The purpose of this study was to evaluate the effects of a morphine-conjugate vaccine (M-KLH) on the acquisition, maintenance, and reinstatement of heroin self-administration (HSA) in rats, and on heroin and metabolite distribution during heroin administration that approximated the self-administered dosing rate. Vaccination with M-KLH blocked heroin-primed reinstatement of heroin responding. Vaccination also decreased HSA at low heroin unit doses but produced a compensatory increase in heroin self-administration at high unit doses. Vaccination shifted the heroin dose-response curve to the right, indicating reduced heroin potency, and behavioral economic demand curve analysis further confirmed this effect. In a separate experiment heroin was administered at rates simulating heroin exposure during HSA. Heroin and its active metabolites, 6-acetylmorphine (6-AM) and morphine, were retained in plasma and metabolite concentrations were reduced in brain in vaccinated rats compared to controls. Reductions in 6-AM concentrations in brain after vaccination were consistent with the changes in HSA rates accompanying vaccination. These data provide evidence that 6-AM is the principal mediator of heroin reinforcement, and the principal target of the M-KLH vaccine, in this model. While heroin vaccines may have potential as therapies for heroin addiction, high antibody to drug ratios appear to be important for obtaining maximal efficacy. Heroin is the most widely abused illicit opioid worldwide Vaccination against heroin has been studied in animals as a mechanistically distinct treatment option for heroin addiction. Vaccination targets the drug itself rather than opioid receptors or other CNS targets. A variety of vaccines have been studied consisting of heroin or morphine conjugated to a foreign carrier protein. Antibodies elicited by vaccination bind heroin and its active metabolites The mechanism underlying the blockade of these behavioral effects is not completely understood for several reasons. First, heroin doses often exceed the binding capacity of available antibodies. Second, heroin is rapidly degraded and sequentially metabolized to its active metabolites 6-monoacetylmorphine (6-AM), morphine, and morphine-6-glucuronide. The metabolite 6-AM is considered important in mediating heroin’s early effects because it is found at higher levels in the brain than heroin or other metabolites shortly after heroin administration and has a higher affinity for the µ opioid receptor than heroin To this end, the current study evaluated the effects of vaccination with the previously characterized M-KLH immunogen on the acquisition of HSA, maintenance of HSA during a dose-reduction protocol, and heroin-primed reinstatement of HSA. The pharmacokinetic correlates of vaccine effects on HSA were then studied by administering repeated i.v. heroin injections to vaccinated and control rats at doses comparable to those consumed during the HSA procedures. Results showed that vaccination with M-KLH altered HSA and reinstatement and that the magnitude of reduction in distribution of 6-AM to brain was consistent with and could account for the self-administration data.2 inhalation using AAALAC approved chambers, and all efforts were made to minimize suffering.This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Animal protocols were approved by the Minneapolis Medical Research Foundation Animal Care and Use Committee (protocol #08-10). All surgery was performed under droperidol/fentanyl anesthesia, animals were euthanized by CODrugs were obtained through the NIH National Institute on Drug Abuse Drug Supply Program  or Sigma-Aldrich . Drug doses and concentrations are expressed as the weight of the base. A well-characterized heroin vaccine (M-KLH) was used, consisting of a morphine hapten conjugated via a tetraglycine linker to keyhole limpet hemocyanin (KLH) Male Holtzman rats  weighing 350 g at arrival were single housed under a 12/12-hour standard light/dark cycle and were placed on restricted feeding (18 g/day). Testing occurred during the light phase. Rats received 25 µg of either M-KLH or unconjugated KLH on days 0, 21, and 42 for the drug distribution and HSA studies as well as once every three weeks throughout HSA testing. Immunogens were injected in a volume of 0.4 ml i.p. with Freund’s complete adjuvant  for the first immunization and Freund’s incomplete adjuvant (Sigma-Aldrich) for subsequent vaccine boosts.Experimental sessions occurred in standard operant-conditioning chambers . The front panel contained two response levers and a stimulus light over each response lever. Each chamber was enclosed in a sound-attenuating box equipped with an exhaust fan that provided masking noise. Heroin was administered via an infusion pump . Presses on the left (active) lever produced an infusion of heroin while presses on the right lever were recorded but had no programmed consequence. A computer with MED-PC IV software  was used for operating the apparatus and recording data.For HSA each rat was implanted with a chronic indwelling jugular catheter under intramuscular (i.m.) droperidol (1.25 mg/kg) and fentanyl (0.025 mg/kg) anesthesia. A silicon catheter (0.51 mm I.D.×0.94 mm O.D.) was inserted into the right jugular vein and advanced to the junction of the vena cava and the right atrium and sutured to tissue surrounding the vein. The catheter was tunneled subcutaneously (s.c.) to the back where it exited between the scapulae and attached to a guide cannula mounted in a harness assembly  on the back of the rat. A stainless steel spring tether attached to the guide cannula allowed connection to a fluid swivel for heroin administration. Rats were allowed to recover for approximately 1 week after surgery, during which each rat received an antibiotic  immediately followed by intravenous (i.v.) infusions of heparinized saline (30 units/ml) for three days to maintain catheter patency. Heparinized saline infusions were continued after each session for the remainder of the experiment.ELISA plates were coated with 5 ng/well morphine conjugated to BSA via a tetraglycine linker in carbonate buffer at 9.6 pH and blocked with 1% gelatin. Goat anti-rat antibodies conjugated to horseradish peroxidase were used as secondary antibodies. Morphine-specific antibody concentrations were calculated based on a previously standardized monoclonal antibody assay The total number of moles per kilogram of morphine-specific IgG in rats vaccinated with M-KLH was estimated as the product of the reported IgG volume of distribution (131 ml/kg) in rats and the plasma antibody concentration, assuming a molecular weight of 150 kDa for IgG. The number of IgG binding sites was calculated as twice that number g for 3 minutes at 4°C. Plasma was diluted 1∶1 with ice-cold 10 mM formate buffer (pH 3.0) prior to extraction. Brains were rinsed with 10 mM formate buffer (pH 3.0), and four parts (by weight) of 10 mM formate buffer pH 3.0 was added to each sample. Samples were homogenized  for 30–40 seconds and stored for 5–60 min at −20°C until extraction.Plasma and brain heroin, 6-AM, and morphine concentrations (bound + unbound) were measured by liquid chromatography/mass spectrometry by a validated method described previously Prior to the acquisition of HSA, rats were vaccinated with M-KLH (n = 13) or KLH . Three days after the third vaccination, jugular catheters were implanted. Blood was drawn from the indwelling cannulas one week following the third vaccination and also one week following the final vaccination  for antibody characterization.Approximately 1 week after surgery, rats were given 2 hr/day access to response-contingent heroin infusions (0.06 mg/kg/infusion) delivered at 50 µl/kg per second Following the last FR 3 session, the heroin unit dose was decreased every five sessions to 0.03, 0.01, 0.003, and 0 mg/kg/infusion to obtain a heroin dose-response curve in rats that acquired HSA. After active-lever responding stabilized under extinction conditions (less than 30% of baseline and no significant trend for three consecutive sessions), each rat received a priming injection of saline or heroin  15 min before an extinction session to examine vaccine effects on reinstatement of HSA responding. Reinstatement tests were conducted on Tuesdays and Fridays provided that responding was stable during the previous session, and the order of the priming dose was counterbalanced across subjects. Each dose was evaluated once. Data for the lowest unit dose were excluded for two KLH control rats because one rat’s catheter lost patency at this dose and the other developed an ear infection. Data for the lowest unit dose were also excluded for one M-KLH rat that pulled out its catheter. As a result, the final sample size at the 0.003 mg/kg unit dose was n = 4 KLH rats and n = 7 M-KLH rats. One M-KLH rat died during the methohexital infusion while checking catheter patency before reinstatement testing could be completed, leaving a final sample size of n = 6 M-KLH rats for this phase.th heroin dose to measure drug levels after all doses had been delivered.Separate groups of rats were used to study effects of vaccination on heroin and metabolite distribution under conditions approximating those observed during HSA as described above. Two groups of 6 rats vaccinated with M-KLH and two control groups vaccinated with KLH received 8 equally spaced i.v. infusions of either 0.17 µmol/kg (0.0625 mg/kg/inf or 0.5 mg/kg/hr) or 0.34 µmol/kg (0.125 mg/kg/inf or 1 mg/kg/hr). These doses were chosen because they approximated the mean heroin exposure during HSA of 0.5 mg/kg/hr heroin in control rats and 1.0 mg/kg/hr heroin in vaccinated rats (during FR3 responding for heroin at 0.06 mg/kg/inf). To avoid respiratory depression 1-hr drug distribution sessions were performed at approximately half of the total doses administered in the 2-hr HSA sessions. This was because animals in the drug distribution studies were drug naïve and anesthetized throughout the entire procedure. Animals were anesthetized 1 week after their final vaccination and blood was withdrawn from the jugular catheters for antibody characterization prior to drug administration. Four minutes after the first infusion of heroin, blood was drawn via the tail vein to quantitate heroin, 6-AM, and morphine levels after a single heroin dose. Rats were decapitated for collection of trunk blood and brain four minutes after infusion of the 8The effect of treatment on HSA was analyzed using two-way analysis of variance with group as a between-subjects factor and day as a within-subject factor followed by multiple t-tests between groups at each session using the False Discovery Rate (FDR) approach with the FDR Q = 5%, a recommended approach when large numbers of post-hoc comparisons are of interest 0+ log Q = log Qk(e−α*Q0*C−1), was used to describe the relationship between heroin consumption and unit price (FR/unit dose). The dependent variable, Q, is the quantity consumed. The independent variable, C, is the cost of heroin based on the unit price. The free parameters, 0Q and α, are estimated from the best-fit function and refer to the maximum level of consumption at zero price  and the rate of change in consumption with increases in unit price, respectively. The range of the exponential function, k, is a constant specifying the range of consumption in log units. The k value is held constant across data sets being compared (set to 1.2 in the present study) because changes in k impact the value of α. The value of α is inversely related to reinforcing strength so that drugs that produce rapidly declining (elastic) demand curves have higher α values and lower reinforcing strength than demand curves with slower declining (inelastic) demand curves. In the present context, vaccines that increase α values for heroin consumption would be those that increase sensitivity of HSA to price (increase elasticity of demand), suggesting that vaccination reduces the reinforcing efficacy or essential value of heroin, independent of changes in heroin potency 0Q and α were compared between groups via a sum-of-squares F-test.To determine whether vaccination reduced the reinforcing efficacy of heroin independent of reducing heroin’s potency, exponential demand curve analysis was performed on heroin intake during HSA unit dose reduction as previously described Effects of vaccination on drug distribution between M-KLH and KLH control groups were analyzed using unpaired t-tests. Differences in antibody titers and concentrations between groups were compared using one-way analysis of variance. Relationships between antibody levels and opioid distribution were analyzed using linear regression.3 and 420±170 µg/ml (mean ± SD), respectively. Titers in the M-KLH vaccinated rats during HSA were 460±260×103 and the antibody concentrations were 470±220 µg/ml (mean ± SD). Titers in the M-KLH vaccinated rats in the drug distribution study were 350±150×103 and antibody concentrations were 390±130 µg/ml (mean ± SD). Antibody titers, and concentrations calculated from these, were not statistically different (p = 0.27) between vaccinated rats in the HSA and drug distribution groups.Vaccination with M-KLH elicited high morphine-specific antibody titers and concentrations in all groups and averaged 400±200×10There was no significant main effect of vaccination on the mean number of infusions per session during the acquisition phase, but significant effects of session  and vaccination×session interaction  . Vaccina2X = 4.20, p<0.05) and 0.003 mg/kg unit doses . During the reinstatement test  . Althougent test , there w2 = 0.88 (±0.06 SEM) and 0.95 (±0.02 SEM) for control and vaccinated rats, respectively). F-test analysis indicated a significantly higher 0Q  in vaccinated compared to control rats (0Q = 3.1 (±0.51 SEM) vs 0.91 (±0.11 SEM), respectively, F = 39.0, p<0.01), but no difference in α values (elasticity of demand) .All plasma heroin concentrations in control rats were below the assay limit of quantitation of 5 ng/ml, but could be estimated because they were above the limit of detection .st infusion of 0.125 mg/kg heroin:1 Mean plasma heroin concentrations were 410-fold greater in vaccinated rats compared to controls  infusion of 0.125 mg/kg heroin (1.0 mg/kg cumulative dose):Final  infusion of 0.0625 mg/kg heroin (0.5 mg/kg cumulative dose):Final  infusion of 0.125 mg/kg heroin (1.0 mg/kg cumulative dose):Final (8 Mean brain heroin concentrations were not significantly reduced in vaccinated rats compared to controls (p = 0.4) but all levels were very low (very low . Brain 6th) infusion of 0.0625 mg/kg heroin (0.5 mg/kg cumulative dose):Final (8 Brain heroin concentrations were not reduced in vaccinated rats compared to controls (p = 0.7) but all levels were very low  after the cumulative 1.0 mg/kg heroin dose  vaccination blocked heroin-primed reinstatement of HSA responding during extinction, 2) vaccination effects on HSA were dose-related, with a decrease in HSA at low heroin unit doses and a compensatory increase in HSA at high unit doses, and 3) changes in brain 6-AM concentrations after vaccination were consistent with the observed changes in HSA at the 0.06 mg/kg/inf heroin unit dose. Vaccination also substantially reduced morphine distribution to brain but morphine levels were lower than those of 6-AM and probably contributed less to the behavioral effects seen in this study. These findings support a potential role for vaccination in treating heroin abuse and provide evidence that 6-AM is a key mediator of the reinforcing effects of heroin.Heroin-primed reinstatement of HSA was blocked in vaccinated rats at a substantial heroin dose . This dose is within the range of rewarding doses in humans 0Q  but not α (no change in sensitivity to price) in the demand curve analysis. Because α provides a standardized measure of reinforcing efficacy that controls for potency differences between groups, this analysis further confirms that vaccination reduced the potency of heroin rather than its reinforcing efficacy. In support of this, brain 6-AM concentrations in vaccinated rats receiving 1.0 mg/kg heroin were similar to those of control rats receiving 0.5 mg/kg. Although heroin and metabolite distribution to brain were not studied at lower heroin doses, vaccine-elicited antibodies presumably reduced brain 6-AM concentrations sufficiently to suppress HSA.The more complex, dose-related effects of vaccination on HSA are most readily explained by vaccination reducing the potency of heroin, as indicated by the rightward shift in the HSA dose-response curve. This effect can be attributed to the binding of antibodies to heroin and its active metabolites in serum, resulting in lower opioid concentrations in brain. Consistent with this interpretation, vaccinated rats receiving 0.06 mg/kg/inf heroin self-administered as much heroin as controls receiving 0.03 mg/kg/inf. Similarly, vaccinated rats receiving 0.03 mg/kg/inf heroin self-administered as much heroin as controls receiving 0.01 mg/kg/inf. Moreover, there was a significant difference in A previous study examining the effects of vaccination with M-KLH on the distribution of a single heroin dose in rats found a marked reduction of 6-AM distribution to brain. Morphine distribution to brain was also reduced but levels were substantially lower than those of 6-AM. Heroin distribution to brain was not reduced despite appreciable binding of heroin in serum It was recently shown that a monoclonal antibody with specificity for 6-AM over heroin or morphine reduced locomotor activity following a single heroin dose in mice Vaccination remained effective even when the total amount of drug administered exceeded that of the available antibodies. However, vaccine effects were most prominent when heroin unit doses were lower than the binding capacity of the available antibodies. An important consideration is that some estimates of single doses used by addicts are as high as 2 mg/kg/inf (and up to 7 mg/kg/day) These findings, along with the substantial reduction of HSA after M-KLH vaccination at the lower heroin unit doses and the blocking of reinstatement of heroin responding by M-KLH, support the ability of M-KLH to alter heroin-associated addiction-relevant behaviors in rats. They are largely consistent with the findings of others with several different heroin vaccines, which also demonstrated reductions in the reinstatement or re-acquisition of heroin self-administration, as well as attenuation of heroin-induced analgesia and locomotor activity It is difficult to directly compare effects of M-KLH with those of other vaccines because of immunological  and behavioral  differences between studies. However, one common measure used to test vaccine efficacy in several studies was anti-nociception, where rats received 1 mg/kg heroin 30 minutes prior to placement on a 54°C hot-plate to measure latency to respond to the noxious stimuli A limitation of the pharmacokinetic experiment is that heroin was administered as evenly spaced doses, in contrast to the less regular dosing pattern during self-administration. We chose this design rather than using yoked controls to minimize variability in the measured levels. Because heroin is metabolized rapidly to 6-AM and morphine, individual differences in heroin dosing patterns just prior to blood sampling for drug level measurement would lead to differences in drug levels that might not be representative of the entire 2-hr self-administration session.Another limitation of this study is that heroin is metabolized to 6-AM more rapidly in rats than in humans, although it is rapid in both S1 Tablest infusion and plasma and brain 4 min after the 8th infusion of heroin in KLH (n = 5–6) and M-KLH (n = 6) rats.Opioid concentrations (mean ± SD) in plasma 4 min after the 1 *p<0.05, **p<0.01, and ***p<0.001 compared to KLH controls. Data corresponds to values shown in (DOCX)Click here for additional data file.


