Spirocyclic chromanes exhibit antiplasmodial activities and inhibit all intraerythrocytic life cycle stages

AbstractWe screened a collection of synthetic compounds consisting of natural-product-like substructural motifs to identify a spirocyclic chromane as a novel antiplasmodial pharmacophore using an unbiased cell-based assay. The most active spirocyclic compound UCF 201 exhibits a 50% effective concentration (EC50) of 350 nM against the chloroquine-resistant Dd2 strain and a selectivity over 50 using human liver HepG2 cells. Our analyses of physicochemical properties of UCF 201 showed that it is in compliance with Lipinski's parameters and has an acceptable physicochemical profile. We have performed a limited structure-activity-relationship study with commercially available chromanes preserving the spirocyclic motif. Our evaluation of stage specificities of UCF 201 indicated that the compound is early-acting in blocking parasite development at ring, trophozoite and schizont stages of development as well as merozoite invasion. SPC is an attractive lead candidate scaffold because of its ability to act on all stages of parasite's aexual life cycle unlike current antimalarials

Post-conflict mental health needs: a cross-sectional survey of trauma, depression and associated factors in Juba, Southern Sudan

BACKGROUND: The signing of the Comprehensive Peace Agreement in January 2005 marked the end of the civil conflict in Sudan lasting over 20 years. The conflict was characterised by widespread violence and large-scale forced migration. Mental health is recognised as a key public health issue for conflict-affected populations. Studies revealed high levels of post-traumatic stress disorder (PTSD) amongst populations from Southern Sudan during the conflict. However, no studies have been conducted on mental health in post-war Southern Sudan. The objective of this study was to measure PTSD and depression in the population in the town of Juba in Southern Sudan; and to investigate the association ofdemographic, displacement, and past and recent trauma exposure variables, on the outcomes of PTSD and depression. METHODS: A cross-sectional, random cluster survey with a sample of 1242 adults (aged over 18 years) was conducted in November 2007 in the town of Juba, the capital of Southern Sudan. Levels of exposure to traumatic events and PTSD were measured using the Harvard Trauma Questionnaire (original version), and levels of depression measured using the Hopkins Symptom Checklist-25. Multivariate logistic regression was used to analyse the association ofdemographic, displacement and trauma exposure variables on the outcomes of PTSD and depression. Multivariate logistic regression was also conducted to investigate which demographic and displacement variables were associated with exposure to traumatic events. RESULTS: Over one third (36%) of respondents met symptom criteria for PTSD and half (50%) of respondents met symptom criteria for depression. The multivariate logistic regression analysis showed strong associations of gender, marital status, forced displacement, and trauma exposure with outcomes of PTSD and depression. Men, IDPs, and refugees and persons displaced more than once were all significantly more likely to have experienced eight or more traumatic events. CONCLUSION: This study provides evidence of high levels of mental distress in the population of Juba Town, and associated risk-factors. Comprehensive social and psychological assistance is urgently required in Juba

Factors associated with post-traumatic stress disorder and depression amongst internally displaced persons in northern Uganda

BACKGROUND: The 20 year war in northern Uganda between the Lord's Resistance Army and the Ugandan government has resulted in the displacement of up to 2 million people within Uganda. The purpose of the study was to measure rates of post-traumatic stress disorder (PTSD) and depression amongst these internally displaced persons (IDPs), and investigate associated demographic and trauma exposure risk factors. METHODS: A cross-sectional multi-staged, random cluster survey with 1210 adult IDPs was conducted in November 2006 in Gulu and Amuru districts of northern Uganda. Levels of exposure to traumatic events and PTSD were measured using the Harvard Trauma Questionnaire (original version), and levels of depression were measured using the Hopkins Symptom Checklist-25. Multivariate logistic regression was used to analyse the association of demographic and trauma exposure variables on the outcomes of PTSD and depression. RESULTS: Over half (54%) of the respondents met symptom criteria for PTSD, and over two thirds (67%) of respondents met symptom criteria for depression. Over half (58%) of respondents had experienced 8 or more of the 16 trauma events covered in the questionnaire. Factors strongly linked with PTSD and depression included gender, marital status, distance of displacement, experiencing ill health without medical care, experiencing rape or sexual abuse, experiencing lack of food or water, and experiencing higher rates of trauma exposure. CONCLUSION: This study provides evidence of exposure to traumatic events and deprivation of essential goods and services suffered by IDPs, and the resultant effect this has upon their mental health. Protection and social and psychological assistance are urgently required to help IDPs in northern Uganda re-build their lives

Consumer and staff perspectives of the implementation frequency and value of recovery and wellbeing oriented practices

Background: Despite advances in our understanding of what mental health systems and services can do to enhance recovery and wellbeing outcomes for people seeking support, there is limited evidence demonstrating that this body of work has translated successfully into mental health service practice. The Collaborative Recovery Model (CRM) is a practice framework that has been designed to support application of recovery and wellbeing oriented principles and practices within mental health service delivery. The aims of this study were to assess consumer and staff perceptions of implementation frequency during service engagement and the value of this approach for assisting recovery within a setting where the CRM approach had been adopted. Methods: The setting was a large Australian community managed mental health organisation. The study involved a cross-sectional analysis of consumer (n = 116) and staff practitioner (n = 62) perspectives. A series of paired sample t-tests assessed for differences between consumer and staff perceptions of the: (i) importance of key practice elements for assisting recovery, and the (ii) frequency that key practice elements are utilised during engagement sessions. Spearman\u27s r correlational analysis explored associations between importance, frequency and helpfulness of sessions. Results: Key practice elements of the model were applied during service interactions at a high level and perceived by the majority of consumers and staff participants as being important or very important for assisting recovery. Significant moderate correlations were found between the extent that practice elements were valued and the level at which they were applied. Higher levels of implementation of CRM practices were associated with higher ratings of perceived session helpfulness. The strongest association was between \u27encouragement to set tasks to complete between support visits\u27 and perceived helpfulness. Conclusions: Consumer and staff responses revealed that the key practice elements of the CRM were frequently implemented during service engagement interactions and were seen as valuable for assisting recovery. The level of agreement between raters suggests firstly, that the key practice elements were apparent and able to be rated as occurring, and secondly that the CRM approach is seen as responsive to consumer needs. The results have implications for translating recovery and wellbeing oriented knowledge into mental health service practice

Habitat selection, facilitation, and biotic settlement cues affect distribution and performance of coral recruits in French Polynesia

Habitat selection can determine the distribution and performance of individuals if the precision with which sites are chosen corresponds with exposure to risks or resources. Contrastingly, facilitation can allow persistence of individuals arriving by chance and potentially maladapted to local abiotic conditions. For marine organisms, selection of a permanent attachment site at the end of their larval stage or the presence of a facilitator can be a critical determinant of recruitment success. In coral reef ecosystems, it is well known that settling planula larvae of reef-building corals use coarse environmental cues (i.e., light) for habitat selection. Although laboratory studies suggest that larvae can also use precise biotic cues produced by crustose coralline algae (CCA) to select attachment sites, the ecological consequences of biotic cues for corals are poorly understood in situ. In a field experiment exploring the relative importance of biotic cues and variability in habitat quality to recruitment of hard corals, pocilloporid and acroporid corals recruited more frequently to one species of CCA, Titanoderma prototypum, and significantly less so to other species of CCA; these results are consistent with laboratory assays from other studies. The provision of the biotic cue accurately predicted coral recruitment rates across habitats of varying quality. At the scale of CCA, corals attached to the “preferred” CCA experienced increased survivorship while recruits attached elsewhere had lower colony growth and survivorship. For reef-building corals, the behavioral selection of habitat using chemical cues both reduces the risk of incidental mortality and indicates the presence of a facilitator

Cognition and bimanual performance in children with unilateral cerebral palsy: Protocol for a multicentre, cross-sectional study

© 2018 The Author(s). Background: Motor outcomes of children with unilateral cerebral palsy are clearly documented and well understood, yet few studies describe the cognitive functioning in this population, and the associations between the two is poorly understood. Using two hands together in daily life involves complex motor and cognitive processes. Impairment in either domain may contribute to difficulties with bimanual performance. Research is yet to derive whether, and how, cognition affects a child's ability to use their two hands to perform bimanual tasks. Methods/Design: This study will use a prospective, cross-sectional multi-centre observational design. Children (aged 6-12 years) with unilateral cerebral palsy will be recruited from one of five Australian treatment centres. We will examine associations between cognition, bimanual performance and brain neuropathology (lesion type and severity) in a sample of 131 children. The primary outcomes are: Motor - the Assisting Hand Assessment; Cognitive - Executive Function; and Brain - lesion location on structural MRI. Secondary data collected will include: Motor - Box and Blocks, ABILHAND- Kids, Sword Test; Cognitive - standard neuropsychological measures of intelligence. We will use generalized linear modelling and structural equation modelling techniques to investigate relationships between bimanual performance, executive function and brain lesion location. Discussion: This large multi-centre study will examine how cognition affects bimanual performance in children with unilateral cerebral palsy. First, it is anticipated that distinct relationships between bimanual performance and cognition (executive function) will be identified. Second, it is anticipated that interrelationships between bimanual performance and cognition will be associated with common underlying neuropathology. Findings have the potential to improve the specificity of existing upper limb interventions by providing more targeted treatments and influence the development of novel methods to improve both cognitive and motor outcomes in children with unilateral cerebral palsy

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome