In 1996, Brazil became the first developing country to provide free, universal access to HAART, laboratory monitoring, and clinical care to any eligible patient. As of June 2014, approximately 400,000 patients were under treatment, making it the most comprehensive HIV treatment initiative implemented thus far in a middle-income country, worldwide. The Brazilian epidemic is highly concentrated among men who have sex with men (MSM).Four national information systems were combined and Cox regression was used to conduct retrospective cohort analysis of HAART availability/access on all-cause mortality among MSM diagnosed with AIDS reported to the information systems between 1998–2008, adjusting for demographic, clinical, and behavioral factors and controlling for spatially-correlated survival data by including a frailty effect. Multiple imputation by chained equations was used to handle missing data.Among 50,683 patients, 10,326 died during the 10 year of period. All-cause mortality rates declined following introduction of HAART, and were higher among non-white patients and those starting HAART with higher viral load and lower CD4 counts. In multivariable analysis adjusted for race, age at AIDS diagnosis, and baseline CD4 cell count, MSM diagnosed in latter periods had almost a 50% reduction in the risk of death, compared to those diagnosed between 1998–2001 . After controlling for spatially correlated survival data, mortality remained higher among those diagnosed in the earliest diagnostic cohort and lower among non-white patients and those starting HAART with higher viral load and lower CD4 lymphocyte counts.Universal and free access to HAART has helped achieve impressive declines in AIDS mortality in Brazil. However, after a 10-years follow-up, differential AIDS-related mortality continue to exist. Efforts are needed to identify and eliminate these health disparities, therefore improving the Brazilian response towards HIV/AIDS epidemic. By the end of 2013, 35 million [33.2 million-37.2 million] people were living with HIV worldwide and 1.5 million [1.4 million-1.7 million] AIDS-related deaths were reported in the latest Epidemiological Bulletin released by UNAIDS. The introduction of combination antiretroviral therapies has led to dramatic improvements in AIDS-related morbidity and mortality in countries where this treatment is available [Highly active antiretroviral therapy (HAART) significantly improves the prognosis of HIV-infected persons by reducing HIV viral load, increasing CD4+ lymphocyte counts and delaying progression to AIDS, ultimately reducing mortality rates ,3.Pre-exposure prophylaxis (PrEP) for HIV infection has greatly improved the field of HIV prevention , and a rEarly detection and management of HIV infection are key challenges worldwide, but a growing body of evidence supports the immediate use of HAART to maintain CD4 count and functionality, limit the size of the HIV reservoir, and reduce the risk of onward viral transmission . FollowiHowever, AIDS-related deaths continue to occur, even in high-income countries, and the emergence of drug-resistant HIV variants and drug toxicities remain major barriers and challenges to successful long-term antiretroviral efficacy ,9.Although stable, on average, the epidemic in Central and South America is currently concentrated in specific groups, mainly among MSM ,10. In BBrazil was the first middle-income country to provide full access to HAART, laboratory monitoring and clinical care at no cost at the point of health care delivery to any eligible patient, since 1996 . As of JRecent Brazilian observational studies have brought essential information about mortality patterns among HIV-positive patients under follow-up in Brazil’s referral centers ,18. HoweHerein, we report differences in survival from AIDS diagnosis according to period of AIDS diagnosis, within the unique Brazilian setting. The study evaluated all MSM receiving treatment in the country between 1998 and 2008, therefore avoiding selection bias present in analyses from specific subsets  of the country’s population living with HIV/AIDS.This study utilized four databases comprising different longitudinal information of all people living with HIV/AIDS (PLWHA) under treatment and care through the Brazilian public health system. These databases comprise all patients receiving any antiretroviral medicine in Brazil since such medicines are not procured, purchased, or delivered by private health facilities or pharmacies for patients who are not hospitalized.i.Socio-demographic and basic clinical (for the sake of diagnosis) information on AIDS cases (SINAN-AIDS - Information System for Notifiable Diseases/AIDS);ii.Data from exams conducted in the network of accredited public laboratories, particularly TCD4+/TCD8 lymphocyte counting and HIV viral load ;iii.Information about monthly ARV refills and therapeutic regimen changes over time (SICLOM - Logistics Control System of ARV Medicines); andiv.The date and cause/s of death .These databases contain the core information of Brazil’s surveillance system. Their basic characteristics are briefly summarized as follows:Whereas patients may seek private medical care and perform laboratory exams in private facilities, all PLWHA receive their antiretroviral drugs through SUS , the single accredited source of ARVs in Brazil, and should be included in SICLOM database. At the time we conducted our analysis, SICLOM data have been updated to improve the comprehensiveness of collected data, which tend to be limited to the core information which is essential for medicines dispensing at the several health services belonging to the network of accredited public health units. Thus, to utilize data from all regions, we could not include additional information such as measures of adherence, side effects, drug regimen shifts, etc. as these data were not yet available for all regions and services.Data from the entire population of PLWHA with AIDS diagnosis between 1998 and 2008, whose transmission category was homo/bisexual contact were extracted from those databanks and merged. The databank linkage procedures have been described in detail elsewhere .For this analysis, participants were included if they were diagnosed as having AIDS between January 1, 1998 and December 31, 2008, and if their most probable route of HIV infection was male-male unprotected anal intercourse. Those patients were included because we aimed to analyze differences in survival from AIDS diagnosis among the MSM population, for which higher rates of initiation and better adherence to HAART during three different AIDS diagnosis periods: 1998–2001, 2002–2005, and 2006–2008 have been documented in the literature and by our own exploratory analyses.3, 200–350 cells/mm3, and >350 cells/mm3. Viral load at initial diagnosis was classified as <4.00 log10 copies, 4.00-5.00 log10 copies, and >5.00 log10 copies.The final merged database comprised the following covariates: date of birth, race, date of AIDS diagnosis, dates of initiation of HAART, CD4 counts and viral load at diagnosis, cause(s) and date of death. CD4 counts at initial diagnosis were classified into three categories: < 200 cells/mmThe primary endpoint of interest in the present study was all-cause mortality during 1998–2008. Survival was calculated as the time elapsed from date of AIDS diagnosis until the date of death. Individuals who remained alive were censored at the end of data collection period . Time from AIDS diagnosis was transformed from days to years since diagnosis. Since analyses were based on secondary data, we did not have access to information on clinical visits; therefore we were not able to calculate losses to follow-up.Kaplan-Meier curves were fitted to compare probabilities of survival according to selected period of diagnosis and CD4 count at diagnosis using the log-rank test. Cox proportional hazard regression modeling was used to examine covariates associated with survival among the following: age at AIDS diagnosis, race, period of AIDS diagnosis , first CD4+ lymphocyte count, HAART uptake, and first HIV-RNA viral load exam. The likelihood ratio test was used to select variables to be entered in the Cox models, adjusting for potential confounders. The assumption of proportional hazards was evaluated through the examination of Schoenfeld residuals .Hazard rates are strongly influenced by selection effects operating in the population , and individuals surviving up to a certain time will on average be less frail than the original population, therefore unobserved individual heterogeneity (or frailty) was also taken into account .With 8.5 million square kilometers and over 202 million inhabitants according to the National Census, 2010, updated as of July 2013  and reguTo estimate confidence intervals for Cox's proportional hazards models, robust methods were used. Maximum penalized likelihood estimation was used to fit frailty models. To handle missing data, we implemented multiple imputation by chained equations using classification and regression trees (MICE-CART) as the conditional models for imputation . This meCreating multiple imputations, as opposed to single imputations, accounts for the statistical uncertainty in the imputations. In addition, the chained equations approach is very flexible and can handle variables of varying types , and has been reported as very reliable when used in different datasets ,28. All No identifiable personal data were used for this study. The dataset used in the study is not openly available. Permission to use non-identifiable, individual data extracted from HIV/AIDS administrative databases was granted by the Brazilian Ministry of Health, Department of STDs, AIDS and Viral Hepatitis. Ethical approval for use of encrypted and aggregated data was also obtained from the Oswaldo Cruz Foundation Research Ethics Committee (Protocol CEP/ENSP 179/08) and the Brazilian National Research Ethics Committee (CONEP 15308).Between January 1 1998 and December 31 2008, 50,683 MSM were diagnosed with AIDS in Brazil. Of these, 20,702 (40.9%) were diagnosed between 1998–2001, 19,280 (38.0%) in 2002–2005, and 10,701 (21.1%) in the last period under analysis, 2006–08. The overall mean age at AIDS diagnosis was 35.4 years (SD: 9.5). Data on race from 39.0% of our sample was missing. Although all patients had a confirmed AIDS  diagnosis, there were no information respecting 29.5% of the CD4 counts and 42.5% HIV-1 RNA viral load determinations in the merged database , with visible improvements among patients from the second and third cohort period (p < 0.0001). Taking into consideration the short follow-up time for participants in diagnostic period 2006–2008, there appeared to be little difference in survival between the last two diagnostic periods  and 2006–2008 , compared to the first period of diagnosis (1998–2001). The unadjusted HR for the period 2006–2008 was higher  when compared to the reference of 2002–2005 to assess difference between latter periods (data not shown).10 copies/ml at diagnosis had a higher risk of death, as well as non-White patients . There was no difference between the cohort diagnosed in 2006–2008 compared to the cohort diagnosed in 2002–2005, after adjustment in the Cox model . Additional predictors of longer survival included younger age at diagnosis and higher CD4 counts at diagnosis. Patients with an HIV-RNA viral load >5logUpon multivariate Cox frailty regression that accounted for a random effect associated with the Brazilian state where patients lived Table , the incThe estimated frailty variance was significantly different from zero, suggesting that the risk of death after AIDS diagnosis was heterogeneous among subjects living in different states Table . We adjuGreater frailty effects  were found in larger states located in the Tropical Rain Forest region and in states located in the Northeast, Brazil’s poorest region. On the other hand, industrialized areas from the Southern and Southeastern regions accounted for the smallest frailty effect Figure .Figure 2This is the first Brazilian nationwide analysis of survival after AIDS diagnosis among MSM. Our study compared different time periods after the full introduction of HAART over the whole country, following the approval of the federal legislation regulating the right to the universal access to antiretroviral medicines for people living with AIDS, as of the end of 1996 . ImprovePrevious papers documented the dramatic improvement of survival before and after HAART , and ideThe observed improvements in the latter periods of diagnosis compared to those diagnosed between 1998–2001 are favorable. No difference, however, has yet been detected between those diagnosed in 2006–2008 compared to those diagnosed in 2002–2005. This finding may be attributed to barriers and problems in the current treatment program and the concrete operations of the respective network of public health services. Among the most relevant of such challenges, some are highlighted as follows: i) the increasing pressures over costs , challenOther problems to be tackled by clinicians and health managers include the progressive, albeit moderate, increase of secondary resistance  and the Our statistical modeling incorporated frailty effects and demonstrated a pronounced effect of geographic, social and/or health care quality upon survival times. It is not possible to disentangle the independent effects of each one of these factors; however, our study highlighted the negative impact on survival among patients living in less industrialized and most deprived regions of Brazil. Patients living in such areas are likely to suffer from an adverse and synergic effect of poverty and lack of social support, receiving less than optimal care in settings where health services are scarce, overburdened, less accessible and of lower quality .As in any analysis of large secondary datasets, there is a trade-off between the augmented comprehensiveness of patient data under analysis and the deficiencies in terms of coverage and quality of databases. In this sense, the missing information identified in the current study constitutes serious limitations, not only in terms of the resulting analyses, but also from the broader perspective of monitoring and policymaking.Such barriers and caveats must be progressively overcome by policymakers, managers, health professionals and the civil society in a continental-sized, deeply heterogeneous country, housing the most comprehensive network of ARV dispensing units worldwide. With increasing costs and the pressing need to switch therapeutic regimens in order to minimize both HIV resistance and different adverse effects of ARVs, substantial improvement of information systems is mandatory and urgently needed, as already highlighted by Grangeiro and colleagues .The improvement in survival from the first period of HAART is undeniable and should be commended. However, results should be viewed in light of some study limitations. First, the process of merging four national databases resulted in missing data among key variables, such as CD4+ lymphocyte counts and viral load measures. Such limitations forced us to conduct multiple imputation (MICE-CART) of several variables before running the survival analysis. We did not conduct MICE-CART for race, a key variable with a significant proportion of missing information. This was a methodological and operational decision: patients with private health insurance usually have scarce information available on national datasets and our MICE-CART could not be accurately conducted with the available information. This problem calls for an urgent need to provide better training of professionals and clerks in charge of monitoring the Brazilian AIDS epidemic and to increase the accountability and consistency of such systems. A second limitation lies in the comparison of survival across time periods of initial diagnosis. Because our dataset is limited to 1998 to 2008, length of follow-up is shorter for those diagnosed in 2002–2005 and 2006–2008, limiting comparisons in survival after six to ten years following diagnosis. Nonetheless, these data are sufficient to allow for comparisons of trends in survival across different periods of diagnosis and CD4 count to AIDS diagnosis during the early years of HAART.Brazil has been a worldwide leader in the global efforts to curb AIDS and to provide a standard of care and treatment for PLWHA at no cost at the point of delivery. Notwithstanding, the concerted effort from across different sectors of government, community leadership, and the civil society at large may be seriously compromised in the absence of a comprehensive and accurate monitoring system. Although our analyses documented some progress since the early years of HAART, current levels of missing information remain unacceptably high - a critical challenge as we enter in the third decade of the HIV/AIDS epidemic, with more complex and costly treatments, more patients under follow-up and more data being collected.


In two comprehensive and fully incentivized studies, we investigate the development of ingroup favoritism as one of two aspects of parochial altruism in repeated social dilemmas. Specifically, we test whether ingroup favoritism is a fixed phenomenon that can be observed from the very beginning and remains stable over time, or whether it develops (increases vs. decreases) during repeated contact. Ingroup favoritism is assessed through cooperation behavior in a repeated continuous prisoner's dilemma where participants sequentially interact with 10 members of the ingroup (own city and university) and subsequently with 10 members of the outgroup (other city and university), or vice versa. In none of the experiments do we observe initial differences in cooperation behavior for interaction partners from the ingroup, as compared to outgroup, and we only observe small differences in expectations regarding the interaction partners' cooperation behavior. After repeated interaction, however, including a change of groups, clear ingroup favoritism can be observed. Instead of being due to gradual and potentially biased updating of expectations, we found that these emerging differences were mainly driven by the change of interaction partners' group membership that occurred after round 10. This indicates that in social dilemma settings ingroup favoritism is to some degree dynamic in that it is enhanced and sometimes only observable if group membership is activated by thinking about both the interaction with the ingroup and the outgroup. Cooperation is an essential prerequisite for human social life, but it often involves social dilemma situations that require individuals to decide whether to maximize selfish or collective interests. A typical social dilemma situation is the following: a team of two people works together on a collectively profitable project where benefits are shared evenly and independently of individual contributions. Although the collective benefit would be highest if both team members contributed as much as possible, the benefit of each individual is even higher if one chooses the non-cooperative option given that the other member cooperates.Numerous factors have been shown to influence the tendency of individuals to behave cooperatively in social dilemmas or not , and a slightly stronger effect on expectations concerning cooperation (d = 0.41). The meta-analysis identified several moderators for ingroup favoritism, such as bilateral knowledge of group membership  or the frequency of interactions (one shot vs. repeated). Although, most of the studies assessing repeated interactions acknowledge that cooperation in general changes over time , none of the studies considers changes in ingroup favoritism over repeated contact.Overall, a comprehensive meta-analysis summarizing the results of 212 studies from 77 publications  is due to parochial altruistic norms, which have an evolutionary origin. According to the theory, ingroup favoritism represents, together with aggressiveness against the outgroup (outgroup hate), a genetic or cultural trait that has co-evolved in humans  whether ingroup favoritism is mainly driven by fixed initial differences or dynamics that develop over repeated interactions, and (ii) whether these dynamics reflect rational updating or an ingroup-favoring generalization bias.Investigating initial differences and potential dynamics of ingroup favoritism is methodologically demanding. To assure high internal and external validity we decided to use a repeated version of a social dilemma game, in which participants interact with different members of both groups . Additionally to avoid effects due to artificial responses, participants interact with real interaction partners and we use real incentives. Also we use relatively salient and to some degree natural groups. Furthermore, to learn more about drivers for possible dynamics, expectations regarding cooperation are repeatedly measured.Interestingly, although there are many studies published on ingroup favoritism in social dilemmas  whether there are higher expectations regarding cooperation behavior for the ingroup as compared to the outgroup and (b) whether there is higher cooperation toward the ingroup compared to the outgroup. We used repeated interactions in a prisoner's dilemma with a stranger-rematching protocol, in which individuals knew that they would never interact with the same partner twice. Participants sequentially interacted (got into contact) with 10 different members from the ingroup and subsequently with 10 different members from the outgroup, or vice versa, which constituted a group change manipulation (contact with both groups) between the two parts of the experiment. Group salience was induced by a Skype conference of about 2 min at the beginning of the experiment, during which participants could confirm that the outgroup actually existed. Participants sitting together with their ingroup in one experimental laboratory (in separate cubicles) could see the outgroup's laboratory, but could not identify the individual participants. Besides the Skype conference, participants in Experiment 1 knew that they would play the prisoner's dilemma game with different people from their own university and city (ingroup) or another university and city (outgroup). To enforce the salience of the ingroup-outgroup differentiation, and to make sure that our manipulation did not prime the common identity of being a student, we conducted Experiment 2 , in which participants were additionally told which university and city their interaction partners came from.On theoretical ground, we investigate the development of ingroup favoritism and the underlying process driving this development. In order to do so, we test for differential hypotheses concerning generalization patterns that follow from different classes of models and examine whether the dynamic development of ingroup favoritism reflects rational updating or an ingroup-favoring generalization