IgG4-related disease (IgG4-RD) belongs to the group of rare diseases in which the identification of the characteristic histology and immunohistochemistry provides with the gold standard in the diagnosis. The variable organ dysfunction reflects the clinical presentation. The examples of different IgG4-RD presentations in the Rheumatology Unit were discussed in this article. The spectrum of IgG4-RD is wide-ranging and manifested in one or more organs synchronously or metachronously. In the presented article, we described five different cases of IgG4-RD. Four cases were reaffirmed in the histopathological assessment. The clinical and laboratory findings were analyzed and the assigned therapy was discussed. According to our experience, the diagnosis of IgG4-RD requires the careful clinicopathological correlation. The diagnosis relies on the coexistence of various clinical, laboratory, radiological, and histopathological findings, although none of them is pathognomonic itself. The time needed for the diagnosis and variety of clinical forms of IgG4-RD shows that there is need of the cooperation among many specialists for the better and earlier recognition of the disease. The IgG4-related disease (IgG4-RD) is a chronic, inflammatory, multi-organ, systemic disease . The namThis article gives examples of different IgG4-RD presentations in the Rheumatology Unit in Eastern Europe.The patients were diagnosed with IgG4-RD in the Rheumatology and the Internal Medicine Department between 2014 and 2016. The data were collected retrospectively. The inclusion criteria were: age >18 years and the histopathological picture of IgG4-RD. The data included the time from the first symptoms to the establishment of IgG4-RD diagnosis, the age and gender of patients, the localization of lesions, histopathological biopsies, IgG4, IgG, and IgM concentration in blood samples, the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values, C3 and C4 values treated with and the responsiveness to corticosteroids (CS), and the history of the atopic disease. Patients with the different IgG4-RD presentations were chosen to illustrate the complexity of IgG4-RD cases treated in the Rheumatology Unit. We performed the literature review following the methods specified by Gasparyan et al. . The seaFive cases of IgG4-RD were diagnosed. Four cases were reaffirmed in the histopathological assessment Fig. . The maiIgG4-RD belongs to the group of rare diseases. Three major histopathological features of IgG4-RD are: the lymphoplasmacytic infiltrates, storiform-type fibrosis of the irregularly whorled pattern resembling that of a straw mat, and the obliterative phlebitis. Sometimes the infiltration of eosinophils is observed in the affected tissues. Some lesions may be described as pseudotumors as in case number five with the first clinical presentation of ileus. Necrosis and granuloma are not found in IgG4-RD. When they are observed, the rheumatologists should think about the different diagnosis or alternative disease . The diaIn the non-biopsy-proven cases, e.g., the pancreas or brain localization, the measurement of the IgG4 concentration in blood samples is useful. Based on IgG4-RD definition, it should be elevated above 135 mg/dl  and it iIn one patient we observed eosinophilia, which occurs in one-third of the patients with IgG4-RD like the allergy history according to the recent publications . Yu ChenThe spectrum of IgG4-RD is wide-ranging, occurring in one or more organs synchronously or metachronously. Moreover, the patients with IgG4-RD usually do not have the constitutional symptoms, such as fever, malaise, night sweats, or the weight loss . MalignaBecause of the similarity to Sjögren syndrome , the diagnosis of the IgG4-RD was postponed for an average of 5 years (64 months). Generally, the clinical signs depended on the localization and organ damage caused by the main infiltration of IgG4 cells. They often formed pseudotumors as in patient number five. Nonetheless, the time for IgG4-RD diagnosis was 17 months late until the patient was admitted to the Rheumatology Unit. The shortest time for the diagnosis of IgG4-RD was in the patient with the unilateral parotid gland enlargement and the concomitant weight loss. The fast recognition of GPA caused the patient to be admitted to the Rheumatology Department. The first suspicion of lymphoma focused the diagnosis on tumor. In the presented paper, patients had been diagnosed by specialists in the general medicine, oncologists, surgeons, endocrinologists, specialists in the travel medicine, and hematologists before they were admitted to the Rheumatology Unit. In all the cases, the first diagnoses included the oncological diseases, e.g., the lacrimal lymphoma, salivary lymphoma, bowel tumor, lung cancer or hepatoma.In the presented case series, the Type 1 (IgG4-related) autoimmune pancreatitis was observed in one patient. It is one of the most common disease manifestations that often devolves into the endocrine and exocrine insufficiency and may complicate the CS treatment. In the described patient, we started the therapy with CS in the recommended doses, despite the diabetes mellitus, with the good clinical response and improvement in the blood glucose level. In the case number four, the pancreatic biopsy was not performed because of the technical problem. In the diagnostic parameters, the IgG4 serum concentration, abdomen ultrasound, and the computed tomography were used, and the good clinical improvement after starting the CS treatment was observed. The diagnosis was ultimately made based on the classification criteria proposed by the Japanese Pancreas Society Revision in 2006 and Mayo Clinic –29.The anti-nuclear antibodies were detected only in one case, but in a very low titer, without any specific antibodies, which is very typical for IgG4-RD compared to other autoimmune diseases. When the antibodies against the specific antigenes are present, the concomitant different disease is the most probable reason. The polyclonal hypergammaglobulinemia will not help in the diagnostic parameters; it is typical for Sjögren syndrome, but was often observed in IgG4-RD too .Lymphadenopathy was very common in IgG4-RD patients, as in the paper of Chen , and occIn our series, the inflammatory markers ESR and CRP were elevated in two cases. The results were comparable with the other authors , 13, 22,In the present study, all the patients were treated with the oral CS in the dose of prednisone of 0.6 mg/kg of the body weight/day. The response to this therapy was good, with the clinical and laboratory improvement. Nevertheless, in the previous publications, among the patients remaining on the long-term steroid therapy, the relapse was common after the cessation of CS . UnfortuThere are some limitations of this study. First of all, there were a small number of patients enrolled only in one Rheumatology Unit. The time for the diagnosis of IgG4-RD was relatively long. In the presented cases, it was the mean of 5 years, suggesting that multicenter prospective study is needed to evaluate the clinical and laboratory features of IgG4-RD more broadly. Moreover, the benefits of the diagnostic methods in the diagnosis of IgG4-RD in the Rheumatology Units should be evaluated in a larger amount of patients. In our experience, the diagnosis of IgG4-RD requires the careful clinicopathological correlation. The diagnosis relies on the coexistence of various clinical, laboratory, radiological, and histopathological findings, although none of them is pathognomonic itself. The time needed for the diagnosis and the variety of clinical forms of IgG4-RD confirmed that there is a need for the cooperation among many specialists for the better and earlier recognition of the disease.


Nonalcoholic fatty liver disease (NAFLD) is increasing worldwide as one of the leading causes of chronic liver disease. Sake lees (SL) are secondary products of sake manufacturing and are considered to have beneficial effects on human health. To investigate these effects, we used high fat diet (HFD)-fed mice treated with or without the SL extract.Mice were the HFD ad libitum for 8 weeks and were administered 500 μL of distilled water with or without the SL extract (350 mg/mL) by a feeding needle daily for the last 4 weeks. Food intake, body weight, and liver weight were measured. Triacylglycerol content and the mRNA and protein expression levels of various lipid and glucose metabolism-related genes were determined in liver tissues. The levels of triglyceride, free fatty acids, glucose, insulin, and liver cell damage markers were determined in serum. Fatty acid-induced lipid accumulation in HepG2 cells was assessed in the presence or absence of the SL extract.Mice fed a HFD and treated with the SL extract demonstrated a significant reduction in hepatic lipid accumulation and mRNA and protein levels of peroxidome proliferator-activated receptor γ (PPARγ), PPARα, CD36, and phosphoenolpyruvate carboxykinase 1 in the liver, while the SL extract did not affect body weight and food intake. Moreover, insulin resistance and hepatic inflammation in HFD-fed mice improved after administration of the SL extract. In HepG2 cells, the SL extract suppressed fatty acid-induced intracellular lipid accumulation.These findings suggest that treatment with the SL extract could potentially reduce the risk of NAFLD development, and that the SL extract may be clinically useful for the treatment of NAFLD. Nonalcoholic fatty liver disease (NAFLD) is emerging as a major public health problem because of its association with increased cardiovascular and liver-related morbidity and mortality –4. Both Functional foods that patients can easily eat on a daily basis may be useful in the treatment of NAFLD. Sake lees (SL) are secondary products of the sake manufacturing process. Sake is a traditional Japanese rice wine, and is used in condiments for making traditional Japanese foods such as soup. SL are thought to have beneficial effects on human health as it contains large proportions of protein, carbohydrates, and vitamins –12, and In this study, we first investigated the effects of the SL extract on lipid and glucose metabolism, and discovered that the SL extract improves hepatic lipid accumulation and insulin resistance in the HFD-fed mice. We then demonstrated that daily intake of the SL extract could be a potentially effective and safe approach to attenuating hepatic lipid accumulation.Sake lees (SL) were produced using a liquefied product of rice slurry as the raw material . The SL were digested by protease Thermoase  at 60 °C for 18 h, filtrated and then lyophilized  were excised, washed in ice-cold 0.9% saline, wiped on filter paper, and then weighed. The obtained serum, liver, and epididymal WAT were stored at −80 °C until use.Six-week-old male C57BL/6 J mice were purchased from Japan SLC Inc. . The mice were housed at 25 °C with a 12 h light, 12 h dark cycle. All experiments were performed in accordance with the Guidelines for Animal Care at Kyoto University. The mice were fed a normal diet (ND) containing 5% fat by weight  and tap water for 1 week. Then, the mice were divided into five groups as follows: Mice in the first group were fed the ND ad libitum for 4 weeks (4 weeks’ ND group). Mice in the second group were fed ad libitum a high fat diet (HFD) 32% fat by weight  for 4 weeks (4 weeks’ HFD group). Mice in the third group were fed the ND ad libitum for 8 weeks and administered 500 μL of distilled water without the SL extract using a feeding needle daily for the last 4 weeks (ND group). Mice in the fourth and the fifth group were the HFD ad libitum for 8 weeks and were administered 500 μL of distilled water with or without the SL extract (350 mg/mL) by a feeding needle daily for the last 4 weeks . The amount of total food intake was measured at 8-week HFD feeding and body weight were measured at each week of HFD feeding. To obtain samples, the animals were anesthetized and humanely sacrificed at the end of the experimental period after fasting for approximately 18 h. Blood was collected from the abdominal vena cava and centrifuged at 3000 × The oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) at 8 week were performed by the methods described previously  with sliThe livers were dissected and cryopreserved in OTC compound  at −80 °C. They were sectioned (4 μm thick) with a Cryostat Leica CM1900  and stained with Oil Red O. Sections were viewed with a light microscope CX41 .g for 10 min at 4 °C. The organic phase was collected, vortexed with 0.6 mL of chloroform/methanol/distilled water (2:1:3) for 30 min, incubated for 30 min, and then centrifuged at 7700×g for 10 min at 4 °C. The organic phase was collected, dried and resuspended in 1 mL of 2-propanol/Triton X-100 (19:1). Triacylglycerol (TG) and total cholesterol (T-CHO) levels were determined using the clinical biochemistry automatic analyzer BioMajesty JCA-BM 2250 .For hepatic lipid measurements, the homogenate of mouse liver (40–60 mg) was extracted with 1 mL of chloroform/methanol (2:1), vortexed for 15 min and then incubated overnight. The supernatant was vortexed with 0.5 mL of distilled water, incubated for 30 min, and then centrifuged at 7700×Serum T-CHO, glucose, aspartate transaminase (AST), and alanine transaminase (ALT) levels were determined using the automatic analyzer. Serum glycoalbumin, free fatty acid (FFA), and ketone bodies levels were determined using the Hitachi 7180 biochemistry automatic analyzer . Serum insulin levels were determined using an Insulin ELISA Kit . The homeostasis model assessment of insulin resistance (HOMA-IR) index was calculated using the following equation to assess insulin resistance :HOMA ‐ IR = fasting serum glucose (pmol/L) × fasting serum insulin (mmol/L)/22.5.2. As described previously [6/well), and were incubated with the medium for 24 h. The cells were then washed twice with phosphate-buffered saline, and the medium was changed to FBS-free DMEM containing 0.5% bovine serum albumin and antibiotics. After incubation for 1 h, the cells were treated with or without the SL extract (0.1 mg/mL or 1.0 mg/mL) and/or fatty acid mixture (100 μM linoleic acid and 100 μM oleic acid)  for 18 h. After treatment, the cells were fixed with 10% formalin, stained with 60% Oil Red O, and the red-stained lipid droplets were observed under a light microscope. To quantify lipid accumulation, Oil Red O from the stained cells was eluted by adding 100% isopropanol and the optical density was detected using a spectrophotometer at 490 nm as previously described [Human hepatoma cell line (HepG2) was obtained from the American Type Culture Collection , and maintained in DMEM medium supplemented with 10% fetal bovine serum (FBS) and 100 U/mL of penicillin-streptomycin at 5% COeviously , HepG2 cThe total RNA was extracted from mouse livers with ISOGEN  and the RNA concentration was determined spectrophotometrically at 260 nm. Reverse transcription-PCR (RT-PCR) was performed using a Revetra Ace Kit . Primers used in this study were shown as Table For the preparation of liver cytosol, frozen liver tissues were homogenized in the RIPA buffer  at 4 °C. The total protein concentrations of the liver tissue extract were determined by using DC protein assay . The proteins were separated by SDS-PAGE and were electrophoretically transferred onto PVDF membrane . The membranes were first incubated with the primary antibodies against peroxisome proliferator-activated receptor γ (PPARγ) , PPARα , CD36 , phosphoenolpyruvate carboxykinase 1 (PCK1) , and β-actin . The membrane was then incubated with the horseradish peroxidase (HRP) -coupled secondary antibodies . Detection was performed with Immuno Star LD . The protein bands were quantified by densitometry using the NIH ImageJ 1.34 s software and normalized to β-actin.All data are expressed as the mean ± SEM. Statistical differences between more than three groups were determined using one-way ANOVA followed by Dunnett’s test. Statistical analyses and graphs were performed using Graph Pad Prism version 5.0 .To elucidate the effects of the SL extract on HFD-induced lipid accumulation, we compared the lipid accumulation in the HFD group and the SL extract group. We assessed the changes in body weight for each group. Although there was no difference in body weight between the HFD group and the SL extract group Fig. , nor fooTo examine whether the effects of the SL extract were the results of a direct or an indirect pathway, we treated HepG2 human hepatoma cells with fatty acids in the presence of or absence of the SL extract to evaluate intracellular lipid accumulation in vitro Fig.  and b. TThe levels of fasting serum glucose, insulin, HOMA-IR, and glycoalbumin were significantly higher in the HFD group than in the ND group Table . These lSerum ALT and AST activities were significantly higher in the HFD group than in the ND group but the enzyme activities in the SL group were significantly lower in than those in the HFD group Table . Serum kTo elucidate the underlying mechanisms of the effects of the SL extract, we measured the mRNA expression of various genes associated with lipid and glucose metabolism Fig. . The levThe protein levels of PPARγ, PPARα CD36, and PCK1 were significantly higher in the liver from the HFD group than in the liver from the ND group and these protein expression levels were significantly lower in the SL extract group than in the HFD group Fig. .In this study, we demonstrated that treatment with the SL extract ameliorates hepatic lipid accumulation and insulin resistance in HFD-fed mice via suppressing fatty acid-induced intracellular lipid accumulation by regulating lipid and glucose metabolism-related molecules.Treatment with the SL extract significantly ameliorated hepatic TG accumulation in the HFD group. The liver weight and lipid content of the SL extract group were significantly lower than those in the HFD group. However, there was no difference in body weight between the HFD group and the SL extract group, nor food intake. We speculate that there may be significant difference in body weight and adipose tissues between the HFD group and the SL extract group, if the SL extract administration period is more than 4 weeks. Indeed, treatment with other extracts for more than 4 weeks has the effect on body weight reduction , 20. TreTreatment with the SL extract improved serum glucose, insulin, and hepatic insulin resistance in HFD-fed mice. Furthermore, our study found that SL extract administration had a suppressive effect on hepatic lipid accumulation by a direct pathway. In patients with NAFLD, insulin cannot suppress gluconeogenesis and does not convert glucose to glycogen after meals, a condition known as hepatic insulin resistance. Previous studies found that the excessive hepatic accumulation of TG and FFA induced hepatic insulin resistance , 26. TheThe elevation of PPARγ mRNA and protein in the SL extract group were significantly suppressed, compared with the HFD group. It has been known that the main role of PPARγ in the liver is related to regulation of glucose and lipid metabolism , 29. PPAMoreover, PCK1 is a main control point for the regulation of gluconeogenesis and is necessary for the integration of hepatic energy metabolism . TreatmeOur study demonstrates that treatment with the SL extract suppresses the increased mRNA expression of PPARγ, PPARα, CD36, and PCK1 in HFD-fed mice. Thus, these results suggested that the SL extract affects the lipid and glucose metabolism. However, there is a possibility that the SL extract administration improves hepatic lipid accumulation in HFD-fed mice by affecting the other pathway. Hepatic energy metabolism is largely controlled at the genomic level by numerous transcription factors and co-regulators .The findings of the present study suggested that SL extract intake suppresses hepatic lipid accumulation and insulin resistance, and could potentially reduce the risk of developing NAFLD. We believe that the SL extract will be clinically useful for the treatment of NAFLD.


Wind turbine foundations are typically cast in place, leaving the concrete to mature under environmental conditions that vary in time and space. As a result, there is uncertainty around the concrete’s initial performance, and this can encourage both costly over-design and inaccurate prognoses of structural health. Here, we demonstrate the field application of a dense, wireless thermocouple network to monitor the strength development of an onshore, reinforced-concrete wind turbine foundation. Up-to-date methods in fly ash concrete strength and maturity modelling are used to estimate the distribution and evolution of foundation strength over 29 days of curing. Strength estimates are verified by core samples, extracted from the foundation base. In addition, an artificial neural network, trained using temperature data, is exploited to demonstrate that distributed concrete strengths can be estimated for foundations using only sparse thermocouple data. Our techniques provide a practical alternative to computational models, and could assist site operators in making more informed decisions about foundation design, construction, operation and maintenance. Wind turbines currently supply 10% of Europe’s electricity ,3, so toFor reinforced-concrete structures, one of the most important initial conditions and quality measures is compressive strength. A concrete’s strength is not just a direct measure of its ability to support load, but also an indirect measure of its elasticity and durability ,17. As sIn the work outlined here, we address these shortcomings by augmenting operator foundation thermocouple measurements with a dense, high-resolution network of 11 additional wireless thermocouples. Temperature data are used with both historical and recently developed methods in fly ash concrete strength and maturity modelling to provide, for the first time, an estimate of the temporal and spatial dependence of the strength distribution within a wind turbine foundation. In a step that we believe is unique to this study, we also verify our strength estimates with core samples. Finally, we extend the study by using the data obtained to train an artificial neural network, which after training, can predict in-situ concrete strengths independently of the supplementary data from the wireless thermocouples . These results could provide models and other SHM techniques with more accurate estimates of the initial states and mechanical properties of concrete foundations . The stuThe methods which we outline here are not the only non-destructive testing techniques for monitoring in-situ concrete strength. Other examples include monitoring the transmission or reflection of ultrasonic waves , the harThis paper begins with a description of the theory behind the maturity and strength modelling of fly ash concrete in The gravity-based wind turbine foundation studied in this work was of a circular, reinforced concrete design, as illustrated in Shortly after freshly-mixed, wet concrete is placed, the alite and belite present within the ordinary Portland cement (OPC) undergo exothermic hydration reactions with water. This produces calcium silicate hydrate (CSH), a gel which binds the suspended aggregates and is responsible for the majority of concrete’s strength. In this work, 30% of the OPC within the concrete was replaced with pulverised fuel ash (PFA), also known as ‘fly ash’. As fly ash is a pozzolan, it produces CSH by undergoing a delayed and endothermic reaction with calcium hydroxide . As a rIt is clear that temperature plays a key role in concrete strength, as heat is both a product and accelerator of the reactions responsible for producing CSH. Indeed, so-called ‘maturity methods’ assume that the level of curing (and so the strength) of a concrete specimen can be derived solely from its age and temperature history. This allows the strength development of real concrete structures to be estimated from a combination of laboratory cube strength tests and temperature measurements in the field.Broadly speaking, there are three steps in applying maturity methods for any given concrete mix and structure. Firstly, the relationship between concrete cube strength and age is established for controlled curing temperatures αar=eHere, kinetics . The metkinetics  and requeratures , or it ceratures . In thisS, and curing time, t, can allow field-measurements of equivalent age to be converted into estimates of compressive strength. The most well-known method for fitting the relationship between data on S and t is the hyperbolic method, featured in ASTM C1074 and put forward by Carino in 1984 [A calibration curve between concrete cube strength,  in 1984 :(4)S(t)=Here, the fitting parameters are Equation , or as iCarino’s equation accurately models the strength dependence of traditional OPC based concretes before 28 days. It is, however, less accurate for late stage strengths, particularly for concretes which contain fly ash, as these introduce added and delayed strength gains from pozzolanic activity . As suchA and Here, Equation  is more Equation  to calcuIn this section, we outline the methods behind the field installation of the wireless thermocouples, the concrete coring and cube tests, and the analysis techniques used to obtain distributed and time-dependent estimates of concrete foundation strength.After the steel reinforcement cage of the foundation was constructed, 11 wireless thermocouple probes with radio frequency identification (RFID) tags were installed in the locations highlighted in All thermocouples were installed along the same sector of the foundation, in the prevailing wind direction. The location of the wireless thermocouples was chosen to complement the readings from the operator’s probes and provide a more complete picture of the thermal gradients within the foundation. Between them, the thermocouples capture temperatures from the hottest points within the structure (at the centre of the pour around the plinth), to those closest to ambient temperatures (at the corner of the foot of the base). After the concrete was cast, all thermocouples logged hourly temperature measurements. These were stored on onboard memory and then downloaded after 14 days. Operator thermocouple measurements ceased after this period, but wireless thermocouples monitored for a further 14 days . The temperature resolutions of the wireless and operator probes were 0.1 Concrete was poured around the reinforcement cage in a single day, from the outer edge of the foot of the base . After 24–72 h of dry curing at a mean temperature of 20 At the same time as foundation casting, approximately 100 cubes of side of 150 mmThe flowchart shown in For both the C35/45 and C45/55 concretes, the relationship between the equivalent age of the concrete cubes  to constrain the interpolation of the results measured by the wireless thermocouples in the field. After foundation temperatures had been established, Nurse-Saul and Arrhenius age-conversion factors were calculated using Equations  and 3),,3), respwithout the supplementary information from wireless thermocouples. This could in principle allow the operator to estimate distributed foundation strengths over other foundations without altering their standard operating procedures.As an extension to the study, we investigated whether operator thermocouple data could alone be used to estimate distributed foundation temperatures, i.e., To achieve this, we used an artificial neural network (ANN)—an effective tool for minimising errors in complicated non-linear fits. The ANN used Levenberg-Marquardt training and one hidden layer made up of 10 neurons, as illustrated in After 170 data points of training data, the weightings are fixed at their optimum values and the final performance of the network is validated using the remaining 170 samples  from the ANN’s predicted values. This can be compared with the distribution that would have been obtained using actual data , as theAn operator may be more interested in knowing when the foundation reaches its 28-day strength or its design strength. These quantities are plotted in The compressive strengths of the three core samples taken from the mid-point of the foundation after 17 days were In future work, better confirmation of core strengths and full quantification of the error could be achieved if: (i) cores were taken earlier; (ii) the cube strength study was extended over a longer period; or (iii) thermocouple measurements of O1 are taken for a longer period (rather than extrapolated as they were in As outlined in The method has clearly been successful for this foundation: contour plots of temperatures, equivalent ages and strengths using ANN predictions are indiscernible from This paper outlines the field application of up-to-date concrete maturity methods to a fly ash concrete wind turbine foundation. The methods described were able to estimate time-dependent and distributed concrete strengths throughout the foundation, based on in-situ wireless thermocouple measurements and cube compression tests. These strength estimates were partly verified by core samples, taken from the foundation after 17 days. In addition, the collected data were used to train an artificial neural network, which was able to provide accurate predictions of distributed foundation strengths based on sparse temperature readings from five low-resolution thermocouples. The acquisition of further datasets may allow for better training of this neural network so that it is able to predict temperatures, and strengths, for a wider variety of turbine bases. Overall, the proposed techniques could assist site operators in making more cost-effective decisions about foundation design, construction, operation, monitoring and maintenance.


Advance care planning (ACP) aids can help prepare patients, family members, and physicians for in-the-moment medical decision-making. We wished to describe the content and approach of paper-based ACP aids in order to characterize existing aids and inform the development of a new ACP aid.Paper-based ACP aids were identified through an environmental scan and screened for eligibility. ACP conceptual frameworks and data were gathered via stakeholder engagement and used to inform the coding framework that two investigators used to independently code each aid. A directed content analysis was conducted on these eligible aids. Aids were categorized through a deliberative process with an investigator abstracting general information for each aid.Fifteen aids met the eligibility criteria. They ranged in length from 6 to 78 pages with the average aid written at an eighth-grade reading level. The content analysis revealed that many aids encouraged choosing a surrogate decision maker and informed users about legal medical documents. Fewer than half of the aids facilitated patient clarification of values regarding quality of life issues. The authors identified and termed the following three categories of aids: informative; semi-action oriented; and action-oriented. It was often unclear whether patients contributed to the development or testing of the ACP aids reviewed.Most existing paper-based ACP aids address legal matters such as completing an advance directive. Only a minority elicited patient values and it was unclear whether any were developed in partnership with patients. Future development of ACP aids should account for patient preferences with a goal of supporting in-the-moment medical decision-making. Advance care planning (ACP) offers individuals the opportunity to clarify their health care goals, concerns, and wishes in preparation for situations where they may be unable to make their own decisions . While An = 15), and have been since explored in more detail [n = 10). Although the preferred aid format might vary based upon characteristics of the patient, provider, and clinical setting [ACP decision aids are designed to facilitate deliberation of preference-based medical decisions, and may benefit patients and alternative decision makers as they prepare to make in-the-moment medical decisions , 8. A ree detail , or were setting , 13, pap setting .While it would be practical for most individuals to initiate ACP prior to becoming ill, evidence indicates that 70% of the general US population do not have advance care plans  in spiteThe purpose of this study was to describe and analyze the content and style of paper-based ACP aids. The study further sought to categorize the aids so as to provide patients and providers with more information that might help to inform their choice of an ACP aid. This work is also anticipated to provide insight into the ways that ACP aids could possibly be designed to further meet the needs of patients, their families, and clinicians as they prepare for possible in-the-moment medical decision-making. Finally, this work could help inform the development of a new ACP tool.Contributing to the environmental scan  to identn = 14) included two patient family advocates, three surgeons, one internist, two health services researchers, four palliative care clinicians and/or researchers, one patient-centered outcomes researcher, and one patient safety and quality researcher. A diverse group of stakeholders were deliberately engaged so as to include a wide-range of perspectives in the discussion surrounding decision aids. Invited participants from each of these stakeholder groups were selected based upon their interest in and experiences with advance care planning, as well as based upon previous work with the research team. Using design-thinking techniques [A stakeholder summit was convened to engage stakeholders and identify relevant elements of paper-based ACP aids. Stakeholders  checklist  to abstrConsistent with a directed content analysis approach  and methContent was coded as pertaining to the clarification of patient priorities and values in general, and specifically in relation to states “worse than death” and patients’ preference for how much leeway a surrogate decision-maker should possess when making decisions on behalf of the patient . Codes wAdditionally, researchers coded information that related to patient discussions about ACP and support for expressing their wishes, including examples of potential ways to start ACP conversations. Finally, the framework also addressed content about legal medical documents and ACP resources, and decisions about after-death issues  –4, 6.The content was described and analyzed qualitatively , 27. CodIn brief, the stakeholders did not recommend the use of content or images that framed ACP from an end-of-life perspective; they felt that end-of-life framing for ACP was “off putting” and could deter patients from engaging with ACP early in their disease course. Stakeholders identified support for patients in choosing a surrogate, opportunities to identify personal priorities, and assistance in enabling patients to imagine states “worse than death.”Of 41 paper-based ACP aids identified, 15 met the inclusion criteria  of the aids scored a one out of four where all of these tools identified the developers’ credentials and/or qualifications. One aid  met two of the four criteria by additionally seeking input from healthcare providers during the development process. It was unclear whether any of the tools had been developed, field-tested, or informed by patient feedback.While not all aids included content from each of the six APC content categories, every aid contained content across more than one category. The following sections describe each of these content categories in more detail.Over half of the aids  explicitly defined ACP. Among these aids, some or all of the following topics were defined as a component of ACP  enabled readers to clarify their role in making health care decisions and contemplation of feelings about potential choices such as “I want to know the basics” or “I want to know as much as I can.” Seven tools  asked patients to imagine different medical or health situations that they could find themselves in and asked patients to specify their advance treatment preferences.The paper-based ACP aids offered patients a variety of opportunities to contemplate and express their values about different aspects of ACP. Nearly half the tools  contained exercises that enabled clarification of priorities and values regarding quality of life with statements such as “In support of communicating patients’ medical wishes, ten aids contained information about ways for patients to start a conversation relating to ACP . The content ranged from example phrases, vignettes, and settings to potential formats  for initiating the ACP conversation (if not in person) and tips for dealing with resistance to that conversation. Beyond offering information about how to start a conversation about ACP, a majority of aids (11/15) also provided information about conversation talking points  did not advocate for or provide assistance with choosing a surrogate. Among the ten that did discuss choosing a surrogate, the type of support ranged from: (i) describing the importance of having a surrogate ; (ii) telling personal stories about choosing a surrogate ; (iii) providing the opportunity to consider different reasons why a person would make a suitable surrogate and comparing individuals across those dimensions . Six of the ten aids also offered patients the opportunity to express how much leeway they were comfortable in granting to surrogates when they were making decisions on the patient’s behalf . Statements within the aids such as “Across all of the paper-based ACP aids, nearly half of the aids  contained content aimed at surrogate decision makers about their roles and responsibility. Additionally, three of the aids provided guidance on making decisions for someone else . Interestingly, some of the aids that did not provide support for designating an alternative decision maker did include information specifically for the surrogate decision maker .Two aids presented information about the odds of survival and presented information about survival statistics for particular treatments . Furthermore, five aids provided users with a description or depiction of different illness trajectories .Almost all of the aids examined in the content analysis  provided information relating to legal and non-legal medical documents. The information included topics such as: (i) explanations of legal medical documents such as advance directives and durable power of attorney of health care; (ii) instructions on how to complete these forms; (iii) treatment definitions that could be of use when completing legal medical documents; (iv) additional resources for where patients could obtain more information; and (v) reminders about when to review and revise medical documents. A minority of aids  also provided opportunities for users to complete wallet cards that specify emergency contact information. The purpose of these wallet cards were such that emergency or medical personal might reference these cards to find the contact information of a surrogate decision maker in the event that the cardholder was unable to speak for her- or himself.The successful implementation of ACP aids could potentially improve the provision of medical care, especially for patients who are more likely to lose medical decision-making capacity.Indeed, the 2015 landmark Institute of Medicine (IOM) report “Dying in America” specifically advocates for more ACP among all patients and their family members . Our stuWhile the reviewed aids were both detailed and informative, the reading level of aids may limit their efficacy. As approximately half of all adults in the U.S. read at or below an eighth grade reading level , the IOMThe content analysis revealed that many stakeholder-identified key components of ACP aids were missing from these paper-based aids. For instance, stakeholders disliked framing ACP from an end-of-life perspective because they felt that this focus could deter patients from engaging with ACP early in their disease course. Yet, most of the examined aids adopted an end-of-life perspective by focusing on legal medical forms and providing information about advance treatment preferences specifically for end-of-life scenarios. Moreover, as some evidence suggests that legal medical documents about advance treatment preferences are limited in terms of their ability to actually inform medical care for patients who cannot speak for themselves , 34–37, ACP conceptual frameworks –4, 6 andInterpretation of these results should take into consideration the study’s limitations. Researchers might have neglected to include useful measures in the development of the coding framework. It was, however, based on components that have been identified previously as meaningful to advance care planning  and to tPatient involvement in the development of these ACP tools was unclear. It is important to gather further stakeholder perspectives and to specifically engage patients and other key stakeholders in the development process of any ACP aid, especially considering that ACP aids should facilitate patient, healthcare professional, and community involvement in decision-making . SubsequThis study identified a need for paper-based aids that support and empower patients to initiate meaningful ACP. All examined aids presented ACP solely within an end-of-life framing. The findings suggest that to meet patients’ needs and create patient-centered ACP aids, active patient involvement is a necessary, and often missing, component and ACP aids need to explore framing beyond specific end-of-life care situations. By identifying and classifying different categories of paper-based ACP aids, the study provides a useful framework that clinicians might use to help inform the selection of an ACP aid that is most appropriate to their patients and to alternative decision makers. Additionally, these findings have helped guide the development of a new ACP aid –41, and


Defined daily doses (DDD) are the gold standard indicator for quantifying prescriptions. Since 2014, the European Centre for Disease Prevention and Control (ECDC) has also been using the number of packages per 1,000 inhabitants per day (ipd), as a surrogate for prescriptions, to report antibiotic consumption in the community and to perform comparisons between European Union (EU) countries participating in the European Surveillance of Antimicrobial Consumption Network (ESAC-Net). In 2015, consumption was reported to range across Europe from 1.0 to 4.7 packages per 1,000 ipd. Our analysis showed that consumption of antibiotics for systemic use per 1,000 ipd was on average 1.3 times greater in France than in Belgium when considering prescriptions in the numerator, 2.5 times greater when considering packages and 1.2 times greater when considering DDD. As long as the same metrics are used over time, antibiotic consumption data aggregated and disseminated by ECDC are useful for assessing temporal trends at the European level and within individual countries; these data may also be used for benchmarking across EU countries. While DDD - although imperfect - are the most widely accepted metric for this purpose, antibiotic packages do not appear suitable for comparisons between countries and may be misleading. In order to compute the overall exposure of the population to antimicrobial drugs and compare drug consumption within Europe, countries participating in the European Surveillance of Antimicrobial Consumption Network (ESAC-Net) report each year to the European Centre for Disease Prevention and Control (ECDC) the number of defined daily doses (DDD). The DDD is a widely used metric defined by the World Health Organization (WHO) , used fo“the best available surrogate for prescriptions” when the latter are unavailable [probably reflect differences in the number of items or dose per item of antibiotics in antibiotic packages” [Since 2014, summaries disseminated by the ECDC have also reported the number of orally administered packages (OAP) per 1,000 ipd in the community for the substances classified as antibacterial drugs for systemic use (J01). This additional indicator is described as vailable . Antibiovailable ,7. Howevackages” ,4.To investigate the validity of OAP, we first compared the two indicators in France during the period from 2006 to 2015. Secondly, since prescription data were publicly available only from Belgium among the countries participating into ESAC-Net , reasonsWe used anonymous individual data from the main general scheme of the French NHI agency which insures salaried workers and covered a constant proportion of around 86% of the French population during the study period. These data comprised all prescriptions and antibiotics prescribed to outpatients, dispensed by outpatient pharmacies, and reimbursed by the NHI from 2006 to 2015  approval DE-2015–190). To take into account French population growth during the study period, we obtained demographic data from the French National Institute for Statistics and Economic Studies . All datThe study targeted oral antibiotics for systemic use (ATC code J01) in the community only. As in ESAC-Net summaries, antibiotics were divided in six main categories according to the ATC level 3 classification: penicillins (J01C), cephalosporins and other beta-lactams (J01D), macrolides, lincosamides and streptogramins (J01F), tetracyclines (J01A), quinolones (J01M) and sulfonamides and trimethoprim (J01E). The other classes accounted for a very small part of overall antibiotic consumption in the community and were thus omitted from the analysis.Over the 10-year study period, an average of 2.71 (range: 2.55–2.87) prescriptions, 5.10 (range: 4.91–5.33) OAP and 28.94 (range: 26.33–30.22) DDD per 1,000 ipd were recorded for oral antibiotics for systemic use, indicating that ca 1.9 OAP were delivered for each prescription. The number of prescriptions, OAP and DDD per 1,000 ipd varied by ATC class . The temWe compared French data to those recorded in Belgium, the only other EU country from which corresponding data were publicly available for the period from 2006 to 2009. These data were retrieved from the supplementary material of the paper by Coenen et al. . Three 1Over the 3-year study period, the numbers of packages and prescriptions in Belgium were comparable for all ATC classes considered . In contCompared with Belgium, consumption of antibiotics for systemic use (J01) per 1,000 ipd was on average greater in France for the three indicators: 1.3 times greater when considering prescriptions in the numerator, 2.5 times greater when considering packages and 1.2 times greater when considering DDD.Variations were also observed according to ATC class. For penicillins, the number of prescriptions and DDD  were similar in France and Belgium, while the number of packages was twice greater in France than in Belgium. Accordingly, the quantity of active substance per package was about half in the French packages compared with Belgium. Our analysis comparing trends in the consumption of antibiotic packages and of DDD in France shows that using antibiotic packages as a metric could be misleading. In addition, comparing antibiotic consumption across EU countries using aggregated packages may also lead to erroneous conclusions in terms of antibiotic exposure of the population, unless package contents are similar.As long as the same metrics are used over time, antibiotic consumption data aggregated and disseminated by ECDC are useful for assessing temporal trends at the European level and within individual countries; these data may also be used for benchmarking across EU countries. While DDD - although imperfect - are the most widely accepted metric for this purpose, antibiotic packages do not appear suitable for comparisons between countries and may be misleading ,15. IndeA dialogue should be initiated at the European level with manufacturers and regulatory authorities regarding the size and harmonisation of antibiotic packages. It is conventionally recognised that the drug dosage per package should correspond to the most common indication for adults. In that case, the average number of packages delivered per prescription should be close to 1, as is the case in Belgium, where packages appear to be a good surrogate for prescriptions ,16,17. TMonitoring antibiotic use is a global priority to inform public health policies. Recently, the Drive-AB group proposed a set of indicators, especially for the outpatient setting , includiCurrently, the use of packages in order to measure the antibiotic consumption appears unsuitable. It could mislead the public to believe that all packages are equal, irrespective of content . Unless harmonisation of packages is achieved across EU countries, using the number of packages as a measure of antibiotic exposure should therefore be limited to providing additional perspectives in order to explain specific evolutions.In conclusion, we advocate not using OAP as a surrogate for prescriptions for benchmarking antibiotic consumption across Europe until package content or prescribed daily doses have been harmonised.


P=0.0027) between study medication and heroin-dose group . Cortisol administration reduced craving in patients receiving a low dose of heroin , but not in patients receiving a medium or high dose of heroin. In a picture-rating task with drug-related pictures, cortisol administration did not affect the ratings for the picture-characteristic craving in all the three heroin-dose groups. Cortisol also did not significantly affect secondary outcome measures. In conclusion, a single administration of cortisol leads to reduced craving in low-dose heroin addicts. The present findings might have important clinical implications with regard to understanding stress effects and regarding treatment of addiction.Heroin dependence is a severe and chronically relapsing substance use disorder with limited treatment options. Stress is known to increase craving and drug-taking behavior, but it is not known whether the stress hormone cortisol mediates these stress effects or whether cortisol may rather reduce craving, for example, by interfering with addiction memory. The aim of the present study was to determine the effects of cortisol administration on craving in heroin-dependent patients and to determine whether the effects depend on the daily dose of heroin consumption. We used a double-blind, placebo-controlled, cross-over study in 29 heroin-dependent patients in a stable heroin-assisted treatment setting. A single oral dose of 20 mg of cortisol or placebo was administered 105 min before the daily heroin administration. The primary outcome measure was cortisol-induced change in craving. Secondary measures included anxiety, anger and withdrawal symptoms. For the visual analog scale for craving, we found a significant interaction ( In case they are, the administration of glucocorticoids in heroin addicts could result in increased craving. On the other hand, exogenous glucocorticoid administration has been shown to induce temporary reduction in the retrieval of different forms of memory, including aversive memory in anxiety disorders,21 and could therefore also reduce addiction-related memory. The neurobiology of drug addiction shares striking commonalities with the neurobiology of learning and memory, including shared neural circuitries and molecular mechanisms.23 In line with these neurobiological models of addiction memory, studies in addicted patients have indicated that the evocation of conditioned responses by drug-associated stimuli is important in the maintenance of drug use and relapse.25 Thus, memory has an important role in addiction as it stores the powerful incentives associated with drug taking that produce a strong feeling of craving.26 Therefore, the administration of cortisol could result in reduced retrieval of addiction memory and, thereby, reduce feelings of craving.Stress  has been found to increase craving and the risk of relapse to opioid use.27To date, it is unknown whether exogenous glucocorticoids would increase or rather decrease craving in heroin-dependent patients. Because of the considerable clinical implications with regard to understanding stress effects and regarding treatment of addiction, the present study examined the effects of a single administration of cortisol on craving in heroin-dependent patients. We also examined whether cortisol effects depend on the daily dose of heroin consumption as glucocorticoids have been shown to interact with the opioid system.28 Additional services include medical care for somatic and psychiatric conditions, weekly individual and group support sessions and help from social workers.All the participants were recruited from a standardized heroin-assisted treatment protocol conducted at the treatment center JANUS, Psychiatric University Clinics Basel, Basel, Switzerland. The heroin-assisted treatment consists of the prescription of pharmaceutical heroin (diacetylmorphine) twice a day combined with additional medical and psychosocial services.Thirty-one participants with opioid dependence according to ICD-10 gave written informed consent to take part in the study. Sample size was estimated on the basis of the assumption of a medium effect size at an alpha level of 0.05 and a power of 0.8. Two participants had to be excluded after study enrollment, one participant because of an additional psychiatric axis I disorder identified during the medical examination for study participation and the other participant because of illicit co-consumption of a not-prescribed tranquilizer (flunitrazepam) during the first study day. The remaining 29 participants  completed the study and were entered in the analyses see . Mean agInclusion criteria consisted of an age older than 18 years, meeting criteria for opioid dependence according to ICD-10 and having a past history of intravenous heroin consumption with an unchanged heroin intravenous substitution for at least 3 months. In addition, participants had to be able to control parallel consumption of street drugs and were told to abstain from illicit drug consumption for the duration of study participation. Blood alcohol level had to be below 30 ml on both the study days. A urine drug test  and a breathalyzer test  were performed at the beginning of both the study days. Drug screen results were considered as additional covariates in the statistical model (see Results).http://clinicaltrials.gov/ct2/show/NCT01718964?term=de+quervain&rank=5). The blinding was maintained throughout the study. All the participants received vouchers for local supermarkets  as compensation for their participation.Exclusion criteria were a recent history of systemic or topical glucocorticoid therapy or hypersensitivity to glucocorticoids, an axis I disorder besides opioid dependence, current medical condition (such as infectious disease), inability to read and understand the study consent form, pregnancy or lactating. The local ethic committee and the Swiss agency for the authorization and supervision of therapeutic products  approved the study. The study was registered with ClinicalTrials.gov (The study took place on two study days (120–135 min duration each) between 1230 and 1630 h at the JANUS center of the Psychiatric University Clinics Basel, Basel, Switzerland in November 2012–July 2013. Both study days were at least 1 week, but no longer than 3 weeks, apart. Besides the initial screening at the beginning of the first study day, both study days had the same procedure see . First, 29 After a washout period of 7–21 days, participants received on the second study day the treatment (cortisol or placebo) that they had not received on the first study day. University Hospital Pharmacy Basel prepared and blinded study medication .The participants were allocated randomly by time of study entry to receive either oral cortisol  or placebo (two similar looking tablets) at the first study day. This dose of cortisol has been used in previous studies investigating the effects of a single administration of cortisol on phobic fear.29Saliva was collected with Salivette . Saliva samples were taken 15 min before (−15) and 60 min after (+60) administration of study medication, directly after stimuli presentation (+90) and after heroin intravenous (+120). Salivary cortisol was analyzed as described before.30 Participants had to indicate the intensity of their craving on a continuous horizontal line (10 cm) with the two end points—not at all (0) and very strong (10). Craving was also measured with the ‘Desire to use heroin' scale of the Heroin Craving Questionnaire (HCQ). The scale originally consists of nine items scored between 1 and 7 .5 To avoid confusion, we excluded questions that contained double negations, resulting in only five items  with a total score between 5 and 35. State anxiety: state anxiety was measured with the German version of the State–Trait Anxiety Inventory. The state scale of STAI consists of 20 items scored between 1 and 4 . State anger: state anger was measured with the Anger Expression Inventory (STAXI). The state scale of STAXI consists of 10 items scored between 1 and 4 . Withdrawal symptoms: withdrawal symptoms were measured by nine selected items of the Short Opiate Withdrawal Scale (SOWS) scored between 0 and 3 .The test battery was administered at four time points on both the study days and included a primary outcome measure  and secondary outcome measures . Craving: craving was the primary outcome measure and assessed by visual analog scales for craving (VASC). Visual analog scales have been successfully used to measure the changes in emotional states.The goal of this task was to investigate whether cortisol affects craving ratings of drug- and nondrug-related pictures. Picture stimuli were presented in a darkened room on one laptop in groups of maximal two participants at the same time. The picture stimuli consisted of drug-related pictures and three categories of nondrug-related pictures , with four different pictures per category. Two comparable versions were used for the two study days. The pictures were pseudo-randomized according to the rule that pictures of the same category never followed one another. Pictures were presented in the same order for all the participants. Each picture was presented for 4 s and followed by a prompt to rate it for the picture-characteristic craving by means of a visual analog scale. All the pictures except the drug-related pictures were taken from the International Affective Picture System. The drug-related pictures were nonstandardized pictures showing themes related to drug use, like drug injection, preparation of drugs and typical drug-consumption situations.http://www.r-project.org/). We applied linear models and linear mixed models (nlme-package) in combination with analysis of variance (SS II), when necessary. In case of repeated measurements, participant was included as the random effect of the mixed model. Dependent variables were the measurements of the five variables of interest. Independent variable was the study medication (placebo or cortisol).The five variables  were measured at four different time points: baseline (I), 60 min (II) and 90 min (III) after study medication intake and after heroin consumption (IV) as described above see also . For eacN=10), medium-dose  and high-dose  heroin consumption. This allocation resulted in the maximal separation between the groups with regard to the daily heroin consumption values. Group assignment was entered as a factor in the model. We tested for main effects of study medication and for interaction effects between heroin group and study medication on our dependent variables. The baseline values (I) of the variables of interest were included as covariate in all the models. We also included treatment order as covariate in all the models. In case of repeated measurement, the time point of measurement (60 min or 90 min) was included as covariate. Due to the five variables of interest and two time points tested, we set the significance threshold to P<0.005 (Bonferroni correction for 10 independent tests). In case of a Bonferroni-corrected significant interaction between heroin group and study medication, we performed post hoc tests for each heroin group separately .To investigate whether cortisol effects depend on the daily heroin dose, we divided the sample into three nearly equally sized heroin groups. This group assignment allowed us to test not only for linear, but also for nonlinear relationships between heroin consumption, study medication and our variables of interest. Because the administered intravenous heroin and the administered oral heroin medicament do not contain exactly the same amount of active pharmaceutical ingredient, we quantified the current daily heroin consumption according to the formula: daily heroin consumption=(daily intravenous heroin medication × 174.2)/200+/200. The three groups were as follows: participants with low-dose =960.09, P<0.00001; =3.69, P=0.039). Post hoc t-tests showed significantly higher cortisol levels in the medium-dose heroin group compared with the high-dose heroin group =8.00, P=0.012), but no significant different cortisol levels between the low- and medium-dose heroin groups (P=0.37) or between the low- and high-dose heroin groups (P=0.12). However, we did not find a significant interaction effect between heroin-dose group and study medication on cortisol levels =1.56, P=0.21). Furthermore, there were no differences between the heroin groups with regard to cortisol levels at baseline or cortisol levels in the course of the experiment in the placebo condition (P⩾0.12).There was a significant main effect of study medication (cortisol/placebo) on salivary cortisol levels, with significant higher cortisol levels under cortisol treatment at the three time points  after medication =8.00, P=0.00067) between medication and heroin group  before heroin consumption, which survived Bonferroni correction. We applied post hoc tests for the three heroin groups to test for an influence of medication on VASC before heroin consumption . Cortisol administration reduced VASC in the low-dose heroin group (t(27)=3.45, P=0.0019; see t(24)=0.4, P=0.70) or high-dose heroin group (t(27)=−1.42, P=0.17). For the interaction between medication and heroin group at the time point after heroin consumption, there was only a trend =2.71, P=0.087). For the sake of completeness, we ran the post hoc tests also for the time point after heroin consumption, which showed the same pattern, meaning that cortisol administration reduced craving in the low-dose heroin group (t(8)=3.56, P=0.0074, see t(7)=−0.63, P=0.55) or high-dose heroin group (t(7)−0.66, P=0.53).For the primary outcome craving, as quantified by VASC, there was a significant interaction =6.19, P=0.0027).In an additional analysis, we included all three time points at once in the same linear mixed model . Here again, we identified a significant interaction between medication and heroin group on VASC =4.59, P=0.035). To analyze whether the three groups differed in the amount of drug co-consumption, we calculated χ2 tests for each screened co-used drug. We found a significant association between heroin group and benzodiazepine co-consumption (χ2(2)=12.50, P=0.0019), as well as a significant association between heroin group and methadone co-consumption (χ2(2)=10.29, P=0.0058). No significant association was found between cocaine co-consumption and heroin group as well as cannabis co-consumption and heroin group =0.78, P=0.47). In addition, we investigated whether the interaction between the three heroin groups and medication on VASC might have been owing to confounding variables, such as employment status, duration of heroin dependency, benzodiazepine co-consumption, cocaine co-consumption, cannabis co-consumption, amount of smoked cigarettes during the resting period, additional treatment with methadone, age or sex. The interaction between heroin group and study medication was still observed when entering these covariates separately in the model . The interaction between heroin group and study medication on HCQ did reach nominal significance (P=0.012), but did not survive Bonferroni correction for multiple comparisons. There were no significant main effects of study medication on the five variables of interest before and after heroin consumption =1.96, P=0.16) and no significant interaction between medication and heroin group on abstinence duration =0.90, P=0.41). Moreover, the significant interaction between heroin group and medication on VASC was still observed when entering the covariate abstinence duration in the model =7.40, P=0.0011).Moreover, we analyzed whether the duration of opiate abstinence interfered with cortisol-related effects on craving. The mean abstinence duration between the last opiate administration in the morning and the beginning of the baseline measures was 5.95 h (s.d.=0.79). There was no significant main effect of heroin group on abstinence duration =8.94, P=0.0003), which survived Bonferroni correction. Post hoc tests for each heroin group separately revealed for the low-dose group a significant main effect of cortisol level on VASC (t(27)=−3.97, P=0.0005), with cortisol reducing craving as quantified by VASC, but no effect of cortisol level on VASC for the medium-dose (t(23)=0.13, P=0.90) or high-dose heroin group (t(23)=1.05, P=0.31) was detected. There was no Bonferroni-corrected significant interaction between cortisol level and HCQ =4.30, P=0.017), STAI =4.78, P=0.01), STAXI =4.16, P=0.019) or SOWS (P=0.38) at the time point before heroin consumption, and no significant main effect of cortisol level on any of these variables (P>0.60). For the time point after heroin consumption, no Bonferroni-corrected significant interaction between cortisol and heroin group  or main effects of cortisol  were detected.To rule out that limited cortisol uptake has masked potential effects in the high-heroin group, we entered the salivary cortisol levels, instead of the factor medication, in the model. We detected a significant interaction between cortisol levels and heroin groups on VASC at the time point before heroin consumption (FN=14) and the higher-dose group . There was a significant interaction between medication and heroin group  on VASC =24.37, P=0.0000008), on HCQ =14.38, P=0.0003) and on STAI =13.43, P=0.0004) before heroin consumption, which survived Bonferroni correction. No significant Bonferroni-corrected interaction between medication and heroin group on SOWS or STAXI  or main effects  were observed. We applied post hoc tests for the two heroin groups separately to test for an influence of medication on VASC, HCQ and STAI before heroin consumption . Cortisol administration significantly reduced craving as quantified by VASC (t(38)=3.92, P=0.0004) and by HCQ (t(38)=2.58, P=0.01), and reduced state anxiety (t(38)=2.39, P=0.02) in the lower-dose heroin group. There was a nominally significant main effect for enhanced VASC in the higher-dose group (t(36)=−2.48, P=0.02), HCQ (t(36)=−2.75, P=0.009) and STAI (t(36)=−2.48, P=0.01), indicating more craving and state anxiety due to cortisol administration for the higher-dose group. For the interaction between medication and heroin group on VASC at the time point after heroin consumption, there was only a trend =4.61, uncorrectedP=0.04) but not for HCQ, STAI, STAXI or SOWS .We initially divided the sample into three heroin groups, which allowed us to test not only for linear, but also for nonlinear relationships between heroin consumption, study medication and our variables of interest. We additionally divided our sample into two equally sized groups, by means of a median split, to achieve more power. The lower-dose heroin group . Furthermore, there was no significant main effect of medication on VASC =0.08, P=0.78), but a significant main effect of picture type, with higher craving ratings of drug-related pictures as compared with nondrug-related pictures =62.71, P<0.001, see In addition, we investigated the effects of the study medication on ratings of drug- or nondrug-related pictures with regard to the picture-characteristic craving. We did not find significant interactions between medication, picture type and heroin-dose group, between medication and picture type, or between medication and the three heroin-dose groups on VASC (χ2 (1)=1.04; P=0.31).The rate of reported adverse events, which mainly consisted of headache, tiredness or agitation, did not differ significantly between the cortisol and placebo condition . State anxiety, state anger and symptoms of opiate withdrawal were not significantly affected by cortisol.19 Although animal studies have suggested that glucocorticoids might be involved in mediating the enhancing effects of stress on craving and relapse,31 studies in humans failed to confirm this postulated role of glucocorticoids.33 The present finding of a cortisol-induced reduction in craving suggests that glucocorticoids are not mediating the enhancing effect of stress on heroin craving, but rather act as a stress buffer. A possible mechanism for the craving-reducing effect of glucocorticoids may be their effects on memory retrieval. Glucocorticoids have been shown to reduce retrieval of previously acquired information in rodents and healthy humans35 and there is evidence suggesting that emotionally arousing information is particularly sensitive to these glucocorticoid effects.36 Furthermore, there is evidence that glucocorticoids can also reduce the retrieval of aversive memory and enhance fear extinction in posttraumatic stress disorder and phobia.37Stress has been found to increase craving and the risk of relapse to opioid dependence.22 It has been proposed that critical neuroadaptations for addiction render brain-reward systems hypersensitive to drugs and drug-associated stimuli.26 Importantly, the powerful incentives associated with drug taking that produce a strong feeling of craving5 are stored in memory; also referred to as addiction memory.24 Moreover, craving is triggered by contextual cues stored in memory.38 Therefore, in the present study, glucocorticoids may have reduced craving by interfering with the retrieval of addiction memory and/or contextual memory. According to this idea, cortisol should have also reduced the rating of drug-related pictures with regard to the picture-characteristic ‘craving'. However, we did not observe a cortisol effect on the appraisal of drug-related cues when they are explicitly presented. A possible explanation for the lack of cortisol effect in this situation might be that explicitly shown drug-related stimuli are too strong to be influenced by cortisol. Interestingly, a similar discrepancy has been found with declarative memory, where cortisol reduces memory retrieval in a free-recall task, but not in a recognition task that involves the explicit presentation of the stimuli.35There is growing evidence that memory and addiction partly share neural circuitries and molecular mechanisms.40 However, the studies are not univocal with regard to the direction of effect. For example, a study in rats has shown that acute glucocorticoid administration acts in the nucleus accumbens to enhance dopamine signaling and potentiate reinstatement of cocaine seeking.39 In contrast, a study in healthy humans has shown that acute glucocorticoid administration induces a global downregulation of the brain's reward circuitry.40Alternatively, or in addition to the glucocorticoid effects on memory, cortisol may have exerted direct effects on the reward system, as previous studies have found that glucocorticoids can effect dopaminergic transmission and reward behavior.42 Alternatively, higher doses may have interfered directly or indirectly with cortisol effects. For example, studies in rodents have shown that glucocorticoids interact with the opioid system to influence memory-retrieval mechanisms.27 Therefore, daily consumption of higher heroin doses might have disturbed this interaction through individual differences in sensitivity of the opioid system or drug-induced downregulation of opioid receptors. Furthermore, since nicotine is a strong modulator of the hypothalamic–pituitary–adrenocortical axis,43 group differences in the amount of daily cigarette smoking or in the smoking abstinence duration before testing might have influenced cortisol effects on craving. Unfortunately, these smoking data were not available, which represents a limitation of the present study. Finally, it is possible that higher doses of cortisol might have been needed to reduce craving in patients receiving higher heroin doses.Interestingly, we found the craving-reducing effect of cortisol only in patients with low-dose heroin consumption (113–305 mg per day). The three subgroups did not differ in age, gender distribution or duration of dependency. Also the salivary cortisol data at baseline or at the other time points of the experiment did not explain why only the low-dose group responded to cortisol administration. However, the medium- and high-dose heroin consumption groups had more frequently an unemployment status as compared with the low-dose consumption group, indicating a more severe substance use disorder, which is generally less responsive to regular treatment interventions.44 and to explore the mechanism and the therapeutic potential of glucocorticoids in drug addiction. In particular, it will be of considerable clinical interest to investigate the effects of repeated administration of glucocorticoids and whether glucocorticoids might enhance exposure-based therapy, as it has been shown in phobia.29 Moreover, it will be of interest to investigate whether cortisol might be suited to prevent relapse in abstinent patients.To conclude, we believe this is the first study to examine the acute effects of cortisol administration in a population of heroin-dependent patients in a controlled study design. It shows that a single administration of cortisol leads to reduced craving. Future studies will need to identify potential factors that influence cortisol effects on craving, such as sex-steroid hormones


