Human behavior is frequently described both in abstract, general terms and in concrete, specific terms. We asked whether these two ways of framing equivalent behaviors shift the inferences people make about the biological and psychological bases of those behaviors. In five experiments, we manipulated whether behaviors are presented concretely  or abstractly . People judged concretely framed behaviors to be less biologically based and, on some dimensions, more psychologically based than the same behaviors framed in the abstract. These findings held true for both mental disorders (Experiments 1 and 2) and everyday behaviors (Experiments 4 and 5), and yielded downstream consequences for the perceived efficacy of disorder treatments (Experiment 3). Implications for science educators, students of science, and members of the lay public are discussed. In everyday life, we tend to frame behaviors in different ways. Sometimes we talk about behavior in general terms . At other times, we talk about those same behaviors with reference to particular people in the context of their lives . The question is whether these different kinds of descriptions matter; that is, does framing affect the inferences we make about those behaviors? Although these abstract and concrete descriptions seem to essentially depict the same behaviors, we found that the two levels of description lead to different judgments about how to explain the behavior. Across five studies, participants favored biological explanations  more for abstract descriptions than for concrete cases and they favored some psychological explanations  more for concrete cases than for abstract descriptions. These shifts in people’s preferences occurred both for ordinary behaviors  and mental disorder symptoms (e.g. delusions). As neuroscience and genetics research have increasingly been capturing the public’s attention, we argue that these results have important implications for science education and for public health communication.A Beautiful Mind; Howard, I Know This Much Is True; Lamb, In the real world, unusual human behaviors (e.g. the symptoms of schizophrenia) are often described at one of two distinct levels of abstraction. At one level, behaviors are described in the abstract, as generalized across individuals. For example, when we google the word “schizophrenia,” the websites that immediately come up—from the National Institute of Mental Health, Mental Health America, National Alliance for the Mentally Ill, Wikipedia, schizophrenia.com, and so on—provide abstract descriptions of schizophrenia and its symptoms (e.g. delusions). Abstract descriptions are also found when we search through an encyclopedia, dictionary, or medical handbook. At another level, we also talk about specific instances of the same behaviors (e.g. a woman who strongly believes that the next-door neighbor is her husband when in fact they have not met). One might learn about the concrete symptoms of schizophrenia via the depiction of a particular person in a film  are not tangible in nature, laypeople may actually see them as being more abstract than biological states, which refer to tangible things such as the physical brain. Furthermore, from a reductionist viewpoint, biological explanations would be considered lower level explanations for behaviors than psychological explanations for the same behaviors. Within the hierarchy of levels of explanation, psychological explanations are more abstract than biological ones, being relatively lacking in concrete, physically grounded detail  and non-generic statements  judgments are affected by the abstract versus concrete framing of behaviors and, if so, in what direction judgments are affected. We tested these hypotheses by measuring people’s endorsements of various biological and psychological explanations for behavior, across a range of equivalent abstract and concrete cases.Diagnostic and Statistical Manual of Mental Disorders , as in nosologies such as the Our prediction is that biological explanations are more strongly endorsed in the abstract than in the concrete, and that psychological explanations of behavior are more strongly endorsed in concrete cases than in the abstract. That is, we would expect laypeople to think that brain chemistry, neural structure, and so on are better explanations of calm performance in general than of Allen’s calm performance in particular. Conversely, we predict that explanations attributing calm performance to intentions or emotions would be endorsed more for Allen’s calm performance than for calm performance in general.We tested these predictions across five experiments. Experiments 1 and 2 compared laypeople’s judgments of the biological  bases of various mental disorders. Each disorder was described in a concretely or abstractly framed vignette, judged by pretest participants to be essentially equivalent. Experiment 3 tested whether these inferences have downstream consequences for how people would choose to intervene on disordered behavior—by using medication or by using psychotherapy. Finally, Experiments 4 and 5 extended these results beyond the domain of mental disorders, examining lay judgments for behaviors that are uncommon (and hence in need of explanation) but not the result of mental disorders.Experiment 1 tested whether laypeople’s causal attributions for disordered behavior are shifted by abstract versus concrete framing. Although clinicians tend to view behaviors as more biologically based in the abstract than in the concrete, and more psychologically based in the concrete than in the abstract .Fifty-one participants were recruited via Amazon Mechanical Turk ; the mean rating for the “good example” question was 8.21 (SD = 0.29). Mean ratings by item were all at least 7.60. Thus, these pretest results verified that each pair of abstract and concrete versions is fairly equivalent.Because we are testing the effect of abstract versus concrete framing of the same behavior, we recruited a separate group of 40 participants from Amazon Mechanical Turk to complete a pretest, measuring whether the abstract and concrete version of each behavior correspond to each other. Each behavior was shown on a separate page and the two versions of each behavior, abstract and concrete, were presented side by side on the page. As an attention check, two filler items not designed to be equivalent were also included. Four participants failed this check. Of the remaining 36 pretest participants, 15 judged whether the abstract version was “a good abstract description” of the concrete version on a scale of 1–9 , while 21 judged whether the concrete version was “a good example” of the abstract version on a scale of 1–9 . The mean rating for the “good abstract description” question was 7.97  to allow for attention and comprehension checks. If participants paid attention to the task, these filler items should receive very high ratings on biological questions and very low ratings on psychological questions. Five participants who did not show this pattern for the two filler items  were excluded from the final data analyses.Q1. Do you think [their/her/his] brain chemistry is different from that of people who [are not like this/do not do this]?Q2. Do you think [their/her/his] brain structures are different from those of people who [are not like this/do not do this]?Q3. Do you think there is a genetic basis for this?For the main experiment, nine questions were developed to measure people’s judgments of the biological and psychological bases of behaviors. Three biological questions were designed to probe beliefs about biological causes of behaviors:Q4. Do you think this is caused by cognitive factors ?Q5. Do you think this is caused by [their/her/his] emotions and desires?Q6. Do you think this is caused by [their/her/his] [personalities/personality]?Q7. Do you think [they are/she is/he is] intentionally [like this/doing this]?Q8. Do you think [they/she/he] should be [held responsible for/given credit for] [being like this/doing this]?Q9. Do you think the causes of this are under [their/her/his] control?Because naïve biology is likely to be limited, only three questions could be developed . In contrast, because the existing literature suggests that naïve psychology encompasses a number of aspects of behavior  were derived from tables of contents of Introductory Psychology textbooks as factors that are frequently addressed in the study of individual differences. Q7, Q8, and Q9  were derived from questions measuring beliefs about agency . For each version of each behavior, the nine questions were presented in randomized order across participants and across items. For each item, participants completed the nine explanation judgments on the same screen, with each item presented on a separate screen.Qualtrics  × 2  within-subjects design.We first computed a biological score for each item by averaging each participant’s responses to the three biological measures , and a psychological score for each item by averaging each participant’s responses to the six psychological measures (α = 0.97).F = 95.68, p < 0.001, ηp2 = 0.70, as shown in Fig. M = 5.37, SD = 1.23) than for the concrete versions , t(42) = −6.32, p < 0.001, d = −0.96, while psychological attributions were higher for the concrete versions  than for the abstract versions , t(38) = 10.85, p < 0.001, d = 1.65.We predicted that biological attributions would be greater for the abstract version than for the concrete version and that psychological attributions would be greater for the concrete version than for the abstract version. To test this, we conducted a 2 (concrete or abstract) × 2  repeated measures ANOVA on each participant’s mean across items. This analysis revealed the predicted interaction, F,42 = 95.Figure F = 17.32, p = 0.009, ηp2 = 0.78. Biological attributions were higher for the abstract versions  than for the concrete versions , t(5) = −2.58, p = 0.049, d = −1.05, while psychological attributions were higher for the concrete versions  than for the abstract versions , t(5) = 5.04, p = 0.004, d = 2.06.The interaction effect also held up in a by-item analysis, using each item’s mean score across participants. A 2 (abstract or concrete) × 2  repeated measures ANOVA on these scores revealed a significant interaction, Experiment 1 found that biological attributions were higher for abstract than concrete descriptions and psychological attributions were higher for concrete than abstract descriptions for the same behaviors. Remarkably, although neither the abstract nor the concrete version explicitly mentioned anything about the causes of the behaviors, attributions were strongly affected by the framing manipulation. Thus, not only expert clinicians .A total of 124 participants were recruited via Amazon Mechanical Turk, of whom nine were excluded . The six psychological questions were split into two groups to equate the total number of questions received across all participants. Sample sizes were determined by power analyses on the data from Experiment 1, with 95% power subject to a minimum of 40 participants per condition (prior to excluding random responders and repeat participants).The stimulus materials were the same as in Experiment 1. Unlike in Experiment 1, the nine questions were grouped into three sets: Biological  = 54.83, p < 0.001, ηp2 = 0.50, as shown in Fig. M = 5.31, SD = 1.20) than for the concrete versions , t(40) = −7.47, p < 0.001, d = −1.67. Conversely, psychological attributions were higher for the concrete than for the abstract versions, both for Psychological Set 1 , t(37) = 3.44, p = 0.001, d = 0.56, and for Psychological Set 2 , t(35) = 8.36, p < 0.001, d = 1.38. As shown in Fig. p < 0.05, two-tailed; cognitive factors reached marginal significance in the predicted direction, p < 0.10).We conducted a 2 × 3 mixed-model ANOVA on each participant’s mean across items, with framing (concrete or abstract) as a within-subjects factor and attribution type  as a between-subjects factor. This analysis revealed the predicted interaction, F = 22.51, p = 0.005, ηp2 = 0.15. Biological attributions were higher for the abstract versions  than for the concrete versions , t(5) = −3.04, p = 0.029, d = −1.24, while psychological attributions were significantly higher for the concrete versions  than for the abstract versions , t(5) = 3.90, p = 0.011, d = 1.59.The interaction effect also held up in a by-item analysis. A 2 (abstract or concrete) × 2  repeated measures ANOVA on the item means revealed a significant interaction, These results show that the strong shifts in attribution shown in Experiment 1 cannot have occurred due to demand to inversely rate biological and psychological causes. Rather, these shifts occur independently, reflecting both a stronger belief in biological causation in the abstract and a stronger belief in psychological causation in the concrete.In Experiment 3, we tested whether the effect of abstract versus concrete framing on biological versus psychological attributions might have a downstream effect on the perceived efficacy of treatments for mental disorders. Such a finding would have implications both for psychiatric intervention and for public health, since perceived treatment efficacy can influence actual treatment efficacy  to 9 (“completely”). Participants were told that psychotherapy refers to “treatment by psychological means, involving repeated verbal interactions between a clinician and a client,” and that medication refers to “treatment by psychiatric, psychoactive, or psychotropic drugs.” These judgments were always made on the same page and their order was counterbalanced so that some participants always made medication judgments first and other participants always made psychotherapy judgments first. The abstract versus concrete framing was a within-subject factor with the order of the items counterbalanced as in Experiment 1, so that the abstract and concrete versions of the same item would appear in separate halves of the experiment.F = 9.61, p = 0.004, ηp2 = 0.20, as shown in Fig. M = 5.71; SD = 1.64) rather than concretely , t(39) = 3.70; p = 0.001; d = 0.58. However, judgments of the effectiveness of psychotherapy did not reliably differ between the abstract  and concrete versions , t(39) = 0.79, p = 0.43, d = 0.13.We conducted a 2 (concrete or abstract) × 2 (medication or psychotherapy) repeated-measures ANOVA on individual participants’ means across items. This analysis revealed the predicted interaction, F1,9 = 9.61,When behaviors are described more abstractly, and biological explanations thereby seem more plausible (as shown in Experiments 1 and 2), the current results suggest that people come to believe that biological interventions on that causal system are more likely to influence those behaviors. These results generalize the effect of abstract and concrete framing on biological attributions to a new measure. That said, it is difficult to say whether or not the effect on treatment decisions is statistically mediated by attributions, since the effect was found for medication but not for psychotherapy. A test for mediation would require a design that measured both attributions and treatments simultaneously.Why did the effect not extend to psychotherapy efficacy judgments? Although it is possible that this occurred because the effect of abstract/concrete framing on psychological explanations is less stable than the effect on biological explanations, we think this is not the most likely explanation. The abstractness manipulation was sufficient to find robust differences for both psychological and biological explanations in Experiments 1 and 2 and this same manipulation was used here in Experiment 3. Instead, the null effect on psychotherapy judgments is likely the result of a ceiling effect: Participants’ judgments for the psychotherapy items were between 6.5 and 7 on a nine-point scale, which may be at ceiling given people’s moderate perceptions of the degree to which psychotherapy has the potential to be effective Jorm, . In contExperiments 1–3 showed that biological and psychological attributions shift depending on abstract versus concrete framing not only for clinicians .Forty-nine lay participants were recruited via Amazon Mechanical Turk, of whom ten were excluded . A separate group of 18 participants judged whether the concrete version was “a good example” of the abstract version on a scale of 1–9 , yielding a mean rating of 7.99 (SD = 0.23). Mean ratings by behavior were all at least 7.33.As for Experiment 1, we conducted a pretest of these items to determine whether the abstract and concrete versions of each behavior were perceived to correspond to each other as intended. We recruited a separate group of 41 participants for this pretest, of whom five were excluded for failing the attention check. Of the remaining 36 pretest participants, 18 judged whether the abstract version was “a good abstract description” of the concrete version on a scale of 1–9 , yielding a mean rating of 7.61  = 33.95, p < 0.001, ηp2 = 0.47, as shown in Fig. M = 4.81, SD = 1.22) than for the concrete versions , t(38) = −4.36, p < 0.001, d = −0.70, while psychological attributions were higher for the concrete versions  than for the abstract versions , t(38) = 4.84, p < 0.001, d = 0.78.Each participant’s biological  and psychological (α = 0.85) attributions were averaged separately. We conducted a 2 (concrete or abstract) × 2  repeated measures ANOVA on each participant’s mean across items. This analysis revealed the predicted interaction, p < 0.05 level (two-tailed t-test against 0), one biological factor reached marginal significance , and two psychological factors did not significantly differ from 0 .As shown in Fig. F = 16.62, p = 0.005, ηp2 = 0.70. Biological attributions were higher for the abstract versions  than for the concrete versions , t(7) = −4.27, p = 0.004, d = −1.51, while psychological attributions were higher for the concrete versions  than for the abstract versions , t(7) = 2.65, p = 0.033, d = 0.94.The interaction effect also held up in a by-item analysis, using each item’s mean score across participants. A 2 (abstract or concrete) × 2  repeated measures ANOVA on these scores revealed the predicted interaction, Experiment 4 found that shifts in attribution occur not only for mental disorders, but for a much broader range of human behaviors. These shifts were consistent across the three biological measures , but somewhat more variable across the psychological measures. Although four of our psychological measures shifted significantly in the predicted direction, two others—cognitive factors and personality—did not.Since all psychological measures shifted significantly in Experiments 1 and 2 depending on framing, it is worth considering why shifts were not seen for cognitive factors and personality in Experiment 4. We speculate that these somewhat less consistent effects of psychological attributions may be due in part to a weaker manipulation of abstractness that we used in Experiment 4, compared to Experiments 1–3. Whereas those previous experiments described the behaviors at the level of a category  that did not invoke any individuals, Experiment 4 described the behaviors in terms of a group of individuals engaging in the behavior. Because even the abstract versions referred to human agents, they might have somewhat triggered psychological explanations. Furthermore, people may consider cognitive factors (e.g. beliefs and intelligence) and personality to be more immutable than the other, more transient psychological factors we tested, such as emotions and intentions. Nonetheless, significant shifts were still obtained for a majority of our measures of psychological attribution—and all measures of biological attribution —testifying to the robustness of the attributional shifts in the face of this weaker manipulation.Experiment 5 sought to replicate the framing effects on attributions for ordinary behaviors, using a between-subjects design as in Experiment 2.N = 9 due to taking similar studies in the past and N = 12 due to random responses on filler items). Thus, data from 219 participants were used for the analyses.Two hundred and forty participants were recruited via Amazon Mechanical Turk, of whom 21 were excluded (N = 36), the Psychological Set 1 (N = 145), or the Psychological Set 2 (N = 38) questions. Sample sizes were determined by power analyses on the data from Experiment 4, with 95% power subject to a minimum of 40 participants per condition (prior to excluding random responders and repeat participants).The stimulus materials were the same as in Experiment 4. The design and the procedure were the same as in Experiment 2 in that participants received either the Biological  = 51.15, p < 0.001, ηp2 = 0.31, as shown in Fig. M = 5.29, SD = 1.11) than for the concrete versions , t(35) = −6.81, p < 0.001, d = −1.13, whereas the responses to the Psychological Set 2 questions were higher for the concrete  than for the abstract versions , t(37) = 5.16, p < 0.001, d = 0.84. The responses to the Psychological Set 1 questions did not differ between the concrete and abstract versions , t(144) = 1.18, p = 0.24, d = 0.10, because cognitive abilities and personality—the two psychological measures that did not reach significance in Experiment 1—were unaffected by the manipulation.  