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Results

PArtner-provided HIV Self-Testing and Linkage (PASTAL) in antenatal care clinics: methodology and delivery of an adaptive cluster-randomised trial in Blantyre, Malawi. 24 Nov 2014

HIV remains a global public health problem with 2.3 million new infections in 2012. Efforts to eliminate paediatric HIV have greatly strengthened HIV testing and counselling (HTC) services in African antenatal care clinics (ANC). HTC is a critical step towards HIV care and prevention, with couple-based testing especially valuable in ANC. In Malawi, >80% of pregnant women but only 15% of male partners undergo HTC. We have recently shown that self-testing (HIVST) is highly acceptable to men and can increase uptake of ART at population level. HIVST may need additional interventions to maximise uptake and subsequent HIV care/prevention services, such as financial incentives, or short messaging services. The wide range of potential interventions, and need for multiple direct comparisons pose methodological challenges in identifying optimal strategies. We propose to develop and apply novel methodologies to evaluate candidate interventions for male partner engagement for which current e vidence is promising but insufficient to proceed to Phase III trials. The broad objectives are to develop statistical methodology required to combine adaptive multi-arm multi-stage designs with cluster-randomized trial methodologies and to use these to identify most promising candidate interventions for encouraging HIVST with linkage by male partners of ANC attendees.

Amount: £235,231
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Non-Invasive Blood Glucose Meters 30 Sep 2015

Diabetes is affecting hundreds of millions of people worldwide who have to monitor their condition using invasive methods (e.g. pricking of finger or insertion of needle into hip region). It is clear that non-invasive, continuous monitoring has the potential to help and encourage patients to monitor their diabetes more closely due to the associated improved quality of life. This incentive will lead to a reduction of hyper/hypoglycaemic episodes and the subsequent reduction of long-term risks, such as morbidity and shorter life expectancy, when this condition is poorly monitored and managed. The Trust has awarded a team, led by Professor Adrian Porch from University of Cardiff, £892k to develop a non-invasive blood glucose monitor (NIBGM). Their device will improve the quality of life of people with diabetes and, with better management of their condition encouraged by the device, improve their life expectancy. It is fundamentally different from all other glucose monitoring systems on the market in that it does not require blood to be extracted from the patient, or for the sensing element to be inserted into the patient’s body. It is merely attached to the person’s hip with adhesive, does not require blood extraction, and provides an instant readout of the blood glucose level on a unit that can be carried in the person’s pocket. The underlying technology for the device is based on microwaves and how they interact with the person’s blood. However, there is no heating (the microwave field strength is much smaller than that generated by a mobile phone) and the only sensation is that of touch. It is envisaged that final device will be around the size of a £2 coin and will be ready for mass-manufacture.

Amount: £97,900
Funder: The Wellcome Trust
Recipient: Cardiff University

Biomedical Vacation Scholarship 22 Jun 2015

Not available

Amount: £7,500
Funder: The Wellcome Trust
Recipient: Cardiff University

Malawi-Liverpool-Wellcome Trust Clinical Research Programme - supplementary award for Chikhwawa infrastructure improvements 27 May 2014

MLW is strategically placed to conduct high quality laboratory, clinical and epidemiological science relevant to health in sub-Saharan Africa. The programme is embedded within a rapidly growing medical school, co-located within the largest teaching hospital in Malawi with direct access to urban and rural populations. In the next 5 years, MLW research will increase fundamental understanding of disease mechanisms and burden, test novel interventions and ensure translation into health care. The cor e programme will ensure MLW delivers the following aims: (1) Pursuit of cutting-edge research focused on health problems with a high disease burden. Research management, mentorship, development of bioinformatics expertise, and clinical and diagnostic laboratory competencies, ensuring the highest quality. (2) Provision of a research training environment for clinicians, epidemiologists and laboratory scientists. Local research infrastructure, operational and financial systems, data manageme nt and research governance support. (3) Development of globally competitive research leaders. Moving towards local leadership, embedded within the University of Malawi College of Medicine, attracting further intermediate and senior Fellows, and encouraging re-entry of trained Malawian scientists. (4) Translation of scientific advances into human health improvements. Defining national and international research agendas through policy relevant evidence; policy committee membership; research synthesis workshops; and public engagement.

