Esophageal cancer incidence is growing worldwide, especially adenocarcinomas in the western world. Outcomes overall are universally poor, with the best survival seen in earlier stages of the disease, where surgery is the mainstay of treatment. Although squamous cell cancers and adenocarcinomas of the esophagus have different etiology, clinical features, biological behavior and prognosis, earlier research studies have frequently combined the two histologies. Several trials in the past three decades have been carried out in the neoadjuvant, adjuvant and perioperative settings in attempts to improve survival further. Most of the initial studies were small and underpowered, and showed no benefit with neoadjuvant or adjuvant treatment over surgery alone. More recent well‐designed trials have now established that the neoadjuvant (in squamous and adenocarcinomas) and the perioperative (in adenocarcinomas) strategies result in superior outcomes compared to surgery alone. However, the optimum neoadjuvant strategy has still not been identified, with both neoadjuvant chemotherapy and chemoradiotherapy (both followed by surgery) showing superior outcomes over surgery alone. Direct comparisons of these two neoadjuvant protocols have not shown a clear benefit of one over the other, although more trials are ongoing and may settle this debate. Future studies using personalized medicine and immunotherapy are required to evaluate their role in the management of esophageal cancers. Several controversies exist about the optimum neoadjuvant treatment strategy for localized esophageal cancer. Both neoadjuvant chemotherapy and chemoradiotherapy (both followed by surgery) show superior outcomes over surgery alone. In this article, we summarize the available evidence, ongoing research and future directions. Intact blood supply to the tumor may improve the delivery and effectiveness of chemotherapy and radiotherapy. There is a potential to downstage the tumor and facilitate curative (R0) resection. It may also help to identify tumors with aggressive biological behavior and therefore guide further treatment. However, associated disadvantages of preoperative therapy have to be taken into consideration as it can increase both morbidity and mortality of surgery. There could be technical difficulties of operating in a pretreated field, especially with the addition of radiation, resulting in impaired healing of anastomosis and an increase in postoperative pulmonary complications. Hence, the ideal neoadjuvant treatment should be able to treat micrometastasis, improve survival by preventing local as well as distant failures, and have minimum toxicity and postoperative complications. Although it is possible that chemotherapy and radiation could act synergistically at a locoregional level, the question remains as to whether there is value in combining two local treatments—radiation and surgery. Hence, the optimal treatment regimen for esophageal cancer is still controversial.2Over the last three decades, extensive research has been done on neoadjuvant treatment for resectable esophageal cancers. Chemotherapy in the preoperative as well as adjuvant setting has been studied. Several randomized trials have compared neoadjuvant chemotherapy (NACT) followed by surgery with surgery alone Table . Two‐druAmong the appropriately powered, large‐scale studies are the US Intergroup trial 113,The next large trial was the Medical Research Council  randomized trial on neoadjuvant chemotherapy in esophageal cancer (OEO2).Further trials in the west which investigated the role of NACT were restricted to adenocarcinoma of esophagus and gastroesophageal junction (GEJ). The MAGIC trialThe French FFCD studyThe Japanese Clinical Oncology Group (JCOG) conducted a trial JCOG 9907Comparing different chemotherapy regimens, OEO5 and FLOT4 are recent studies of importance. The UK MRC OEO5 trial3Neoadjuvant chemoradiation (NACRT) has the advantage of combining chemotherapy and radiation prior to surgery, and addressing both locoregional disease as well as micrometastases. Several trials were carried out to evaluate whether neoadjuvant chemoradiation followed by surgery could improve survival over surgery alone Table ; most ofThe EORTC trialThe Trans‐Tasman Radiation Oncology Group (TROG) and the Australasian Gastro‐Intestinal Trials Group (AGITG) randomized 256 patients equally to surgery alone (128) or to neoadjuvant chemoradiation followed by surgery (128).P = .003). There was no significant difference in postoperative morbidity or mortality in the two groups. Long‐term results of the CROSS trialThe role of NACRT has now been widely accepted globally after the publication of the CROSS trial.4The important controversy of the optimal neoadjuvant treatment regimen to treat esophageal cancer remains unresolved—there are very few trials comparing NACT with NACRT therapy. The POET trialA phase II trial being conducted at the authors’ institute , compares NACT with NACRT in squamous esophageal cancer. Similar to the NeoRes trial, the primary endpoint of our trial is response rates, with survival and toxicity being secondary endpoints. The JCOG 1109 NExT trial5Several years ago, there was a lot of promise and hype about targeted therapy and this has been assessed in a few studies. Panitumumab was evaluated in a German phase II trial (NEOPECX)6Surgery remains the mainstay of treatment for non‐metastatic esophageal cancer. The addition of neoadjuvant treatment is now clearly known to improve outcomes over surgery alone. However, what is unclear is whether neoadjuvant chemoradiation is superior to neoadjuvant chemotherapy alone. Several trials are ongoing which are likely to answer this question. Future trials should also evaluate the potential of immunotherapy to improve outcomes.Funding: No funding was received for this study.Conflicts of Interest: Authors declare no conflicts of interest for this article.


A subset of the overweight subjects (n = 39 for each group) underwent a supervised 3-month exercise program combining both moderate intensity aerobic exercise and resistance training with treadmill. UCN3 levels in SAT were measured by immunofluorescence and RT-PCR. Circulatory UCN3 in plasma was assessed by ELISA and was correlated with various clinical and metabolic markers. Our data revealed that plasma UCN3 levels decreased in overweight subjects without T2D compared with normal-weight controls , whereas plasma UCN3 levels increased with concomitant T2D . UCN3 plasma levels were independently associated with glycemic index; fasting plasma glucose and hemoglobin A1c  and were significantly different between both overweight, with and without T2D, and normal-weight individuals . Conversely, the UCN3 patterns observed in SAT were opposite to those in circulation; UCN3 levels were significantly increased with body weight and decreased with T2D. After a 3-month supervised exercise protocol, UCN3 expression showed a significant reduction in SAT of both overweight groups . In conclusion, UCN levels are differentially dysregulated in obesity in a tissue-dependent manner and can be mitigated by regular moderate physical exercise.Urocortin3 (UCN3) regulates metabolic functions and is involved in cellular stress response. Although UCN3 is expressed in human adipose tissue, the association of UCN3 with obesity and diabetes remains unclear. This study investigated the effects of Type 2 diabetes (T2D) and increased body weight on the circulatory and subcutaneous adipose tissue (SAT) levels of UCN3 and assessed UCN3 modulation by a regular physical exercise. Normal-weight ( Chronic metabolic stress and low-grade inflammation are key factors in obesity, insulin resistance and Type 2 diabetes (T2D) and involve the impairment of mechanisms in both central and peripheral tissues . CorticoUCN3 is the least studied member of the CRF family, but it is known to bind and signal selectively via CRF receptor 2 (CRFR2) , 11. UCNIncreased expression of UCN3 is thought to protect from high-fat diet-induced hyperglycemia and can increase energy expenditure .ThereforRegular physical exercise has become a key component in the non-pharmacologic treatment and lifestyle management of people with obesity and diabetes , 20. SevConsidering the available data on UCN3 and its family members, we hypothesized that UCN3 expression is increased in adipose tissue and blood in obese people and decreased with diabetes and thus affecting the cross talk between the brain and peripheral organs. Hence, this study investigated the following: (1) UCN3 levels in the blood and subcutaneous adipose tissue (SAT) from normal-weight and overweight individuals with and without T2D; (2) the association between UCN3 levels and physical, clinical, and biochemical markers; and (3) the effect of a 3-month physical exercise program on UCN3 levels in obesity and T2D.n = 37), overweight without T2D (n = 107), and overweight with T2D (n = 98). Written informed consent was obtained from all participants prior to starting this study, which was approved by the Review Board of Dasman Diabetes Institute and was conducted in line with the principles of the Declaration of Helsinki. People who performed regular physical exercise within the last 6 months prior enrollment to the study or those with history of major illness or medications not related to diabetes were excluded.The study included 3 groups of adults: normal-weight without T2D (n = 39 for each overweight group) were enrolled in a supervised exercise program at the Medical Fitness Center (MFC) of Dasman Diabetes Institute. Prior to exercise prescription each subject underwent the Cardiopulmonary exercise test “CPET”  using electromagnetically braked cycle ergometer to measure the maximum heart rate (max HR) and maximum oxygen consumption (VO2max). Physical fitness was assessed thereafter to determine the muscle strength, endurance, and flexibility by performing grip strength (dynamometer), push-ups upper body strength, sit ups and forward bending test (upper and lower body flexibility). The exercise program involved a combination of both resistance training with treadmill or cycling and moderate intensity aerobic exercise. Each exercise session included 10 min warming up and cooling down steps at 50–60% of max HR with 40 min of the mentioned program at 65–80% of max HR. Under the supervision of qualified fitness professionals at MFC, subjects exercised 3 times per week for a period of 3 months. They were monitored to maintain the recommended heart rates during the training. Exercise effectiveness was assessed at the end of the 3-month exercise program using similar fitness tests performed at baseline.All eligible subjects  were deparaffinized and rehydrated followed by the antigen retrieval using DAKO solution at pH 6  in a pressurized cooker. The endogenous peroxidase was quenched using 3% H2O2 for 1 h at room temperature (RT). Sections were blocked with 5% fat-free milk for 1 h at RT, followed by 1% BSA for 1 h. Then the tissue sections were incubated at 4°C for overnight with primary antibodies (dilution 1:100). Primary antibodies used were anti-UCN3 antibody  and anti-adiponectin . Antibody performance was assessed using negative controls (slides incubated without primary antibody or with unspecific IgG). Staining with Alexa Fluor 488-conjugated rabbit secondary antibody  was used at 1:1,000 dilution and incubated at RT for 1 h. Human pancreas biopsies were used as positive controls for UCN3 expression. DAPI was used at 0.05% for nuclear staining. The sections were analyzed using a Zeiss LSM 710 confocal laser-scanning microscope , and 12 fluorescent images of the representative areas of the SAT were photographed at 40 × objective for each subject. The staining intensities were quantified using the ZEN software .Formalin-fixed, paraffin-embedded SAT sections (8 μm) from normal-weight and overweight with and without T2D subjects (Mouse preadipocyte (3T3-L1) and macrophage cells (RAW264.7) were obtained from ATCC , cultured and differentiated in their growth media as previously reported . For IndAfter treatment with RAW264.7 cells conditioned media, 3T3-L1 cells were washed twice with PBS, fixed with 10% formalin for 1 h at RT, washed twice again with PBS, and incubated with 60% isopropanol for 5 min. Finally, cells were incubated with 0.3% Oil Red O solution for 20 min. Coverslips were washed with distilled water five times and mounted onto a slide. Images were captured using a panoramic digital slide scanner. Non-treated cells were used as control.gapdh. The primers used are presented in Total RNA was extracted from SAT using RNeasy Lipid Tissue MiniKit . For cell lines, total RNA was extracted using TRIZOL reagent. cDNA was synthesized from total RNA samples using High Capacity cDNA Reverse Transcription Kit . Conventional qRT-PCR was performed using the Applied Biosystem7500 system with Taqman gene expression assays normalized to Western blots were performed using 3T3-L1 cells. Whole cell extracts were prepared in RIPA buffer . Protein concentration was determined by the Bradford method using β-globulin as a standard. Twenty microgram of protein was prepared in sample loading buffer containing β-mercaptoethanol heated at 95°C for 10 min, then resolved on 12% SDS-PAGE gels. Proteins were then transferred at 100 V for 75 min onto PVDF membranes, blocked with 5% non-fat dried milk in Tris-buffered saline containing 0.05% Tween 20 (TBST) for 2 h at RT, and then probed with the anti-UCN3 primary antibody   for overnight at 4°C. After washing, the membranes were incubated with Rabbit horseradish peroxidase conjugated secondary antibody  for 2 h at RT, and finally detection was performed using super sensitivity West Femto ECL reagent . Protein bands were visualized by chemiluminescence and the images captured by using the Versadoc 5000 system . GAPDH was used as internal control to monitor for protein loading, with the anti-GAPDH . For densitometric analysis, the intensity of bands was determined using Quantity One Software .t-test was used for skewed variables. To evaluate the effects of groups, we conducted two-way repeated measures ANOVA test with post-hoc Bonferroni on the whole population. A paired t-test was used to determine the significance of differences in means within each group before and after exercise. Correlations between variables were calculated using the Spearman's correlation coefficient. Multivariable linear regression analysis was performed to examine the predictive effect of each factor with odd ratios (ORs), and their 95% confidence intervals for associated factors were estimated. All p < 0.05 were considered statistically significant.SPSS software  was used to perform the statistical analyses. All descriptive statistics in the study are reported as mean ± standard deviation. A Chi-square test was used for categorical variables and the Wilcoxon non-parametric p < 0.01) and higher TGL levels (p < 0.001) than the normal weight and overweight without T2D groups. Moreover, the overweight without T2D group displayed significantly higher systolic blood pressure (SBP) and lower maximal oxygen consumption (VO2max) levels than the normal-weight group (p < 0.01), whereas the overweight with T2D group had the highest SBP (p < 0.05) and lowest VO2max (p < 0.01). Altered hormone profiles were also observed in the overweight groups, with higher levels of leptin, glucagon, glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP) than the normal-weight group (p < 0.05). The levels of circulating UCN3 were significantly decreased with increased body mass index (BMI) (p < 0.001) and significantly increased with T2D in the overweight group (p < 0.01) ( < 0.01) .p < 0.05).Considering the observed increased UCN3 levels with T2D, we further assessed UCN3 levels by dividing the T2D group into controlled and uncontrolled HbA1c groups . UCN3 levels were significantly higher in the uncontrolled HbA1c group than in the controlled HbA1c group  but were negatively correlated with insulin (p < 0.01) in the whole population and in the two overweight groups separately. Moreover, UCN3 levels were significantly correlated with FPG and HbA1c (p < 0.05) but were negatively correlated with RANTES (p < 0.05) in all subjects.Spearman's correlation analysis between UCN3 plasma levels and various parameters was performed for all participants and separately for each group . Brieflyp < 0.05; p < 0.05). Multivariate binary logistic regression analyses were then performed using either normal-weight or overweight without T2D as reference .To further assess the independent association of UCN3 with these markers, a multivariate stepwise linear regression analysis for UCN3 as a dependent variable was performed separately for the whole study population and separately for each group . Indepeneference . Plasma 2, n = 39 for each group) before and after exercise to assess the effect of 3 months of moderate physical exercise. We previously reported the impact of exercise on various markers and showed that it was more prominent in people without T2D, where adiposity markers  were significantly decreased, along with ameliorated cardiorespiratory markers (HR and VO2max) (p < 0.05) was reached only in the overweight without T2D group.A pairwise comparison of UCN3 levels was also performed using various clinical and metabolic parameters in a subset of overweight subjects (BMI ≥ 30 kg/m VO2max) , 28. Tabp < 0.01)  and mRNA (p < 0.001) levels in the overweight without T2D individuals compared with the normal-weight individuals. However, UCN3 expression was significantly decreased in the overweight with T2D individuals compared with those without T2D . As a control, adiponectin staining was assessed in SAT from the same individuals and revealed lower levels in the overweight without T2D individual compared with the normal-weight individual and was further decreased in the overweight with T2D individual (p < 0.01), as indicated by the clear decrease in UCN3 protein staining assessed by IF confocal microscopy  (p < 0.05) and its receptor, as well as lipid droplet accumulation   as well  < 0.05) . Finallymulation . The incmulation .This study is the first to report UCN3 levels in blood and SAT from normal and overweight adults with and without T2D and the modulation of UCN3 levels by physical exercise. The main findings of this study are: (1) plasma UCN3 levels decreased with BMI; (2) UCN3 plasma levels were independently associated with glycemic index  and were significantly different between overweight individuals with and without T2D; (3) the UCN3 expression in SAT was increased with BMI and blunted with T2D; and (4) a 3-month supervised exercise protocol showed a significant reduction of UCN3 expression in both overweight group SAT.Our findings of impaired UCN3 levels in obesity and T2D with opposite pattern between plasma and SAT indicate the complexity of mechanisms under these conditions. Despite the well-established role of impaired feedback in the inhibition of insulin secretion in hyperinsulinemia and insulin resistance , 30, mulIn line with this and contrary to the pattern of circulating UCN3 observed in our study population, we found that UCN3 expression SAT increased with obesity and blunted with T2D in this tissue likewise previous reports showing decreased levels of UCN3 in β-cells people with diabetes . In plasAlthough UCN3 is expressed in human adipocytes and adipose tissue , 37, itsOn the other hand, the observation that the expression of UCN3 mRNA and protein in SAT was increased by the adiposity but not by the concomitant presence of T2D in overweight subjects might indicates that, UCN3 expression is primarily associated with SAT expansion. In addition, in diabetic obese SAT, we and others have previously reported further increased inflammation and ER stress , 40. ThiFurthermore, SAT expansion in obesity is known to create hypoxic microenvironment which amplifies inflammation and hyperglycemia . Interes2max. The increase in UCN3 levels was also consistent with reduced insulin levels. We and others have previously reported the beneficial effects of regular exercise in individuals without T2D compared with those with T2D , which was approved by the Review Board of Dasman Diabetes Institute and was conducted in line with the principles of the Declaration of Helsinki.SK, AK, and AT designed the study, analyzed the data and wrote and revised the manuscript. SK performed the experiments. SD performed statistical analysis. JT contributed to the discussion and the revision of the manuscript. DM, MH, JA, and FA-M revised the manuscript.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.