The aim of the work reported in this article was to investigate the effects of medium temperature and industrial by-products on the key hardened properties of high performance concrete. Four concrete mixes were prepared based on a water-to-binder ratio of 0.35. Two industrial by-products, silica fume and Class F fly ash, were used separately and together with normal portland cement to produce three concrete mixes in addition to the control mix. The properties of both fresh and hardened concretes were examined in the laboratory. The freshly mixed concrete mixes were tested for slump, slump flow, and V-funnel flow. The hardened concretes were tested for compressive strength and dynamic modulus of elasticity after exposing to 20, 35 and 50 °C. In addition, the initial surface absorption and the rate of moisture movement into the concretes were determined at 20 °C. The performance of the concretes in the fresh state was excellent due to their superior deformability and good segregation resistance. In their hardened state, the highest levels of compressive strength and dynamic modulus of elasticity were produced by silica fume concrete. In addition, silica fume concrete showed the lowest level of initial surface absorption and the lowest rate of moisture movement into the interior of concrete. In comparison, the compressive strength, dynamic modulus of elasticity, initial surface absorption, and moisture movement rate of silica fume-fly ash concrete were close to those of silica fume concrete. Moreover, all concretes provided relatively low compressive strength and dynamic modulus of elasticity when they were exposed to 50 °C. However, the effect of increased temperature was less detrimental for silica fume and silica fume-fly ash concretes in comparison with the control concrete. There are many ways of exposing concrete structural members to a medium temperature in the range of 20–50 °C. Some of the most common types of concrete exposed to such a medium temperature are those used in power plants, chemical plants, and nuclear reactors. Also in hot weather, where the temperature is sometimes over 35 °C, direct sunrays can increase the temperature of concrete members up to 50 °C. In these cases, the properties of high performance concrete may undergo distinct changes. Generally, at a temperature of 50 °C, the movement of moisture from the concrete surface could affect the hardened properties of concrete, resulting in increased drying shrinkage cracking. Also, microcracks might appear due to thermal stress and thus would affect the hardened properties of concrete. Therefore, this study investigated the compressive strength and dynamic modulus of elasticity of different high performance concretes exposed to a medium temperature range of 20–50 °C. Furthermore, the initial surface absorption and the rate of moisture movement into concrete are linked with its pore structure or microstructure and therefore may act as the key indicators for the durability performance of concrete in service conditions. The incorporation of certain industrial by-products could enhance the durability performance of concrete by reducing water absorption or moisture movement into concrete. Hence, this study also examined the initial surface absorption and the rate of moisture movement into different high performance concretes incorporating two industrial by-products, namely silica fume and fly ash.High performance concrete (HPC) has opened manifold opportunities for the construction of concrete structures. According to Forster , “High pHPC can be made with the same basic materials used for ordinary concrete; the major differences are the mix proportions and water-to-binder (W/B) ratio. The W/B ratio of HPC is much lower than that of ordinary concrete. While ordinary concrete has a W/B ratio between 0.50 and 0.75, it ranges from 0.20 to 0.35 for HPC [HPC has been used to construct many novel concrete structures in the world. In 1988, 120 MPa HPC was used in Seattle, USA to construct the columns for a 52-storey building at 2 Union Square . In the et al. [et al. [et al. [et al. [One of the most essential practices that must be given high priority for stringent quality control in the production of HPC is the curing of concrete at a proper temperature. Many researchers have investigated the effects of curing technique, temperature, and environmental and climatic impacts on the mechanical and durability characteristics of various concretes including HPC ,21,22,23et al.  reportedet al. . Meanwhi [et al.  found th [et al.  research [et al.  found th [et al.  research [et al. .The temperature in concrete and surroundings are expected to influence the performance of different concretes including HPC ,18,21,22The present study investigated the effects of three different medium temperatures of 20, 35 and 50 °C as well as two industrial by-products, silica fume and fly ash, on the key hardened properties such as compressive strength and dynamic modulus of elasticity of HPC. The hardened concrete specimens were tested for the aforementioned hardened properties after curing in water at 20 °C for selected periods  and then exposing them to a medium temperature of 35 or 50 °C until the day of testing. A number of concrete specimens water cured at 20 °C were also tested to observe the effect of silica fume and fly ash on the initial surface absorption (ISA) and moisture movement into concrete.3 and that of coarse aggregate was 1550 kg/m3. Both coarse aggregate and fine aggregate fulfilled the grading requirements of ASTM C33/C33M-13 [Coarse aggregate , fine aggregate , normal portland cement , tap water, silica fume (imported microsilica), fly ash , and SP were used to produce the concrete mixes. The maximum size of coarse aggregate was 19 mm and that of fine aggregate was 4.75 mm. The bulk specific gravity of coarse aggregate and fine aggregate was 2.62 and 2.60, respectively. The absorption of fine aggregate and coarse aggregate was 1.20% and 0.90%, respectively. The unit weight of fine aggregate was 1720 kg/m/C33M-13 . The finThe cement required for this study was taken from the same batch of production to avoid additional variables. The cement conformed to the requirements of normal portland cement stated in ASTM C150/C150M-15 . The speFour different concrete mixes using a W/B ratio of 0.35 were produced. The Sherbrooke mix design method  was foll3 for all concrete mixes. The binder content of HPC generally ranges from 392 kg/m3 to 557 kg/m3 [3. For HPC, the coarse aggregate content normally ranges from 950 kg/m3 to 1150 kg/m3 for different particle shapes [The concrete mixes were proportioned to have a minimum slump of 19 cm and a minimum slump flow of 50 cm. The W/B ratio of 0.35 was used to fulfill the minimum strength requirement (50 MPa) of HPC . The mix57 kg/m3 . The coae shapes . The finSilica fume and fly ash were used to produce three HPC mixes . In SFC mix, silica fume was used by replacing 10% of cement on weight basis. Theoretically, the optimum silica fume content for obtaining high strength is around 20% to 25% of cement by weight. However, considering the cost of silica fume and other admixtures, the practical and economic optimum content is closer to 10% by weight of cement . Therefo3) conforming to BS 1881: Part 125: 2013 [The constituent materials were mixed in a rotating pan type mixer . However, the strength achievement was the highest in the case of SFC. Test results show that after 91 days and at the temperature of 35 °C, SFC produced a compressive strength of 70 MPa. Silica fume is a highly reactive SCM. It readily reacts with water to produce additional hydration products (pozzolanic reaction products). The open channels in SFC are blocked by the high pozzolanic reaction products of silica fume. Besides, silica fume has the micro-filling ability because of its extremely small particle size, as discussed earlier in All SCM concretes were less sensitive to the increased curing temperatures. At the medium temperature of 50 °C, SCM concretes produced higher compressive strength than NPCC. This observation is clearly perceptible in The results of the dynamic modulus of elasticity test for different types of concrete are presented in Test results show that the dynamic modulus of elasticity increased continuously up to 91 days when curing was carried out at 20 °C. It was also observed that the continuous water curing up to 91 days exhibited the highest dynamic modulus of elasticity compared with 7 days and 14 days of water curing refer to . Hence, All SCM concretes produced a higher dynamic modulus of elasticity than NPCC at all ages and temperatures refer to . The incThe exposure temperature affected the dynamic modulus of concrete. At 35 °C and 50 °C, the values of dynamic modulus of elasticity decreased after 28 days for all concrete types compare . The dynThe effect of medium temperature depends on curing periods and moisture content. In this study, the effects of three medium temperatures, 20, 35 and 50 °C were studied. After 3, 7, and 14 days of water curing at 20 °C, the concrete specimens were transferred to two ovens and dried at the medium temperatures of 35 and 50 °C. The dried specimens were tested for compressive strength and dynamic modulus of elasticity at the ages of 28 and 91 days. Test results show that the temperature environment at 35 °C produces higher compressive strength and dynamic modulus than the temperature environment at 50 °C. This implies that the numerical values of the two above-mentioned hardened properties decrease with the increase in temperature. This is because the exposure to a higher medium temperature increases the moisture movement (moisture loss), which affects the microstructure of concrete due to interrupted cement hydration as discussed in All SCM concretes exhibited higher compressive strength and dynamic modulus of elasticity as well as lower ISA and moisture movement rate than NPCC. However, amongst SCM concretes, silica fume concrete produced excellent performance. The incorporation of SCMs increases the number of fine particles in the system . The preSCMs influence the behavior and characteristics of the transition zone in concrete. When a concrete is subjected to stresses including thermal stress, the cracks begin to develop in the transition zone. If large pores and microcracks are present in the transition zone, the aggregate simply plays no role in determining the strength of concrete. Therefore, by using SCMs especially silica fume, the weakest link in the transition zone can be controlled and thus the strength and other properties of concrete can be improved. Silica fume produces a denser transition zone and thereby enhances the physical role of the granular skeleton of concrete . In thisThe concrete mixes provided a slump, slump flow, and V-funnel flow as specified for HPC. The addition of silica fume required a higher dosage of SP than any other type of concrete to get the required flowability.The period of water curing was a critical factor to reduce the detrimental effect of concrete drying at medium temperature. Fourteen (14) days of water curing before exposure to the medium temperatures of 35 and 50 °C greatly improved the hardened properties of concrete. This is because more moisture was available for additional days to continue cement hydration, thus resulting in more hydration products that further improved the hardened properties of concrete.SCM concretes produced lower ISA and moisture movement rate than NPCC. Especially, SFC provided the lowest levels of ISA and moisture movement rate. These results were attributable to the physical (microfilling) and chemical (pozzolanic reaction) effects of silica fume that contribute to produce a refined pore structure and decrease the porosity of concrete.SCM concretes produced greater compressive strength and dynamic modulus of elasticity than NPCC. In particular, silica fume concrete provided the highest levels of compressive strength and dynamic modulus of elasticity when exposed to medium temperatures. This indicates that the accelerating pozzolanic reaction of SCM (particularly silica fume) at medium temperatures increases the strength and improves the quality of concrete.The compressive strength and dynamic modulus of elasticity of the concretes dried at 35 °C were higher than those of the concretes dried at 50 °C. This indicates that the compressive strength and dynamic modulus of elasticity of concrete decreased as the temperature increased. However, the effect of temperature rise was less detrimental in SCM concretes than NPCC.The concrete element exposed to a higher medium temperature should be well-cured to ensure high performance of concrete. The evaporation of water from concrete at an early age must be prevented to avoid the decrease in strength, modulus of elasticity, and other hardened properties of concrete. The suitable medium temperature environment associated with an adequate period of water curing  plays an important role in the hydration process to produce the concrete with desired hardened properties.The following conclusions were drawn from the results of this study regarding the effects of medium temperature and industrial by-products on the hardened properties of HPC: