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When reprehensible conduct is explicable in terms of the offender's life history or underlying biology, blame is mitigated. Despite their shared capacity for blame mitigation, here we focus on differences between historical and biological explanations for bad conduct. We argue that historical explanations generate greater uncertainty about blameworthiness than do biological explanations. They do so because they have both competing and tentative implications regarding agent control. Furthermore, we argue that the blame uncertainty engendered by historical explanations enables motivated cognition in the blame process. We provide evidence for these claims in four studies. In Study 1, we show that computer mouse trajectories are less direct—suggesting uncertainty—when blame assessments are made in cases of historical as compared to biological causation. Studies 2, 3, and 4 test our claims regarding susceptibility to biased cognition. Predisposition to blame was measured in Studies 2 and 3 and manipulated in Study 4. In all studies, predisposition to blame was more potent in shaping blame judgments in cases of historical as compared to biological causation. Evidence suggests that this happened because cases of historical causation are relatively amenable to divergent construals regarding agent control, whereas the implications of biological causation are more definitive. Discussion centers on the importance of motivation—a “merciful mindset”—for effecting blame mitigation in cases where the offender has endured an unfortunate life history. [ABSTRACT FROM AUTHOR]

Background Clinical coding data provide the basis for Hospital Episode Statistics and Healthcare Resource Group codes. High accuracy of this information is required for payment by results, allocation of health and research resources, and public health data and planning. We sought to identify the level of accuracy of clinical coding in general surgical admissions across hospitals in the Northwest of England. Method Clinical coding departments identified a total of 208 emergency general surgical patients discharged between 1st March and 15th August 2013 from seven hospital trusts (median = 20, range = 16-60). Blinded re-coding was performed by a senior clinical coder and clinician, with results compared with the original coding outcome. Recorded codes were generated from OPCS-4 & ICD-10. Results Of all cases, 194 of 208 (93.3%) had at least one coding error and 9 of 208 (4.3%) had errors in both primary diagnosis and primary procedure. Errors were found in 64 of 208 (30.8%) of primary diagnoses and 30 of 137 (21.9%) of primary procedure codes. Median tariff using original codes was £1411.50 (range, £409-9138). Re-calculation using updated clinical codes showed a median tariff of £1387.50, P = 0.997 (range, £406-10,102). The most frequent reasons for incorrect coding were “coder error” and a requirement for “clinical interpretation of notes”. Conclusions Errors in clinical coding are multifactorial and have significant impact on primary diagnosis, potentially affecting the accuracy of Hospital Episode Statistics data and in turn the allocation of health care resources and public health planning. As we move toward surgeon specific outcomes, surgeons should increase collaboration with coding departments to ensure the system is robust. [ABSTRACT FROM AUTHOR]

In a Phase 2 clinical trial, BMS-986020, a lysophosphatidic acid receptor-1 (LPA 1) antagonist, produced hepatobiliary toxicity (increased ALT, AST, and ALP; cholecystitis) and increases in plasma bile acids (BA). Nonclinical investigations conducted to identify a potential mechanism(s) for this toxicity examined BMS-986020 and two LPA 1 antagonists structurally distinct from BMS-986020 (BMS-986234 and BMS-986278). BMS-986020 inhibited hepatic BA efflux transporters BSEP (IC 50 1.8 μM), MRP3 (IC 50 22 μM), and MRP4 (IC 50 6.2 μM) and inhibited BA canalicular efflux in human hepatocytes (68% at 10 μM). BMS-986020 inhibited mitochondrial function (basal and maximal respiration, ATP production, and spare capacity) in human hepatocytes and cholangiocytes at ≥10 μM and inhibited phospholipid efflux in human hepatocytes (MDR3 IC 50 7.5 μM). A quantitative systems toxicology analysis (DILIsym®), considering pharmacokinetics, BA homeostasis, mitochondrial function, oxidative phosphorylation, and reactive intermediates performed for BMS-986020 recapitulated clinical findings ascribing the effects to BA transporter and mitochondrial electron transport chain inhibition. BMS-986234 and BMS-986278 minimally inhibited hepatic BA transporters (IC 50 ≥20 μM) and did not inhibit MDR3 activity (IC 50 >100 μM), nor did BMS-986234 inhibit BA efflux (≤50 μM) or mitochondrial function (≤30 μM) (BMS-986278 not evaluated). Multiple mechanisms may be involved in the clinical toxicity observed with BMS-986020. The data indicate that this toxicity was unrelated to LPA 1 antagonism since the mechanisms that likely influenced the adverse clinical outcome of BMS-986020 were not observed with equipotent LPA 1 antagonists BMS-986234 and BMS-986278. This conclusion is consistent with the lack of hepatobiliary toxicity in nonclinical and clinical safety studies with BMS-986278. • BMS first LPAR1 antagonist associated with bile acid transporter inhibition. • BMS first LPAR1 antagonist associated with phospholipid transporter inhibition. • BMS first LPAR1 antagonist associated with decreased mitochondrial function. • In vitro risk factors for DILI mitigated with BMS 2nd generation LPA1 antagonists. • Hepatobiliary toxicity is unrelated to antagonism of LPAR1. [ABSTRACT FROM AUTHOR]

Abstract: The present work challenges the idea that implicit evaluative associations with outgroups necessarily provide information about negative or prejudiced attitudes. We argue that the manner in which one explains outgroup status and action shapes whether one''s implicit “negative” associations are prejudice-based or empathy-based. Four studies are consistent with this possibility. Study 1 suggests that whereas implicit “negative” associations are predictive of negative explicit attitudes among those who reject external explanations for African American status and action, such implicit “negativity” predicts positive explicit attitudes among those who endorse external explanations. Study 2 provides experimental evidence that the provision of external explanations results in the formation of implicit “negative” associations that are predictive of compassionate responding. Study 3 provides more direct support for the idea that implicit “negative” associations are empathy-based among external explainers by showing that such “negative” associations are positively correlated with a measure of dispositional empathy-proneness. Finally, Study 4 demonstrates that IAT “negativity” is associated with automatic activation of empathy-related associations among those who strongly endorse external explanations. Discussion centers on the importance of considering factors—such as social explanations—that may moderate whether implicit “negativity” is prejudice-based or empathy-based. [Copyright &y& Elsevier]

One conclusion emerging from the stereotyping literature is that behavioral information can undercut stereotyping of individuals. Two studies examined whether this holds for descriptive but not prescriptive stereotypes. In Study 1, participants whose descriptive and prescriptive stereotypes had been measured chose between equally qualified male and female job applicants. Results indicated that descriptive stereotypes did not predict gender bias, but prescriptive stereotypes did. In Study 2, participants whose descriptive and prescriptive stereotypes had been measured provided evaluations of either male or female job applicants who were enacting either masculine or feminine roles. Results indicated that descriptive stereotypes did not predict gender bias, but prescriptive stereotypes fostered—among male participants—a bias against females enacting masculine roles and in favor of males enacting masculine roles. These studies suggest that prescriptive stereotyping can persevere after behavioral information has undercut descriptive stereotyping. Thus, the studies underline both the tenacity of stereotyping and the need to reconsider the generalization that information deters stereotyping. [Copyright &y& Elsevier]

Adenosine A 2A receptors are putative therapeutic targets for neurological disorders. The adenosine A 2A receptor antagonist istradefylline is approved in Japan for Parkinson's disease and is being tested in clinical trials for this condition elsewhere. A 2A receptors on neurons and astrocytes may contribute to Alzheimer's disease (AD) by impairing memory. However, it is not known whether istradefylline enhances cognitive function in aging animals with AD-like amyloid plaque pathology. Here, we show that elevated levels of Aβ, C-terminal fragments of the amyloid precursor protein (APP), or amyloid plaques, but not overexpression of APP per se, increase astrocytic A 2A receptor levels in the hippocampus and neocortex of aging mice. Moreover, in amyloid plaque-bearing mice, low-dose istradefylline treatment enhanced spatial memory and habituation, supporting the conclusion that, within a well-defined dose range, A 2A receptor blockers might help counteract memory problems in patients with Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Abstract: Background: MIR137 is implicated in brain development and encodes a microRNA that regulates neuronal maturation and adult neurogenesis. Recently, a common genetic variant within MIR137 showed genome wide evidence of association with schizophrenia, and with altered amygdala activation in those at genetic risk for schizophrenia. Following this evidence, we investigated the effects of MIR137 genotype on neuronal activity during face processing. Methods: By grouping 81 healthy participants as carrier or non-carriers of the MIR137 rs1625579 risk allele associated with schizophrenia, we investigated MIR137's effects on altered cortical response during an fMRI face processing task and altered functional connectivity using the amygdala as a seed region. Results: Homozygous carriers of the risk allele were observed to show relatively increased functional connectivity between the right amygdala and frontal regions that play a key role in emotion processing and regulation (e.g. the cingulate and prefrontal cortex). Conclusions: Our findings provide the first evidence that the rs1625579 variant affects fronto-amygdala functional connectivity, providing further evidence that MIR137 may contribute to forms of psychosis in which affective symptoms are more prominent. [Copyright &y& Elsevier]

Abstract: A common polymorphism within the nitric oxide sythanse-1 (NOS1) gene (rs6490121), initially identified as risk variant for schizophrenia, has been associated with variation in working memory and IQ. Here we investigated how this variation might be mediated at the level of brain structure and function. In healthy individuals (N=157), voxel based morphometry was used to compare grey matter (GM) volume between homozygous and heterozygous carriers of the ‘G’ allele (i.e. the allele associated with impaired cognition and schizophrenia risk) and homozygous carriers of the non-risk ‘A’ allele. Functional brain imaging data were also acquired from 48 participants during performance of a spatial working memory (SWM) task, and analysed to determine any effect of NOS1 risk status. An a priori region-of-interest analysis identified a significant reduction in ventromedial prefrontal GM volume in ‘G’ allele carriers. Risk carriers also exhibited altered patterns of activation in the prefrontal cortex, caudate, and superior parietal lobe, which were characteristic of abnormal increases in activation in frontoparietal working memory networks and a failure to disengage regions of the default mode network. These functional changes suggest a NOS1-mediated processing inefficiency, which may contribute to cognitive dysfunction in schizophrenia. While the mechanisms by which NOS1 may influence brain structure and/or function have not yet been well delineated, these data provide further evidence for a role of NOS1 in risk for schizophrenia via an impact upon cognitive function. [Copyright &y& Elsevier]

Abstract: ZNF804A rs1344706 is the first genetic risk variant to achieve genome wide significance for psychosis. Following earlier evidence that patients carrying the ZNF804A risk allele had relatively spared memory function compared to patient non-carriers, we investigated whether ZNF804A was also associated with variation in brain volume. In a sample of 70 patients and 38 healthy participants we used voxel based morphometry to compare homozygous (AA) carriers of the ZNF804A risk allele to heterozygous and homozygous (AC/CC) non-carriers for both whole brain volume and specific regions implicated in earlier ZNF804A studies—the dorsolateral pre-frontal cortex, the hippocampus, and the amygdala. For patients, but not for controls, we found that homozygous ‘AA’ risk carriers had relatively larger gray matter volumes than heterozygous/homozygous non-carriers (AC/CC), particularly for hippocampal volumes. These data are consistent with our earlier behavioral data and suggest that ZNF804A is delineating a schizophrenia subtype characterized by relatively intact brain volume. Establishing if this represents a discrete molecular pathogenesis with consequences for nosology and treatment will be an important next step in understanding ZNF084A''s role in illness risk. [Copyright &y& Elsevier]