Decadal prediction of the North Atlantic subpolar gyre in the HiGEM high-resolution climate model

This paper presents an analysis of initialised decadal hindcasts of the North Atlantic subpolar gyre (SPG) using the HiGEM model, which has a nominal grid-spacing of 90 km in the atmosphere, and 1/3 ∘∘ in the ocean. HiGEM decadal predictions (HiGEM-DP) exhibit significant skill at capturing 0–500 m ocean heat content in the SPG, and outperform historically forced transient integrations and persistence for up to a decade ahead. An analysis of case-studies of North Atlantic decadal change, including the 1960s cooling, the mid-1990s warming, and the post-2005 cooling, show that changes in ocean circulation and heat transport dominate the predictions of the SPG. However, different processes are found to dominate heat content changes in different regions of the SPG. Specifically, ocean advection dominates in the east, but surface fluxes dominate in the west. Furthermore, compared to previous studies, we find a smaller role for ocean heat transport changes due to ocean circulation anomalies at the latitudes of the SPG, and, for the 1960s cooling, a greater role for surface fluxes. Finally, HiGEM-DP predicts the observed positive state of the North Atlantic Oscillation in the early 1990s. These results support an important role for the ocean in driving past changes in the North Atlantic region, and suggest that these changes were predictable

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Salmonella Typhi Vi capsule prime-boost vaccination induces convergent and functional antibody responses

Vaccine development to prevent Salmonella Typhi infections has accelerated over the past decade, resulting in licensure of new vaccines, which use the Vi polysaccharide (Vi PS) of the bacterium conjugated to an unrelated carrier protein as the active component. Antibodies elicited by these vaccines are important for mediating protection against typhoid fever. However, the characteristics of protective and functional Vi antibodies are unknown. In this study, we investigated the human antibody repertoire, avidity maturation, epitope specificity, and function after immunization with a single dose of Vi-tetanus toxoid conjugate vaccine (Vi-TT) and after a booster with plain Vi PS (Vi-PS). The Vi-TT prime induced an IgG1-dominant response, whereas the Vi-TT prime followed by the Vi-PS boost induced IgG1 and IgG2 antibody production. B cells from recipients who received both prime and boost showed evidence of convergence, with shared V gene usage and CDR3 characteristics. The detected Vi antibodies showed heterogeneous avidity ranging from 10 μM to 500 pM, with no evidence of affinity maturation after the boost. Vi-specific antibodies mediated Fc effector functions, which correlated with antibody dissociation kinetics but not with association kinetics. We identified antibodies induced by prime and boost vaccines that recognized subdominant epitopes, indicated by binding to the de–O-acetylated Vi backbone. These antibodies also mediated Fc-dependent functions, such as complement deposition and monocyte phagocytosis. Defining strategies on how to broaden epitope targeting for S. Typhi Vi and enriching for antibody Fc functions that protect against typhoid fever will advance the design of high-efficacy Vi vaccines for protection across diverse populations

Benefits and Limitations of an Employer-Led, Structured Logbook to Promote Self-Directed Learning in the Clinical Workplace

A structured logbook, consisting of a competency log and a learning contract, was designed and implemented as part of a two-week structured work placement for final-year veterinary students to help them become more self-directed in the workplace. The competency log encompassed 48 core skills and, along with the learning contract, was reviewed at the start and end of the placement. To assess their perceptions of the logbook in promoting self-directed learning, students and supervisors were asked to complete a questionnaire pre- and post-placement and to participate in focus groups (students) and interviews (supervisors) after the placement. The study found significant increases pre- to post-placement in students' perceived levels of competence in all 48 skills and their confidence in being self-directed. However, student attitudes toward the logbook significantly decreased in terms of it encouraging supervisors to take a clearly designed role in structuring learning and facilitating alignment of employer and student expectations. Although supervisors were generally positive about the logbook, some had not been able to review it with their students, which affected students' perceptions of the logbook's usefulness. Some supervisors felt they had not received enough training, and most, erroneously, believed the logbook to be an external research initiative rather than having been designed by the head of their own organization. This study demonstrated that a structured logbook may be useful in helping students become more self-directed; however, supervisor support for the logbook is critical. To facilitate this, supervisors require training and support from senior management

Putting the brakes on the brakes: negative emotion disrupts cognitive control network functioning and alters subsequent stopping ability

The ability to inhibit unwanted responses is critical for effective control of behavior, and inhibition failures can have disastrous consequences in real-world situations. Here, we examined how prior exposure to negative emotional stimuli affects the response-stopping network. Participants performed the stop-signal task, which relies on inhibitory control processes, after they viewed blocks of either negatively emotional or neutral images. In Experiment 1, we found that neural activity was reduced following negative image viewing. When participants were required to inhibit responding after neutral image viewing, we observed activation consistent with previous studies using the stop-signal task. However, when participants were required to inhibit responding after negative image viewing, we observed reductions in the activation of ventrolateral prefrontal cortex, dorsolateral prefrontal cortex, medial frontal cortex, and parietal cortex. Furthermore, analysis of neural connectivity during stop-signal task blocks indicated that across participants, emotion-induced changes in behavioral performance were associated with changes in functional connectivity, such that greater behavioral impairment after negative image viewing was associated with greater weakening of connectivity. In Experiment 2, we collected behavioral data from a larger sample of participants and found that stopping performance was impaired after negative image viewing, as seen in longer stop-signal reaction times. The present results demonstrate that negative emotional events can prospectively disrupt the neural network supporting response inhibition