Amount: £160,976
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Regulation of T cell function by enzymatic proteolysis of L-selectin 03 Oct 2013

Our experiments are directed at enhancing the potency of adoptive T cell immunotherapy (ACT). To date, all three applicants have made a series of independent observations on different aspects of T cell biology following genetic manipulation of mouse T cells. Each of these genetic changes has had the effect of significantly promoting anti-tumour immune responses. A natural progression of these findings, to be pursued in this grant, is to explore in the context of adoptive T cell immunotherapy, the potential overlapping, additive or synergistic effects of combining these genetic manipulations of T cells. Specifically, in this proposal we will: Determine whether adoptive transfer of CD8 T cells with maintained L-selectin and/or deficiency in SHP-1 induces regression of vascularised tumours in mouse Determine whether the removal of Tregs from the tumour bearing hosts has an additional or synergistic effect on CD8 mediated tumour regression in mice Determine whether human CD8+ T cell reactivity to tumour antigens can be similarly modified by maintained L-selectin and/or SHP-1 deficiency and whether sensitivity to Tregs is altered

Amount: £68,092
Funder: The Wellcome Trust
Recipient: Cardiff University

Generation of standards for structural and quantitative assays of novel lipids generated by innate immune cells in humans 11 Aug 2014

This grant will focus on extending our understanding of the biological actions and potential therapeutic applications of recently-described hydroxyeicosatetraenoic acid-phospholipids (HETE-PLs), generated by platelets, neutrophils and monocytes/macrophages. A multidisciplinary approach combining biophysics, chemistry, genetics, cell biology and in vivo techniques will be utilized. Basic biochemical studies will be complemented by in vivo murine studies, and clinical studies in a human disorder with known elevated risk of thrombosis and plasma lipid peroxidation. A series of integrated aims is proposed: 1. Determine their role in regulating membrane biophysical behaviour (lysosome formation, phagolysosome fusing, microvesicle formation, etc). 2. Determine their role in regulating function of membrane proteins that require lipid microdomains, e.g. TLRs and their accessory proteins. 3. Determine how they regulate activity of coagulation enzymes at the cell surface. 4. Determine th eir function as ligands for innate immune receptors. 5. Determine how the regulate complement binding to activated immune cells. 6. Determine their role in the pathogenesis of antiphospholipid syndrome in human patients.

Amount: £129,897
Funder: The Wellcome Trust
Recipient: Cardiff University

Institutional Strategic Support Fund FY2013/14 14 Oct 2013

Supported by ISSF funding, LSTM has offered a number of competitive challenge grants to LSTM based research projects in the general area of resistance (with a focus on drugs and insecticides – RDI). These projects will need to be completed within two years (Oct 2016).The research will focus on an area relevant to RDI, will involve PIs from more than one discipline (including external partnerships with NHS Trusts, other academic groups and industry partners), and will have the potential to generate data that can leverage further competitive research funding on completion. Funding: Renewal of Gates-funded IVCC and AWOL programmes, the latter with a major component using a novel mouse model for basic and translational research Reachout consortium. funded by EU to look at strengthening health systems through close-to-community services Cookstove project in Malawi funded by MRC MRC New Investigator Award – "Is targeting vascular remodelling by filarial parasites a viable anti-morbidity solution" CouNTDown programme for NTD implementation research funded by DFID (Adams, Reimer) Health Impact: Development of innovative ‘tiny target’ control systems for tsetse flies (Torr) Discovery of a previously unidentified reservoir of Schistosoma infection in pre-school children (Adams). Introduction of intermittent preventive therapy during pregnancy as a WHO policy recommendation (Terlouw). Development and validation of a human challenge model for Streptococcus pneumonia (Glennie). Development of new monitoring and evaluation systems for malaria surveillance (Terlouw) LSTM’s improving and rapidly growing media visibility and social media presence are beneficial in creating attention for our various PE initiatives

Amount: £500,000
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Institutional Strategic Support Fund FY2013/14 14 Oct 2013

The Trust’s major directions for use of this Fund are as follows: 1. To assist the Institution in developing its research strategy across College’s and Schools 2. To encourage new inter-departmental synergies, cross-disciplinary collaborations, and inter-institutional initiatives 3. To add value to existing Wellcome Trust investments in the Institution. Strengthening Biomedical and Clinical SciencesCardiff University will build on successes of the first ISSF Award, widening the portfolio to encompass all the priority research areas in the College of Biomedical and Life Sciences (CBLS). We will build new links with relevant research in computing, physical sciences, humanities and social sciences and consolidate ties with partner Universities in the South West. CBLS, which includes all the Health-related Schools in the University, has recently completed a comprehensive review of its research portfolio and identified five Themes around which investment will be focused: Immunology, Infection & Inflammation; Mind, Brain & Neuroscience; Cancer; Public Health & Integrative Biosystems. The ISSF Award will impact in all these areas. Previous ISSF success 2013The Award, with matched funding, supported new academic appointments, seven project grants, thirty-one seedcorn grants and eight mobility awards. Infrastructure was supported through substantial spend on new equipment. Public engagement was supported through contributions to high profile local events and stand-alone meetings.

Amount: £750,000
Funder: The Wellcome Trust
Recipient: Cardiff University

Exploring conflict and trust within community engagement activities as part of a community-based HIV/TB intervention trial in urban Blantyre, Malawi. 14 Apr 2014

SPECIFIC OBJECTIVES 1. To map out the roles of community representatives as Key Informants and Cluste2. To explore perceptions of cluster representatives from the perspective of comm3. To critically examine concepts around trust within the context of the interven4. To document specific case studies where trust or distrust has impacted on rela5. To provide recommendations for future community-based intervention trials on oMETHODOLOGY This will be a small qualitative research study in urban Blantyre, Malawi. Recruiting cluster representatives, study team members and communities we willcombine Focus Group Discussions with individual semi-structured interviews. Participants will be purposively selected and data analysed iteratively to build understanding through targeted interviewing in pursuit of the research objectives. DATA COLLECTION We will begin data collection with community level meetings in each of the three study wards to minimize potential concerns about the study amongst communities and cluster representatives. The Senior Community Liaison Officerwho established the system for the HIV/TB intervention will conduct the research. A total of 6 focus group discussions (FGD) will be conducted, two with each of the three groups of interest: cluster representatives, study teams and communities. Three at the start of the fieldwork with a defined setof deductively generated themes and three at the end to respond to and clarifyfindings from the individual semi-structured interviews. We expect a total ofapproximately 15 semi-structured interviews, five with each participant group,selected purposively following the initial FGDs. Themes for these interviews will be generated inductively from preliminary analysis of the initial FGDs and iteratively as understanding is developed.

TNF superfamily forward and reverse signalling in neural development. 01 Apr 2014

Our work over the past 5 years has revealed that multiple members of the TNFSFare selective positive or negative regulators of axon growth throughout the developing mousenervous system. Two very recent key discoveries arising from this work underpin the proposed programme and take our research in exciting new directions that will significantly advance our understanding of how the nervous system gets wired up in development. First, we discovered that TNFR1 expressed in sympathetic target tissues activates reverse signalingvia membrane integrated TNFalpha expressed by sympathetic axons as they ramify within thesetissues, promoting axon growth and tissue innervation (Kisiswa et al., Nature Neuroscience, 2013, 16:865-873). This discovery raises a host of interesting and important questions about the cell biology and mechanism of action of TNFalpha reverse signalling and why this has evolved to regulate axon growth in the developing nervous system. It also raises the question of how extensively reverse signaling operates within the TNFSF in the nervous system and what is the balance between forward and reverse signaling in the regulation of neural process growth. Second, we discovered that certain TNFSF signaling loops that either promote or inhibit axon growth are very sensitive to the ambient neurotrophin concentration. This reveals the existence of unsuspected feedback loops that selectively modulate the response of neurons to the neurite growth-promoting effects of neurotrophins. This raises questions about how, where and when these feedback loops operate and what it their significance for establishing patterns of innervation in vivo.

Amount: £2,043,743
Funder: The Wellcome Trust
Recipient: Cardiff University

The cognitive thalamus: more than a relay. 01 Apr 2014

How do brain circuits support different but complementary aspects of event memory? The answer lies in distributed networks across the medial temporal lobe, prefrontal cortex and parietal cortex. Via their widespread connectivity, nuclei within the rostral thalamus support these memory networks. Indeed, one group (the anterior thalamic nuclei) forms the backbone of the extended hippocampal system, thought to be vital for episodic memory. We know remarkably little, however, about the nature of rostral thalamic information and how it impacts upon memory. We have recently discovered neurons in the rostral thalamus of freely-moving rats with hitherto unsuspected spatial properties. These cells are unlike any previously described in the region as they closely resemble place cells, boundary vector cells, and grid-cells (Fig.1A-F) found in hippocampal and parahippocampal regions. This discovery is set to transform our understanding of the region.

Amount: £1,070,115
Funder: The Wellcome Trust
Recipient: Cardiff University

Improving neonatal health in remote rural areas in China and Vietnam. 25 Mar 2014

Newborn (first 4 weeks of life) health remains a significant problem in China and Vietnam, especially in rural areas where they are 3 to 4 times more likely to die than in more developed areas. Most newborns can be treated with cost-effective interventions at facility and community levels, which do not require high-level training or costly equipment. Achieving high coverage of these interventions in the poorest areas could reduce neonatal deaths by at least 70%. While NH practice guidelines exist in China and Vietnam at national and local levels to guide on appropriate care and treatment, a major problem is ineffective implementation of the guidelines. This development study will assess the feasibility of using a participatory problem-solving intervention with local health managers to improve NH guideline implementation. If feasible, it will inform the design of a full-scale study to evaluate the effectiveness of the intervention. In the full-scale study, the research team would support local health managers through problem-solving and planning workshops, mentoring and capacity development to (1) assess the effectiveness of current guidelines; (2) identify barriers to improved implementation relating to service delivery (e.g. workforce issues, transport, equipment and supplies) and service demand (limited by remote access and traditional beliefs); (3) develop feasible strategies within current resource constraints e.g. re-organising services and the workforce, and using suitable community engagement models to stimulate demand for improved services; and 4) develop appropriate methods to monitor impact and unintended consequences. To assess the intervention's feasibility in remote, rural China and Vietnam the development study must address 4 questions: 1. What are the current health service management practices and the degree of freedom for decision-making at different systems levels for improving NH outcomes? 2. What are the opportunities for developing or strengthening community actions to support improved NH outcomes? 3. What is the potential for monitoring NH outcomes and measuring cost-effectiveness of interventions at different health systems levels? 4. What is the feasibility for local managers to use a participatory problem-solving intervention to implement existing practice guidelines for improving NH outcomes covering community, primary and referral levels and what would be the best vehicle for the intervention? We plan to conduct desk-based reviews of NH practice guidelines, challenges of monitoring NH impact in remote areas and NH intervention cost-effectiveness, before holding a 2-day workshop in Beijing to refine our field work plan and data collection tools and conduct 3 national key informant interviews (KIIs). We will then collect data in Guizhou, China using 4 methods: (i) KIIs: community level representatives, local health service managers, frontline health workers and provincial level policy makers and senior health officials; (ii) focus group discussions: recent mothers and community members; (iii) document review of community action agreements and provincial/national policies and plans; (iv) observation of health management information systems (HMIS) and accounting systems. A smaller research team will repeat this data collection protocol in Tay Nguyen, Vietnam, before analysing the two country datasets. This will inform the design the full-scale study and facilitate stakeholder engagement. We will produce 3 outputs on monitoring NH services in remote areas; practicalities of monitoring NH in remote China and Vietnam; and national policy space and local decision making freedom to improve NH services. Three levels of stakeholders will benefit: local (health service managers and staff), national (policy makers in China's MCH centres and Vietnam's NH technical working group) and international (e.g. Unicef, WHO, PMNCH and implementation science groups like WHO-led Implementation Research Platform).

Amount: £22,882
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Treating netting eave baffles with pirimiphos-methyl to control indoor-feeding Anopheles funestus malaria vectors at an affordable cost 25 Nov 2013

The arsenal of insecticides available for vector control is limited to only four classes and resistance to both pyrethroids and organo-chlorines has emerged among malaria vectors in Zambia. The new organophosphate pirimiphos-methyl is an attractive alternative for inclusion in resistance management strategies because its biochemical mode of action is distinct from both these classes and it is activated by the oxidases that mediate cross-resistance to pyrethroids and organo-chlorines [28]. Howeve r this insecticide is prohibitively expensive to treat all roofs and walls by conventional indoor residual spraying (IRS). I therefore propose to develop and evaluate netting eave baffles treated with pirimiphos-methyl placed around the eaves of houses [3,36] as means to target lower quantities of insecticide to entry and exit points for mosquitoes. Treating netting eave baffles should also have practical programmatic advantages over IRS because it can be safely achieved by soaking at the level of centralized pre-treatment facilities all the way down to communities and households. I therefore aim to demonstrate that the application of pirimiphos-methyl eave baffles, at the lowest dosage required to achieve maximum mortality of vectors can be far more efficacious, durable and affordable than spraying the whole house using conventional IRS at recommended dosage.

Amount: £68,840
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Identification of genes for insecticide resistance in the lymphatic filariasis vector Culex quinquefasciatus. 25 Nov 2013

Culex quinquefasciatus (Diptera: Culicidae) is a pantropical pest and urban vector of Bancroftian filariasis. Studies to detect incipient resistance and the underlying mechanisms in field populations of Culex to public health insecticides is very important to design effective strategies to control both lymphatic filariasis and malaria occurred. In the present project we will exploit the Culex quinquefasciatus whole genome microarray already available to investigate range of resistance mechanis ms and type of cross resistance are involved in the resistance of Cx. quinquefasciatus against insecticidal classes licensed for public health. Here, we will: (i) Describe the distribution of insecticide resistance in the Cx. quinquefasciatus from selected sites throughout Benin, ii) Apply a whole transcriptome microarray to identify genes associated with resistance to deltamethrin (used for ITN) and bendiocarb (used for IRS), iii) To use in vitro expression systems to confirm that the candidate genes identified from interact and/or metabolize the insecticide used.

Amount: £100,336
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Supporting excellence in basic and clinical research: A flow cytometry/sorting and cell imaging platform for the genotypic and phenotypic analysis of Hazard Group 3 pathogens. 25 Jun 2014

Funding is requested for a BD-FACS-Aria-Fusion cell-sorter and a Zeiss-LSM-710-confocal microscope to be housed in LSTM's Hazard-Group-3 (HG3)-containment laboratories. This equipment is principally to support Trust-funded investigators/fellows requiring HG3-biosafety to comply with HSE requirements. The Schools focus on pathogens (many HG3) that cause disease rather than non-pathogenic surrogates has imposed stringent biological safety requirements. The ability to carry out technically ch allenging image-based science for our internal programmes and clinical samples derived from Wellcome Trust Overseas Programmes (e.g.Malawi/Kenya/Vietnam) while ensuring the highest levels of operator safety requires investment. The complementary imaging platform of flow-cytomety (with sorting) and confocal microscopy (real-time live imaging of cells/tissues) will allow PIs the ability of genotyping and phenotyping live HG3-pathogens. This is an essential requirement in order to facilitate s tudies into the temporal responses of important pathogens to experimental perturbations and the isolation of organisms/cells with specific genotypic/phenotypic traits for further investigation. The described HG3-imaging facility, set in one of CTIDs 22 HG3-containment laboratories, will be the first dedicated facility in the North West and possibly the UK, supporting LSTM's and UK's position as an international leader in tropical disease research.

Amount: £598,054
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Open access publishing costs 2014/15. 15 Sep 2014

Not available

Amount: £72,725
Funder: The Wellcome Trust
Recipient: Cardiff University

Induced pluripotent stem cell-derived microglia as a model for Alzheimer’s disease 14 Jul 2014

The role of microglia in Alzheimer’s disease pathogenesis is still controversial. Activated microglia are found to be associated with amyloid plaques in brains of AD patients and in mouse models. They may play a neuroprotective role by secreting proteolytic enzymes that degrade Abeta and expressing receptors involved in its clearance and phagocytosis. However, microglia might also contribute to disease progression through production of inflammatory mediators. Despite the recognised importance for research into the role of microglia in AD, there is currently an unmet need for human cell models that enable in-depth mechanistic studies. One route to the development of highly informative cell models is the differentiation of human patient-derived iPS cells, which intrinsically incorporate human genetics and bridge the gap between clinical AD and animal models. This project will develop AD microglial models by building on work that has established a standardised protocol for the derivation of microglia from human iPSCs. The project will be structured to firstly gain an in-depth characterisation of iPSC-derived microglia. Secondly, the iPSC-derived microglial model will be validated against anticipated microglial phenotypes. Finally, once established, the model will be used to investigate the role of AD risk genes in aspects of microglial biology.

Amount: £149,985
Funder: The Wellcome Trust
Recipient: Cardiff University

The Role of Imprinted Grb10 in Brain and Behavior 14 Jul 2014

The imprinted gene Grb10 is subject to epigenetic regulation leading to tissue specific differential parental-allelic expression. While the paternal allele is expressed exclusively in the CNS, the maternal allele is excluded from the CNS (and expressed in many non-CNS tissues) [1, 2]. The maternal allele is involved in aspects of development [3], and is thought to be key for coordinating the maternal-pup physiologies [4]. However, other than our original observation of a role in social dominance behaviour [1], very little is known about the brain and behavioural function of paternal Grb10. This project will examine aspects of neural function at the molecular, cellular and behavioural level. Specifically, cellular and molecular analyses will focus on examining the neurogenic potential of Grb10KO ES cells and, separately, the phenotype of cells with CRISPR altered epigenetic regulation of Grb10. We will aim to use these neural findings, and previous studies [1], to guide the exploration of a number of other behaviours in Grb10KO mice, including aspects of cognition. Finally, we will explore the interaction of maternal diet whilst pregnant and subsequent Grb10 regulation and expression in offspring brain.

Amount: £149,985
Funder: The Wellcome Trust
Recipient: Cardiff University