Kevin Outterson and colleagues outline a model to address access, conservation, and innovation of antibiotics. The current business model for antibiotics is plagued by market failures and perverse incentives that both work against conservation efforts and provide insufficient rewards to drive the development of much-needed new treatments for resistant infection.Many new incentive mechanisms have been proposed to realign incentives and support innovation and conservation over the long term. The most promising of these are based on the idea of delinking rewards from sales volume of the antibiotic—the notion of “delinkage.”Some critical design issues for delinkage remain, such as how to secure access to badly needed new products when resistance renders existing treatments ineffective, an increasingly urgent global problem. The issue of global access to antibiotics is not sufficiently addressed de facto by a delinked mechanism, and, as such, it must be addressed explicitly through specific design features of new mechanisms, including defining the eligibility criteria for delinkage rewards and appropriate management of intellectual property.The idea of establishing a new business model to drive antibiotic development and improve conservation currently has the world’s attention. We must now work quickly to examine the remaining design questions to address this major public health concern for the longer term.Senior political leaders are now aware of the threat to human health and, indeed, the global economic toll posed by the growing level of antibiotic resistance. An Executive Order issued in 2015 by US President Barack Obama addressed antibiotic resistance . The RevMost of the commonly prescribed classes of antibiotics were discovered before the 1960s, with only a few novel classes being discovered and approved for clinical use in recent decades –7. The iA number of different proposals and research and development (R&D) models for stimulating antibiotic innovation have been proposed ,10, eachA new antibiotic business model must be globally coordinated, as national or regional approaches to addressing the problem will not alone ensure that benefits of antibiotic innovation are equitably shared, nor will they be sufficient to effectively address the cross-border consequences of antibiotic overconsumption. Different options exist. Coordination could be through a body hosted by WHO, in collaboration with relevant intergovernmental agencies, or be set up more independently. Stronger legal and financial commitment mechanisms could be in the form of a treaty or a WHO regulation that covers access, conservation, and innovation .How more funding can be raised efficiently and equitably for unmet R&D needs has been a longstanding and largely unresolved issue in global health. For example, the Consultative Expert Working Group on Research and Development established by WHO recommended governments commit at least 0.01% of GDP for health needs in low- and middle-income countries (LMICs) , a targeFor financing antibiotic innovation through global resources, a number of incremental steps are needed. First, the global resource commitments required to tackle the challenge of antimicrobial resistance, including the cost of R&D incentives, need to be estimated. Second, that funding should be spent in line with agreed global priorities. Even if most of this funding will be under the control of national governments, a substantial proportion should be allocated to a pooled funding mechanism coordinated globally, given that parts of it will need to cover delinkage rewards. It should be noted that complete financial participation from a large number of countries may not be necessary to initiate a new business model. For example, a contribution of 0.01% of GDP from the Organization for Economic Cooperation and Development (OECD) countries alone could yield between US$4 billion and US$5 billion annually. Other members of the G20 and BRICS  might also participate, as these countries constitute large antibiotic markets . All couA key question is how to attract pharmaceutical innovators, both small- and medium-sized enterprises and larger multinational companies, to increase investments in R&D for antibiotics. Drug companies want their new products to be sold, but for antibiotics, for excellent public health reasons, we want the newest antibiotics to be used sparingly. This dynamic uniquely disfavors investments in antibiotic R&D . New antPhysicians and health systems will become increasingly cautious about prescribing new antibiotics, except for the still relatively rare case in which existing antibiotics are ineffective. For example, novel antibiotics effective against Carbapenem-resistant Enterobacteriaceae (CRE) should, for sound clinical reasons, be reserved for patients in whom the pathogen and its resistance profile are known, which is usually in a hospital setting. These antibiotics will therefore not be available for widespread use in primary care, where over 80% of antibiotics are prescribed . This reIn order to increase the rewards for investing in R&D, increased incentives for R&D will be needed at three different entry points of the antibiotic lifecycle . At the The third entry point for incentives is after marketing approval and registration. It is at this stage that incentives are implemented to break the link whereby R&D is principally financed from revenue streams stemming from sales volume. Instead, companies producing a truly novel antibiotic should receive rewards after receiving marketing approval, linked not to sales but to R&D costs invested or potential therapeutic value. The magnitude of these delinkage rewards should be adjusted for net public investment across the R&D lifecycle. One option is to pay the innovator a significant one-time payment, adjusted to R&D costs and potential clinical value, shortly following marketing approval. This option may look attractive due to its simplicity; however, evidence of novelty and clinical value is likely to be insufficient upon marketing approval of a new antibiotic. Public funders may therefore risk rewarding innovators for drugs that over time prove unable to meet unmet clinical needs. An alternative is therefore to implement a staged approach, in which a minimum base reward covers R&D expenses and the cost of building a supply chain, and subsequent annual payments may increase depending on data regarding clinical effectiveness, resistance profiles, and other data indicating the social value of the new drug .At the early preclinical stage, broad qualification standards should be applied when making grants to fund basic scientific work in antibiotic research. At the clinical and post-registration stage , incentive levels should be guided by a periodically updated global threat and needs assessment, and larger incentives should only apply to drug candidates with the potential to address significant unmet medical needs resulting from drug-resistant bacteria. Within these broad lines, the choice of target pathogen(s) has clear implications for geographic usefulness and global access. Ideally, incentives should be directed toward the development of new antibiotics intended for last-resort use as well as toward new agents with immediate therapeutic value due to high levels of resistance.As an example, we may face, due to varying levels of antibiotic resistance across geographic regions, future scenarios in which a novel antibiotic is reserved as a last resort in high-income settings, while being required for immediate clinical use in financially impaired markets in LMICs. It is therefore important that delinkage, in addition to being an innovation incentive, also address global access. Delinkage was introduced in the global health community as an incentive mechanism in which markets and market-shaping mechanisms were insufficient or not working as signals for innovation investments. By more directly rewarding innovation, it also in effect became an access-related approach, since licensing arrangements potentially could secure competition in manufacturing, thereby allowing for generic level prices . Full deTo enable global access, a delinked incentive framework must also address the management of intellectual property (IP). Intellectual property has historically been a contentious issue with respect to global access, with the most prominent example being civil society and governments in LMICs clashing with multinational pharmaceutical companies over IP policies that restricted access to antiretroviral treatment for HIV/AIDS . StrugglDelinkage should also have an inherent rational use component in that it ideally, in return for rewards, should commit the innovator to not overmarket and oversell the drug. The antibiotic can be used solely based on clinical needs rather than the need to achieve profitable sales targets.Finally, antibiotic delinkage should commit innovators to appropriate sharing of information on effectiveness, distribution, sales, and other data about the product, which should be made distinct from marketing practices to the extent possible. The commitments to information sharing should be incorporated into the conditions for reward eligibility, and these should be agreed to with the innovator also in the case of partial delinkage models. Overall, a delinked incentive framework should present policymakers with options to enable global access while maintaining reasonable control over antibiotic sales and distribution.The delinkage principle applied to antibiotics is a powerful one and has attracted attention not just from academics and NGOs but also from key figures in industry , high-le


Gestational diabetes mellitus (GDM) is associated with substantial morbidity for mothers and their offspring. While clinical and basic research activities on this important disease grow constantly, there is no concise analysis of global architecture of GDM research. Hence, it was the objective of this study to assess the global scientific performance chronologically, geographically and in relation to existing research networks and gender distribution of publishing authors.On the basis of the New Quality and Quantity Indices in Science (NewQIS) platform, scientometric methods were combined with modern visualizing techniques such as density equalizing mapping, and the Web of Science database was used to assess GDM-related entries from 1900 to 2012.Twelve thousand five hundred four GDM-related publications were identified and analyzed. The USA (4295 publications) and the UK (1354 publications) dominated the field concerning research activity, overall citations and country-specific Hirsch-Index, which quantified the impact of a country’s published research on the scientific community. Semi-qualitative indices such as country-specific citation rates ranked New Zealand and the UK at top positions. Annual collaborative publications increased steeply between the years 1990 and 2012 (71 to 1157 respectively). Subject category analysis pointed to a minor interest of public health issues in GDM research. Gender analysis in terms of publication authorship revealed a clear dominance of the male gender until 2005; then a trend towards gender equity started and the activity of female scientists grew visibly in many countries. The country-specific gender analysis revealed large differences, i.e. female scientists dominated the scientific output in the USA, whereas the majority of research was published by male authors in countries such as Japan.This study provides the first global sketch of GDM research architecture. While North-American and Western-European countries were dominating the GDM-related scientific landscape, a disparity exists in terms of research output between developed and low-resource countries. Since GDM is linked to considerable mortality and morbidity of mothers and their offspring and constitutes a tremendous burden for the healthcare systems in underserved countries, our findings emphasize the need to address disparities by fostering research endeavors, public health programs and collaborative efforts in these nations. Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance with onset or first recognition during pregnancy . AlthougGlucose intolerance during pregnancy is common in almost every population around the globe . GeneticControversy still remains regarding the diagnosis and treatment of GDM . ScientiWe employed the previously validated New Quality and Quantity Indices in Science (NewQIS) platform to identify all research published on GDM since 1900 , 28. OurSimilar to previous studies, we used the Web of Science database  for data collection. This resource enabled us to conduct a unique citation analysis in addition to the assessment of publication activity , 39. No NewQIS studies are based on unique search terms that encompass the disease of interest. Hence, we generated the GDM-specific search term “Topic = diabetes AND ” to approximate the overall number of published items. The term was applied in a “Topic” search identifying the search term in the title, abstract and author’s keywords. The analyzed timeframe for GDM research covered the years between 1900 (01–01) and 2012 (31–12). Results from 2013 onwards were not considered due to incomplete data acquisition at the time the study was performed.According to the previously described workflow , 28, we http://data.worldbank.org/country/).After transfer of the downloaded and unedited WoS plain text data files to excel charts, the findings were illustrated in diagrams and visualized by DEMPs. The current DEMPs were based on the algorithm of Gastner and Newman . Here, tIn order to determine gender aspects of global GDM research, we calculated the proportion of male to female authors  based on all authors’ names listed in the publications. We conducted a manual search  if first names were not gender-specific or quoted as initials. In particular, Asian names were difficult to assign to a specific gender. To avoid imprecision, only countries were considered with a minimum of 500 authors who published more than 700 items in total and whose author’s gender could clearly be determined in over 50 % of names. This methodology has been previously described in earlier research .t-test. A p-value <0.05 was regarded as statistically significant.To analyze scientific co-operations between different countries, author affiliations stated on the identified GDM-related publications were analyzed as previously described , 40. Onlhttp://data.worldbank.org/country/).The research output of the ten most productive high-income, eight upper-middle income and three lower-middle income countries was related to the number of inhabitants aiming to analyze a country’s scientific productivity in the context of manpower. The following index was calculated: publications/population-index: number of publications/population in millions. We obtained the 2012 population statistics from the World Bank , followed by the United Kingdom , Australia (p: 635), Canada (p: 584), Italy (p: 550), Germany (p: 536), France (p: 497), Sweden (p: 430), Israel (p: 367) and Spain (p: 366). This distribution of the global research productivity is depicted in the DEMP-analysis Fig. : Here, tWhen we analyzed the total citation activity, the USA was the leading nation with 93,567 citations, followed by the UK with 44,443 citations, and Australia with 12,341 citations. Canada had 11,136 citations and Sweden 10,719 citations, followed by France , Germany  and Italy . The Netherlands was ranked 9th with 5,823 citations and Finland 10th with 5,580 citations.DEMP illustrating the citation analysis Fig.  demonstrThe calculation of the country specific h-Index demonstrated a leading position of the USA with 125 GDM-related publications being cited at least 125 times. The USA was followed by the UK with a country specific h-Index of 97, Canada (h-Index: 55), Sweden (h-Index: 53), Australia (h-Index: 48), Germany (h-Index: 47) and France (h-Index: 45). Italy had a country-specific h-Index of 42 and Finland and Denmark both 41. Again, countries from Asia, Africa, Eastern Europe, South and Central America occupy only a minimized area on the DEMP map corresponding with their extremely low modified h-Indices Fig. .Fig. 2DeThe country citation rate (CR) is a semi-qualitative measure  in contrast to absolute parameters such as the total publication and total citation counts. In this analysis of GDM-specific research, New Zealand was ranked first with a CR of 36.26 . Again, the UK occupied the second place with a CR of 32.82, followed by Sweden (CR 24.93), Belgium (CR 23.78), Netherlands (CR 23.77), Switzerland (CR 22.48), and Finland (CR 21.81). The USA was only ranked 8th with a CR 21.79 followed by Norway (CR 20.55) and Australia (CR 19.43) Fig. .When the gender analysis of authors active in GDM research was performed, an increase in the percentage of female authorship occurred from 2005 onwards. In the assessment of the 15 most productive countries, large differences were present as demonstrated by 1107 female versus 832 male scientists who authored all US-American publications (m:f ratio of 0.8). In Canada, the gender distribution was almost equal as seen by 134 female versus 131 male authors (m:f ratio of 1.0). In striking contrast, 97 male versus 27 female scientists (m:f ratio of 3.6) were identified for Japanese authors of GDM-related publications . The annual number of collaborative publications increased steeply between the years 1990 and 2012 (71 to 1157 respectively). Bilateral cooperations issued 1,261 publications and were the most common type, followed by trilateral collaborations (195 publications). Cooperations between four countries authored 41 items and collaborative efforts between five countries created 21 publications. 15 publications were issued by authors working in six different countries. Again, the USA dominated this analysis with 702 collaborative articles . Most productive cooperations were established between the USA and the UK (110 joint publications), followed by the USA and Israel (83 publications), the USA and Canada (69 publications) and the USA and Sweden (66 publications). The UK was part of 459 cooperations , while Italy - as the third most active collaborating country - issued 177 publications . A spider chart exemplifies the extent of cooperations between all investigated countries  or low-income countries (p: 0.001).We also assessed the percentage of collaborative publications among all country-specific publications as shown in Table The subject categories of all GDM-related articles were analyzed in five-year intervals from 1963 to 2012 with regard to their percentage proportion in order to gain insights into the field’s activity and scientific priorities Fig. . OverallWhen GDM-specific research output was related to population size, we documented the following ranking: Israel was leading the analysis with 46.4 GDM-specific publications per citizen, followed by Sweden (45.2 GDM-specific publications per citizen), Australia (27.9 GDM-specific publications per citizen), UK (21.3 GDM-specific publications per citizen) and Canada (16.8 GDM-specific publications per citizen). The USA (13.7 GDM-specific publications per citizen) dropped to position six among the 10 most productive high-income countries. Very low indices were found for countries with large population sizes such as China (0.2 GDM-specific publications per citizen) and India (0.1 GDM-specific publications per citizen) , we deduce that collaborative efforts between countries of different economic capabilities have to be further increased to improve the research productivity of low-resource nations. Challenges to establish these fruitful collaborations are manifold and include cultural differences, a diverging perspective regarding the conduct of research and unrealistic assessment of the local research capacity and resources . CollaboNumerous studies validated that hyperglycemia during pregnancy translates into increased perinatal morbidity for mother and child; these complications can be avoided and lessened by the better detection and management of the condition . Hence, By analyzing quantitative and semi-qualitative aspects of the scientific output related to GDM, we provided an objective assessment of the research performance in the field. Also, the first sketch of the global research architecture was presented. Clearly, the USA dominated most parameters. However, other countries that usually also dominate the top five most productive countries such a Japan, did not exhibit an extremely high publication activity in GDM compared to other fields of medicine. Many low-resource countries that are affected by a considerable burden by GDM are underrepresented in the global map of GDM research. To lower the public health burden attached to GDM and to tackle the existing disparities, dedicated research needs to be tailored to apparent needs and fostered by strengthening and funding collaborative efforts between industrialized and underserved countries.