bias.Experiment 1 assesses whether ingroup favoritism is a fixed phenomenon that can be observed from the first interaction onwards and that remains stable over time, or whether it is a dynamic construct that develops over time. Besides, Experiment 1 aims to identify drivers for potential dynamics in ingroup favoritism.Orsee  were recruited via the online recruitment tool Greiner,  and tookAll participants were informed about the structure of the game by detailed instructions which they read before beginning with the experiment. Communication was forbidden throughout the experiment. After reading the instructions, participants answered six control questions to assure they had understood the rules. Answers were checked by the experimenters and questions were answered individually. After participants had read the instructions and answered the control questions, we arranged a live Skype conference with the other lab to assure our participants that they would interact with people from another lab in real time and to make group affiliation salient. As a manipulation check for the effectiveness of our ingroup–outgroup manipulation, before starting with the prisoner's dilemma game, we assessed perceived interpersonal closeness with both groups using a pictorial scale containing seven graphical items for the overlap of self and ingroup as well as self and outgroup , as compared to self and outgroup , prior to playing the prisoner's dilemma game , indicating that our ingroup–outgroup manipulation was successful and induced a large effect.The interpersonal closeness scale reveals that people felt a higher overlap between self and ingroup  = 3.07, p = 0.003, d = 0.21  = 3.00, p = 0.004, d = 0.24  regressions over all rounds, which predicted cooperation behavior and expectations by group affiliation of the interaction partner . For the regressions, we clustered at the individual level Rogers,  and contb = 0.21, t(18) = 5.10, p < 0.001, which is in line with the dynamic perspective. Hence, in each of the 20 rounds, favoring the ingroup over the outgroup increased by 0.21 Talers, which is represented by the red regression line in Figure In order to examine whether ingroup favoritism is a fixed phenomenon that remains stable or whether it develops dynamically over repeated contact, we calculated a mean bias score (difference between ingroup and outgroup cooperation) for each round and collapsed over all participants, resulting in 20 data points (one for each round). Running a regression predicting this bias score by the variable round, we found that ingroup favoritism significantly increased over time (rounds), b = −0.85, t(69) = −1.05, p = 0.298  = 1.94, p = 0.056  in the first round, Furthermore, we aimed to investigate what drives the change in ingroup favoritism over time and led to the development of ingroup favoritism after the first round. Since ingroup favoritism concerning cooperation was not observable in the first round, rational updating cannot account for the observed dynamics. We therefore focus the investigation on the ingroup-favoring generalization bias. According to an ingroup-favoring generalization bias, positive experiences should be more strongly generalized over the ingroup, as compared to the outgroup, and vice versa for negative experiences. Stated differently, receiving more than one expects should lead to a stronger increase in expectations about members from the ingroup as compared to the outgroup in the following round. Conversely, receiving less than one expects should lead to a stronger decrease in expectations for the outgroup, as compared to the ingroup. Figure b = 0.03, t(70) = 0.51, p = 0.610 and negative experiences, b = −0.01, t(68) = −0.09, p = 0.93.As indicated by the similar slope of the regression lines for ingroup and outgroup, and as further confirmed by a statistical analysis, no differential effects were observed (interaction between experience and ingroup) for positive, For exploratory reasons, we further investigate whether changing groups had any effect, which might activate social identity by making group membership more salient. Comparing cooperation rates between round 10 (last round with one group) and 11 (first round with the other group), there is indeed a sharp increase in ingroup favoritism, as indicated by a significant interaction between round (round 10 vs. 11) and ingroupb = −1.25, t(69) = −1.41, p = 0.16 and strong ingroup favoritism was observed in the first interaction with the new group b = 2.35, t(69) = 3.21, p = 0.002. This is also illustrated in Figure When analyzing cooperation in round 10 and 11 separately there was even a slightly lower cooperation rate toward the ingroup as compared to the outgroup in round 10, b = 3.26, CI95:].Interestingly, when controlling for expectations, the group change effect is no longer significant either, indicating that changes in expectations mediate the effects of activated social identity due to group change Table , Model 2In Experiment 1, we find ingroup favoritism to be a dynamic phenomenon that develops over contacts with the ingroup and the outgroup. This dynamic ingroup-favoring effect is not driven by differences in generalizing experiences or gradual changes over rounds. In contrast, we find that differences are mainly driven by one specific event, namely the change of groups that occurred after round 10. This finding can be due to the fact that a group change activates social identity by making the distinction between outgroup and ingroup more salient.However, before rejecting the ingroup-favoring generalization bias as a potential influence factor, one has to point to several potential limitations of our experiment. First, it has to be acknowledged that the power of the experiment was limited due to the relatively low number of participants. Second, in one of the two labs involved (the lab in the city of Erfurt), mainly 1st year students (95%) took part in the experiment, who might still have had low identification with their university, perceived lower status or other characteristics that were not observable.With our second experiment, we aimed to overcome these limitations and to test the stability of the findings more generally. To increase the chances of observing rational updating or generalization biases from the beginning, we made social identity more salient from the beginning by revealing to participants that they would interact with different people from the University of Bonn or the University of Erfurt. The resulting increase in group distinctiveness can be expected to affect group perceptions  were recruited in the same way as in Experiment 1. Participants' payments depended on their decisions, and earnings ranged from 6.70 to 21.70 Euros (approx. USD 9.00 to USD 29.30). We applied the same procedure as in Experiment 1, with the exception that this time we explicitly named the city of the interaction partner in the instructions so that all participants were aware of whether they were interacting with students from the University of Bonn or Erfurt. Everything else remained the same.M = 5.25, SD = 1.63), as compared to self and outgroup , prior to playing the prisoner's dilemma game, t(95) = 9.75, p < 0.001, d = 1.06.Again, the group manipulation proved to be successful in that people indicated a higher interpersonal closeness between self and ingroup  = 4.93, p < 0.001, d = 0.28 and the same holds for expectations, b = 1.15, t(95) = 5.58, p < 0.001, d = 0.36  = 3.90, p = 0.001, again speaking for the ingroup favoritism to be dynamic. Hence, in each of the 20 rounds, favoring the ingroup over the outgroup increases by 0.11 Taler. Furthermore, we replicate the effect that there is no significant difference in cooperation in the first round, b = 0.69, t(93) = 0.94, p = 0.347  = 2.84, p = 0.005  = 0.88, p = 0.383  = 5.46, p < 0.001. There is no indication for a generalization bias in updating of expectations neither for positive, nor for negative experiences, although there is a strong effect of experience on updating in general . In contrast, ingroup favoritism does not change over repeated interactions with several members from the ingroup or the outgroup, as indicated by the fact that there are no systematic differences between rounds 1 and 10, b = −0.52, t(167) = −0.82, p = 0.415, as well as rounds 11 and 20, b = 0.20, t(167) = 0.34, p = 0.736. Overall, this result indicates that the dynamics we have observed are mainly due to changing groups, which makes the comparison between groups more salient. Gradual effects of biased generalization in repeated interactions are not observed and findings after the first interaction with a member from the respective group are more in line with rational models of belief updating that do not assume differential effects between ingroups and outgroups. A detailed development of cooperation by experimental session is shown in Figure Generally, there is clear evidence for a dynamic development of ingroup favoritism in cooperation since we find that ingroup favoritism (as indicated by the round-specific bias score) significantly increases over time, b = 0.81, t(167) = 1.71, p = 0.089, which diminishes and even reverses in subsequent interactions with members from the same group up to round 10, b = −1.18, t(167) = −1.82, p = 0.071. No systematic differences can be observed between rounds 11 and 20, b = −0.74, t(167) = −1.12, p = 0.226.Expectations Figure , right sA recent meta-analysis  is conveyed by increasing expectations when the interaction partner is from the ingroup compared to the outgroup. When controlling for expectations, the effect of group change on ingroup favoritism disappears.Given that our result concerning the factors driving dynamics in ingroup favoritism leads to different results than a priori expected, and since Experiment 2 replicated the jump after group change only as a tendency, more studies are needed to validate our findings and conclusions further. We think that the research paradigm developed for this study is useful for this purpose, since it allows us to conduct investigations in a highly controlled setting. Although we did not find evidence supporting the ingroup-favoring generalization bias in our experiments, we would not exclude the possibility that such patterns might occur in other settings with more homogeneous groups or less anonymous intergroup contact. Additionally, strictly speaking we only have 3 (Experiment 1) and 4 (Experiment 2) independent observations, since all participants in one session were connected. Further studies with more observations would be recommended. However, there are natural limitations for running more subjects since the organization of such experiments in two labs that require full participation is rather cumbersome.The present studies assess the development of ingroup favoritism, which is one aspect of parochial altruism. Parochial altruism explains intergroup conflict through two phenomena that have been closely linked in human evolution: the readiness to benefit the ingroup (ingroup love) and to harm the outgroup (outgroup hate). The prisoner's dilemma used in the current investigation allows one to study ingroup love elaborately. At the same time, the prisoner's dilemma does not allow one to assess people's motivation to harm the outgroup. Future studies should rely on extended paradigms that allow one to measure both components of parochial altruism separately De Dreu,  and to iThe 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.


