Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors

Background: Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. We compared standard practice in the UK with shorter inter-donation intervals used in other countries. Methods: In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants. Findings: 45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99·5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1·69 units (95% CI 1·59–1·80; approximately 795 mL) in the 8-week group and by 0·79 units (0·69–0·88; approximately 370 mL) in the 10-week group (p<0·0001 for both). In women, compared with the 16-week group, it increased by 0·84 units (95% CI 0·76–0·91; approximately 395 mL) in the 12-week group and by 0·46 units (0·39–0·53; approximately 215 mL) in the 14-week group (p<0·0001 for both). No significant differences were observed in quality of life, physical activity, or cognitive function across randomised groups. However, more frequent donation resulted in more donation-related symptoms (eg, tiredness, breathlessness, feeling faint, dizziness, and restless legs, especially among men [for all listed symptoms]), lower mean haemoglobin and ferritin concentrations, and more deferrals for low haemoglobin (p<0·0001 for each) than those observed in the standard frequency groups. Interpretation: Over 2 years, more frequent donation than is standard practice in the UK collected substantially more blood without having a major effect on donors' quality of life, physical activity, or cognitive function, but resulted in more donation-related symptoms, deferrals, and iron deficiency. Funding: NHS Blood and Transplant, National Institute for Health Research, UK Medical Research Council, and British Heart Foundation

Evolutionary Pathways of the Pandemic Influenza A (H1N1) 2009 in the UK

The emergence of the influenza (H1N1) 2009 virus provided a unique opportunity to study the evolution of a pandemic virus following its introduction into the human population. Virological and clinical surveillance in the UK were comprehensive during the first and second waves of the pandemic in 2009, with extensive laboratory confirmation of infection allowing a detailed sampling of representative circulating viruses. We sequenced the complete coding region of the haemagglutinin (HA) segment of 685 H1N1 pandemic viruses selected without bias during two waves of pandemic in the UK (April-December 2009). Phylogenetic analysis showed that although temporal accumulation of amino acid changes was observed in the HA sequences, the overall diversity was less than that typically seen for seasonal influenza A H1N1 or H3N2. There was co-circulation of multiple variants as characterised by signature amino acid changes in the HA. A specific substitution (S203T) became predominant both in UK and global isolates. No antigenic drift occurred during 2009 as viruses with greater than four-fold reduction in their haemagglutination inhibition (HI) titre (“low reactors”) were detected in a low proportion (3%) and occurred sporadically. Although some limited antigenic divergence in viruses with four-fold reduction in HI titre might be related to the presence of 203T, additional studies are needed to test this hypothesis

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

History, Commemoration, and Belief: Abraham Lincoln in American Memory, 1945-2001

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91765/1/Schuman-History_Commemoration_Belief.pd

Longer-term efficiency and safety of increasing the frequency of whole blood donation (INTERVAL): extension study of a randomised trial of 20 757 blood donors

Background: The INTERVAL trial showed that, over a 2-year period, inter-donation intervals for whole blood donation can be safely reduced to meet blood shortages. We extended the INTERVAL trial for a further 2 years to evaluate the longer-term risks and benefits of varying inter-donation intervals, and to compare routine versus more intensive reminders to help donors keep appointments. Methods: The INTERVAL trial was a parallel group, pragmatic, randomised trial that recruited blood donors aged 18 years or older from 25 static donor centres of NHS Blood and Transplant across England, UK. Here we report on the prespecified analyses after 4 years of follow-up. Participants were whole blood donors who agreed to continue trial participation on their originally allocated inter-donation intervals (men: 12, 10, and 8 weeks; women: 16, 14, and 12 weeks). They were further block-randomised (1:1) to routine versus more intensive reminders using computer-generated random sequences. The prespecified primary outcome was units of blood collected per year analysed in the intention-to-treat population. Secondary outcomes related to safety were quality of life, self-reported symptoms potentially related to donation, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin and other factors. This trial is registered with ISRCTN, number ISRCTN24760606, and has completed. Findings: Between Oct 19, 2014, and May 3, 2016, 20 757 of the 38 035 invited blood donors (10 843 [58%] men, 9914 [51%] women) participated in the extension study. 10 378 (50%) were randomly assigned to routine reminders and 10 379 (50%) were randomly assigned to more intensive reminders. Median follow-up was 1·1 years (IQR 0·7–1·3). Compared with routine reminders, more intensive reminders increased blood collection by a mean of 0·11 units per year (95% CI 0·04–0·17; p=0·0003) in men and 0·06 units per year (0·01–0·11; p=0·0094) in women. During the extension study, each week shorter inter-donation interval increased blood collection by a mean of 0·23 units per year (0·21–0·25) in men and 0·14 units per year (0·12–0·15) in women (both p<0·0001). More frequent donation resulted in more deferrals for low haemoglobin (odds ratio per week shorter inter-donation interval 1·19 [95% CI 1·15–1·22] in men and 1·10 [1·06–1·14] in women), and lower mean haemoglobin (difference per week shorter inter-donation interval −0·84 g/L [95% CI −0·99 to −0·70] in men and −0·45 g/L [–0·59 to −0·31] in women) and ferritin concentrations (percentage difference per week shorter inter-donation interval −6·5% [95% CI −7·6 to −5·5] in men and −5·3% [–6·5 to −4·2] in women; all p<0·0001). No differences were observed in quality of life, serious adverse events, or self-reported symptoms (p>0.0001 for tests of linear trend by inter-donation intervals) other than a higher reported frequency of doctor-diagnosed low iron concentrations and prescription of iron supplements in men (p<0·0001). Interpretation: During a period of up to 4 years, shorter inter-donation intervals and more intensive reminders resulted in more blood being collected without a detectable effect on donors' mental and physical wellbeing. However, donors had decreased haemoglobin concentrations and more self-reported symptoms compared with the initial 2 years of the trial. Our findings suggest that blood collection services could safely use shorter donation intervals and more intensive reminders to meet shortages, for donors who maintain adequate haemoglobin concentrations and iron stores. Funding: NHS Blood and Transplant, UK National Institute for Health Research, UK Medical Research Council, and British Heart Foundation

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression