NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigating the epidemiology of CFS/ME in children using the ALSPAC cohort.
Funder: Medical Research Council

Abstract: We will use data ALSPAC, a birth cohort (www.alspac.bris.ac.uk). OBJECTIVE 1. Describe the prevalence and persistence of CFS/ME in adolescence We will estimate the prevalence (total and by gender) of CFS/ME at 16 and 17 years by identifying adolescents with CFS/ME at 16 years. We will combine data with prevalence at 13 years and define adolescents with persistent fatigue at > 2 time points. We will examine the receiver-operator characteristics curves, of the Chalder fatigue scale to determine a threshold for severe fatigue. OBJECTIVE 2. Investigate the heterogeneity of CFS/ME in adolescence We will use latent class analysis (fitted with MPlus software) to identify symptom based phenotypes of CFS/ME at 17, compare these with a specialist clinic cohort and investigate whether associations of risk factors for CFS/ME differ between phenotypes. We will describe how many 17 year olds with CFS/ME fit the definition for chronic pain syndrome. OBJECTIVE 3. Investigate risk factors for incidence of CFS/ME at 13, 16 and 17 years We will investigate risk factors for CFS/ME at 13, 16 &17 years. We will use: logistic regression to relate each of the potential risk factors adjusted for age and sex; directed acyclic graphs (DAGs) to identify confounding and mediating factors; fractional polynomials to investigate the linearity of the relationship between activity and CFS/ME; linear regression to examine the continuous outcome (Chalder fatigues score) at age 16. For exposures measured at multiple times, we will create categorical variables coded as 0, 1, 2 or 3+ episodes, identify critical periods that are biologically plausible and compare regression models using likelihood ratio tests. OBJECTIVE 4. We will use logistic regression to investigate predictors of persistent fatigue Missing data: Where multiple imputation is appropriate, we will generate 50 imputed datasets, and combine estimates using Rubin's rules and we will explore whether weighting is helpful


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: The Good Schools Study: A cluster randomised controlled trial of an intervention to prevent violence against children in Ugandan primary schools
Funder: Medical Research Council

Abstract: The Good Schools Study consists of a cluster randomised controlled trial, a qualitative study, an economic evaluation and a nested cohort study. We are conducting a process evaluation but are seeking funds for that elsewhere. Trial. The trial is a 2-arm, unblinded, cluster randomised controlled trial with parallel assignment (NCT01678846, clinicaltrials.gov). Clusters are 42 primary schools registered in Luwero District, Uganda. Within each primary school, all school staff and a random sample of up to 130 children in Primary 5, 6 and 7 are eligible to participate. Two cross-sectional surveys, one completed in July 2012, and one to be conducted in June-July 2014, are being used to assess children's and schools staffs' experiences/use of violence, and to compare the randomised groups. Our main analysis will be a cross-sectional comparison at follow-up. Qualitative study. The main aims of the qualitative study relate to exploring possible causal pathways through which the intervention is operating and how different aspects of context may affect scalability of the intervention. A range of qualitative methods of data collection will be used with education officials, headteachers, school management committees (which include parents), school staff and learners. We will draw on a range of analytic techniques, including techniques from Grounded Theory, such as constant comparison and seeking deviant cases. Economic evaluation. An economic evaluation of the Good School Toolkit will be performed in order to assess the cost effectiveness of implementing the intervention compared to a 'do nothing' alternative. We will do a full economic costing from the provider's perspective. Nested cohort study. A nested cohort study of all school staff and children in Primary 5 at baseline is also being included to examine changes in educational outcomes and mental health within individuals over time. We will also be able to follow school staff longitudinally.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Can enhancing SWS improve daytime function in patients with CFS?
