423 research outputs found
Initial 4D seismic results after CO 2 injection start-up at the Aquistore storage site
The first post-CO2-injection 3D time-lapse seismic survey was conducted at the Aquistore CO2 storage site in February 2016 using the same permanent array of buried geophones used for acquisition of three previous pre-CO2-injection surveys from March 2012 to November 2013. By February 2016, 36 kilotons of CO2 have been injected within the reservoir between 3170 and 3370 m depth. We have developed time-lapse results from analysis of the first post-CO2-injection data and three pre-CO2-injection data sets. The objective of our analysis was to evaluate the ability of the permanent array to detect the injected CO2. A ā4D-friendly simultaneousā processing flow was applied to the data in an effort to maximize the repeatability between the pre- and post-CO2-injection volumes while optimizing the final subsurface image including the reservoir. Excellent repeatability was achieved among all surveys with global normalized root-mean-square (Gnrms) values of 1.13ā1.19 for the raw prestack data relative to the baseline data, which decreased during processing to Gnrms values of approximately 0.10 for the final crossequalized migrated data volumes. A zone of high normalized root-mean-square (nrms) values (0.11ā0.25 as compared with background values of 0.05ā0.10) is identified within the upper Deadwood unit of the storage reservoir, which likely corresponds to approximately 18 kilotons of CO2. No significant nrms anomalies are observed within the other reservoir units due to a combination of reduced seismic sensitivity, higher background nrms values, and/or small quantities of CO2 residing within these zones
Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per Ī¼L: secondary outcome results from a randomised controlled trial.
BACKGROUND: The effects of antiretroviral therapy on risk of severe bacterial infections in people with high CD4 cell counts have not been well described. In this study, we aimed to quantify the effects of immediate versus deferred ART on the risk of severe bacterial infection in people with high CD4 cell counts in a preplanned analysis of the START trial.
METHODS: The START trial was a randomised controlled trial in ART-naive HIV-positive patients with CD4 cell count of more than 500 cells per Ī¼L assigned to immediate ART or deferral until their CD4 cell counts were lower than 350 cells per Ī¼L. We used Cox proportional hazards regression to model time to severe bacterial infection, which was defined as a composite endpoint of bacterial pneumonia (confirmed by the endpoint review committee), pulmonary or extrapulmonary tuberculosis, or any bacterial infectious disorder of grade 4 severity, that required unscheduled hospital admissions, or caused death. This study is registered with ClinicalTrials.gov, number NCT00867048.
FINDINGS: Patients were recruited from April 15, 2009, to Dec 23, 2013. The data cutoff for follow-up was May 26, 2015. Of 4685 HIV-positive people enrolled, 120 had severe bacterial infections (immediate-initiation group n=34, deferred-initiation group n=86; median 2Ā·8 years of follow-up). Immediate ART was associated with a reduced risk of severe bacterial infection compared with deferred ART (hazard ratio [HR] 0Ā·39, 95% CI 0Ā·26-0Ā·57, p
INTERPRETATION: Immediate ART reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count. This is partly explained by ART-induced increases in CD4 cell count, but not by increases in neutrophil count.
FUNDING: National Institute of Allergy and Infectious Diseases National Institutes of Health, Agence Nationale de Recherches sur le SIDA et les HĆ©patites Virales, Bundesministerium fĆ¼r Bildung und Forschung, European AIDS Treatment Network, Australian National Health and Medical Research Council, UK National Institute for Health Research and Medical Research Council, Danish National Research Foundation
Kinome and Transcriptome Profiling Reveal Broad and Distinct Activities of Erlotinib, Sunitinib, and Sorafenib in the Mouse Heart and Suggest Cardiotoxicity From Combined Signal Transducer and Activator of Transcription and Epidermal Growth Factor Receptor Inhibition
BACKGROUND: Most novel cancer therapeutics target kinases that are essential to tumor survival. Some of these kinase inhibitors are associated with cardiotoxicity, whereas others appear to be cardiosafe. The basis for this distinction is unclear, as are the molecular effects of kinase inhibitors in the heart.
METHODS AND RESULTS: We administered clinically relevant doses of sorafenib, sunitinib (cardiotoxic multitargeted kinase inhibitors), or erlotinib (a cardiosafe epidermal growth factor receptor inhibitor) to mice daily for 2Ā weeks. We then compared the effects of these 3 kinase inhibitors on the cardiac transcriptome using RNAseq and the cardiac kinome using multiplexed inhibitor beads coupled with mass spectrometry. We found unexpectedly broad molecular effects of all 3 kinase inhibitors, suggesting that target kinase selectivity does not define either the molecular response or the potential for cardiotoxicity. Using inĀ vivo drug administration and primary cardiomyocyte culture, we also show that the cardiosafety of erlotinib treatment may result from upregulation of the cardioprotective signal transducer and activator of transcription 3 pathway, as co-treatment with erlotinib and a signal transducer and activator of transcription inhibitor decreases cardiac contractile function and cardiomyocyte fatty acid oxidation.
CONCLUSIONS: Collectively our findings indicate that preclinical kinome and transcriptome profiling may predict the cardiotoxicity of novel kinase inhibitors, and suggest caution for the proposed therapeutic strategy of combined signal transducer and activator of transcription/epidermal growth factor receptor inhibition for cancer treatment
Clinical Research in Resource-Limited Settings: Enhancing Research Capacity and Working Together to Make Trials Less Complicated
Accelerating clinical development of a live attenuated vaccine against Salmonella Paratyphi A (VASP): study protocol for an observer-participant-blind randomised control trial of a novel oral vaccine using a human challenge model of Salmonella Paratyphi A infection in healthy adult volunteers
Introduction:Ā This is the first efficacy study of an oral live attenuated vaccine againstĀ SalmonellaĀ Paratyphi A using a human challenge model of paratyphoid infection.Ā S. Paratyphi A is responsible for 3.3 million cases of enteric fever every year, with over 19 000 deaths. Although improvements to sanitation and access to clean water are vital to reduce the burden of this condition, vaccination offers a cost-effective, medium-term solution. Efficacy trials of potentialĀ S. Paratyphi vaccine candidates in the field are unlikely to be feasible given the large number of participants required. Human challenge models therefore offer a unique, cost-effective solution to test efficacy of such vaccines.
Methods and analysis:Ā This is an observer-blind, randomised, placebo-controlled trial phase I/II of the oral live-attenuated vaccine againstĀ S. Paratyphi A, CVD 1902. Volunteers will be randomised 1:1 to receive two doses of CVD 1902 or placebo, 14 days apart. One month following second vaccination all volunteers will ingestĀ S. Paratyphi A bacteria with a bicarbonate buffer solution. They will be reviewed daily in the following 14 days and diagnosed with paratyphoid infection if the predefined microbiological or clinical diagnostic criteria are met. All participants will be treated with antibiotics on diagnosis, or at day 14 postchallenge if not diagnosed. The vaccine efficacy will be determined by comparing the relative attack rate, that is, the proportion of those diagnosed with paratyphoid infection, in the vaccine and placebo groups.
Ethics and dissemination:Ā Ethical approval for this study has been obtained from the Berkshire Medical Research Ethics Committee (REC ref 21/SC/0330). The results will be disseminated via publication in a peer-reviewed journal and presentation at international conferences.
Trial registration number:Ā ISRCTN15485902
Chemical exchange saturation transfer MRI in central nervous system tumours on a 1.5 T MR-Linac
Purpose: To describe the implementation and initial results of using Chemical Exchange Saturation Transfer (CEST) for monitoring patients with central nervous system (CNS) tumours treated using a 1.5 tesla MR-guided radiotherapy system. Methods: CNS patients were treated with up to 30 fractions (total dose up to 60 Gy) using a 1.5 T Elekta Unity MR-Linac. CEST scans were obtained in 54 subjects at one or more time points during treatment. CEST metrics, including the amide magnetization transfer ratio (MTRAmide), nuclear Overhauser effect (NOE) MTR (MTRNOE) and asymmetry, were quantified in phantoms and CNS patients. The signal was investigated between tumour and white matter, across time, and across disease categories including high- and low-grade tumours. Results: The gross tumour volume (GTV) exhibited lower MTRAmide and MTRNOE and higher asymmetry compared to contralateral normal appearing white matter. Signal changes in the GTV during fractionated radiotherapy were observed. There were differences between high- and low-grade tumours, with higher CEST asymmetry associated with higher grade disease. Conclusion: CEST MRI using a 1.5 T MR-Linac was demonstrated to be feasible for in vivo imaging of CNS tumours. CEST images showed tumour/white-matter contrast, temporal CEST signal changes, and associations with tumour grade. These results show promise for the eventual goal of using metabolic imaging to inform the design of adaptive radiotherapy protocols
Understanding the treatment benefit of hyperimmune anti-influenza intravenous immunoglobulin (Flu-IVIG) for severe human influenza
Background: Antibody-based therapies for respiratory viruses are of increasing importance. The INSIGHT 006 trial administered anti-influenza hyperimmune intravenous immunoglobulin (Flu-IVIG) to patients hospitalized with influenza. Flu-IVIG treatment improved outcomes in patients with influenza B but showed no benefit for influenza A.
Methods: To probe potential mechanisms of Flu-IVIG utility, sera collected from patients hospitalized with influenza A or B viruses (IAV or IBV) were analyzed for antibody isotype/subclass and FcĪ³ receptor (FcĪ³R) binding by ELISA, bead-based multiplex, and NK cell activation assays.
Results: Influenza-specific FcĪ³R-binding antibodies were elevated in Flu-IVIGāinfused IBV- and IAV-infected patients. In IBV-infected participants (n = 62), increased IgG3 and FcĪ³R binding were associated with more favorable outcomes. Flu-IVIG therapy also improved the odds of a more favorable outcome in patients with low levels of anti-IBV Fc-functional antibody. Higher FcĪ³R-binding antibody was associated with less favorable outcomes in IAV-infected patients (n = 50), and Flu-IVIG worsened the odds of a favorable outcome in participants with low levels of anti-IAV Fc-functional antibody.
Conclusion: These detailed serological analyses provide insights into antibody features and mechanisms required for a successful humoral response against influenza, suggesting that IBV-specific, but not IAV-specific, antibodies with Fc-mediated functions may assist in improving influenza outcome. This work will inform development of improved influenza immunotherapies
A pragmatic, multicentre, randomised controlled trial comparing stapled haemorrhoidopexy to traditional excisional surgery for haemorrhoidal disease (eTHoS): study protocol for a randomised controlled trial
Background: Current interventions for haemorrhoidal disease include traditional haemorrhoidectomy (TH) and
stapled haemorrhoidopexy (SH) surgery. However, uncertainty remains as to how they compare from a clinical,
quality of life (QoL) and economic perspective. The study is therefore designed to determine whether SH is more
effective and more cost-effective, compared with TH.
Methods/Design: eTHoS (either Traditional Haemorrhoidectomy or Stapled Haemorrhoidopexy for Haemorrhoidal
Disease) is a pragmatic, multicentre, randomised controlled trial. Currently, 29 secondary care centres are open to
recruitment. Patients, aged 18 year or older, with circumferential haemorrhoids grade II to IV, are eligible to take part.
The primary clinical and economic outcomes are QoL profile (area under the curve derived from the EuroQol Groupās 5
Dimension Health Status Questionnaire (EQ-5D) at all assessment points) and incremental cost per quality adjusted life
year (QALY) based on the responses to the EQ-5D at 24 months. The secondary outcomes include a comparison of the
SF-36 scores, pain and symptoms sub-domains, disease recurrence, complication rates and direct and indirect costs
to the National Health Service (NHS). A sample size of n =338 per group has been calculated to provide 90% power
to detect a difference in the mean area under the curve (AUC) of 0.25 standard deviations derived from EQ-5D
score measurements, with a two-sided significance level of 5%. Allowing for non-response, 400 participants will
be randomised per group. Randomisation will utilise a minimisation algorithm that incorporates centre, grade of
haemorrhoidal disease, baseline EQ-5D score and gender. Blinding of participants and outcome assessors is not
attempted.
Discussion: This is one of the largest trials of its kind. In the United Kingdom alone, 29,000 operations for haemorrhoidal
disease are done annually. The trial is therefore designed to give robust evidence on which clinicians and health
service managers can base management decisions and, more importantly, patients can make informed choices.
Trial registration: Current Controlled Trials ISRCTN80061723 (assigned 8 March 2010
Response to the editorial by Dr Geraghty
This article is written in response to the linked editorial by Dr Geraghty about the adaptive Pacing, graded Activity and Cognitive behaviour therapy; a randomised Evaluation (PACE) trial, which we led, implemented and published. The PACE trial compared four treatments for people diagnosed with chronic fatigue syndrome. All participants in the trial received specialist medical care. The trial found that adding cognitive behaviour therapy or graded exercise therapy to specialist medical care was as safe as, and more effective than, adding adaptive pacing therapy or specialist medical care alone. Dr Geraghty has challenged these findings. In this article, we suggest that Dr Geraghtyās views are based on misunderstandings and misrepresentations of the PACE trial; these are corrected
Motivational Interviewing as an intervention to increase adolescent self-efficacy and promote weight loss: Methodology and design
<p>Abstract</p> <p>Background</p> <p>Childhood obesity is associated with serious physiological and psychological consequences including type 2 diabetes, higher rates of depression and low self-esteem. With the population of overweight and obese youth increasing, appropriate interventions are needed that speak to the issue of readiness to change and motivation to maintain adherence to healthy behavior changes. Motivational Interviewing (MI) is a method of therapy found to resolve ambivalence, enhance intrinsic motivation and promote confidence in a person's ability to make behavior changes. While MI has shown promise in the adult obesity literature as effecting positive lifestyle change, little is known about the effectiveness of MI with overweight and obese youth. This study aims to: 1) demonstrate that MI is an effective intervention for increasing a person's self-efficacy; 2) demonstrate that exposure to MI will facilitate healthy behavior changes; 3) explore psychological changes related to participation in MI and 4) compare physiological and anthropometric outcomes before and after intervention.</p> <p>Methods/Design</p> <p>The current investigation is a prospective study conducted with ongoing participants who regularly attend an outpatient pediatric care center for weight-loss. Overweight youth (BMI > 85<sup>th </sup>%ile) between the ages of 10 and 18 who meet eligibility criteria will be recruited. Participants will be randomly assigned to a control group (social skills training) or a treatment group (MI). Participants will meet with the therapist for approximately 30 minutes prior to seeing the dietician, over the course of 6 months. Participants will also undergo a full day assessment at the beginning and end of psychology intervention to evaluate body fat, and metabolic risk (screening for diabetes, high cholesterol, high blood pressure and fitness level). The paper and pencil portions of the assessments as well as the clinical testing will occur at baseline and at the conclusion of the intervention (6 months) with a repeat assessment 6 months following the completion of the intervention.</p> <p>Discussion</p> <p>Results from this study are expected to enhance our understanding of the efficacy of MI with children and adolescents who are overweight or obese.</p> <p>Trial registration</p> <p>Current Controlled Trials #<a href="http://www.clinicaltrials.gov/ct2/show/NCT00326404">NCT00326404</a>.</p
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