A Prospective Longitudinal Study of the Clinical Outcomes from Cryptococcal Meningitis following Treatment Induction with 800 mg Oral Fluconazole in Blantyre, Malawi

Introduction: Cryptococcal meningitis is the most common neurological infection in HIV infected patients in Sub Saharan Africa, where gold standard treatment with intravenous amphotericin B and 5 flucytosine is often unavailable or difficult to administer. Fluconazole monotherapy is frequently recommended in national guidelines but is a fungistatic drug compromised by uncertainty over optimal dosing and a paucity of clinical end-point outcome data. Methods: From July 2010 until March 2011, HIV infected adults with a first episode of cryptococcal meningitis were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Patients were treated with oral fluconazole monotherapy 800 mg daily, as per national guidelines. ART was started at 4 weeks. Outcomes and factors associated with treatment failure were assessed 4, 10 and 52 weeks after fluconazole initiation. Results: Sixty patients were recruited. 26/60 (43%) died by 4 weeks. 35/60 (58.0%) and 43/56 (77%) died or failed treatment by 10 or 52 weeks respectively. Reduced consciousness (Glasgow Coma Score ,14 of 15), moderate/severe neurological disability (modified Rankin Score .3 of 5) and confusion (Abbreviated Mental Test Score ,8 of 10) were all common at baseline and associated with death or treatment failure. ART prior to recruitment was not associated with better outcomes. Conclusions: Mortality and treatment failure from cryptococcal meningitis following initiation of treatment with 800 mg oral fluconazole is unacceptably high. To improve outcomes, there is an urgent need for better therapeutic strategies and point-of-care diagnostics, allowing earlier diagnosis before development of neurological deficit

Determining research knowledge infrastructure for healthcare systems: a qualitative study

<p>Abstract</p> <p>Background</p> <p>This study examines research knowledge infrastructures (RKIs) found in health systems. An RKI is defined as any instrument (<it>i.e</it>., programs, interventions, tools) implemented in order to facilitate access, dissemination, exchange, and/or use of evidence in healthcare organisations. Based on an environmental scan (17 key informant interviews) and scoping review (26 studies), we found support for a framework that we developed that outlines components that a health system can have in its RKI. The broad domains are climate for research use, research production, activities used to link research to action, and evaluation.</p> <p>The objective of the current study is to profile the RKI of three types of health system organisations--regional health authorities, primary care practices, and hospitals--in two Canadian provinces to determine the current mix of components these organisations have in their RKI, their experience with these components, and their views about future RKI initiatives.</p> <p>Methods</p> <p>This study will include semistructured telephone interviews with a purposive sample region of a senior management team member, library/resource centre manager, and a 'knowledge broker' in three regional health authorities, five or six purposively sampled hospitals, and five or six primary care practices in Ontario and Quebec, for a maximum of 71 interviewees. The interviews will explore (a) which RKI components have proven helpful, (b) barriers and facilitators in implementing RKI components, and (c) views about next steps in further development of RKIs.</p> <p>Discussion</p> <p>This is the first qualitative examination of potential RKI efforts that can increase the use of research evidence in health system decision making. We anticipate being able to identify broadly applicable insights about important next steps in building effective RKIs. Some of the identified RKI components may increase the use of research evidence by decision makers, which may then lead to more informed decisions.</p

Using eye-tracking and click-stream data to design adaptive training of children's inhibitory control in a maths and science game

Computerised educational neuroscience interventions that train within-domain inhibitory control (IC) can improve children's coun- terintuitive reasoning. However, the HCI or adaptive design of such en- vironments often receive less attention. Eye-tracking and click data were used to compare four versions of an IC-training game in terms of their HCI design and potential for supporting adaptive feedback. Our results provide insights for developing an adaptive system to scaffold pupils' transition towards using IC in un-cued, self-regulated scenarios

Network analysis of human muscle adaptation to aging and contraction.

This is the final version. Available from Impact Journals via the DOI in this record. Resistance exercise (RE) remains a primary approach for minimising aging muscle decline. Understanding muscle adaptation to individual contractile components of RE (eccentric, concentric) might optimise RE-based intervention strategies. Herein, we employed a network-driven pipeline to identify putative molecular drivers of muscle aging and contraction mode responses. RNA-sequencing data was generated from young (21±1 y) and older (70±1 y) human skeletal muscle before and following acute unilateral concentric and contralateral eccentric contractions. Application of weighted gene co-expression network analysis identified 33 distinct gene clusters ('modules') with an expression profile regulated by aging, contraction and/or linked to muscle strength. These included two contraction 'responsive' modules (related to 'cell adhesion' and 'transcription factor' processes) that also correlated with the magnitude of post-exercise muscle strength decline. Module searches for 'hub' genes and enriched transcription factor binding sites established a refined set of candidate module-regulatory molecules (536 hub genes and 60 transcription factors) as possible contributors to muscle aging and/or contraction responses. Thus, network-driven analysis can identify new molecular candidates of functional relevance to muscle aging and contraction mode adaptations.Wellcome Trust Institutional Strategic Support AwardBiotechnology and Biological Sciences Research Counci

Enhanced cytotoxicity of reovirus and radiotherapy in melanoma cells is mediated through increased viral replication and mitochondrial apoptotic signalling.

Oncolytic viruses selectively target and replicate in cancer cells, providing us with a unique tool with which to target and kill tumour cells. These viruses come from a diverse range of viral families including reovirus type 3 Dearing (RT3D), a non-pathogenic human double-stranded RNA oncolytic virus, which has been shown to be an effective therapeutic agent, both as a mono-therapy and in combination with traditional chemotherapeutic drugs. This study investigated the interaction between RT3D and radiotherapy in melanoma cell lines with a BRAF mutant, Ras mutant or BRAF/Ras wild type genotype. The data indicates that RT3D combined with radiotherapy significantly increased cytotoxicity relative to either single agent, independent of genotype, both in vitro and in vivo. The mechanism of enhanced cytotoxicity was dependent on an increase in viral replication, mediated by CUG2 up-regulation and subsequent down-regulation of pPKR and p-eIF2α, leading to the activation of mitochondrial apoptotic signalling resulting in increased cell death

Implementing health research through academic and clinical partnerships : a realistic evaluation of the Collaborations for Leadership in Applied Health Research and Care (CLAHRC)

Background: The English National Health Service has made a major investment in nine partnerships between higher education institutions and local health services called Collaborations for Leadership in Applied Health Research and Care (CLAHRC). They have been funded to increase capacity and capability to produce and implement research through sustained interactions between academics and health services. CLAHRCs provide a natural ‘test bed’ for exploring questions about research implementation within a partnership model of delivery. This protocol describes an externally funded evaluation that focuses on implementation mechanisms and processes within three CLAHRCs. It seeks to uncover what works, for whom, how, and in what circumstances. Design and methods: This study is a longitudinal three-phase, multi-method realistic evaluation, which deliberately aims to explore the boundaries around knowledge use in context. The evaluation funder wishes to see it conducted for the process of learning, not for judging performance. The study is underpinned by a conceptual framework that combines the Promoting Action on Research Implementation in Health Services and Knowledge to Action frameworks to reflect the complexities of implementation. Three participating CLARHCS will provide indepth comparative case studies of research implementation using multiple data collection methods including interviews, observation, documents, and publicly available data to test and refine hypotheses over four rounds of data collection. We will test the wider applicability of emerging findings with a wider community using an interpretative forum. Discussion: The idea that collaboration between academics and services might lead to more applicable health research that is actually used in practice is theoretically and intuitively appealing; however the evidence for it is limited. Our evaluation is designed to capture the processes and impacts of collaborative approaches for implementing research, and therefore should contribute to the evidence base about an increasingly popular (e.g., Mode two, integrated knowledge transfer, interactive research), but poorly understood approach to knowledge translation. Additionally we hope to develop approaches for evaluating implementation processes and impacts particularly with respect to integrated stakeholder involvement

SUPPORT Tools for evidence-informed health Policymaking (STP) 10: Taking equity into consideration when assessing the findings of a systematic review

This article is part of a series written for people responsible for making decisions about health policies and programmes and for those who support these decision makers