as a within-subjects factor and attribution  as a between-subjects factor. This analysis revealed the predicted interaction, F = 38.80, p < 0.001, ηp2 = 0.85. Biological attributions were higher for the abstract versions  than for the concrete versions , t(7) = −5.33, p = 0.001, d = −1.88, while psychological attributions were marginally higher for the concrete versions  than for the abstract versions , t(7) = 2.15, p = 0.069, d = 0.76. Follow-up analyses conducted separately on the two sets of psychological measures showed that this marginally significant effect on psychological attributions occurred because concrete items were rated significantly higher than abstract items on the Psychological Set 2 measures , t(7) = 2.49, p = 0.041, d = 0.88, while the concrete and abstract items were rated similarly on the Psychological Set 1 measures , t(7) = 0.59, p = 0.57, d = 0.21.The interaction effect also held up in a by-item analysis. A 2 (abstract or concrete) × 2  repeated measures ANOVA on the item means revealed a significant interaction, In sum, the results of Experiment 5 fully replicate the findings of Experiment 4, where biological attributions were consistently stronger in the abstract and psychological attributions were typically stronger in the concrete (with two of six measures failing to reach significance). Finding these same effects in a between-subjects design shows that the framing shifts cannot be due to a perceived demand to rate the psychological and biological explanations inversely.In daily life, people often describe behaviors at differing levels of abstraction—as abstract generalizations across individuals or as concrete behaviors of individuals. We hypothesized that this distinction between abstract and concrete framing would lead to different explanatory preferences; namely, a stronger preference for biological explanations in the abstract and more reluctance to accept biological explanations for concrete cases.The results across Experiments 1, 2, 4, and 5 corroborated this hypothesis. Both in contemplating disordered (Experiments 1 and 2) and everyday behaviors (Experiments 4 and 5), participants generally judged explanations in terms of genetics, neural chemistry, and brain structure to be more appropriate when faced with abstract descriptions of behavior than when faced with concrete cases. These differing explanatory stances also had downstream consequences such that people preferred a more “biological” intervention (medication) for treating disorders when described abstractly than when described in terms of a concrete case (Experiment 3).It should also be noted that our claims are only about whether endorsement of biological and psychological explanations was influenced by abstract descriptions relative to concrete descriptions. Thus, we are not claiming that abstract framing would increase endorsement of biological explanations to the extent that they would be preferred to psychological explanations. In fact, this was not the case in Experiments 3–5. Similarly, we are not claiming that concrete framing would make psychological explanations be endorsed more than biological explanations; again, the current results failed to show that consistently (Experiments 1 and 2). Preferences for biological versus psychological explanations can vary greatly simply due to the nature of the events. For instance, “Don is full of himself” would be difficult to explain in terms of biological factors and thus although an abstract framing like “Some people are full of themselves” may make biological accounts more plausible, psychological accounts may still be more dominant than biological accounts even in the abstract framing.In addition, we acknowledge that other factors may influence the availability of biological versus psychological explanations, including individual differences in theory of mind  = −0.38, p = 0.013, and failed to reach significance in Experiment 3, r(37) = 0.34, p = 0.16. Taken together, these findings speak against the possibility that those who are more likely to endorse mind–body dualism are more likely to be subject to the abstract/concrete framing effect. Nonetheless, these null results should be taken with caution, in part because the dualism scale may have become a less valid measure of dualist beliefs in recent years. That is, the pervasiveness of biological accounts of human behaviors may have made laypeople deny mind–body dualism when confronted explicitly, as is the case in the dualism scale. Future research, using more implicit measures of dualism, can help us better understand the shape and the scope of dualist beliefs that laypeople hold.That said, our results do not present any direct demonstrations of Cartesian dualism, the claim that mind and body are distinct substances. We collected participants’ dualists beliefs at the end of Experiments 1 and 4, presenting them with the dualism scale from Stanovich , and fouPeople hold lay theories across many domains that differ dramatically from more formal scientific theories, including theories in biology (Shtulman, Very little is known, however, about what circumstances lead individuals to apply their formal versus intuitive theories to a problem when these theories disagree. We speculate that people may be more likely to rely on their formal theories in the abstract and more likely to default to their earlier, intuitive theories in the concrete. This idea can provide a further mechanism for the current findings. Whereas folk psychology is a natural and early-emerging mode of explanation (e.g. Gergely & Csibra, One way to test the formal education hypothesis would be to ask whether an analogous effect arises in other domains. Would people apply different lay economic theories in contemplating one individual country versus countries in general? Would people apply different lay theories of evolution in contemplating one particular species versus species in general? Would people give different advice about how to maximize happiness if the advice is applied to a particular person versus people in general? To the extent that formal and intuitive theories may give different verdicts, these questions may be of considerable practical importance.A second way to test the hypothesis would be to conduct developmental studies. Presumably, young children do not have a formal education in biology or neuroscience, so if the effect is indeed driven by formal education, it should not arise among young children. By contrast, if the effect is driven by an intuition that biological explanations are tied to immutability and hence essentialism, it might arise much earlier in development. For instance, Cimpian and Markman  found thWe found that, like clinicians (Kim et al., Our finding also has implications for science education more broadly. Science educators have long debated the relative value of abstract and concrete teaching materials (see Fyfe, McNeil, Son, & Goldstone, We explain human behaviors in multiple ways. We can emphasize the importance of responsibility, controllability, intentions, beliefs, and desires. We can also explain human behavior in terms of biological forces, such as genes, neural chemistry, and brain structure. Our results showed that biological theories of behavior are more privileged when contemplating abstract descriptions rather than concrete cases. Thus, even though abstract and concrete descriptions of behavior are both ubiquitous in the world, and often seemingly equivalent, they can nonetheless lead to very different inferences about the causes underlying the behavior.


The objective of this study was to profile plasma amino acids (AA) and derivatives of their metabolism during the periparturient period in response to supplemental rumen-protected methionine (MET) or rumen-protected choline (CHOL). Forty cows were fed from −21 through 30 days around parturition in a 2 × 2 factorial design a diet containing MET or CHOL. MET supply led to greater circulating methionine and proportion of methionine in the essential AA pool, total AA, and total sulfur-containing compounds. Lysine in total AA also was greater in these cows, indicating a better overall AA profile. Sulfur-containing compounds  were greater in MET-fed cows, indicating an enriched sulfur-containing compound pool due to enhanced transsulfuration activity. Circulating essential AA and total AA concentrations were greater in cows supplied MET due to greater lysine, arginine, tryptophan, threonine, proline, asparagine, alanine, and citrulline. In contrast, CHOL supply had no effect on essential AA or total AA, and only tryptophan and cystine were greater. Plasma 3-methylhistidine concentration was lower in response to CHOL supply, suggesting less tissue protein mobilization in these cows. Overall, the data revealed that enhanced periparturient supply of MET has positive effects on plasma AA profiles and overall antioxidant status. Around parturition, the increased demand for nutrients to sustain fetal growth and lactation coupled with depressed dry matter intake (DMI) impose tremendous metabolic stress on dairy cows. Consequently, health problems and compromised production performance likely occur not only due to negative energy balance-induced increases in circulating free fatty acids, but a negative amino acid (AA) balance ,2,3. ForS-adenosyl methionine (SAM) [Methionine (Met) is an essential sulfur-containing AA associated with various key physiologic events. Previous research has underscored the importance of Met as a limiting AA for milk protein synthesis in many diets ,11. Aparne (SAM) . Furtherne (SAM) . In factne (SAM) .An unfavorable circulating AA profile around parturition likely occurs due to (1) increased production of positive acute-phase proteins (APP) and immune-related proteins induced by oxidative stress and inflammation; (2) enhanced carcass protein mobilization to provide AA for gluconeogenesis; and/or (3) limited uptake of other AA and increased N excretion due to lack of Met. Recent research with periparturient dairy cows has demonstrated benefits to overall health and production performance in response to MET supplementation ,9,14. HoAlthough choline (CHOL) is not an AA, it may regulate AA metabolism by altering AA requirements, especially Met, around parturition. For instance, Met can be regenerated when homocysteine receives a methyl group from CHOL through betaine ,16,17, sFew studies have attempted to characterize the profile of circulating AA and their derivatives around parturition in dairy cows ,18,19,20n = 20), with no MET or CHOL supplementation; Smartamine , CON plus MET at a rate of 0.08% of DM; Reashure , CON + CHOL at 60 g/days; or Smartamine and Reashure , CON + MET + CHOL. Dosage of MET was based on Osorio et al. [2H3)-CHOL and -Met indicated, based on differences in Met methyl flux rates, that the product has CHOL bioavailability of 72% [All procedures for this study (protocol no. 13023) were approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Illinois. Details of the experimental design have been described previously ,23. Brieo et al. ; therefoy of 72% ; therefoy of 72% , thus, iy of 72%  did not Dry cows were housed in a ventilated enclosed barn during the dry period and fed individually once daily at 06:30 am using an individual gate system . After parturition, cows were housed in a tie-stall barn and were fed a common lactation diet once daily. Feed offered was adjusted daily to achieve ~10% refusals.Blood was sampled from the coccygeal vein at −30 and −10 days relative to expected parturition date and at 4, 14 and 28 days relative to actual parturition date before the AM feeding. On average, prepartum samples were harvested at −30.8 ± 1.4 days and −10.9 ± 1.3 days relative to actual calving date. Samples were collected into evacuated tubes  containing lithium heparin for isolation of plasma.Plasma was used to analyze the concentrations of free arginine (Arg), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), threonine (Thr), tryptophan (Trp), valine , asparagine (Asn), aspartate (Asp), alanine (Ala), glutamate (Glu), glutamine (Gln), glycine (Gly), proline (Pro), serine (Ser), tyrosine (Tyr), citrulline (Cit), carnosine, ornithine (Orn), sarcosine (Sar), cystathionine, cystine, homocystine, taurine, α-aminoadipic acid, α-aminobutyric acid, β-alanine, γ-aminobutyric acid (GABA), hydroxylysine, hydroxyproline, phosphoserine, 1-methyl histidine, and 3-methyl histidine at the University of Missouri Agriculture Experiment Station Chemical Laboratories  using high performance liquid chromatography ,28. PlasLiver was sampled via puncture biopsy  from cowmth animal (cow); p < 0.05). Plasma AA and derivatives and hepatic gene expression were analyzed at various time points that were not equally spaced. Therefore, the first order ante-dependence covariance structure 1 (ANTE(1)) was used for repeated measures. Variables were assessed for normality of distribution using the Shapiro-Wilk test. When the normality assumption was rejected, data were log-transformed before statistical analysis. Back transformed data are reported in tables and figures for ease of interpretation. Data reported are least square means for each time point and least square means separation between treatments and time points were performed using the PDIFF statement. Statistical differences were declared significant at p < 0.05 and tendencies at p < 0.10.Data were analyzed using PROC MIXED of SAS  according to the following model:p < 0.01, p < 0.01, p < 0.01, p > 0.10, p > 0.10, p = 0.02) also was detected for Lys, the second most-limiting AA for milk production, mainly due to greater plasma concentrations at −10 days and 14 days  in MET cows owing to greater concentrations at −10 days and 14 days  was detected in these cows. In addition to greater (p < 0.01) Trp in MET cows, a main effect of CHOL also was detected for Trp  in response to MET mainly owing to greater EAA concentration prepartum  in response to MET or CHOL, TAA in MET-supplemented cows was greater  cystine and cystathionine concentrations were also detected in response to MET due to greater plasma level at −10, 14, and 28 days .Main effects of MET, CHOL, and their interactions with time for non-proteinogenic AA and derivatives are presented in pyruvate carboxylase (PC) and phosphoenolpyruvate carboxykinase 1 (PCK1) are presented in p > 0.05) for the mRNA expression of PC and PCK1.Main effects of MET, CHOL, and their interactions with time for expression of A detailed discussion of production performance and immunometabolic status of the cows has been published elsewhere ,9,23.MET and Lys in the MP are the most-limiting AA in a wide-range of diets for dairy cows due to their low concentrations in feed protein relative to their “apparent required amounts in digestible protein” . During Apart from greater plasma Met, the fact that various proteinogenic circulating EAA , NEAA  and non-proteinogenic AA (Cit) were greater in response to rumen-protected MET supplementation is an indication of a better circulating AA profile during the periparturient period. However, it cannot be ignored that MET cows had greater DMI both prepartum and postpartum ,23. TherConsidering the overall greater milk yield, milk protein %, and milk protein yield ,23, it iAround parturition, the demand for AA for glucose and protein synthesis increases abruptly and results in greatly increased AA uptake from the circulation . The fewAlthough circulating concentrations of multiple AA  and derivatives  in MET-supplemented cows were already greater at −10 days compared with cows without MET supplementation and regained greater levels at 14 days postpartum, the circulating concentrations of all AA and derivatives at 4 days were similar regardless of MET supplementation. Whether the lack of difference in circulating concentrations of these AA at 4 days in MET cows was due to inadequate supply in the circulation   or enhanIn terms of AA utilization, a previous study detected the greatest liver uptake of EAA at 4 days postpartum in dairy cows . SimilarPC and PCK1.It is also noteworthy that a reduction in net flux of carbon from volatile fatty acids across the liver and an increase in glucose release was detected early postpartum in a previous report , indicatMet and cysteine are the two sulfur-containing AA that are incorporated into proteins. Apart from their well-known role in contributing sulfur bonds during protein synthesis, Met and cysteine are precursors for downstream functional compounds  and, thus, are considered the principal components in vivo of the sulfur-containing compound pool . The facIt is noteworthy that other than Met, all other plasma sulfur-containing compounds measured are components of the transsulfuration pathway. Considering plasma homocysteine concentrations are highly-dependent on intracellular homocysteine metabolism in liver , and cysAround parturition, the increased demand for nutrients and energy leads to an increase in the production reactive oxygen metabolites (ROM), the accumulation of which could deplete antioxidants and give rise to oxidative stress that may cause substantial tissue damage and render cows more susceptible to various health disorders ,43. BecaAA derivatives have unique metabolic properties and, thus, many have been adopted as biomarkers for metabolic status. For instance, because 3-methylhistidine is released from the catabolism of actin and myosin in skeletal muscle and is not further metabolized in the body, it has been regarded as a reliable marker for tissue protein mobilization . AssuminThe antioxidant activity of carnosine in non-ruminants has been demonstrated both in terms of reducing oxidative damage and improving the enzymatic and non-enzymatic activity of other antioxidants . The facAs a neurotransmitter distributed in both neural and non-neural tissue, GABA has various physiologic functions including feed intake regulation . In ratsThe greater Ala, Arg, and Lys together with cystine and cystathionine concentrations at −10 days and 14 days, but not at 4 days, in cows fed MET indicated greater utilization of these AA and derivatives at the time of most-severe negative AA balance. The enriched circulating sulfur-containing compound pool together with greater α-aminobutyric acid revealed enhanced transsulfuration pathway activity in response to MET supplementation. Despite the greater circulating cystine in CHOL cows, the lower proportion of Met in TSC indicates enhanced flux through the transsulfuration pathway at the expense of Met. Whether the decrease in the proportion of Met was due to insufficient choline supplementation remains unknown. As a precursor for Met synthesis in vivo, it is possible that increasing periparturient choline supplementation could mitigate a decrease in Met. Although plasma GSH did not differ in response to MET due to barely detectable concentrations in plasma, the greater circulating taurine and carnosine indicate less oxidative stress in MET-supplemented cows. In conclusion, the overall better health and production performance reported previously in MET cows was due, at least in part, to a better plasma AA profile and overall lower oxidative stress status. Hence, the lack of change in AA profiles could be one of the reasons preventing CHOL-fed cows from achieving comparable performance and health benefits during the periparturient period.


Each year in the United States, approximately two million persons become infected with antibiotic-resistant bacteria, at least 23,000 persons die as a direct result of these infections, and many more die from conditions complicated by a resistant infection . AntibioClostridium difficile infections, which are associated with considerable costs to patients and the health care system  identified that antibiotic use could have been improved in 37% of cases . FrequenStreptococcus, for which antibiotic treatment is recommended, yet antibiotics are prescribed for approximately 60% of ambulatory care visits for adult pharyngitis  is especially problematic because of their potential for increased selection of resistant bacterial populations and their role in treating serious infections. Among U.S. ambulatory care visits during 2007–2009, broad-spectrum antibiotics accounted for 74% of antibiotics prescribed to patients during visits for respiratory conditions  .Measures promoting appropriate antibiotic prescribing in inpatient settings are primarily implemented through antimicrobial stewardship programs, which CDC recommends for all hospitals in the United States (ts.html) . In a rets.html) , both rehttp://www.cdc.gov/getsmart) inform consumers and providers about antibiotic use and resistance, promote adherence to clinical practice guidelines, and support state- and local-level appropriate antibiotic use programs.Educational campaigns aim to decrease inappropriate antibiotic prescribing by promoting judicious prescribing among providers and by increasing general public and provider knowledge about antibiotic resistance. Strategies to further employ appropriate antibiotic use messages include distribution of public health messages via pharmacies, child daycare centers, and workplaces. The CDC “Get Smart: Know When Antibiotics Work” and “Get Smart for Healthcare” campaigns . These actions include preventing the development and spread of resistant infections, increasing surveillance efforts, developing new drugs and diagnostic tests, and promoting international collaboration to prevent and control antibiotic resistance. In the United States, changes in health care delivery and increased implementation of quality measures provide opportunities to integrate antibiotic stewardship practices. Tracking antibiotic prescribing, regardless of clinical setting, is important in identifying opportunities to improve prescribing and maintain provider accountability. Priority should be placed on reducing prescribing for diagnoses for which inappropriate antibiotic prescribing is common  and on U.S. regions with higher antibiotic prescription rates. Reducing inappropriate antibiotic use and addressing the threat of antibiotic resistance is critical to improve health care quality and to safeguard patient safety across all health care settings.In March 2015,


Expanding antimicrobial resistance patterns in the face of stagnant growth in novel antibiotic production underscores the importance of antibiotic stewardship in which de-escalation remains an integral component. We measured the frequency of antibiotic de-escalation in a tertiary care medical center with an established antimicrobial stewardship program to provide a plausible benchmark for de-escalation.A retrospective, observational study was performed by review of randomly selected electronic medical records of 240 patients who received simultaneous piperacillin/tazobactam and vancomycin from January to December 2011 at an 885-bed tertiary care medical center. Patient characteristics including antibiotic regimen, duration and indication, culture results, length of stay, and hospital mortality were evaluated. Antibiotic de-escalation was defined as the use of narrower spectrum antibiotics or the discontinuation of antibiotics after initiation of piperacillin/tazobactam and vancomycin therapy. Subjects dying within 72 h of antibiotic initiation were considered not de-escalated for subsequent analysis and were subtracted from the study population in determining a modified mortality rate.p = 0.82).The most commonly documented indications for piperacillin/tazobactam and vancomycin therapy were pneumonia and sepsis. Of the 240 patients studied, 151 (63%) had their antibiotic regimens de-escalated by 72 h. The proportion of patients de-escalated by 96 h with positive vs. negative cultures was similar, 71 and 72%, respectively. Median length of stay was 4 days shorter in de-escalated patients, and the difference in adjusted mortality was not significant (The empiric antibiotic regimens of approximately two-thirds of patients were de-escalated by 72 h in an institution with a well-established antimicrobial stewardship program. While this study provides one plausible benchmark for antibiotic de-escalation, further studies, including evaluations of antibiotic appropriateness and patient outcomes, are needed to inform decisions on potential benchmarks for antibiotic de-escalation. Antimicrobial resistance continues to increase at alarming rates. Moreover, the rate at which new, novel antimicrobial agents have been developed and approved for therapy of infections has considerably decreased. Consequently, efforts to promote judicious and appropriate use of antibiotics are of significant importance. Antibiotic de-escalation, in which broad, empiric antimicrobial therapy is either discontinued or replaced with a narrowed spectrum antibiotic, has been an area of increasing focus for decreasing or improving antibiotic use –4.Studies have demonstrated that antibiotic de-escalation is safe and not associated with poorer outcomes –12. AntiThe practice of antibiotic de-escalation is not standardized, and several barriers to antibiotic de-escalation have been reported. These barriers include complex sensitivity patterns of the offending organism, inconclusive microbiological data, colonization with multi-drug resistant pathogens, and receipt of previous antibiotic therapy . Other sThe frequency with which antibiotic regimens are de-escalated or should be de-escalated in the hospital setting is not well described. The few studies that are available suggest a variable frequency of antibiotic de-escalation which ranges from 10 to 70% , 18. FurThe study took place at Wake Forest Baptist Medical Center (WFBMC), an 885-bed tertiary care referral center with an active ASP. A list of 2,937 candidate patients ≥18 years of age was generated through a pharmacy database identifying inpatients who were prescribed the simultaneous combination of intravenous piperacillin/tazobactam and vancomycin from January to December 2011. This particular combination of antibiotics was used as inclusion criteria because in antibiotic utilization reports in previous years, it represented the most common broad spectrum empiric antibiotic regimen prescribed in the inpatient setting at WFBMC.A sample of 20 patients per month was randomly selected from the candidate list using an online random number generator. If a study patient was admitted and initiated on piperacillin/tazobactam and vancomycin twice within the same month, only data from the first hospital admission was considered. Patients were stratified by month to account for seasonal variability in antibiotic use and inpatient prescriber differences. A retrospective chart review of the electronic medical record was subsequently performed on the selected patients.Data collected included age, sex, hospital service, attending physician, documented indication for antibiotics, number of days on piperacillin/tazobactam and vancomycin, de-escalated antibiotic regimens, culture data, radiographic diagnoses, occurrence of antibiotic de-escalation at 24, 48, 72 and 96 h time points, length of stay, final clinical diagnosis, continuation of antibiotics after discharge, and in-hospital mortality. The primary outcome assessed was the frequency of antibiotic de-escalation at 72 h.Antibiotic de-escalation in patients with both positive and negative bacterial cultures was quantified in order to evaluate the impact of culture data on the frequency of antibiotic de-escalation. Antibiotic de-escalation at 96 h was assessed to account for clinical decision making that may have occurred using culture data at 72 h incubation.Antibiotic de-escalation was defined as the use of narrower spectrum antibiotics or the discontinuation of antibiotics after initiation of broad spectrum empiric antibiotic therapy. An antibiotic regimen change that resulted in narrowed coverage of a group of pathogens, yet also expanded coverage to include an additional group of pathogens, was not considered to represent an antibiotic de-escalation event. For example, while excluding anti-pseudomonal therapy, a transition from piperacillin/tazobactam to ertapenem was not considered a de-escalation event, as coverage of extended spectrum beta-lactamase producing organisms was incorporated. Similarly, an antibiotic change of one broad-spectrum class to another was not considered a de-escalation event. For example, if piperacillin/tazobactam was changed to cefepime, this was not considered to represent de-escalation even though anaerobic activity was dropped.Similar to how previous studies have analyzed patients who were lost to follow up, patients were evaluated in the context of the unfavorable outcome group. Therefore, patients who expired within 72 h of initiation of broad spectrum antibiotics were considered not eligible for de-escalation and were therefore analyzed as not having their antibiotics de-escalated. These patients were subsequently excluded from analysis in determining a modified mortality rate. Patients who were discharged within 72 h had their antibiotic regimens analyzed analogous to those admitted for longer than 72 h.The indication for antibiotic therapy was ascertained from documentation in the electronic medical record by the primary team at the time of simultaneous piperacillin/tazobactam and vancomycin use. Sepsis was recorded as the indication for antibiotics in patients who either had “sepsis” or “SIRS” documented in their medical record as the reason for initiation of antibiotics. Sepsis as a consequence of a known source (e.g. pneumonia) was considered as the source infection and not sepsis. Patients who had defined microbiological data from any source were considered to have positive cultures.The ASP at WFBMC had been in place for 11 years at the time of the study. The core team consisted of two Infectious Diseases (ID) physicians acting as primary and associate medical directors, two ID PharmDs, an ID PharmD administrator, and an ID Pharmacy resident. The main components of the program during this entire time period were prospective audit and feedback (PAF) and preauthorization for selected antimicrobials. PAF was conducted 3 times per week by an ID PharmD in which patients were identified by an informatics generated list of positive sterile body fluids, use of selected antimicrobials, diagnosis of a selected infection, or referral by another clinical ward PharmD. Identified patient records were examined and improvements in antibiotic use were communicated back to the prescribing physician by phone. Antibiotic de-escalation, if appropriate, would be suggested at that time. The emphasis of PAF varied over the time period of the study depending on the ASP priority needs for intervention.Antibiotics that had been selected for PAF at least one time during the period before or during the study included carbapenems, linezolid, aztreonam, oral vancomycin, and intravenous fluoroquinolones. Intravenous vancomycin or piperacillin/tazobactam was not selected for PAF specifically, but may have been included in an intervention when they were used for a scrutinized infection, or by other PharmD referral. Broad spectrum antibiotics that required pre-authorization included carbapenems, aztreonam, ceftazidime, linezolid, and daptomycin, but not cefepime, vancomycin or piperacillin/tazobactam.De-escalation interventions other than PAF included ASP team suggestions for subsequent de-escalation at the time of pre-authorization, review of antibiotics by the ASP team or other clinical PharmD at the time of patient transfer (particularly intensive care unit transfer to the ward), ward or intensive care unit (ICU) clinical PharmD suggestion during daily rounds, quarterly housestaff case-based education, and ongoing provider education in large group presentations or at departmental meetings. Automatic stop orders or formal antibiotic “time-outs” were not used. Electronic medical record clinical decision support is not a component of the ASP, but electronic order sets that include antibiotics are available for commonly encountered infections. Local guidelines are available on the ASP website.Odds Ratios with 95% confidence intervals were calculated to determine differences between groups of categorical data. Quantile regression was performed to evaluate differences in hospital length of stay between patients whose antibiotics were de-escalated and not de-escalated.Data was collected from 240 patients who were treated with the simultaneous combination of piperacillin/tazobactam and vancomycin during the study period. Patient age ranged from 19 to 94 years with a median age of 64 years. Antibiotic regimens were de-escalated in 151 (63%) and 175 (73%) patients by 72 and 96 h, respectively.At 24, 48, 72, and 96 h, the percentage of patients who did not have their antibiotics de-escalated was 62, 43, 37, and 27% respectively. Of the patients whose antibiotic regimen was de-escalated, the greatest proportion occurred in the 0–24 h time period. Successive 24-h time increments reveal less dramatic proportions of de-escalation.Antibiotic disposition at 72 h among patients who had their antibiotics de-escalated was heterogeneous Fig. . NotablyThe most commonly documented indications for initiation of broad spectrum antibiotics were pneumonia, sepsis, and skin and soft tissue infections Table . We obsen = 27). Of these, 17 (63%) patients would have been appropriate for de-escalation based on their defined microbiologic data. Eight (30%) patients would have not been appropriate for de-escalation, and two (7%) died within 24 h, and consequently, would not have been eligible.Overall, 234 patients (98%) in the study population had microbiologic culture specimens obtained during their hospitalization. Of those, 94 (40%) patients had positive culture results. Antibiotic regimens were de-escalated by 96 h in 67 (71%) patients with positive culture results and in 101 (72%) patients with negative culture results. This difference was not statistically significant. A subsequent analysis was performed on patients with positive cultures whose regimens were not de-escalated (Patients admitted to oncology services had a higher frequency (71 vs. 63%) of antibiotic de-escalation at 72 h compared to the study population as a whole, although this was not statistically significant. Patients admitted to the remainder of services, including critical care units, had a similar frequency of antibiotic de-escalation to that observed in the overall study population (Table p = 0.0003. One hundred fourteen (48%) patients were discharged home on antibiotics. The median length of stay for those patients was 5 days as compared to 9 days for those who were not discharged on antibiotics, p = 0.01.The median length of stay was 4 days shorter in patients who had their antibiotics de-escalated compared to those who did not (6 vs.10 days), p = 0.002, Mortality Odds Ratio = 0.31 (95% CI: 0.14–0.65). However, 12 patients expired within 72 h of initiation of piperacillin/tazobactam plus vancomycin and were not eligible to have their antibiotic regimen de-escalated at 72 h. Therefore, a secondary analysis or modified mortality rate was also calculated to account for the impact these patients would have on the difference in mortality rates between groups (Table Thirty-four (14%) study patients experienced in-hospital mortality. Mortality rates were significantly lower among patients who had their antibiotic regimens de-escalated compared to patients who did not, This study of antibiotic de-escalation for one of the most commonly prescribed broad spectrum antibiotic regimens for empiric therapy, vancomycin plus piperacillin/tazobactam, showed that the majority of patients, approximately two-thirds, had their antibiotic regimens de-escalated by 72 h