Frontiers in Public Health to contribute this comment in response to Patricia Goodson’s article Questioning the HIV–AIDS hypothesis: 30 years of dissent . For those most vulnerable to medical misinformation, especially people dealing with the trauma of a life threatening medical diagnosis, it can be difficult to distinguish the fraudulent claims of AIDS denialists from credible science and medicine.At the expense of her own credibility as well as the reputation of policies –11. The Goodson’s article is a primer on AIDS denialism unlike any seen in what is purportedly a peer-reviewed journal. Goodson relies on material found in articles more than two decades old, a time when HIV first emerged and there were legitimate questions raised about a then unknown pathogen. Goodson’s article relies on self-published books, blog posts, essays, and fringe articles. There is no credible research offered by Goodson to support her opinion that there is any debate about HIV as the cause of AIDS, simply because there is no such debate.Denying AIDS (Denying AIDS, I note that at the start of the AIDS crisis there were numerous potential explanations offered to explain this new disease. However, the fact that AIDS is caused by an infectious agent, to become called HIV, was determined within just a few years. But despite the facts, a small group of rogue scientists, headed by Peter Duesberg, held fast to failed theories. Although they consider themselves dissident scientists, they are actually denialists because they utilize specific tactics to evade and deny reality. AIDS denialists were obscure and mostly ignored until the advent of the world-wide-web. The rise of the Internet afforded denialists to amplify their volume and expand their reach. AIDS denialists have created a pseudoscience that has had its own “journals” and has even conducted unethical and illegal human research. While some AIDS denialists have advanced degrees, none has credibility in the scientific community. At best, Goodson has confused AIDS denialists’ credentials with credibility. At worst, she intentionally ignores their notoriety.Goodson is dismissive of science and medicine. Like the AIDS denialists she gives credence, her views are myopic. Consider her summary of the leading “scientists” who have, for decades, questioned HIV as the cause of AIDS. Sadly, Goodson has not been forthright in her characterization of these characters despite having full awareness of their complete records. She cites my book ing AIDS , which dFor example, Goodson describes Peter Duesberg as a Professor of Molecular and Cell Biology at University of California, Berkeley and a member of the National Academy of Sciences. While it is true that he was part of the group that isolated the first cancer gene and mapped the genetic structure of retroviruses in 1970, Duesberg later claimed, and still claims, that no such genes exist . DuesberJournal of Scientific Exploration and is a leading authority on the existence of the Loch Ness Monster (It is also true that Kary Mullis was a 1993 Nobel Laureate who developed polymerase chain reaction. What Goodson chooses to ignore is that Mullis is also a self-proclaimed avid user of LSD and tells of how he was abducted by aliens . John F. Monster , 18. GooFrontiers in Public Health.As academics and scientists, our credentials are based on the degrees we receive and the appointments we hold, neither of which are typically revocable. However, our credibility is earned by the sum of our accomplishments, not just those things that we say and write that suit an opinion. When his life’s work is considered in total, are we to believe that Henry Bauer is a serious scientist? Should we conclude that his views on HIV causing AIDS are as credible as his research on the monsters of Loch Ness? Does Dr. Mullis’ Nobel Prize offer him a lifetime pass on all of his views, including those on the use of LSD, faking data, alien abductions, and HIV not causing AIDS? Does being elected to the National Academy of Sciences mean that Peter Duesberg is to be taken seriously when he claims that there are no genetic influences involved in any form of cancer and that HIV is harmless? The full record of a scientist should be taken into account when considering credibility. Publishing an article that blindly gives credence to AIDS denialism is now part of the record for Patricia Goodson and Editor Sanjay Zodpey, at the unfortunate expense of The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Corrosion cracking of reinforced concrete caused by chloride salt is one of the main determinants of structure durability. Monitoring the entire process of concrete corrosion cracking is critical for assessing the remaining life of the structure and determining if maintenance is needed. Fiber Bragg Grating (FBG) sensing technology is extensively developed in photoelectric monitoring technology and has been used on many projects. FBG can detect the quasi-distribution of strain and temperature under corrosive environments, and thus it is suitable for monitoring reinforced concrete cracking. According to the mechanical principle that corrosion expansion is responsible for the reinforced concrete cracking, a package design of reinforced concrete cracking sensors based on FBG was proposed and investigated in this study. The corresponding relationship between the grating wavelength and strain was calibrated by an equal strength beam test. The effectiveness of the proposed method was verified by an electrically accelerated corrosion experiment. The fiber grating sensing technology was able to track the corrosion expansion and corrosion cracking in real time and provided data to inform decision-making for the maintenance and management of the engineering structure. One of the main causes of structure durability failure is reinforcement corrosion. The maintenance of corrosive concrete structures costs an estimated $100 billion annually around the world [At present, commercial sensors based on electrochemical principles, such as the anode ladder sensor  and elecAlthough these sensors can detect information about the corrosive environment, the detection or monitoring of concrete strain caused by reinforcement corrosion has not been achieved. The Brillouin Optical Time Domain Analysis (BOTDA) ,10 is a Compared to BOTDA, Fiber Bragg Grating (FBG) sensing technology has the advantages of high precision and low cost. Therefore, it can be used as an effective method for the monitoring of reinforced concrete corrosion cracking. Lee  and Lo  proposedIn this paper, packaged concrete corrosion monitoring sensors based on FBG (CCM-FBG) were embedded into concrete. The coefficient between the grating wavelength and strain was calibrated by an equal strength beam test. The effectiveness of the proposed method was verified by an electrically accelerated corrosion experiment. It was found that CCM-FBG was able to track the corrosion expansion and corrosion cracking in real-time and also provided data for decision-making regarding the maintenance and management of the engineering structure.(1)Elastic deformation: Concrete behaved as an elastic material, such that non-linear deformation was not considered;(2)Uniform corrosion: Corrosion products uniformly arranged around the steel; therefore, the expansion stress acting on the concrete cover was uniform;(3)No leakage of corrosion products: Corrosion products did not leak out of the concrete cover; therefore, expansion stress increased with increasing amounts of corrosion products.Concrete elastically deforms before cracking; therefore, elastic mechanical principles were used to explain the mechanism of corrosion-induced concrete expansion. In this paper, three main assumptions were made:The mechanical model of reinforced concrete corrosion is illustrated in p is the internal pressure, d is the external diameter of the circular ring, a is the internal diameter of the circular ring, r is the distance from the analysis point to the centre, ε is the hoop strain at the analysis point; and E is the elastic modulus of concrete. From the equations above, it is clear that there is a linear relationship between corrosion-induced expansion (Δd) and concrete strain (ε). Therefore, one can estimate concrete expansion by monitoring hoop strain, which can be recorded by CCM-FBG.According to the theory of elasticity, the equation for the uniform internal stress in a circular ring is described in Equations (1)–(3): The structure of FBG fiber grating is shown in Bλ) reflected at the sensor is determined by Bn is the reflective index and Λ is the spatial pitch. When projecting a wide spectrum light source onto the optical fibers, the narrow band spectrum, satisfying Equation (4), is reflected back due to the effect of the gratings.FBG is a periodic and permanent modification of the core refractive index value along the optical fiber axis . The FBGBλ) and changes in strain and temperature in the grating region (gε) is expressed as ερ is the effective light pressure coefficient, and α and β represent the thermal expansion and thermo-optic coefficients, respectively. Any changes in external parameters  alter the grating characteristics and result in a shift of the reflected Bragg wavelength.The relationship between the reflective Bragg wavelength shift Suitable size: In order to avoid stress concentration around the CCM-FBG, the size should be minimized.(2)Sufficient stiffness: In order to ensure high rate of successful embedding, the CCM-FBG should be sufficiently stiff to resist the impact force during concrete casting.(3)Temperature compensation: Because the wavelength variation of FBG is also dependent on temperature, the coefficient between the wavelength and the temperature should be determined.It is difficult to guarantee that the bare FBG sensor remains intact and functional after embedding into the concrete. Alternatively, the coefficient could not be established unless the packaging was finished. Thus, a specific packaging process and calibrating test were performed. When embedding CCM-FBG into the concrete, the size of the sensor was a serious consideration. The packaged CCM-FBG needs to meet the following requirements:Based on the above principles, the size of the CCM-FBG designed as 10 mm × 5 mm × 3 mm (length × width × thickness). The structure and packaging process of the CCM-FBG are shown in An equal strength beam test was performed in order to determine the coefficient between the wavelength and strain. The CCM-FBG and the traditional resistance strain gauges were bonded to the surface of the equal strength beam at the same time. Loads were added at the end of the equal strength beam, 5.0 N each time until 50.0 N was added. CMM-FBG was connected to the SM 130 MOI interrogator, and then, the wavelengths of CCM-FBG were recorded for each load level. As well, the strain of the equal strength beam was recorded by the resistance strain gauges. The layout of the calibration test is shown in The calibration test results are shown in As shown in The correlation coefficients between the wavelength and strain were close to 1, indicating that the strain of structure can be calculated with high precision from the data of CCM-FBG. The wavelength/strain coefficient of CCM-FBG (S)-1 was twice that of CCM-FBG (S)-2 and CCM-FBG (S)-3. The main reason was that the mixture proportion of resin and curing agent influenced the elastic modulus of the hardened epoxy resin. However, it is difficult to precisely control the mixture proportion.The wavelength of FBG is also affected by temperature, and thus temperature compensation should be considered for long-term corrosion monitoring. In this paper, the calibration test of wavelength/temperature coefficient of CCM-FBG was conducted. The CCM-FBG was immersed in 80 °C water, and then the temperature was gradually decreased to 10 °C. During this time, the wavelength of CCM-FBG (S) and CCM-FBG (T) was recorded for every 10 °C reduction. These results are shown in There was a linear relationship between the wavelength variation of CCM-FBG and temperature variation. The data were fitted with a linear regression model, as shown in εΔλ is the wavelength variation of CCM-FBG (S); TΔλ is the wavelength variation of CCM-FBG (T); εα is the wavelength/temperature coefficient of CCM-FBG (S); Tα is the wavelength/temperature coefficient of CCM-FBG (T); and εβ is the wavelength/strain coefficient of CCM-FBG (S).The correlation coefficients between the wavelength and temperature were close to 1, indicating that temperature compensation could be easily applied. According to the calibration test, the strain caused by the concrete corrosion cracking can be calculated by the following formula: 2 to ensure slow corrosion so that abundant data was generated for analysis.Because concrete corrosion in a natural environment occurs over a long period of time, accelerated corrosion achieved with the use of electro chemistry is generally induced for concrete durability research. The evolution process of reinforcement concrete corrosion can still be observed in accelerated corrosion and thus the method was adopted in this study. A steel bar was connected to the positive electrode, and the stainless steel net was connected to the negative electrode of a DC power supply. The specimen was immersed in a 5% NaCl solution. The direct current density was set to 100 A/cmThe size of the concrete specimen was 150 mm × 150 mm × 150 mm. The concrete strength grade was C30, and the ratio of water: cement: sand: stone was 1:0.52:1.94:3.19. The concrete cover was 30 mm [The concrete corrosion cracking due to reinforcement rusting normally occurs at the bottom surface or the lateral side of the RC beam, but the specific location of the cracking is random. Therefore, three FBG sensors were applied to consider the randomness. Three CCM-FBG units were distributed along the reinforcement, and the diameter of the ring was 40 mm. All sensors were connected to the SM 130 MOI interrogator and the data was collected in real-time. The layout of the experiment is shown in The experiment lasted for two months, and the specimen had not been moved during this whole experimental period. In order to observe the surface of the concrete specimen, the NaCl solution was extracted with a small pump regularly every day. With accelerating corrosion, the rust overflowed into the solution along the crack and made the solution turbid and difficult to pump. With the purpose of reducing any disturbance to the corrosive specimen, corrosion products were not cleaned until the end of the experiment.Concrete strain was calculated using Equation (6). The concrete strains recorded by CCM-FBG (S)-1, CCM-FBG (S)-2, and CCM-FBG (S)-3 during the entire experiment are shown in (1)Expansion stage.As observed in This stage lasted about nine days without cracking. The rust kept filling the pore and caused the concrete corrosion expansion force to increase rapidly. The details of strain variations are shown in (2)Initial cracking stage.During the first three days, the concrete strains obtained by all CCM-FBG (S) were mostly consistent. Then, the increasing concrete strain obtained by CCM-FBG (S)-3 was significantly higher than those recorded by CCM-FBG (S)-1 and CCM-FBG (S)-2. Finally, the maximum strain captured by CCM-FBG (S) occurred at different time. The concrete corrosion crack also appeared near the side of CCM-FBG (S)-3. Alternatively, the corrosion expansion force inside of the concrete was not uniform. (3)Crack propagation stage.Once the expansion force of concrete exceeded the tensile strength of concrete, the crack of the concrete appeared at the surface. At the same time, the stress of concrete redistributed and tensile stresses were partially released. As shown in Although some corrosion products flowed out during this stage, the filling by the corrosion product still increased the concrete corrosion force; however, the increasing rate was obviously lower than before cracking, as shown in (1)The cost of monitoring was low, and the packaging technology was simple.A kind of concrete corrosion monitoring sensor had been previously developed based on BOTDA . The BOT(2)High precision could be beneficial to study and solve scientific problems.Traditional resistance strain gauges cannot be buried within internal concrete. The BOTDA technology has a relevant lower precision (±20 με); moreover, it is short of high spatial resolution . In this paper, the size of the CCM-FBG was 10 mm× 5 mm × 3 mm, and it could obtain the concrete corrosion force with high precision. The test results show that the concrete corrosion strain behaved heterogeneously in all three stages, and these results asserted the mechanism of the corrosion.(3)The packaging technology needs to be improved for application in practical engineering.The simple packaging method was an acceptable approach for short-term research. Once applied to practical engineering, some problems such as service life and material creeping would need to be addressed. Some packaging methods for other sensors based on FBG have already been developed and therefore could be applied to CCM-FBG.(4)The application of the proposed sensor needs to overcome some challenges.Although the packaging of the sensor can improve the strength of FBG, the transmission optical fiber cannot be armored and is still brittle; therefore we need to solve the problem of embedding the sensors with low survival. Also, the procedure of embedding the sensor is so complicated that it requires professional staff and a specialized interrogator to obtain data, which is difficult for routing inspection.Chloride is one of the main causes of failure of reinforcement concrete structures. It is critical to evaluate the remaining service life of structures and make decisions on potential maintenance. In this paper, a CCM-FBG sensor with a size of 10 mm × 5 mm × 3 mm was investigated. The coefficients of wavelength/strain and wavelength/temperature were calibrated. The validity of the CCM-FBG was proved by conducting a two-month accelerated corrosion test. The CCM-FBG accurately reflected the expansion strain, and the real-time monitoring data can be beneficial for determining the mechanism of the corrosion. The technology could be used in practical engineering after further design and improved encapsulation. The sensors provided an effective, long-term, and stable detection and monitoring method of a reinforced concrete structure in a chloride environment. The collected data can inform decision-making for the maintenance and management of engineering structures.


Paradoxically, the N400 to nouns in the metaphorical expressions was indistinguishable from that to nouns in the literal abstract expressions, but only for the more concrete subgroup of metaphors; the N400 to the less concrete subgroup of metaphors patterned with that to nouns in the literal concrete expressions. In sum, we not only find evidence for conceptual concreteness separable from lexical concreteness but also that the processing of metaphorical expressions is not driven strictly by either lexical or conceptual concreteness.Metaphorical expressions very often involve words referring to physical entities and experiences. Yet, figures of speech such as metaphors are not intended to be understood literally, word-by-word. We used event-related brain potentials (ERPs) to determine whether metaphorical expressions are processed more like physical or more like abstract expressions. To this end, novel adjective-noun word pairs were presented visually in three conditions: (1) Physical, easy to experience with the senses ; (2) Abstract, difficult to experience with the senses ; and (3) novel Metaphorical, expressions with a physical adjective, but a figurative meaning . We replicated the N400 lexical concreteness effect for concrete vs. abstract adjectives. In order to increase the sensitivity of the concreteness manipulation on the expressions, we divided each condition into high and low groups according to rated concreteness. Mirroring the adjective result, we observed a N400 concreteness effect at the noun for physical expressions with high concreteness ratings vs. abstract expressions with low concreteness ratings, even though the nouns  The term that refers to the source domain is also called the vehicle, the proposition that is stated about the topic term that in turn refers to the concept of the target domain. Even though the source domains are concrete, they are not intended for literal interpretation. For instance, the expressions “thick book” and “steamy book” are both noun phrases comprising an adjective evoking a physical property, followed by a noun. In the first case, the expression as a whole is understood literally, as an object with the physical property of thickness. In contrast, “steamy book” is not understood literally as a tome emitting steam but rather figuratively as a salacious romantic novel.Metaphors are pervasive in everyday language, arguably being much more than mere rhetorical or poetic tools, possibly even serving as key instruments of linguistic change and innovation Bréal, . The higEmbodied cognition  properties of individual words (adjectives) and/or concepts (expressed by adjective-noun pairs) play in novel metaphor comprehension in real-time. To that end, we employ an online methodology that permits moment-by-moment examination of the metamorphosis from concrete, literal language into metaphorical, emergent concepts. Specifically, we recorded event-related brain potentials (ERPs)—a method enabling not just quantitative, but also qualitative, comparisons of the neural processing related to linguistic phenomena as they unfold in time.ERP studies of metaphor processing are often centered on the N400 ERP component. The visual N400  vs. literal (“whiskey is a strong intoxicant”) expressions , not the vehicles (“lions”) that carry the figurative