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 × 10 10 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 10 10 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 t...

Background: Patients with some types of immunodeficiency can experience chronic or relapsing infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This leads to morbidity and mortality, infection control challenges, and the risk of evolution of novel viral variants. The optimal treatment for chronic coronavirus disease 2019 (COVID-19) is unknown. Objective: Our aim was to characterize a cohort of patients with chronic or relapsing COVID-19 disease and record treatment response. Methods: We conducted a UK physician survey to collect data on underlying diagnosis and demographics, clinical features, and treatment response of immunodeficient patients with chronic (lasting > _21 days) or relapsing (> _2 episodes) of COVID-19. Results: We identified 31 patients (median age 49 years). Their underlying immunodeficiency was most commonly characterized by antibody deficiency with absent or profoundly reduced peripheral B-cell levels; prior anti-CD20 therapy, and X-linked agammaglobulinemia. Their clinical features of COVID-19 were similar to those of the general population, but their median duration of symptomatic disease was 64 days (maximum 300 days) and individual patients experienced up to 5 episodes of illness. Remdesivir monotherapy (including when given for prolonged courses of < _20 days) was associated with sustained viral clearance in 7 of 23 clinical episodes (30.4%), whereas the combination of remdesivir with convalescent plasma or anti-SARS-CoV-2 mAbs resulted in viral clearance in 13 of 14 episodes (92.8%). Patients receiving no therapy did not clear SARS-CoV-2. Conclusions: COVID-19 can present as a chronic or relapsing disease in patients with antibody deficiency. Remdesivir monotherapy is frequently associated with treatment failure, but the combination of remdesivir with antibody-based therapeutics holds promise. (J Allergy Clin Immunol 2021;nnn:nnn-nnn.)

Background Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19.Methods A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK, between 19 th June to 28 th October 2020. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0.1-10.0mg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20).Findings 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p<0.001), ranging from 8% (3/39; 0.1mg) to 61% (14/23; 10.0mg) in ELISA and 46% (18/39; 0.3mg) to 87% (20/23; 5.0mg and 10.0mg) in a post-hoc immunoblot assay. Geometric mean (GM) anti-S IgG concentrations ranged from 74 (95% CI, 45-119) at 0.1mg to 1023 (468-2236) ng/mL at 5.0mg (p<0.001) and was not higher at 10.0mg. Neutralisation of SARS-CoV-2 by participant sera was measurable in 15% (6/39; 0.1mg) to 48% (11/23; 5.0mg) depending on dose level received.Interpretation Encapsulated saRNA is safe for clinical development, is immunogenic at low dose levels but failed to induce 100% seroconversion. Modifications to optimise humoral responses are required to realise its potential as an effective vaccine against SARS-CoV-2.

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Background: The effects of ethnic and social inequalities on patient outcomes in acute healthcare remain poorly understood. Methods: Prospectively-defined analysis of registry data from four acute NHS hospitals in east London including all patients ≥ 18 years with a first emergency admission between 1st January 2013 and 31st December 2018. We calculated adjusted one-year mortality risk using logistic regression. Results are presented as n (%), median (IQR), and odds ratios (OR) with 95% confidence intervals. Findings: We included 203,182 patients. 43,101 (21%) patients described themselves as Asian, 21,388 (10.5%) Black, 2,982 (1.4%) Mixed, 13,946 (6.8%) Other ethnicity, and 100,065 (49%) White. We excluded 21,700 (10.7%) patients with undisclosed ethnicity. 16,054 (7.9%) patients died within one year. Non-white patients were younger (Asian: 43 [31–62] years; Black: 48 [33–63] years; Mixed 36 [26–52] years) than White patients (55 [35–75] years), with a higher incidence of comorbid disease. In each age-group, non-white patients were more likely to be admitted to hospital. This effect was greatest in the ≥ 80 years age-group (32% non-white admitted to hospital versus 23% non-white in community population). Deprivation was associated with increased mortality in all ethnic groups (OR 1.41 [1.33–1.50]; p < 0.001). However, when adjusted for age, Asian (0.69 [0.66–0.73], p < 0.0001) and Black patients (0.79 [0.74–0.85]; p < 0.0001) experienced a lower mortality risk than White patients. Interpretation: Ethnic and social disparities are associated with important differences in acute health outcomes. However, these differences are masked by statistical adjustment because patients from ethnic minorities present at a younger age. Funding: None

Background Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. Methods Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. Results In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77–82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. Conclusions Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin.

A rapid rise in diagnosis of acute kidney injury (AKI) has been observed in the UK and worldwide. It is unclear whether this reflects true growth in incidence or improved detection. To investigate this, aggregate data from Hospital Episode Statistics database on all admissions to National Health Service (NHS) hospitals in England 1998/1999 to 2019/2020 were used to extract the number of AKI diagnoses in different age groups and compare them to diseases of similar incidence (pneumonia, heart failure, dementia) based on ICD-10 coding. Haemofiltration procedures were used as proxy for acute kidney replacement therapy (KRT) in a critical care setting. Temporal trends in usage of AKI-specific ICD-10 codes were examined. A total of 356 million inpatient episodes of care over 22 years were analysed. Between 1998/1999 and 2019/2020, primary AKI diagnoses increased from 1.2 to 5.3 per thousand finished consultant episodes. From 2012/2013, when first recorded, secondary diagnoses doubled from 22.8 to 43.2 per thousand finished consultant episodes. The rate of growth in AKI was significantly greater than that of dementia, but not pneumonia or heart failure. The proportion of acute KRT procedures to total AKI diagnoses decreased. This could suggest that the substantial increase in AKI cases observed within NHS in the last two decades is a result of improved detection and coding, particularly of mild cases. In 2019/2020, 96% of AKI cases were encoded as N17.9 (Acute renal failure, unspecified), despite 11 other codes being available. We believe that adoption of clinically orientated coding could facilitate further improvements in detection with benefits for clinical practice and research.

This article provides an overview of current use of robotics in hip and knee arthroplasty. Several studies have reported radiographic improvements in joint alignment using robotic-assisted arthroplasty surgery. The economic case made for introducing robotics in joint arthroplasty largely focuses on the hypothesis of reduced hospital stay and reduction in the rate of revisions. This awaits robust data from long-term studies along with the documentation of clinical benefits that will follow the larger implementation of robotic-assisted surgery. However, modern robotic systems offer an opportunity for reproducible implementation of a preoperative plan, with low complication rates. Growing clinical use may in future present robust data demonstrating an appreciable clinical benefit that justifies the large scale clinical use of robotic technology.