15 research outputs found
Glucuronidation by UGT1A1 Is the Dominant Pathway of the Metabolic Disposition of Belinostat in Liver Cancer Patients
10.1371/journal.pone.0054522PLoS ONE81
Targeting epigenetic pathways in acute myeloid leukemia and myelodysplastic syndrome: a systematic review of hypomethylating agents trials
Model-based adaptive phase I trial design of post-transplant decitabine maintenance in myelodysplastic syndrome
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
PET Scans for Staging and Restaging in Diffuse Large B-Cell and Follicular Lymphomas
Positron emission tomography (PET)-CT was recommended in updated international guidelines for staging/restaging of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). In FL, PET was previously regarded as a research application only. This review concentrates on new publications related to PET in these diseases. In DLBCL, PET appears appropriate for staging using prognostic indices established with CT and baseline PET parameters, e.g. metabolic tumour volume, are prognostic of outcome. Early complete metabolic response (CMR) predicts end-of-treatment CMR with excellent prognosis. Patients without CMR at interim should not have treatment altered, but have a worse prognosis, and patients with other high risk features may need closer monitoring. The end-of-treatment scan is confirmed as the standard for remission assessment using Deauville criteria, which are also predictive for patients undergoing ASCT. In FL, PET is more sensitive for staging than CT but misses bone marrow involvement. PET-CT identifies patients at risk of progression after induction chemotherapy better than CT
What Is eHealth (6): Perspectives on the Evolution of eHealth Research
BACKGROUND: The field of eHealth holds promise for supporting and enabling health behavior change and the prevention and management of chronic disease. OBJECTIVE: In order to establish areas of congruence and controversy among contributors to the early development, evaluation, and dissemination of eHealth applications, as well as the desire to inform an evaluation research funding agenda, 38 semistructured, qualitative interviews were conducted among stakeholders in eHealth between May 2002 and September 2003. METHODS: Participants were asked about their perspectives on the credibility, value, and future potential of information technology for health behavior change and chronic disease management. Interviews were coded and analyzed for emergent themes using qualitative methods. RESULTS: Consistent themes were identified across stakeholder groups, with slight differences in emphasis. These topics included the following: (1) consensus and standardization—most stakeholders expressed a strong desire for a more coordinated, rigorous effort to define and integrate the field; (2) evaluation methods and challenges—demonstrating outcomes is required to establish eHealth quality and efficacy, but stakeholders were not satisfied with the sensitivity, validity, and reliability of existing outcome measures; (3) quality, value, and future potential—the intersection between eHealth’s potential cost-effectiveness, efficiency, and improved clinical status among users generated a high degree of interest; and (4) health disparities—many stakeholders contended that traditionally underserved populations will particularly benefit from eHealth applications, although others argued that the underserved are also disadvantaged in terms of access to technology. CONCLUSIONS: Recommendations included the need for improvement and formalization of development and evaluation standards across private and public sectors, additional research on the technology needs and preferences of traditionally underserved populations, and long-term epidemiologic studies of the impact of eHealth on outcomes and cost-effectiveness