SL) is frequently carried out in patients with advanced gastric cancer. However, some clinical questions are being debated and consensus must be obtained. With this aim, a literature search of PubMed/MEDLINE was carried out using the keywords “gastric cancer,” “SL,” and “diagnostic laparoscopy”. Articles published online up to February 2019 were analyzed, focusing on the following questions. (i) What is an adequate indication for SL? (ii) How do you carry out SL? (iii) Does SL provide accurate information about peritoneal dissemination? (iv) Is the yield of SL different by tumor location? (v) Is SL a safe procedure? (vi) Is “repeat SL” needed? (vii) Does SL provide oncological benefit? Results provided the following responses: (i) In Western countries, clinically resectable advanced tumor is an indication for SL. Terms to be introduced for adequate indication include “location,” “type 4 (linitis feature),” “large tumor,” “equivocal computed tomography  Exploration of the entire peritoneal cavity is preferable. (iii) Detection rate of peritoneal disease is 43%‐52% in Japanese institutions and 7.8%‐40% in other countries. False‐negative findings during SL were 0%‐17%, and 10%‐13% when limited to cytology. (iv) Yield of SL was higher in gastric cancer compared with esophagogastric junctional tumor. (v) SL‐related complications were estimated to occur in 0.4%. (vi) Repeat SL is important after treatment. (vii) If the efficacy of neoadjuvant chemotherapy for patients with P0CY1 is established, SL can provide oncological benefit. SL can be carried out safely and effectively. Considering the prevalence of neoadjuvant treatment, the role of SL will become more important.Staging laparoscopy ( In some therapeutic guidelines,The main purpose of SL is to detect occult peritoneal dissemination Figure , aiming 2The present review was based on articles from PubMed and MEDLINE and carried out in February 2019. “Gastric cancer”, “staging laparoscopy” and “diagnostic laparoscopy” were used as search terms. After a full‐text search for 79 articles published after 2000, a final set of 41 studies was extracted with a sample size of patients who underwent SL larger than 50. If not satisfied with this condition, the articles including important information were included in this review.This review was constructed to answer the following clinical questions: (i) What is an adequate indication for SL? (ii) How do you carry out SL? (iii) Does SL provide accurate information about peritoneal dissemination? (iv) Is the yield of SL different by tumor location of either esophagogastric junctional cancer (EGJ) or gastric cancer (GC)? (v) Is SL a safe procedure? (vi) Is “repeat SL” needed? (vii) Does SL provide oncological benefit?3Results provided responses to the seven questions based on the database search.3.1The main purpose of SL is to detect occult peritoneal disease (P and/or CY) that cannot be definitively diagnosed using imaging examinations.Indications for SL are discussed in two ways Table . First, 3.2Surgical procedure for SL has been established, and it was similar in each study. It must be determined as to whether exploration inside the omental bursa is mandatory. If GC was located at the posterior side of the stomach, there could be peritoneal dissemination inside the omental bursa only. Several studies described inspection inside the omental bursa,3.3Reports on the detection of P1 and/or CY1 that were not seen by imaging examinations are listed in Table “False negative for SL” is listed in Table CY0 at initial SL may change to CY1 at the following laparotomy. Yamagata et alPeritoneal disease can be confirmed by SL, but the extent of local invasion from GC could not be completely explored. Diagnosis may change from “resectable” to “unresectable” following laparotomy not only as a result of peritoneal dissemination but also as a result of unexplored local invasion during SL. de Graaf et al3.4Some studies about SL from Western countries included not only GC, but also EGJ cancer or lower esophageal cancer (including squamous cell carcinoma) for the indication of SL. Yield of SL was higher in cases with GC compared with EGJ in all studies except one Table .3.5Staging laparoscopy is considered a safe procedure carried out within one hour under general anesthesia. Some reported intestinal injury during SL.3.6“Repeat SL” refers to a second SL carried out after chemotherapy. Thiels et al3.7Detection of occult peritoneal disease can avoid non‐therapeutic laparotomy and shorten the interval to induction of chemotherapy. However, the survival benefit was obscured because the therapeutic strategy of systemic chemotherapy without gastric resection was the same in both groups. Burke et alDo patients who are cytology positive only without macroscopic peritoneal dissemination (P0CY1) during SL survive longer by induction chemotherapy than patients with POCY1 who immediately underwent surgery after diagnosis? In their review, Jamel et al4A Canadian review teamPatient selection for SL is still controversial. According to the results of the REGATTA trial,51 SL after chemotherapy is also important for detecting occult peritoneal disease especially in case that NAC is not effective  for patients with bulky N and PAN is NAC followed by extended surgery. In this clinical trial, SL was mandatory to avoid occult peritoneal disease. Irino et ale Figure , even if“False‐negative SL” is a problem. In many studies from Japanese institutions, the proportion of “false negative” rates was reportedly over 10%. The indication for SL in those studies was large type 3 and type 4 that had a high potential of peritoneal disease, so the incidence of “false negative” rates was high. Hato et alIn many reports, patients with P0CY1 have a poor prognosis, along with patients with macroscopic peritoneal dissemination.5A current literature review suggests that staging laparoscopy is very important for determining the correct therapeutic strategy for the treatment of advanced gastric cancer. (i) Indication for SL is patients with some of the following: “whole stomach,” “type 4 (linitis feature),” “large tumor,” “equivocal CT findings,” and “lymph node swelling”. (ii) The exploration of the entire peritoneal cavity is preferable especially for CY1 patient. (iii) SL has the benefit of detecting occult peritoneal disease, but the false‐negative finding during SL was 0%‐17%. (iv) Yield of SL was higher in gastric cancer compared with esophagogastric junctional tumor. (v) SL‐related complications were estimated to occur in 0.4%. (vi) Repeat SL is important after chemotherapy, especially to enable decision‐making on the need for conversion surgery. (vii) Selection of the “good responder” after chemotherapy for CY1 patients can provide oncological benefit.Conflicts of Interest: Author declares no conflicts of interest for this article.


The strengthening method of using hybrid fiber reinforced polymer is an effective way to increase the strengthening efficiency and lower the cost. This paper focuses on simulating the flexural behavior of reinforced concrete beam strengthened by prestressed C/GFRP (Carbon-Glass hybrid Fiber Reinforced Polymer) with different hybrid ratios and prestress levels. An elastoplastic damage constitution is used to simulate the mechanical behavior of concrete. A cohesive zone model under mixed mode is adopted to describe the debonding behavior of the FRP-concrete and concrete-steel interface. The results show good agreement with the experiment in the load-deflection curve, load-stress curve of steel, and HFRP. Furthermore, the failure mode of concrete and FRP debonding obtained from numerical simulation is the same as the test. Considering the improvement of the bending capacity, stiffness, and ductility of the strengthened beam in this paper, the best hybrid ratio of carbon to glass fiber is 1:1, and the suitable prestress level is between 30 and 50% of its ultimate strength. Environmental factors, material aging, and overloading may affect the bearing capacity of reinforced concrete structures . Compared with demolition and reconstruction, FRP (Fiber Reinforced Polymer) strengthening can reduce costs and optimize investment. CFRP (Carbon Fiber Reinforced Polymer) is the most commonly used FRP. The modulus and strength of CFRP are higher compared to the values of GFRP (Glass Fiber Reinforced Polymer), but the drawback is that the elongation of CFRP is relatively low, which makes the failure mode of the reinforced concrete structure brittle. Besides, the price of CFRP is very high. If high elongation and less expensive fiber such as glass fiber can be mixed with CFRP, not only the strength and elongation of HFRP (Hybrid Fiber Reinforced Polymer) can be improved, but the cost can be significantly reduced.Experiments were performed to investigate the strengthening effect of HFRP. Attari et al. , HawilleIn the aspect of the numerical simulation of FRP strengthened concrete structures, most of the studies focused on the modeling and analysis of uncracked concrete structures strengthened by FRP , while nIn order to take full advantage of FRP, it is necessary to have a good understanding of the failure mechanism of each component material and the failure process of the strengthened structure. Therefore, in this paper, the constitutive models of concrete and interface are proposed and implemented by the user subroutine UMAT of the finite element software Abaqus, and the strengthening effect of HFRP is numerically studied.F (Equation (1)) includes two parts: plastic potential dQ (Equation (3)) [The mechanical behavior of concrete under uniaxial compressive stress is different from that under multiaxial compressive stress . The strion (3)) .(1)F=Q˜D is damage variable. S is a material parameter describing the softening behavior of concrete, and ϕ is the damage evolution parameter.As concrete is a porous material with volume compressibility, the yield of concrete is controlled by both effective stress and hydrostatic stress. In Equation (2), α is the pressure sensitive property constant of concrete, λ is a plastic damage operator, which can be calculated from the plastic damage loading condition as: y is the yield function, and the Newton–Raphson iteration expression is:In this model, damage evolution is coupled with plastic strain. Plasticity and damage evolution are described as follows .(6)Δεp=The stress increment can be obtained as:ε can be obtained as Considering the plastic consistency condition, the relationship between Δλ and Δ density .The flowchart of the plastic damage model of concrete is shown in i, corresponding to three engineering stresses σi, where Δ1 and Δ2 are displacement jumps in the shear direction, and the equivalent shear displacement jump is 3 is the displacement jump in the normal direction, The Cohesive Zone Model (CZM)  was usedK is the penalty stiffness and When the interface is in a uniaxial compression state, the interface will not debond. Debonding of the interface is trigged by tensile stress or shear stress. In the actual engineering structure, the interface is always in the state of mixed loading in which tensile and shear stress exist at the same time. Therefore, it is necessary to determine the failure criteria of the interface in the mixed mode. The modulus of the cohesive zone model in Abaqus is the same in the normal and shear direction. However, the modulus of FRP/concrete and FRP/steel interface in the normal and shear direction is different. Therefore, the constitutive relation of the interface under mixed mode is: follows .