in a single institution with a well-established and resourced ASP. In addition, over half of patients had their regimens de-escalated by 48 h. The high proportion of patients de-escalated from the study antibiotics was reflected across a range of clinical services and presenting infections.While the frequency with which hospital-wide antibiotic de-escalation occurs is not well-described in the literature, published estimates of antibiotic de-escalation are widely variable and range from 10 to 70% , 18. In Singh et al. found that patients whose antibiotic regimens were de-escalated were less likely to develop antibiotic resistant super-infections compared to those whose regimen was not de-escalated  [Previous studies on antibiotic de-escalation are largely confined to the intensive care setting, are disease-specific, and highlight that de-escalation is safe and is not associated with worse outcomes. For example, in a randomized, prospective trial of 81 intensive care unit (ICU) patients with ventilator-associated pneumonia (VAP), = 0.017) .A number of study observations warrant further discussion. First, patients admitted to oncology services were observed to have the highest frequency of antibiotic de-escalation. While the high proportion of de-escalation in this population is surprising, the oncology patients captured in this study comprised a minority of the study population and cefepime, not piperacillin/tazobactam, plus/minus vancomycin, were the fever-neutropenia protocol indicated antibiotics. Although fever was the most common documented indication for broad spectrum antibiotics on oncology services, only two of these patients had concurrent neutropenia documented. Additionally, while hyperpyrexia in immunocompromised patients may have led prescribers to utilize empiric broad spectrum antimicrobial therapy, they were also quick to de-escalate therapy which may reflect recognition of limited instances where anti-MRSA therapy was indicated, even if broad spectrum gram negative coverage was.Next, we did not observe significant differences in the proportion of patients de-escalated when they were stratified according to the documented indication for antibiotics, with the exception of urinary tract infections. The higher frequency of antibiotic de-escalation in patients with urinary tract infections (94%) compared to the overall study population is likely related to several different factors. First, patients with urinary tract infections represented a very small percentage of the total study population (7%). Additionally, piperacillin/tazobactam plus vancomycin is not a regimen that is typically used for the empiric treatment of urinary tract infections. Thirdly, culture results are often available for these patients by 48 h. Thus, prescribers are likely to de-escalate these regimens quickly.The vast majority of patients in our study had culture data available to assist prescribers with decision-making. However, no appreciable difference was observed in the frequency of de-escalation between patients who had positive cultures when compared to patients with negative cultures (71 and 72% respectively). While the majority of patients with positive cultures were de-escalated, a secondary analysis of patients with positive cultures whose regimens were not de-escalated revealed that 17 (63%) would have been appropriate for de-escalation based on defined microbiologic isolates. In most cases, the presence of culture data, either positive or negative, may facilitate de-escalation of antibiotic therapy, but further study is needed to determine how clinicians use culture data in their de-escalation practice. While positive cultures can define microbiology and allow prescribers to tailor antibiotic regimens to the isolated organisms, negative cultures may provide reassurance for prescribers as they de-escalate antibiotic regimens. The ultimate decision to de-escalate therapy is likely influenced by an interplay of dynamic clinical variables that may be further compounded by severity of illness and complex susceptibility patterns.Another interesting finding is the large proportion of patients whose antibiotic regimen was de-escalated within 24 h. The decision to de-escalate in this timeframe is likely not based on culture results, but instead on the patient’s clinical status and the decision that the patient’s clinical picture did not warrant the use of broad spectrum antimicrobial therapy.Finally, observed mortality rates and hospital length of stay were both lower in patients who had their antibiotics de-escalated compared to those who did not. However, these associations may be surrogate markers of overall clinical status and the severity of illness, which were not controlled for in this study. Nevertheless, our data highlights that de-escalation was not associated with an increase in mortality.Limitations of this study include the retrospective study design and the reliance on medical record documentation for data collection, including the indications for empiric vancomycin and piperacillin/tazobactam. Certain patient populations were also under-represented in this study, such as oncology patients and patients with urinary tract infections. This study measured the frequency of antibiotic de-escalation at a single center with an established ASP, and as a result, may not be applicable to all institutions. Additionally, only patients who were empirically started on piperacillin/tazobactam and vancomycin were included in the study. Consequently, we did not measure all antibiotic de-escalation that may have occurred during the study period and frequency of de-escalation may differ for other broad spectrum empiric antibiotic regimens. Finally, this study did not evaluate the appropriateness of antibiotics including both empiric and de-escalated regimens.De-escalation of empiric antibacterial therapy is increasingly recognized as an important principle of antibiotic stewardship. While antibiotic de-escalation may not be feasible or appropriate in every instance, this study adds to the literature as potential benchmarks for antibiotic de-escalation are being considered. Future studies should examine the frequency of antibiotic de-escalation at other institutions both with and without established ASPs. In addition, longitudinal comparisons of the frequency of antibiotic de-escalation may add important information on whether frequencies change over time at a given institution. While our study measured the frequency of antibiotic de-escalation, we did not assess appropriateness of either the empiric or de-escalated antibiotic regimen. Interpreting the occurrence of antibiotic de-escalation in the context of appropriateness would assist in determining whether a 72-h antibiotic de-escalation frequency of 60–70% is a reasonable benchmark.


A 20:1 combination of cafedrine:theodrenaline (Akrinor®) is widely used in Germany for the treatment of hypotensive states during anesthesia and in emergency medicine. Although this drug formulation has been available since 1963, there are few studies relating to its use and many of the data are only available in German. In this article, we summarize the available data and propose mechanisms for the effects of cafedrine/theodrenaline on cardiac muscle cells and vascular smooth muscle cells. Cafedrine/theodrenaline leads to a rapid increase in mean arterial pressure that is characterized by increased cardiac preload, stroke volume, and cardiac output. Systemic vascular resistance and heart rate remain mostly unchanged. Factors which impact the effects of cafedrine/theodrenaline are gender, high arterial pressure at baseline, use of β-blockers, and heart failure. Importantly, the drug is frequently used in obstetric anesthesia without detrimental effects on umbilical cord pH or APGAR score. Hypotension occurs frequently after induction of anesthesia or in emergency medicine. Some organs are especially susceptible to hypotension  and theodrenaline  called Akrinor® is used for the treatment of hypotension in adults that occurs during emergency situations, general anesthesia, and regional anesthesia, especially during cesarean sections . The German and English results were screened manually for relevance. Reference lists of internal reports provided by the manufacturer of the drug were screened for additional publications.−1. Cafedrine is metabolized to norephedrine and several minor metabolites, as summarized by Koch and Knoth , since both drugs contain the non-selective PDE inhibitor theophylline  by 28%; this effect decreases gradually up to 20 min after administration  increase 9 ± 4 min after drug administration) was observed. The increase in MAP after 5 min was 11 ± 14 mmHg and after 10 min 14 ± 16 mmHg. The ED50 of cafedrine/theodrenaline was 1.49/0.075 mg.kg−1 to achieve a 10% increase in MAP after 5 min, and 0.53/0.027 mg.kg−1 to achieve a 10% increase after 10 min. Analysis of data from different dose groups in the range from 0.31 ± 0.07 mg/kg to 1.25 ± 0.44 suggested a direct dose-response. Cafedrine/theodrenaline's effect on mean arterial pressure was significantly less substantial in patients with heart failure and in patients with a higher MAP at baseline. Furthermore, male patients showed a less substantial effect than females. The authors suggested that a higher intravascular fluid volume in women might explain this difference  patients exhibited a drop in blood pressure. Fifty-six patients whose systolic blood pressure remained within defined limits, i.e., ≥120 mmHg or >80% of baseline blood pressure, were assigned to the non-treatment group and were compared with the hypotensive patients treated with cafedrine/theodrenaline  a more comprehensive description of the pharmacokinetics ; (b) further elucidation of the mechanism of action of each of the components and their cleavage products; (c) characterization of the inotropic, bathmotropic, and chronotropic effects of cafedrine/theodrenaline (possibly involving the use of isolated Langendorff preparations); (d) characterization of the temporal relationship between cafedrine/theodrenaline administration and vasoconstriction or vasodilatation in isolated venous and arterial vessel preparations; and (e) comparison of the effects of cafedrine/theodrenaline and alternative drugs on blood pressure, heart rate, and cardiac output in a clinical context . A multicenter, non-interventional study of cafedrine/theodrenaline vs. ephedrine for the treatment of perioperative hypotensive states is currently ongoing, and is registered in ClinicalTrials.gov (NCT02893241) and in the German Clinical Trials Register (DRKS-ID: DRKS00010740).In this review article we focus on cafedrine/theodrenaline, but there are other antihypotensive agents available. Phenylephrine stimulates predominantly the α-receptors and is a strong vasopressor which leads to an increase in blood pressure and a reflex bradycardia. The vascular resistance is increased, which in turn leads to a decrease of the cardiac output . BB reports personal fees from ratiopharm GmbH, Pulsion Medical Systems, Air Liquide International, Orion Pharma, MSD, GE Healthcare, CNSystems, Edwards Life Sciences, CSL Behring, and Abbvie outside the submitted work. TC receives support for his research by the German Network for Heart Research , ratiopharm GmbH, Ulm, Germany and Xention Ltd, Cambridge, UK. Furthermore he received a speaker honorary from ratiopharm GmbH.