meaning; in Tartter et al. , where they typically exhibit more anterior, and more right lateralized, scalp topographies  and a more concrete (source) concept. After controlling for potential confounding factors between concrete and abstract words, recent work shows behavioral processing advantages for abstract words  to more concrete relative to more abstract words. Against this background literature, we set out to assess whether metaphorical expressions created by combining physical adjectives that do not literally modify nouns  are processed more like concrete or abstract adjective-noun expressions.To sum up, metaphorical expressions very often rely on physical expressions denoting concrete source domains to describe abstract target domains. Whereas figurative meaning clearly goes beyond the sum of its parts , it is less clear to what extent (and when) the physical senses of constituent concrete words impact immediate processing of metaphorical expressions. Electrophysiological studies of metaphor processing generally show We adopted the word pair paradigm of Huang et al.  in whichAt issue was whether processing of MET expressions would be driven (1) by the concrete  nature of the adjective —in which case ERPs to the MET nouns would mimic those to the CL nouns; (2) by the non-literal abstract nature of the noun phrases—in which case ERPs to the MET nouns would mimic those to the AL nouns; or (3) by the non-literal, metaphorical nature of the noun phrase interpretation —in which case ERPs to the MET nouns would differ from those to both the CL and AL nouns, eliciting the largest N400 and/or late negativity as in most ERP studies of novel metaphors.per se that drives processing and interpretation (such that the MET noun is processed as if it followed an abstract adjective) then the MET and AL nouns would elicit equivalently reduced N400 amplitudes (CL > MET = AL). If, however, the system concurrently distinguishes between emergent concreteness, and between abstract concepts that are literal vs. those that are metaphorical, then the N400 to metaphors may be even larger than the N400 for abstract expressions (MET > AL) due to increased processing demands of understanding a novel expression formed by an adjective referring to a physical trait that a noun cannot literally possess. This outcome would converge with the ERP metaphor literature, and with the differential sensitivity of the N400 to independent factors of concreteness and ease of processing/expectancy.We consider several potential outcomes in the N400 window (300–500 ms) of the adjective as well as the noun. We will first inspect the ERPs elicited by the adjectives to obtain a lexical concreteness effect baseline. We expect to see larger N400s to concrete adjectives (easily experienced with the senses) in both the CL and MET conditions compared to the abstract adjectives (not easily experienced with the senses) in the AL condition. If the concreteness of the adjective drives the processing and interpretation of the noun phrase, then we expect to see an N400 concreteness effect at the noun such that CL expression, but also the MET expressions, exhibit larger N400s than AL expressions (CL = MET > AL). Conversely, if it is the abstractness of the emergent concept to which the noun phrase refers rather than the abstractness of the adjective To create the two-word expressions used in the ERP study, each of 212 nouns was combined with 3 different adjectives to form 636 novel word pairs. The nouns were polysemous in that metaphorical (MET), concrete literal (CL) or abstract literal (AL) expressions could result from modification by the different adjectives. Examples of the stimuli can be seen in Table M = 0.11, SD = 0.11).The AL word pairs consisted of abstract adjectives modifying nouns to form expressions referring to abstract concepts. In the CL and MET conditions, adjectives were concrete, but in the MET condition adjectives modified nouns in a non-literal manner: 43% of the adjectives were shared across these two conditions. CL expressions referred to entities easily experienced by the senses, whereas AL and MET expressions referred to entities not easily experienced with the senses. Word pairs were designed to be meaningful but novel, with novelty controlled for by corpus measures. All word pairs appeared 4 times or less in the BNC and the probability of a noun following an adjective was less than 0.01. Semantic relatedness between constituents of expressions was low, as measured by Latent Semantic Analysis (LSA)  on seven point Likert-scales: . The three tasks assigned randomly to individual word pairs were: (1) “How easy is it to experience with the senses?”; 2) “How literal is it?”; and (3) “How meaningful is it?” We chose a literalness rating in order to avoid the explanation or definition of “metaphorical” and/or “figurative”, suspecting that it might be easier to determine whether something is meant literally than figuratively. Each participant saw every word pair but rated individual expressions along only one dimension. Across participants, all word pairs were rated for all dimensions. Pairs in which the CL expression was rated more abstract than the AL expression, or for which the MET was rated more literal than the CL or AL expressions, were excluded. Of the 212 normed items, the two rated least meaningful were discarded. Of the remaining 210 items, the half (105) rated most meaningful  were used as stimuli, with the rest assigned to be fillers. Item norming statistics are summarized in Table  “How litF = 162.3, p < 0.001, F = 387.9, p < 0.001, F = 114, p < 0.001, F = 7.84, p < 0.001, and meaningfulness, F = 5.04, p < 0.01, and there was a strong trend for literalness, F = 3, p = 0.051. Therefore, the Tamhane post hoc test was used for pairwise comparisons. All conditions were significantly different from each other in concreteness (p < 0.001), and literalness (p < 0.05), while in meaningfulness AL and CL expressions were not significantly different, with only MET differing from the other conditions .A one-way ANOVA revealed significant differences between conditions with respect to concreteness, Participants read each adjective-noun pair followed by a probe word that was either related or unrelated to the two-word phrase. Examples of stimuli and related probe words are shown in Table M = 21). Of the 42 participants, 7 were excluded from further analysis due to excessive eye blink or movement artifacts, which left a remaining 35 participants whose data we continued to examine.Forty-two UCSD volunteers  participated for course credit or were compensated at 7 h. Participants were right-handed, native English speakers with normal or corrected-to-normal vision, ranging from 18–29 years old  was related to the adjective-noun pair . Importantly, this technique encouraged participants to comprehend the novel metaphorical expressions in a figurative rather than a literal sense. Response hand was counterbalanced across participants and lists. Stimuli were centrally presented in white Arial 26 point font on a black background on a CRT monitor. Participants completed 6 blocks of 35 items each with short breaks between them. Each trial started with a blank screen (1000 ms), followed by a fixation cross “+” (1000 ms). The adjective appeared centrally for 200 ms, followed by a 300 ms blank screen, followed by the noun for 200 ms, followed by a 1500 ms blank screen, and finally a probe word appeared for 200 ms. After 800 ms following the probe onset, a question mark “?” was displayed until participants responded with a button press. A small red dot was presented centrally and slightly below the text throughout the trials, except during the question mark and the first 1000 ms blank screen; participants were instructed not to blink when it was present. Participants saw all 105 target nouns once, and each was paired with a single adjective once, resulting in 35 items from each condition, along with 105 filler expressions. Items were arranged in 5 different lists to avoid order effects. Each of the 5 lists was separated into 3 sublists so that each noun was paired with all 3 adjectives across participants.The electroencephalogram (EEG) was recorded from 26 electrodes arranged geodesically in an Electro-cap, each referenced online to an electrode over the left mastoid. Blinks and eye movements were monitored from electrodes placed on the outer canthi and under each eye, also referenced to the left mastoid. Electrode impedances were kept below 5 KΩ. The EEG was amplified with Grass amplifiers with a band pass of 0.01–100 Hz and was continuously digitized at a sampling rate of 250 samples/second.Trials contaminated by eye movements, excessive muscle activity, or amplifier blocking were rejected off-line before averaging: these trials  were excluded from further analysis. Data were re-referenced off-line to the algebraic mean of the left and right mastoids and averaged for each experimental condition, time-locked to adjective onsets. ERPs were computed for epochs extending from 500 ms pre- to 1500 ms post-adjective onset, using a pre-stimulus baseline of 500 ms. Since we were interested in the processing of the two word adjective-noun expression, we baseline corrected only prior to the adjective, practically treating the two-word combination as one experimental unit.ANOVAs were used to analyze mean amplitude ERPs over 6 medial central electrodes  where concreteness effects in the N400 time window are commonly observed: these were the same electrode sites over which adjective concreteness effects were assessed to determine inclusion in statistical analyses. Based on the literature, we analyzed concreteness effects in the following time windows: (1) an adjective N400 time window (300–500 ms post-adjective onset); and (2) a noun N400 time window (300–500 ms post-noun onset).M = 88%, SD = 6%) for button presses indicating whether or not the probe was related to the word pair suggested that the word pairs were read for comprehension.Overall response accuracy  = 10.65, p < 0.001, with CL and MET adjectives showing greater N400 mean amplitude  than AL adjectives (−0.67 µV). Planned pairwise comparisons indicated that the mean amplitudes for CL and AL adjectives and for MET and AL adjectives were significantly different (p < 0.001).An ANOVA with 3 levels of word type and 6 levels of electrode location revealed a main effect of word type, F = 15.59, p < 0.001, with high concreteness adjectives eliciting a greater negativity (mean amplitude = −1.73 µV) than low concreteness adjectives (−0.62 µV). As these results were nearly identical to the results for our labeled conditions, we assume that the difference between AL and CL adjectives indeed reflects lexical concreteness.Our AL and CL conditions were based on adjective-noun pair concreteness ratings. However, to ensure that these labels also matched the concreteness of the adjectives alone, we obtained concreteness ratings for adjectives in the CL and AL conditions from Brysbaert et al. . For 46 F = 1.24, p = 0.3. In order to increase the sensitivity of the concreteness manipulation, we sorted the data based on paired concreteness ratings into the most concrete and least concrete items within conditions. The most concrete  and least concrete  items were compared to MET items in order obtain a clearer pattern of concreteness effects—if they were indeed present in the data.A concreteness effect in the expected direction is visible, with nouns in the CL condition eliciting a larger N400 than AL nouns. MET nouns appear to be patterning with CL nouns, also eliciting a larger N400 relative to AL nouns. However, an ANOVA with 3 levels of word type and 6 levels of electrode location showed no main effect of word type, F = 4.38, p < 0.05, with CL-high and MET nouns showing greater mean N400 amplitude  than AL-low nouns (mean amplitude = −0.29 µV) . Thus the N400 pattern at the noun resembles that at the adjective.An ANOVA with 3 levels of word type  and 6 levels of electrode location revealed a main effect of word type, F = 5.98, p < 0.05: the MET-low group was associated with a larger N400 mean amplitude (−1.62 µV) than the MET-high group (−0.53 µV). We next compared these two MET groups to the high and low CL ERPs  and 6 levels of electrode revealed a significant main effect of word type, F = 3.18, p < 0.05, with MET-high nouns showing a reduced N400 mean amplitude (−0.53 µV) compared to CL-high nouns (−1.39 µV). Pairwise comparisons showed that the difference between MET-high and CL-high nouns was borderline significant (p = 0.08) and there was no statistical difference between MET-high and AL-low nouns (p = 0.58).First, the high-concreteness MET group was compared to the most abstract and most CL conditions described above. An ANOVA with 3 levels of word type  and 6 levels of electrode location revealed a main effect of word type, F = 4.10, p < 0.05, with MET-low nouns showing increased N400 mean amplitude (−1.62 µV) compared to AL-low nouns (−0.29 µV). Pairwise comparisons showed that the difference between MET-low and AL-low nouns was statistically significant (p < 0.05) and there was no statistical difference between MET-low and CL-high nouns (p = 0.66).Second, the low-concreteness MET group was compared to the most abstract and most CL conditions described above. An ANOVA with 3 levels of word type  and 6 levels of electrode location revealed a main effect of word type, F = 8.73, p < 0.001, with a significant difference between AL-low and both CL-high (p < 0.001) and MET (p < 0.01). The ANOVA including MET-high (−1.71 µV), CL-high and AL-low also showed a main effect of word type, F = 6.98, p < 0.01, where only MET-high was different compared to AL-low (p < 0.05). The ANOVA with MET-low (−2.32 µV), CL-high, and AL-low likewise revealed a main effect of word type, F = 7.64, p < 0.01, where only MET-low was different from AL-low (p < 0.01). In sum, while the pattern of N400 effects at the noun mimicked that at the adjective in the (high vs. low) literal conditions, this was not the case for the high vs. low MET conditions, which reversed their direction from adjective to noun.To ensure that the observed differences at the noun are not merely spillover from the adjectives, we conducted three ANOVAs as above in the adjective N400 time window (300–500 ms post-adjective onset). Comparing MET (−2.01 µV), CL-high (−2.35 µV), and AL-low (−0.8 µV) revealed a main effect of word type, In the current study we examined the real-time processing of novel metaphorical (“sticky meeting”), AL (“constructive meeting”), and CL (“loud meeting”) two-word (adjective-noun) expressions. We replicated the well-known N400 lexical concreteness effect on the initial adjectives of the two word expressions. A reliable concreteness effect also emerged for the nouns of the literal expressions when the most CL expressions were compared with the most AL expressions—despite the absence of any difference in rated lexical noun concreteness. We also found that on average the N400 to the metaphorical expressions patterned with that to the most CL expressions rather than with that to the most AL expressions, contrary to what we expected. Upon dividing the metaphorical expressions into more concrete vs. more abstract subgroups based on pair concreteness ratings we found that, paradoxically, the more abstract subgroup of metaphors were associated with a larger N400 than not only the most AL expressions but also the more concrete metaphor expressions.The N400 concreteness effect on the prenominal adjectives resembles that reported for single words  = 0.59, p < 0.001) and the more abstract metaphorical expressions did elicit a larger N400 than the more AL expressions, they did not differ from the more CL expressions. If the increased negativity for metaphors in comparison with more AL expressions . On this possibility, our finding of equivalent N400s for more AL expressions and more concrete metaphorical expressions  suggests that readers need not necessarily construct the literal  interpretation of a novel metaphorical expression before understanding its figurative meaning. This interpretation is consistent with parallel models of metaphor comprehension  = 0.53, p < 0.001 , in ways left as yet unspecified, than the original, encoded, lexical concept. Forgács specifies this broadening/narrowing in terms of the abstract-concrete dimension: FLUFFY* could broaden the lexical concept FLUFFY by activating more of its abstract properties , but narrow the lexical concept by suppressing all of its concrete/physical properties . This approach is similar to Glucksberg  abstract property for the vehicle term (“fluffy”), creating “superfluous, cushy speech”. This is not merely a paraphrase, however, because expressing superfluous with “fluffy” brings along with it several cognitive consequences, such as deniability, negotiability, etc., much like indirect speech (cf. Pinker et al., Forgács  has deveucksberg  categoryreadily grasped, and as rapidly digested as AL expressions, although not strictly driven by concreteness.To sum up, our results suggest that the concreteness effect does not merely reflect the concreteness of individual words, but may also be sensitive to the concreteness of higher-level conceptual information. At least in the N400 time window, and seemingly only for more meaningful, more concrete adjectival metaphors, our findings suggest that metaphorical language may be processed and presumably understood in an abstract manner, despite the concrete nature of its constituent parts. In conclusion, it appears that comprehending certain metaphorical expressions created from physical concepts and words can be as Bálint Forgács conceived research; Bálint Forgács, Megan D. Bardolph, Ben D. Amsel, Katherine A. DeLong, and Marta Kutas designed research; Bálint Forgács, Megan D. Bardolph performed research; Bálint Forgács, Megan D. Bardolph, Ben D. Amsel, Katherine A. DeLong, and Marta Kutas analyzed data; Bálint Forgács, Megan D. Bardolph, Ben D. Amsel, Katherine A. DeLong, and Marta Kutas wrote the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


IgG4-related disease is rare, but a frequent differential diagnosis for malignant and for autoimmune diseases. Li and colleagues report the largest cohort of patients with IgG4-related sialadenitis. The observations reveal that the most important diagnostic step is obtaining biopsies. In addition, the IgG4 serum concentration may be a biomarker for the disease progression. Li and colleagues  a large hlebitis . Meanwhihlebitis . IgG4-RDWithin IgG4-RD, at least two major subgroups appear to be present: a subgroup with only head or neck involvement, which affects females and males equally; and a subgroup with either systemic involvement of many organs or of one organ outside the head and neck region, which affects mostly males (80 %) . Both foTo answer these questions on IgG4-RD, an exact diagnosis and therefore optimization of the diagnostic procedures is crucial. We thank Li et al.  for thein = 42) were carefully analyzed. Confirming earlier studies and different from patients with the systemic subgroup of IgG4-RD involving abdominal organs, females were more frequently involved than males. Concomitant autoimmune pancreatitis was observed in only 9 % of the patients, but the majority of the patients had a history of allergies. CT scans were more sensitive than the clinical examination in detection of enlarged salivary glands. In our opinion, ultrasound and magnetic resonance imaging (MRI) should be compared with CT scans in subsequent studies, since these techniques avoid radiation exposure, ultrasound would be easier to obtain, and MRI is currently the standard in assessing glandular structure.A large number of patients with IgG4-related sialadenitis  are helpful parameters in raising the suspicion of IgG4-RD, but similar to elevated IgG4 do not differentiate from malignancies. The most important diagnostic procedure is therefore a biopsy, which should be taken from a major salivary gland, preferably from the submandibular glands. In immunohistochemistry not only the previously defined features of IgG4-RD such as obliterative phlebitis or storiform fibrosis were identified, but also eosinophilia, present in 47 % of the patients, was helpful. Most important, biopsies can distinguish IgG4-related sialadenitis from malignancies of the glands, confirm the diagnosis, and justify the subsequent prolonged corticosteroid therapy.The findings of Li et al.’s study help to distinguish IgG4-related sialadenitis from Sjögren’s syndrome, which historically were considered to be related or even identical diseases. IgG4-related sialadenitis more often affects males and manifests as diffuse gland swelling rather than localized involvement of the parotid glands, the IgG4 is elevated, the presence of SS-A antibodies is rare, and histologically the plasma cells infiltrating the glands express IgG4 and the fibrosis is more pronounced as in Sjögren’s syndrome and storiform.This study by Li et al. is the largest so far with regard to histological analysis of the glands of patients with IgG4-related sialadenitis. Interestingly, the IgG4 serum concentration correlated with the glandular fibrosis and the reduction of saliva production and could therefore be a future biomarker for the disease progression. This is a new finding, which may be important in monitoring the efficacy of treatment of IgG4-related sialadenitis.Not all of the open questions on IgG4-RD can be answered by this study. The data give us information on diagnostic procedures and stress the importance of obtaining biopsies. The fact that most of the patients have an elevated IgE, a history of allergies, and eosinophilic infiltrates in the affected glands suggests an influence of interleukin-4 in the pathogenesis but does not yet prove an allergic rather than an autoimmune etiology of the disorder.