNOTs and Rn-type gates, the long-range CNOTs should be transformed into several adjacent CNOTs or layout of qubits should be changed. That is, more resources than in the method of in Fig. 14 for Shor algorithm, the controlled-S gate is used 641,013,760 times in total. This means that reducing one depth in decomposition of the controlled-S gate affects 641,013,760 computing in Shor’s algorithm.We note that from Fig. 8.(a) in ref.2. The total number of gates of the QFT for n qubits (denoted QFT(n)) is obtained asThe quantum Fourier transform (QFT) is the key ingredient for quantum factoring and many other quantum algorithmsQFTM1(n), QFTM2(n), QFTM3(n) and QFTI1(n) denote the total number of gates by Method 1, Method 2, Method 3 and Improvement 1, respectively, as follows:c means average number of gates over 10,000 runs for an approximation of Rn with angle π/2n−1 corresponding to the precision of Table ε = 10−10 then c = 253. Thus, the benefit of Improvement 1 for Method 3 is obtained asn. In this paper, we only consider the error rate in approximation of Rn gate not the overall error rate in approximation of QFT. However, we can notice that Method 3 and Improvement 1 have the same number of Rn gate, and Improvement 1 has smaller number of gates than Method 3. Thus, the overall error rate in approximation of QFT for Improvement 1 might be not greater than that for Method 3. From Table Now, we compare the total number of gates for the QFT by applying each decomposition method. Rn gate since it is an important two-qubit gate. One method has been proposed that utilized a single ancillary qubit to reduce the number of gates. In this work, we have extended this method for three purposes: to reduce the number of gates, to find a good mapping for an architecture with only nearest-neighbor interactions, and to minimize the critical path. Specifically, we have realized that the proposed method reduces the number of gates for the quantum Fourier transform.We have investigated the decomposition problem for the controlled-As future work, we will consider three issues. First, we need to check whether the proposed methods are optimal. In addition, it would be interesting to investigate how much performance gain is possible for quantum algorithms such as Shor’s factoring algorithm since it heavily uses the quantum Fourier transform. For more general situations, we need to develop a decomposition method for controlled multi-qubit unitary transforms.Proof of Theorem 1.αi are complex numbers and Let U be an operator denoted byCij denotes a CNOT gate with control qubit i and target qubit j. Then,Let an unitary operator Thus,Proof of Theorem 2.αi are complex numbers and U be the operator denoted byCij denotes a CNOT gate with control qubit i and target qubit j. Then,Let Thus,Proof of Theorem 3.αi are complex numbers and Cij denotes a CNOT gate with control qubit i and target qubit j.Let Thus,


Opioid overdose deaths quadrupled from 8,050 in 1999 to 33,091 in 2015 and accounted for 63% of drug overdose deaths in the United States in 2015. During 2010–2015, heroin overdose deaths quadrupled from 3,036 to 12,989  underlying cause-of-death codes X40–X44  or Y10–Y14 (undetermined)Full-year estimates of fentanyl or heroin drug reportsThe rate of deaths involving heroin increased during 2006–2015 nationally and in all four U.S. Census regions . Total dDuring 2013–2015, deaths involving synthetic opioids without heroin increased at faster rates than did deaths involving heroin without synthetic opioids in the Northeast, Midwest, and South  Figure . Deaths Three interconnected trends drove increases in unintentional or undetermined deaths involving heroin and synthetic opioids in the United States during 2006–2015: increases in the supply and use of heroin  accounted for most of the increase in deaths involving synthetic opioids . These data, coupled with recent public health and law enforcement reports, continue to demonstrate that increases in deaths involving synthetic opioids are primarily driven by IMF  involved, and this percentage varies widely by state , a synthetic opioid, into the heroin market. Deaths involving both heroin and synthetic opioids increased sharply after 2013. The largest increases were in regions where white powder heroin is primarily used. Deaths involving synthetic opioids without heroin also increased sharply after 2013, indicating emergence of synthetic products without heroin or mixing of IMF into other drugs, including cocaine.Changes in the supply and potency of illicit drug products can substantially contribute to increases in overdose deaths regardless of rates of opioid misuse. With continued increases in the heroin and synthetic opioid supply and deaths in the context of prescription opioid misuse, sustained, targeted, and multisectoral responses to the opioid overdose epidemic are needed, including timely surveillance, safer opioid prescribing, education on opioid overdose and naloxone, linkage and access to treatment, leveraging of community-based services, and collaboration between public health and public safety agencies.


