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 and Purpose The aim of our study was to investigate plasma and genetic risk factors for rupture of cerebral aneurysms.Methods In London, a case-control study was made of 56 consecutive patients admitted to a regional neurosurgical service for treatment of ruptured cerebral aneurysm and of 93 control subjects. A further 40 consecutive patients admitted in Arhus with ruptured cerebral aneurysm also were studied.Results The British case-control study showed that smoking was associated with an increased risk of ruptured cerebral aneurysm (odds ratio, 9.1; 95% confidence interval [CI], 3.4 to 23.8; P<.001 for a history of >10 pack years). After age and sex adjustment, factors associated with ruptured cerebral aneurysm included a cholesterol concentration in the highest tertile (^6.3 mmol/L; odds ratio, 10.2; 95% CI, 3.9 to 26.7; P<.001), an apolipoprotein B concentration in the highest tertile (a0.84 g/L; odds ratio, 6.4; 95% CI, 2.5 to 16.3; / > <.001), and concentrations of HDL cholesterol in the lowest tertile (<1.1 mmol/L; odds ratio, 3.6; 95% CI, 1.4 to 8.2; P<.01). History of hypertension was of less importance (odds ratio, 4.0; 95% CI, 1.41 to 11.7; /><.01). Smoking history

α₁-Antitrypsin (α₁-AT) deficiency may play a role in arterial aneurysmal disease by allowing increased proteolysis of arterial structural proteins. α₁-AT levels are influenced by variation at the PI (protease inhibitor) locus. PI phenotypes were determined in 173 patients with abdominal aortic aneurysms (77 from Pitsburgh, 96 from London) and in 72 patients with intracranial aneurysms (26 from Pittsburgh, 46 from London). No excess of PI deficiency alleles was observed in either of the aortic aneurysm data sets or in the Pittsburgh intracranial aneurysm data. The PPZ deficiency allele frequency in the London intracranial aneurysm data was 8-fold higher than in controls; however, this was not significant after correcting for multiple comparisons. PI phenotype had no effect on aneurysm age-at-diagnosis within any of the data sets. Smoking history had an effect on aneurysm age-at-diagnosis only within the Pittsburgh intracranial-aneurysm data.

ObjectivesPilot feasibility randomised controlled trial (RCT) for the singing groups for people with aphasia (SPA) intervention to assess: (1) the acceptability and feasibility of participant recruitment, randomisation and allocation concealment; (2) retention rates; (3) variance of continuous outcome measures; (4) outcome measure completion and participant burden; (5) fidelity of intervention delivery; (6) SPA intervention costs; (7) acceptability and feasibility of trial and intervention to participants and others involved.DesignA two-group, assessor-blinded, randomised controlled external pilot trial with parallel mixed methods process evaluation and economic evaluation.SettingThree community-based cohorts in the South-West of England.ParticipantsEligible participants with post-stroke aphasia were randomised 1:1 to SPA or control.InterventionThe manualised SPA intervention was delivered over 10 weekly singing group sessions, led by a music facilitator and assisted by an individual with post-stroke aphasia. The intervention was developed using the Information-Motivation-Behavioural skills model of behaviour change and targeted psychosocial outcomes. Control and intervention participants all received an aphasia information resource pack.Outcome measuresCollected at baseline, 3 and 6 months post-randomisation, candidate primary outcomes were measured (well-being, quality of life and social participation) as well as additional clinical outcomes. Feasibility, acceptability and process outcomes included recruitment and retention rates, and measurement burden; and trial experiences were explored in qualitative interviews.ResultsOf 87 individuals screened, 42 participants were recruited and 41 randomised (SPA=20, control=21); 36 participants (SPA=17, control=19) completed 3-month follow-up, 34 (SPA=18, control=16) completed 6-month follow-up. Recruitment and retention (83%) were acceptable for a definitive RCT, and participants did not find the study requirements burdensome. High fidelity of the intervention delivery was shown by high attendance rates and facilitator adherence to the manual, and participants found SPA acceptable. Sample size estimates for a definitive RCT and primary/secondary outcomes were identified.ConclusionsThe SPA pilot RCT fulfilled its objectives, and demonstrated that a definitive RCT of the intervention would be both feasible and acceptable.Trial registration numberNCT03076736.

The reported familial clustering of abdominal aortic aneurysm (AAA) indicates the possible rewards of family-based screening programmes with respect both to the number of asymptomatic aneurysms detected and to identifying associated genes. Ultrasonographic screening of 28 families (25 brothers and 28 sisters) was carried out together with collecting a history and a blood sample for analysis of the cholesterol level and genetic markers. Among the screened siblings six (11 per cent), all > 60 years old, had an AAA > or = 3.0 cm in diameter. A further 11 siblings (21 per cent), six of whom were < 60 years old, had a wide (2.5-2.9 cm) aorta. The presence of an aneurysmal or wide aorta was significantly associated with smoking (P = 0.027), male sex (P = 0.008) and a proband age of < 60 years (P = 0.031). Polymorphic genetic markers for type III collagen and haptoglobin were not informative in these families. These results indicate that the efficiency of screening siblings of patients with AAA could be improved by limiting it to brothers with a smoking history and/or siblings of younger patients. The familial component appears to be greatest in these younger patients.