Assurance of neuroattenuation of a live vaccine against West Nile virus: A comprehensive study of neuropathogenesis after infection with chimeric WN/DEN4Δ30 vaccine in comparison to two parental viruses and a surrogate flavivirus reference vaccine

The upsurge of West Nile virus (WNV) human infections in 2012 suggests that the US can expect periodic WNV outbreaks in the future. Availability of safe and effective vaccines against WNV in endemic areas, particularly for aging populations that are at high risk of West Nile neuroinvasive disease (WNND), could be beneficial. WN/DEN4Δ30 is a live, attenuated chimeric vaccine against WNV produced by replacement of the genes encoding the pre-membrane and envelope protein genes of the vaccine virus against dengue virus type 4 (DEN4Δ30) with corresponding sequences derived from a wild type WNV. Following intrathalamic inoculation of nonhuman primates (NHPs), a comprehensive neuropathogenesis study was performed and neurovirulence of WN/DEN4Δ30 vaccine candidate was compared to that of two parental viruses (i.e., WNV and DEN4Δ30), as well as to that of an attenuated flavivirus surrogate reference (i.e., yellow fever YF 17D). Clinical and virological data, as well as results of a semi-quantitative histopathological analysis, demonstrated that WN/DEN4Δ30 vaccine is highly attenuated for the central nervous system (CNS) of NHPs in comparison to a wild type WNV. Importantly, based on the virus replicative ability in the CNS of NHPs and the degree of induced histopathological changes, the level of neuroattenuation of WN/DEN4Δ30 vaccine was similar to that of YF 17D, and therefore within an acceptable range. In addition, we show that the DEN4Δ30 vaccine tested in this study also has a low neurovirulence profile. In summary, our results demonstrate a high level of neuroattenuation of two vaccine candidates, WN/DEN4Δ30 and DEN4Δ30. We also show here a remarkable sensitivity of our WNV-NY99 NHP model, as well as striking resemblance of the observed neuropathology to that seen in human WNND. These results support the use of this NHP model for translational studies of WNV neuropathogenesis and/or testing the effectiveness of vaccines and therapeutic approaches.     

Evolving beyond antiracism: Reflections on the experience of developing a cultural safety curriculum in a tertiary education setting

There is an inextricable link between cultural and clinical safety. In Australia high-profile Aboriginal deaths in custody, publicised institutional racism in health services and the international Black Lives Matter movement have cemented momentum to ensure culturally safe care. However, racism within health professionals and health professional students remains a barrier to increasing the number of Aboriginal and Torres Strait Islander Health professionals. The Australian Health Practitioner Regulation Agency's Aboriginal and Torres Strait Islander Health Strategy's objective to ‘eliminate racism from the health system’, and the recent adoption of the Aboriginal and Torres Strait Islander peoples led cultural safety definition, has instigated systems level reflections on decolonising practice. This article explores cultural safety as the conceptual antithesis to racism, examining its origins, and contemporary evolution led by Aboriginal and Torres Strait Islander peoples in Australia, including its development in curriculum innovation. The application of cultural safety is explored using in-depth reflection, and the crucial development of integrating critical consciousness theory, as a precursor to culturally safe practice, is discussed. Novel approaches to university curriculum development are needed to facilitate culturally safe and decolonised learning and working environments, including the key considerations of non-Indigenous allyship and collaborative curriculum innovations and initiatives.     

Traumatic events and their relative PTSD burden in Northern Ireland: a consideration of the impact of the ‘Troubles’

Purpose

Over a 30-year period in its recent history, daily life in Northern Ireland (NI) was characterised by civil violence, colloquially termed as the ‘Troubles’. The current report examines exposure to 29 traumatic event types and the associated conditional prevalence of post-traumatic stress disorder (PTSD) among the Northern Ireland population, with a focus on the impact of traumatic events that were characteristic of the NI ‘Troubles’.

Method

Results presented are based on analysis of data from the Northern Ireland Study of Health and Stress (NISHS). The NISHS is a representative epidemiological study of mental health among the NI adult population (N = 4,340) and part of the World Mental Health Survey Initiative.

Results

Perpetration of violence, physical assault by a spouse or partner and private events were the event types associated with the highest conditional prevalence of PTSD. Despite this elevated risk, collectively these events accounted for just 16.8 % of the overall public burden of PTSD, given their low prevalence among the general population. Events that were characteristic of civil conflict, including unexpected death of a loved one, witnessing death or a dead body or someone seriously injured and being mugged or threatened with a weapon accounted for the highest proportion of the overall public health burden of PTSD (18.6, 9.4 and 7.8 %, respectively). These findings are a feature of the higher prevalence of these events among the general population coupled with their moderate to above average risk of PTSD.

Conclusions

Despite the formal end to conflict in NI in 1999, a substantial proportion of the adult population continue to suffer the adverse mental health effects of chronic trauma exposure. Given rates of recovery of PTSD in the absence of evidence-based treatments, it is likely that the legacy of mental ill health associated with conflict, if not adequately addressed, will endure for many years.     

Self-harm in secure settings: Exploring the lived experiences of people who self-harm in secure hospitals

Globally, an increasing number of people who Self-Harm (SH) are being treated in mental health hospitals. Incidences of SH are common in secure hospitals, with those using the behaviour being highly dependent on staff for care and support but impacting on often limited resources. While literature related to the lived experiences of people who SH exists, this is in its infancy in African countries. The aim of this study was to explore the lived experiences of people who SH in two secure mental health hospitals in Ghana. Interpretive Phenomenological Analysis (IPA) was used to explore the experiences of people who SH in two secure mental hospitals in Ghana. A convenience sample of nine participants were recruited and face-to-face in-depth semi structured interviews were used to collect data. With the permission of each participant, all interviews were audio recorded and notes were made by the researcher (first author). Each interview was transcribed and analysed using the IPA seven-step approach, with three superordinate and 11 subordinate themes being identified. The superordinate themes were: Being let down; Living with the negative self; Forces of the supernatural and religion. Findings demonstrate that there is a need to develop a collaborative health care package if appropriate care and support is to be offered to people in secure settings who use high-risk behaviours, such as SH. To ensure care is holistic, culturally, and temporally relevant research is needed, particularly in Sub-Saharan Africa.     

FROM THE NEUROBIOLOGY OF EXTINCTION TO IMPROVED CLINICAL TREATMENTS

The neural circuitry underlying the fear response is extremely well conserved across mammalian species, which has allowed for the rapid translation of research findings in rodent models of fear to therapeutic interventions in human populations. Many aspects of exposure‐based psychotherapy treatments in humans, which are widely used in the treatment of PTSD, panic disorder, phobias, and other anxiety disorders, are closely paralleled by extinction training in rodent fear conditioning models. Here, we discuss how the neural circuitry of fear learning and extinction in rodent animal models may be used to understand the underlying neural circuitry of fear‐related disorders, such as PTSD in humans. We examine the factors that contribute to the pathology and development of PTSD. Next, we will review how fear is measured in animal models using classical Pavlovian fear conditioning paradigms, as well as brain regions such as the amygdala, which are involved in the fear response across species. Finally, we highlight the following three systems involved in the extinction of fear, all of which represent promising avenues for therapeutic interventions in the clinic: (1) the role of the glutamatergic N‐methyl‐d ‐aspartate (NMDA) receptor, (2) the role of the brain‐derived neurotrophic factor (BDNF)–tyrosine kinase B (TrkB) induced signaling pathway, and (3) the role of the renin‐angiotensin system. The modulation of pathways underlying fear learning and extinction, such as the ones presented in this review, in combination with extinction‐based exposure therapy, represents promising avenues for therapeutic intervention in the treatment of human fear related disorders.     

Psychometrics evaluation of Charcot‐Marie‐Tooth Neuropathy Score (CMTNSv2) second version,using Rasch analysis

Charcot‐Marie‐Tooth Neuropathy Score second version (CMTNSv2) is a validated clinical outcome measure developed for use in clinical trials to monitor disease impairment and progression in affected CMT patients. Currently, all items of CMTNSv2 have identical contribution to the total score. We used Rasch analysis to further explore psychometric properties of CMTNSv2, and in particular, category response functioning, and their weight on the overall disease progression. Weighted category responses represent a more accurate estimate of actual values measuring disease severity and therefore could potentially be used in improving the current version. Copyright © 2014 John Wiley & Sons, Ltd.     

Sural sensory nerve action potential,epidermal nerve fiber density,and quantitative sudomotor axon reflex in the healthy elderly

Introduction: Polyneuropathy evaluation in older patients is often challenging due to conflicting data regarding normative values for peripheral nerve testing. Methods: We characterized the results of sural nerve conduction studies, intraepidermal nerve fiber density (IENFD), and quantitative sudomotor axon reflex testing (QSART) in a prospective study of 50 healthy subjects aged ≥60 years. Results: Of the 50 subjects, 48 (96%) had an obtainable sural sensory nerve action potential (SNAP). Using quantile regression, we estimated the lower limit of normal (LLN) for sural amplitudes to be 3 μV for patients 60–70 years, 1 μV for those 70–74 years, and <1 μV (absent) for those ≥75 years of age. IENFD and QSART volume were reduced with advancing age, although IENFD was lower in men and QSART volume was lower in women. Conclusions: We propose that an absent sural SNAP in patients up to 75 years of age should be considered abnormal. Our findings also support age‐ and gender‐stratified normative data for IENFD and QSART. Muscle Nerve 49:564–569, 2014     

Pseudopapilledema and association with idiopathic intracranial hypertension

Purpose

Diagnosing idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, can be challenging in children. Diagnosis is based on lumbar puncture, opening pressures, and appearance of the optic disk. Misdiagnosis of papilledema, a typical finding, may lead to unnecessary treatments and procedures. We report 52 children over a 6-year period to better identify the true incidence of pseudopapilledema and other factors that may confound the diagnosis of IIH.

Methods

A retrospective chart review approved by the Institutional Review Board was performed. Fifty-two children under the age of 21 referred to us based on suspected IIH or papilledema from 2007 to 2013 are included in this study. Patients were assessed by a pediatric ophthalmologist and a neurosurgeon.

Results

Fifty-two children were initially diagnosed with IIH and/or papilledema; 26 diagnoses were revised to pseudopapilledema after pediatric ophthalmological review. Out of those 26 patients with pseudopapilledema, 14 had undergone lumbar punctures, 19 had MRIs, 9 had CTs, and 12 were taking medications—these medications were discontinued upon revision of the diagnoses. The difference in the CSF opening pressure between children diagnosed with true IIH (32.7 cm H₂O) and children diagnosed with pseudopapilledema (24.7 cm H₂O) was statistically significant.

Conclusions

IIH diagnosis is heavily reliant on the appearance of the optic disk. Pediatric ophthalmological assessment is essential to carefully examine the optic disk and prevent further unnecessary investigation and treatments. Close communication between pediatricians, ophthalmologists, and neurosurgeons can avoid invasive procedures for children who do have pseudopapilledema, and not IIH or associated papilledema.