A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function.

INTRODUCTION: Delayed graft function (DGF) following renal transplantation is a manifestation of acute kidney injury (AKI) leading to poor long-term outcome. Current treatments have limited effectiveness in preventing DGF. Interleukin-18 (IL18), a biomarker of AKI, induces interferon-γ expression and immune activation. GSK1070806, an anti-IL18 monoclonal antibody, neutralizes activated (mature) IL18 released from damaged cells following inflammasome activation. This phase IIa, single-arm trial assessed the effect of a single dose of GSK1070806 on DGF occurrence post donation after circulatory death (DCD) kidney transplantation. METHODS: The 3 mg/kg intravenous dose was selected based on prior studies and physiologically based pharmacokinetic (PBPK) modeling, indicating the high likelihood of a rapid and high level of IL18 target engagement when administered prior to kidney allograft reperfusion. Utilization of a Bayesian sequential design with a background standard-of-care DGF rate of 50% based on literature, and confirmed via extensive registry data analyses, enabled a statistical efficacy assessment with a minimal sample size. The primary endpoint was DGF frequency, defined as dialysis requirement ≤7 days post transplantation (except for hyperkalemia). Secondary endpoints included safety, pharmacokinetics and pharmacodynamic biomarkers. RESULTS: GSK1070806 administration was associated with IL18-GSK1070806 complex detection and increased total serum IL18 levels due to IL18 half-life prolongation induced by GSK1070806 binding. Interferon-γ-induced chemokine levels declined or remained unchanged in most patients. Although the study was concluded prior to the Bayesian-defined stopping point, 4/7 enrolled patients (57%) had DGF, exceeding the 50% standard-of-care rate, and an additional two patients, although not reaching the protocol-defined DGF definition, demonstrated poor graft function. Six of seven patients experienced serious adverse events (SAEs), including two treatment-related SAEs. CONCLUSION: Overall, using a Bayesian design and extensive PBPK dose modeling with only a small sample size, it was deemed unlikely that GSK1070806 would be efficacious in preventing DGF in the enrolled DCD transplant population. TRIAL REGISTRATION: NCT02723786

The fate of Böhler's angle in conservatively-treated displaced intra-articular calcaneal fractures

Purpose: Although the predictive value of Böhler's angle on outcome remains subject of debate, the initial angle at the time of trauma still guides treatment. Changes in Böhler's angle during follow-up are frequently reported following surgical treatment of displaced intra-articular calcaneal fractures (DIACF). The aim of the present study was to determine the changes in Böhler's angle as a measure of secondary fracture displacement following conservative management of DIACF. Methods: Thirty-eight patients with a total of 44 displaced intra-articular calcaneal fractures treated conservatively with a minimum of two lateral radiographs during follow-up were analysed. Böhler's angle at different follow-up times was measured by three observers. The change in angle was compared with the angle at trauma, and influence of trauma mechanism and common calcaneal fracture classifications were determined. Results: The results showed a significant decline over time of the Böhler's angle in conservatively-treated patients of more than 11° on average at a mean follow-up of 29.2 weeks. This decrease was not related to gender, the initial angle, or the Essex-Lopresti or Sanders classification. A statistically significantly higher decrease was detected in high energetic trauma compared with low energetic trauma. Conclusion: The conservative treatment of displaced intra-articular calcaneal fractures is still a viable option, yet a significant secondary displacement in time should be taken into account, as reflected in a decrease of Böhler's angle of 11° up to one year following trauma

Death and Science: The Existential Underpinnings of Belief in Intelligent Design and Discomfort with Evolution

The present research examined the psychological motives underlying widespread support for intelligent design theory (IDT), a purportedly scientific theory that lacks any scientific evidence; and antagonism toward evolutionary theory (ET), a theory supported by a large body of scientific evidence. We tested whether these attitudes are influenced by IDT's provision of an explanation of life's origins that better addresses existential concerns than ET. In four studies, existential threat (induced via reminders of participants' own mortality) increased acceptance of IDT and/or rejection of ET, regardless of participants' religion, religiosity, educational background, or preexisting attitude toward evolution. Effects were reversed by teaching participants that naturalism can be a source of existential meaning (Study 4), and among natural-science students for whom ET may already provide existential meaning (Study 5). These reversals suggest that the effect of heightened mortality awareness on attitudes toward ET and IDT is due to a desire to find greater meaning and purpose in science when existential threats are activated

Brain activity underlying negative self- and other-perception in adolescents: The role of attachment-derived self-representations

One of teenagers' key developmental tasks is to engage in new and meaningful relationships with peers and adults outside the family context. Attachment-derived expectations about the self and others in terms of internal attachment working models have the potential to shape such social reorientation processes critically and thereby influence adolescents' social-emotional development and social integration. Because the neural underpinnings of this developmental task remain largely unknown, we sought to investigate them by functional magnetic resonance imaging. We asked n = 44 adolescents (ages 12.01-18.84 years) to evaluate positive and negative adjectives regarding either themselves or a close other during an adapted version of the well-established self-other trait-evaluation task. As measures of attachment, we obtained scores reflecting participants' positive versus negative attachment-derived self- and other-models by means of the Relationship Questionnaire. We controlled for possible confounding factors by also obtaining scores reflecting internalizing/externalizing problems, schizotypy, and borderline symptomatology. Our results revealed that participants with a more negative attachment-derived self-model showed increased brain activity during positive and negative adjective evaluation regarding the self, but decreased brain activity during negative adjective evaluation regarding a close other, in bilateral amygdala/parahippocampus, bilateral anterior temporal pole/anterior superior temporal gyrus, and left dorsolateral prefrontal cortex. These findings suggest that a low positivity of the self-concept characteristic for the attachment anxiety dimension may influence neural information processing, but in opposite directions when it comes to self- versus (close) other-representations. We discuss our results in the framework of attachment theory and regarding their implications especially for adolescent social-emotional development and social integration

Neuroanatomical Abnormalities in Violent Individuals with and without a Diagnosis of Schizophrenia

Several structural brain abnormalities have been associated with aggression in patients with schizophrenia. However, little is known about shared and distinct abnormalities underlying aggression in these subjects and non-psychotic violent individuals. We applied a region-of interest volumetric analysis of the amygdala, hippocampus, and thalamus bilaterally, as well as whole brain and ventricular volumes to investigate violent (n = 37) and non-violent chronic patients (n = 26) with schizophrenia, non-psychotic violent (n = 24) as well as healthy control subjects (n = 24). Shared and distinct volumetric abnormalities were probed by analysis of variance with the factors violence (non-violent versus violent) and diagnosis (non-psychotic versus psychotic), adjusted for substance abuse, age, academic achievement and negative psychotic symptoms. Patients showed elevated vCSF volume, smaller left hippocampus and smaller left thalamus volumes. This was particularly the case for non-violent individuals diagnosed with schizophrenia. Furthermore, patients had reduction in right thalamus size. With regard to left amygdala, we found an interaction between violence and diagnosis. More specifically, we report a double dissociation with smaller amygdala size linked to violence in non-psychotic individuals, while for psychotic patients smaller size was linked to non-violence. Importantly, the double dissociation appeared to be mostly driven by substance abuse. Overall, we found widespread morphometric abnormalities in subcortical regions in schizophrenia. No evidence for shared volumetric abnormalities in individuals with a history of violence was found. Finally, left amygdala abnormalities in non-psychotic violent individuals were largely accounted for by substance abuse. This might be an indication that the association between amygdala reduction and violence is mediated by substance abuse. Our results indicate the importance of structural abnormalities in aggressive individuals

Schizophrenia and the Scaffolded Self

This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this recordA family of recent externalist approaches in philosophy of mind argues that our psychological capacities are synchronically and diachronically “scaffolded” by external (i.e., beyond-the-brain) resources. Despite much interest in this topic, however, it has not found its way to philosophy of psychiatry in a substantive way. I here consider how these “scaffolded” approaches to mind and self might inform debates in phenomenological psychopathology. First, I introduce the idea of “affective scaffolding”. I distinguish three forms of affective scaffolding and support this taxonomy by appealing to different sources of empirical work. Second, I put the idea of affective scaffolding to work. Using schizophrenia as a case study, I argue — along with others in phenomenological psychopathology — that schizophrenia is fundamentally a self-disturbance. However, I offer a subtle reconfiguration of these approaches. I argue that schizophrenia is not simply a disruption of ipseity or minimal self-consciousness but rather a disruption of the scaffolded self, established and regulated via its ongoing engagement with the world and others. I conclude that this way of thinking about the scaffolded self is potentially transformative both for our theoretical as well as practical understanding of the causes and character of schizophrenic experience, insofar as it suggests the need to consider new forms of intervention and treatment