(14)Δmfy is its yield strength and εy is the yield strain. In the finite element model of this paper, the strain of the steel bar does not exceed the hardening strain. The yield criterion for steel is the Mises criterion. The mechanical properties of steel were obtained from the tensile test of a steel bar sample with a length of 500 mm of Ou [The elastic-plastic model of the steel bar is shown in mm of Ou  and listThe mechanical behavior of HFRP is supposed to be elastic, and the mechanical properties are shown in The experiment this paper simulated was carried out by Ou . The sizThe whole simulation process was the same as the test of Ou . The beaIn order to simulate the damaged bridge that needs strengthening, the beam was first loaded to crack. The pre-cracking load was 24 kN (about 50% of the ultimate load of the reference beam). Crack distribution and the von Mises stress of steel after pre-cracking are shown in After pre-cracking, the beam was strengthened by FRP. It is noted that higher prestress level led to greater stress concentration at the end of FRP, as shown in The load deflection curves and flexural capacity of the beam obtained from the test and numerical simulation are compared in As shown in In the second stage, with the increase of load, the concrete in the tension zone withdrew from work because of cracking, and the tension stress was undertaken by the steel bar and C/GFRP; the stiffness of the beam obviously decreased. With the development of cracks, the rate of deflection was faster, which led to the change of the slope of the load-deflection curve. As shown in In the third stage, the stress of C/GFRP increased greatly after the steel bar yielded, and the slope of the load-deflection curve changed obviously. C/GFRP played a major role in restraining the beam deformation; therefore, the deflection of the strengthened beams under the same load was less than that of the reference beam. Under the same prestress level, the higher the carbon content in C/GFRP, the smaller the deflection, which indicated that the stiffness of the strengthened beam was significantly improved. However, considering the ductility and the residual strength of FRP when the beam failed, the most appropriate one was CG11. The stress-load curve of steel and C/GFRP obtained by numerical simulation was similar to the development trend of the test curve , and theThe failure mode observed in the test and numerical simulation is shown in In this paper, the bending behavior of RC beams strengthened with prestressed hybrid FRP was studied. The elastic-plastic damage constitutive model of concrete and the mixed mode cohesive model of the interface were introduced into the numerical simulation by the UMAT subroutine provided by Abaqus. The results of the numerical simulation agreed well with the experimental results such as load-deflection curve, ultimate flexural capacity, ductility, and failure modes. The hybrid ratio and prestress level of C/GFRP were introduced as the influencing factors. The yield load, ultimate load, stress development of C/GFRP and steel bar, and deflection development were analyzed. The strengthening effect was evaluated by the improvement of bending capacity, stiffness, and ductility. The main conclusions are as follows:(1) Compared with the reference beam, the bearing capacity of beams strengthened by prestressed C/GFRP was significantly improved, and the method of pre-stressed C/GFRP strengthening was an effective active strengthening method for damaged bridges.(2) For the beam simulated in this paper, the characteristic loads of the prestressed GFRP strengthened beam were the lowest ones. The yield load of the prestressed C/GFRP strengthened beam increased with carbon fiber content in C/GFRP. However, the carbon fiber content had no significant effect on the ultimate load of the beam. Compared with CG11, the residual strength of CG31 and CG21 was large, which was unnecessarily excessive for high strength materials, and the ductility of the strengthened beam was relatively low. After comparison of the capacity and ductility of the beam strengthened by C/GFRP with different carbon content, CG11 was the best mixing ratio. (3) For CG11 strengthened beams in this paper, it was appropriate to keep the prestress level between 30 and 50% of the ultimate strength. It should be noted that a higher prestress level leads to greater stress concentration at the end of C/GFRP, which may cause stress concentration and cracks. In addition, if the prestress level of C/GFRP was too large, small deformation of the beam would lead to premature fracture of C/GFRP and decrease the bearing capacity of the beam. Therefore, the prestress level of C/GFRP should not be too high. In addition, effective anchoring methods can be considered to reduce the impact of debonding on the beam.


Thus, strengthening health systems in these countries is a prerequisite for improving disease prevention and care. After three decades of HIV/AIDS policy-making in Iran, conducting a comprehensive analysis on the policy process seems to be essential. In the present study, we aimed to analyse the HIV/AIDS policy-making process in Iran from 1986 to 2016.A huge number of people living with HIVThis was a theory-based, multi-method and retrospective study. Interviewing of key informants and review of policy documents were concurrently conducted to identify and include further key informants (39 participants) and documents in the study. Framework analysis was used to analyse data.The mean age of participants working in HIV/AIDS policy-making was of 48 years and participants had a mean of 14 years of working experience. Findings were categorized as contextual factors, content of HIV/AIDS policies, actors involved in the policy process, and evidence use in the policy process. Contextual effective factors on the HIV/AIDS policy-making process were categorized into five major themes, namely situational factors, structural-managerial factors, socioeconomic factors, political and legal factors, and international factors. The HIV/AIDS phenomenon in Iran was identified to be deeply rooted in the culture and traditions of society. The HIV/AIDS policy content has, recently, been crystallized in the national strategic plans and harm reduction policies of the country. The policy process has been conducted with a solely governmental top-down approach and is now suffering from poor evidence and lack of sufficient consideration of contextual factors.There is a great need for change in the approach of government towards the issue and to increase the participation of non-governmental sectors and civil society in the policy process. Until recently, Iran was classified among the countries with a low prevalence of HIV/AIDS . HoweverApproximately 90% of PLHIV live in developing countries , which uIn Iran, in response to the HIV/AIDS epidemic, health policy activists established the AIDS Supreme Council 1 year after the diagnosis of the first cases , implemeNow, after three decades of HIV/AIDS policy-making, planning and executive activities in Iran, the conducting of a comprehensive analysis of the policy-making process seems to be essential. Due to lack of HIV/AIDS control , 22, 23,the way in which policies are initiated, developed or formulated, negotiated, communicated, implemented and evaluated”. In the present study, we aimed to analyse the HIV/AIDS policy-making process in Iran from 1986 to 2016, with the hope to provide a clear presentation on the complex relations at play in the process. Our aim was also to obtain a better understanding on how the Iranian public health policy-makers approached the HIV/AIDS issue, as a multi-dimensional phenomenon with a variety of influences. Policy analysis on the issue may be helpful in providing appropriate frameworks with considerations on Iran’s cultural, social and political context as well as the nature of the disease. This study may also help policy-makers in finding a better understanding on the transparency, efficiency and effectiveness of their policy-making process with the hope to develop effective and sustainable HIV/AIDS policies in the future.Following a review of the literature we found little evidence on HIV/AIDS policy analysis in Iran. To the best of our knowledge, no study has yet investigated the HIV/AIDS policy-making process in Iran. As defined by Buse et al. , a policIn this theory-based, multi-method study with conventional content analysis methodology, we conducted a health policy analysis at the national level. The conceptual framework developed by Green et al.  was usedThis study was designed and implemented in Tehran, Iran, at the national level, from January 2013 to October 2016. Although the level of policy analysis was national, the opinions of key informants working on HIV/AIDS programmes at the local levels were also investigated.We initiated the study with a review on the most prominent HIV/AIDS documents, to identify both the core key informants and the other important documents.A comprehensive search on the internet was conducted to select the websites of relevant government institutions, international and national NGOs, health professional councils and associations, as well as religious medical bureaus and research networks. We used the search engine Google to locate such websites, which we then navigated by the tabs and menus available on the homepage . In addition, we searched Google Scholar using the following keywords in various combinations with Boolean operators : agenda, health policy, health system, guidelines, strategies, plans, and reports. We checked the reference lists of the documents found to expand the list of included documents. Importantly, we used the websites as an entry point to other repositories for national policy documents. More details on this process are previously published .To minimise selection bias, two independent reviewers (BM and RB) screened all documents and selected those that were appropriate for our research question. Our selection involved the use of a pre-determined inclusion and exclusion criteria. We included all agenda-specific published documents relevant to health policy and systems produced between 2000 and 2015.Where possible, a hardcopy of identified documents was obtained from relevant centres. Some other documents were also identified and obtained through a purposeful approach to the content of documents and to the guidance of key informants during the interviews. A total of 48 documents, including upstream documents , circulars, regulations, guidelines, provisions approved by the government as well as the papers and important research projects and prevention documents related to the HIV/AIDS policy content in Iran were studied. We had access to the policy documents after providing approval from the centres where these documents were developed. In order to review the documents, a review topic guide was developed based on the issues reported in UNAIDS 2015 progress reports submitted by Iran, Pakistan, Tanzania, Vietnam, Ukraine, and Brazil . To answWe used two methods to identify and to interview key informants. Purposive sampling was used to identify informants in the key roles across sectors relevant to HIV/AIDS policy process. During initial reviews on HIV/AIDS documents, the first three key informants were identified and recruited based on their expertise and their position within the Iranian Research Center for HIV/AIDS (IRCHA). Further informants were recruited through snowball sampling, which involved asking the interviewees to nominate other people they knew with knowledge and experience relevant to the HIV/AIDS policy process. The informants were from different levels of the Iranian health system, including primary, secondary and tertiary health services, intermediate and long-term care services, health policy-makers, healthcare managers, HIV/AIDS clinical practitioners, health education and promotion officers, and faculty members in medical universities. Further key informants and documents were identified and included in the study during interviews and policy document reviews, which were conducted concurrently.All interviews were conducted by the first author, who has a considerable experience in conducting qualitative interviews with health policy-makers. Our objectives were first described to the participants and all participants signed an informed consent form before the interviews. The semi-structured interviews were conducted applying an interview topic guide. The topic guide was provided based on the issues reported in UNAIDS 2015 progress reports submitted by the abovementioned countries . All intFramework analysis  was usedThe qualitative data analysis software MAXQDA v10 (2011) was applied to organise and to manage the coding process. The transcripts were read and re-read, and then the initial codes were drawn from data. The codes were collated into themes and a coding frame was developed. All interviews and analyses were conducted by the first author, who was in close discussion within the research team. By his preconceptions, he tried to derive the themes. During data analysis, he had the theoretical framework-based research questions  in mind.Credibility, conformability, dependency and transferability were considered as the criteria for data trustworthiness , 34. FirIn order to increase dependency, we tried to consider and apply all comments noted by the research team members. The results of data analysis were presented to some participants, and their feedback was considered in the data analysis process. To increase transferability, we also tried to include appropriate participants in the study. Data collection and analysis were carried out simultaneously.The mean age of participants was 48 years and the mean number years of working experience in HIV/AIDS policy-making was 14. The level of education for a majority of participants was philosophy and general medical doctor. The study findings are presented in four sections, namely contextual factors, content, actors and evidence. Figure Keeping in mind the Lichter approach  and baseThe findings on interviews with the PLHIV were mainly around the pervasive stigma of HIV/AIDS. The patients believed that they were not understood by other people who did not have exposure to HIV-positive patients and complained about medical and healthcare personnel. They explained that they are usually stigmatized as sex workers (particularly women), which makes them face negative mental consequences, like humiliation, chronic stress and anxiety, and depression Table .Figure The first aid programmes to quit drugs and to develop harm reduction policies were planned in prisons followed by implementation in communities. The harm reduction policies were directed toward the distribution of sterile needles and syringes for single use to avoid common injection (the main transmission pathway of HIV at that time) between the consumers. Provision of methadone treatment for addicts was another harm reduction policy. Subsequently, some policies were put into action, including the distribution of condoms in prisons and communities, the distribution of disposable razors to avoid common use between prisoners, and the provision of religious meeting rooms for prisoners and their wives to have safe sexual relations./AIDS programme was developed. Although the Iranian cabinet did not approve the programme, some efforts were made to implement it within the country. In 2003, the Supreme Council for HIV/AIDS Prevention Planning (SCHAPP) was formed and approved by the cabinet and, accordingly, national and provincial committees were formed as a subset of the council. Three years later, in 2006, SCHAPP was dissolved and integrated into the Health Supreme Council and Food Security, with the previously mentioned committees also becoming its subsets. The dissolution of SCHAPP reduced the effectiveness of its subcommittees so that the majority were semi-active, inactive or passive, except for two subcommittees, namely the Care and Treatment subcommittee, which was responsible for providing and updating the treatment guidelines for sufferers, and the Harm Reduction subcommittee, which operated as a subset for an anti-drug campaign.In 2001, Iran participated in UNGASS and, 1 year later, the first HIVYou see that the index of condom use among the target groups of the programmes is still less than 50%. Different studies have shown this. I believe that with such new policies that are now being applied in the country, such indices will surely get worse.” (participant 20).“Although the pattern of HIV transmission is getting shifted towards sexual relations, in my idea, the injection way is still the most important way. More attention should be paid to harm reduction policies, also, the range of under coverage individuals for such policies should be increased.” (participant 4).“In recent years, Iran’s policy content in the area of HIV/AIDS has been crystallized in the national strategic plans. The third strategic plan, which ended in 2015, included specific HIV/AIDS strategies and operational goals approved by the cabinet. This plan indicated the content of Iran’s policies on the disease and emphasized the domains of education and information, harm reduction, prevention from sexual transmission, consultation, care and treatment services, patient support, mother-to-child transmission prevention, and the political and organisational infrastructure. Some quotations are presented below:The multi-sectoral nature of HIV/AIDS prevention and its close relationship with the fields of addiction and social harms urge the need for wide inter-sectoral coordination. The HIV/AIDS Supreme Council was formed to determine the policies of executive agencies, and to coordinate the stakeholders. However, in recent years, the mechanisms of inter-sectoral coordination have actually been weakened after the integration of the SCHAPP into the Health Supreme Council and Food Security. Since the council was in charge of public health with a lot of different agendas, some public health concerns other than HIV/AIDS were given greater priority and were paid more attention by stakeholders and politicians. Some of these public health concerns included the goals and challenges related to the health development plan, the increasing rate of non-communicable diseases like cancer, coronary heart diseases and sedentary lifestyle, as well as food security issues. Figure Although the National Strategic Plan is determined by the prime minister, there is not such an executive guarantee for the plan. In my idea, the AIDS office is not fully supported to completely execute the programmes” (participant 2).“… the first and the second plan [the national strategic plans] were only written on sheets and were delivered to the related organizations, and the third plan were presented with the signature of the vice president. But, no money is allocated to a plan, how it can be implemented?!” (participant 7).“ Some actors believed that returning to the HIV/AIDS Supreme Council is a solution for the current situation. Some others posed the current challenges in the work of National Committee and suggested the lack of the governmental authority system (the MOH) in giving priority to HIV/AIDS prevention programmes. Some other key informants considered HIV/AIDS prevention policy-making as a complex task and believed there was a great lack in HIV/AIDS policy-making. They believed that a higher-level structure of the government should be involved in the process rather than an executive branch like the MOH. For instance, at least three branches of the government have to be involved into HIV/AIDS policy-making process to assure the necessary authority needed for strategic policy-making. The reason for this high-level integration was announced to be the existence of serious cultural and attitudinal obstacles that may be only resolved by a good level of interaction between the three branches. The following are some quotations:In the disseminated national HIV/AIDS reports, in some domains, like the sexual and MSM issues, there is no evidence to be cited. It is clear, the lack of evidence will surely deviate the vision and the policies” (participant 8).“In the current national AIDS strategic plan, the cost-effectiveness and cost-benefit analyses are ignored. Well, this results in wrong evaluation and infirm evidence” (participant 23).“Some evidences are approached politically in the higher level of the government, and some other considerations are focused. For example, the politic of country is not to highlight the issue [that evidence shows].” (participant 15).“As the key informants noted, the first problem of HIV/AIDS policy-making in Iran was a lack of evidence in some specific areas . They believed on a lack of strong, reliable and nationwide evidence in many aspects of the issue, and commented that a majority of the evidence was based on local research in particular places and time periods. Since HIV/AIDS researchers usually pursue their personal interests, appropriate investigations were inadequate. Additionally, minimum budgets were often allocated to HIV/AIDS research. Another problem reported by participants was the lack of person-power and facilities to produce evidence. Managers were reported to be not interested in producing evidence, and thus little evidence was produced from running programmes. This lack of evidence has often resulted in various problems, in a way that using trial and error was usually common in the executive agencies. The associate managers sometimes have to meet the everyday needs of people, and may temporarily set aside the evidence. For example, despite the evidence emphasizing inefficiency and even harmfulness of gathering addicts from streets and transferring them to camps, the Iranian managers still approach the issue in this manner as an effort to respond to people’s urgent requests for a drug-free environment. Sometimes, the political viewpoints or the personal opinions of the managers affect the decision of whether or not to use evidence. Lack of interested and competent management in applying evidence, lack of accountability among the managers, high workload of managers and lack of time to refer to evidence were other managerial factors affecting evidence non-use. However, it should be acknowledged that the evidence relating to some policies, like harm reduction programmes, has been advantageously used in many cases. Moreover, the presence of international organisations, such as UNAIDS and WHO, has improved the use of evidence in HIV/AIDS policy-making in Iran. Here are some quotations from the participants:Based on our results, the main outcomes of the HIV/AIDS policy process in Iran were harm reduction policies and an HIV/AIDS national strategic plan, which have had effects on different areas of the issue. Harm reduction programmes in Iran were initially presented in the form of triangular clinics established in the communities and prisons throughout the country. Iran’s efforts in controlling HIV/AIDS in prisons have been known as one of the most successful efforts in the world . Harm reAs participants explained, a challenge of implementing harm reduction policies was the failure of Iranian governments in generalizing the programme towards risky sexual behaviours due to difficulties in engaging sufferers into the programme, such as the reluctance of sufferers to join the programme, legal gaps and lack of suitable strategies. In contrast, other countries, like Vietnam, achieved success in controlling HIV/AIDS through similar programmes , 38. OurAlthough the fifth Iranian development plan implementation is over, there is still a superficial understanding on the true nature of the HIV/AIDS programme in Iranian society. As participants reported, the contextual factors have not been well considered and analysed. As a consequence, the total responsibility of HIV/AIDS programme was given to the MOH, which means that HIV/AIDS was considered a health issue rather than a sociocultural concern. Therefore, a challenge in inter-sectoral response was aroused and, eventually, the programme failed to achieve the desired goals. Such an issue was reported in the HIV/AIDS programme of other countries, including South Africa . Our parOne of the main objectives of the NSP was strengthening HIV/AIDS programme infrastructure such as alleviating the legal gap and winning the support of high and influential officials for the policies . HoweverIn terms of the HIV/AIDS policy content, our participants reported a gap between the data and required evidence and, thus, there was no precise plan in the NSP to approach some high-risk groups like men who have sex with men . As partFinally, a lack of precise HIV/AIDS laws was reported to intensify the confusion in policy-making, administrative systems and non-effective trustees, which may have negatively impacted the role of key stakeholders in the policy-making process. Our participants also reported a lack of interaction between responsible institutions for controlling HIV/AIDS, particularly among high-risk populations. All these problems may cause serious social damage to Iranian society, like those caused by drug addiction.Applying a pre-defined framework for this study was helpful in systematic analysis of the policy process and research. However, there is the fact that some important factors and features may be neglected, which should be considered as a limitation for our study. To overcome this limitation, we maintained a critical view on the codes and a deep contemplation about their nature during data analysis. Although the limitation may not entirely be overcome, this approach was definitely helpful. Moreover, discussing and comparing the results of our study with those of other studies with and without a particular framework provided us with a comprehensive analysis on the HIV/AIDS policy process in Iran.Considering the significance of context in Iranian HIV/AIDS policy-making and its high impact on the other parts of framework, we chose it as the basis for our study. In summary, the framework by Green et al.  was founOur results demonstrated that the HIV/AIDS policy process in Iran was considered a governmental process alone, and the role of civil society and the NGOs within the process seems to be entirely ignored. The historical and political context of public policy-making in Iran has strengthened such an approach towards HIV/AIDS policy-making. Moreover, several challenges were identified in the policy process, including difficult access to high-risk groups, a low level of population coverage in HIV/AIDS prevention/treatment programmes, and lack of strong and sufficient evidence for policy-making. In order to overcome the challenges, there is a great need for change in the government’s approach towards the issue, and for active participation of non-governmental sectors and civil society in the policy process. Furthermore, the dominance of therapeutic approaches within the health system, and too much emphasis on the aspects of treatment and rehabilitation rather than prevention in both the addiction and HIV/AIDS domains, urge the need for overall reorientation in HIV/AIDS policy-making.The analysis of HIV/AIDS policy-making process conducted in the present study may be helpful in answering the question of why the HIV/AIDS initial challenges are still present in Iranian society after three decades of the emergence of the disease in the country.


With the advancement in pavement design and performance analysis procedures, the coefficient of thermal expansion (CTE) of concrete has emerged as a significant design input with a direct impact on concrete pavement performance parameters including transverse cracking, joint faulting, and pavement roughness. CTE is the measure of change in concrete volume with temperature change and the resulting curling of concrete pavement slab is directly proportional to CTE. Un-Bonded Concrete Overlay (UBCO) is a cost-effective and sustainable rehabilitation technique on Jointed Plain Concrete Pavements (JPCP) to improve the performance of deteriorated concrete pavements. This study examines the effects of variability of CTE on the performance of unbonded JPCP overlays for two different climatic regions. Simulations were conducted using AASHTO pavement ME design software with varying CTE values in the range of 6.8–10.8 micro-strain/°C and keeping all other design variables as constant. The performance predictions were evaluated for different values of CTE and the results indicated that with an increase in CTE value, the performance of UBCO is adversely affected by the increase in pavement distresses. Amongst all the performance parameters, transverse cracking is the most significantly affected parameter with the change in CTE. The impact of geometric properties of overlay pavement including transverse joint spacing and slab thickness on the pavement performance was also analyzed which indicated that these have a direct impact on the performance parameters. The overlay performance can be improved by increased overlay slab thickness or reduced joint spacing and with these modifications, the adverse effects of higher CTE can be compensated. Field performance data of UBCO extracted from the LTPP database showed that the pavement ME design software can accurately predict the performance of UBCO pavement systems. Jointed plain concrete pavement (JPCP) is a widely used rigid pavement type in the United States and unbonded concrete overlay (UBCO) is a cost-effective rehabilitation technique to improve the performance of the existing deteriorated JPCP. UBCO is a sustainable solution for improved management of pavement assets and the primary purpose of an unbonded overlay is to restore the structural capacity of an existing deteriorated/damaged pavement. UBCO involves placement of an inter-layer of hot mix asphalt (HMA), which acts as a separation layer between the existing concrete pavement and the unbonded overlay. It is also called the de-bonding layer and is usually a thin HMA layer of 25.4–50.8 mm (1–2 inch) thickness. Factors that affect the performance of UBCO include traffic volume, climate, concrete material properties, existing pavement condition, and design life. The latest pavement performance prediction tools such as the pavement mechanistic-empirical (ME) design has provided the opportunity to analyze the performance of concrete pavements rehab designs. Wholesome literature is available on the effects of various concrete properties on the performance of concrete pavements but there has not been much research on the performance analysis of UBCOs. In a recent study of the sensitivity of various material properties on rigid pavement performance, Schwartz et al. McCarthy et al. The CTE of Paving mixes is tested according to AASHTO T-336 test protocol •Quantifying the effects of CTE inputs on the performance of unbonded JPCP overlays including joint faulting, transverse cracking, and pavement roughness for two different climatic regions.•Mitigating the effects of higher CTE on overlay performance by modifying the geometric properties of the overlay pavement.The structural parameters of JPCP which is a single layer concrete pavement and UBCO are different as the JPCP involves placement of concrete slab over the unbound layers whereas UBCO comprises the overlay concrete slab over the cracked concrete pavement with a flexible HMA layer between the two. The behavior of the two pavements to the temperature and wheel loads should be entirely different based on their structure especially with the insertion of the flexible interlayer in UBCO. The available literature is focused on the effects of CTE on single layer concrete pavements and there was a need to evaluate the impact of CTE on the performance of UBCO. This study focuses on the effects of CTE variation on the performance of unbonded JPCP overlay of existing JPCP. In this study, simulations were conducted in Pavement ME design version 2.3 for two climatic regions with different CTE values of overlay concrete and keeping all other material, traffic and other design parameters as constant to analyze the impact of CTE variability on the performance over the design life of unbonded JPCP overlays. The two climatic regions were considered to observe the effects of CTE along with different climatic conditions. Modifications in pavement structural/geometric properties were considered to minimize the effects of CTE on overlay performance. The objectives of this study are as under:2The pavement ME design procedure was initially developed under the National Cooperative Highway Research Program (NCHRP) project 1-37A and further revised under continuing research projects. AASHTO eventually adopted the procedure as the standard for pavement design in 2008 2.1The performance indicators for unbonded JPCP overlays are joint faulting, transverse cracking and pavement roughness. The threshold and reliability limits for each of the performance indicator is required to be set by the pavement design engineer. The ME design default performance criteria were selected for the analysis of the results of this study which is tabulated in 2.1.1MOR = Modulus of rupture of the concrete; σ = Critical stress in the slab; Napplied = Applied number of load applications; Nallowable = Allowable number of load applications; C1, C2, C4, C5 = Calibration coefficients.This parameter is a combination of top-down and the bottom-up transverse cracks. The overlay pavement slab experiences two types of curling depending on the temperature gradient through the slab thickness commonly known as upward curling and downward curling. Upward curling occurs when there is a positive temperature gradient in the slab  whereas the downward curling occurs when there is a negative temperature gradient in the overlying slab. Bottom-up cracking occurs due to the downward curling and top-down cracking is due to the upward curling. Major factors that affect transverse cracking are CTE of overlay concrete, slab thickness, joint spacing, and concrete strength. In Pavement ME Design, the transverse slab cracking predictions are calculated from a set of equations as follows Tcrack = Total transverse cracking (percent); CrackBottom-up = Predicted amount of bottom-up transverse cracking (fraction); CrackTop-down = Predicted amount of top-down transverse cracking (fraction).Total transverse cracking predictions are calculated as follows 2.1.2m = Mean joint faulting at the end of month m; ΔFAULTi = Incremental change (monthly) in mean joint faulting during month I; FAULTMAXi = Maximum mean transverse joint faulting for month I; FAULTMAX0 = Initial maximum mean transverse joint faulting; EROD = Base/subbase erodibility factor; DEi = Differential density of energy of subgrade deformation accumulated for month I; δcurling = Maximum mean monthly slab corner upward deflection in PCC due to temperature curling and moisture warping; Ps = Overburden on subgrade; P200 = Percent subgrade material passing #200 sieve; Wet Days = Average annual number of wet days; C1, 2, 3, 4, 5, 6, 7, 12, 34 = Calibration coefficients.Transverse joint faulting measures the differential elevation across the transverse joint. Pavement ME design predicts the mean faulting of all the transverse joints in a pavement section and the unit of joint faulting is mm or inch. Joint faulting is directly proportional to upward curling of the overlying slab that is dependent on the CTE of overlay concrete. The upward curling results in the creation of void spaces beneath the slab edges and with the repeated heavy axle load the erosion of the sublayer starts. This erosion causes the faulting of the slab edges. Transverse joint faulting is calculated from the following set of equations 2.1.3IRI = Predicted IRI; IRIini = Initial smoothness measured as IRI; CRK = Percent slabs with transverse cracks ; SPALL = Percentage of joints with spalling (medium and high severities); TFAULT = Total joint faulting cumulated; SF = Site factor; C1, 2, 3, 4 = Calibration coefficients; JSP = Joint spacing.Pavement roughness can be defined as an expression of irregularities in the overlay surface that adversely affect the ride quality. Roughness affects the ride quality, vehicle delay costs, fuel consumption and maintenance costs. Roughness is quantified using international roughness index (IRI). It is the characteristic of the longitudinal profile of a traveled wheel-track and constitutes a standardized roughness measurement 2.2The CTE of paving concrete varies over a broad range depending on the constituent materials. As coarse aggregate accounts for 50% to 60% of the volume of concrete thus the mineralogy of coarse aggregate is the most significant factor affecting CTE of concrete. The average CTE values of paving concrete with regards to the coarse aggregate/gravel type are shown in 3Simulations were conducted in pavement ME version 2.3 for analysis of unbonded JPCP overlay of existing/deteriorated JPCP. The software requires various inputs including design life, traffic volume, overlay structure, concrete thermal and strength properties, properties of sub-layers, and condition of existing JPCP. To evaluate the impact of CTE variability, all the design inputs were considered constant for entire simulation work except the CTE of overlay concrete. The traffic and climatic details were considered