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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. 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. 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. 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. NHS Blood and Transplant, National Institute for Health Research, UK Medical Research Council, and British Heart Foundation.

ObjectivesTo prospectively investigate in patients with severe COVID-19-associated cytokine storm syndrome (CSS) whether an intensive course of glucocorticoids with or without tocilizumab accelerates clinical improvement, reduces mortality and prevents invasive mechanical ventilation, in comparison with a historic control group of patients who received supportive care only.MethodsFrom 1 April 2020, patients with COVID-19-associated CSS, defined as rapid respiratory deterioration plus at least two out of three biomarkers with important elevations (C-reactive protein >100 mg/L; ferritin >900 µg/L; D-dimer >1500 µg/L), received high-dose intravenous methylprednisolone for 5 consecutive days (250 mg on day 1 followed by 80 mg on days 2–5). If the respiratory condition had not improved sufficiently (in 43%), the interleukin-6 receptor blocker tocilizumab (8 mg/kg body weight, single infusion) was added on or after day 2. Control patients with COVID-19-associated CSS (same definition) were retrospectively sampled from the pool of patients (n=350) admitted between 7 March and 31 March, and matched one to one to treated patients on sex and age. The primary outcome was ≥2 stages of improvement on a 7-item WHO-endorsed scale for trials in patients with severe influenza pneumonia, or discharge from the hospital. Secondary outcomes were hospital mortality and mechanical ventilation.ResultsAt baseline all patients with COVID-19 in the treatment group (n=86) and control group (n=86) had symptoms of CSS and faced acute respiratory failure. Treated patients had 79% higher likelihood on reaching the primary outcome (HR: 1.8; 95% CI 1.2 to 2.7) (7 days earlier), 65% less mortality (HR: 0.35; 95% CI 0.19 to 0.65) and 71% less invasive mechanical ventilation (HR: 0.29; 95% CI 0.14 to 0.65). Treatment effects remained constant in confounding and sensitivity analyses.ConclusionsA strategy involving a course of high-dose methylprednisolone, followed by tocilizumab if needed, may accelerate respiratory recovery, lower hospital mortality and reduce the likelihood of invasive mechanical ventilation in COVID-19-associated CSS.

In a multicenter, blinded end-point, open-label trial, adults undergoing maintenance hemodialysis were assigned to receive high-dose iron proactively or low-dose iron reactively. High-dose iron therapy was noninferior and led to lower doses of erythropoiesis-stimulating agent.

BackgroundVitamin D has an immunomodulatory role but the effect of therapeutic vitamin D supplementation in SARS-CoV-2 infection is not known.AimEffect of high dose, oral cholecalciferol supplementation on SARS-CoV-2 viral clearance.DesignRandomised, placebo-controlled.ParticipantsAsymptomatic or mildly symptomatic SARS-CoV-2 RNA positive vitamin D deficient (25(OH)D<20 ng/ml) individuals.InterventionParticipants were randomised to receive daily 60 000 IU of cholecalciferol (oral nano-liquid droplets) for 7 days with therapeutic target 25(OH)D>50 ng/ml (intervention group) or placebo (control group). Patients requiring invasive ventilation or with significant comorbidities were excluded. 25(OH)D levels were assessed at day 7, and cholecalciferol supplementation was continued for those with 25(OH)D <50 ng/ml in the intervention arm. SARS-CoV-2 RNA and inflammatory markers fibrinogen, D-dimer, procalcitonin and (CRP), ferritin were measured periodically.Outcome measureProportion of patients with SARS-CoV-2 RNA negative before day-21 and change in inflammatory markers.ResultsForty SARS-CoV-2 RNA positive individuals were randomised to intervention (n=16) or control (n=24) group. Baseline serum 25(OH)D was 8.6 (7.1 to 13.1) and 9.54 (8.1 to 12.5) ng/ml (p=0.730), in the intervention and control group, respectively. 10 out of 16 patients could achieve 25(OH)D>50 ng/ml by day-7 and another two by day-14 [day-14 25(OH)D levels 51.7 (48.9 to 59.5) ng/ml and 15.2 (12.7 to 19.5) ng/ml (p<0.001) in intervention and control group, respectively]. 10 (62.5%) participants in the intervention group and 5 (20.8%) participants in the control arm (p<0.018) became SARS-CoV-2 RNA negative. Fibrinogen levels significantly decreased with cholecalciferol supplementation (intergroup difference 0.70 ng/ml; P=0.007) unlike other inflammatory biomarkers.ConclusionGreater proportion of vitamin D-deficient individuals with SARS-CoV-2 infection turned SARS-CoV-2 RNA negative with a significant decrease in fibrinogen on high-dose cholecalciferol supplementation.Trial register numberNCT04459247.