Funder: Medical Research Council

Abstract: "Alterations in slow wave sleep (SWS) and slow wave activity (SWA), the most reliable markers of sleep homeostasis, suggest there may be homeostatic dysregulation in CFS. SWS enhancement improves daytime sleepiness and performance on a number of tasks and the detrimental effects of sleep deprivation on performance can be rescued by administering SWS enhancing drugs. We hypothesised that pharmacological enhancement of SWS may lead to improvements in sleep main-tenance and daytime function in CFS patients suffering from non-restorative sleep. This may represent a new avenue for future treatment. The objective of the research is to compare aspects of daytime performance, notably sleepiness, memory, subjective well-being and fatigue after a night's sleep in which SWS has been enhanced with sodium oxybate in comparison with placebo. This is a randomised, double-blind, placebo-controlled crossover study in patients with CFS. 24 patients will spend two 20-hr periods in the research centre, separated by at least a week, where they will have their sleep recorded overnight. They will be given oral liquid sodium oxybate (3g) or matching placebo in divided doses; 15 minutes prior to usual bedtime and again after 3 hours. Sleep will be recorded continuously until subjects' usual rise time or after a maximum of 10 hours. The following day, assessments of sleep propensity (MSLT) will be made, by the standard method of creating sleep opportunities every 2 hours and measuring time to fall asleep. Tests of vigilance, memory, visual processing, executive function and subjective experience will be made at intervals during the day. Sleep will be scored using standard methods and spectral analysis will be used to obtain measures of microarchitecture. Subject's daily routines will be measured with actigraphy for the entire study duration. The results will be published in peer-reviewed journals and more widely in the non-academic community, and will be used to plan future research."


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Development and validation of an automated test of animal affect and welfare for laboratory rodents
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: To assess whether refinements to laboratory procedures do indeed improve animal welfare, it is essential that we use scientifically validated measures of welfare. A key determinant of welfare is an animal's affective (emotional) state. Subjective emotions cannot be measured directly so proxy indicators are used instead. Existing indicators have significant shortcomings and we have therefore developed a new approach, inspired by the links between emotion and cognition observed in humans, and grounded in theoretical models of decision-making. The core hypothesis is that individuals in negative affective states judge ambiguous stimuli negatively compared to happier individuals. We have developed a task to test for such 'cognitive biases' in animals and have found, in several species, that putative affective state is related to judgement bias as predicted. However, our tests are time-consuming and have not yet been extended to mice, the most commonly used laboratory species. We will therefore develop an automated version of our generic judgement bias task for laboratory rodents. We will use environmental and pharmacological manipulations of affective state to validate our new test. We will investigate whether judgement bias size relates to intensity of the induced state (using dose-response studies), and hence whether our approach can quantify emotional intensity. We will also investigate whether the test can detect the cumulative effects of long-term experience on affective state (e.g. by comparing animals kept in enriched and standard housing conditions). An industrial partner has expressed interest in further implementing the test that we develop for widespread use. The study will also produce computational models of how affective states change in response to external events. These may provide the basis for modelling the effects of experimental treatments on an animal's affective state, hence facilitating better and more humane planning of studies.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Validating reward-related behaviour for welfare assessment, and improving welfare through increased predictability of events
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Animal welfare can be measured on a scale of poor to good, and will at any one point reflect the balance of their positive and negative affective states. Behaviour is the most accessible measure of welfare, being the result of all the animal's own individual decision making processes and also expressing their emotions. By measuring anticipatory behaviour to announced rewards, we can determine an animal's reward sensitivity, which reflects the brain's evaluation of its subjective state and the environment. Behavioural activation in anticipation of a reward involves mesolimbic dopaminergic systems; these systems are known to be sensitized by stressors suggesting the biological mechanism underlying the use of such behaviour in welfare assessment. The animal is adapted to select the most efficient (ie most rewarding) response, and those with more stress will show higher levels of anticipatory behaviours for a reward, whilst those with positive experiences with have less anticipatory behaviour. The first goal is to validate this measure, with a battery of other welfare measures in macaques and dogs in a working laboratory environment, to show practicality. The second goal is to manipulate signalled predictability to inform laboratory animals of what will happen to them. Evidence strongly suggests that animals prefer predictable events, be they positive (eg appetitive) or negative. Knowing, through a reliable signal which can be classically conditioned over paired trials, when events will happen is good for welfare (the preparatory hypothesis), and also informs animals when they are safe (the safety signal hypothesis). The project will systematically investigate and validate this new welfare assessment tool, and assess an associated Refinement that is cost effective, requires no changes to the physical infrastructure, and can be implemented widely to improve welfare and reduce the adverse impact of procedures, with potential to improve the quality of scientific output.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Establishment of consensual husbandry protocols for laboratory Xenopus laevis using novel physiological and behavioural techniques.
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: The African Clawed frog, Xenopus laevis, is an extremely widely used laboratory animal but comprehensive, consensually developed Best Practice (BP) guidelines for housing and husbandry in this species are lacking. Our work will develop an entirely novel, non-invasive, no-contact biochemical assay for measuring corticosterone (stress hormone) in tank water for X. laevis. We have recently developed and fully validated these methods for Hymenochirus boettgeri (close relative of X. laevis) and used them to detect significantly higher levels of corticosterone release in a more 'stressful' condition compared to a less 'stressful' one. Development of this technique for use with X. laevis will enable non-invasive physiological stress assessment in this species for the first time. The assay would be used to refine the huge variation in a range of key current X. laevis husbandry recommendations by experimentally investigating tank water depth and volume ranges; water change frequency; water temperature and pH ranges and lighting regime to identify conditions associated with lower corticosterone release. A fully comprehensive ethogram of X. laevis behaviour (also lacking) will be compiled. The behavioural responses of animals will then be directly quantified for different enrichments (physical, social and their interactions) and these correlated with concomitant corticosterone measurements to evaluate these for husbandry use. From this we will develop a novel, non-invasive Behavioural Stress Score (BSS) for this species by using our data to outline a putative scale of behaviours known to be associated with varying degrees of corticosterone release. Comprehensive discussion with X. laevis users (through invited workshops) will enable us to test the potential of this BSS for wide use as a welfare monitoring tool. This work will enable direct refinement of husbandry/housing for this animal and reduction in animal use through improved welfare monitoring and increased re-use.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: The detection, assessment and alleviation of pain in laboratory zebrafish.
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: The use of fish as experimental models has resulted in a significant increase in the numbers used in licensed procedures in the UK (+23% in 2010). Fish are subject to many routine procedures that result in tissue damage that would give rise to pain in mammals. For example, the removal of tissue in fin clipping for identification purposes and genetic screens; invasive tagging where tags are introduced into the body cavity; scraping of skin for disease screening; and invasive surgery with recovery. This project will identify robust behavioural and physiological indicators to detect and assess pain in a model species, the zebrafish, and use the data collected to develop a simple, cost effective monitoring tool. Video recordings of fish subject to four potentially painful procedures shall be compared with undisturbed and sham treated fish along with non-invasive physiological measures of stress (ventilation rate and water cortisol). An intelligent monitoring system will be produced that can classify individuals according to behavioural measures and will provide an unequivocal means of determining whether fish are behaving normally, are stressed or experiencing pain. This project will also determine what preferences zebrafish have for physical enrichments and social context using a choice chamber paradigm. Once the top preferences are identified these shall be investigated as a means of improving welfare and the recovery from pain by comparison with fish held under standard, barren conditions. Finally, a range of immersion analgesic and local anaesthetic drugs shall be tested to examine whether they effectively reduce the indicators of pain in zebrafish and what the effective dose is.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Assessing welfare in fish: the answer is in the water!
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: The stress response in fish is very similar to that in other vertebrates and can be described in three stages. The primary response involves the activation of the hypothalamus-sympathetic-chromaffin cell axis which produces cathecolamines (adrenaline and noradrenaline); the hypothalamic-pituitary-interrenal tissue (HPI) axis which produces mainly cortisol in teleost fish. The secondary response is the physiological and behavioural adjustment to stress conditions. It includes the activation of a number of metabolic pathways which induce changes in blood chemistry and haematology, respiration, acid-base disturbances with ion losses at the gills, cellular response and immune function As a direct consequence of elevated circulating levels of catecholamines and cortisol, a wide range of secondary changes are evoked including the changes in rates of turnover of brain neurotransmitters such as dopamine and serotonin. If exposure to the stressor is prolonged tertiary responses occur, which are changes in the whole organism and have an eventual impact on the population via immuno-suppression and inhibition of reproduction. We are interested in the consequences of primary and secondary responses, particularly changes in brain monoamine (BMAs) levels. We hypothesise that these change with feelings and moods in fish, and can be developed into a welfare marker in fish. Since our ultimate aim is to produce a tool that can be used routinely, we will focus on the tank water as the substrate for the marker. In addition to targeted analysis of BMAs and their metabolites in the water, we will employ two novel approaches for collecting and analysing the water chemistry; the concentration of bio-molecules present in the water by polar organic chemical integrative samplers (POCIS) and the analysis of the resulting water extracts by comparative metabolomics.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Quantifying the behavioural and facial correlates of pain in laboratory macaques
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: The identification of behavioural indices of affective states in animals is central to assessing the benefits and costs of research and for efforts to refine methods and improve welfare. While affective signals do not directly indicate subjective experience, these potentially differentiate responses to negative stimuli more precisely (e.g. as fear or pain), than physiological or valence measures alone. The proposed study aims to use detailed analyses of facial movement to examine subjective states in laboratory housed macaques. Human observers are disproportionately attentive to facial cues when assessing animal welfare; to exploit this bias requires both the validation of facial cues in the assessment of subjective states and the development evaluation tools that can be applied in the laboratory context. In humans and rodents, micro-analyses of facial movements indicate consistency in the expression of pain across individuals. We have developed a standardised tool for the measurement of facial expression in macaques (MaqFACS) and identified facial correlates of pain within a neuroscience laboratory. However, it is important to validate this method across contexts, with different types of procedures and surrounding protocols. Given that facial expressions are also social signals, we expect the presence of conspecifics or animal care staff to impact upon both the form and frequency of expressions produced. Understanding this relationship is important for the application of behavioural methods in the assessment of pain.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Refinement of rearing practices in marmosets
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: The project will investigate how to refine breeding and rearing to promote best practice for welfare and research in the common marmoset (Callithrix jacchus). This small monkey is the most frequently used New World primate in European laboratories, primarily for toxicology. There are considerable welfare problems associated with breeding marmosets, including high infant mortality from large litter sizes (twins are the norm in the wild), birth complications, and rearing practices that often necessitate early deprivation from the family which is known to have adverse effects on behaviour and physiology. Studies will be conducted at a breeding facility which supplies marmosets to laboratories. Carefully designed experiments will compare infant development, family interactions, response to routine stressors, weight gain, learning and motivation in marmosets born to litters of different sizes and reared in different conditions. These conditions include (a) marmoset-reared twins (control) (b) marmoset-reared infants from triplets (c) rotationally-reared triplets (d) foster-reared triplets (e) human-reared infants from triplets and (f) marmoset-reared singletons. The findings, combined with back record analyses will determine factors affecting litter size, dam mortality and best rearing practices for welfare when litters exceed two. Should, as anticipated, the results demonstrate that marmoset-reared twins have the best welfare, the lowest mortality, fewest birth complications and produce the best models, then evidenced-based recommendations to husbandry to promote twin births will be trialled. As heavier dams produce larger litters, this may include maintaining dams at weights similar to wild counterparts to increase the incidence of twins births. When litters exceed two, another Refinement may be to train marmosets to allow care staff to provide supplementary food for carried infants to obviate separation. The findings should have far-reaching implications for quality of life of marmosets in breeding facilities, and for the reliability of the marmoset as a model in research and testing.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Taming anxiety and variation in laboratory mice
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Routine handling and restraint of laboratory animals has profound - but variable - effects on anxiety, stress physiology and underlying neurochemistry. Recently, we have shown remarkably strong differences in anxiety, aversion and behavioural variation in response to alternative methods for routine handling of laboratory mice. The aim of this studentship will be to extend our initial studies to establish practical approaches that can easily be implemented to reduce anxiety and stress responses of laboratory mice to routine handling, restraint and mild procedures. This has the capacity to substantially improve the lifetime experience of mice used in research. The student will also explore whether such approaches reduce variation in experiments that are likely to be influenced by stress and anxiety responses, and will increase reproducibility between experimenters. This has the potential to reduce the numbers of animals needed for research.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: DISPUTED AETIOLOGY AND OTHER