according to the studies conducted by Hasan et al. , 17. PriAccording to 44.1The analysis of CTE variation on the transverse cracking parameter of UBCO was conducted. The comparison of results of transverse cracking after 30 years of service life for both the climatic regions is presented in For the moderate climatic region, the overlay fails to meet the design criteria of transverse cracking at the age of 17 years when CTE value reaches 9.9 micro-strain/°C (5.5 micro-strain/°F) and with further increase in CTE values the overlay fails even earlier. For the cold region, the overlay fails to meet the transverse cracking threshold at the life of 13 years with the CTE value of 8.1 micro-strain/°C (4.5 micro-strain/°F). The analysis shows that transverse cracking increases as the CTE of overlay concrete increases and the effect is more pronounced in the cold climate. The general trend of the decline in overlay performance confirms that higher CTE is associated with higher curling resulting in higher lift off from the pavement slab which results in higher stresses in the pavement slab due to the combined effect of traffic loading and curling. The significant difference in the overlay performance between the two climatic regions can be linked with many climatic factors including precipitation, humidity, number of freeze-thaw cycles and temperature variation pattern. With regards to CTE, the temperature variation pattern is the most critical factor. The average variation between day and night temperature for the moderate region is 6.6 °C (44 °F) and for the cold region, it is 15.5 °C (61 °F). As the day/night temperature variation results in the temperature gradient through the thickness of the pavement slab and higher temperature difference corresponds to a higher temperature gradient resulting in higher curling. Higher curling combined with traffic loading results in higher stresses and early deterioration of the pavement. The variation in performance can also be linked with the number of freeze/thaw cycles as loading/traffic volume and other design variables remained constant for these simulations. The cold region has a much higher number of freeze/thaw cycles in comparison with the moderate climatic region and the overlay pavement undergoes much more cracking in the cold region than in the moderate region.To minimize the performance issues, either lower CTE concrete should be used or the pavement structure needs to be revised/modified for the higher CTE concrete so that overlay can perform within the prescribed performance parameters.4.2The impact of CTE variation on the performance of overlay with regards to joint faulting was analyzed and the results for both the climatic regions are presented in With regards to the variation of performance between the two climatic regions, the primary factor is the difference in the day/night temperature variation. As noted previously, the average variation between day and night temperature for the moderate region is 10 °C (50 °F) and 15.5 °C (60 °F) for the cold region. As the day/night temperature variation results in a temperature gradient through the thickness of the pavement slab and higher temperature difference corresponds to a higher temperature gradient resulting in higher curling. Thus, for the same CTE, higher joint faulting is observed for the cold region as compared to the moderate region.4.3The effects of CTE variation on the IRI were evaluated and the results for both the climatic regions are shown in The decline in the performance of UBCO with regards to pavement roughness with an increase in CTE of overlay concrete is principally attributed to higher transverse cracking and higher joint faulting while other design variables being constant. As discussed earlier in this paper, cracking and faulting distresses increase with an increase in concrete CTE thus, IRI also increases with increase in CTE.For different climatic regions, there is another crucial factor of freezing index in the performance prediction model of pavement ME design. The higher freezing index will result in higher IRI and the same trend has been observed in the simulation results as the overlay pavement in the cold region experienced higher pavement roughness due to higher freezing index as compared to the moderate region with lower freezing index. To mitigate the effects of higher CTE and to improve the overlay performance the overlay design needs to be modified to achieve the ultimate design life.4.4As variation in performance predictions was observed with varying CTE of overlay concrete thus, a sensitivity analysis was performed to quantify the impact of CTE increase on the three performance parameters and to determine the most significantly affected performance measure. The normalized percent change for cracking, faulting and IRI were obtained for a unit change in CTE for different ranges of CTE and the results are shown in Figs. 4.5According to the performance criteria set forth for this study, the UBCO fails if it does not comply with the prescribed performance threshold until the end of design life. As evident from the results shown earlier that many design simulations do not meet the performance standards, both in the moderate climatic region and cold region. Many different measures can be taken to improve the overlay performance and to mitigate the effects of higher CTE and to ensure that the overlay pavement can perform up to the designed life. These measures include increased overlay thickness, reduced joint spacing, increased dowel size, widened slabs, enhancing concrete strength properties, and tied shoulders. For this study, two of these measures were considered for further evaluation with regards to transverse cracking, which is the most affected performance parameter. These were the reduction in joint spacing and increase in overlay slab thickness.4.5.1Simulations were conducted for CTE range of 8.1–10.8 micro-strain/°C with a different transverse joint spacing of overlay slab to observe the impact of joint spacing on transverse cracking. The results are presented in Figs. 4.5.2Revised simulations were conducted with various overlay slab thicknesses ranging from 203 to 304 mm to evaluate the effect of slab thickness on transverse cracking for different CTE values ranging from 8.1 to 10.8 micro-strain/°C. The comparison is presented in Figs. 4.6The simulation results were validated by comparison of the performance data of actual UBCO projects constructed in various parts of the United States under the Long-Term Pavement Performance (LTPP) program. Material properties and field performance data from five (5) unbonded jointed PCC overlays over JPCP pavements constructed under General Pavement Study (GPS)-9 were extracted from the LTPP database. This was an important step to validate the simulation results presented earlier. These projects were given case # A to E for data analysis and comparison. The location and construction details of these projects are given in The overlay concrete of these projects had varying material properties including compressive strength, elastic modulus, flexural strength, and CTE. The CTE values of overlay concrete ranged from 6.8 to 8.8 micro-strain/°C with different types of coarse aggregates. The traffic volume for these highways was also different for every project. These details are presented in Based on the material properties, design properties, traffic volume, and climate data, simulations were conducted in pavement ME design software to obtain the performance predictions for these projects. Different climate stations were used for each of these projects based on their location. The field performance data of actual projects was obtained from the LTPP database and comparison was conducted with the simulation results. The comparison is presented in 5•CTE of overlay concrete is directly related to the performance of unbonded concrete overlay and with an increase in CTE the overlay performance, including transverse cracking, faulting, and roughness, is adversely affected. Transverse cracking is the most affected parameter with the change in CTE as compared to pavement roughness and joint faulting. The major contributing factor of this phenomenon is a higher amount of slab curling and increased curling stresses due to higher CTE which consequences in void space beneath the slab, making the pavement slab un-supported that results in increasing stresses due to traffic loading. These adverse effects are more severe in cold climatic regions as compared to moderate climate region due to higher temperature gradient resulting in higher curling stresses. The climatic pattern including the variation in day/night temperature and freeze-thaw cycles also affect the performance of UBCO pavement as observed with the difference between the pavement performance predictions of moderate and cold climatic regions with all other design inputs as constant.•The geometric properties of overlay pavement including transverse joint spacing and slab thickness have a direct impact on the performance parameters. The average decrease in cracking distress is around 8.5% for the moderate climate and 19.7% for the cold region with 0.3 m reduction in joint spacing. The average decrease in cracking with an increase in overlay thickness of 25 mm is 8% for the moderate region and 23% for the cold region. Thus it is evident that the overlay performance can be improved by increased overlay slab thickness or reduced joint spacing and with these modifications, the adverse effects of higher CTE can be compensated.Gauhar Sabih: Conceived and designed the analysis; Analyzed and interpreted the data; Contributed analysis tools or data; Wrote the paper.Tahmidur Rahman, Rafiqul A. Tarefder: Contributed analysis tools or data; Wrote the paper.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.The authors declare no conflict of interest.No additional information is available for this paper.


