NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Sleep circuitry: linking homeostasis, sedation and stress
Funder: Wellcome Trust

Abstract: This proposal aims to understand:
1) What circuitries sense the inexorable drive to sleep when we are sleep-deprived?  We will investigate if sleep need is sensed locally in the brain by a distributed circuit network that feeds into a central hub, the lateral hypothalamus, providing global restorative sleep. We have identified neurons in the mouse prefrontal cortex, preoptic hypothalamus, and ventral tegmental area (VTA) that sense sleep need and contribute to inducing sleep after sleep deprivation. Learning how responses to sleep deprivation are embedded in distributed sleep circuitry would explain how sleep homeostasis works at the circuit level.
2) Do sedative drugs promote these restorative sleep pathways? How do two important drugs, propofol and dexmedetomidine, intervene in the sleep-homeostasis circuitry? We will search for cells that respond to sedatives to induce restorative  sleep without deleterious effects (hypothermia). Understanding this circuitry may identify new drug targets.
3) What is the significance of sleep-promoting circuitry we have discovered in the basal ganglia and midbrain (globus pallidus to lateral habenula to VTA to lateral hypothalamus), which overlaps with circuitry that responds to aversive outcomes and stress? We will investigate if this basal ganglia-triggered sleep helps offline processing of negative experience.

Lay Abstract: We sleep for 30% of our lives, but why we do remains a mystery. We will address several questions centred around sleep’s restorative properties: what circuitries sense the inexorable drive to sleep when we are sleep deprived, and do sedative drugs hijack these natural restorative sleep pathways? Why do things feel better after a good night’s sleep - how does sleep mitigate negative experiences? We will use the latest genetic, physiological and behavioural techniques  with mice to identify the circuitries involved. Our work will aid understanding of feedback processes that sense the sleep drive, and identify whether drugs can be developed that provide natural sleep’s restorative benefits; we will determine whether side-effects (e.g. hypothermia) of sedative drugs can be reduced. Finally, our discovery of sleep-promoting circuitry in the basal ganglia, which overlaps with circuitry that controls how we react to negative experiences, could allow new approaches to improve mental health.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: MENTAL HEALTH;NEUROLOGICAL
Award Title: Sleep regulation by neuron-astrocyte interactions
Funder: Medical Research Council

Abstract: A better understanding of neurobiology in sleep is extremely important for our health. However, the regulatory mechanism of REM sleep remains elusive compared to NREM sleep. Previous studies have suggested that the sublaterodorsal nucleus (SLD) plays a central role in REM sleep regulation. However, it remains unclear how SLD neurons are regulated across the sleep-wake cycle in vivo. Although accumulating evidence also suggests that astrocytes are involved in sleep homeostasis as a wakefulness integrator, our preliminary results show higher calcium signals during NREM sleep in SLD astrocytes, implying that SLD astrocytes play a role in NREM sleep maintenance and REM sleep induction.  To investigate the regulatory mechanism of calcium signals in SLD astrocytes across the sleep-wake cycle, we will test the hypothesis that activity of GABAergic neurons in the ventrolateral periaqueductal gray (vlPAG) modifies calcium signals in SLD astrocytes across the sleep-wake cycle. By combining optogenetic and calcium imaging approaches in mice, we will investigate how SLD-projecting vlPAG GABAergic neurons ('vlPAG->SLD GABAergic neurons') are active across the sleep-wake cycle, and whether the optogenetic activation of vlPAG->SLD GABAergic neurons can increase calcium level in SLD astrocytes. To explore the functional role of calcium signals in SLD astrocytes, with respect to sleep regulation, we will test the hypothesis that calcium signals in SLD astrocytes play a role in NREM sleep maintenance and REM sleep genesis. By combining chemogenetic, calcium extruder and calcium imaging, we will investigate how artificial manipulations of calcium level in SLD astrocytes affects sleep architecture.  This study will shed new light on the importance of astrocyte for sleep regulation.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL
Award Title: Smartphone application for effective prostate cancer screening utilising machine learning- enhanced ultrasound PSA-density measurement
Funder: Cancer Research UK

Abstract: Background
Prostate cancer (PCa) is the commonest male cancer. Prostate-specific antigen (PSA) testing is the first-line investigation used for referral to secondary care. Around half of the 120,000 patients/year referred in the UK are ultimately diagnosed with PCa, highlighting the inefficiencies in the current system, including utility of MRI as an expensive resource, and biopsy as an invasive procedure. A common reason for raised PSA levels is benign prostate overgrowth; PSA-density corrects for enlarged gland volume and can therefore better indicate the presence of clinically significant cancer. Ultrasound (US) can measure gland volume, however, US is currently performed in secondary care by specialised practitioners, which increases costs, and may delay cancer pathways. Making US volume calculations automated, cheap, and potentially available in primary care would avoid such limitations.  

Aims 
We will perform system optimisation of a prototype device for automated US measurement of prostate volume and validate its performance in a patient cohort. The device will feature: 
[1] A real-time miniaturised tracker paired with a smartphone to track US-probe position 
[2] A workflow-optimised smartphone application importing real-time video streaming of US images and presenting them to clinicians 
[3] A machine learning algorithm that detects, segments, and reconstructs real-time 3D-prostate volume, allowing PSA-density calculation

Methods 
The miniaturised tracking system uses a wireless reusable tracker that integrates with a MEMS-based gyroscope, magnetometer sensor, and tracking software. The tracker will be compact and can be clipped onto any existing US machine/probe. The smartphone application will simultaneously capture positional data from the tracker and prostate images from the US scanner. The utility and workflow of the device will be first optimised on a prostate phantom. A proof-of-principle clinical study will then be performed comparing smartphone/machine learning-derived PSA-density in a 20-patient cohort undergoing clinical MRI, for gold-standard comparison. 

How the results of this research will be used
We will validate our device prototype in a small prospective trial of tertiary-care patients to demonstrate efficacy and to statistically power larger clinical trials in primary care and inform subsequent licensing/commercialisation. Our disruptive technology will potentially allow screening of prostate patients in GP practices, to obtain accurate PSA-density prior to urology referral. This will improve patient management and reduce costs by rationalising MRI use, allowing appropriate avoidance of further investigations in some patients, and triaging other patients for more urgent MRI. This technique offers potential for quick translation into primary-care for screening and optimisation of cancer-care pathways.


Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: CANCER AND NEOPLASMS
Award Title: Southampton Clinical Trials Unit
Funder: Cancer Research UK

Abstract: The Southampton Clinical Trials Unit (SCTU), at the University of Southampton, is a UKCRC registered CTU which is integrated within the Southampton CRUK Centre, Experimental Cancer Medicine Centre (ECMC) and Centre of Cancer Immunology (CCI) with strong links to the Wessex Investigational Sciences Hub laboratory (a CRUK CDD Biomarker Centre of excellence for immunomonitoring).

 SCTU has good representation of its statisticians and clinical investigators on all the relevant NCRI Clinical Studies Groups.


Patient and public involvement runs through the whole SCTU system, from the initial review of whether to take on a trial, through funding application, delivery of the trial and dissemination of results.

SCTU has a highly efficient operational set up and state of the art clinical trial information systems, which has resulted in trial set-up times which are among the best in the UK academic sector.

 We have a growing portfolio of innovative experimental therapeutic studies and a range of large scale studies combining important clinical questions with extensive correlative science, in order to maximise the information we derive from every study subject. As well as a strong track record of precision medicine studies SCTU has experience of establishing of a nationwide platform for molecular phenotyping in aggressive lymphoma which it plans to mirror in other tumour sites.


SCTU's principal tumour sites of interest are upper gastrointestinal cancer, lymphoma and urology, although studies in other sites such as head & neck, breast and mesothelioma are supported, especially if they align with the SCTU expertise and focus in cancer immunology. SCTU supports a number of innovative experimental medicine studies of immune-oncology reagents developed in the laboratories of Southampton CCI/ECMC, with an expanding portfolio in this field working in partnership with industry, spanning all the way from first-in-man to large scale randomised trials.

A growth area for SCTU is early detection, increasing links with the NCRI Screening, Prevention and Early Diagnosis CSG and building on successful recruitment of a very large cohort of 20 000 people with potential symptoms of early malignancy, from whom blood samples that have been stored for future analysis in collaborations addressing early cancer detection. SCTUs links to public health and primary care in Southampton will be important assets in this area.

Our CRUK core funding will allow us to contribute to CRUK’s vision of bringing forward the day when all cancer is cured and 3 in 4 patients will survive their cancer by 2034.


Research Activity Codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health Categories: CANCER AND NEOPLASMS
Award Title: Spatial and network phylodynamics of COVID-19 in Scotland
Funder: Chief Scientist Office, Scotland

Abstract: Viral phylogenetic data (i.e. the family trees of viruses obtained from infected individuals) provide unprecedented detail on virus spread and inform our understanding of “who infected whom?” However, data issues, including variations in evolutionary rates and incomplete, biased sampling can hamper their utility, and influence our interpretation of events. For example, the number of transmission events that are deemed to occur before or after a policy change influences our understanding of its efficacy and our estimates of this is skewed by biases. As COVID-19 genetic data relies heavily on self-reported community tests, these biases can be substantial. By combining viral genetic data with Scotland-specific demographic and COVID-19 cases data (including dates and locations of tests, types of test, age and gender), we shall generate analytical tools to account for these issues and ask important questions about the COVID-19 epidemic’s control, including: i) How close did Scottish measures come to eradicating COVID-19 in the summer of 2020, and how important was travel with other countries in perpetuating the epidemic? ii) What impact could long distance movement restrictions have had in slowing down the spread of the Alpha and Delta variants across Scotland? iii) Can we estimate region-specific differences in control measure efficacy? By addressing these questions, we shall be developing methods that will allow us, in future, to robustly inform policy questions in real time. These tools will also be invaluable for analysing other infectious diseases in Scotland such as influenza or future pandemics), further increasing the utility of this project


