The Impact of Temporal Geopotential Variations on GPS

Lemoine et al. (2006) and Lemoine et al. (2010) showed that applying more detailed models of time-variable gravity (TVG) improved the quality of the altimeter satellite orbits (e.g. TOPEX/Poseidon, Jason-1, Jason-2). This modeling include application of atmospheric gravity derived from 6-hrly pressure fields obtained from the ECMWF and annual gravity variations to degree & order 20x20 in spherical harmonics derived from GRACE data. This approach allowed the development of a consistent geophysical model for application to altimeter satellite orbit determination from 1993 to 2011. In addition, we have also evaluated the impact of TVG modeling on the POD of Jason-1 and Jason-2 by application of a weekly degree & order four gravity coefficient time series developed using data from ten SLR & DORIS-tracked satellites from 1993 to 2011 (Lemoine et al., 2011)

Conversation therapy with people with aphasia and conversation partners using video feedback: a group and case series investigation of changes in interaction

Conversation therapies employing video for feedback and to facilitate outcome measurement are increasingly used with people with post-stroke aphasia and their conversation partners; however the evidence base for change in everyday interaction remains limited. We investigated the effect of Better Conversations with Aphasia (BCA), an intervention that is freely available online at https://extend.ucl.ac.uk/. Eight people with chronic agrammatic aphasia, and their regular conversation partners participated in the tailored 8 week program involving significant video feedback. We explored changes in: (i) conversation facilitators (such as multi-modal turns by people with aphasia); and (ii) conversation barriers (such as use of test questions by conversation partners). The outcome of intervention was evaluated directly by measuring change in video-recorded everyday conversations. The study employed a pre-post design with multiple 5 minute samples of conversation before and after intervention, scored by trained raters blind to the point of data collection. Group level analysis showed no significant increase in conversation facilitators. There was, however, a significant reduction in the number of conversation barriers. The case series data revealed variability in conversation behaviors across occasions for the same dyad and between different dyads. Specifically, post-intervention there was a significant increase in facilitator behaviors for two dyads, a decrease for one and no significant change for five dyads. There was a significant decrease in barrier behaviors for five dyads and no significant change for three dyads. The reduction in barrier behaviors was considerable; on average change from over eight to fewer than three barrier behaviors in 5 minutes of conversation. The pre-post design has the limitation of no comparison group. However, change occurs in targeted conversational behaviors and in people with chronic aphasia and their partners. The findings suggest change can occur after eight therapy sessions and have implications for clinical practice. A reduction in barrier behaviors may be easier to obtain, although the controlled case series results demonstrate a significant increase in conversation facilitators is also possible. The rehabilitation tool is available online and video technology was central to delivering intervention and evaluating change

Design and results of the ice sheet model initialisation experiments initMIP-Greenland: an ISMIP6 intercomparison

Earlier large-scale Greenland ice sheet sea-level projections (e.g. those run during the ice2sea and SeaRISE initiatives) have shown that ice sheet initial conditions have a large effect on the projections and give rise to important uncertainties. The goal of this initMIP-Greenland intercomparison exercise is to compare, evaluate, and improve the initialisation techniques used in the ice sheet modelling community and to estimate the associated uncertainties in modelled mass changes. initMIP-Greenland is the first in a series of ice sheet model intercomparison activities within ISMIP6 (the Ice Sheet Model Intercomparison Project for CMIP6), which is the primary activity within the Coupled Model Intercomparison Project Phase 6 (CMIP6) focusing on the ice sheets. Two experiments for the large-scale Greenland ice sheet have been designed to allow intercomparison between participating models of (1) the initial present-day state of the ice sheet and (2) the response in two idealised forward experiments. The forward experiments serve to evaluate the initialisation in terms of model drift (forward run without additional forcing) and in response to a large perturbation (prescribed surface mass balance anomaly); they should not be interpreted as sea-level projections. We present and discuss results that highlight the diversity of data sets, boundary conditions, and initialisation techniques used in the community to generate initial states of the Greenland ice sheet. We find good agreement across the ensemble for the dynamic response to surface mass balance changes in areas where the simulated ice sheets overlap but differences arising from the initial size of the ice sheet. The model drift in the control experiment is reduced for models that participated in earlier intercomparison exercises

Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study

Background: Locally advanced/recurrent head and neck squamous cell carcinoma (HNSCC) is associated with significant morbidity and mortality. To target upregulated ErbB dimer expression in this cancer, we developed an autologous CD28-based chimeric antigen receptor T-cell (CAR-T) approach named T4 immunotherapy. Patient-derived T-cells are engineered by retroviral transduction to coexpress a panErbB-specific CAR called T1E28ζ and an IL-4-responsive chimeric cytokine receptor, 4αβ, which allows IL-4-mediated enrichment of transduced cells during manufacture. These cells elicit preclinical antitumor activity against HNSCC and other carcinomas. In this trial, we used intratumoral delivery to mitigate significant clinical risk of on-target off-tumor toxicity owing to low-level ErbB expression in healthy tissues. // Methods: We undertook a phase 1 dose-escalation 3+3 trial of intratumoral T4 immunotherapy in HNSCC (NCT01818323). CAR T-cell batches were manufactured from 40 to 130 mL of whole blood using a 2-week semiclosed process. A single CAR T-cell treatment, formulated as a fresh product in 1–4 mL of medium, was injected into one or more target lesions. Dose of CAR T-cells was escalated in 5 cohorts from 1×107−1×109 T4+ T-cells, administered without prior lymphodepletion. // Results: Despite baseline lymphopenia in most enrolled subjects, the target cell dose was successfully manufactured in all cases, yielding up to 7.5 billion T-cells (67.5±11.8% transduced), without any batch failures. Treatment-related adverse events were all grade 2 or less, with no dose-limiting toxicities (Common Terminology Criteria for Adverse Events V.4.0). Frequent treatment-related adverse events were tumor swelling, pain, pyrexias, chills, and fatigue. There was no evidence of leakage of T4+ T-cells into the circulation following intratumoral delivery, and injection of radiolabeled cells demonstrated intratumoral persistence. Despite rapid progression at trial entry, stabilization of disease (Response Evaluation Criteria in Solid Tumors V.1.1) was observed in 9 of 15 subjects (60%) at 6 weeks post-CAR T-cell administration. Subsequent treatment with pembrolizumab and T-VEC oncolytic virus achieved a rapid complete clinical response in one subject, which was durable for over 3 years. Median overall survival was greater than for historical controls. Disease stabilization was associated with the administration of an immunophenotypically fitter, less exhausted, T4 CAR T-cell product. // Conclusions: These data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC

CXCR2 Inhibition – a novel approach to treating CoronAry heart DiseAse (CICADA): study protocol for a randomised controlled trial

Abstract Background There is emerging evidence of the central role of neutrophils in both atherosclerotic plaque formation and rupture. Patients with lower neutrophil counts following acute coronary syndromes tend to have a greater coronary flow reserve, which is a strong predictor of long-term cardiovascular health. But so far, no data are available regarding the impact of neutrophil inhibition on cardiovascular clinical or surrogate endpoints. Therefore, the aim of this study is to investigate the effects of AZD5069, a cysteine-X-cysteine chemokine receptor 2 (CXCR2) inhibitor, on coronary flow reserve and coronary structure and function in patients with coronary artery disease. Methods/Design Ninety subjects with coronary artery disease undergoing percutaneous coronary intervention will be included in this investigator-driven, randomised, placebo-controlled, double-blind, phase IIa, single-centre study. Participants will be randomised to receive either AZD5069 (40 mg) administered orally twice daily or placebo for 24 weeks. Change in coronary flow reserve as determined by 13N-ammonia positron emission tomography-computed tomography will be the primary outcome. Change in the inflammatory component of coronary plaque structure and the backward expansion wave, an invasive coronary physiological measure of diastolic function, will be assessed as secondary outcomes. Discussion Cardiovascular surrogate parameters, such as coronary flow reserve, may provide insights into the potential mechanisms of the cardiovascular effects of CXCR2 inhibitors. Currently, ongoing trials do not specifically focus on neutrophil function as a target of intervention, and we therefore believe that our study will contribute to a better understanding of the role of neutrophil-mediated inflammation in coronary artery disease. Trial registration EudraCT, 2016-000775-24 . Registered on 22 July 2016. International Standard Randomised Controlled Trial Number, ISRCTN48328178 . Registered on 25 February 2016

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

Epidemiological dynamics of Mycobacterium bovis and population suppression in badgers (Meles meles)

Bovine TB in cattle is a major economic problem in the UK, costing the government approximately £100m a year. Badgers are a wildlife host of the infection that causes bovine TB, and there is strong evidence that they transmit the infection to cattle. Understanding the ecology and epidemiology of infected badger populations is therefore crucial for implementing disease management strategies relating to badgers. Genetic and phenotypic data of badgers captured during a large-scale field trial of repeated, widespread badger culls were used to assess the importance of parental roles on the impacts of badger culling. Further ecological and epidemiological dynamics were investigated through developing a stochastic simulation model of an infected badger population. An estimated 72.8% of badgers were captured during initial culls of the trial, and an estimated 57.8% during follow-up culls, based on badger parentage assignments. Further analyses of these parentage assignments revealed evidence of a genetic predisposition in infection susceptibility from parents to cubs, but no evidence of a significant infection transmission route from mothers to their young, dependent cubs. There was also no evidence that badger welfare was compromised during the trial through not capturing dependent cubs of culled mothers. Analysis of a simulation model found that moderate levels of disease-induced mortality in an infected badger population could significantly reduce the size of badger social groups with a higher prevalence of infection. The impact of these findings relating to potential disease management strategies is discussed, together with suggested directions for future research.Open Acces