An Engineered Bivalent Neuregulin Protects Against Doxorubicin-Induced Cardiotoxicity With Reduced Proneoplastic Potential

Background—Doxorubicin (DOXO) is an effective anthracycline chemotherapeutic, but its use is limited by cumulative dose-dependent cardiotoxicity. Neuregulin-1β is an ErbB receptor family ligand that is effective against DOXO-induced cardiomyopathy in experimental models but is also proneoplastic. We previously showed that an engineered bivalent neuregulin-1β (NN) has reduced proneoplastic potential in comparison with the epidermal growth factor–like domain of neuregulin-1β (NRG), an effect mediated by receptor biasing toward ErbB3 homotypic interactions uncommonly formed by native neuregulin-1β. Here, we hypothesized that a newly formulated, covalent NN would be cardioprotective with reduced proneoplastic effects in comparison with NRG. Methods and Results—NN was expressed as a maltose-binding protein fusion in Escherichia coli. As established previously, NN stimulated antineoplastic or cytostatic signaling and phenotype in cancer cells, whereas NRG stimulated proneoplastic signaling and phenotype. In neonatal rat cardiomyocytes, NN and NRG induced similar downstream signaling. NN, like NRG, attenuated the double-stranded DNA breaks associated with DOXO exposure in neonatal rat cardiomyocytes and human cardiomyocytes derived from induced pluripotent stem cells. NN treatment significantly attenuated DOXO-induced decrease in fractional shortening as measured by blinded echocardiography in mice in a chronic cardiomyopathy model (57.7±0.6% versus 50.9±2.6%, P=0.004), whereas native NRG had no significant effect (49.4±3.7% versus 50.9±2.6%, P=0.813). Conclusions—NN is a cardioprotective agent that promotes cardiomyocyte survival and improves cardiac function in DOXO-induced cardiotoxicity. Given the reduced proneoplastic potential of NN versus NRG, NN has translational potential for cardioprotection in patients with cancer receiving anthracyclines.Stem Cell and Regenerative Biolog

Violent aggression predicted by multiple pre-adult environmental hits

Early exposure to negative environmental impact shapes individual behavior and potentially contributes to any mental disease. We reported previously that accumulated environmental risk markedly decreases age at schizophrenia onset. Follow-up of matched extreme group individuals (≤1 vs. ≥3 risks) unexpectedly revealed that high-risk subjects had >5 times greater probability of forensic hospitalization. In line with longstanding sociological theories, we hypothesized that risk accumulation before adulthood induces violent aggression and criminal conduct, independent of mental illness. We determined in 6 independent cohorts (4 schizophrenia and 2 general population samples) pre-adult risk exposure, comprising urbanicity, migration, physical and sexual abuse as primary, and cannabis or alcohol as secondary hits. All single hits by themselves were marginally associated with higher violent aggression. Most strikingly, however, their accumulation strongly predicted violent aggression (odds ratio 10.5). An epigenome-wide association scan to detect differential methylation of blood-derived DNA of selected extreme group individuals yielded overall negative results. Conversely, determination in peripheral blood mononuclear cells of histone-deacetylase1 mRNA as 'umbrella mediator' of epigenetic processes revealed an increase in the high-risk group, suggesting lasting epigenetic alterations. Together, we provide sound evidence of a disease-independent unfortunate relationship between well-defined pre-adult environmental hits and violent aggression, calling for more efficient prevention

Clinician Perspectives of the Evidence Underpinning Suicide Risk Assessment: A Mixed Methods Study

In recent years, suicide risk assessment has become the subject of a vigorous academic debate, due in part to several meta-analyses that have cast doubt on the accuracy of risk categorisation. Little is known about how clinicians make sense of this academic debate. However, it is anticipated that it may pose a tension due to organisational expectations that multidisciplinary health professionals, including social workers, assess and manage suicide risk. As part of a larger mixed methods study to be reported elsewhere, we conducted a qualitative study aiming to explore clinician perspectives on the evidence underpinning suicide risk assessment before and after being presented with the results of two meta-analyses. Findings highlight three modes of reasoning: academic, emotive, and experiential. Perceptions of accuracy of assessing suicide risk at baseline interviews and after hearing the evidence were influenced by heuristics and cognitive biases. IMPLICATIONS Mental health practitioners, including social workers, employed in mental health settings may be more likely to use experiential reasoning to inform their practice in suicide risk assessment. Social work practitioners in general health settings may be more likely to use academic reasoning when making decisions about suicide risk assessment. Further research is required on how social workers and other mental health professionals can best respond to the crisis of suicide. © 2021 Australian Association of Social Workers

Prevalence and Assessment of Malingering in Homicide Defendants Using the Mini-Mental State Examination and the Rey 15-Item Memory Test

This study surveyed malingering prevalence in pretrial homicide defendants and assessed the usefulness of the Mini-Mental State Examination (MMSE) and the Rey 15-Item Memory Test (FIT) in detecting malingering among them. Malingering prevalence was 17%. MMSE and FIT scores were positively correlated. The MMSE and FIT had modest positive predictive value (67% and 43%), but reasonably good negative predictive value (93% and 89%), for malingering. Overall, the MMSE outperformed the FIT, with no advantage to combined use of the MMSE and FIT over the MMSE. The widely used MMSE, traditionally a bedside test of cognition, may have a role in malingering assessment

The abject single: exploring the gendered experience of singleness in Britain

This paper explores the gendered experience of singleness in Britain through a theoretical and empirical understanding of the abject. Drawing on the writings of Judith Butler, we argue that singleness is culturally pathologised as an abject ‘other’, a liminal state which renders the legitimation of the single subject unintelligible. Through 14 active interviews with British singles, we demonstrate how our participants negotiate their marginal status vis-à-vis the marketplace and the broader society that continue to uphold heterosexual partnership as a normative form of intimacy. Our data uncovers persistent and powerful gender stereotypes of how singles ought to organise their lives and conform both to social, as well as market-driven pressures. We therefore highlight research gaps in the experience of singleness and critique the heteronormative framework that remains dominant, yet concealed, in gender research