Ageing and Episodic Memory: Combining Neuropsychological and Event-Related Potential Approaches to Investigate Strategic Retrieval

This thesis investigates the effect of normal ageing on the strategies adopted during episodic memory retrieval, using a combination of neuropsychological profiling and neuroimaging data measured during performance on a source memory exclusion task. The exclusion task is a type of source memory task where participants distinguish between targets (studied items from one source e.g. female voice), non-targets (studied items from another source e.g. male voice) and new items. Unlike a source memory task where three separate buttons are pressed for each item at test, in the exclusion task one button is pressed for targets and a second for non-target and new items. As this task is more complex than a normal source memory paradigm and also allows participants to perform the task in more than one way, it places high emphasis on the use of strategies to facilitate retrieval and is therefore ideal for investigating strategic retrieval. Previous source memory studies have shown that while older adults are reasonably good at recognising whether items are old or new, they show marked impairments at remembering the source in which items were presented at study. Dual process theories propose that the age-related decline in source memory occurs because recollection becomes impaired with ageing whereas familiarity remains relatively spared. The results reported in this thesis support dual process theory. Experiment 2a showed that, behaviourally, as expected, the young outperformed the elderly. Event-related potentials (ERPs), recorded while a source memory exclusion test was performed, revealed that both young and older adults showed bilateral frontal and left parietal old/new effects, thought to index familiarity and recollection respectively. Importantly, the magnitude of the left parietal effect was significantly reduced in the older adults. The ERP findings also suggested that dual process theories represent an oversimplification of episodic memory decline with age. In Experiment 1a, three temporally and topographically distinct late frontal old/new effects were present in the younger adults: a bilateral anterior frontal effect (450-900ms post stimulus), a right prefrontal effect (900-1300ms) and a right frontal effect (1300-2000ms). Significant positive correlations between the magnitude of these effects and performance on neuropsychological tests of executive functioning in Experiment 1b, revealed that the bilateral anterior frontal effect was related to working memory, strategy use and planning; the right prefrontal effect was related to working memory and planning while the right frontal effect was related to planning. By contrast, the older adults in Experiment 2a only produced the right frontal effect, which correlated with planning across all three time windows in Experiment 2c. Post-retrieval monitoring in older adults therefore appeared to be qualitatively different than their younger counterparts. Performance on the neuropsychological tests in Experiment 2b, revealed that the older adults’ working memory and strategy use was impaired compared to the young, whereas planning was relatively intact, suggesting that age-related differences in post retrieval processing may be due to reduced executive functioning in older adults. Identifying distinct late frontal effects and demonstrating a relationship between these effects and specific executive functions is a novel finding. The presence of a left parietal target greater than non-target difference in the young adults from Experiment 1a and 2a was interpreted as the young reducing recollection of irrelevant non-target information. The modulation did not differ in magnitude for targets and non-targets in the elderly adults from Experiment 2a, suggesting they were less able to reduce activation of goal irrelevant non-target information. The results in the young adults from Experiment 1a also highlight the importance of considering the context of source information on the processes engaged at retrieval. The bilateral frontal effect was significant for the retrieval of the intrinsic context (source information inherent to the studied item), but not the extrinsic context (source information not inherent to the studied item). This finding was interpreted within a unitisation framework, where the intrinsic context became unitised with the item and enhanced familiarity based remembering. The findings also highlight that in order to fully understand post retrieval processing in both young and old adults, focus should move away from examining quantitative differences in the right frontal effect over long time periods and instead identify qualitatively distinct late frontal effects that may reflect the engagement of various executive functions over time

Guidelines for e-reference library services for distance learners and other remote users.

Until recently the provision of distance education was undertaken mainly by various professional associations and commercial agencies offering vocational training. Library provision to meet the needs of registered students was limited. Over the past 30 years, however, the delivery of higher and further education to students studying at a distance has become a core part of the activity of many academic institutions: a few specialist higher education institutions such as the Open Universities established in Britain and India, and some conventional universities that established teaching centres away from their main campuses

A RhoA-FRET Biosensor Mouse for Intravital Imaging in Normal Tissue Homeostasis and Disease Contexts.

The small GTPase RhoA is involved in a variety of fundamental processes in normal tissue. Spatiotemporal control of RhoA is thought to govern mechanosensing, growth, and motility of cells, while its deregulation is associated with disease development. Here, we describe the generation of a RhoA-fluorescence resonance energy transfer (FRET) biosensor mouse and its utility for monitoring real-time activity of RhoA in a variety of native tissues in vivo. We assess changes in RhoA activity during mechanosensing of osteocytes within the bone and during neutrophil migration. We also demonstrate spatiotemporal order of RhoA activity within crypt cells of the small intestine and during different stages of mammary gestation. Subsequently, we reveal co-option of RhoA activity in both invasive breast and pancreatic cancers, and we assess drug targeting in these disease settings, illustrating the potential for utilizing this mouse to study RhoA activity in vivo in real time

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Editorial - The NCRI Cancer Experiences Collaborative: defining self-management

Many people want an active role in managing problems associated with cancer and other potentially life limiting conditions as part of their daily lives. UK policy aims to enhance the practice of patient centred care, patient choice and patient involvement in care decisions and service development (Department of Health, 2006; Department of Health, 2005 Department of Health, National Service Framework for Long-term Conditions, Department of Health, London (2005).Department of Health, 2005; National Institute for Clinical Excellence, 2004) including people at the end of life (UK End of Life Care Strategy is in development). Policy initiatives also promote patients as experts in their own care and management (Department of Health, 2001) but there is little evidence regarding how best to support this, particularly in supportive and palliative care. A systematic literature review explored the empirical evidence of what people do to help themselves following a cancer diagnosis (Foster et al., 2005) and concluded that self-management is poorly defined and lacks a theoretical framework. Few studies specifically explore what patients do to help themselves, what enables them to do so, and how this can be supported. There is also insufficient evidence to determine whether helping people to help themselves live with cancer actually enhances their physical and psychological well being. Limited knowledge and approaches for helping patients to help themselves, commonly called ‘self-management’, indicates that attention should be directed at supporting individuals to manage problems associated with their illness themselves, even while dying. However, to achieve this, there is a need to enhance good quality research in supportive, palliative and end of life care and also increase the number of skilled researchers in this field

Fish shrinking, energy balance and climate change

International audienc