US Blood Research Articles

Recent viral infection in US blood donors and health-related quality of life (HRQOL).

Blood donors are considered to be one of the healthiest populations, but relatively little is known about their perceived quality of life. The objective was to examine HRQOL in donors infected with HIV, HBV, HCV or HTLV and a comparison group. Donors with confirmed viral infection (cases) and donors who tested false-positive (controls) participated in a multicenter study of US blood donors (2010-2013), funded by the National Heart, Lung and Blood Institute (NHLBI). HRQOL was measured by the EuroQol Five Dimension (EQ-5D) instrument and EQ-5D visual analogue scale (VAS). The lower 25th ‰ of EQ-5D index or VAS score of controls was defined as a "lower HRQOL." A total of 1574 controls completed the HRQOL assessment with a mean EQ-5D index of 0.94 (SD=0.10) and EQ-VAS of 87.6 (SD=10.6). Mean EQ-5D index for 192 HIV-, 315 HCV- and 195 HTLV-positive donors were significantly lower than the controls (0.86, 0.83 and 0.87; SD=0.18, 0.20 and 0.16, respectively, p<0.001). HBV-positive donors (n=290) had a similar mean EQ-5D index (0.93, SD=0.14, p=0.05) to controls. Anxiety/depression was reported by 34% of cases, compared with 13% of controls. In multivariable modeling, the odds of lower HRQOL in HIV, HBV, HCV and HTLV cases were 2.1, 1.6, 2.6 and 2.3 times that of controls, respectively (p<0.05). HRQOL reported by blood donors with recent viral infections was relatively high but lower than controls. On average, HRQOL among HCV-positive donors was the lowest and HBV-positive donors reported scores similar to donors without infection.

Motivations for donating and attitudes toward screening policies in US blood donors with viral infection.

Differences in motivating factors that contribute to the decision to donate blood between infected and uninfected donors may help to identify areas for improving donor education. As part of a risk factor study, confirmed-positive donors (cases) based on serology-only (human T-lymphotropic virus [HTLV]) or serology and nucleic acid testing (NAT) or NAT-only (human immunodeficiency virus [HIV], hepatitis B virus [HBV], hepatitis C virus [HCV]), and serology-unconfirmed, NAT-negative false-positive donors (controls) were asked about motivations and opinions toward blood donation. "Test seeking" was inferred if a donor answered "yes" to "I wanted to get my test results" and one of the following: "blood center testing is confidential," "free," "more accurate than other test centers," or "tests will identify problems with my blood." Cases were compared to controls using descriptive and multivariable analyses. Whether a case or control, the most common donation reason was "to help someone in need" (>90% in each group). After adjusting for demographic characteristics, test seeking was not significantly associated with infection status. Test seeking was more common in first-time, younger males and nonwhite, non-Hispanic donors. Of donors with HIV, 13% considered selection policies to be unfair, compared with 1, 2, 0.5, and 6% of donors with HBV, HCV, and HTLV and controls, respectively (adjusted odds ratio for HIV cases vs. controls, 3.9; 95% confidence interval, 2.3-6.7). Most donors give to help those in need, including HIV-positive donors. Our results establish a baseline from which additional studies can be compared focused on alternate ways to reduce noncompliance and improved messaging to ensure that high-risk potential donors understand the reasons for blood donor screening policies.

Global burden of stroke and risk factors in 188 countries, during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

The contribution of modifiable risk factors to the increasing global and regional burden of stroke is unclear, but knowledge about this contribution is crucial for informing stroke prevention strategies. We used data from the Global Burden of Disease Study 2013 (GBD 2013) to estimate the population-attributable fraction (PAF) of stroke-related disability-adjusted life-years (DALYs) associated with potentially modifiable environmental, occupational, behavioural, physiological, and metabolic risk factors in different age and sex groups worldwide and in high-income countries and low-income and middle-income countries, from 1990 to 2013. We used data on stroke-related DALYs, risk factors, and PAF from the GBD 2013 Study to estimate the burden of stroke by age and sex (with corresponding 95% uncertainty intervals [UI]) in 188 countries, as measured with stroke-related DALYs in 1990 and 2013. We evaluated attributable DALYs for 17 risk factors (air pollution and environmental, dietary, physical activity, tobacco smoke, and physiological) and six clusters of risk factors by use of three inputs: risk factor exposure, relative risks, and the theoretical minimum risk exposure level. For most risk factors, we synthesised data for exposure with a Bayesian meta-regression method (DisMod-MR) or spatial-temporal Gaussian process regression. We based relative risks on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks, such as high body-mass index (BMI), through other risks, such as high systolic blood pressure (SBP) and high total cholesterol. Globally, 90·5% (95% UI 88·5-92·2) of the stroke burden (as measured in DALYs) was attributable to the modifiable risk factors analysed, including 74·2% (95% UI 70·7-76·7) due to behavioural factors (smoking, poor diet, and low physical activity). Clusters of metabolic factors (high SBP, high BMI, high fasting plasma glucose, high total cholesterol, and low glomerular filtration rate; 72·4%, 95% UI 70·2-73·5) and environmental factors (air pollution and lead exposure; 33·4%, 95% UI 32·4-34·3) were the second and third largest contributors to DALYs. Globally, 29·2% (95% UI 28·2-29·6) of the burden of stroke was attributed to air pollution. Although globally there were no significant differences between sexes in the proportion of stroke burden due to behavioural, environmental, and metabolic risk clusters, in the low-income and middle-income countries, the PAF of behavioural risk clusters in males was greater than in females. The PAF of all risk factors increased from 1990 to 2013 (except for second-hand smoking and household air pollution from solid fuels) and varied significantly between countries. Our results suggest that more than 90% of the stroke burden is attributable to modifiable risk factors, and achieving control of behavioural and metabolic risk factors could avert more than three-quarters of the global stroke burden. Air pollution has emerged as a significant contributor to global stroke burden, especially in low-income and middle-income countries, and therefore reducing exposure to air pollution should be one of the main priorities to reduce stroke burden in these countries. Bill & Melinda Gates Foundation, American Heart Association, US National Heart, Lung, and Blood Institute, Columbia University, Health Research Council of New Zealand, Brain Research New Zealand Centre of Research Excellence, and National Science Challenge, Ministry of Business, Innovation and Employment of New Zealand.

Genetically Engineered In Vitro Erythropoiesis.

BackgroundEngineered blood has the greatest potential to combat a predicted future shortfall in the US blood supply for transfusion treatments. Engineered blood produced from hematopoietic stem cell (HSC) derived red blood cells in a laboratory is possible, but critical barriers exist to the production of clinically relevant quantities of red blood cells required to create a unit of blood. Erythroblasts have a finite expansion capacity and there are many negative regulatory mechanisms that inhibit in vitro erythropoiesis. In order to overcome these barriers and enable mass production, the expansion capacity of erythroblasts in culture will need to be exponentially improved over the current state of art. This work focused on the hypothesis that genetic engineering of HSC derived erythroblasts can overcome these obstacles.ObjectivesThe objective of this research effort was to improve in vitro erythropoiesis efficiency from human adult stem cell derived erythroblasts utilizing genetic engineering. The ultimate goal is to enable the mass production of engineered blood.MethodsHSCs were isolated from blood samples and cultured in a liquid media containing growth factors. Cells were transfected using a Piggybac plasmid transposon.ResultsCells transfected with SPI-1 continued to proliferate in a liquid culture media. Fluorescence-activated cell sorting (FACS) analysis on culture day 45 revealed a single population of CD71+CD117+ proerythroblast cells. The results of this study suggest that genetically modified erythroblasts could be immortalized in vitro by way of a system modeling murine erythroleukemia.ConclusionGenetic modification can increase erythroblast expansion capacity and potentially enable mass production of red blood cells.

A prospective evaluation of chronic Babesia microti infection in seroreactive blood donors.

Babesia microti is the foremost infectious risk to the US blood supply for which a Food and Drug Administration (FDA)-licensed test is unavailable for donation screening. Characterization of the antibody response to B. microti and correlation with parasitemia is necessary to guide screening and donor management policies. During an FDA licensure trial, blood donors were prospectively screened (July-November 2013) using a B. microti-specific antibody enzyme immunoassay (EIA, Immunetics) in highly endemic (New York [NY]; n = 13,688), moderately endemic (Minnesota [MN]; n = 4583), and nonendemic (New Mexico [NM]; n = 8451) regions. Blood donors with repeat-reactive (RR) results participated in a 12-month prospective cohort study using B. microti EIA, immunofluorescent assay, polymerase chain reaction (PCR), blood smear, and clinical questionnaire. Thirty-seven (61.67%; 24 NY, seven MN, six NM) of 60 eligible RR donors enrolled in the study; 20 of 37 (54%) completed the 12-month follow-up visit of which 15 (75%) were still seroreactive. Nine PCR-positive donors were identified during index screening; five participated in the follow-up study, three were PCR positive at 6 months, and two remained positive at final follow-up (378 and 404 days). Most RR donors displayed low-level seroreactivity that was either stable or waning during follow-up. The level and pattern of reactivity correlated poorly with PCR positivity. The findings indicate prolonged seropositivity in blood donors. Although rare, asymptomatic, persistent PCR positivity supports the current policy of indefinite deferral for donors with a history of babesiosis or positive test results. Repeat testing by PCR and serology will be necessary if reinstatement is to be considered.

Declining blood collection and utilization in the United States.

The Department of Health and Human Services National Blood Collection and Utilization Survey (NBCUS) has been conducted biennially since 1997. Data are used to estimate national blood collection and utilization. The 2013 Department of Health and Human Services NBCUS is a cross-sectional survey of all US blood collection centers and hospitals as listed in the 2012 American Hospital Association Annual Survey database that perform at least 100 inpatient surgical procedures annually. The study objective was to estimate, with 95% confidence intervals (CIs), the number of blood and blood components collected and transfused in the United States. In 2013, a total of 14,237,000 whole blood and apheresis red blood cell (RBC) units (95% CI, 13,639,000-14,835,000) were collected with 13,395,000 available for transfusion. Of these, 13,180,000 (95% CI, 12,389,000-13,972,000) whole blood and RBC units were transfused. This represented a 4.4% decline in the number of transfused units compared to 2011. Outdated (i.e., expired without being transfused) whole blood and RBC units declined by 17.3%. Apheresis (2,318,000; 95% CI, 2,154,000-2,482,000) and whole blood-derived platelet (PLT; 130,000; 95% CI, 23,000-237,000) distribution declined in 2013. Total PLT transfusions increased in 2013 (2,281,000) in comparison to 2011 (2,169,000). Total plasma units distributed (4,338,000) and transfused (3,624,000) declined. Both blood collection and utilization have declined, but the gap between collection and utilization is narrowing. As collections decline further and hospitals decrease transfusions and manage products more efficiently, the decline in surplus inventory may be a concern for disaster preparedness or other unexpected utilization needs.

Differences in Early Cytokine Production Are Associated With Development of a Greater Number of Symptoms Following West Nile Virus Infection.

West Nile virus (WNV) is an emerging cause of meningitis and encephalitis in the United States. Although severe neuroinvasive disease and death can occur in rare instances, the majority of infected individuals remain asymptomatic or present with a range of clinical manifestations associated with West Nile fever. To better understand the interindividual variability associated with the majority of WNV infections, we evaluated the association of cytokine/chemokine production and outcome of infection among 115 WNV-positive US blood donors identified in 2008-2011. All subjects self-reported symptoms as having occurred during the 2 weeks following blood donation, using a standardized questionnaire. We discovered that, prior to seroconversion, an early potent, largely type I interferon-mediated response correlated with development of a greater number of symptoms in WNV-infected individuals. Interestingly, individuals who developed fewer symptoms had not only a more modest type I interferon response initially, but also a protracted cytokine response after seroconversion, marked by the production of monocyte and T-cell-associated chemokines. Collectively, our data suggest that, although an early type I interferon response appears to be crucial to control WNV infection, successful immunity may require a modest early response that is maintained during the course of infection.

Long-term effects of neighbourhood deprivation on diabetes risk: quasi-experimental evidence from a refugee dispersal policy in Sweden

Although studies have shown associations between neighbourhood quality and chronic disease outcomes, such associations are potentially confounded by the selection of different types of people into different neighbourhood environments. We sought to identify the causal effects of neighbourhood deprivation on type 2 diabetes risk, by comparing refugees in Sweden who were actively dispersed by government policy to low-deprivation, moderate-deprivation, or high-deprivation neighbourhoods. In this quasi-experimental study, we analysed national register data for refugees who arrived in Sweden aged 25-50 years, at a time when the government policy involved quasi-random dispersal of refugees to neighbourhoods with different levels of poverty and unemployment, schooling, and social welfare participation. Individuals in our sample were assigned to a neighbourhood categorised as high deprivation (≥1 SD above the mean), moderate deprivation (within 1 SD of the mean), or low deprivation (≥1 SD below the mean). The primary outcome was new diagnosis of type 2 diabetes between Jan 1, 2002, and Dec 31, 2010. We used multivariate logistic and linear regressions to assess the effects of neighbourhood deprivation on diabetes risk, controlling for potential confounders affecting neighbourhood assignment and assessing effects of cumulative exposure to different neighbourhood conditions. We included data for 61 386 refugees who arrived in Sweden during 1987-91 and who were assigned to one of 4833 neighbourhoods. Being assigned to an area deemed high deprivation versus low deprivation was associated with an increased risk of diabetes (odds ratio [OR] 1·22, 95% CI 1·07-1·38; p=0·001). In analyses that included fixed effects for assigned municipality, the increased diabetes risk was estimated to be 0·85 percentage points (95% CI -0·030 to 1·728; p=0·058). Neighbourhood effects grew over time such that 5 years of additional exposure to high-deprivation versus low-deprivation neighbourhoods was associated with a 9% increase in diabetes risk. This study makes use of a pre-existing governmental natural experiment to show that neighbourhood deprivation increased the risk of diabetes in refugees in Sweden. This finding has heightened importance in the context of the current refugee crisis in Europe. US National Heart, Lung, and Blood Institute, US National Center for Advancing Translational Sciences, US National Institute on Minority Health and Health Disparities, Swedish Research Council.

Redefining the role of blood establishments as raw material suppliers, manufacturers, and distributors for new cell therapies: the Blood Systems experience.

Redefining the role of blood establishments as raw material suppliers, manufacturers, and distributors for new cell therapies: the Blood Systems experience.

Experimental transfusion-induced Babesia microti infection: dynamics of parasitemia and immune responses in a rhesus macaque model.

Babesiosis is an emerging tick-borne infection in humans. The increasing numbers of reported cases of transfusion-associated babesiosis (TAB), primarily caused by Babesia microti, represents a concern for the safety of the US blood supply. This study investigated kinetics of parasitemia and innate immune responses and dynamics of antibody responses during B. microti infection in rhesus macaques (RMs) using blood smears, quantitative polymerase chain reaction (qPCR), flow cytometry, and indirect fluorescent antibody testing. A total of six monkeys were transfused with either hamster or monkey-passaged B. microti-infected red blood cells (two and four monkeys, respectively) simulating TAB. The prepatent period in monkeys inoculated with hamster-passaged B. microti was 35 days compared with 4 days in monkeys transfused with monkey-passaged B. microti; the latter monkeys also had markedly higher parasitemia levels. The duration of the window period from the first detected parasitemia by qPCR analysis to the first detected antibody response ranged from 10 to 17 days. Antibody responses fluctuated during the course of the infection. Innate responses assessed by the frequencies of monocytes and activated B cells correlated with the kinetics and magnitude of parasitemia. On Day 14, additional activation peaks were noted for CD14+CD16+ and CD14-CD16+ monocytes and for CD11c+ myeloid dendritic cells, but only in animals transfused with monkey-passaged B. microti. Parasitemia persisted in these immunocompetent animals, similar to human infection. The results suggest that transfusion-associated transmission of B. microti leads to rapid onset of parasitemia (Day 4) in RMs, detectable antibody response 14 days later, and persistent parasitemia.

Community health worker-based intervention for adherence to drugs and lifestyle change after acute coronary syndrome: a multicentre, open, randomised controlled trial

Adherence to drugs and healthy lifestyles is low after acute coronary syndrome. We assessed whether trained community health workers could improve adherence to drugs, lifestyle changes, and clinical risk markers in patients with acute coronary syndrome in India. In this study done at 14 hospitals in India we randomly assigned (1:1) patients with acute coronary syndrome 1 or 2 days before discharge from hospital to a community health worker-based intervention group or a standard care group. Patients were randomly assigned with a telephone randomisation service. In the intervention group, during four in-hospital and two home visits, community health workers used unstructured discussions, visual methods, and patient diaries to educate patients on healthy lifestyle and drugs, and measures to enhance adherence. The primary outcome was adherence to proven secondary prevention drugs (antiplatelet drugs, β blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins) estimated using a Composite Medication Adherence Scale at 1 year. The secondary outcomes were difference in lifestyle factors (diet, exercise, and tobacco and alcohol use), and clinical risk markers (blood pressure, bodyweight, BMI, heart rate, and lipids). All analyses were by intention to treat. This trial is registered with the Clinical Trial Registry of India, number REF/2013/03/004737, and ClinicalTrials.gov, number NCT01207700. Between Aug 23, 2011, and June 25, 2012, 806 participants were randomly assigned (405 to a community health worker-based intervention group and 401 to a standard care group). At 1 year, 40 patients had died and 15 had discontinued or been lost to follow-up, so 750 (93%) were included in the analyses (375 in each group). Secondary prevention drugs prescribed at discharge were 98% (786/803) for any antiplatelet drug, 79% (638/803) for dual antiplatelet drugs, 69% (555/803) for β blockers, 69% (552/803) for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and 95% (762/803) for statins. At one year, overall adherence (≥80%) to prescribed evidence-based drugs was higher in the intervention group than in the control group (97% vs 92%, odds ratio [OR] 2·62, 95% CI 1·32-5·19; p=0·006). For individual drugs, we recorded significant differences for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (97% [233/240] in the intervention group vs 93% [223/240] in the control group; p=0·036) and statins (97% [346/356] vs 93% [321/345]; p=0·011). The intervention group had significantly greater adherence to smoking cessation (85% [110/129] vs 52% [71/138], OR 5·46, 95% CI 3·03-9·86; p<0·0001), regular physical activity (89% [333/375] vs 60% [226/375], OR 5·23, 95% CI 3·57-7·66; p<0·0001), and healthy diet (score 5·0 vs 3·0, OR 2·47, 95% CI 1·88-3·25; p<0·0001). More patients in the intervention group had stopped alcohol use at 1 year (87% [64/74] vs 46% [46/67], OR 2·92, 95% CI 1·26-6·79; p =0·010). At 1 year, the mean systolic blood pressure (124·4 mm Hg [SD 13·5] vs 128·0 mm Hg [15·9]; p=0·002), weight (65·0 kg [11·0] vs 66·5 kg [11·5]; p<0·0001), cholesterol (157·0 [40·2] vs 166·9 [48·4]; p=0·184), LDL (81·0 [20·6] vs 87·3 [29·9]; p=0·191), HDL (42·0 [11·4] vs 38·2 [6·5]; p=0·042), and BMI (24·4 kg/m(2) [SD 3·7] vs 25·0 kg/m(2) [3·8]; p<0·0001) were lower in the intervention group than in the control group. However, we noted no significant difference in diastolic blood pressure and heart rate. A community health worker-based personalised intervention strategy in patients with acute coronary syndrome improved adherence to evidence-based drugs and healthy lifestyles, and resulted in an improvement in clinical risk markers. Integration of trained community health workers can improve secondary prevention in coronary artery disease. US National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Department of Health and Human Services, and the UnitedHealth group, USA.

Using design methods to provide the care that people want and need.

Kim Erwin is an Assistant Professor at IIT Institute of Design and trained in user-centered design methods, which put people at the center of any problem space so as to develop solutions that better fit their everyday lives, activities and context. Her expertise is in making complex information easier to understand and use. Her research targets communication tools and methods for collaborative knowledge construction built through shared experiences. Her book, Communicating the New: Methods to shape and accelerate innovation focuses on helping teams explore, build and diffuse critical knowledge inside organizations. Jerry Krishnan is a Professor of Medicine and Public Health, and Associate Vice President for Population Health Sciences at the University of Illinois Hospital & Health Sciences System. He pioneered the use of Analytic Hierarchy Process to elicit the expressed needs of stakeholders for research. He previously served as Chair of the US FDA Pulmonary and Allergy Drugs Advisory Committee and is a Principal Investigator in NIH and Patient Centered Outcomes Research Institute (PCORI)-funded research consortia. He chairs the US National Heart, Lung, and Blood Institute (NHLBI) Clinical Trials review committee and the PCORI Improving Healthcare Systems merit review panel.

Complex Relationship of Blood Group H, ABO Glycans, and Von Willebrand Factor Levels

BackgroundABO(H) is a carbohydrate blood group system expressed in multiple tissues including red blood cells, blood vessels, and mucosal surfaces. ABO is the largest known genetic modifier of plasma VWF level (VWF:Ag). It has been hypothesized that the effect of ABO on VWF is mediated by H glycan density. FUT2, the gene underlying Secretor phenotype, encodes a glycosyltransferase synthesizing H antigen in mucosal tissues, and variation in the gene has also previously been associated with VWF:Ag, but past studies have been conflicting. To clarify these relationships, we studied the relationship between VWF:Ag, ABH glycans, and FUT2 genotype. MethodsThe primary study group was a representative cohort of US blood donors from the Retrovirus Epidemiology Donor Study (REDS, N=499). A validation cohort of unrelated individuals was created from the Genes and Blood Clotting Study (GABC), healthy siblings between ages 14 and 35 years from University of Michigan, Ann Arbor, by choosing a random individual from each family (N=488). VWFAg was determined by ELISA in platelet poor plasma. Forensic techniques were adapted to detect ABH glycans in whole blood (REDS) or RBC-rich, frozen buffy coat (GABC). A and B glycans were detected using anti-A or anti-B (Immucor). A biotinylated Ulex europaeus agglutinin (UEA lectin, Vector Labs) was used to detect H. Relative A, B, and H antigen density was quantified on dot blots with ImageQuant (GE). In REDS, functional FUT2 alleles (Secretor) were determined by Sanger sequencing of FUT2 exon 2. FUT2 copy-number was assayed with real-time quantitative PCR. In GABC, FUT2 genotypes were determined through SNP genotyping (Illumina).In REDS, genotype data was phased (BEAGLE) to identify functional haplotypes. In GABC, functional alleles were inferred from the genotypes of two SNPs (rs601338, rs1047781) that determined secretor status in nearly all samples in REDS (see below). Multivariate regression was applied to VWF:Ag as a function H antigen density and O vs. non-O blood group, both separately and within the same model. All models were adjusted for age, gender, and self-reported ethnicity. ResultsABO blood group frequencies in both cohorts were similar to that of the US population. VWF:Ag differed significantly between ABO blood groups with lower values in blood group O versus non-O (REDS: ratio = 0.75, 95% CI [0.71, 0.80], p<2.2e-16, log-linear regression). H glycan density also differed between ABO blood group (p<2.2e-16, Kruskal-Wallis; O vs. non-O, ratio = 2.03, 95% CI [1.88, 2.19], p<2.2e-16). A significant fraction of H glycan density variation was attributable to ABO (REDS r2 =0.45; GABC r2 =0.34), but a wide range of H glycan density was observed in all blood groups, including within blood group O. In multivariate regression, both H glycan density and O versus non-O blood group, considered separately or in the same model, were significantly associated with VWF:Ag (REDS combined model: p = 2.9e-5 and 2.7e-4 for H glycan and blood group, respectively). In GABC but not in REDS, regression was also significant for an interaction between H glycan density and blood group (p = 0.031). Both cohorts estimated a stronger association of VWF:Ag with H in non-O blood groups.FUT2 sequencing in the REDS cohort identified 22 distinct FUT2 haplotypes. 99.5% (497/499) of individuals could be accurately assigned FUT2 genotypes based on the common W154* (rs601338) polymorphism alone. In GABC, this decreased to 94% (476/488) due to higher frequency of a hypomorphic allele (rs1047781) more commonly found in Asian individuals. In REDS, quantitative PCR did not identify copy-number variation at FUT2. There was no significant association between FUT2 genotype-predicted function and VWF:Ag or H glycan density in either cohort. ConclusionH glycan density correlated with VWF:Ag in both cohorts. H glycan density could mediate the association between ABO blood group and VWF:Ag. If so, this suggests a non-linear, complex relationship between H and VWF and a separate ABO mechanism cannot be excluded. In both cohorts, there was no association of FUT2 (Secretor) genotype with VWF. Our data suggest prior focused approaches to FUT2 genotyping are at risk to undercall non-functional alleles, particularly in cohorts with non-European ancestries. Taken together, these indicate blood group H may be a significant modifier of VWF:Ag, and that this effect is not due to the influence of Secretor phenotype. DisclosuresJohnsen:Octapharma: Other: Speaker; Biogen: Research Funding; CSL Behring: Other: Speaker.

