NIHRDataInsights/HRCSData huggingface dataset:
Title: From Airborne Exposures to Biological Effects (FABLE): the impact of nanoparticles on health
Funder: Natural Environment Research Council

Abstract: Lay summary Nanoparticles (NPs - very small particles less than 1 hundred millionth of a meter in size) are increasingly being used in the manufacture of a wide range of goods and for other beneficial uses. They are also found in vehicle and industrial emissions and yet we know little about their capability to harm health. Although there are ways to achieve a risk assessment for chemicals in the environment based on the levels that exist and their known biological effects, there is insufficient information available to allow a risk assessment of NPs. This work will address almost three quarters of the priority objectives recently set by Defra in relation to NPs and human and environmental health and thus will make a major step-change in the assessment of risks from NPs. To do this requires the collaboration of scientists with different types of skills and knowledge (ranging from chemistry, physics, molecular and cellular biology, toxicology, exposure measurement, materials science and health/medicine ) to join forces in an approach to understand the extent of human exposures to NPs and how they affect the body. In this project, we will measure levels of NPs outdoors in urban and rural locations, indoors and also personal levels of exposure. We will concentrate on 3 metals (cerium, zinc and vanadium) as these are found in vehicle exhaust. We will use these real life levels (rather than the usual approach of using high concentrations) in a series of lab experiments to define where these NPs go once breathed in and what damage they might do. We will work out how these metal NPs (which have different shapes, sizes and chemical make up) find their way into cells in laboratory tests. We will also work out in cells from the human lung and the inside of the nose in the laboratory how these NPs move once they have got inside these cells. As asthmatic subjects may be more susceptible to these effects we will also look at cells from asthma patients. NPs are able to get inside nerve cells and as this may allow them to get to the brain, we will also look at how this possible route of entry. Once NPs have entered cells they are in a position to cause harm and we will study, using state of the art technology, which molecules are stimulated to appear once these NPs have entered the cells. This will tell us what sorts of processes might occur (e.g. inflammation) and consequently will allow us to establish possible 'safe' levels of exposure. We will then be able to advise on the safe development and use of NPs through interaction with the Health and Safety Executive and the Department of Environment, Food and Rural Affairs (Defra) who are responsible for the regulation of NPs in the UK.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;RESPIRATORY
Title: Improving the health systems response to chronic diseases in Africa
Funder: Medical Research Council

Abstract: Primary health care services in Africa are facing a growing burden of chronic diseases (CDs), due to the rapidly increasing incidence of chronic non-communicable diseases (NCDs) and because HIV infection has become a manageable chronic condition. In many countries, health services are ill equipped to respond to this situation: accurate data required for planning are scarce, policies on CDs inadequate and standardised protocols for diagnosis and management often not available. Health workers have little training in providing CD care including the provision of anti-retroviral therapy. The choice of drugs for NCDs is rarely rational, and drug supplies are erratic. In consequence a large proportion of patients with CDs are inadequately managed. We propose a research programme in southern Uganda and northern Tanzania that will address this complex problem through a multi-faceted approach. The programme will be planned and implemented in close collaboration with health policy makers and programme managers. During the first phase of the research we will (i) document existing policies and epidemiological data, (ii) assess the burden of HIV infection and other important CDs (including hypertension, cardiac failure, diabetes, asthma and epilepsy) through a cross-sectional population survey of 800 participants in each of the countries, recruited from urban, peri-urban and rural areas using a stratified multi-stage sampling approach, and (iii) conduct a survey of the quality of current CD services in about 24 health facilities in both countries. The results will be used to plan and implement an intervention that aims to improve the health system so that it will cope more effectively with CDs. The intervention will reflect the fact that the requirements for the management of chronic HIV infection and non-communicable CDs are similar. It will comprise standardized diagnostic, treatment and referral procedures, opportunistic screening for CD risk factors and symptoms, training and supervision of health workers, and health education for patients and communities. The intervention will be introduced stepwise. Facilities will be randomised to receiving the intervention earlier or later, stratified by type of facility. After 12 months of implementation, we will evaluate effectiveness using a controlled design. Through substudies we will investigate cost-effectiveness, possible adverse effects on other essential services, and changes of perceptions of CDs at community level. Working with policy makers and service managers, the results will be used to facilitate changes in health policy aiming to improve CD services in general.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: NEUROLOGICAL;RESPIRATORY;INFECTION;METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Lab-on-an-Organ: A droplet based portable continuous chemical sensor
Funder: Engineering and Physical Sciences Research Council

Abstract: We propose to develop a novel portable continuous chemical sensor. The sensor is a new type of monitoring technology, with novelties on fluidics sampling, online and offline chemical analysis and system integration. Continuous measurement of biomolecule/drug concentrations directly from tissue or the other body fluids offers the exciting possibility of understanding physiological or pathological processes, recording responses to stimuli, drug metabolism, and even developing new therapies that use biomarker levels to guide treatment in real time. However, such measurement is challenging - the fluids are complex mixtures, the volumes can be very small, and detection methods are limited. Here a multidisplinary team from engineering, medicine and health science, propose to tackle this challenge through the development of an enabling portable sensor device. The device combines microdialysis and droplet microfluidic techniques, will sample body fluids into nano litre droplets, perform assays and measurements in situ, and communicate wirelessly to the user. We aim to develop the whole sensor package and test it in clinical settings for dermal, brain microdialysis and free flap surgery. We envisage this novel technology will revolutionize the current practices of sampling and chemical sensing, and find broad applications in disease diagnostics and monitoring, drug development, organ transplantation and the other areas.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;SKIN
Title: Towards a unified, computationally-implemented neural network for understanding semantic cognition and its disorders.
Funder: Medical Research Council

Abstract: Semantic memory refers to the rich database of knowledge we have about the meanings of words, objects, people and all the stimuli present in our environment. This information is crucial for both verbal and nonverbal activities, and so when it disintegrates or becomes inaccessible, patients become significantly disabled. Semantic impairment is a feature in many different types of neurodegenerative and chronic brain disease including semantic dementia, Alzheimer's disease, stroke and herpes simplex encephalitis. For some of these, semantic impairment is central to diagnosis (e.g., semantic dementia) whilst for others it can be a common feature (e.g., we found that around 1/3 stroke aphasic patients have measurable semantic impairment when assessed with suitable materials). The core aims of our continuing research programme, therefore, are (a) to implement a neuroanatomically-constrained, computational model of semantic processing; (b) to catalogue and investigate all types of patient with semantic impairment; (c) to mimic and test key hypotheses about the nature and neural basis of semantic processing via transcranial magnetic stimulation studies; (d) to use functional MRI and MR tractography to map the core semantic regions and their connectivity (both structural and functional); and (e) to amalgamate this rich empirical database through the new 'neurocomputational' model in order to understand the causes of the patients' different impairments. These steps will be used to improve: detection of semantic deficits; differential diagnosis; clinical management; and evidence-based interventions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;STROKE
Title: Small vessel diseases and vascular contributions to neurodegeneration and dementia
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Clinical impact: Small vessel diseases (SVD) affect perforating cerebral vessels less than 500 microns in diameter resulting in diverse brain disorders. They cause most vascular dementia and worsen Alzheimer’s disease (AD), in total causing up to 45% of dementias. SVD also causes 25% of ischaemic and 90% of haemorrhagic strokes,1 worsens stroke outcome,2 and increases future risk of dementia, stroke and death.3 Patients present to different services, resulting in lack of awareness of SVD’s wide impact on the brain, mechanistic understanding or effective interventions.4 SVD and neurodegeneration: Visible SVD lesions, e.g. white matter hyperintensities (WMH), lacunes, microbleeds, perivascular spaces (PVS), recent small subcortical (lacunar) infarcts, atrophy,5 share clinical effects, epidemiology, pathology, and occur in AD6 as does microvessel dysfunction.6,7,8 SVD affects the brain diffusely: peri-lesion white matter is abnormal;9 global white matter integrity declines as SVD burden increases;10 SVD lesions cause focal/regional cortical,11 long tract and global brain atrophy.1 SVD is dynamic: acute lesions can disappear, remain a WMH or cavitate;1 WMH increase12 and regress, both in sporadic13 and monogenic SVDs.14 Although lesion dynamics are poorly understood, progression worsens cognition and physical function, while regression resulted in less cognitive decline, disability or recurrent stroke in our cohort9 (in review).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;STROKE
Title: Non-Clinical Lectureship - Nele Demeyere - Aligning assessments for predicting the natural history of post-stroke cognition.
Funder: Stroke Association

Abstract: The aim of this project is twofold. First, to address the missing link between standardized cognitive assessments and functional measurements for acute stroke survivors. This entails an investigation into the correspondence between a standardized cognitive assessment measure (the Oxford Cognitive Screen, OCS) and the more holistic functional assessments as carried out routinely by occupational and physio-therapists. The second aim is to investigate changes in cognition and functional performance over time. Although many early cognitive deficits recover, a significant number of patients continue to have chronic cognitive problems or will deteriorate and develop vascular dementia. I will investigate whether the severity, nature (domain-specific or domain-general) and functional impact of the cognitive deficit, assessed early on post-stroke, can be predictive of recovery. This ‘recovery’ will be measured in terms of standardised cognitive assessments, self-reported cognitive difficulties, functional outcomes as measured by therapists and observable activities of daily life.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: NEUROLOGICAL;STROKE
Title: Stroke Association / Chief Scientist Office Senior Clinical Lectureship - Fergus Doubal - A platform for patient focused trials to prevent cerebral small vessel disease
Funder: Stroke Association

Abstract: Cerebral small vessel disease (cSVD) leads to stroke and dementia, is devastating to patients and their families, and costs about £16 billion p.a. in the UK. There have been few trials in cSVD. There are no treatments proven to prevent SVD progression. cSVD has several different clinical (stroke, dementia), and pre-clinical (mild cognitive/physical disabilities) manifestations, that typically present to different services. Trials are further hampered by imprecise information on long term outcomes, lack of robust practical methods to stratify patients at trial entry or capture outcomes, little information on what matters to patients, or no consensus on which outcomes to use. This project aims to improve trial design to prevent cSVD by determining: 1. Long term outcome event rates in clinical and preclinical manifestations of cSVD through multiple sources: systematic literature reviews and meta-analyses of cohort data. 2. What matters to patients and carers through focus groups obtaining opinions on approaches to baseline/outcome assessments and trial design options. 3. Thirdly what are the best predictors of outcome to improve stratification, power and efficiency of trials (using data from the SPS3 trial) and fourthly in small focused studies, assess retinal or brain vascular function as possible early efficacy markers.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);8.1 ORGANISATION AND DELIVERY OF SERVICES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL;STROKE
Title: Mechanisms of oxygen toxicity in the context of mitochondrial dysfunction
Funder: Medical Research Council

Abstract: Background: Recent pre-clinical studies indicate that high oxygen levels are toxic in the context of mitochondrial dysfunction, but the underlying mechanisms are not known. The prevailing hypothesis is that impaired mitochondrial oxidative phosphorylation (OXPHOS) reduces cellular oxygen consumption, leading to local tissue hyperoxia. In this context, further oxygen will compromise adenosine triphosphate (ATP) synthesis. Approach: We aim to test this hypothesis in humans, comparing room air (20% oxygen) to 55% oxygen in two complementary disease groups: (1) Rare inherited mitochondrial disorders to provide proof-of-principle; and (2) Traumatic Brain Injury (TBI) to show broader medical relevance. Our prediction is that inhaling 55% oxygen for one hour will lead to decreased ATP synthesis in both contexts, but not in controls. Our primary in vivo measure will be ATP synthesis measured in brain using 31-phosphorus magnetic resonance spectroscopy (31P-MRS). We will also measure brain N-acetyl aspartate (NAA) by 1H-MRS as an established marker of neuronal mitochondrial function; and tissue oxygen delivery and extraction using non-invasive oximetry. In the TBI group we will also perform in situ tissue microdialysis and brain tissue oxygen sensors allowing direct measurement of brain oxygen levels, oxidative and glycolytic metabolism. In both groups we will carry out linked to ex vivo exploratory measurements in lymphocytes and serum which we anticipate will provide a mechanistic link. Importance: The parallel evaluation of ex vivo measures and non-invasive monitoring will guide the development of clinical biomarkers of oxygen toxicity, enabling the design of new management approaches matching oxygen delivery (tissue oxygenation) to local consumption (modulating mitochondrial function).


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: NEUROLOGICAL;STROKE
Title: Understanding the cellular neurobiology of paediatric stroke and moyamoya disease
Funder: Medical Research Council

Abstract: This research project will examine the physiology of the response of young brains to ischaemia - seen in acute arterial stroke and moyamoya disease. Both rodent tissue and human tissue (discarded from neurosurgery) from individuals of different ages will be studied (with rodent age chosen to mimic human ages). Rodent models of ischaemia, in brain slices and in vivo in anaesthetised animals, will be used. My research partner's laboratory has transgenic mice labelling pericytes (NG2-dsRed) and sensing pericyte [Ca2+] (NG2-GCaMP6), and labelling microglia (Iba-1-GFP), and paranodes (Caspr-GFP, to define the node of Ranvier) to facilitate the work. The experiments will examine 4 themes: (1) Responses of brain capillaries to ischaemia in the juvenile brain. Two-photon microscopy will be used to assess pericyte-mediated capillary constriction in normal tissue from juveniles of different ages and tissue which has been subjected to ischaemia. (2) Responses of axons (myelinated and unmyelinated) to ischaemia during development. Immunohistochemistry and electrophysiology will be used to examine axonal function and myelination following ischaemia. (3) Responses of the node of Ranvier to ischaemia during development. Immunohistochemisty and mathematical modelling of conduction will be used to examine the effect of ischaemia on the structure and function of the node. (4) Microglial function in the juvenile ischaemic brain. Two-photon microscopy and assays of microglial surveillance activity will be used to examine the response to ischaemia. The mechanistic information from these experiments will identify potential therapeutic targets for intervention, and will synergise the basic science expertise of the host lab with my clinical experience and membership of the UK's largest paediatric neurovascular service.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;STROKE
Title: The Role of Extracellular Vesicles in Post-Stroke Vascular Dysfunction
Funder: Alzheimer's Research UK

Abstract: Stroke is a major health issue and 1 in 10 stroke patients will develop dementia. This may be because the blood vessels in their brain function differently after a stroke. This project aims to understand how the brain sends out signals that cause the function of blood vessels to change after stroke. Extracellular vesicles (EVs) are thought to be one way by which the brain might send out these signals. EVs are 'bubbles' of information, less than 1/10th the size of a cell, which are shed from all cells. Under any kind of stress, like inflammation or lack of oxygen, cells produce more of these 'bubbles' as a way of communicating. My research has shown that after a stroke, the number of EVs in the blood increases and that these EVs can affect the function of other cells. My hypothesis for this project is that EVs affect how blood vessels work after a stroke, which could lead to complications like dementia during recovery. In this project I therefore aim to discover three main things about EVs in stroke: 1) where they come from; 2) what they do to cells; 3) what they do to whole blood vessels.

Lay abstract: Stroke is a major health issue and 1 in 10 stroke patients will develop dementia. This may be because the blood vessels in their brain function differently after a stroke. This project aims to understand how the brain sends out signals that cause the function of blood vessels to change after stroke. Extracellular vesicles (EVs) are thought to be one way by which the brain might send out these signals. EVs are 'bubbles' of information, less than 1/10th the size of a cell, which are shed from all cells. Under any kind of stress, like inflammation or lack of oxygen, cells produce more of these 'bubbles' as a way of communicating. My research has shown that after a stroke, the number of EVs in the blood increases and that these EVs can affect the function of other cells. My hypothesis for this project is that EVs affect how blood vessels work after a stroke, which could lead to complications like dementia during recovery. In this project I therefore aim to discover three main things about EVs in stroke: 1) where they come from; 2) what they do to cells; 3) what they do to whole blood vessels.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;STROKE