Delusions and prediction error: clarifying the roles of behavioural and brain responses

Griffiths and colleagues provided a clear and thoughtful review of the prediction error model of delusion formation [Cognitive Neuropsychiatry, 2014 April 4 (Epub ahead of print)]. As well as reviewing the central ideas and concluding that the existing evidence base is broadly supportive of the model, they provide a detailed critique of some of the experiments that we have performed to study it. Though they conclude that the shortcomings that they identify in these experiments do not fundamentally challenge the prediction error model, we nevertheless respond to these criticisms. We begin by providing a more detailed outline of the model itself as there are certain important aspects of it that were not covered in their review. We then respond to their specific criticisms of the empirical evidence. We defend the neuroimaging contrasts that we used to explore this model of psychosis arguing that, while any single contrast entails some ambiguity, our assumptions have been justified by our extensive background work before and since.     

MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage

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Advances in understanding the mechanisms of retinal degenerations

Photoreceptor death is an important contributor to irreversible vision loss worldwide. In this review, I outline our work examining the role that purines, such as adenosine triphosphate (ATP), have in normal retinal function and in retinal disease. Our work shows that the actions of ATP, mediated by P2X receptors, are expressed in various retinal layers including photoreceptor terminals, and when stimulated by excessive levels of ATP is associated with rapid death of neurons. Treatment with a compound that blocks the action of P2X and some P2Y receptors reduces photoreceptor death in a mouse model of retinal degeneration. Our observations not only provide a means for developing a potential treatment for reducing photoreceptor death, but also provides a novel way of studying the neural plasticity effects that develop in the inner retina following photoreceptor death. There are a range of inner retinal changes that could influence the effectiveness of retinal prostheses. Indeed, using an ATP-induced degeneration model, we established that the amount of electrical stimulation required to elicit a response in the visual cortex was affected by the level of glial scarring. However, changes in P2X7 receptor expression by OFF ganglion cells during retinal degeneration can also be exploited by photoswitches to restore light sensitivity to degenerated retinae. Finally, our work has also considered how P2X7 expression by innate immune cells, and its role as a scavenger receptor, contributes to age-related macular degeneration (AMD). Our results show that loss of P2X7 function is associated with thickening of Bruch's membrane as well as increased risk of advanced disease in people with AMD. Overall, our work over the last 20 years highlights the importance of purinergic signalling in normal retinal function and retinal disease and suggest that developing therapies that target P2X7 function could be of benefit for these diseases.     

Extended thromboprophylaxis in the acutely ill medical patient after hospitalization – a paradigm shift in post-discharge thromboprophylaxis

Venous thromboembolism (VTE) is a significant healthcare burden with approximately 900,000 events annually in the United States, over half of which are healthcare-associated. This number is anticipated to double by 2050. Group prophylaxis strategies confined to the inpatient setting appear to have minimal impact on the reduction of post-discharge VTE in medically ill patients due to shortened lengths of stay and a heterogenous population that includes patients at low risk for VTE. In accordance with current guideline recommendations, very few (<5%) medically ill patients are discharged with extended prophylaxis, which potentially creates a clinical gap for at-risk patients as VTE risk has been shown to persist for up to 90 days. Initial studies of extended thromboprophylaxis in acutely ill medical patients with enoxaparin, rivaroxaban and apixaban showed little to no benefit towards VTE reduction that was consistently outweighed by increased bleeding. The more recent APEX study that compared betrixaban to enoxaparin in an enriched patient population at high-risk for VTE was the first study of extended thromboprophylaxis that showed similar efficacy in VTE prevention without an increase in major bleeding. Based on the APEX results, betrixaban recently gained FDA approval for extended thromboprophylaxis in acutely ill medical patients. Recognition that up to half of medically ill patients are not at sufficient risk to warrant thromboprophylaxis has driven extensive research towards development of scientifically derived and validated VTE risk assessment models intended to identify patients who do not warrant prophylaxis, as well as those at high risk who may derive benefit from extended thromboprophylaxis. This article will review prior and ongoing extended thromboprophylaxis studies, VTE and bleed risk assessment models, incorporation of biomarkers in VTE risk assessment and key issues in the paradigm shift towards individualized VTE prophylaxis in acutely ill medical patients.     

Structural Inequities and Social Networks Impact Hormone Use and Misuse Among Transgender Women in Los Angeles County

In order to reduce gender dysphoria and combat stigma, transgender women often affirm their gender through social and medical transition, which may include cross-sex hormone therapy. This study examined associations between medically monitored hormone use and hormone misuse (non-prescribed hormone use including “fillers”), structural inequities (access to housing, health insurance, and income), and social network dynamics among 271 transgender women in Los Angeles. Hormone use status was coded trichotomously (hormone use, hormone misuse, no hormone use), and robust multinomial logistic regression as well as novel social network analysis was conducted to examine associations. Results demonstrated that younger, African-American/Black transgender women were most likely to engage in hormone misuse compared to transgender women who were older or non-African-American/Black. One-third of the sample reported sex work as a main source of income, and this group was more likely to misuse hormones than those with another primary source of income. Transgender women with access to stable housing and health insurance were most likely to engage in medically monitored hormone use. Social network analysis revealed that transgender women with a greater number of hormone-using network alters were most likely to misuse hormones, but that using the Internet to find transgender friends mitigated this association. Results demonstrate the multifaceted risk profile of transgender women who use and misuse hormones, including that social networks play an important role in hormone usage among transgender women.