Hepatitis E virus: seroprevalence and frequency of viral RNA detection among US blood donors

Hepatitis E virus (HEV) is a nonenveloped emerging virus of increasing worldwide interest. Antibody prevalence, RNA frequencies, and transfusion transmissions have been reported. We investigated the HEV RNA and antibody frequencies in US blood donors. Individual-donation HEV RNA testing was performed on 18,829 donations from six US geographic regions using a CE-marked nucleic acid test (95% limit of detection, 7.9 IU/mL). Repeat-reactive donations were confirmed by in-house, real-time polymerase chain reaction (PCR; 10.3 IU/mL). Total HEV seroprevalence in a randomly selected subset of donations (n = 4499) was assessed by a direct, double-antigen sandwich assay; reactives were further tested for immunoglobulin (Ig)G and IgM. As part of the total antibody confirmatory algorithm, the cutoff was adjusted. Two donations tested confirmed-positive for RNA (PCR not quantifiable, IgM/IgG positive; and 14 IU/mL, antibody negative) for a frequency of 1 in 9500 (95% confidence interval [CI], 1:2850-1:56,180) and 99.96% specificity (95% CI, 99.92%-99.98%); both donors were from the Midwest United States. Antibody prevalence was 9.5% (95% CI, 8.7-10.5) before the cutoff adjustment and 7.7% (95% CI, 7.0%-8.5%) after adjustment; 0.58% (95% CI, 0.39%-0.85%) were IgM positive. We confirmed comparatively low rates and low viral loads of HEV RNA in US blood donors indicating the need for individual-donation testing if screening is implemented. Antibody prevalence rates were comparable to those reported by one US study using a different assay, but lower than those reported in another study using yet a third assay. We did not answer the question of whether US blood donation screening is warranted. Selective strategies involving providing HEV-negative blood to severely immunosuppressed patients at risk of developing hepatitis may be considered.

Admission glucose and in-hospital mortality in patients with acute myocardial infarction, with and without diabetes, from 2001 to 2011 (the China PEACE-Retrospective Acute Myocardial Infarction Study): a retrospective analysis

BackgroundThe relation between blood glucose concentrations on hospital admission and in-hospital mortality in patients with acute myocardial infarction, with and without diabetes, has not been well characterised in Chinese patients. MethodsUsing the China PEACE-Retrospective Acute Myocardial Infarction Study, we took a representative sample of patients with acute myocardial infarction from 2001, 2006, and 2011 and classified them according to their blood glucose concentrations on admission to hospital (<3·9, 3·9–7·8, 7·8–11·1, ≥11·1 mmol/L). We compared in-hospital mortality across these admission glucose categories, stratified by diabetes status. The central ethics committee at the China National Center for Cardiovascular Diseases approved the study, with a waiver of patients' written consent. This study is registered with www.ClinicalTrials.gov, NCT01624883. FindingsDespite an increase in the proportion of patients with diabetes admitted to hospital for acute myocardial infarction in 2001–11 (17·5% in 2001, 20·1% in 2006, and 23·1% in 2011; p=0·0001), in-hospital mortality associated with hyperglycaemia on admission did not change (p=0·2). The relation between blood glucose concentration on admission and in-hospital mortality risk in patients with acute myocardial infarction with or without recognised diabetes was consistent across different study years (p value for interaction 0·9). After adjustment for patients characteristics and clinical status, compared with euglycaemic patients (7·8–11·1 mmol/L), hyperglycaemia (≥11·1 mmol/L) was associated with an increase in mortality risk both in patients with known diabetes (odds ratio [OR] 2·49, 95% CI 1·59–3·90) and in patients without known diabetes (2·59, 2·17–3·09). By contrast, hypoglycaemia (<3·9 mmol/L) was associated with a greater risk of in-hospital mortality only in patients with known diabetes (2·93, 1·16–7·39). A U-shaped relation exists between blood glucose concentrations on admission and in-hospital mortality in patients with diabetes, but a more linear relationship exists in patients without diabetes. InterpretationIn Chinese patients with acute myocardial infarction, both hyperglycaemia and hypoglycaemia on admission to hospital are associated with an increased risk for in-hospital mortality in patients with diabetes. However, only hyperglycaemia, but not hypoglycaemia, is a predictor of increased mortality for patients without diabetes. FundingThis project was partly supported by the Research Special Fund for Public Welfare Industry of Health (201202025) from the National Health and Family Planning Commission of China, the National Key Technology R&D Program (2013BAI09B01) from the Ministry of Science and Technology of China, and grant 20131100501 from State Administration of Foreign Experts Affairs of China. HMK is supported by grant U01 HL105270-05 (Center for Cardiovascular Outcomes Research at Yale University) from the US National Heart, Lung, and Blood Institute. The sponsors had no role in the conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation or approval of the abstract.

Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1–2 dose de-escalation study

The optimum preparative regimen for unrelated donor marrow transplantation in patients with severe aplastic anaemia remains to be established. We investigated whether the combination of fludarabine, anti-thymocyte globulin, and total body irradiation (TBI) would enable reduction of the cyclophosphamide dose to less than 200 mg/kg while maintaining engraftment and having a survival similar to or better than that with standard regimens using a cyclophosphamide dose of 200 mg/kg (known to be associated with significant organ toxicity) for unrelated donor transplantation for severe aplastic anaemia. We have previously shown that cyclophosphamide at 150 mg/kg resulted in excess toxicity and its omission (0 mg/kg) resulted in unacceptable graft failure (three of three patients had secondary graft failure). Here we report results for the 50 mg/kg and 100 mg/kg cohorts. In a multicentre phase 1-2 study, patients (aged ≤65 years) with severe aplastic anaemia, adequate organ function, and an unrelated adult marrow donor HLA matched at the allele level for HLA A, B, C, and DRB1 or mismatched at a single HLA locus received bone marrow grafts from unrelated donors. All patients received anti-thymocyte globulin (rabbit derived 3 mg/kg per day, intravenously, on days -4 to -2, or equine derived 30 mg/kg per day, intravenously, on days -4 to -2), fludarabine (30 mg/m(2) per day, intravenously, on days -5 to -2), and TBI (2 Gy). Cyclophosphamide dosing started at 150 mg/kg and was de-escalated in steps of 50 mg/kg (to 100 mg/kg, 50 mg/kg, and 0 mg/kg). The primary endpoint was the selection of the optimum cyclophosphamide dose based on assessments of graft failure (primary or secondary), toxicity, and early death during 100 days of follow-up after the transplant; this is the planned final analysis for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT00326417. 96 patients had bone marrow transplant. At day 100, 35 (92%) of 38 patients were engrafted and alive in the cyclophosphamide 50 mg/kg cohort and 35 (85%) of 41 in the 100 mg/kg cohort. Cyclophosphamide 50 mg/kg and 100 mg/kg resulted in posterior means for fatality without graft failure of 0·7% (credible interval 0-3·3) and 1·4% (0-4·9), respectively. Three patients (8%) had graft failure with cyclophosphamide 50 mg/kg and six (15%) with cyclophosphamide 100 mg/kg. Four (11%) patients had major regimen-related toxicity with cyclophosphamide 50 mg/kg and nine (22%) with cyclophosphamide 100 mg/kg. The most common organ toxicity was pulmonary (grade 3 or 4 dyspnoea or hypoxia including mechanical ventilation), and occurred in three (8%) and four (10%) patients given cyclophosphamide 50 mg/kg and 100 mg/kg, respectively. Cyclophosphamide at 50 mg/kg and 100 mg/kg with TBI 2 Gy, fludarabine, and anti-thymocyte globulin results in effective conditioning and few early deaths after unrelated donor transplantation for severe aplastic anaemia. These doses of cyclophosphamide provide a framework for further regimen optimisation strategies. US National Heart, Lung, and Blood Institute and National Cancer Institute.

Risk factors and epidemiology of human T-lymphotropic virus types 1 and 2 in US blood donors

Blood donations in the US are routinely screened for markers of human T-lymphotropic virus (HTLV). Seroprevalence and risk factors associated with HTLV-1 and -2 infection from the US Retrovirus Epidemiology Donor Study (REDS-II) Transfusion-Transmitted Viral Infection (TTVI) Rate and Risk Factor Study are reported. Among 14,809,334 blood donations screened during 2011-2012, 516 HTLV confirmed seropositive cases were identified, with an overall prevalence of 3.5 infections per 1,0 donations (95% CI: 3.2-3.8). A case-control study of risk factors from 90 donors with serology-confirmed HTLV-1 infection, 102 with HTLV-2 (cases), and 1,587 donors with false-positive results (controls) was conducted. Frequencies and adjusted odds ratios (AORs) from separate multivariable logistic regression analyses for HTLV-1 and -2 cases compared to controls are reported. Mean age was 48.0 (SD: 12.4), 52.3 (SD: 11.0) and 41.7 (SD: 15.7) years for HTLV-1, HTLV-2 cases and controls, respectively. Being a first-time donor, older, non-white, non-Hispanic female were significant demographic factors associated with both infections. HTLV-1 cases were more likely than controls to be Black (AOR: 13.3, 95% CI: 6.1-29.2), born outside of the US (AOR: 8.6, 95% CI: 4.0-18.4), have migrated (family or self) from an endemic area (AOR: 1.8, 95% CI: 1.2-2.7), report sex with an IDU (AOR: 10.9, 95% CI: 3.6-33.4) or have multiple partners (AOR: 3.1, 95% CI: 1.5-6.1). HTLV-2 cases were more likely to be Black (AOR: 15.4, 95% CI: 6.9-34.3), Native Americans (AOR: 10.7, 95% CI: 1.5-77.0), report sex with an IDU (AOR: 27.2, 95% CI: 9.7-75.8) or have multiple partners (AOR: 2.9, 95% CI: 1.5-5.7). US blood donors with HTLV-1 or -2 infection present with the known risk factors. Migration from endemic areas is mainly associated with HTLV-1 infection, while HTLV-2 is associated with Native American donors. Sexual risk behavior and IDU continue to be risk factors for both viruses.

Blood donor deferral for men who have sex with men: the Blood Donation Rules Opinion Study (Blood DROPS).

In the United States, any man who discloses having had sex with another man (MSM) even once since 1977 is currently deferred from donating blood. A study was conducted to assess noncompliance with the policy at four geographically dispersed blood centers. Male donors 18+ years of age with e-mail addresses were randomly selected and invited to complete a confidential online survey between August and October 2013. No additional recruitment e-mails were sent. Survey content included demographics, sexual history, donation history, compliance with the policy, and opinions about current and modified policies. Response rate was 11.5% but varied by center (6.3% to 21.7%). Of 3183 completed surveys, 2.6% of respondents (95% confidence interval, 2.1%-3.2%) reported donation after male-male sex. Noncompliance was not statistically different among the centers (p = 0.1), but was related to age with 5.7, 4.6, 2.5, and 1.0% of donors 18 to 24, 25 to 34, 35 to 54, and 50+ years of age, respectively, reporting noncompliance (p < 0.001). Of all respondents, 6.8% reported at least six female and 0.3% reported at least six male sex partners in the past 5 years. Opinions about the current MSM policy were mixed with noncomplying donors more supportive of change than complying donors. Approximatey half of noncompliers indicated they would adhere to a 1-year deferral. Noncompliance with the MSM policy is evident and may be increasing compared to earlier data. Any change from the current policy will require close monitoring to determine whether it affects residual risk of HIV in the US blood supply.

Cryptic Hepatitis B and E in Patients With Acute Hepatitis of Unknown Etiology.

Up to 30% of acute viral hepatitis has no known etiology. To determine the disease etiology in patients with acute hepatitis of unknown etiology (HUE), serum specimens were obtained from 38 patients residing in the United Kingdom and Vietnam and from 26 healthy US blood donors. All specimens tested negative for known viral infections causing hepatitis, using commercially available serological and nucleic acid assays. Specimens were processed by sequence-independent complementary DNA amplification and next-generation sequencing (NGS). Sufficient material for individual NGS libraries was obtained from 12 HUE cases and 26 blood donors; the remaining HUE cases were sequenced as a pool. Read mapping was done by targeted and de novo assembly. Sequences from hepatitis B virus (HBV) were detected in 7 individuals with HUE (58.3%) and the pooled library, and hepatitis E virus (HEV) was detected in 2 individuals with HUE (16.7%) and the pooled library. Both HEV-positive cases were coinfected with HBV. HBV sequences belonged to genotypes A, D, or G, and HEV sequences belonged to genotype 3. No known hepatotropic viruses were detected in the tested normal human sera. NGS-based detection of HBV and HEV infections is more sensitive than using commercially available assays. HBV and HEV may be cryptically associated with HUE.

Association of hospital admission and forced vital capacity endpoints with survival in patients with idiopathic pulmonary fibrosis: analysis of a pooled cohort from three clinical trials

Mortality is an impractical primary endpoint for clinical trials in patients with idiopathic pulmonary fibrosis who have mild-to-moderate physiological impairment because event rates are low. Change in forced vital capacity (FVC) is widely accepted as a surrogate for mortality and is the most common primary endpoint in clinical trials for this disorder. Use of hospital admission as a predictor for mortality, independent of FVC decline, has not been well defined. We aimed to ascertain the independent and combined association of hospital admission and at least a 10% decrease in FVC with all-cause mortality. We did a pooled cohort study of 517 patients with idiopathic pulmonary fibrosis from three IPFnet multicentre randomised controlled trials. We compared the incidence of non-elective hospital admission and a 10% or greater reduction in FVC across strata of baseline physiological impairment. We used Cox proportional-hazards models to assess the risk of all-cause mortality associated with these surrogate events, occurring up to a predefined landmark timepoint. The three studies are registered at ClinicalTrials.gov, numbers NCT00650091, NCT00517933, and NCT00957242. Seven patients died before the landmark timepoint. Of the 510 patients remaining, 38 (7%) were admitted to hospital up to the predefined timepoint and 58 (11%) had a categorical decrease in FVC of at least 10%. Most patients admitted to hospital did not have a 10% or greater decrease in FVC (30 vs eight). Both surrogate events were associated with subsequent time to death from any cause (hazard ratio [HR] for admission 4·05, 95% CI 1·36-12·11 vs HR for 10% or greater decline in FVC 4·68, 1·83-11·99). When causes of hospital admission were considered, only respiratory events were associated with mortality (5·97, 1·81-19·74). Hospital admission might be an appropriate component of a clinically meaningful composite endpoint that improves the feasibility of clinical trials in idiopathic pulmonary fibrosis. Further studies are needed to refine the most appropriate definition of hospital admission for future trials. US National Heart, Lung, and Blood Institute (NHLBI), and The Cowlin Family Fund at the Chicago Community Trust.