IntroductionThere is a lack of evidence that the benefits of screening for atrial fibrillation (AF) outweigh the harms. Following the completion of the Screening for Atrial Fibrillation with ECG to ...Reduce stroke (SAFER) pilot trial, the aim of the main SAFER trial is to establish whether population screening for AF reduces incidence of stroke risk.Methods and analysisApproximately 82 000 people aged 70 years and over and not on oral anticoagulation are being recruited from general practices in England. Patients on the palliative care register or residents in a nursing home are excluded. Eligible people are identified using electronic patient records from general practices and sent an invitation and consent form to participate by post. Consenting participants are randomised at a ratio of 2:1 (control:intervention) with clustering by household. Those randomised to the intervention arm are sent an information leaflet inviting them to participate in screening, which involves use of a handheld single-lead ECG four times a day for 3 weeks. ECG traces identified by an algorithm as possible AF are reviewed by cardiologists. Participants with AF are seen by a general practitioner for consideration of anticoagulation. The primary outcome is stroke. Major secondary outcomes are: death, major bleeding and cardiovascular events. Follow-up will be via electronic health records for an average of 4 years. The primary analysis will be by intention-to-treat using time-to-event modelling. Results from this trial will be combined with follow-up data from the cluster-randomised pilot trial by fixed-effects meta-analysis.Ethics and disseminationThe London—Central National Health Service Research Ethics Committee (19/LO/1597) provided ethical approval. Dissemination will include public-friendly summaries, reports and engagement with the UK National Screening Committee.Trial registration number ISRCTN72104369.
Vascular prevention trials typically use dichotomous event outcomes although this may be inefficient statistically and gives no indication of event severity. We assessed whether ordinal outcomes ...would be more efficient and how to best analyse them.
Chief investigators of vascular prevention randomised controlled trials that showed evidence of either benefit or harm, or were included in a systematic review that overall showed benefit or harm, shared individual participant data from their trials. Ordered categorical versions of vascular event outcomes (such as stroke and myocardial infarction) were analysed using 15 statistical techniques and their results then ranked, with the result with the smallest p-value given the smallest rank. Friedman and Duncan's multiple range tests were performed to assess differences between tests by comparing the average ranks for each statistical test.
Data from 35 trials (254,223 participants) were shared with the collaboration. 13 trials had more than two treatment arms, resulting in 59 comparisons. Analysis approaches (Mann Whitney U, ordinal logistic regression, multiple regression, bootstrapping) that used ordinal outcome data had a smaller average rank and therefore appeared to be more efficient statistically than those that analysed the original binary outcomes.
Ordinal vascular outcome measures appear to be more efficient statistically than binary outcomes and provide information on the severity of event. We suggest a potential role for using ordinal outcomes in vascular prevention trials.
In this study, we show that the hyaluronan synthase 1 (HAS1) gene undergoes aberrant intronic splicing in multiple myeloma (MM). In addition to HAS1 full length (HAS1FL), we identify 3 novel splice ...variants of HAS1, HAS1Va, HAS1Vb, and HAS1Vc, detected in patients with MM or monoclonal gammopathy of undetermined significance (MGUS). HAS1Vb and HAS1Vc undergo intronic splicing with creation of a premature stop codon. MM cells expressing one or more HAS1 variants synthesize extracellular and/or intracellular hyaluronan (HA). Expression of the HAS1Vb splice variant was significantly correlated with reduced survival (P = .001). Together, alternative HAS1 gene splicing, the correlations between HAS1 splicing and HA synthesis, and the correlations between HAS1 splicing and reduced survival of MM patients support the hypothesis that the family of HAS1 protein plays a significant role in disease progression. Further, expression of HAS1Vb, in conjunction with HAS1FL and/or other HAS1 variants, may lead to accumulation of intracellular HA molecules and an impact on receptor for HA-mediated motility (RHAMM)-mediated mitotic abnormalities in MM. This study highlights the potential importance of HAS1 and its alternative splicing in pathophysiology of MGUS and MM. (Blood. 2005;105: 4836-4844)
ISIS 104838 is a 20-mer phosphorothioate antisense oligonucleotide (ASO) that binds tumor necrosis factor-alpha (TNF-alpha) mRNA. It carries a 2'-methoxyethyl modification on the five 3' and 5' ...nucleotide sugars, with 10 central unmodified deoxynucleotides. ISIS 104838 was identified from a 264 ASO screen in phorbol myristate acetate-activated keratinocytes, and the dose response was assessed in lipopolysaccharide (LPS)-activated monocytes. Healthy males received multiple intravenous (i.v.) ISIS 104838 infusions in a placebo-controlled dose escalation trial (0.1-6 mg/kg). Additional volunteers received single or multiple subcutaneous (s.c.) injections. ISIS 104838 suppressed TNF-alpha protein by 85% in stimulated keratinocytes. The IC50 for TNF-alpha mRNA inhibition in stimulated monocytes was <1 microM. For i.v., C(max) occurred at the end of infusion. The effective plasma half-life was 15 to 45 min at 0.1 to 0.5 mg/kg and 1 to 1.8 h for higher doses. The apparent terminal plasma elimination half-life approximated 25 days. Obese subjects had higher plasma levels following equivalent mg/kg doses. For s.c. injections, C(max) occurred at 2 to 4 h and was lower than with equivalent i.v. dosing. Plasma bioavailability compared with i.v. was 82% following a 200 mg/ml s.c. injection. Transient activated partial thromboplastin time prolongation occurred after i.v. infusions and minimally after s.c. injections. Two subjects experienced rash, one a reversible platelet decrease, and mild injection site tenderness was noted. TNF-alpha production by peripheral blood leukocytes, induced ex vivo by LPS, was decreased by ISIS 104838 (p < 0.01). ISIS 104838, a second-generation antisense oligonucleotide, was generally well tolerated intravenously and subcutaneously. The pharmacokinetics support an infrequent dosing interval. Inhibition of TNF-alpha production ex vivo was demonstrated.
Binding immunoglobulin protein (BiP) is a human endoplasmic reticulum-resident stress protein. In pre-clinical studies it has anti-inflammatory properties due to the induction of regulatory cells. ...This randomized placebo-controlled, dose ascending double blind phase I/IIA trial of BiP in patients with active RA, who had failed accepted therapies, had the primary objective of safety. Potential efficacy was measured by DAS28-ESR and changes in biomarkers.
Twenty-four patients with active RA who had failed one or more DMARDs were sequentially assigned to three groups each of eight patients randomly allocated to receive placebo (two patients) or BiP (six patients), 1, 5 or 15 mg. Patients received a single i.v. infusion over 1 h and were observed as inpatients overnight. A 12-week follow-up for clinical, rheumatological and laboratory assessments for safety, efficacy (DAS28-ESR) and biomarker analysis was performed.
No infusion reactions or serious adverse drug reactions were noted. Adverse events were evenly distributed between placebo and BiP groups with no BiP-related toxicities. Haematological, renal and metabolic parameters showed no drug-related toxicities. Remission was only achieved by patients in the 5 and 15 mg groups, and not patients who received placebo or 1 mg BiP. Good DAS28-ESR responses were achieved in all treatment groups. The BiP responding patients showed significantly lower serum concentrations of CRP, 2 weeks post-infusion compared with pre-infusion levels, and of VEGF and IL-8 from the placebo group.
BiP (⩽15 mg) is safe in patients with active RA. Some patients had clinical and biological improvements in RA activity. BiP merits further study.
ISRCTN registry, http://isrctn.com, ISRCTN22288225 and EudraCT, https://eudract.ema.europa.eu, 2011-005831-19.
Consensus following a literature review and open conference on the value of self measurement of blood pressure in detecting hypertension. The advantages and disadvantages associated with self ...monitoring are tabulated, and consideration given to its role in reducing blood pressure and improving long term control. Differences between home and clinic readings are discussed. (BNI unique abstract) 37 references
Rheumatoid arthritis (RA) is an autoimmune disease which causes significant pain, joint deformity, functional disability. The pathological hallmark of RA is inflammation of the synovium characterized ...by involvement of inflammatory and resident stromal cells, soluble mediators and signalling pathways leading to irreversible joint destruction. The treatment goal in RA has evolved over the last decade towards a target of disease remission that is achieved in less than a third of patients in clinical trials. The lack of therapeutic response to current treatments is suggestive of alternative drivers of RA pathogenesis that might serve as promising therapeutic targets. There are data to justify the use of synovial tissue in early drug development. Synovial tissue represents an appropriate compartment to be studied in patients with inflammatory arthritis and provides information that is distinct from peripheral blood. Modern techniques have made the procedure much more accessible and ultrasound guided biopsies represent a safe and acceptable option. Advances in analytic technologies allowing transcriptomic level of analysis can provide unique inside to target organ/tissue following the exposure to investigational medicinal product. However, there are still caveats with regard to both the choice of technique and analytical methods. Therefore the significance of synovial biopsy remains to be determined in future clinical trials. The aim of the current debate is to explore the potential for accessing and evaluating synovial tissue in early drug development, to summarize lessons we have learned from clinical trials and to discuss the challenges that have arisen so far.
Abstract Introduction Prasugrel, a P2Y12 adenosine diphosphate (ADP) receptor antagonist effectively inhibits ADP-mediated platelet activation and aggregation, and may be useful in reducing ...vaso-occlusive crises in sickle cell disease (SCD). In this study, we assess the effect of prasugrel on biomarkers of platelet activation and coagulation in patients with SCD. Materials and Methods Twelve adult patients with SCD and 13 healthy subjects were examined before and after 12 ± 2 days of 5.0 or 7.5 mg/day oral prasugrel. Assessed cellular biomarkers included monocyte- and neutrophil-platelet aggregates, activated glycoprotein IIb-IIIa (GPIIbIIIa), P-selectin, CD40 ligand (CD40L), tissue factor (TF) expression on circulating platelets and on monocyte-platelet aggregates, and platelet-erythrocyte aggregates. Soluble biomarkers included CD40L, prothrombin fragment 1.2 (F1.2), thromboxane B2 (TXB2 ), P-selectin, and TF. Results Patients with SCD had increased platelet baseline activation compared to healthy subjects, as measured by percentages of monocyte-platelet aggregates, neutrophil-platelet aggregates, and platelets expressing CD40L. Likewise, baseline levels of soluble F1.2 and TXB2 were elevated in patients with SCD compared to healthy subjects. After 12 days of prasugrel, patients with SCD had a significant reduction in platelet-monocyte aggregates that was not observed in healthy subjects. Following prasugrel administration, those with SCD maintained higher levels of monocyte-platelet aggregates and soluble F1.2, but had lower levels of platelet-erythrocyte aggregates and soluble TF compared to healthy subjects. Conclusions These results provide evidence for chronic platelet activation in the SCD steady state, activation that was in part attenuated by prasugrel, thereby suggesting that ADP may mediate platelet activation in SCD.
Initial immune investigations revealed a distinctive phenotype of a high CD4/CD8 ratio (10:1) with low numbers of CD8+ T cells (0.29 x 109/L) and normal immunoglobulins (see Table E1 in this ...article's Online Repository at www.jacionline.org). Because of the child's poor clinical response to conventional treatment, continued deterioration in respiratory function, skin ulcers, abnormal immune function, and family history, she underwent a stem cell transplantation for an undefined immunodeficiency. Appendix Subset Pretransplant Posttransplant Reference range Lymphocytes (x109/L) 4.2 3.7 1-5 T-cell enumeration CD4 (x109/L) 3.0 1.2 0.4-2.1 CD8 (x109/L) 0.29 0.9 0.2-1.2 CD4/CD8 ratio 10 1.3 1-3.6 Naive CD4 (% of CD4+ T cells) 72 53 25-55 Naive CD8 (% of CD8+ T cells) 88 11 10-50 TCR Vβ expression 82 86 >70% T-cell function Unstimulated (cpm) 261low * 288dagger 1,435low */376dagger Anti-CD3 (cpm) 5,638low * 136.617dagger 158,306low */201,034dagger Anti-CD3 + IL-2 (cpm) 477,291low * 261,708dagger 464,012low */280,034dagger PMA (cpm) 7,003low * 125,751dagger 299,981low */114,851dagger PMA + ionophore (cpm) 380,870low * 177,818dagger 291,281low */182,116dagger PHA (cpm) 146,845low * 270,906dagger 259,052low */271,222dagger ConA (cpm) 316,114low * 227,533dagger 256,313low */178,131dagger NK-cell enumeration (% NK cells) NK cells (x109/L) 0.13 0.8 0.07-1.2 CD56bright NK cells (% NK cells) 46 7 1-10 Triple KIR/NKG2A+ NK cells 43 <2 <2 Cognate MHC-KIR+ NK cells <2 37 ND Table E1 Lymphocyte phenotype and in vitro proliferative responses at pretransplantation and posttransplantation time points Con A, Concanavalin A; cpm, counts per minute; ND, not determined; PHA, phorbol 12-myristate 13-acetate.
BACKGROUND: Predicted increases in stream temperature due to climate change will have a number of direct and indirect impacts on stream biota. A potential intervention for mitigating stream ...temperature rise is the use of wooded riparian zones to increase shade and reduce direct warming through solar radiation. To assess the effectiveness of this intervention, we conducted a systematic review of the available evidence for the effects of wooded riparian zones on stream temperature. METHODS: We searched literature databases and conducted relevant web searches. Inclusion criteria were: subject - any stream in a temperate climate; intervention - presence of trees in the riparian zone; comparator - absence of trees in the riparian zone; outcome measure - stream temperature. Included studies were sorted into 3 groups based on the scale of the intervention and design of the study. Two groups were taken forward for synthesis; Group 1 studies comparing water temperature in streams with and without buffer strips/riparian cover and Group 2 comparisons of stream temperatures in open and forested landscapes. Temperature data were extracted and quantitative synthesis performed using a random effects meta-analysis on the differences in mean and maximum temperature. RESULTS: Ten studies were included in each of Groups 1 and 2. Results for both groups suggest that riparian wooded zones lower spring and summer stream temperatures. Lowering of maximum is greater than lowering of mean temperature. Further analysis of environmental variables that might modify the effects of the intervention was not possible using the limited set of studies. CONCLUSIONS: Wooded riparian zones can reduce stream temperatures, particularly in terms of maximum temperatures. Because temperature is known to affect fish, amphibian and invertebrate life history, the reported effect sizes are likely to have a biological significance for the stream biotic community. Consequently investment in creation of wooded riparian zones might provide benefits in terms of mitigating some of the ecological effects of climate change on water temperature. Considerable uncertainty lies in the environmental variables that may modify the cooling effect of wooded riparian zones, and therefore it is not possible to identify when the use of this intervention for cooling would be most valuable.
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