The Material Deposition Method (MDM) is enjoying increasing attention as an additive method to create concrete mortar structures characterised by a high degree of form-freedom, a lack of geometrical repetition, and automated construction. Several small-scale structures have been realised around the world, or are under preparation. However, the nature of this construction method is unsuitable for conventional reinforcement methods to achieve ductile failure behaviour. Sometimes, this is solved by combining printing with conventional casting and reinforcing techniques. This study, however, explores an alternative strategy, namely to directly entrain a metal cable in the concrete filament during printing to serve as reinforcement. A device is introduced to apply the reinforcement. Several options for online reinforcement media are compared for printability. Considerations specific to the manufacturing process are discussed. Subsequently, pull-out tests on cast and printed specimens provide an initial characterisation of bond behaviour. Bending tests furthermore show the potential of this reinforcement method. The bond stress of cables in printed concrete was comparable to values reported for smooth rebar but lower than that of the same cables in cast concrete. The scatter in experimental results was high. When sufficient bond length is available, ductile failure behaviour for tension parallel to the filament direction can be achieved, even though cable slip occurs. Further improvements to the process should pave the way to achieve better post-crack resistance, as the concept in itself is feasible. In the last few years, 3D printing in the construction industry has enjoyed rapid growth. Additive manufacturing of concrete and cementitious materials (AMoC), in particular, is expanding briskly. After a phase in which showcase objects have been presented that were not intended for structural applications or actual load regimes  tensile capacity, as the processes that are being applied generally do not yet provide that inherently . In the limited number of projects that have been realised up to now, the strategy generally is to use the printed concrete as lost formwork for conventional reinforced concrete ,21. AlteAn altogether different approach has been adopted by Chinese contractor HuaShang Tengda  in a proHowever, all these strategies have an important drawback: they seriously limit the level of form-freedom and automation, which are the key selling points of 3D printing. Khoshnevis  already Another possibility is to include fibers to achieve ductility in the print material itself. Hambach and Volkmer  reportedHack and Lauer  presentedevelop a suitable entrainment device and determine a suitable medium to act as reinforcement,globally establish pull-out characteristics such as bond strength and anchorage length of this medium in printed and cast concrete,achieve ductile failure behaviour of printed concrete beams in bending,explore any process-characteristic behaviour, aspects, and issues to be considered in further development of this concept.One of the techniques that is being developed at the TU Eindhoven (TU/e) builds on the idea of embedding a coil. Bos et al.  publisheThis paper will go on to describe the reinforcement entrainment device and discuss print process considerations and reinforcement medium selection . Some ba3 4-DOF gantry robot , is shown in Initial tests were performed with Ø 0.35 mm fishing line and Ø 0.4 mm steel wire. These proved to have insufficient flexibility and to be too thin, causing them to cut through and pull out of the concrete. Subsequent tests were done with several types of chain . The ste® cables  may be understood as consisting of a complex combination of at least three phenomena: adhesion, dilatancy, and friction, with the former two, adhesion and dilatancy, occurring before failure and together constituting the bond resistance, and the latter happening after failure and determining the post-failure resistance . The res3) than NSC because the material cannot be compacted after printing. The conditions of the concrete applied in 3D concrete printing are rather different from normal cast concrete. Up to and including the current project, the 3DCP research program has used a mortar with strength properties approximately equal to C10/12 grade concrete, but with a maximum grain size of 1 mm, i.e., significantly lower than is usually applied in structural concrete in buildings. Furthermore, the density of printed concrete is lower . Besides the steel quality, this is due to the woven structure of the cable. First, the stress-strain behaviour of these cables differs from normal reinforcement steel. According to Eurocode 2, B-grade reinforcement steel, which is commonly used for instance in the Netherlands, yields at εFurthermore, the cable surface is smooth. Thus, their pull-out behaviour is likely more comparable to the smooth reinforcement bars that have been used in concrete structures in the past. Since the 1970s, the use of smooth bars has been discontinued in Europe in favour of ribbed bars because of their far superior bond properties caused by the much higher dilatancy resistance. The bond resistance of ribbed bars is found to be approximately 6.6 times as high as for smooth bars . This, nContrary to conventional reinforcement, the cables applied in this research are galvanised . Galvanising reinforcement is a technique that has been commonly applied to increase the corrosion resistance of the reinforcement  since the 1930s, especially in saline environments . GalvaniFinally, common bond stress methods assume the concrete matrix can be considered a homogenous material. Applicability often features limits, such as minimal reinforcement diameters and maximum embedment lengths, e.g., 5 times the diameter (5·d [mm]) for the pull out tests of NEN-EN 100080 . HoweverIn many ways, the pull-out behaviour of the cables is likely comparable to that of straight steel fibres in terms of proportions between adhesion, dilatancy and friction, considering their small diameter and smooth surface. The parameters that effect these values are mostly similar to those effecting conventional reinforcement, and include concrete matrix composition and strength, water:cement ratio, fiber geometry, length and orientation, fiber surface treatment, and load rate ,53,54,55It may be concluded that existing experimental data and models for reinforcement behaviour provide a frame of reference to analyse the cable reinforcement behaviour in 3DCP. However, with regard to geometry, material behaviour of both concrete and steel, as well as the manufacturing method, significant differences exist that call for caution when interpreting results.The bond behaviour of three types of cable reinforcement was investigated by pull-out tests on cast and printed concrete samples with different embedment lengths.For the pull-out tests on cast concrete specimens, rectangular blocks were cast around cables, that were slightly pre-stressed in order to guarantee their straightness, and compacted on a vibrating table for 10 s. The same 3DCP print mortar, described by , was usecs = 15 and 35 mm. The results of an initial test series with lcs = 25 mm were abandoned because of deviating concrete quality, which led to incomparable results. Throughout the experimental part of the research, each series consisted of five specimens. Consequently, 30 cast specimens were prepared and tested.After casting, the specimens were wrapped in foil to prevent dehydration, and left to cure for 14 days at ambient lab temperature. Several series of specimens were produced, with three different cables . The specimens were left to cure under foil on the print table for one day, and then submerged in water until testing at 14 days old. The printed specimens were taken from three subsequently printed objects a. In eacThe specimens were subjected to a displacement controlled pull-out test at 0.5 mm/min, performed in an Instron universal test rig equipped with a 5 kN load cell. The cable slip was recorded by averaging measurement results of 2 LVDT’s fitted to the cables at the bottom side of the specimen as shown in adh, δadh) and the ultimate bond strength  are listed in u = Fu/pl. Although it is known that the shear stress distribution will not be distributed equally along the cable length, but rather peak at the top side where the load is introduced, this approach is commonly applied in reinforcement-matrix pull-out analyses and therefore maintained here as well. All specimens in both the cast and printed series failed on cable pull-out, except for the C35A series, in which gradual breakage of individual strands within the cable introduces failure.anchorage = F/τmaxp. These are listed in As failure in all printed specimens occurs through cable pull-out and the results show no clear trend in bond strength development over embedment length, basic anchorage lengths can be calculated from the cable data  and the The load-slip curves of the cast specimens show a clear steep branch representing the adhesive bond , and a consecutive branch with partial bonding and dilatancy. After the maximum bond strength is reached, a gradual degrading branch starts caused by friction. It should be noted that the adhesive branch for the C cables is less steep. This is caused by the structure of that cable, with a core and a mantle.In neither of the cast specimen series does the embedded length influence the ultimate bond stress. Although at first glance there seems to be an influence in the A-cable specimens , this diThe adhesive bond stress on the other hand, seems to decrease slightly with increasing embedded length . This miadh/τu ranges from 0.6 to 0.8. As discussed previously, this is comparable to values found for smooth rebar, where the adhesive bond accounts for around 60% of the ultimate bond strength. In absolute terms, the maximum bond stress is somewhat higher than expected for smooth rebar.The ratio τThe differences in adhesive and maximum bond stresses between the series are considerable and do not show a consequent pattern. An explanation, therefore, remains elusive. The scatter in results is also substantial, but does not seem to depend on embedded length or cable type.Like the cast specimens, the printed specimens show a clear adhesive branch that is less steep with the C cables. After the adhesive strength is reached though, a drop in load occurs in about 40% of the specimens, indicating a sudden release of the cable that is less counteracted by dilatancy. The inferior concrete matrix quality, as shown in Contrary to the cast specimens, no clear trend (decreasing or increasing) in the adhesive bond stress over increasing embedment length can be noticed. Again, the reduced matrix quality is likely to blame: any increase in shorter embedment lengths due to an altered stress distribution is annulled by a relatively increasing effect of matrix defects. adh/τu ratio is comparable to the cast specimens, but can run to slightly higher values from 0.6 to 0.9 . Both the adhesive and ultimate bond stress are significantly lower than for the cast specimens—again caused by the inferior matrix quality. Nevertheless, the ultimate bond strength is still close to what could be expected of smooth rebar. The scatter in results for cable type A is clearly larger than for cable types B and C. The reason for this is unclear. The τFinally, it is noted that the anchorage lengths calculated in The pull-out tests have shown that considerable ultimate bond strengths (better than smooth rebar) can be achieved between the cables and cast concrete. Additionally, reasonable ultimate bond strengths (comparable or slightly worse than smooth rebar) can be achieved between the cables and printed concrete. However, the difference between the bond strength with cast and printed concrete is significant. This is likely caused by differences in the concrete matrix quality. Improvement of the bond strength in printed concrete should, therefore, be pursued. An additional advantage is likely to be a reduced scatter in strength.u exceeds the crack moment Mcr. For the concept to be comparable to conventional reinforcement in terms of performance, Mu > Mcr is a precondition. The beam specimen design included cables in each layer, as that is a likely situation in printed objects in which this technique is applied. Furthermore, the dimensions were chosen so that, from a simple analytical calculation, the failure moment MBos et al.  show thau,cable = the ultimate force in a cable, taken from Fn = the number of cablesavez = the average internal lever arm, taken as avez = 0.9 × dave, with dave = the average distance from the reinforcement heart line to the beam top. Based on [layer = 11 mm, the width b = 50 mm. Based on , each reThe crack moment was determined by:cmf = 1.9 MPa was applied. This value is based on unpublished tensile tests and has been known to deviate. It should therefore be considered an approximation. This simplified equation is applicable as the influence of the cables on the crack resistance is negligible (<1%). For the concrete flexural strength, c and the load-to-support distance a should exceed the anchorage length: a + c > lanchorage.The beam length and span proportions were selected based on the test rig dimensions and calculated anchorage lengths from the pull-out tests. With a single cable A in each layer and the available print nozzle, it proved difficult to achieve dimensions in which the failure moment would be higher than the crack moment. This requirement was therefore abandoned for cable type A (not for the other two). Obviously, this indicates that cable A is less suitable than cables B and C as replacement of conventional reinforcement in printed concrete.These considerations led to a beam section of three layers in height , 1000 mmThe four-point bending specimens were taken from three subsequently printed objects. Each object is three layers high; reinforcement cable  are entrained in each layer. After printing, the objects were covered in foil for one day, subsequently submerged in water, and left to cure for 28 days. The long straight sides were then sawed into beams with a diamond saw. Three specimens with cable A were tested, six with cable B and five with cable C.The test results of the four-point bending tests are listed in The crack moment of the beams with cable type A (19.2 Nm) is slightly higher than the analytically calculated value (17.1 Nm). This could be caused by geometrical deviations or the actual concrete flexural strength. Failure occurs by cable breakage, as desired. The failure moment is practically equal to the calculated value. This confirms the suitability of analytical analysis methods for conventional concrete also for printed concrete with cable reinforcement. As expected, the failure moment does not exceed the crack moment. This fits with the single localised crack that occurs.u . Considering the previous results  than the analytical value. Contrary to the A-cable beams, however, the failure moment is significantly lower than the analytical result. On average, it barely exceeds the crack moment, is this entirely due to one specimen outperforming the rest . The cause for this discrepancy is the failure mode. Instead of cable breakage, cable slip occurs. This also results in a higher scatter for Mresults . The crack moment of the C-cable specimens is significantly lower than that of the A- and B-cable beams, and lower than the analytical value as well. Again, deviations in concrete geometry and strength are the likely cause. The failure moment, on the other hand, is significantly higher than both the crack moment and the failure moments of the other beams, due to the higher reinforcement strength. Still, it does not come near the analytical value as here, too, failure is induced by cable slip instead of cable breakage. In the study of , this waIn the B- and C-cable beams unexpected failure caused by cable slip occurs. The internal pressure may influence the adhesion. An additional cause could be the peak stresses at the load side of the cable. They will reach a certain value that may cause gradual debonding that will induce eventual failure regardless of the anchorage length. The low concrete strength and the matrix defects that occur particularly to the underside of the cable, may cause this effect to occur before the cable has had the chance to activate sufficient anchorage length to break itself. The pull-out tests did not signal such an effect, but the forces in those tests stayed well below the strengths of cables B and C. This effect might only occur at larger embedment lengths. Further research is required.The four-point bending tests have shown that the presented in-print reinforcement method is feasible and can result in considerable post-crack resistance, similar to conventionally reinforced concrete. However, premature bond failure results in underachievement of the cables and high scatter. Thus, improvement of the concept is necessary. In comparing cables A, B, and C, it is apparent that cable A currently provides the most predictable structural behaviour, but is nevertheless less suitable as its absolute strength is limited. Only when the concrete filament size is significantly reduced or the number of cables per layer is increased, can this cable provide sufficient strength. Cables B and C, on the other hand, provide sufficient strength but suffer from adhesion problems. Process improvements should eliminate this in the future.Directly entrained cables have been introduced as a reinforcement method for 3D-printed concrete. A device was presented to entrain these cables directly during printing, resulting in a single automated manufacturing process. Two experiments have been conducted: a pull-out test on cast and printed concrete with different embedment lengths and three types of reinforcement cables, and a four-point bending test on printed beams with the same three cables. The pull-out tests showed the bond strength of cables in cast concrete is low compared to conventional ribbed rebar, but somewhat higher than that of smooth rebar. In printed concrete, the bond strength was considerably lower than in cast concrete, and towards the lower end of what would be expected of smooth rebar. The concrete matrix showed substantial defects, particularly underneath the reinforcement cable.Subsequently, the four-point bending tests showed significant post-crack resistance can be achieved with the B- and C-type cables. However, failure of the respective specimens was governed by cable slip, which was not expected based on the pull-out tests. This increases the scatter, and results in failure moments (far) below the analytically determined potential based on cable breakage. In the A-cable beams, cable slip did not occur. Rather, failure was induced by cable breakage resulting in failure moments close to the analytically determined values. Nevertheless, these were below the crack moment due to the limited cable strength. The bending tests confirmed the suitability of analytical analysis methods to determine the resistance of conventional concrete also for printed concrete with cable reinforcement, at least to obtain global estimates on moment resistance. The concept of directly entrained cable reinforcement has been shown to be a feasible reinforcement method that can achieve performances similar to conventional reinforcement in cast concrete. However, effort needs to be taken to improve the bond strength and scatter on the B- and C-type cables, so that their failure strengths can be reached before cable slip occurs. The A-type cable works well, but does not seem to be strong enough for practical applications.


IgG4-related disease is a recently described pathologic entity. This is the case of a patient with nephrotic syndrome and lymphadenopathy due to IgG4-related disease. Such a kidney involvement is quite peculiar and has only been described a few times recently. Renal biopsy showed a glomerular involvement with membranous glomerulonephritis in association with a tubulo-interstitial nephropathy. Moreover, the patient was not suffering from pancreatitis.The patient is a middle-aged man of Moroccan origin. He has developed recurrent episodes of diffuse lymphadenopathies, renal failure and nephrotic syndrome. Renal biopsies showed membranous glomerulonephritis.The diagnostic approach of this atypical presentation is discussed in this case report as well as diagnostic criteria, therapeutic strategies, biomarkers and pathophysiology of IgG4-related disease. IgG4-related membranous glomerulonephritis is a well-established cause of membranous glomerulonephritis. It must be sought after in every patient with a previous diagnosis of IgG4-related disease and in every patient with this histological finding on renal biopsy. Corticoids are still the first-line treatment of IgG4-related disease. New therapeutic strategies are needed to avoid glucocorticoids long term side-effects. Interestingly, the patient was prescribed cyclophosphamide in addition to glucocorticoids for an immune thrombocytopenia. This treatment had a very good impact on his IgG4-related disease. IgG4-related disease (IgG4-RD) was first described 50 years ago as a pancreatitis with hypergammaglobulinemia and called autoimmune pancreatitis (AIP). The immunoglobulins involved in this AIP were thereafter characterized as belonging to the IgG4 subclass. Multisystemic involvement of the disease was noticed only in 2003 and the name IgG4-RD finally chosen to designate this pathology. All denominations previously used such as “IgG4 syndrome” or “IgG4-related sclerosing disease were subsequently abandoned. Moreover, new denominations were established for each organ involved i.e. “IgG4-related kidney disease” (IgG4-RKD) for kidney involvement. Therefore, several diseases named before the knowledge of their belonging to the IgG4-RD entity had to be renamed. For example, “IgG4-related pancreatitis” is now the correct name for AIP, as is “IgG4-related dacryoadenitis and sialadenitis” the correct name for Mikulicz syndrome , 2.IgG4-RD is more common in middle-aged men and can involve every organ. Tumefactive lesions are characteristic of the disease with pseudotumoral swelling often being its first clinical manifestation. Organ dysfunction, imaging or biopsic findings can also reveal IgG4-RD. The histological pattern of lesions is fibro-inflammatory with a lymphoplasmocytic infiltrate enriched with IgG4+ plasma cells and storiform pattern of fibrosis. Obliterative phlebitis and eosinophilic infiltration are also commonly observed. The degree of fibrosis depends on the tissue involved and increases with time. Marked fibrosis is often described in IgG4-related retroperitoneal fibrosis  and in IgG4-related thyroid disease (previously Riedel’s thyroiditis). Pancreatitis is the most common manifestation of IgG4-RD and is often associated with lymphadenopathy, salivary glands and kidney involvement. IgG4-RD without pancreatitis is much less common , 3.2), low serum C3 and C4 levels and hypergammaglobulinemia . Anti-nuclear antibodies (ANA) were positive at 1/640. Anti-dsDNA were negative. Urine tests showed proteinuria (444 mg/L). A thoraco-abdominal computed tomography and positron-emission tomography/computed tomography (PET/CT) were performed. The images were compatible with a lymphoproliferative disorder. Heterogeneous uptake was also noticed in kidneys. Lymph node biopsy was performed and ruled out a hematologic malignancy. Immunohistochemistry showed more than 10 IgG4+ plasma cells per high powered field (HPF) of biopsy sample with more than 40% of IgG+ plasma cells being IgG4+ .A 40-year old male patient of Moroccan origin was admitted in 2012 for diffuse lymphadenopathy confirmed with ultrasound. Blood tests revealed renal insufficiency , low serum C3 and C4 levels and hypergammaglobulinemia (4590 mg/dL) had already been found. Urine tests showed high proteinuria (13800 mg/l) with hypoalbuminemia characteristic of a nephrotic syndrome. Renal ultrasound showed diffuse kidney enlargement. PET/CT showed the same results as the one performed in 2012. A lymphoproliferative disorder was excluded by whole skeleton X-Ray, bone marrow and lymph node biopsy. A renal biopsy was then performed and showed membranous glomerulonephritis (MGN) with IgG and C3d deposits  developed a few weeks later with anti-dsDNA found on blood sample (1/80). Thrombocytopenia was refractory to perfusion of immunoglobulins, GC and cyclophosphamide (CYP). Plasmapheresis and splenectomy were then performed. CYP was next continued for 6 cycles (500 mg/cycle) with good efficacy. Relapsing thrombocytopenia was successfully treated by additional regiments of immunoglobulins and GC. The last cycle of CYP was completed at the end of 2008. Thereafter, the patient experienced a long period without any problem until the next hospitalization in 2012.In 2008, the first relapse occurred with the same clinical picture that in 2004 (nephrotic syndrome and lymphadenopathy). Full assessment was repeated yielding similar results except for renal biopsy: MGN with IgG and C3d deposits was found again but chronic interstitial nephropathy replaced the severe TIN. Indeed, a mononuclear infiltrate was present in the interstitium without clear sign of tubular involvement. A severe thrombocytopenia  antibodies were negative. Diagnosis of IgG4-RD was finally made on the basis of the lymph node biopsy, with IgG4-related generalized lymphadenopathy and IgG4-related MGN (associated with IgG4-related TIN in 2004). The patient was given GC again at high dose (methylprednisolone 96 mg daily) for 1 month followed by a progressive decrease of the dose. Rituximab use was discussed in 2013, due to a new relapse in spite of maintenance low dose GC therapy and development of side effects; unfortunately, the patient failed to obtain the reimbursement and the medication could not be given in this context. For now, the patient is well stabilized with low dose GC. Rituximab in compassionate use could be reconsidered in case of a new relapse. Figure This atypical presentation of a rare pathology (i.e. the patient never experienced any episode of pancreatitis) made difficult the diagnosis of IgG4-RD. Moreover, IgG4-RD was not well known at the time of the first symptoms in 2004 and PLA2R antibodies were not available in daily practice at that time.First of all, hematologic malignancies had to be excluded in the presence of lymphadenopathy and biological abnormalities. Moreover, a higher risk of developing lymphoma or neoplasia is highly suspected in IgG4-RD patients [IgG4-RD is considered as definite in this case because all three comprehensive diagnostic criteria are met: diffuse swelling in lymph nodes, elevated serum IgG4 concentration ≥ 135 mg/dL (2790 mg/dL in 2012) and lymph node infiltration of IgG4 + plasma cells with ratio of IgG4+/IgG+ cells > 40% and >10 IgG4+ plasma cells per HPF [MGN are responsible for 30% of adult nephrotic syndromes. Eighty percent of MGN are idiopathic whereas the other 20% are caused by various pathologies which we searched for such as infections, cancers and systemic diseases. Circulating antibodies to the PLA2R (which is a transmembrane protein located on podocytes) are found in 70% of idiopathic membranous glomerulonephritis (IMGN). These antibodies are of IgG4 subclass but high serum IgG4 levels are not encountered in IMGN. The observation of glomerular deposits of PLA2R antibodies on biopsy seems to be more sensitive than their detection in serum. However, this could not be done here giving the absence of a recent renal biopsy .Kidney involvement in IgG4-RD or IgG4-RKD occurs in approximately 15% of IgG4-RD patients. It has the remarkable property to result in two well distinct types of lesions: first, TIN which is most commonly encountered and second, glomerulopathy. Pyelitis have also been described. Glomerular involvement is very rare (7% of IgG4-RKD). Lymphoplasmocytic infiltrate and storiform pattern of fibrosis need not be present for its diagnosis. MGN is the only glomerular lesion that can be reliably attributed to IgG4-RD. However, other forms of glomerulopathy such as mesangioproliferative glomerulonephritis, IgA nephropathy and membranoproliferative glomerulonephritis have also been described by Saeki et al. ). UnfortSpecific diagnostic criteria exist for IgG4-RKD . They weAll patients with active IgG4-RD and a subset of asymptomatic patients require treatment, sometimes urgently. GC are currently the main first-line treatment with initial good clinical and biological response, especially when a low degree of fibrosis is present. However, relapses are very common as seen in this case report and maintenance GC is often required after induction therapy. Patients who relapse for the first time after successful induction should be inducted again by GC. Introduction of steroid-sparing immunosuppressive agents should be considered for following relapses due to the frequency of side effects associated with long term GC therapy . MycopheIt is interesting to note that the patient received CYP in 2008 for immune thrombocytopenia. This treatment was followed by 3 years without any manifestation of the IgG4-RD, in the absence of maintenance GC. CYP was also given with GC to a patient with IgG4-related TIN in Australia, and similarly allowed clinical and radiological remission as well as stabilization of renal failure . AlexandIgG4-RD follow-up is based on biological markers such as serum CH50, C3c, C4, IgG and IgG4 values. In case of relapsing IgG4-RD, a lowering of serum complement level is classically noticed  as well as increased IgG and IgG4 levels, as shown in Fig. IgG4-RD pathophysiology is not completely understood yet. Excess of T helper 2 (Th2) cells and regulatory T (Treg) cells has been described in involved organs. This could explain fibrosis (since transforming growth factor-beta is secreted by Treg) and increased production of IgG4 (because cytokines secreted by Th2 and Treg stimulate IgG4 class switch). Excess of Th2 can also explain IgE excess and hyper eosinophilia , 16. ThiAn important question remains: are IgG4 pathogenic or not in IgG4-RD? The recent discovery of serum IgG4-negative IgG4-RD raises questions about the causative role of the IgG4 molecule . ANA areWe have described the rare history of a patient with MGN secondary to IgG4-RD without pancreatitis.Several mechanisms still remain to be discovered about IgG4-RD such as the role of IgG4 antibodies and even the nature of the pathology itself. However, it is now a better defined pathology with comprehensive diagnostic criteria and a large number of cases are now described.GC therapy is a potent initial treatment in IgG4-RD, avoiding end-stage renal disease in IgG4-RKD for example. It must be initiated before occurrence of fibrosis for better response. This emphasizes the importance of early diagnosis. However, resistance and side effects to GC finally occur and steroid-sparing immunosuppressive agents have to be considered. Rituximab seems to be a promising treatment. CYP also proved to be a very good therapy in our case and in others: these case observations would justify the design of controlled clinical trials to evaluate its effectiveness in IgG4-RD.IgG4-RD follow-up can be based on biological markers such as serum CH50, C3c, C4, IgG and IgG4 values, but they are imperfect predictors. PET/CT could be more reliable for the follow-up.The differential diagnosis of IgG4-related generalized lymphadenopathy from lymphoproliferative disorders  is very difficult. PET/CT is not helpful in this indication and lymph node biopsies are crucial to exclude hematologic malignancies. Diagnosis of IgG4-RD does not dispense to perform new lymph nodes biopsies when relapse occurs. Indeed, higher risk of developing lymphoma in IgG4-RD patients is suspected.Kidney involvement is rare without associated pancreatitis. Glomerular involvement (mainly MGN) is even more uncommon especially without associated TIN. Further studies of MGN secondary to IgG4-RD will be welcome to improve our current knowledge of this disease. Nevertheless IgG4-related MGN appears already to be a well-established cause of MGN which must be sought after in every patient with a previous diagnosis of IgG4-RD but also in every patient with MGN found on renal biopsy.


This work presents the design, construction and testing of a new embedded sensor system for monitoring concrete curing. A specific mote has been implemented to withstand the aggressive environment without affecting the measured variables. The system also includes a real-time monitoring application operating from a remote computer placed in a central location. The testing was done in two phases: the first in the laboratory, to validate the functional requirements of the developed devices; and the second on civil works to evaluate the functional features of the devices, such as range, robustness and flexibility. The devices were successfully implemented resulting in a low cost, highly reliable, compact and non-destructive solution. Monitoring of concrete properties introduces many challenges in the design of non-destructive sensing systems. The miniaturization of the sensors taking advantage of technological advances is crucial for their placement inside the concrete. In recent years the growing importance of the so-called structural health monitoring is demanding intelligent systems based on sensors embedded into concrete, capable of controlling and monitoring the curing process mainly by measuring the temperature, or both temperature and humidity ,2. OtherDigital temperature and/or humidity sensors are widely known and their evolution continues to progress. These small systems incorporate the sensor, conditioning electronics, analog to digital conversion and digital processing necessary for connecting to a digital bus in one integrated circuit of reduced dimensions. Digital sensors provide advantages in terms of size, cost, reduced wiring, high noise immunity and direct connection to digital buses, allowing for the connection of large number of sensors without auxiliary electronics. However, the available digital temperature and/or moisture sensors cannot be used directly into the concrete, since their packages are not able to withstand the adverse conditions, especially in terms of sealing and compression. On the other hand, wired sensing increases the cost of the monitoring system . MoreoveThis paper describes our experience with the introduction and development of an experimental sensor embedded into concrete. The sensor exhibits temperature measurement capability. According to most of the available thermo-chemical models for concrete ,13,14,15Concerning the integration of a wireless embedded sensor into an instrumentation system , issues such as ease of connection or signal degradation due to the transmission process must be taken into account. The proposed sensor presents a number of features that are particularly useful for this application and that can be extended for structural health: (1) the energy consumption of the sensor node is optimized in such way that it can be powered by batteries. In this way, the energy supply is ensured throughout the lifetime of the node; (2) the simplicity of the proposed solution results in a low cost device, further guaranteeing robustness, accuracy and high resolution; (3) it can be connected directly to a standard instrumentation system. Thus, the developed embedded sensor includes an I2C full-duplex serial digital port ; (4) the sensor is equipped with a specifically designed virtual instrument, which allows acquiring and storing measurements in different formats, configuring the parameters of the sensor, reprogramming and controlling the sensor via Internet from a PC; (5) connection features in the developed sensor are significant, both in terms of quality  and the cost-savings involved in not having to transmit and condition analog signals outside the device; (6) a low cost and low power consumption solution with optimized size has been developed. The paper is organized as follows: Advances in low power wireless technologies made possible the immersion of a wireless node completely surrounded by the building material. Several wireless technologies, such as Bluetooth Low Energy, IEEE 802.15.4, ZigBee, Ultra-Wide Band (UWB) and Radio Frequency IDentification (RFID) ,17,18 coWireless sensor networks are composed of smart low rate devices or motes, which are generally battery-powered. The number of nodes can vary from a few to thousands. These networks allow for a dynamic network configuration, which is a feature particularly important for concrete curing, since a failure in one node is compensated by rerouting through other nodes. IEEE 802.15.4 was chosen for communications because in the last few years it has become a reference for wireless applications with low data rates and high energy efficiency. This standard, specifically designed for LR-WPAN networks, is a low-complexity protocol that offers low cost and energy features, as well as high versatility for the development of different topologies. The network consists of a number of wireless nodes embedded into concrete, and needs to merge particular and commercial solutions. Regarding the radio propagation, the high signal attenuation and the antenna detuning must be considered. These issues can result in very high error rates, so the information exchange mechanism must adapt to it. In addition, the optimization of the energy consumption is degraded since more errors in the data transmission will require more retransmissions, and thus higher energy consumption. Finally, the transmission power must be high to avoid problems of attenuation. It is common practice to place steel reinforcement to provide strength against tensile stresses and avoid excessive cracking of concrete. Moreover, the wet concrete is shaped in a mould comprised of formwork, which is most commonly steel or wood, being more problematic the presence of steel for the signal transmission. Therefore, if we want to monitor the concrete curing since when it is first poured, a careful design of the wireless network topology must be accomplished since the presence of steel may degrade the transmission of data. This fact imposes a wireless network topology of linear type, which involves an asymmetry in the network. Thus, the nodes that are further away have to send data through a long list of intermediate nodes. In turn, these intermediate nodes will waste part of their energy in the tasks of rerouting data. Considering the former problems, routing and synchronization algorithms have been designed to minimize the following characteristics: energy consumption, error rate, complexity and the probability of loss of a node. The energy consumption is decreased by synchronizing messages, whereas the rest of the time the node is idle. The use of very short messages allows balancing the workload between nodes, improving the error rate. Moreover, when a node performs a data transmission to all nodes within its coverage range (broadcast transmission), reliability is quite high since several nodes will receive the data message, so the loss of information is rather unlikely. The transmitting node waits for an acknowledgment message that validates its transmission. Then, it enters in low power state, reducing the time it is active. Concerning the complexity, the network is previously configured so that each node is assigned a task at the time when the network is created. The initial synchronization of the clocks is carried out in an outstation. Finally, to decrease the probability of losing a node an external watchdog is used, and different strategies will be applied depending on the level of the battery. The smart wireless devices or motes basically consist of a radio module including the antenna, a processor, a power supply and sensors mounted on the mote itself or connected to it. The radio module transmits and receives data through the IEEE 802.15.4 communication standard. The processor controls all the functions of the node. The power supply consists of a battery that uses a high performance power converter. The motes buried in concrete include sensors which measure temperature. In addition, an external environmental mote has also been implemented to measure the ambient temperature, since the study of concrete curing requires the analysis of both internal and external variables. Some of the nodes in the wireless sensor network may communicate with a computer through a gateway. Taking into account the environment in the concrete, the requirements that have been considered for the design of these devices are the following: (1) low cost and low power consumption; (2) use of long-lasting energy sources and reduced size; (3) a robust radio technology; (4) use of interfaces to connect different sensor nodes; (5) a package suitable to protect the wireless node from the concrete but that does not affect the measure of temperature.The mote consists of a microcontroller, a radio transceiver, a lithium-thionyl dichloride primary unit cell, an embedded antenna and a waterproof enclosure. The requirements of the microcontroller were ultra-low power consumption and low voltage. Two candidates were evaluated: a CC430F6137  which includes a CC1101 transceiver that allows several frequency bands below 1 GHz (868 MHz and 433 MHz), and a CC1125 transceiver, also from Texas Instruments, alongside with an MSP430 microcontroller . The power supply consists of a 3.6 V battery connected to a TPS62730 DC/DC converter  of 2.1 V and efficiency of 95%, especially suitable for wireless applications. The mote equipped with a CC1125 transceiver, shown in The power consumption of each mote has been estimated considering the period of time at which measurements are taken as required by the concrete curing monitoring. The battery used was a LS14250 , with 1100 mAh capacity, a hermeticity guaranteed up to 110 degrees Celsius, and a small form factor . This battery lasts around three months, which is more than enough time for the concrete curing monitoring.Regarding the sensor, a specific package assembly was developed initially, with details of the construction shown in The sensor layer consists of a commercial SHT21P humidity and temperature sensor . This is a digital sensor that can be easily integrated into any circuit due to its ability to be directly connected to any microprocessor system. The claimed performance of the sensor shows good accuracy, good repeatability and good response time. Besides the capacitive relative humidity sensor and a band gap temperature sensor, the sensor chip includes an amplifier, an A/D converter, OTP memory and a processing unit. The developed sensor generates an electrical signal directly related to the temperature and moisture, which is subsequently converted inside the same device into digital format. This sensor transmits data in two packets, the first for the humidity reading and the second for the temperature reading.A second alternative for the sensor was considered. The classical method of monitoring concrete curing is to only monitor the temperature profile. The DS18B20 digital temperature sensor from Maxim Integrated  was chosen. This sensor is fairly precise, can provide up to 12 bits of resolution and works with any microcontroller using a single digital pin. The sensor covers the range of temperatures for the target application. Moreover, in order to avoid developing a specific package for the sensor, it was coated with a special lacquer and resin. The suitability of this protection was evaluated and tested to ensure accurate measurement of the temperature, but also protection from direct contact. This ensures a simpler solution which is crucial for developing a low cost and compact non-destructive sensing system suitable to be embedded into concrete.Regarding the antenna, an internal antenna was always used, because of the risks related to maintaining the watertightness, and also impact risks with the aggregates of concrete  being poured from the mixer truck to the moulds to be filled. Different antenna types were used, these being a dipole quarter wave (85 mm), a custom design on a PCB and a chip antenna. Our final design uses a dipole quarter wave antenna with an RP-SMA connector. The language used in programming is almost entirely a C variant for microcontrollers which intended to be as portable as possible, so excluding lower level parts  it can be read as ANSI C. In any case, this microcontroller comes with very limited memory, so it is often preferred to include assembly code directly, although this is usually limited to certain functions related to wireless transmission. The firmware of the microcontroller is programmed by Code Composer or IAR for a device from the MSP430 family. The MSP FET430 programmer-debugger connects to the device via the JTAG or SWD protocol and allows for the step by step debugging and the use of breakpoints. Concerning the wireless controller, it is programmed using the protocol stack from Texas Instruments (SimpliciTI). It has been used for the programming of the nodes in different phases, and for the implementation of network algorithms. Synchronization processes and waiting periods have had to be defined as the protocol stack does not implement them. Sending messages will always be coordinated in stages as shown in The time required to send data always corresponds to a very low percentage of the total, so that the duty cycle will be below 1%, which allows for the device to be inactive most of the time (deep sleep state) as shown in Thanks to these mechanisms a very low energy consumption is achieved and the use of small batteries becomes appropriate.The monitoring application is a program that receives and stores data from the sensor nodes, and shows the data read from the sensors in a graphical user interface. The software has been developed with additional features in order to provide flexibility. Thus, the user can identify each node. The data from the sensors is periodically sent and stored within the database, and it is visualized in real time. In addition, the sampling period can be modified by the user. In fact, during the first days after the concrete is poured, the activity of the curing process is greater, requiring a large number of measurements. Some alarms received from the sensors, related to battery failure and voltage values lower than a preset threshold, have also been included. Traditionally, for conventional Portland concrete a limit of 3 days for curing, 7 days for rapid hardening, and 28 days for the development of the characteristic strength of the concrete is considered. Considering a tradeoff between the accuracy of a thermo-chemical-mechanical model that could analyze the concrete curing and the use of a wireless sensor network with motes supplied from batteries, the sampling period of temperature for the sensors was set as follows: four measurements every hour for the first three days. From day four, one measurement every hour until the seventh day. Between day 7 and day 28, one temperature measurement is performed every three hours. To save power consumption, several sensor readings are stored and sent together in the same message. This approach provides lower power consumption in the radio module, but the longer frames increase the error rate. Thus, a maximum of 128 bytes per frame was set. The estimation of power consumption, including a safety margin, determines a minimum battery capacity of 707 mAh. The average power consumption of each mote has been estimated using a Simulink model and considering each component separately. After the model, real world estimations have been taken into account, like battery discharge caused by temperature, loss of efficiency on components and non-linear effects such as communication issues. Therefore, the selected battery has a capacity of 1100 mAh. Once the DS18B20 sensor was chosen all efforts were devoted to checking the suitability of the protection based on lacquer and resin. The accuracy and linearity of the sensor were monitored, as well as the effect that the protection had on the accuracy. Nevertheless, the suitability of the package in On the other hand, the transmission of each node was analyzed under different situations, especially considering the power of the output signal, which is a critical parameter taking into account the attenuation due to the concrete and the steel. A preliminary test was performed to verify the validity of the specifications on several specimens of concrete as shown in A simple LabVIEW program was designed to interact with the sensors, logging the time, temperature readings and also from which sensor the data was received. The designed motes and the wireless sensor network were introduced in a construction site. The place is located in a viaduct of the high-speed Antequera-Granada railway in the region of Andalucia, in the South of Spain. The preliminary study of the location of the motes determined the use of the 869.4 MHz to 869.65 MHz band given by ETSI EN 300 220 and short-range device (SRD)of unspecified use, with a transmission power of 500 mW (+27 dBm). This need arises from the distances to be treated being around three meters, which are larger than the ones tested in the laboratory, and therefore the dynamic range should be increased. Thus, to reach the mentioned power level, it is necessary to include in the design an output power amplifier and a linear noise amplifier to improve the reception of signals.For a distance of 1.5 m the motes can transmit from within the concrete to the outside, with a signal loss between 48 dBm and 64 dBm. Given an initial signal of −36 dBm and an error margin, it’s the maximum distance where a sniffer can receive packets in order to debug the deployment, considering a sensibility of −102 dBm. Eight points of measurement are taken, as indicated in The higher temperatures inside the concrete structure did not affect the operation of the wireless sensor network, and measurements were gathered with the expected sensor accuracy, which is protected from impacts produced during the pouring process. cf), the Young’s modulus (E) and splitting tensile strength (stf) of the employed concrete at early age and at 28 days. These results were obtained in laboratory by means of standard tests on cubic and cylindrical concrete specimens [The applicability of the developed monitoring system in civil engineering is evident. For example, by considering a thermo-mechanical model of the hydration kinetics of the cement (see for example ), the depecimens .3. The concrete parameters necessary to perform the thermal analysis were a density of 2240 kg/m3, a coefficient of thermal expansion of 10−5 K−1, a thermal conductivity of 2.5 W/mK, a specific heat of 922 J/kgK, a film coefficient between concrete-air of 9 W/m2∙K and a room temperature of 18 °C. The behavior of the material was considered linear and elastic with a Young modulus ranging with age according to the values indicated in In order to confirm the reliability of the results, a thermo-chemical-mechanical finite element model (FEM) of the concrete footing has been implemented in ABAQUS. Details about the hydration kinetics modeling of the concrete employed in this analysis are given in . The comAs observed from the results shown in A non-destructive wireless sensing system has been implemented, with a low cost and compact design suitable to be embedded into concrete for monitoring the curing process. This application demands small sized sensing nodes with low power requirements, complicating the design. Preliminary tests were accomplished in the laboratory to validate the accuracy and the protection of the developed sensors, and the data transmission to a data acquisition system located outside the concrete. Finally, the wireless system was used in a civil construction and the data from the sensors was successfully transmitted during the period required to monitor the concrete from the first pour.