Research Activity Codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health Categories: INFECTION
Award Title: Spatiotemporal Control of Signalling of the GLP-1R Variant Ala316Thr in Pancreatic Beta Cells
Funder: Diabetes UK

Abstract: The glucagon-like peptide-1 receptor (GLP-1R) is an important target for type 2 diabetes (T2D) therapy that improves beta cell function amongst other beneficial effects. GLP-1R non-synonymous genetic variants are associated with alterations in beta cell responses potentially linked to pharmacogenetic changes GLP-1R agonist effects and/or varying T2D risk. Individuals with the GLP-1R single nucleotide polymorphism Ala316Thr present with decreased T2D and cardiovascular risk, as well as lower fasting glucose without insulin sensitivity changes.

As the spatiotemporal regulation of signalling is key to control GLP-1R responses, the student will investigate trafficking and signalling characteristics associated with GLP-1R Ala316Thr to identify specific mechanisms by which this allele reduces T2D risk. We have detected reduced basal clustering, increased lateral diffusion and cAMP versus β-arrestin-2 signal bias for this variant, which correlate with sustained in vitro insulin secretion, reduced trafficking to degradative compartments and increased segregation to perinuclear endosomes. Here, the student will characterise changes in GLP-1R-lipid nanodomain interactions, post-translational modifications, specific binding partners and intracellular signalling signatures for this allele employing state-of-the-art quantitative microscopy, biochemical assays and mass spectrometry-based proteomics. Additionally, they will study in vivo this variant and its regulation by β-arrestin-2 in GLP-1R Ala316Thr knock-in mice ± beta cell-specific β-arrestin-2 knockouts.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: METABOLIC AND ENDOCRINE
Award Title: Standardising surgical Interventions and Co-interventions: development of a quality assurance intervention for surgical RCTs (STItCh-IT)
Funder: Medical Research Council

Abstract: Well designed and conducted surgical RCTs are essential to establish evidence-based practice. Currently, few surgical RCTs are undertaken and existing ones are often methodologically weak. An unaddressed challenge relates to the complexity of surgical interventions, which comprise multiple components and co-interventions that are delivered by surgeons with differing expertise. This complexity can mean interventions are not delivered as intended, creating unexpected differences between and within trial groups. Differences can be further exaggerated through the introduction of performance bias, which occurs if healthcare providers become aware of treatment allocations during the RCT. In pharmaceutical RCTs, performance bias is reduced through blinding staff and care givers; however, this is difficult in surgical settings. Alternative strategies are therefore required. This project will create a 'quality assurance intervention (QAI)' to optimise the quality assurance of surgical interventions and co-interventions in RCTs. This will involve development and use of i) a typology to systematically deconstruct surgical (co-)interventions into their component parts; ii) methods to maximise the efficiency of systematic reviews to summarise existing evidence about how each component of the (co-)interventions should be standardised, thereby identifying evidence gaps; iii) methods to undertake qualitative research in the operating theatre, to address the evidence gaps; and iv) consensus methods for trials teams to agree on the standards of surgery within an RCT. I will pilot the QAI using exemplar cases, create a guidance document and develop an interactive online platform. This will provide a practical solution for optimising the QA of surgical interventions during RCT design, reduce performance bias and improve the transparency of intervention delivery, so surgical procedures can be more accurately replicated in clinical practice.


Research Activity Codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Steel inclusion detection using high resolution X-ray non-destructive testing
Funder: Innovate UK

Abstract: SilverRay Ltd is a start-up company whose primary goal is to exploit a proprietary technology developed for the production of large area, high sensitivity X-ray detectors for real-world applications. This proprietary technology has demonstrated a 2-3 orders of magnitude higher X-ray detection sensitivity than conventional organic detectors, whilst operating at low voltages and offering excellent shaping to complex surfaces. Further, the technology has detected X-radiation over a broad energy range, from 60 kV to 6 MV, making it applicable for a variety of end applications such as medical radiography, non-destructive testing, and security border controls, amongst others.



The current, dominant technology for non-destructive testing (NDT) by radiography is the use of advanced digital X-ray imaging technology based on inflexible flat panel detectors, with outputs displayed directly on to a computer screen. The detectors cannot be flexed, and need to be used in its rigid form with care due to its high expense and fragility. This is in comparison to the traditional and widely used flexible photographic film technology which allows access to complex parts/corners of an object but which does not offer real-time imaging or digital manipulation.



At SilverRay Ltd, we have developed a detector active material consisting of a printable 'X-ray sensitive ink' containing two elements: an interpenetrating network of organic material and inorganic nanoparticles. The 'X-ray sensitive ink' can be used to coat X-ray sensitive pixelated films over a wide range of substrates, including the development of flexible detectors.



Thus far, small area detectors (<1 cm2) have been successfully developed by SilverRay Ltd. The aim of the current project is to scale up the technology to large area (8x2.5 cm2) conformable, multi-pixel, digital devices suitable for X-ray imaging in NDT applications. Readout electronics will be developed allowing for remote NDT examination in a manufacturing setting. With the project collaborator, Tata Steel, detector performance will be tested in a real world application on safety critical products used in the construction industry.



The X-ray imaging system produced as an outcome of this feasibility programme will allow SilverRay to demonstrate their proprietary large area digital film based technology at a scale suitable for many other applications including NDT. This novel breakthrough technology is backed by a US granted patent application, and will be initially adopted to manufacture detectors suitable for NDT applications such as for the safety critical products identified here.


Research Activity Codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Strategic assessment of NIHR investment in Mental Health Research in the North of England
Funder: Department of Health and Social Care

Abstract: Overall aim: To describe the mental health research population needs in the North of England, taking account of NIHR national mental health research priorities, to provide a strategic assessment of NIHR investment and inform consideration of future options._x000D_
_x000D_
The specific objectives are to:_x000D_
- Highlight areas of strength and important content gaps in MHR relevant to Northern population needs._x000D_
- Identify future mental health research and capacity development priorities in Northern HEIs._x000D_
- Outline opportunities for increasing the number of clinicians active in mental health research._x000D_
- Explore methods for encouraging interdisciplinary working and better accommodating research collaborations (between, for example, mental health, social care, digital innovations, education, the environment, and disciplines across the arts and humanities) in MH research in the North._x000D_
- Identify mechanisms for encouraging and facilitating different specialities/disciplines to contribute to and get involved in mental health research.

Lay Abstract: To describe the mental health research population needs in the North of England, taking account of NIHR national mental health research priorities, to provide a strategic assessment of NIHR investment and inform consideration of future options.

Research Activity Codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health Categories: MENTAL HEALTH
Award Title: Stratification and phenotyping of pulmonary vascular disease with imaging
Funder: Wellcome Trust

Abstract: Pulmonary hypertension is a severe disorder with a poor outcome. The disease is heterogenous even in idiopathic pulmonary arterial hypertension (IPAH) its purest form. There is a grand challenge to link genetic subphenotypes that link genetic mutation data to pathological features and clinical outcomes. COPD is a huge health burden and the need is urgent to better characterise pulmonary vascular disease (PVD) in COPD and identify a subphenotype(s) that responds to therapy. I will use MRI and CT computational imaging models with the following aims:
 
(a) Diagnose, subphenotype and prognosticate patients with pulmonary hypertension. Statistical and computational modeling approaches I have developed in ~1000 patients in the ASPIRE having MRI and right heart catheterisation. 
 
(b) Study genetic imaging subphenotypes of IPAH utilising the national IPAH cohort (~n=1000), matching existing and new genetic variants with imaging pathological features and clinical outcome.
 
(c) Investigate the association of PVD and lung structure and function in COPD, employing imaging models in the MESA-lung cohort (n=3000) to probe the associations between genetics, CT lung structure, lung function, PVD and patient outcome.
 
(d) Study PAH therapy response in COPD in the ASPIRE registry on treatment (n=~80, estimated n=15 responders) identifiying imaging subphenotype(s) that responds to therapy.

Lay Abstract: Pulmonary hypertension (PH) is when a person has high blood pressure in the pulmonary arteries within the lungs; patients are short of breath, fatigued and have poor life expectancy. Even in the pure form called idiopathic pulmonary arterial hypertension there can be big differences in the disease from patient to patient. There is a grand challenge to better understand the different types of disease, particularly IPAH and lung diseases, in terms of genetics, response to treatment and life expectancy.
 
Using computer-based methods to combine information from magnetic resonance images (MRI); together with computed tomography (CT_ scans, I aim to better diagnose patients, identify patients with common clinical and scan features (called phenotypes) and predict life expectancy. Working with the national IPAH cohort (~1000 patients) I will perform a detailed analysis of CT and MRI scans comparing with genetic mutations. In addition, working with researchers in the USA on a group of chronic obstructive pulmonary disease (COPD) patients (~3000 patients) I will use patient images alongside genetic data to investigate which patients are prone to developing PH, how PH is related to the lung disease in COPD (e.g. amount of lung destruction) and the effect on life expectancy.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CARDIOVASCULAR;RESPIRATORY