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Enriched Marine Oil Supplements Increase Peripheral Blood Specialized Pro-Resolving Mediators Concentrations and Reprogram Host Immune Responses: A Randomized Double-Blind Placebo-Controlled Study.
Souza, PR, Marques, RM, Gomez, EA, Colas, RA, De Matteis, R, Zak, A, Patel, M, Collier, DJ, Dalli, J
Circulation research. 2020;126(1):75-90
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Specialized pro-resolving mediators (SPM) are derived from essential fatty acids and promote resolution of inflammation. The main aim of this study was to establish the relationship(s) between supplement dose, peripheral blood SPM concentrations, and cellular responses using a novel enriched marine oil preparation. This study is a double-blind, randomized, crossover, dose escalation placebo-controlled study in healthy volunteers. Participants (n=22) were randomised to one of eight groups. Results show supplementation with refined marine oils lead to a rapid upregulation of peripheral blood SPM concentrations and reprograming of peripheral blood cell responses to sterile and infectious stimuli, changes that were found to persist after SPM concentrations returned to baseline. Authors conclude that enriched marine oil supplementation leads to a dose-and time-dependent increase of plasma SPM concentrations.
Abstract
RATIONALE Specialized pro-resolving mediators (SPM-lipoxins, resolvins, protectins, and maresins) are produced via the enzymatic conversion of essential fatty acids, including the omega-3 fatty acids docosahexaenoic acid and n-3 docosapentaenoic acid. These mediators exert potent leukocyte directed actions and control vascular inflammation. Supplementation of animals and humans with essential fatty acids, in particular omega-3 fatty acids, exerts protective actions reducing vascular and systemic inflammation. Of note, the mechanism(s) activated by these supplements in exerting their protective actions remain poorly understood. OBJECTIVE Given that essential fatty acids are precursors in the biosynthesises of SPM, the aim of the present study was to establish the relationship between supplementation and peripheral SPM concentrations. We also investigated the relationship between changes in plasma SPM concentrations and peripheral blood platelet and leukocyte responses. METHODS AND RESULTS Healthy volunteers were enrolled in a double-blinded, placebo-controlled, crossover study, and peripheral blood was collected at baseline, 2, 4, 6, and 24 hours post administration of placebo or one of 3 doses of an enriched marine oil supplement. Assessment of plasma SPM concentrations using lipid mediator profiling demonstrated a time- and dose-dependent increase in peripheral blood SPM concentration. Supplementation also led to a regulation of peripheral blood cell responses. Here we found a dose-dependent increase in neutrophil and monocyte phagocytosis of bacteria and a decrease in the diurnal activation of leukocytes and platelets, as measured by a reduction in adhesion molecule expression. In addition, transcriptomic analysis of peripheral blood cells demonstrated a marked change in transcript levels of immune and metabolic genes 24 hours post supplementation when compared with placebo. CONCLUSIONS Together, these findings demonstrate that supplementation with an enriched marine oil leads to an increase in peripheral blood SPM concentrations and reprograms peripheral blood cells, indicating a role for SPM in mediating the immune-directed actions of this supplement. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT03347006.
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The effect of optimised patient information materials on recruitment in a lung cancer screening trial: an embedded randomised recruitment trial.
Parker, A, Knapp, P, Treweek, S, Madhurasinghe, V, Littleford, R, Gallant, S, Sullivan, F, Schembri, S, Rick, J, Graffy, J, et al
Trials. 2018;(1):503
Abstract
BACKGROUND Written participant information materials are important for ensuring that potential trial participants receive necessary information so that they can provide informed consent. However, such materials are frequently long and complex, which may negatively impact patient understanding and willingness to participate. Improving readability, ease of comprehension and presentation may assist with improved participant recruitment. The Systematic Techniques for Assisting Recruitment to Trials (MRC START) study aimed to develop and evaluate interventions to improve trial recruitment. This study aimed to assess the effectiveness of an optimised participant information brochure and cover letter developed by MRC START regarding response and participant recruitment rates. METHODS We conducted a study within a trial (SWAT) embedded in the EarlyCDT Lung Cancer Scotland (ECLS) trial that aimed to assess the effectiveness of a new test in reducing the incidence of patients with late-stage lung cancer at diagnosis compared with standard care. Potential participants approached for ECLS were randomised to receive the original participant information brochure and accompanying letter (control group) or optimised versions of these materials which had undergone user testing and a process of re-writing, re-organisation and professional graphic design (intervention group). The primary outcome was the number of patients recruited to ECLS. The secondary outcome was the proportion of patients expressing an interest in participating in ECLS. RESULTS In total, 2262 patients were randomised, 1136 of whom were sent the intervention materials and 1126 of whom were sent the control materials. The proportion of patients enrolled and randomised into ECLS was 180 of 1136 (15.8%) in the intervention group and 176 of 1126 (15.6%) in the control group (OR = 1.016, 95% CI, 0.660 to 1.564). The proportion of patients who positively responded to the invitation was 224 of 1136 (19.7%) in the intervention group and 205 of 1126 (18.2%) in the control group (OR = 1.103, 95% CI, 0.778 to 1.565). CONCLUSIONS Optimised patient information materials made little difference to the proportion of patients positively responding to a trial invitation or to the proportion subsequently randomised to the host trial. TRIAL REGISTRATION ClinicalTrials.gov, NCT01925625 . Registered on 15 August 2015. Study Within A Trial, SWAT-23. Registered on 12 April 2016.
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Network analysis reveals distinct clinical syndromes underlying acute mountain sickness.
Hall, DP, MacCormick, IJ, Phythian-Adams, AT, Rzechorzek, NM, Hope-Jones, D, Cosens, S, Jackson, S, Bates, MG, Collier, DJ, Hume, DA, et al
PloS one. 2014;(1):e81229
Abstract
Acute mountain sickness (AMS) is a common problem among visitors at high altitude, and may progress to life-threatening pulmonary and cerebral oedema in a minority of cases. International consensus defines AMS as a constellation of subjective, non-specific symptoms. Specifically, headache, sleep disturbance, fatigue and dizziness are given equal diagnostic weighting. Different pathophysiological mechanisms are now thought to underlie headache and sleep disturbance during acute exposure to high altitude. Hence, these symptoms may not belong together as a single syndrome. Using a novel visual analogue scale (VAS), we sought to undertake a systematic exploration of the symptomatology of AMS using an unbiased, data-driven approach originally designed for analysis of gene expression. Symptom scores were collected from 292 subjects during 1110 subject-days at altitudes between 3650 m and 5200 m on Apex expeditions to Bolivia and Kilimanjaro. Three distinct patterns of symptoms were consistently identified. Although fatigue is a ubiquitous finding, sleep disturbance and headache are each commonly reported without the other. The commonest pattern of symptoms was sleep disturbance and fatigue, with little or no headache. In subjects reporting severe headache, 40% did not report sleep disturbance. Sleep disturbance correlates poorly with other symptoms of AMS (Mean Spearman correlation 0.25). These results challenge the accepted paradigm that AMS is a single disease process and describe at least two distinct syndromes following acute ascent to high altitude. This approach to analysing symptom patterns has potential utility in other clinical syndromes.
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Impact of atorvastatin among older and younger patients in the Anglo-Scandinavian Cardiac Outcomes Trial Lipid-Lowering Arm.
Collier, DJ, Poulter, NR, Dahlöf, B, Sever, PS, Wedel, H, Buch, J, Caulfield, MJ, ,
Journal of hypertension. 2011;(3):592-9
Abstract
OBJECTIVE Older patients experience higher rates of cardiovascular disease than younger patients, but may be undertreated with statins due to doubts about efficacy and safety. The Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial allowed an evaluation of the efficacy and safety of atorvastatin among older (≥ 65 years) and younger (<65 years) patients with hypertension. METHODS A total of 10 305 patients with hypertension, at least three other cardiovascular risk factors, total cholesterol concentrations of 251 mg/dl or less, and no known coronary heart disease (CHD) were randomized to receive atorvastatin 10 mg or placebo. The primary endpoint was a composite of nonfatal myocardial infarction and fatal CHD. RESULTS There were 4445 patients in the older group (mean 71 years) and 5860 patients (mean 57 years) in the younger group. Among those taking placebo, the older group experienced a higher rate of primary endpoints than the younger group (11.7 vs. 7.6 events per 1000 patient years, respectively). After a median follow-up of 3.3 years, the primary endpoint was reduced by a similar proportion in both older and younger patients (37 vs. 33%, respectively). Although older patients reported more serious adverse events than younger patients, there were no significant differences between atorvastatin and placebo within each age group. CONCLUSION Atorvastatin reduced the risk of major cardiovascular events to a similar relative extent in both older and younger patients with treated hypertension. However, given that event rates were higher in older patients, the absolute benefits of atorvastatin were greater for older than younger patients.
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Symptoms of infection and acute mountain sickness; associated metabolic sequelae and problems in differential diagnosis.
Bailey, DM, Davies, B, Castell, LM, Collier, DJ, Milledge, JS, Hullin, DA, Seddon, PS, Young, IS
High altitude medicine & biology. 2003;(3):319-31
Abstract
Infections and acute mountain sickness (AMS) are common at high altitude, yet their precise etiologies remain elusive and the potential for differential diagnosis is considerable. The present study was therefore designed to compare clinical nonspecific symptoms associated with these pathologies and basic changes in free radical and amino-acid metabolism. Nineteen males were examined at rest and after maximal exercise at sea level before (SL(1)/SL(2)) and following a 20 +/- 5 day ascent to Kanchenjunga base camp located at 5100 m (HA). Four subjects with symptoms consistent with an ongoing respiratory and recent gastrointestinal infection were also diagnosed with clinical AMS on the evening of day 1 at HA. These and six other subjects recovering from symptoms consistent with a respiratory infection presented with a greater increase (HA minus SL(1)) in AMS scores and resting venous concentration of lipid hydroperoxides (LH) and in total creatine phosphokinase and ratio of free tryptophan/branched chain amino acids, and greater decrease in glutamine (Gln) compared to healthy controls (n = 9, p < 0.05). The decrease in Gln was consistently related to the altitude/exercise-induced increase in LH (r = -0.69/r = -0.45; p < 0.05) and altitude-induced increase in myoglobin (r = -0.73, p < 0.05). These findings highlight the potential for the misdiagnosis of altitude illness due to the similarity of nonspecific constitutional symptoms associated with infection and AMS. Both conditions were characterized by parallel changes in peripheral biomarkers related to free-radical, skeletal muscle damage and amino acid metabolism. While clearly not establishing cause and effect, free radical-mediated changes in peripheral amino acid metabolism known to influence immune and cerebral serotoninergic function may enhance susceptibility to and/or delay recovery from altitude illness.