Background Older age is the most powerful risk factor for adverse coronavirus disease-19 (COVID-19) outcomes. It is uncertain whether leucocyte telomere length (LTL), previously proposed as a marker ...of biological age, is also associated with COVID-19 outcomes.
Methods We associated LTL values obtained from participants recruited into UK Biobank (UKB) during 2006–2010 with adverse COVID-19 outcomes recorded by 30 November 2020, defined as a composite of any of the following: hospital admission, need for critical care, respiratory support, or mortality. Using information on 130 LTL-associated genetic variants, we conducted exploratory Mendelian randomisation (MR) analyses in UKB to evaluate whether observational associations might reflect cause-and-effect relationships.
Findings Of 6775 participants in UKB who tested positive for infection with SARS-CoV-2 in the community, there were 914 (13.5%) with adverse COVID-19 outcomes. The odds ratio (OR) for adverse COVID-19 outcomes was 1·17 (95% CI 1·05–1·30; P = 0·004) per 1-SD shorter usual LTL, after adjustment for age, sex and ethnicity. Similar ORs were observed in analyses that: adjusted for additional risk factors; disaggregated the composite outcome and reduced the scope for selection or collider bias. In MR analyses, the OR for adverse COVID-19 outcomes was directionally concordant but non-significant.
Interpretation Shorter LTL is associated with higher risk of adverse COVID-19 outcomes, independent of several major risk factors for COVID-19 including age. Further data are needed to determine whether this association reflects causality.
Funding UK Medical Research Council, Biotechnology and Biological Sciences Research Council and British Heart Foundation.
IntroductionAtrial fibrillation (AF) is a common arrhythmia associated with 30% of strokes, as well as other cardiovascular disease, dementia and death. AF meets many criteria for screening, but ...there is limited evidence that AF screening reduces stroke. Consequently, no countries recommend national screening programmes for AF. The Screening for Atrial Fibrillation with ECG to Reduce stroke (SAFER) trial aims to determine whether screening for AF is effective at reducing risk of stroke. The aim of the pilot study is to assess feasibility of the main trial and inform implementation of screening and trial procedures.Methods and analysisSAFER is planned to be a pragmatic randomised controlled trial (RCT) of over 100 000 participants aged 70 years and over, not on long-term anticoagulation therapy at baseline, with an average follow-up of 5 years. Participants are asked to record four traces every day for 3 weeks on a hand-held single-lead ECG device. Cardiologists remotely confirm episodes of AF identified by the device algorithm, and general practitioners follow-up with anticoagulation as appropriate. The pilot study is a cluster RCT in 36 UK general practices, randomised 2:1 control to intervention, recruiting approximately 12 600 participants. Pilot study outcomes include AF detection rate, anticoagulation uptake and other parameters to incorporate into sample size calculations for the main trial. Questionnaires sent to a sample of participants will assess impact of screening on psychological health. Process evaluation and qualitative studies will underpin implementation of screening during the main trial. An economic evaluation using the pilot data will confirm whether it is plausible that screening might be cost-effective.Ethics and disseminationThe London—Central Research Ethics Committee (19/LO/1597) and Confidentiality Advisory Group (19/CAG/0226) provided ethical approval. Dissemination will be via publications, patient-friendly summaries, reports and engagement with the UK National Screening Committee.Trial registration numberISRCTN72104369.
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.
Blood donors attending a donation session may be deferred from donating blood due to a failure to meet low hemoglobin (Hb) thresholds. This costs the blood donor service and donors valuable time and ...resources. In addition, donors who are deferred may have more symptoms, and as a direct and/or indirect effect of their experience, return rates of donors deferred for low Hb are reduced, even in repeat donors. It is therefore vital that low Hb deferral (LHD) is minimized. The aim of this updated systematic review is to expand the evidence base for factors which affect a donor's risk of deferral due to low Hb. Studies were identified by searching MEDLINE, Embase, The Cochrane Library, and the WHO International Clinical Trials Registry to March 2019. Demographic data, donor history, hematological/biological factors, and the primary outcome of deferral due to low Hb were extracted. Our primary outcome was deferral due to low Hb. Analyses were descriptive and quantitative; pooled odds ratios (ORs) and 95% confidence intervals (CIs) were obtained by meta-analysis using random-effects models. A total of 116 studies met the inclusion criteria. Meta-analysis showed a significantly greater risk of LHD in females compared with males in studies applying universal Hb thresholds for males and females (OR 14.62 95% CI 12.43-17.19) and in those which used sex-specific thresholds (OR 5.73, 95% CI 4.36-7.53). Higher rates of LHD were also associated with increasing age in men, low body weight, shorter interdonation interval, donors of Hispanic or African descent, higher ambient temperature, donors with low ferritin levels, and donation in a fixed donor center. There was conflicting evidence on the effect of new and repeat donor status, and blood group. This work has strengthened the evidence of the previous review in identifying factors that should be considered in studies of donor deferral and highlighting areas in need of further study, including ABO and Rh blood groups, previous platelet donation, diet, smoking, time of day, and genetic data. These factors may lead to individually tailored donation criteria for safe and efficient donation in the future.
•Evidence from 116 studies identifies factors associated with low hemoglobin deferral.•Risk of deferral increased in older male donors and those with lower body weight.•Hispanic or African donors at greater risk of deferral than white donors.•Higher risk of deferral occurs with shorter interval between blood donations.•Higher ambient temperature and donation site increase the risk of deferral.•Further evidence required for smoking, diet, blood group, and genetic factors.
Background
Frailty is a multidimensional syndrome of decline that affects multiple systems and predisposes to adverse health outcomes. Although chronological age is the major risk factor, ...inter‐individual variation in risk is not fully understood. Leucocyte telomere length (LTL), a proposed marker of biological age, has been associated with risk of many diseases. We sought to determine whether LTL is associated with risk of frailty.
Methods
We utilized cross‐sectional data from 441 781 UK Biobank participants (aged 40–69 years), with complete data on frailty indicators and LTL. Frailty was defined as the presence of at least three of five indicators: weaker grip strength, slower walking pace, weight loss in the past year, lower physical activity, and exhaustion in the past 2 weeks. LTL was measured using a validated qPCR method and reported as a ratio of the telomere repeat number (T) to a single‐copy gene (S) (T/S ratio). Association of LTL with frailty was evaluated using adjusted (chronological age, sex, deprivation, smoking, alcohol intake, body mass index, and multimorbidity) multinomial and ordinal regression models, and results are presented as relative risk (RRR) or odds ratios (OR), respectively, alongside the 95% confidence interval (CI). Mendelian randomization (MR), using 131 genetic variants associated with LTL, was used to assess if the association of LTL with frailty was causal.
Results
Frail participants (4.6%) were older (median age difference (95% CI): 3 (2.5; 3.5) years, P = 2.73 × 10−33), more likely to be female (61%, P = 1.97 × 10−129), and had shorter LTL (−0.13SD vs. 0.03SD, P = 5.43 × 10−111) than non‐frail. In adjusted analyses, both age and LTL were associated with frailty (RRR = 1.03 (95% CI: 1.02; 1.04) per year of older chronological age, P = 3.99 × 10−12; 1.10 (1.08; 1.11) per SD shorter LTL, P = 1.46 × 10−30). Within each age group (40–49, 50–59, 60–69 years), the prevalence of frailty was about 33% higher in participants with shorter (−2SD) versus longer telomeres (+2SD). MR analysis showed an association of LTL with frailty that was directionally consistent with the observational association, but not statistically significant (MR‐Median: OR (95% CI): 1.08 (0.98; 1.19) per SD shorter LTL, P = 0.13).
Conclusions
Inter‐individual variation in LTL is associated with the risk of frailty independently of chronological age and other risk factors. Our findings provide evidence for an additional biological determinant of frailty.
ObjectivesTo identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis.MethodsHere we conduct a genome-wide association study ...in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies.ResultsA locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10−9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures.ConclusionWe have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.
Vasovagal reactions (VVRs) are the most common acute complications of blood donation. Responsible for substantial morbidity, they also reduce the likelihood of repeated donations and are disruptive ...and costly for blood services. Although blood establishments worldwide have adopted different strategies to prevent VVRs (including water loading and applied muscle tension AMT), robust evidence is limited. The Strategies to Improve Donor Experiences (STRIDES) trial aims to reliably assess the impact of four different interventions to prevent VVRs among blood donors.
STRIDES is a cluster-randomised cross-over/stepped-wedge factorial trial of four interventions to reduce VVRs involving about 1.4 million whole blood donors enrolled from all 73 blood donation sites (mobile teams and donor centres) of National Health Service Blood and Transplant (NHSBT) in England. Each site ("cluster") has been randomly allocated to receive one or more interventions during a 36-month period, using principles of cross-over, stepped-wedge and factorial trial design to assign the sequence of interventions. Each of the four interventions is compared to NHSBT's current practices: (i) 500-ml isotonic drink before donation (vs current 500-ml plain water); (ii) 3-min rest on donation chair after donation (vs current 2 min); (iii) new modified AMT (vs current practice of AMT); and (iv) psychosocial intervention using preparatory materials (vs current practice of nothing). The primary outcome is the number of in-session VVRs with loss of consciousness (i.e. episodes involving loss of consciousness of any duration, with or without additional complications). Secondary outcomes include all in-session VVRs (i.e. with and without loss of consciousness), all delayed VVRs (i.e. those occurring after leaving the venue) and any in-session non-VVR adverse events or reactions.
The STRIDES trial should yield novel information about interventions, singly and in combination, for the prevention of VVRs, with the aim of generating policy-shaping evidence to help inform blood services to improve donor health, donor experience, and service efficiency.
ISRCTN: 10412338. Registration date: October 24, 2019.
Beta-2-microglobulin (B2M) has been suggested as an emerging biomarker for cardiovascular diseases (CVD), including coronary heart disease (CHD) and stroke, and mortality.
Three databases were ...searched from inception to January 2, 2020, supplemented by scanning reference lists of identified studies. We identified studies that reported associations of baseline serum or plasma B2M and CVD incidence, CVD mortality, or CHD and stroke separately, in either general populations or patients with renal disease. Relative risks (RR) were extracted and harmonized to a comparison of the highest versus lowest third of the distribution of B2M, and the results were aggregated.
Sixteen studies (5 in general populations, and 11 in renal disease populations) were included, involving 30,988 participants and 5391 CVD events. Based on random-effects meta-analysis, the pooled adjusted RRs comparing the highest versus lowest third of the distribution of B2M were 1.71 (95%CI: 1.37–2.13) for CVD, 2.29 (1.51–3.49) for CVD mortality, 1.64 (1.14–2.34) for CHD, and 1.51 (1.28–1.78) for stroke, with little to high heterogeneity between studies (0.0% ≤ I2 ≤ 80.0%). The positive associations between B2M and risks of CVD outcomes remained broadly significant across subgroup analyses. Moreover, the pooled adjusted RRs were 2.51 (1.94–3.26; I2 = 83.7%) for all-cause mortality and 2.64 (1.34–5.23; I2 = 83.1%) for infectious mortality.
Available observational data show that there are moderate positive associations between B2M levels and CVD events and mortality, although few studies have been conducted in general populations.
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•Available epidemiological evidence shows that circulating B2M levels are moderately associated with CVD events and mortality.•Future large-scale general population-based prospective studies and genetic studies are needed to assess the causality.
SARS-CoV-2 antibody tests are used for population surveillance and might have a future role in individual risk assessment. Lateral flow immunoassays (LFIAs) can deliver results rapidly and at scale, ...but have widely varying accuracy.
In a laboratory setting, we performed head-to-head comparisons of four LFIAs: the Rapid Test Consortium's AbC-19TM Rapid Test, OrientGene COVID IgG/IgM Rapid Test Cassette, SureScreen COVID-19 Rapid Test Cassette, and Biomerica COVID-19 IgG/IgM Rapid Test. We analysed blood samples from 2,847 key workers and 1,995 pre-pandemic blood donors with all four devices.
We observed a clear trade-off between sensitivity and specificity: the IgG band of the SureScreen device and the AbC-19TM device had higher specificities but OrientGene and Biomerica higher sensitivities. Based on analysis of pre-pandemic samples, SureScreen IgG band had the highest specificity (98.9%, 95% confidence interval 98.3 to 99.3%), which translated to the highest positive predictive value across any pre-test probability: for example, 95.1% (95% uncertainty interval 92.6, 96.8%) at 20% pre-test probability. All four devices showed higher sensitivity at higher antibody concentrations (“spectrum effects”), but the extent of this varied by device.
The estimates of sensitivity and specificity can be used to adjust for test error rates when using these devices to estimate the prevalence of antibody. If tests were used to determine whether an individual has SARS-CoV-2 antibodies, in an example scenario in which 20% of individuals have antibodies we estimate around 5% of positive results on the most specific device would be false positives.
Public Health England.
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