To the editor: I read with great interest the article by Ndeikoundam Ngangro et al. entitled ‘Bacterial sexually transmitted infections (STI) in France: recent trends and patients’ characteristics in 2016’, which showed an increased number of cases of syphilis, rectal lymphogranuloma venereum (LGV) and gonorrhoea in France between 2014 and 2016 [N.gonorrhoeae and XDR Mycoplasma genitalium, (iii) increase in the number of sexual partners per year among MSM, (iv) gastrointestinal (GI) and liver diseases related to the faecal-oral route of transmission particularly among MSM, (v) appearance of blood-borne diseases such as hepatitis C in the subgroup of highly sexually active MSM, (vi) discovery of possible sexual route of transmission for emerging infectious diseases , (vii) possibility for these latter diseases to be transmitted months after cure and (viii) history as story repeats itself [The reason why French public health specialists only recommend the test and treat approach for STI instead of prevention needs to be better explained; the continuous and marked surge of gonorrhoea and rectal LGV in men that have sex with men (MSM), for example, likely warrants more than a test and treat approach. There are at least eight reasons to worry about this continuous increase of STI: (i) re-occurrence of severe complications of gonorrhoea and syphilis with high rate of sequelae, (ii) worldwide increase of resistance to antibiotics including STI agents as recently illustrated with extensively drug-resistant (XDR) s itself .Is it possible that sexually transmitted disease history, including AIDS history, has been largely forgotten? From a historical perspective, AIDS epidemics in MSM were preceded by an increase in the number of sexual partners, STI diagnoses (such as gonorrhoea and syphilis) and outbreaks of faecal-orally transmitted GI and liver diseases . On anotWith a continuous increase in STI, it is surprising that condom use and safer sex is not more actively promoted by public health authorities . A majorIndeed, promoting the repeated use of antibiotics for treatment of recurrent STI and the use of PrEP for prophylaxis of HIV infection is questionable, as condoms are an effective and harmless prevention tool. Moreover, this contrasts with the current recommendations for controlled use of antimicrobial therapy to lower antimicrobial resistance .In conclusion, it should be highlighted that prevention of STI, through condom use and safer sex, is better, less harmful and cheaper than a cure . This is


We hypothesized that the presence of these cells in peripheral blood could serve as disease activity parameter in GPA.An important limitation in granulomatosis with polyangiitis (GPA) is the lack of disease activity markers. Immunoglobulin G4-positive (IgG4n = 15), remission as BVAS of 0 (n = 17), and low disease activity (LDA) as BVAS of 1–2 and clinical remission (n = 3). Healthy subjects (n = 10), patients with systemic lupus erythematosus (n = 24), and patients with rheumatoid arthritis (n = 19) functioned as control subjects. An additional longitudinal study was performed in ten patients with GPA. Using a validated qPCR test, we measured the IgG4:IgG RNA ratio in all groups and compared the results with known biomarkers.We included 35 proteinase 3-antineutrophil cytoplasmic antibodies-positive patients with GPA in a cross-sectional study. Active disease was defined as Birmingham Vasculitis Activity Score (BVAS) ≥ 3  and outperformed other known disease activity parameters in detecting activity. A cutoff qPCR score of 11.2% differentiated active disease from remission/LDA accurately (AUC 0.993). The qPCR test correlated well with the BVAS . In the longitudinal study, a decrease in BVAS correlated with qPCR score reduction .The median qPCR score was higher in active GPA  than in remission/LDA   contains supplementary material, which is available to authorized users. Granulomatosis with polyangiitis (GPA), formerly called Wegener’s disease, is a hallmark form of primary small vessel vasculitis. In GPA, the disease activity often fluctuates over time, making titration of therapy challenging . Both diCurrent practice relies on general and unspecific inflammation parameters, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), that do not correlate well with disease activity in vasculitis. Although GPA is associated with antineutrophil cytoplasmic antibodies (ANCA), these antibodies are more reliable in diagnosing the disease than in monitoring disease activity –9. Instr+) cells have been implicated in the pathogenesis of GPA. Several studies have reported increased levels of IgG4 antibodies in both serum and tissue in ANCA-associated vasculitis (AAV) ) were significantly higher in the active group, such as physician VAS , CRP , and ESR . However, prednisolone use  and PR3-ANCA titer  did not differ significantly between the groups.The active disease group had a higher BVAS than the remission/LDA group  and those in the remission/LDA group (BVAS 0–2). The BVAS symptoms can be found in Additional file We hypothesized that the qPCR test could be used as a disease activity parameter because IgG4p < 0.0001) . Both qPCR score and BVAS did not differ significantly between both groups  . The healthy control subjects had the lowest qPCR scores, and their result is shown as a reference value . Four patients were in stable remission/LDA, and two (A1 and B) were unsuccessfully treated between the initial and follow-up time points   Fig. b.The unmet need for biomarkers in GPA lies in the ability to distinguish GPA activity from mimics such as infections. To investigate whether the IgG4 qPCR would be able to differentiate between GPA activity and mimics, we performed the IgG4 qPCR test in a real-life clinical situation where clinical symptoms could be caused by either GPA activity or GPA mimics. We tested six patients. Two patients were from the cross-sectional cohort (CS1 and CS2), and four patients were from the longitudinal cohort  Table . We usedIn patients in whom the symptoms were caused by mimics, the qPCR scores were normal . In the ten patients from the longitudinal cohort, we calculated a ∆BVAS and ∆qPCR . Correlation was excellent in the lower disease range. However, the correlation slightly decreased, especially in the patients showing high ∆BVAS and ∆qPCR. Further studies are needed to analyze whether this reflects nonlinearity when measuring vasculitis activity by the qPCR, by the BVAS, or both.We observed that the BVAS and qPCR showed a significant correlation  and sensitivity (ESR) Table  4, 7–9]–97–9]. TThe qPCR test is based on earlier NGS results in IgG4-RD, where we showed that the qPCR test can accurately discriminate the biliary form of IgG4-RD from its mimics and quantitatively correlates with disease activity in the individual patient . The qPC+ cells, as measured by the qPCR test in this study, raises the hypothesis that there is a shared (patho-)physiological mechanism involved. This mechanism might by exploited as a potential therapeutic target in the future.The fact that similar results are now found in AAV is not unexpected, given the clear overlap in clinical, histological, and even laboratory features between IgG4-RD and GPA , 23–31. not reflect an increase in the amount of IgG4 protein present in serum, but rather represents either an increase in the number of IgG4-producing B-lineage cells and/or an increase in the number of IgG4 mRNA molecules expressed per cell, such as during differentiation from mature B cells to plasmablasts. Although we extensively studied the relationship between the qPCR test and the presence of such BCR clones in IgG4-RD previously, we once more confirmed this in one of the patients with GPA  and systemic  disease groups did not show any differences in qPCR score, suggesting that the IgG4Furthermore, one could argue that although not significantly different between the groups, the remission/LDA group had a longer duration since diagnosis and therefore possibly had more cumulative treatment, which could explain these results. However, years since diagnosis and qPCR score did not correlate, indicating that a longer disease duration is unlikely to yield lower qPCR scores  did the qPCR scores decrease. Second, most patients were included at first presentation of active disease , when more potent agents such as RTX and CYC are yet to be initiated. Only four subjects were included at a moment during induction therapy when they had received one or more cycles of RTX or CYC. Our findings do not indicate that the IgG4 qPCR score is directly altered by these agents, implying that the IgG4 qPCR reflects disease activity. Nevertheless, we want to emphasize that this study is too small to make definite conclusions. A larger longitudinal study is needed to study the relationship between drugs and IgG4 qPCR scores. Such a study would need enough responders and nonresponders receiving each drug to differentiate the effect of a drug from a change in disease activity as a cause of the change in IgG4:IgG mRNA ratio. Moreover, the long-term effects of B-cell-depleting therapies such as RTX on the IgG4:IgG mRNA ratio are unknown and would require a study that addresses the relationship between the IgG4 qPCR score and circulating B-cell subsets, including plasmablasts. In IgG4-RD, prednisone was also shown to decrease plasmablast counts, which in turn was correlated with disease activity , 19. DisWe report that the IgG4:IgG RNA ratio as measured by a qPCR test might be a new and promising disease activity marker in GPA. The qPCR test is able to accurately distinguish disease activity from remission/LDA and outperforms frequently used disease activity parameters in GPA. Furthermore, it seems feasible to use the qPCR test as a monitoring tool and discriminate disease activity from mimics such as infection. A major limitation of this study is the lack of independent validation of the results. Therefore, the value of the test should be further explored in longitudinal studies. If the present results are confirmed, it will help to optimize treatment, thus preventing morbidity and mortality from under- and overtreatment.Additional file 1:Table S1. BVAS division per active (a) and low disease activity (LDA) subject with the most involved (dominant) organ and qPCR score. The final column shows the number the subject has in Fig. Table S2. Coordinates of the curve: the critical cutoff values for the qPCR test, producing different values for sensitivity and specificity. Table S3. Average qPCR score per dominant organ. Table S4. Patient characteristics for SLE (n = 24) and RA (n = 19) cohorts. IgG4-RD (n = 15) and HC (n = 10) are shown as reference groups. na = not annotated, ns = not significant. (DOCX 25 kb)Supplementary methods. Additional file 2:Figure S1. ROC curve portraying sensitivity and specificity of the qPCR test to distinguish active GPA from remission. The blue arrow points toward the cutoff that yields the highest specificity with the least loss of sensitivity. (JPG 40 kb)Additional file 3:Figure S2. Active GPA vs remission GPA (without LDA). Scatter dot plot portraying the percentage of IgG4 from total IgG RNA molecules in the active vs remission groups in GPA without LDA. (BMP 3716 kb)Additional file 4:Figure S3. Serum IgG4 vs qPCR test. Scatter dot plot portraying the correlation between serum IgG4 (x-axis) and the percentage of IgG4 from total IgG RNA molecules (y-axis) (Spearman’s r correlation). (BMP 3413 kb)Additional file 5:Figure S4. Systemic GPA vs limited GPA. Scatter dot plot with in (a) the qPCR result within the active GPA group divided by systemic and limited disease and in (b) the matching BVAS for this group. (BMP 13494 kb)Additional file 6:Figure S5. Active GPA vs active IgG4-RD. Scatter dot plot portraying the percentage of IgG4 from total IgG RNA molecules in the active GPA vs active IgG4-RD control groups. ns = not significant. (BMP 3861 kb)Additional file 7:Figure S6. NGS data on IgG4+ BCR clones. NGS data portraying the frequency of IgG4+ BCR clones (red) and IgG clones (black) in a GPA patient  and a representative healthy control subject . See an earlier study for a complete description of the amplification protocol [protocol . Brieflyprotocol .