Effects of XX-catalysts on quantum annealing spectra with perturbative crossings

In adiabatic quantum annealing the required run-time to reach a given ground-state fidelity is dictated by the size of the minimum gap that appears between the ground and first excited state in the annealing spectrum. In general the presence of avoided level crossings demands an exponential increase in the annealing time with the system size which has consequences both for the efficiency of the algorithm and the required qubit coherence times. One promising avenue being explored to produce more favourable gap scaling is the introduction of non-stoquastic XX-couplings in the form of a catalyst - of particular interest are catalysts which utilise accessible information about the optimisation problem in their construction. Here we show extreme sensitivity of the effect of an XX-catalyst to subtle changes in the encoding of the optimisation problem. In particular, we observe that a targeted catalyst containing a single coupling at constant strength can significantly reduce the gap closing with system size at an avoided level crossing. For slightly different encodings of the same problems however, these same catalysts result in closing gaps in the annealing spectrum. To understand the origin of these closing gaps, we study how the evolution of the ground-state vector is altered by the presence of the catalyst and find that the negative components of the ground-state vector are key to understanding the response of the gap spectrum. We also consider how and when these closing gaps could be utilised in diabatic quantum annealing protocols - a promising alternative to adiabatic quantum annealing in which transitions to higher energy levels are exploited to reduce the run time of the algorithm.Comment: 19 pages, 13 figure

Social determinants of ethnic disparities in SARS-CoV-2 infection: UK Biobank SARS-CoV-2 Serology Study

Background: The social determinants of ethnic disparities in risk of SARS-CoV-2 infection during the first wave of the pandemic in the UK remain unclear. Methods: In May 2020, a total of 20 195 adults were recruited from the general population into the UK Biobank SARS-CoV-2 Serology Study. Between mid-May and mid-November 2020, participants provided monthly blood samples. At the end of the study, participants completed a questionnaire on social factors during different periods of the pandemic. Logistic regression yielded ORs for the association between ethnicity and SARS-CoV-2 immunoglobulin G antibodies (indicating prior infection) using blood samples collected in July 2020, immediately after the first wave. Results: After exclusions, 14 571 participants (mean age 56; 58% women) returned a blood sample in July, of whom 997 (7%) had SARS-CoV-2 antibodies. Seropositivity was strongly related to ethnicity: compared with those of White ethnicity, ORs (adjusted for age and sex) for Black, South Asian, Chinese, Mixed and Other ethnic groups were 2.66 (95% CI 1.94–3.60), 1.66 (1.15–2.34), 0.99 (0.42–1.99), 1.42 (1.03–1.91) and 1.79 (1.27–2.47), respectively. Additional adjustment for social factors reduced the overall likelihood ratio statistics for ethnicity by two-thirds (67%; mostly from occupational factors and UK region of residence); more precise measurement of social factors may have further reduced the association. Conclusions: This study identifies social factors that are likely to account for much of the ethnic disparities in SARS-CoV-2 infection during the first wave in the UK, and highlights the particular relevance of occupation and residential region in the pathway between ethnicity and SARS-CoV-2 infection

“You just can’t do that in dementia care”: Barriers to partnership working within dementia services for people from South Asian communities

Background: People from South Asian communities are under-represented at all levels of dementia services. Consequently, there is pressure for the statutory sector to deliver services in partnership with Voluntary, Community, Faith and Social Enterprises (VCFSEs). This study set out to explore the constraints to effective partnership working which prevent dementia care from being delivered in an equitable way.Methods: Data collection consisted of two phases. First, we interviewed seven people with experience of partnership working and developed three fictional vignettes that were representative of the challenges they faced. We then used these vignettes to stimulate discussion in focus groups and interviews with 13 VCFSE and 16 statutory sector participants. Data was analysed using deductive thematic analysis.Findings: Three themes were developed during the analysis. First, White British-centric services focused on the challenges for statutory services in meeting the needs of South Asians, developing flexible, responsive services and making inclusive partnership working truly meaningful. Second, VCFSE participants (but not statutory service participants) associated a failure to deliver effective partnership working with unconscious bias operating within systems, leading to the devaluing of their expertise and to their views being ignored. Finally, participants emphasised the need to prioritise relationships if they were to meet the challenges of developing partnership working.Conclusion: We identified three constraints acting to prevent effective partnership working. First, the different meanings that statutory and VCFSE participants attach to challenges threatens their ability to develop a shared understanding of the needs of communities. Second, a reluctance to explicitly address service deficiencies can mean that stereotypes remain unaddressed. Finally, while both parties lacked power to change the fundamentals of service delivery, power and resources were also unbalanced with VCSFE services being more reliant on the statutory sector

Persistence of SARS-CoV-2 antibodies over 18 months following infection: UK Biobank COVID-19 Serology Study

Background Little is known about the persistence of antibodies after the first year following SARS-CoV-2 infection. We aimed to determine the proportion of individuals that maintain detectable levels of SARS-CoV-2 antibodies over an 18-month period following infection. Methods Population-based prospective study of 20 000 UK Biobank participants and their adult relatives recruited in May 2020. The proportion of SARS-CoV-2 cases testing positive for immunoglobulin G (IgG) antibodies against the spike protein (IgG-S), and the nucleocapsid protein (IgG-N), was calculated at varying intervals following infection. Results Overall, 20 195 participants were recruited. Their median age was 56 years (IQR 39–68), 56% were female and 88% were of white ethnicity. The proportion of SARS-CoV-2 cases with IgG-S antibodies following infection remained high (92%, 95% CI 90%–93%) at 6 months after infection. Levels of IgG-N antibodies following infection gradually decreased from 92% (95% CI 88%–95%) at 3 months to 72% (95% CI 70%–75%) at 18 months. There was no strong evidence of heterogeneity in antibody persistence by age, sex, ethnicity or socioeconomic deprivation. Conclusion This study adds to the limited evidence on the long-term persistence of antibodies following SARS-CoV-2 infection, with likely implications for waning immunity following infection and the use of IgG-N in population surveys

From Children to Adults: Motor Performance across the Life-Span

The life-span approach to development provides a theoretical framework to examine the general principles of life-long development. This study aims to investigate motor performance across the life span. It also aims to investigate if the correlations between motor tasks increase with aging. A cross-sectional design was used to describe the effects of aging on motor performance across age groups representing individuals from childhood to young adult to old age. Five different motor tasks were used to study changes in motor performance within 338 participants (7–79 yrs). Results showed that motor performance increases from childhood (7–9) to young adulthood (19–25) and decreases from young adulthood (19–25) to old age (66–80). These results are mirroring results from cognitive research. Correlation increased with increasing age between two fine motor tasks and two gross motor tasks. We suggest that the findings might be explained, in part, by the structural changes that have been reported to occur in the developing and aging brain and that the theory of Neural Darwinism can be used as a framework to explain why these changes occur

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

Reversal of NA+-K+ pump inhibition in the failing heart

Abnormally raised cytosolic Na+ concentration in cardiac myocytes is a nodal point of multiple interacting abnormalities that perpetuate the heart failure syndrome. Understanding regulation of the Na+-K+ pump in the context of heart failure (HF) is therefore necessary for the development of successful therapies for a syndrome that currently has no curative treatment. This thesis investigated a novel mechanism of oxidative regulation of the Na+-K+ pump in a rabbit model of HF, whether this mechanism is associated with the efficacy of current treatments of HF, and its potential as a therapeutic target. Clinical efficacy of βAR blockade remains a paradox in HF treatment, however data presented in this thesis strongly suggests that reversal of oxidative inhibition of the Na+-K+ pump is a mechanism of β1AR blockade. A β3AR agonist shown to increase function of the Na+-K+ pump in vitro, also demonstrated reversal of oxidative inhibition of the Na+-K+ pump and significantly improved clinical indices such as pulmonary congestion. An additive clinical benefit of combined β1AR blockade and β3AR agonism was not observed. Data from this thesis has lead in part to the commencement of a Phase II clinical trial; Beta 3 Agonist Treatment in Heart Failure (Beat-HF) ClinicalTrials.gov Identifier: NCT01876433

What is the optimum design for my animal experiment?

Within preclinical research, attention has focused on experimental design and how current practices can lead to poor reproducibility. There are numerous decision points when designing experiments. Ethically, when working with animals we need to conduct a harm–benefit analysis to ensure the animal use is justified for the scientific gain. Experiments should be robust, not use more or fewer animals than necessary, and truly add to the knowledge base of science. Using case studies to explore these decision points, we consider how individual experiments can be designed in several different ways. We use the Experimental Design Assistant (EDA) graphical summary of each experiment to visualise the design differences and then consider the strengths and weaknesses of each design. Through this format, we explore key and topical experimental design issues such as pseudo-replication, blocking, covariates, sex bias, inference space, standardisation fallacy and factorial designs. There are numerous articles discussing these critical issues in the literature, but here we bring together these topics and explore them using real-world examples allowing the implications of the choice of design to be considered. Fundamentally, there is no perfect experiment; choices must be made which will have an impact on the conclusions that can be drawn. We need to understand the limitations of an experiment’s design and when we report the experiments, we need to share the caveats that inherently exist