The HGF/c-MET pathway is active in the development of digestive system cancers, indicating that inhibition of HGF/c-MET signaling may have therapeutic potential. Various HGF/c-MET signaling inhibitors, mainly c-MET inhibitors, have been tested in clinical trials. The observed efficacy and adverse events of some c-MET inhibitors were not very suitable for treating digestive system cancers. The development of new HGF/c-MET inhibitors in preclinical studies may bring promising treatments and synergistic combination  strategies provided anacceptable safety and tolerability. Insights into miRNA biology and miRNA therapeutics have made miRNAs attractive tools to inhibit HGF/c-MET signaling. Recent reports show that several microRNAs participate in inhibiting HGF/c-MET signaling networks through antagonizing c-MET or HGF in digestive system cancers, and the miRNAs-HGF/c-MET axis plays crucial and novel roles for cancer treatment. In the current review, we will discuss recent findings about inhibitors of HGF/c-MET signaling in treating digestive system cancers, and how miRNAs regulate digestive system cancers via mediating HGF/c-MET pathway. Digestive tract malignancies, mainly including gastric cancer, hepatocellular carcinoma (HCC), pancreatic cancer, esophageal cancer, and colon and rectal cancer, are highly common cancers and causes of cancer deaths worldwide . Despite1349 and Tyr1356) results in an activated C-terminal docking site, which has been identified to be able to recruit intracellular adaptor proteins . mi. mimiRNAng c-MET  and longl cancer . SynthetmiRNA-335-5p could inhibit pancreatic cancer via mediating c-MET (c-MET, and thus inhibit cell growth, migration, and invasion, and promote apoptosis via activating the HGF/c-MET signaling pathway. Moreover, NEAT1, a nuclear-restricted long noncoding RNA, suppresses the microRNA-335-5p/c-MET axis to promote pancreatic cancer malignancy . I. ImiRNA- reduced . On one patients  91]. In. InmiRNAc-MET, VEGFA, VEGFR1, VEGFR2, and MMP2. Consistently, miR-199a-3p may inhibit the proliferation of HCC cells via targeting c-MET and antagonizing downstream signals STAT3, mTOR, and ERK1/2 [miR-335 has been confirmed to inhibit the migration of cancer cells via binding c-MET mRNA in pancreatic and breast cancer [The function of miRNAs-HGF/c-MET axis in several human cancers has also been explored, including NSCLC, renal cancer, breast cancer, bladder cancer, and other cancers ,106,107.t cancer ,106. TheThe HGF/c-MET pathway is emerging as a therapeutically relevant target in multiple cancers. The discovery and development of c-MET inhibitors has been gradually increasing, including nonselective and selective inhibitors. c-MET inhibitors were diverse for digestive system cancers, however, safety and efficacy have become the main problems in clinical stage studies. New drug developments for c-MET inhibitors offer the potential for better cancer treatment. Clinical trials of these c-MET inhibitors need to be performed to confirm the efficacy and safety. Moreover, insight into the improved safety and efficacy of clinical cancer therapy based on combined medication will provide a new research direction for treating digestive system cancers. In addition, miRNA biology therapy is still in the preclinical stage. Further investigation of the miRNA-HGF/c-MET may supply effective and promising therapy in human cancers, including digestive system cancers.


Electronic cigarettes are at the center of a public health policy debate which leverages scientific publications. This study characterizes e-cigarette publication trends over the past 15 years via a bibliometric analysis. Scopus was searched for “electronic cigarette”, “e-cig”, “e-cigarette”, “vape”, “vaping”, “juul”, or “electronic nicotine delivery system” between 2003–2018. Data included Hirsch index, document type and frequency, and publications by institution, journal, and country. VOSviewer was used to visualize authorship network maps. A total of 4490 e-cigarette publications were identified, most (62.8%) being articles. After 2009, the annual growth rate for e-cigarette publications was the largest in 2014. The annual growth rate was nearly flat in 2017 but increased in 2018. The U.S. produced 51.6% of publications. Annual National Institutes of Health NIH funding for tobacco research mapped closely with the annual volume of e-cigarette publications. Author network analyses illustrated investigator collaborative patterns. The frequency of e-cigarette publications increased significantly in the past decade. A strong relationship of NIH funding for tobacco research and e-cigarette publications demonstrates the importance of e-cigarettes in tobacco research. Electronic cigarettes (e-cigarettes) are battery-powered devices that can deliver nicotine and non-nicotine solutions to the user through inhalation of a heated liquid. The first commercial e-cigarette was created in Beijing, China in 2003  and, whiIt is well established that scientific research plays a role in the development of health policy ,7,8. As Bibliometric analyses have been conducted on a wide range of health topics ,11,12, aFor this analysis, Scopus, an online database with the largest source of over 22,600 available journals across all fields of research, was used . Scopus Search keywords included: “electronic cigarette”, “e-cig”, “e-cigarette”, “vape”, “vaping”, “juul”, and “electronic nicotine delivery system” under the “Article title, Abstract, Keywords” field, in publications between 1 January 2003 and 31 December 2018. We included documents published in all languages. A total of 4692 documents were found. Books, book series, conference proceedings, conference papers, erratum, trade publications, and undefined documents were excluded from analysis, resulting in a final sample of 4490 documents. Data on Hirsch index (h-index), document type, number of articles published annually, institutions, journals, most cited articles, top keywords, and top authors were collected. The h-index is a common bibliometric index that represents an author’s quantity and impact of publications. An author with an index of h has h papers that have attracted h citations . Use of Document type, top institution, and top journal by frequency and percentage, amount of annual publications by frequency, and growth rate were reported. Growth rate was calculated using the following equation:Authorship networks were visualized using VOSviewer, which allows for the construction of bibliometric networks using citation files . CitatioFor the authorship network analysis, we included authors with at least 20 electronic cigarette publications. We excluded authors that did not have at least one publication with another author. There were 47 authors who met these criteria.We obtained information on NIH funding using categorical spending data that are provided annually using the NIH Research Portfolio Online Reporting Tools (RePORT)  . The funWe generated two keyword word clouds in TagCrowd ; one clon = 2822, 62.8%), followed by reviews , and notes . Letters , editorials , articles in press , and short surveys  made up the remaining electronic cigarette publications.Of the 4490 publications from 2003–2018, the h-index was 109 as of January 2019; that is, there were 109 papers that were each cited at least 109 times. For context, the h-index of e-cigarette articles in the 2014 analysis was 27 . An h-inThe frequency of e-cigarette publications by year is seen in The most prolific institutions with electronic cigarette publications from 2003–2018 included the University of California, San Francisco , Johns Hopkins Bloomberg School of Public Health , and the University of North Carolina at Chapel Hill . The Virginia Commonwealth University, University of Southern California, Roswell Park Cancer Institute, King’s College in London, Centers for Disease Control and Prevention, and the Food and Drug Administration—Center for Tobacco Products all had fewer than 2% of publications each but were the next most prolific institutions. Of the top 10 most published institutions, nine were based in the United States and one was based in the United Kingdom.After excluding those articles with “undefined” countries or territories, the United States produced 1666 publications (51.9%), the United Kingdom had 443 publications (13.8%), followed by Australia with 156 publications (4.9%). Italy, Canada, Germany, France, Switzerland, Greece, and China were also included in the top 10 countries publishing e-cigarette papers.Nicotine and Tobacco Research , Tobacco Control , and Addictive Behaviors . The International Journal of Environmental Research and Public Health, Addiction, Drug and Alcohol Dependence, BMJ Online, Preventive Medicine, American Journal of Preventive Medicine, and PLOS One were the remaining top 10 journals.The journals containing the most electronic cigarette publications included: The most cited electronic cigarette publications are indicated in The network of authorship in the field of electronic cigarettes is shown in The top 50 indexed and author-provided keywords are shown in In 2018, some keywords increased in the proportionality of usage. These include “adolescent”, “behavior”, “clinical”, “lung”, and “vaping”. In 2018, new keywords emerged in the top 50, including “cancer”, “child”, “school”, and “student”. Other keywords like “cessation” and “drug” had a decreased proportion of usage in 2018.This bibliometric analysis demonstrates that the amount of publications in the field of electronic cigarette research increased notably as e-cigarettes grew in popularity, as well as the health concerns surrounding their use as well as their potential as a harm reduction product. Although e-cigarette research has grown quickly, there was stagnation in 2017, followed by another rise in 2018.In considering influences on the growth pattern of e-cigarette publications, the funding of tobacco research is certainly a contributing factor. The trajectory of e-cigarette publications, with a 5-year time lag, maps very closely onto NIH tobacco research funding, except in 2018. Funding increased steeply between 2008 and 2010, then slowed in 2011 and flattened in 2012. The corresponding e-cigarette publication curve was very steep from 2013 to 2015 and flattened in 2016 and 2017. This 5-year lag could align with the time frame of obtaining funding, conducting a study, and preparing and publishing the results. The fact that tobacco research funding, not specific e-cigarette research funding, mapped so closely onto e-cigarette publications, illustrates that electronic cigarette research was a rapidly growing area within the tobacco field. Funding initiatives should be sure not to neglect emerging health issues, such as e-cigarettes, to drive scholarly output that enhances the success of current tobacco control efforts. The inverse relationship between funding in 2013 and publications in 2018 raises questions, but the link between funding and scholarly output should be studied in greater detail in future research.The network map of authors provides interesting insight as to the e-cigarette scholarship landscape. These collaborative author groupings or clusters tend to have a distinct theme and/or are geographically grouped. For examine, the cluster in yellow  is based at the University of Southern California and their research focuses primarily on youth e-cigarette use and concerns regarding gateway issues. The cluster in green  is a diverse group whose work focuses on population-level policy and harm-reduction issues. The cluster in red (which includes but is not limited to Goniewicz and Eisenberg) focuses on e-cigarette products and features, such as exposure and constituents. The cluster in pink  are EU researchers who were some of the early investigators in harm reduction. Of note, this cluster as well as the orange  and brown cluster (Glantz) are somewhat isolated. Through this type of novel information, one can see how the spectrum of e-cigarette research activity interacts as a function of the themes and authors themselves. This approach could help the research community to better explore cross-disciplinary and cross-institutional, and perhaps most importantly, cross-“belief-system” efforts.Journal of the American Medical Association and the New England Journal of Medicine. There may be so few articles in these journals to date that they will not show up in bibliometric analyses yet and, thus, are harder to analyze. However, their impact on policy decisions could be very important.Interestingly, four of the top 10 articles with the most citations were from journals that did not make the list of journals with the highest volume of e-cigarette manuscripts. Reviews made up under 10% of all electronic cigarette publications but made up half of the top 10 most cited electronic cigarette publications. These facts illustrate the difference between publication volume (quantity) and impact. In recent years, e-cigarette use has become a more prevalent public health problem, and thus, articles regarding their use have appeared in more high-impact sources, including the Most research in the e-cigarette field is conducted by United States researchers and institutions. As seen in This study expands upon previous efforts to analyze the literature surrounding electronic cigarettes, using a more inclusive search method. One limitation of this study is that institutions and nations are given the “credit” solely based upon the first author’s affiliation. This might make it appear as though there is less collaboration in the field than there is in reality. Despite this, we conducted a thorough search using Scopus, used more comprehensive and up to date e-cigarette terminology, and included more recent publications. The inclusion of publications after 2014 allowed us to capture 2018’s large growth in publications after 2017’s stagnation. This study provides the first publication keyword analysis in the field of electronic cigarettes and might provide insight to tobacco researchers on emerging areas of research within the field. This study also provides the first author network analysis for e-cigarette research, and authors might be able to use this information to identify other groups to collaborate with in the future.