Patients with transfusion-dependent β-thalassemia were randomly assigned to receive luspatercept (a binder for TGF-β family member ligands) or placebo. During any 12-week period, a greater percentage of patients in the luspatercept group than in the placebo group had a reduction of at least 33% (70.5% vs. 29.5%) or at least 50% (40.2% vs. 6.3%) in the transfusion requirement.

Whole-blood donors are at increased risk for iron deficiency and anaemia. The current standard of haemoglobin monitoring is insufficient to ensure the maintenance of proper iron reserves and donor health. We aimed to determine the effects of ferritin-guided donation intervals for blood donor health and blood supply in the Netherlands. In this stepped-wedge cluster-randomised trial (FIND'EM), the 138 fixed and mobile donation centres in the Netherlands are organised into 29 geographical clusters and the clusters were randomly assigned to four treatment groups, with two groups being further split into two per a protocol amendment. Eligible donors were whole-blood donors who consented for use of their leftover material in the study. Each group was sequentially crossed over from the existing policy (haemoglobin-based screening; control) to a ferritin-guided donation interval policy over a 3-year period. In the intervention groups, in addition to the existing haemoglobin screening, ferritin was measured in all new donors and at every fifth donation in repeat donors. Subsequent donation intervals were extended to 6 months if ferritin concentrations were 15–30 ng/mL and to 12 months if they were less than 15 ng/mL. Outcomes were measured cross-sectionally across all donation centres at four timepoints. Primary outcomes were ferritin and haemoglobin concentrations, iron deficiency, and haemoglobin-based deferrals. We assessed all outcomes by sex and menopausal status and significance for primary outcomes was indicated by a p value of less than 0·0125. This trial is registered in the Dutch trial registry, NTR6738, and is complete. Between Sept 11, 2017, and Nov 27, 2020, 412 888 whole-blood donors visited a donation centre, and we did measurements on samples from 37 621 donations from 36 099 donors. Over 38 months, ferritin-guided donation intervals increased mean ferritin concentrations (by 0·18 log10 ng/mL [95% CI 0·15–0·22; p<0·0001] in male donors, 0·10 log10 ng/mL [0·06–0·15; p<0·0001] in premenopausal female donors, and 0·17 log10 ng/mL [0·12–0·21; p<0·0001] in postmenopausal female donors) and mean haemoglobin concentrations (by 0·30 g/dL [95% CI 0·22–0·38; p<0·0001] in male donors, 0·12 g/dL [0·03–0·20; p<0·0074] in premenopausal female donors, and 0·16 g/dL [0·05–0·27; p<0·0044] in postmenopausal female donors). Iron deficiency decreased by 36–38 months (odds ratio [OR] 0·24 [95% CI 0·18–0·31; p<0·0001] for male donors, 0·49 [0·37–0·64; p<0·0001] for premenopausal female donors, and 0·24 [0·15–0·37; p<0·0001] for postmenopausal female donors). At 36–38 months, haemoglobin-based deferral decreased significantly in male donors (OR at 36–38 months 0·21 [95% CI 0·10–0·40, p<0·0001]) but not significantly in premenopausal or postmenopausal female donors (0·81 [0·54–1·20; p=0·29] and 0·50 [95% CI 0·25–0·98; p=0·051], respectively). Ferritin-guided donation intervals significantly improved haemoglobin and ferritin concentrations and significantly decreased iron deficiency over the study period. Haemoglobin-based deferrals decreased significantly for male donors, but not female donors. Although this intervention is overall beneficial for maintenance of iron and haemoglobin concentrations in donors, increased efforts are needed to recruit and retain donors. The Sanquin Research Programming Committee.

A randomized trial of transfusion therapy versus standard therapy showed a reduction in cerebral infarcts among children with sickle cell anemia whose hemoglobin S levels were kept below 30%. Transfusion risks seem to be outweighed by the neurologic benefits. Sickle cell anemia affects 1 of every 396 1 black newborns and approximately 100,000 persons in the United States. 2 , 3 Among children with sickle cell anemia (defined as homozygous hemoglobin S or hemoglobin S-β 0 thalassemia), silent cerebral infarcts are the most common neurologic injury. 4 In contrast to overt stroke (hereinafter referred to as stroke), a silent cerebral infarct is not associated with obvious neurologic impairment and cannot be detected on neurologic examination. 5 However, children with a silent cerebral infarct are at increased risk for stroke, new or enlarged silent cerebral infarcts, 6 poor academic achievement, 7 and lower IQ, as compared either with . . .

ObjectiveIron deficiency is a common complication in patients with IBD and oral iron therapy is suggested to exacerbate IBD symptoms. We performed an open-labelled clinical trial to compare the effects of per oral (PO) versus intravenous (IV) iron replacement therapy (IRT).DesignThe study population included patients with Crohn's disease (CD; N=31), UC (N=22) and control subjects with iron deficiency (non-inflamed, NI=19). After randomisation, participants received iron sulfate (PO) or iron sucrose (IV) over 3 months. Clinical parameters, faecal bacterial communities and metabolomes were assessed before and after intervention.ResultsBoth PO and IV treatments ameliorated iron deficiency, but higher ferritin levels were observed with IV. Changes in disease activity were independent of iron treatment types. Faecal samples in IBD were characterised by marked interindividual differences, lower phylotype richness and proportions of Clostridiales. Metabolite analysis also showed separation of both UC and CD from control anaemic participants. Major shifts in bacterial diversity occurred in approximately half of all participants after IRT, but patients with CD were most susceptible. Despite individual-specific changes in phylotypes due to IRT, PO treatment was associated with decreased abundances of operational taxonomic units assigned to the species Faecalibacterium prausnitzii, Ruminococcus bromii, Dorea sp. and Collinsella aerofaciens. Clear IV-specific and PO-specific fingerprints were evident at the level of metabolomes, with changes affecting cholesterol-derived host substrates.ConclusionsShifts in gut bacterial diversity and composition associated with iron treatment are pronounced in IBD participants. Despite similar clinical outcome, oral administration differentially affects bacterial phylotypes and faecal metabolites compared with IV therapy.Trial registration numberclinicaltrial.gov (NCT01067547).

Objective To investigate the effects of delayed umbilical cord clamping, compared with early clamping, on infant iron status at 4 months of age in a European setting.Design Randomised controlled trial.Setting Swedish county hospital.Participants 400 full term infants born after a low risk pregnancy.Intervention Infants were randomised to delayed umbilical cord clamping (≥180 seconds after delivery) or early clamping (≤10 seconds after delivery).Main outcome measures Haemoglobin and iron status at 4 months of age with the power estimate based on serum ferritin levels. Secondary outcomes included neonatal anaemia, early respiratory symptoms, polycythaemia, and need for phototherapy.Results At 4 months of age, infants showed no significant differences in haemoglobin concentration between the groups, but infants subjected to delayed cord clamping had 45% (95% confidence interval 23% to 71%) higher mean ferritin concentration (117 μg/L v 81 μg/L, P<0.001) and a lower prevalence of iron deficiency (1 (0.6%) v 10 (5.7%), P=0.01, relative risk reduction 0.90; number needed to treat=20 (17 to 67)). As for secondary outcomes, the delayed cord clamping group had lower prevalence of neonatal anaemia at 2 days of age (2 (1.2%) v 10 (6.3%), P=0.02, relative risk reduction 0.80, number needed to treat 20 (15 to 111)). There were no significant differences between groups in postnatal respiratory symptoms, polycythaemia, or hyperbilirubinaemia requiring phototherapy.Conclusions Delayed cord clamping, compared with early clamping, resulted in improved iron status and reduced prevalence of iron deficiency at 4 months of age, and reduced prevalence of neonatal anaemia, without demonstrable adverse effects. As iron deficiency in infants even without anaemia has been associated with impaired development, delayed cord clamping seems to benefit full term infants even in regions with a relatively low prevalence of iron deficiency anaemia.Trial registration Clinical Trials NCT01245296.

Higher-protein diets, meal replacements, and greater early weight loss have separately been associated with greater weight loss. We compared a high-protein, meal replacement program with daily energy restriction (DER) to one which provided greater energy restriction adding alternate day fasting (ADF + DER; alternating days of modified-fasting and DER plus 1 ad libitum day/week) on retention, weight loss, physiological, nutritional, and behavioral markers. Participants were randomized to ADF + DER or DER for 16 weeks (n = 162, age 40 ± 8 years BMI 36 ± 6 kg/m2 (Mean ± SD)) plus 8 weeks weight maintenance. At week 16 weight change was −10.7 ± 0.5 kg and −11.2 ± 0.6 kg in ADF + DER and DER groups (treatment NS). Fat mass, visceral adipose tissue, and lean mass (p < 0.05) were similarly reduced between treatments. Weight loss was sustained to 24 weeks (treatment NS). Fasting LDL-cholesterol, triglycerides, insulin, hsCRP, glucose, and blood pressure all improved (p < 0.05; treatment NS). Transferrin saturation, ferritin, serum zinc, folate, and B12 improved (p < 0.05; treatment NS). Plasma thiamine and vitamin D levels decreased, reflecting lower carbohydrate intakes and seasonal changes, respectively. Food cravings, quality of life, and mood improved (treatment NS). Energy, fatigue, and pain improved slightly more in DER (p < 0.05). This study supports the use of higher protein, meal replacement programs with or without ADF in weight management.