Immunoglobulin G4 (IgG4)-related sclerosing disease is a systemic inflammatory syndrome, and an understanding of its characteristics is currently evolving. IgG4-related cholecystitis is a manifestation of IgG4-related sclerosing disease in the gallbladder. This case report describes the clinical, radiographic, and histopathological findings in a young male patient who presented with a synchronous mass in the gallbladder. Serum levels of IgG4 and the IgG4/IgG ratio were normal, and there was no associated autoimmune pancreatitis. Therefore, establishing a preoperative diagnosis of IgG4-related cholecystitis was very difficult, and a differential diagnosis of gallbladder cancer infiltrating the liver was suggested. Postoperative histopathological examination established a diagnosis of IgG4-related cholecystitis definitively. A preoperative diagnosis of IgG4-related cholecystitis, although possible, would have been highly challenging in this case. It is difficult to establish whether surgical intervention is necessary in IgG4-related cholecystitis. Because malignant tumors are frequently suspected with this clinical presentation, surgical intervention should be undertaken only after due deliberation. Immunoglobulin G4 (IgG4)-related sclerosing disease, a systemic inflammatory syndrome characterized by obliterative phlebitis and extensive infiltration of IgG4-positive plasma cells and lymphocytes with fibrosis in the pancreas, gallbladder, bile duct, salivary gland, kidney, retroperitoneum, and esophagus –5, has bIgG4-related cholecystitis does not present with characteristic symptoms of cholecystitis and is often accompanied by IgG4-related sclerosing cholangitis (IgG4-SC). The major clinical symptoms of IgG4-related cholecystitis or IgG4-SC are obstructive jaundice, nausea, fatigue, loss of appetite, and yellowish discoloration of the skin and frequently lead to bile duct stenosis.IgG4-related sclerosing disease generally displays a preponderance in elderly males, frequent elevation of serum IgG4 levels, and dramatic response to steroid therapy. In most patients with this disease, serum IgG4 levels are elevated but can be normal . A serumTo date, there have been several reports in the literature of IgG4-SC misdiagnosed as biliary cancer. However, IgG4-related cholecystitis mimicking gallbladder cancer has been rarely reported –9. Here,An 18-year-old man was referred to our hospital with acute onset of painless obstructive jaundice, nausea, fatigue, loss of appetite, and icterus but no fever or past history of similar complaints.3 (3500–9700/mm3), hemoglobin 14.5 g/dL (13.6–18.3 g/dL), hematocrit 43.2 % (40.4–51.9 %), platelet count 295,000/mm3 , aspartate aminotransferase 214 IU/L (0–40 IU/L), alanine aminotransferase 314 IU/L (5–45 IU/L), alkaline phosphatase 2367 IU/L (104–338 IU/L), total bilirubin 8.1 mg/dL (0.3–1.2 mg/dL), direct bilirubin 6.0 mg/dL (0–0.4 mg/dL), amylase 74 U/L (39–134 U/L), total protein 8.1 g/dL (6.5–8.2 g/dL), albumin 4.4 g/dL (3.7–5.5 g/dL), and urine bilirubin 3+ (negative). Serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) levels were within normal limits as was the serum IgG4  and IgG  levels.Laboratory tests revealed the following results : white blood cell count 5270/mm2. Doppler ultrasonography of the abdomen revealed a hypoechoic lesion of the gallbladder that showed good vascularity and direct hepatic invasion as well as intrahepatic bile duct dilatation. Exfoliative cytology of the bile duct revealed inflammatory cells without atypia. Positron emission tomography (PET)-CT was not performed. As a malignancy could not be ruled out, surgical resection was proposed. First, we decided to perform right hemihepatectomy with caudate lobectomy. However, we chose extended cholecystectomy and intrahepatic cholangiojejunostomy because we found a benign region for intraoperative consultation. We had to resect the common bile duct because the inflammation of the gallbladder was severe and had spread to the common bile duct.Contrast-enhanced computed tomography (CT) revealed abnormal thickening of the gallbladder wall, which appeared to invade the adjacent portion of the liver. Other imaging findings included an infiltrative low-density mass  involving the gallbladder neck, upper biliary tract, and hilar bile duct as well as intrahepatic bile duct dilatation. The pancreas was not enlarged Fig. . MagnetiGross pathologic examination of the surgical specimen (a 4.5-cm mass) revealed invasion of the gallbladder and hilum of the liver; the liver was depressed by the mass but not invaded Fig. . HistopaThe postoperative course was uneventful, there was no added steroid therapy, and the patient was discharged 17 days after the surgery without any additional treatment. At the 1-year follow-up, the patient had no symptoms or signs of the disease.In recent years, IgG4-related sclerosing disease has become an increasingly intriguing clinicopathologic entity. The pathology involves diffuse or focal organ enlargement and mass-forming or thickening lesions, caused by heavy infiltration of IgG4-positive plasma cells and lymphocytes with fibrosis –12, in vDiagnostic criteria for IgG4-related sclerosing disease were published by Deshpande et al.  wherein Most IgG4-related sclerosing diseases are associated with autoimmune pancreatitis (AIP) , which wIn view of all of these aspects, establishing a preoperative diagnosis of IgG4-related cholecystitis was possible but highly challenging and it was too difficult to determine whether surgical intervention was actually necessary in this case. This patient was developing worse obstructive jaundice rapidly in a short time. We did not perform both PET and EUS-FNA. In this case, a preoperative diagnosis was difficult. We could not assess the benign region (xanthogranulomatous cholecystitis or IgG4-related cholecystitis) or cancer; therefore, we decided to perform operation and intraoperative consultation. Although there is much to be understood with regard to IgG4-related cholecystitis, it is conceivable that a trial of steroid therapy may be warranted if this disease entity is suspected before surgery. A poor response to steroid therapy should indicate the possibility of a diagnosis of gallbladder cancer with a need for re-evaluating the diagnosis. Thus far, there are several reasons why a definitive preoperative diagnosis cannot be established in such a case. Moreover, because malignant tumors were frequently suspected under these conditions, surgical intervention should be undertaken after due deliberation.At present in Japan, there are no reports describing a presentation of IgG4-related cholecystitis without AIP. Herein, we report the first case in the literature of a young man with only IgG4-related cholecystitis and normal serum IgG4 concentrations.In 2010, Leise et al. reported a case of an ill-defined tumor (6 cm) in the liver hilum that appeared to surround the gallbladder, which was established to be IgG4-related cholecystitis on examination of the surgical specimen . In 2005In conclusion, we reported the case of a young man with only IgG4-related cholecystitis and normal serum IgG4 concentrations. It was important for preoperative differential diagnosis of IgG4-related cholecystitis from other benign diseases and gallbladder cancer. When we could not diagnose IgG4-related cholecystitis by usual examination, we performed additional examinations. Although we did not succeed, we concluded that EUS-FNA was useful for differential diagnosis. Nevertheless, preoperative diagnosis may be difficult. In that case, operation and intraoperative consultation should be considered.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.


Hepatocellular carcinoma (HCC) patients with active hepatocyte growth factor (HGF)/c-Met signaling have a significantly worse prognosis. c-Met, a high affinity receptor for HGF, plays a critical role in cancer growth, invasion and metastasis. c-Met and CD44 have been utilized as cell surface markers to identify mesenchymal tumor-initiating stem-like cells (TISC) in several cancers including HCC. In this work, we examine the complex relationship between c-Met and CD44s (standard form), and investigate the specific role of CD44s as a tumor initiator and stemness marker in HCC.in vivo tumor assays were performed to investigate the role of CD44+ cells as TISCs. Student’s t-test or one-way ANOVA with Tukeys post-hoc test was performed to test for differences amongst groups with a p < .05 as significant.Gene and protein expression assays were utilized to investigate the relationship between CD44s and c-Met in HCC cell lines. Tumor-sphere assays and +/c-Met+. The knockdown of c-Met in MHCC97-H cells decreased CD44s, reduced TISC characteristics and decreased tumorsphere formation. Furthermore, we demonstrate that the inhibition of PI3K/AKT signaling decreased CD44s expression and subsequently decreased tumorsphere formation. The down-regulation of CD44s leads to a significant loss of a TISC and mesenchymal phenotype. Finally, the down-regulation of CD44s in MHCC97-H cells decreased tumor initiation in vivo compared with the scrambled control.In an immunohistochemical and immunoblot analysis of human HCC samples, we observed that more than 39% of human HCC samples express c-Met and CD44. To study the relationship between c-Met and CD44, we used MHCC97-H cells, which are CD44In summary, our data suggest that CD44s is modulated by the c-Met-PI3K-AKT signaling cascade to support a mesenchymal and TISC phenotype in HCC cells. Moreover, c-Met could be a potential therapeutic drug for targeting HCC cells with TISC and mesenchymal phenotypes.The online version of this article (doi:10.1186/s12885-015-1166-4) contains supplementary material, which is available to authorized users. Moreover, recent evidence suggests that TISCs have mesenchymal features such as low expression of E-cadherin and high expression of Fibronectin and Zeb1 [Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide . Evidencand Zeb1 . Furtherand Zeb1 ,10.+, and c-Met expression is associated with a poor prognosis [c-Met is a receptor tyrosine kinase that, upon activation by its ligand hepatocyte growth factor (HGF), promotes malignant progression and metastasis in multiple cancers, including HCC ,12. Interognosis ,13,14. Arognosis ,16. Althrognosis ,18.CD44 is a transmembrane cell adhesion glycoprotein that participates in many cellular processes, including the regulation of cellular growth, survival, differentiation, lymphocyte homing, and motility ,20. The +/c-Met+ cells have been demonstrated to be tumorigenic with stemness characteristics in pancreatic cancer, which suggests a dual role of c-Met and CD44 as regulators of tumor initiation [CD44itiation . More reitiation . Thus, uitiation . In the 2 at 37°C.The human HCC cell line MHCC97-H was provided by Dr. Xinwei Wang, from the National Cancer Institute (NCI), under agreement with the Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China, and was cultured as previously described ,29. The c-Met siRNA was acquired from Thermo Scientific . Stable shRNA: TG320418 HuSH 29mer shRNA constructs against c-Met in the pGFP-V-RS vector was purchase from OriGene . The following constructs have been validated using real-time PCR assays and have been used for developing stable c-Met knock-down cell line. The c-Met shRNA targeting sequence of construct 1: 5′-TACTGCTGACATACAGTCGGAGGTTCACT-3′ and construct 2: 5′-ACACTCCTCATTTGGATAGGCTTGTAAGT-3′. The scrambled shRNA construct with the pGFP-V-RS backbone was purchased from OriGene (Cat# TR30013). Short-hairpin construct oligonucleotide inserts of CD44s were generated for the psiRNA-h7SK G1 (clone sites: Bbsl/Bbsl) expression vector. Sequencing was performed to verify the presence of the siRNA. The CD44s shRNA targeting construct was 5′-CAAGTGGACTCAACGGAGA-3′. MHCC97-H cells were transfected with either scrambled shRNA, c-Met shRNA, or CD44s shRNA using Fugene 6 transfection reagents per manufactures recommendation . Twenty-four hours after transfection, puromycin (2 μg/ml) was added to select stable c-Met shRNA clones, and 100 μg/ml of zeocin was added to select stable CD44s clones. Multiple pooled clones of stable MHHCC97-H cells containing scrambled shRNA and CD44s shRNA and single clones containing c-Met shRNA were isolated and expanded. Knock-down of c-Met and CD44s expression was validated using both real-time PCR and western blot assays as previously described ,32.RNA isolation and quantitative polymerase chain reaction experiments were performed as previously described .c-Met, phospho-c-Met (1349), phospho-c-Met (1234/1235), AKT, phospho-AKT, ERK1/ERK2, phospho-ERK1/ERK2, CD44, E-cadherin, vimetin, and moesin antibodies were purchased from Cell Signaling Technology . β-actin antibody was obtained from Sigma . CD44v6 was obtained from eBioscience  and fibronectin was obtained from BD Sciences . All human HCC samples were obtained through an IRB approved protocol (IRB#27146). Tissue samples were incubated with lysis buffer and incubated on ice for 10 min followed by disruption by the TissueLyser  per manufacturer’s recommendation. 