Four-point bending tests of concrete beam were conducted before and after chloride ion erosion in order to determine effect of rubber aggregate on the durability of rebar. Results showed that rebar corrosion degree decreased with the increase of rubber aggregate in concrete. Besides, the more the dosage of rubber is, the better the anti-crack performance of cement concrete. This will postpone the crack development and reduce the peak of rebar corrosion.Erosion effect of chloride ions from the marine, deicing salt, saline-alkali land and some industrial environments will cause the corrosion of rebar in concrete, which is one of the most harmful factors affecting the durability of concrete structure. It had been proved that the incorporation of rubber aggregates increase the capillary saturation of cement concrete and reduce the corrosion degree of rebar. This paper investigated the rebar corrosion behavior in rubber aggregate concrete under the chloride electro-accelerated corrosion condition and such an investigation has not been seen in any public literature. Two water-cement ratios (0.45 and 0.55) and four rubber contents (0, 50, 100, and 150 kg/m Different types of concrete have been widely used in construction and water conservancy projects due to their different strength, different shapes, and good overall performance. However, rebar corrosion, the most commonly disease, caused by chloride ion erosion from the marine environment, deicing salt, saline-alkali land, and some industrial sites is a major threat to the durability of concrete structure. This also results huge direct and indirect economic losses. Research had showed that the corrosion rate of reinforced concrete was affected by the saturated degree of capillary pores. The use of rubber aggregates can improve the capillary pore saturation and reduce the rebar corrosion in the concrete. The weight loss rate decreased with the increase of rubber content.For a long time, researchers have devoted themselves to improve the concrete strength. Unfortunately, shortcomings such as brittleness and cracks of concrete would rise prominently with the improvement of strength. In recent decades, scholars have begun to apply rubber particles in the concrete. This not only improves the deadweight, brittleness, and other disadvantages of concrete, but also expands the use of waste rubber as recycled resources. The rubber cement concrete is a composite material, which is made by mixing the waste rubber particles and base cement concrete. As a superelastic material, rubber improves the internal structure of concrete through physical action without changing the chemical properties of concrete. The rubber elastic modulus is almost negligible when compared with concrete. The rubber particles, uniformly distributes in the concrete and replaces part of the aggregate, can be seen as elastic holes to prevent the generation and development of micro cracks in the concrete, and forms the deformed center that absorbs strain energy. Many scholars have studied the physical and mechanical properties of rubber aggregate concrete and found that rubber particles can significantly improve the crack resistance of concrete. At the same time, rubber cement concrete will not suddenly undergo brittle failure when they are destroyed. In addition, rubber particles also have positive effects in improving the frost resistance of concrete and the migration of chloride ions. Pelisser et al.  studied Thomas et al.  pointed Oikonomou et al.  found thIt could be seen that the rubber aggregate was helpful to weaken the chloride ions diffusion, but effects of rubber content on the strength of concrete and the chloride ions diffused characteristic were unknown. Therefore, this paper investigated the corrosion mechanism of rebar in rubber cement concrete in the environment of chloride salt. Accelerated corrosion test was conducted using concrete beams with 0.45 and 0.55 water-cement ratios and different rubber contents. Electrochemically accelerated methods were used to simulate corrosion of the rebar in the etching medium (3.5% NaCl solution). The concrete weight loss rate and crack width after two corrosion cycles  were evaluated. Finally, the flexural performance of concrete beams after corroding was tested. Bearing capacity, deflection and failure modes with different rubber contents before and after corroding were analyzed.The key of experiment is to form a corrosion current loop. Besides, it must be ensured that oxygen, water and chloride ions are present around the rebar. Almusallam et al.  used eleIn the test, the voltage output of DC power is 0–30 V, the maximum output electric current is 5 A. Concrete specimens were beams with a scale 100 mm × 100 mm × 515 mm. Half of the beams in vertical direction were submerging in the 3.5% NaCl solution, Two rebar with a diameter of 5 mm were built in the part above water level. The concrete cover depth was 10 mm. As the anode, the rebar are connected to the positive pole of the power. The cathode is a stainless wire-steel arranged at the bottom of specimens. A resistance is connected in the loop, its value is 10.8 Ω. Concrete proportions are shown in All of the specimens were cured by 28 days firstly. After that they were taken out for accelerated corrosion. The corrosion periods 5 and 10 days was selected in this study. During the test, every rebar was connected with a resistance and then paralleled connected with power . A constIn this paper, evaluation on rebar corrosion was conducted according to standard GBT50344-2004. Half-cell potential method for electrochemical analysis was adopted. The corrosion instrument, DJXS-05 was adopted for potential test. Before measuring the potential, the applied electric field was turned off, and after measuring the potential, the applied electric field was restored. To avoid the variability of the potential, potential was measured until the power was switching off for 10 min. Meanwhile, repeated measurements of the potential were adopted to reduce the variability of the potential in the experiment. In accordance with standard GBT50344-2004, the measured potential was accepted if the error of two consecutive measurements was less than 10 mV. Otherwise, repeated measurements would be carried out until the error was less than the requirements of the specifications.On that basis, a four-point bending test was conducted on the reinforced concrete beams, as shown in 3. At the same time, it can also be found that longitudinal cracks generated on the side and upper surface of control specimen, as shown in 3 rubber did not crack. As shown in The corrosion test specimen is shown in It is generally considered that spot corrosion occurs under natural environment, and uniform corrosion occurs under the condition of applied electric power. Nevertheless, rebar which was taken out and rusted from the concrete specimen had been slightly corroded on spots, as shown in Rebar corrosion potential values of 5 d power supplying are shown in From As shown in After the accelerated corrosion test, the concrete specimens were broken, the bars removed from that were polished using steel brushes and sandpaper to remove residual concrete and rust from the surface. Then they were soaked in dilute sulfuric acid at a concentration of 10% for 15 min, and then they were re-polished until to the fresh surface. Finally, it was placed in an oven to dry, and it was weighed with accuracy of 0.01 g.As shown in As shown in After the accelerated corrosion test, four-point bending test was performed as a mechanical index to evaluate effect of chloride ion diffusion on the concrete. Considering the uncertainty of failure load in the test, the load corresponding to 2.5 mm at mid-span and corresponding fracture energy were analyzed in this paper.(1) Load-Displacement characterThe load-displacement contours obtained in the test are shown in As can be seen in In this paper, the load corresponding to 2.5 mm is compared. As shown in (2) Unit intensity energy consumptionThe incorporation of rubber in the concrete reduces the strength of the concrete, energy dissipation is compared using the ratio of the load corresponding to 2.5 mm to cubic compressive strength. It means the contribution of cubic compressive strength to the anti-cracking property. The larger this parameter is, the greater the contribution is.As shown in For the concrete facing the chloride salt environment, the rebar corrosion is mainly affected by the capillary pore pressure. Considering the contact angle effect, incorporation of rubber reduces the capillary pores pressure and rebar corrosion. The rebar corrosion was delayed and reduced.The cracks of rubber concrete are dispersed along the longitudinal direction, it is different with the completely crack of control concrete.Rebar corrosions of rubber aggregate concrete and control concrete are spot corrosion. Concrete with a higher water-cement ratio will have a better anti-corrosion performance.3 of rubber aggregate concrete is less than 5%.The load-displacement curve shows that the bearing capacity loss of the concrete beam basically decreases with the increase of rubber aggregate. With the increase of the corrosion cycle, the loss of bearing capacity increases, and the amount of 150 kg/mAdding rubber aggregate into concrete opens a new approach to address the rebar corrosion problem.