NIHRDataInsights/HRCSData huggingface dataset:
Title: Concordance in Diabetic Foot Ulceration
Funder: Department of Health (England)

Abstract: Diabetes affects more than 2 percent of the UK population and poorly controlled blood sugar levels can lead to complications and problems with the feet. Foot ulcers affect many people with diabetes at some time in their life. They are associated with reduced quality of life higher healthcare costs increased mortality and morbidity. Some ulcers become infected and the vast majority of foot / leg amputations in people with diabetes are preceded by a diabetic foot ulcer infection. Amputation is expensive and dramatically reduces quality of life. Identifying infection and treating it is therefore very important in caring for people with diabetes and foot ulcers.CODIFI is a multicentre study involving people with diabetes who have a foot ulcer with suspected infection requiring antibiotic therapy. The study aims to recruit 400 patients over a 15 month period from multidisciplinary primary and secondary care based foot ulcer/diabetic clinics and hospital wards throughout the UK. Consenting patients will have bacteria collected from their ulcer in two ways: a swab and curettage (small scraping of the ulcer bed). Results will be compared to see if swabs and curettage reported the same number and types of bacteria and clinicians will evaluate whether patient treatment would have differed based on the results. Twenty patients will also be included in a sub-study to test whether DNA fingerprinting techniques identify bacteria better than growing the bacteria in the laboratory as is currently done.The study sets out to provide a recommendation for the most appropriate sampling technique to be used by clinicians when collecting bacteria from a clinically infected wound. This would stop clinicians from using poor tests which do not provide enough information or if both tests agree then the test which is most acceptable to patients can be used safely.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION;METABOLIC AND ENDOCRINE;SKIN
Title: Cold Plasma to Treat Post-Surgical Orthopedic Infection
Funder: Medical Research Council

Abstract: Orthopaedic infection is life-threatening and current treatments are only sparingly successful. Despite aggressive peri-operative antibiotic treatments, 1.5% of knee revisions, 0.7 to 11.9%, of spinal infections (depending on the complexity of the procedure) and up to 27% of open fractures become infected. Moreover, the complexity of tissues interfacing with the biofilm-prone orthopaedic instrumentation complicates bacterial eradication making current treatments prolonged and expensive. To address this serious issue, we propose to combat the infection using cold plasma and cold plasma activated liquid (PAL). Our pilot data show that these novel modalities can be tailored for high microbicidal activity coupled with immune stimulatory properties without the risk of antibiotic resistance. Importantly, these modalities have not been used to combat bone infections. To utilize this technology to address orthopaedic infection, a tri-partite consortium of international research teams at the forefront of cold plasma technology from the US, the Republic of Ireland and Northern Ireland have been assembled. This consortium unites expertise in plasma engineering, microbiology, material science, chemistry, cell biology, and clinical medicine. There are three Specific Aims. (1) To determine the effect of direct cold plasma treatment on MRSA biofilms and immune cell response; (2) To determine the mechanisms of action, and efficacy of Plasma Activated Liquid (PAL) alone and in combination with direct cold plasma treatment to eradicate infection; and (3) To resolve infection through combined cold plasma and PAL treatments in a clinically relevant animal model of infected osteotomy. We will develop cold plasma and PAL treatments that will directly disrupt biofilms and eradicate bacteria while stimulating the immune response. At the end of this study, we will have developed a simple and effective non-antibiotic treatment protocol to cure surgical site infection through combined immune activation and direct eradication of bacteria. Clinically, this cold plasma+PAL treatment protocol can be seamlessly integrated with existing clinical protocols to enhance and eventually replace our reliance on antibiotic therapies.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: INFECTION;MUSCULOSKELETAL
Title: The impact of daily toothbrushing on oral health, respiratory pathogens and pneumonia in adults with a neuro-disability at the Royal Hospital of Neuro-disability (RHN)
Funder: Royal Hospital for Neuro-disability

Abstract: To assess the effect of once daily toothbrushing with 0.2% chlorhexidine (CHX) gel on oral health, respiratory pathogens, and pneumonia amongst PEG fed patients with a neuro-disability.


Research activity codes: 6.8 COMPLEMENTARY
Health categories: INFECTION;NEUROLOGICAL
Title: COVID-19 Neurological Disease: a Global Meta-Analysis and Prospective Case Control Study in Brazil, India and Malawi.
Funder: Medical Research Council

Abstract: Building on our NIHR Global Health Research Group on Acute Brain Infections ("Brain Infections Global" or, "BIGlobal"), which we have recently repurposed to start understanding COVID-19 neurology, we will: 1. Conduct an individual patient data meta-analysis of patients with COVID-19associated neurological disease, identified through the BIGlobal COVID-Neuro Network to define the full spectrum of manifestations. 2. Establish a prospective case control study of hospitalised COVID-19 patients in Brazil, India and Malawi, comparing those with neurological disease to those patients without neurological disease, focusing on risk factors which may be modifiable. 3. Examine outcomes of hospitalised patients with COVID-19 associated neurological disease, looking for prognostic factors associated with a poor outcome. 4. Building on our strong Patient, Public and Community Engagement and Involvement Programme, and close relationship with WHO and national policymakers, use the information from 1, 2, and 3, above to develop national and international clinical care guidelines to improve patient outcomes and reduce disability. 5. Strengthen capacity for emerging brain infections research in partner countries. The case control study will test the primary hypothesis that among hospitalised patients with COVID-19, acute neurological disease is associated with hypoxia. The meta-analysis, case control study, and work with policymakers will run in parallel, to ensure rapid delivery of the changes needed to impact on practice. The study builds on 25 years of research on brain and emerging infections from the Liverpool group, much of which has been translated into new policy and practice.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: INFECTION;NEUROLOGICAL
Title: Understanding how the brain recovers from cerebral malaria
Funder: Medical Research Council

Abstract: Cerebral malaria (CM) is one of the most severe complications of malaria, responsible for hundreds of thousands of deaths, each year. At present the only treatment for CM is anti-malarial drugs, which is a non-specific sub-optimal treatment that fails to prevent death in 20% of cases, with 15-30% of survivors of CM also experiencing long-lasting and life-changing neurological sequela. Brain swelling, due to vasogenic oedema, is a key pathological event in CM that, in severe cases, can cause brain stem herniation and death, or cause structural damage in survivors. Thus, there is increasing recognition that the successful recovery from CM depends upon the rate and effectiveness of oedematous fluid removal from the brain. However, the pathways that control vasogenic oedema clearance during the recovery from CM remain unknown. Moreover, the physiologic systems that ultimately cleanse the brain tissue of noxious blood-derived products concomitant with removal of vasogenic oedema to return the brain to immunological homeostasis during resolution of CM have yet to be addressed. In this project, we will use a murine model of CM (experimental cerebral malaria; ECM), which we have validated, and use interdisciplinary combinations of dynamic brain imaging (MRI and SPECT-CT), quantitative microscopy (stereomicroscopy, tissue clearing and 3D reconstruction, and confocal), and compartmental tracer injections, to identify and mechanistically test the routes that fluid and blood-derived products are drained from the brain during recovery from CM. We will subsequently identify how fluid and macromolecule efflux is interconnected with the influx of CSF into the brain tissue during recovery from ECM, and how CSF influx is essential to clean the brain tissue and reestablish brain function and ameliorate neuroinflammation during recovery from ECM. Our results will transform our understanding of how the brain recovers from CM, identifying new therapies for this devastating syndrome.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: INFECTION;NEUROLOGICAL
Title: Fungi on the Brain: Interrogating Host-Pathogen Interactions during Fungal Meningitis
Funder: Medical Research Council

Abstract: Cryptococcus neoformans is a human fungal pathogen that causes >200,000 deaths per year. This pathogen infects most organs, yet predominantly localises to the lungs and central nervous system (CNS). The CNS tropism of this fungus is not well understood, and neither is the host response by CNS-resident microglia. Interactions between macrophages and C. neoformans are highly dynamic; macrophages produce antifungal inflammatory molecules such as nitric oxide (NO), and C. neoformans attempts to counteracts these insults by secreting immune-modulators that reduce NO-dependent fungal killing. Although these seminal studies have provided key insights into how C. neoformans responds to macrophage attack and identified critical host molecules for antifungal defence, most studies did not specifically analyse tissue-resident macrophages. Although related to macrophages, microglia exhibit important ontogenic and functional differences, and we therefore cannot extrapolate lessons from these models to specialised tissue-resident cells. To address this issue, I will use transgenic animals that I have adapted for use with in vivo fungal infection models to carefully analyse microglia interactions with C. neoformans. My preliminary data using these unique models indicate that microglia are detrimental for the control of CNS infection. To gain insights into this phenotype, I will examine how microglia-depletion affects fungal invasion and CNS inflammation in order to interrogate the mechanism of microglia-supported infection (Aims 1, 2) and work to understand how this is reversed by adjunctive IFNg immune-therapy (Aim 3). Collectively, this research will provide a novel in-depth analysis of antifungal responses in the CNS, which is needed to help tackle the global burden of this currently poorly understood disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;NEUROLOGICAL
Title: Dissecting how the NLRP3 inflammasome provokes blood brain barrier dysfunction during cerebral malaria
Funder: Medical Research Council

Abstract: Cerebral malaria (CM) is one of the most severe complications of malaria, responsible for hundreds of thousands of deaths, each year. At present the only treatment for CM is anti-malarial drugs, which is a non-specific sub-optimal treatment that fails to prevent death in 20% of cases, with 15-30% of survivors of CM also experiencing long-lasting and life-changing neurological sequela. Brain swelling, due to vasogenic oedema, is a key pathological event in CM that, in severe cases, can cause brain stem herniation and death, or cause structural damage in survivors. Our preliminary data suggest that inflammation caused by the NLRP3 inflammasome is responsible for damaging the integrity of the blood-brain barrier and exacerbating vasogenic oedema. In this project, we will use a murine model of CM (experimental cerebral malaria; ECM), which we have validated, and use a combination of imaging, biochemical, and immunological techniques to determine the temporal and spatial regulation of NLRP3 inflammasome activation, the proximity of this event to areas of blood-brain barrier disruption, and how NLRP3-dependent inflammation signals to affect vasogenic oedema. The full translational relevance of our discoveries in the pre-clinical model will be established in human post-mortem brain tissue from fatal paediatric cerebral malaria. The outcome of this project will be a step-change in our understanding of how the NLRP3 inflammasome controls blood-brain barrier opening during CM and following anti-malarial drug treatment. This work will allow us to identify crucial new adjunct therapies to rapidly limit fluid influx, brain swelling and neuroinflammation, transforming the treatment success of this devastating condition. More broadly, our results will reveal fundamental new insights into how the NLRP3 inflammasome is activated and causes vasculopathy within the brain.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFECTION;NEUROLOGICAL
Title: The dysregulation of protein synthesis in amyotrophic lateral sclerosis
Funder: Wellcome Trust

Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder which involves the death of motor neurons. Several recent studies have shown that this may be caused in part by the inhibition of new protein production. I will use ribosome profiling, a high-throughput technique that detects which mRNA regions are being translated at a given time-point (Brar and Weissman, 2015), to analyse protein synthesis in cellular and mouse models of ALS containing a mutation in the RNA-binding protein FUS (Fused in Sarcoma). Moreover, I will use a recently developed variant of this method, called ‘disome profiling’, to identify regions on mRNAs where protein synthesis is stalled (Arpat et al., 2019; Han et al., 2019). To explore the reasons behind the observed transcriptomic changes, I will use proximity ligation assays (Soderberg et al., 2006), which enable detection of single molecule interactions, to study a putative mechanism of dysregulation that involves the translational regulator FMRP. Impact: We will unravel how and why protein synthesis is inhibited in ALS. We will generate several publicly available datasets that will be valuable for many purposes. Through the use of high-throughput protein synthesis assays we may identify candidate drugs that alleviate inhibition of protein synthesis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;NEUROLOGICAL
Title: Molecular basis of parasite-induced disruption of host circadian outputs
Funder: Wellcome Trust

Abstract: Sleep/wake cycles are arguably the most important circadian behavioural output controlling many aspects of animal physiology. However, some infections induce disruptions to these cycles, leading to pathology. Sleeping sickness is an infection caused by the African trypanosome Trypanosoma brucei. One of the most puzzling symptoms of this disease is the profound alteration in sleep patterns, which is now recognised as circadian disorder. This disease provides an ideal framework to study how pathogens disrupt host circadian behaviour. I will use single-cell transcriptomics to profile the responses of key hypothalamic nuclei controlling circadian behaviour during infection. I will also characterise the population of parasites residing in the brain compared to bloodstream parasites to identify mechanisms of glial activation, neuroinflammation, and parasite survival in the CNS. These outputs will provide novel and unprecedented insights into the host-pathogen interactions in the hypothalamus that lead to disruptions of sleeping patterns. My ultimate aim is to understand how pathogens interfere with the function of the central nervous system leading to changes in physiology and behaviour. The outcomes of my fellowship will provide a new understanding of infection-induced circadian disorders and will reveal factors that can be exploited for intervention and treatment of infections affecting the brain.

Lay abstract: Circadian rhythms are near-24h long periods of physiological events that help us to adapt to our environment; for example, the sleep/wake patterns during light/dark cycles. However, infections cause disruptions of these rhythms leading to circadian disorders. African trypanosomiasis, also known as sleeping sickness, is a neglected tropical disease that disrupts circadian behaviour, but the mechanisms leading to these alterations are unknown. I propose to understand these mechanisms from a host and a parasite perspective. I will study gene expression profiles of specific brain regions during infection, as well as in parasites residing in the brain. Together with behavioural studies, this information will enable me to predict which genes and cells are driving circadian disorders during infection. My work will identify critical host and parasite mechanisms leading to infection-induced circadian disorders and will reveal factors that can be broadly exploited for the treatment of other infections affecting the brain.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION;NEUROLOGICAL
Title: Self-propagating protein conformations as targets of intracellular immunity
Funder: Wellcome Trust

Abstract: Recent discoveries in neurodegeneration support the cell-to-cell transmission and replication of certain ‘prion-like’ proteins in a manner highly reminiscent of viral infection. This suggests that antiviral mechanisms could potentially be used to treat neurodegenerative diseases. The novel antibody receptor TRIM21 engages immune complexes in the cytoplasm and elicits their proteasome-dependent destruction. This activity prevents infection by viruses that enter the cell with antibodies attached to them. Preliminary data show that seeds of tau, a cytoplasmic prion-like protein that aggregates in Alzheimer’s disease, can similarly be neutralized in this way. This study will combine high-content cellular seeding assays, degradation assays and two mouse models of tau pathology to investigate the mechanism of antibody protection during immunotherapy. Using antibody engineering and knockout mice lines, I will quantify the contribution of TRIM21 and classical Fc receptors to immunotherapeutic protection against neurodegeneration. I will determine how cellular machinery elicits the inactivation of prion-like proteins. This combined approach will support an understanding of intracellular inactivation of prion-like proteins and relate it to disease progression. Current understanding has not translated into disease-modifying therapeutic interventions for neurodegeneration. These studies may inform new strategies aimed at limiting spread of pathogenic protein assemblies using antibodies.

Lay abstract: The immune system is tasked with the detection and destruction of pathogens. Prion-like proteins, whose replication is thought to underlie neurodegenerative diseases, are the simplest type of pathogen but the hardest to protect against. This is because they are formed from self-derived material, making them difficult to detect; and they are highly compact structures, making them difficult to destroy. There is accordingly little understanding of how the immune system can effectively limit the spread of prion-like proteins. I have co-discovered a novel antibody receptor, TRIM21, which can detect antibody-coated viruses inside the cell and strip them apart, preventing them from replicating. In this proposal I will investigate how this mechanism could be redirected to target prion-like proteins using therapeutic antibodies. I have established experimental systems to allow the replication of tau, a prion-like protein in Alzheimer’s disease, to be studied in detail. These assays will be used to determine the molecular mechanisms by which protein pathogens are neutralized. In parallel, I will use mouse and stem cell-derived models of tau pathology to test whether this TRIM21-dependent mechanism can provide protection in a physiological setting. These results could provide a mechanism-based strategy towards antibody-based therapies for neurodegeneration.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;NEUROLOGICAL
Title: Albumin to prevent infection in Acute-on-Chronic Liver Failure (Acronym: ATTIRE Albumin To prevenT Infection in liveR failurE)
Funder: Department of Health (England)

Abstract: Liver disease is the 5th commonest cause of death in the UK and the only one of the top 10 currently rising. Approximately 110,000 patients with symptoms of advanced cirrhosis, (commonly related to alcohol excess) e.g. jaundice, confusion and bleeding from the stomach, were admitted to UK hospitals in 2011-12. The most common cause of death in these patients is infection. These patients have a weakened immune system making them highly vulnerable to infection and no effective strategy exists to improve this. We discovered that the cause of this vulnerability is an increase in blood levels of a lipid hormone called Prostaglandin E2 (PGE2) which reduces white blood cell function, the cells that fight infection. We have discovered that their immune systems can be boosted for at least 24 hours by infusing albumin into a vein which reduces PGE2's effects. This safe process is currently given when patients need extra fluid e.g. those with kidney damage. We propose this new exciting use for albumin to be given daily to improve cirrhosis patients' immune systems and therefore prevent infection. We hope that this will save lives and reduce health-care costs and propose to investigate this in a large scale clinical trial.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION;ORAL AND GASTROINTESTINAL