15-30 μg of cell lysates were collected and western blot was performed as previously described [http://www.ncbi.nlm.nih.gov/geo (accession number GSE38343).Using the MHCC97-H CD44s shRNA, MHCC97-H c-Met shRNA or MHCC97-H scrambled shRNA cells, mRNA was hybridized to an Illumina human gene chip as previously described by the Penn State Functional genomics core . Experim5 MHCC97-H cells were transfected with 25pM of c-Met siRNA or scrambled siRNA  followed by transfection of pBabe CD44s construct or pBabe EV and incubated for an additional 24 hours. The cells were counted with trypan blue exclusion and 5x103 cells were plated onto low adherent 6-well plates for an additional 2 weeks.The capability of self-renewal and cell viability assays were assessed as previously described . Briefly4 cells/100 mL, 1X103 cells/100 mL and 1X102 cells/100 mL. Serial diluted cells were inoculated into 10-week-old female nude mice . Tumor initiation was checked every 3–4 days after injection. Caliper measurements of tumor volume (length × width × height) were conducted at the end of the study. The mice were sacrificed, and tumor tissues were fixed for histology studies or frozen for protein extraction.Nude Mice  were fed and housed as previously described . All of t test was used comparing two groups. One-way ANOVA was used when comparing multiple groups followed by Tukeys post-hoc test to look for differences amongst groups. All analysis with a p < 0.05 was considered statistically significant.Microarray statistical analysis was performed as describe . StudentParaffin embedded slides were labeled with anti-CD44  and anti-c-Met antibodies  and stained as previously described . Slides FACS experiments were performed using one million cells, incubated with mouse anti-human CD44-PE  or anti-human c-Met/2-APC . Analysis was performed using a FACS Calibur . Post-FACS analysis was performed using the Flow-Jo program . Positive and negative gates were determined using immunoglobulin G (IgG)-stained and unstained controls.+ CD44+  compared with vehicle (DMSO) control but only a slight change with MAPK inhibition , the fifth most common cancer in men and seventh in women, is on the rise in the United States . Due to + and CD44+ cells demonstrate increased TISC gene expression profile, increased tumor-sphere formation, and efficient tumor initiation in limited dilution studies [HCC patients with an active c-Met signaling or TISC transcriptome profile have a poor prognosis. In solid tumors, c-Met studies ,28,39-42 studies . However studies . We discThe relationship between c-Met and CD44v6 is well established . SpecifiIn this work, we demonstrate the importance of the c-Met/AKT/CD44s cascade in promoting a TISC phenotype. The down regulation of CD44s significantly decreased tumorsphere formation compared with c-Met shRNA cells. However, CD44s was not able to fully rescue tumorsphere formation after c-Met inhibition, suggesting that c-Met may regulate tumorsphere formation independent of CD44s. The c-Met/HGF signaling cascade is important for morphogenesis during embryonic development and organ regeneration by inducing EMT and can be high-jacked by cancer cells to promote metastasis ,50. Furt+/CD24− TISCs [Prior studies have demonstrated that the PI3K/AKT signaling cascades promote a mesenchymal phenotype. Studies have suggested that constitutive PI3K/AKT signaling is required for EMT in squamous cell carcinoma, whereas PI3K/AKT signaling is required for TGFβ induced EMT in breast cancer cells ,52. Furt4− TISCs . Here, win vitro and in vivo. Our data provide insight into how c-Met induces hepatocarcinogenesis and further support the idea that c-Met represents a potential target for the treatment of c-Met + HCC.In this study, we demonstrate a positive correlation between CD44s and c-Met in clinical HCC samples and show, for the first time, a functional relationship between CD44s and c-Met within HCC. We present evidence that c-Met regulates CD44s to drive a mesenchymal and TISC phenotype and that the down regulation of CD44s decreases tumor initiation both


Hepatic inflammatory pseudotumor (IPT) is a rare disease which often mimics a malignant tumor and is therefore often misdiagnosed and surgically resected. Recently, a concept of IgG4-related diseases (IgG4-RD) has been proposed that is becoming widely recognized and includes IgG4-related hepatic IPT. Corticosteroids are widely accepted as the standard treatment.A 72-year-old Japanese man, who had been followed for ten years after surgery and chemotherapy for treatment of hilar and lower bile duct cancers, developed intermittent fever and abdominal pain and visited this hospital. Blood examinations revealed an inflammatory reaction, worsened glucose intolerance, and an increased level of serum IgG4 (137 mg/dL). Computed tomography (CT) revealed a 5 cm-sized mass in hepatic segment 7. Because of his cancer history, not only was a benign mass suspected, but there was also the possibility of a recurrent biliary malignancy. Liver biopsy was performed and the histology met the criteria for IgG4-related IPT. Corticosteroid therapy was initiated and his symptoms quickly resolved. However, two months later, a repeat CT demonstrated that the hepatic mass had been replaced by an abscess. The abscess was initially refractory, despite tapering corticosteroid treatment, controlling diabetes by intensive insulin therapy, administration of antibiotics, and percutaneous abscess drainage. Finally, after six months, the condition resolved.The diagnosis of hepatic IPT is sometimes difficult. To differentiate it from a malignant tumor, histological examination is necessary. Although corticosteroids are recognized as the standard therapy, unexpected and critical complications can develop in cases of IgG4-related hepatic IPT. Hepatic inflammatory pseudotumor (IPT) is a rare entity that has been thought to be a composition which develops through a variety of pathogeneses, such as infections with a virus  or bacte1c (HbA1c): 6.4–7.4 %, normal range: 4.6–6.2 %].A Japanese man was being followed after he underwent left hepatectomy and pancreatoduodenectomy for a mucin-producing hilar cholangiocarcinoma  and lower bile duct carcinoma  10 years ago when he was 62 years of age. He had also undergone chemoradiation therapy during the year following surgery . Follow up was continued after this chemoradiation management, and the patient’s course was uneventful without recurrence, except for new onset of diabetes after surgery [serum hemoglobin A1c (8.8 %), and IgG4 . Serum levels of hepatobiliary enzymes, carcinoembryonic antigen, carbohydrate antigen 19-9, and α-fetoprotein were within the normal range. Computed tomography (CT) revealed a 5-cm mass lesion in hepatic segment 7  , alkaline phosphatase , C-reactive protein (CRP) , HbAt 7 Fig. , but no t 7 Fig. . No canct 7 Fig.  and the 1c (9.5 %), but normalized IgG4 (84.5 mg/dL). CT revealed an extensive low-density area in the hepatic segment 7–8 . Concerning about exacerbation of his hyperglycemia, we accelerated the steroid tapering. After treatment with oral steroids, he had no symptoms and his laboratory data reached the nearly normal levels  and the shrinkage of the IPT was recognized by US. However, after three months from starting the steroid tapering, his fever and abdominal pain recurred afterward. Again, blood tests were abnormal as follows: elevated levels of WBCs (15000 /μL with 94.1 % neutrophils), CRP (12.7 mg/dL), HbA7–8 Fig. . The lesIn general, hepatic IPTs are difficult to differentiate from malignant tumors, as their incidence is rare, their pathogenesis is diverse, and imaging findings are varied , 7, 11. From the viewpoints of differentiating their pathogenesis or subtypes, biopsy is recommended in cases of a suspected hepatic IPT. As described above, this tumor is caused by a variety of pathogeneses –7, 11, aAccording to a keyword search in PubMed, a total of 11 cases of IgG4-related hepatic IPT were identified –23  and steroid withdrawal syndrome. In autoimmune pancreatitis or one of the most popular subtypes of IgG4-RD, many cases actually show improvement in diabetes by steroid treatment , as theyThe diagnosis of hepatic IPT is difficult, especially in terms of differentiation from malignant tumors. Histological diagnosis is essential and percutaneous needle biopsy is effective for the diagnosis of IgG4-related IPT. Clinicians must bear in mind that corticosteroid treatment is not always ideal and may cause critical adverse events in cases with IgG4-RD.CT, computed tomography; HbA1c, hemoglobin A1c; HPF, high power field; IgG4, immunoglobulin G4; IgG4-RD, IgG4-related disease; IPT, inflammatory pseudotumor; US, ultrasonography


Tire derived aggregate (TDA) has been proposed as a possible lightweight replacement for mineral aggregate in concrete. The role played by the amount of TDA replacing coarse aggregate as well as different treatment and additives in concrete on its properties is examined. Conventional concrete (without TDA) and concrete containing TDA are compared by examining their compressive strength based on ASTM C39, workability based on ASTM C143, splitting tensile strength based on ASTM C496, modulus of rupture  based on ASTM C78, and bond stress based on ASTM C234. Results indicate that while replacement of coarse aggregates with TDA results in reduction in strength, it may be mitigated with addition of silica fume to obtain the desired strength. The greatest benefit of using TDA is in the development of a higher ductile product while utilizing recycled TDA. It is estimated that, in the USA, each person discards one car tire per year. With a population of over 300 million people, it indicates that every year there are a total of 300 million tires that need to be disposed –3. In reIt is with this environmental concern that the US government through the Environmental Protection Agency (EPA) encourages more studies on methods of recycling tires . One ben3 (1600–2080 kg/m3) while TDA's unit density ranges from 40 to 45 lb/ft3 (640–720 kg/m3) [It is hoped that TDA can be a lightweight substitute for mineral aggregates as its density is less than half of that of mineral aggregate. Mineral aggregates have a unity density ranging from 100 to 130 lb/ft″ size and 1″ size only refers to the maximum size of TDA particle but in total, the TDA would contain all sizes of particles below that size as shown in the particle size distribution obtained through sieve analysis in The major raw materials used in this experiment were coarse aggregates with maximum size of 1.5 in (38.1 mm) and fine aggregates with maximum size of 0.187 in (4.75 mm) both meeting ASTM C33 requirements. Two sizes of tire derived aggregate (TDA) were used, one with a maximum size of 1 in (25.4 mm) and the other with a maximum size of 2 in (50.8 mm). Both sizes of TDA came from the same batch and only sieving was done to differentiate the two sizes. The designation of 2μm sieve) and a Blaine of 540 m2/kg. The silica fume used in this study was compacted silica fume which is pozzolanic material composed of highly refined silicon dioxide in noncrystalline form. Commercially available epoxy, PC Products, PC-Concrete 600 mL Concrete Bonding Agent, was used.Other raw materials were tap water from local municipality and commercially available Type III Portland cement with a fineness of 98% passing a 325 mesh (45 Concrete proportioning was done following the Absolute Volume Method as described by Portland Cement Association . The 28-The 6 in × 12 in (150 mm × 300 mm) cylinders and 20 in × 6 in × 6 in (510 mm × 150 mm × 150 mm) beams were cast. The cylinders were used to test for compressive strength following ASTM C39 . The 20 From each batch several cylinders and beams were cast. The molded cylinders and beams were cured at 80°F (26°C) and relative humidity of about 100%. One set of three cylinders or beams was tested after 7 days and another set of three after 28 days for every batch. ASTM C39 test method was followed for compression tests where the applied load was measured using a load cell and displacement was measured using two linear variable differential transformers (LVDTs) all of which were connected to a computer system. The computer system included a Vishay Scanner, Model 5100B, and a laptop computer with Strainsmart5000 software. The two LVDTs were attached on a tailored cylinder which was screwed to the body of the concrete cylinder to measure displacement of the concrete directly as shown in The splitting tensile test followed the ASTM C496 and flexural strength followed ASTM C78, the applied load was measured using a load cell, and displacement of the testing machine head was measured using Novotechnik position transducers (TR 100) with a range of 0–100 mm.Pull-out tests were also performed based on ASTM 234. The purpose was to determine the bond strength between concrete and deformed steel reinforcing bars due to the adhesion of the paste to the steel, the friction between the steel and the concrete, and the bearing of the concrete against the lugs of the deformed steel bars. The direct pull-out is used to test the bond strength of reinforcing rods in concrete. ASTM 234 recommends using the direct pull-out test for determining the bond strength developed between the concrete and reinforcing steel. The moulds used in this experiment were the 6 in × 12 in (150 mm × 300 mm) cylinders and #4 steel bars.The direct pull-out test method consisted of a #4 steel bar embedded through a cylindrical concrete specimen. The specimens had the steel bar embedded at the depth of  4 in (101.6 mm) of the full length of the cylindrical specimen (12 inches (300 mm)). The concrete was constrained and the steel rod was pulled from one end of the specimen. The bond strength of the concrete is determined from the force applied to the rebars divided by the interfacial contact area of the rebar bonded region.One of the objectives of the study was to establish an optimum amount of TDA that can be used to replace coarse aggregates without significantly compromising the strength of the concrete. The starting point was to replace 100% of coarse aggregate and then the amount of TDA was reduced until an optimum amount was obtained. To this end a control batch (batch with no TDA) was first prepared. The mix composition is shown in Once the compressive strength of the control batch and the TDA batch was determined, if there was a big drop in strength, the amount of TDA was dropped and the experiment repeated again. The different amounts of coarse aggregates replaced with an equal amount of TDA (by volume) were 100%, 17%, 10%, and 7.5%. Once the optimum amount of TDA was obtained, all the other tests  were done on the batch with the optimum amount of TDA.″ (50.8 mm) to 1″ (25.4 mm). The TDA particle distribution is shown in The optimum amount of TDA was determined to be between 7.5 and 10%. At this percentage, several other options were explored to improve the strength further in the TDA batches. One of them was to reduce the size of TDA from a maximum of 2Other options explored to improve strength of the concrete with TDA were treatment of TDA particles with sodium hydroxide (NaOH) solution, epoxy, and incorporation of silica fume into the concrete batch. Earlier studies had suggested that treatment with NaOH enhanced bonding with concrete  and hencNaOH was used in two ways. At first, a third of the total water required was set aside and used to prepare a 1-Molar NaOH solution where the TDA was immersed in the solution for 30 minutes prior to introduction of both the solution and the TDA to the mixer. When this method did not yield good results as shown in When the two-part epoxy was used, TDA was placed in a container and the two parts of epoxy were added to it, mixed, and then introduced to the mixer immediately well before the epoxy started to set. The rest of the procedure was then followed as described in the earlier section.Workability is defined in terms of the amount of mechanical work or energy required to produce full compaction of the concrete without segregation . WorkabiIncorporation of TDA into concrete results in an increase of the slump by an average of 1 inch at the same water/cement ratio when compared to the control. Higher slump implies better workability when shaping fresh concrete into desired shapes during construction. Aiello and Leuzzi  made theIt was found out that one should consider silica fume as a cementitious material in calculating amount of water required when silica fume is incorporated in concrete if the same workability is to be achieved in the absence of either a water reducer or superplasticizers. This conclusion is from the observed reduction in slump with the introduction of silica fume .At low doses of 3 percent or less, silica fume serves to liquefy the concrete by fitting in between the cement grains due to their small size that they displace water, which becomes free to help with the flowability of the concrete. In effect, it becomes its own water reducer. But when you add more and more silica fume, up to the neighborhood of 5 percent of cementitious material, the surface area of the silica fume begins to outweigh its water displacement function, surface forces begin to have a strong effect, and water reducer, superplasticizer, or both must be added to overcome the need for more water .″), the TDA concrete developed only 8% of the strength of that of the control concrete at 7 days. This was a very drastic drop and it was concluded that only very little amount of TDA can be used as a substitute for coarse aggregates. These results are consistent with Siddique and Naik [Strength is defined as a measure of the stress required to fracture a material. and Naik  who had ″) with an equal volume of TDA, all other factors remaining constant saw a 45% drop in strength at 7 days and 40% drop at 28 days in comparison with the control concrete. This drop was still considered large and therefore unacceptable. It was then decided to drop the quantity of TDA further in order to improve on the strength. These results confirm those of Huang et al. [Replacing 17% of coarse aggregates  was replaced with an equal volume of TDA, there was a slight mitigation of the properties, with a drop of 28.6% and 33.8% at 7 days and 28 days, respectively, when compared to the control batch (Control-0% TDA). This drop in compression strength is still high but it was deemed that it would be impractical to further reduce the amount of TDA. At this point ways of improving concrete strength were sought.When 10% of coarse aggregate (10% TDA-2″-NaOH Sol) into the concrete did not improve the bonding between the concrete constituents and the rubber chips and in fact the overall compressive strength declined when compared with the samples with an equal amount of TDA but with no NaOH treatment as seen from Also a summary of compressive strength is shown in ″-NaOH) saw the strength of the concrete being equal to that with equal amount of TDA but no treatment with NaOH (7.5% TDA-1″).This is the opposite of results obtained by Pelisser et al.  and Segr3A) and gypsum in the presence of water. Formation of ettringite slows down the hydration of C3A by creating a diffusion barrier around C3A therefore allowing for more time for tricalcium silicate (C3S) to hydrate. C3S is the cement compound that is responsible for strength development.Possible negative effect of NaOH could have been increased solubility of gypsum in the cement leading to flash set in the concrete. NaOH addition may also result in undesirable morphology and nonuniformity of hydration products in the pastes, thus reducing cement strength. Addition of NaOH generally decreases ettringite formation . EttringAfter 7 days of curing the 2-part epoxy did not result in improvement of strength but had a significant impact after 28 days. The 28-day strength was 18% less compared to the control batch. This showed that the epoxy improved the TDA concrete by about 23% when compared to TDA concrete without epoxy at 28 days. Since no improvement was noted at 7 days (early strength) when using epoxy, this method was considered unattractive.″-SF-R) but addition of silica fume (7.5% TDA-2″-SF-A) on top of the cement into had a positive effect on concrete strength. At 10% coarse aggregate replacement with TDA and addition of silica fume equal to 20% of cement, the drop in strength was 12.4% at 7 days and 16.5% at 28 days compared to the control batch. Pelisser et al. [Replacing part of cement with silica fume did not have any positive effect on strength as seen from r et al.  observedr et al.  found a r et al. . SchimizThe overall compressive strength of about 3900 psi (≈27 MPa) was also deemed acceptable and falls within the range of structural concretes. Mindess et al.  define s2 and the large surface area [Silica fume (SF) functions in a concrete as a highly efficient pozzolan, that is, it reacts chemically with the calcium hydroxide produced by the hydration of the Portland cement to form calcium silicate hydrates (C-S-H) which bind the concrete together. Silica fume is highly reactive due to the high proportion of noncrystalline SiOace area .Silica fume can be used in concrete in two ways: as an addition , to enhance properties of the fresh and/or hardened concrete or as a partial cement replacement (5–10% by mass of cement) to maintain the 28-day compressive strength at lower cement content  while reducing the heat of hydration and improving durability . From th2/kg—they can “pack” between the cement particles and provide a finer pore structure. This property is particularly important because it is likely that TDA could be increasing the void content due to poor bonding to the concrete resulting in the low strength in concretes with TDA. The final strength of the concrete is in a large part a function of the amount of compaction; a small increase in void content (or decrease in relative density) will lead to a large decrease in strength. In the early stages of hydration, silica fume can help accelerate the hydration process, because its tiny particles provide nucleation sites for hydration.The functions of silica fume in Portland cement concrete are twofold, both physical and chemical in nature. Physically, there are three major attributes for silica fume. Because the silica fume particles are much smaller than the cement particles—with a surface area in the neighborhood of 20,000 mIn the nucleation process, a silica fume particle provides a site on which material in solution can “nucleate” or “center,” which helps the material precipitate sooner than it might otherwise do. And once it precipitates, the concentration of that material in solution is reduced, which tends to get more material into solution from elsewhere, speeding the process. Silica fume can dramatically reduce bleeding as it introduces a lot of surface area into the mix, which in turn helps hold the water in place.Chemically, if time and moisture are allowed to do their job, silica fume has a very strong pozzolanic reaction, so that when the cement grains hydrate and generate calcium hydroxide, the silica fume will react with that and create more calcium silicate hydrate. In this instance, more space is filled up within the concrete, which gives much more strength, and improves resistance to intrusion from a number of factors. These benefits include radically reduced permeability to water and reduced diffusivity to chloride ions.A further reduction of quantity of TDA to 7.5% replacement had only a marginal effect even with incorporation of silica fume into the batch as seen from the results in From these results it was concluded that small amounts of TDA with a maximum size of 2 inches in the range of 7.5–10% can be used to replace coarse aggregates in concrete whose compressive strength is about 4000 psi (28 MPA). To achieve this compressive strength, strength enhancing materials like silica fume would need to be used. This recommendation is about half of what Khatib and Bayomy  recommenHowever, if the size of TDA is reduced, the results in Apart from the positive environmental effect of using TDA as a lightweight replacement for mineral aggregates, it was hoped that TDA would improve some other properties of concrete like ductility. Rubber which is the source of TDA under same stress conditions would deform much more than mineral aggregates since it has a lower elastic modulus but the material would deform at almost constant volume as Poisson's ratio for TDA is approximately 0.48 . Another−3 [At high stress level, the strain no longer remains proportional to the applied stress, and it becomes permanent; that is, it would not be reversed if the specimen is unloaded. This strain is called plastic or inelastic strain. Typically under compression, concrete appears to show inelastic strain at fracture of the order of 2 × 10−3 . Ductili″ and Control-0% TDA) are compared in ″ 1/2/3-No silica. On an average, the deformation the concrete with TDA can sustain before failure as shown in Two concretes (7.5% TDA-1″-SF-A). Silica fume is noted to have improved the consistency of TDA concrete and its strength but appears to have had a negative effect on the amount of strain the concrete can sustain before failure when comparing 7.5% TDA-1″-SF-A and 7.5% TDA-1″ total strain in ″, and 7.5% TDA-1″-SF-A was 0.0136 in (0.3461 mm), 0.0228 in (0.58 mm), and 0.0198 in (0.5038 mm), respectively. Since the original cylinder length was 12 in (300 mm), the percent elongation for the three types of concrete is 0.11%, 0.19%, and 0.17% for Control-0% TDA, 7.5% TDA-1″, and 7.5% TDA-1″-SF-A, respectively.Ductility can also be quantified in terms of percent elongation or reduction in length in a tensile or compressive test, respectively. The percent elongation/reduction provides additional information on the deformational characteristics of the material and is an indicator of ductility. The average total displacement  for the Control-0% TDA, 7.5% TDA-1The energy required to break the material, the product of force and distance, is represented by the area under the curve of the stress-strain plot. The term modulus of toughness is a measure of this energy.Calculation of area under the curves in Figures 3 to 40 × 103 MPa (2 × 106 to 6 × 106 psi) [The modulus of elasticity is defined as the ratio between the stress and the reversible strain. It is a measure of stiffness of a component. The elastic modulus of concrete in compression varies from 14 × 10106 psi) . The sigσ-ε curve at any point on the curve, secant modulus given by the slope of a line drawn from the origin to a point on the curve corresponding to a 40% stress at failure load, and chord modulus given by the slope of a line drawn between two points on the σ-ε curve. The chord modulus was used in the calculations by shifting the base from the origin to correct the slight concavity observed at the beginning of the σ-ε curve up to a point about 40% of the stress at failure.However, due to concrete nonlinearity, three methods are used to compute the modulus giving rise to three types of moduli. These are the tangent modulus given by the slope of a line drawn tangent to the ″/in while the concrete with TDA would deform elastically to a minimum of 0.00125 in/in as shown in Figures However if a stress of 3000 psi (20.68 MPa) is applied to each material, the concrete without TDA deforms elastically to a maximum of 0.001fc′, because under the short-term loading the microcracks in the interfacial transition zone remain undisturbed. For stresses above this point, the curve shows a gradual increase in curvature up to about 0.75fc′ to 0.9fc′ then it bends sharply  and finally descends until the specimen is fractured [Generally, the stress-strain curve shows a linear, elastic behavior up to about 30% of the ultimate strength, ractured .″) fracture line can be up to 45° from the direction of the load, not straight, and does not run through the specimen. This may explain why the TDA concrete does not have a brittle failure like the control concrete in Concrete contains void spaces of various sizes and shapes in the matrix and microcracks at the interfacial zone therefore failure modes vary with the type stress. In uniaxial compression, as stress increases, cracks are initiated within the matrix; their number and size increase progressively. Eventually cracks in the matrix and the interfacial transition zone (shear-bond cracks) eventually join up, and generally a failure surface develops at about 20° to 30° from the direction of the load. The difference between the two concretes was the amount of course aggregates. One had part of coarse aggregates replaced by TDA. The difference in behavior of the two concretes is thought to have been caused by changes in the interfacial transition zone characteristics due to the different size, shape, and surface texture of the aggregate particles therefore affecting the concrete strength and failure modes. It is also believed that due to the smooth surface of TDA particles, a weak physical bond between TDA particle and the hydrated cement particle is formed which is responsible for the lower strength of TDA containing concrete.Two characteristics of aggregates have an important influence on proportioning concrete mixtures. These are grading (particle size distribution) and nature of the particle . The aggregates are predominantly responsible for the unit weight, elastic modulus, and dimensional stability of the concrete. These properties of concrete depend to a large extent on the bulk density and strength of the aggregate, which in turn are determined by physical rather than chemical characteristics of the aggregate. Grading is important for attaining an economical mixture because it affects the amount of concrete that can be made with a given amount of cement and water.fc′. The standard by which all concrete strengths are compared is that of fc′ for the identical mix, cured under the identical conditions, and at the same age. For the two batches, the control batch developed an average of 10.4% of fc′ while the batch with 7.5% of coarse aggregates replaced with an equal volume of TDA developed 13.1% of fc′. fc′ was taken to be 4500 psi (≈31 MPa) for control concrete and 4000 psi for TDA concrete.Another important consideration in the testing of concrete mixes is the percent a particular strength parameter compares to the 28-day design compressive strength, At 7 days (early strength), the average splitting strength for the control batch was also 466 psi (3.2 MPa) while the batch with 7.5% of coarse aggregates replaced with an equal volume of TDA was 431 psi (3.0 MPa). This represented 7.6% drop in splitting tensile strength for the batch with TDA compared with the control batch at 7 days. Generally, splitting tensile strength is used in the design of structural lightweight concrete members to evaluate the shear resistance provided by concrete and to determine the development length of reinforcement. From the results at 28 days, it was concluded that, in this respect, the TDA concrete would perform satisfactorily or superior to the control concrete in the long time.″) developed multiple fracture lines which were not joined as loading was increased probably due to the presence to TDA particles between the fracture lines. This may explain the superior performance noted for TDA concrete in terms of ultimate splitting tensile test.As seen from ″-SF-A) had a modulus of rupture of 480 psi (3.31 MPa) while the batch which did not include silica fume (7.5% TDA-1″) developed a modulus of rupture of 535 psi (3.69 MPa). This represented a drop of 15.8% and 6.1% for TDA concrete with and without silica fume, respectively. At 7 days, this drop was 22.9% and 8.6% drop from the control batch, respectively.A plot of modulus of rupture (psi/MPa) against displacement (in/mm) is shown in The calculated peak bond stress results from the pull-out test are as shown in A plot of the bond stress against rebar slip is shown in the Small amounts of waste tires (TDA) in the range of 7.5% to 10% can be used in concrete with a target compressive strength of up to 4000 psi (≈28 MPa) but strength enhancing materials like silica fume need to be used. As TDA increase, the compressive strength drops. At 7.5% of TDA replacing coarse aggregates, this drop is found to be approximately 10% compared to the control concrete if silica fume is added into the mixture. However, this amount of strength can also be achieved without using strength enhancing materials (silica fume) if the top TDA size is lowered from 2 in to 1 in.Using TDA to substitute for mineral aggregates lowers the modulus of elasticity of concrete by about 20% but increases the concrete toughness and ductility. However silica fume, as much as it increases compressive strength and consistency, has a negative effect to ductility. Workability of fresh concrete with TDA is slightly better as it has a slump of averagely 1 in higher compared to the control concrete. However if a stress of 3000 psi is applied to each material, the concrete without TDA deforms elastically to a maximum of 0.001 in/in while the concrete with TDA would deform elastically to a minimum of 0.00125 in/in. Therefore concrete with TDA would deform elastically 20% more compared with concrete without TDA.TDA lowers the modulus of rupture of concrete but it increases displacement up to 50% (improved concrete deformation) during loading. The splitting tensile strength improves by 12.7% with introduction of TDA into concrete. The bond strength of the TDA concrete is not significantly different from that of the control concrete but TDA improves postcracking behavior of the concrete as noted from the pull-out tests.


Self-Medication (SM), i.e. using medications to treat oneself, is a major concern for health researchers and policy makers. The terms “self medication” or “self-medication” (SM terms) have been used to explain various concepts while several terms have also been employed to define this practice. Hence, retrieving relevant publications would require exhaustive literature screening. So, we assessed the current situation of SM terms in the literature to improve the relevancy of search outcomes.In this Systematic exploration, SM terms were searched in the 6 following databases and publisher’s portals till April 2012: Web of Science, Scopus, PubMed, Google scholar, ScienceDirect, and Wiley. A simple search query was used to include only publications with SM terms. We used Relative-Risk (RR) to estimate the probability of SM terms use in related compared to unrelated publications. Sensitivity and specificity of SM terms as keywords in search query were also calculated. Relevant terms to SM practice were extracted and their Likelihood Ratio positive and negative (LR+/-) were calculated to assess their effect on the probability of search outcomes relevancy in addition to previous search queries. We also evaluated the content of unrelated publications. All mentioned steps were performed in title (TI) and title or abstract (TIAB) of publications.1999 related and 1917 unrelated publications were found. SM terms RR was 4.5 in TI and 2.1 in TIAB. SM terms sensitivity and specificity respectively were 55.4% and 87.7% in TI and 84.0% and 59.5% in TIAB. “OTC” and “Over-The-Counter Medication”, with LR+ 16.78 and 16.30 respectively, provided the most conclusive increase in the probability of the relevancy of publications. The most common unrelated SM themes were self-medication hypothesis, drug abuse and Zoopharmacognosy.Due to relatively low specificity or sensitivity of SM terms, relevant terms should be employed in search queries and clear definitions of SM applications should be applied to improve the relevancy of publications. Self-medication (SM) is a subcategory of self-care  and is aThe growing body of SM literature raises concerns about the best way of retrieving relevant publications in a reasonable amount of time. In one hand, excess of terms and phrases for the SM practice confronts us with complexity of understanding and working with the SM literature. Self-care, self-treatment, self-prescription, personal care, and drug self administration are among different terms which have been used in SM related publications , 7–16. OThere have been researches and reviews about terms and taxonomy in other concepts of health care, such as drug safety, medication errors and patient adherence to solve part of the misinterpretation and uncertainty resulted from terms overload and dissimilarity in their particular field as their primary intention –22. HoweThe purpose of this study was to analyze SM related and unrelated publications retrieved from well-known bibliographic databases. We also investigated terms associated with SM to help researchers improve their literature search relevancy.We carried out a systematic exploration of the relative usefulness of SM terms (self-medication and self medication) for retrieval of related publications. In overview we evaluate the pattern of publications related to SM. We investigate the characteristics of SM terms and SM synonyms and related terms in the literature over the study period.The study was approved by the research council of Research Center for Rational Use of Drugs, Tehran University of Medical Sciences (TUMS).http://www.sciencedirect.com/), and Wiley online library (http://onlinelibrary.wiley.com/) without any limitation. The search strategy was “self medication” or “self-medication” (SM terms) within the title, abstract, keywords or MeSH according to each search engine characteristics. Search strategies for databases and publishers’ search engines are provided in the We performed a systematic search of the literature using several bibliography databases and publishers’ search engines including Web of Science, Scopus, PubMed, Google scholar, ScienceDirect .In this step we calculated the frequency of related publications which used SM terms (self medication or self-medication) in the title (TI). The proportion of related publications with the terms in TI to total number of related publications was calculated. The same procedure was carried out for the unrelated publications.Relative risk (RR) was used to estimate the probability of SM terms use in the TI of related publications compared to the unrelated ones. In addition, we calculated the sensitivity and specificity of SM terms if they were used as keyword in ‘title search query’. All the aforementioned steps were carried out considering the SM terms in title or abstract (TIAB) of publications.We looked for systematic and narrative reviews related to SM concepts in order to extract the terms relevant to SM practice which were used in their search strategies.Afterwards, utilization of every extracted relevant term (RT) in TI of related and unrelated publications was investigated. Likelihood ratio positive (LR+) and likelihood ratio negative (LR-) were calculated for each RTs in TI of publications. LR indicates that how much the chance of article relevancy changes in the presence (LR+) or absence (LR-) of any RT. All the aforementioned steps were also carried out in TIAB of related and unrelated publications.Based on LR concept, RTs with LR+>10 provide large and often conclusive increase in the likelihood of a publication relevancy. Terms with 5<LR+<10 point out a moderate increase in the probability and LR+<5 indicates a small effect on increasing the probability of publication relevancy.After classifying publications as related and unrelated, we searched for authors’ assigned keywords (KWs) of the related citations if not presented in the library. We used the ‘subject bibliography tool’ to extract the KWs bibliographic data. Afterwards, KWs were categorized based on city/country/continent, drug/pharmacologic group, disease/disorders, profession, herbs, field of science, organism, sex, and age group. We calculated the frequency of authors’ assigned KWs and the proportion of publications containing each KW among related publication.Two reviewers categorized unrelated publications according to the study concept identified in the title and abstract.Initially, 5464 publications were identified. All duplicates were excluded (n = 1548), resulting in 3916 publications. Of these, 1917 were tagged as unrelated. Thereby, 1999 related publications remained for the final analysis after confirmation by three reviewers .The first study was published in 1888. As it is shown in Frequency of related and unrelated publications with SM terms in TI was 55.4% and 12.3% respectively (RR = 4.5). The RR indicates that the probability of using SM terms in the TI of related publications is 4.5 times to the unrelated publications. In TIAB, SM was used in 84.3% and 40.5% of related and unrelated publications respectively (RR = 2.1) .The proportion of related and unrelated publications which used SM terms in their TI or TIAB is illustrated across time in Figs We estimated that SM in TI would have a sensitivity of 55.4%. This suggests that if search strategy includes word SM in TI, about 55% of total related publications would be retrieved. Moreover, the specificity of SM in TI would be 87.7%; this means that approximately 12% of retrieved publications would be unrelated.A hypothetical search query of SM in TIAB would have a sensitivity and specificity of 84.0% and 59.5% respectively.Nineteen RTs were identified from the search strategies of ten narrative and systematic reviews  which demonstrates that the absence of RTs in the search strategy would have no considerable effect in the likelihood of findings relevancy. This means that if there is a publication in our findings which RTs are not used in its TI or AB, it cannot be decided that the publication is probably related or unrelated.Manual searches for publications with KWs yielded to 825 articles with a total of 2251 KWs. The ‘frequent KWs’, i.e. used in more than 10 publications, are listed in the After categorizing unrelated SM publications, they could be classified as self-medication hypothesis (SMH), addiction and alcohol consumption, drug abuse and case reports of toxicity due to overdoses or non-medical products use, and animal self-medication (Zoopharmacognosy).In the present study, we investigated the trend of SM related and unrelated publications retrieved by a simple search query. We also calculated the sensitivity and specificity of the query to understand the extent to which the SM terms have been used to describe concepts other than ‘self-medication’ as defined by the WHO. In addition, we investigated a group of RTs to find possible strategies to improve relevancy of search results.Titles and abstracts are important parts of publications because they are commonly indexed in bibliographic databases  and reseThe numbers of related and unrelated publications increased over time. During 90s, related publications comprised the majority of citations and the WHO definition of SM was introduced in 1998. We did not observe a major effect of the WHO guidance on the proportion of related to unrelated publications during 2000s. However, a positive shift in the trend of SM terms utilization in the related publications could be observed since early 2000s. The trend of SM terms use in the unrelated publications did not change significantly over time.As it was expected, the probability of using SM terms in TI or TIAB of related publications is relatively higher than the unrelated ones over the study period. Nevertheless, the sensitivity of SM terms in TI was relatively low (approximately 50%) which indicates that half of the related publications had not included the SM terms in TIs. However, a relatively high specificity of 88% showed that publications with SM terms in TI will probably be related to SM. On the other hand, SM terms in TIAB would result in 84% sensitivity and 60% specificity.It has been stated that by searching simple queries  thousands of documents would be retrieved and ranking their relevancy is a huge problem . We encoWe aimed to assess the effect of using RTs in addition to the simple search query of SM terms as one of the strategies for improving the relevancy of search outcomes. So in order to collect an inclusive list of synonyms and keywords as suggested , we usedIf we use one RT in a search strategy, the existence of the term in a group of citations could mean that they are more likely to be relevant in comparison to those without the term. Based on the LR concept, as the LR+ increases, the probability of relevancy for the publication with the RT rises. Nevertheless, LR- figures close to 1 for the RTs not appearing in the publication may not imply of the probability of the publication being related or unrelated.We observed changes in LR+ for some RTs when they are placed in TI compared to TIABs. This suggests a possible change in their effect on the probability of publication relevancy. For instance, when “Nonprescription” is in TI instead of TIAB this would increase the likelihood of being related from moderate to large . In other words if it is searched in TI, the probability of the publications with the RT in their title being related to SM is higher and more conclusive.As we learned in this study, each RT with its sensitivity and LR gives us a part of related publications; some of the related publications are overlapped , and also there are many relevant publications which did not use any RT in addition to the SM terms. So these terms on their own or in addition to other terms could not provide all of the related publications. This would lead researchers to use multiple RTs at a time in search strategy to increase the relevancy of results.Keywords are terms (words or concise-phrase) which expose the main focus of the study  and we uA content evaluation of the unrelated library showed that the most repetitive unrelated concepts were about alcohol consumption and addiction (self-medication hypothesis or SMH) , 35, druOur search was limited to English language only and our findings should not be extrapolated to all published literature. However, English publications are the mainstay of bibliography searches. We judged the relevancy of publications only by screening titles and abstracts because they are used by bibliographic databases to cite publications. In addition, this approach is accepted for rigorous systematic reviews for early screening of search outcomes. The study purpose was to assess the characteristics of “self-medication” and “self medication” terms in related publications. Since there is no specific database which includes all the related SM publications we were obligated to use the most common terms in this concept (SM terms) to make our own database for further evaluation.Use of SM terms alone cannot provide researchers with desirable search outcomes due to relatively low specificity and or sensitivity. Researchers should employ other possible RTs to improve publications relevancy. Due to overlap in the utilization of SM terms (self-medication and self medication) in different concepts with specific different definitions such as zoophamacognosy and SMH, searching SM terms leads to deterioration in the relevancy of search results. This is happening despite the fact that self-medication has been defined by WHO. So there is a need for clearer definitions and limited utilization of different SM applications.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.