US Blood Research Articles

HIV antiretroviral therapy and prevention use in US blood donors: a new blood safety concern

AbstractAntiretroviral therapy (ART) to treat and pre-exposure prophylaxis (PrEP) to prevent HIV infection are effective tools to help end the HIV epidemic. However, their use could affect HIV transfusion-transmission risk. Three different ART/PrEP prevalence analyses in blood donors were conducted. First, blood samples from HIV-positive and a comparison group of infection-nonreactive donors were tested under blind using liquid chromatography-tandem mass spectrometry for ART. Second, blood donor samples from infection-nonreactive, 18- to 45-year-old, male, first-time blood donors in 6 US locations were tested for emtricitabine and tenofovir. Third, in men who have sex with men (MSM) participating in the 2017 Centers for Disease Control and Prevention National HIV Behavioral Surveillance (NHBS) from 5 US cities, self-reported PrEP use proximate to donation was assessed. In blind testing, no ART was detected in 300 infection-nonreactive donor samples, but in 299 HIV confirmed-infected donor samples, 46 (15.4%; 95% confidence interval [CI], 11.5% to 20.0%) had evidence of ART. Of the 1494 samples tested from first-time male donors, 9 (0.6%; 95% CI, 0.03% to 1.1%) had tenofovir and emtricitabine. In the NHBS MSM survey, 27 of 591 respondents (4.8%; 95% CI, 3.2% to 6.9%) reported donating blood in 2016 or 2017 and PrEP use within the same time frame as blood donation. Persons who are HIV positive and taking ART and persons taking PrEP to prevent HIV infection are donating blood. Both situations could lead to increased risk of HIV transfusion transmission if blood screening assays are unable to detect HIV in donations from infected donors.

Use of a rapid electronic survey methodology to estimate blood donors' potential exposure to emerging infectious diseases: Application of a statistically representative sampling methodology to assess risk in US blood centers.

BackgroundRisk assessments of transfusion‐transmitted emerging infectious diseases (EIDs) are complicated by the fact that blood donorsʼ demographics and behaviors can be different from the general population. Therefore, when assessing potential blood donor exposure to EIDs, the use of general population characteristics, such as U.S. travel statistics, may invoke uncertainties that result in inaccurate estimates of blood donor exposure. This may, in turn, lead to the creation of donor deferral policies that do not match actual risk.Study Design and MethodsThis article reports on the development of a system to rapidly assess EID risks for a nationally representative portion of the U.S. blood donor population. To assess the effectiveness of this system, a test survey was developed and deployed to a statistically representative sample frame of blood donors from five blood collecting organizations. Donors were directed to an online survey to ascertain their recent travel and potential exposure to Middle East respiratory syndrome coronavirus (MERS‐CoV).ResultsA total of 7128 responses were received from 54 256 invitations. The age‐adjusted estimated total number of blood donors potentially exposed to MERS‐CoV was approximately 15 640 blood donors compared to a lower U.S. general population‐based estimate of 9610 blood donors.ConclusionThe structured donor demographic sample–based data provided an assessment of blood donorsʼ potential exposure to an emerging pathogen that was 63% larger than the U.S. population–based estimate. This illustrates the need for tailored blood donor–based EID risk assessments that provide more specific demographic risk intelligence and can inform appropriate regulatory decision making.

Advancing Research on the Complex Interrelations Between Atrial Fibrillation and Heart Failure: A Report From a US National Heart, Lung, and Blood Institute Virtual Workshop.

The interrelationships between atrial fibrillation (AF) and heart failure (HF) are complex and poorly understood, yet the number of patients with AF and HF continues to increase worldwide. Thus, there is a need for initiatives that prioritize research on the intersection between AF and HF. This article summarizes the proceedings of a virtual workshop convened by the US National Heart, Lung, and Blood Institute to identify important research opportunities in AF and HF. Key knowledge gaps were reviewed and research priorities were proposed for characterizing the pathophysiological overlap and deleterious interactions between AF and HF; preventing HF in people with AF; preventing AF in individuals with HF; and addressing symptom burden and health status outcomes in AF and HF. These research priorities will hopefully help inform, encourage, and stimulate innovative, cost-efficient, and transformative studies to enhance the outcomes of patients with AF and HF.

COVID-19 and the impact of social determinants of health

COVID-19 and the impact of social determinants of health

Convalescent plasma to treat coronavirus disease 2019 (COVID-19): considerations for clinical trial design.

KEY IDEAS Case series studying convalescent plasma use in the treatment of COVID‐19 have been promising, but additional, high‐quality studies are needed to determine the efficacy of the treatment when applied for prophylaxis, for early phases of illness, and for severe illness.Previous studies of convalescent plasma in treating other viral diseases have identified factors to consider when designing treatment protocols, including timing of administration relative to onset of illness, timing of donation relative to resolution of symptoms, severity of illness of the donor, pretransfusion serology of the recipient, and antibody titers of the donor.There are many clinical trials studying treatment of, and prophylaxis against, COVID‐19 using convalescent plasma. In addition to clinical trials, the FDA also allows treatment through two other pathways: the “Expanded Access to Convalescent Plasma for the Treatment of Patients with COVID‐19” protocol, and emergency investigational new drug applications. The FDA also provides criteria for donation of convalescent plasma.

Strategic issues currently facing the US blood system.

Strategic issues currently facing the US blood system.

Low prevalence red blood cell antigens: transfusions, babies, and changing demographics

See article on page 870–874, in this issue

Transfusion-associated adverse events and implementation of blood safety measures - findings from the 2017 National Blood Collection and Utilization Survey.

Serious transfusion-associated adverse events are rare in the United States. To enhance blood safety, various measures have been developed. With use of data from the 2017 National Blood Collection and Utilization Survey (NBCUS), we describe the rate of transfusion-associated adverse events and the implementation of specific blood safety measures. Data from the 2017 NBCUS were used with comparison to already published estimates from 2015. Survey weighting and imputation were used to obtain national estimates of transfusion-associated adverse events, and the number of units treated with pathogen reduction technology (PRT), screened for Babesia, and leukoreduced. The rate of transfusion-associated adverse events requiring any diagnostic or therapeutic interventions was stable (275 reactions per 100,000 transfusions in 2015 and 282 reactions per 100,000 transfusions in 2017). In 2017 among US blood collection centers, 16 of 141 (11.3%) reported screening units for Babesia and 28 of 144 (19.4%) reported PRT implementation; 138 of 2279 (6.1%) hospitals reported transfusing PRT-treated platelets. In 2017, 134 of 2336 (5.7%) hospitals reported performing secondary bacterial testing of platelets (50,922 culture-based and 63,220 rapid immunoassay tests); in 2015, 71 of 1877 (3.8%) hospitals performed secondary testing (87,155 culture-based and 21,779 rapid immunoassay tests). Nearly all whole blood/red blood cell units and platelet units were leukoreduced. Besides leukoreduction, implementation of most blood safety measures reported in this study remains low. Nationally, hospitals might be shifting from culture-based secondary bacterial testing to rapid immunoassays.

Skeletal maturation and long-bone growth patterns of patients with progeria: a retrospective study

Hutchinson-Gilford progeria syndrome (termed progeria in this Article) is a rare sporadic genetic disorder. One early clinical manifestation of progeria is abnormal skeletal growth, yet this growth has not been fully characterised. We aimed to characterise the skeletal maturation and long-bone growth patterns of patients with the clinical phenotype of progeria. For this retrospective study, we reviewed skeletal surveys of patients (aged <20 years) with progeria obtained over a 9·5-year period. Most surveys included radiographs of the hands and long bones (humeri, radii, ulnas, tibias, and fibulas). Bone ages of these patients were estimated by the standards of Greulich and Pyle. Following the established methods for studying long-bone growth, the study cohort was separated into two overlapping age groups: longitudinal bone length measurements were made between physes for the childhood group (aged 12 years or younger) and from the upper margins of the proximal to the lower margin of the distal ossified epiphyses for the adolescent group (aged 10 years or older). Bone age estimates and bone length measurements were plotted against the chronological age of patients and compared with reference standards. Statistical analyses were based on mixed models. 85 patients with progeria and 250 skeletal surveys were included in our study. For both sexes, bone age estimates showed a more advanced skeletal maturation rate throughout all chronological ages than the normal rate of 1 (p<0·0001), with the rate of maturation being 1·09 (SE 0·02) for boys and 1·14 (0·02) for girls. Longitudinal long-bone lengths began to deviate from normal standards by age 1-2 years. Growth curves for these long bones plateaued at about half the normal eventual bone length, and the half-life (the time taken to grow to half the eventual bone length) was also about half the time compared with normal standards. Our study established growth curves that might serve as reference standards for skeletal maturation and long-bone growth of patients with the clinical phenotype of progeria. The Progeria Research Foundation, the US National Heart, Lung and Blood Institute, the Dana-Farber Cancer Institute Stop&Shop Pediatric Brain Tumor Program, the US National Center for Research Resources, US National Institutes of Health.

Slowing decline in blood collection and transfusion in the United States - 2017.

The National Blood Collection and Utilization Survey (NBCUS) has demonstrated declines in blood collection and transfusion in the United States since 2008, including declines of 11.6% in red blood cell (RBC) collections and 13.9% in RBC transfusions during 2013-2015. This study described the 2017 NBCUS results. The 2017 NBCUS was distributed to all US blood collection centers, all hospitals performing at least 1000 surgeries annually, and a 40% random sample of hospitals performing 100 to 999 surgeries annually. Weighting and imputation were used to generate national estimates for units of blood and components collected, deferred, distributed, transfused, and outdated. Response rates for the 2017 NBCUS were 88% for blood collection centers and 86% for transfusing hospitals. Compared with 2015, the number of RBC units collected during 2017 (12,211,000; 95% confidence interval [CI], 11,680,000-12,742,000) declined by 3.0%, and transfused RBC units (10,654,000, 95% CI, 10,314,000-10,995,000) declined by 6.1%. Distributed platelet (PLT) units (2,560,000; 95% CI, 2,391,000-2,730,000 units) increased by 5.1%, and transfused PLT units (1,937,000, 95% CI, 1,794,000-2,079,000) declined by 2.3%. Distributed plasma units (3,209,000; 95% CI, 2,879,000-3,539,000) declined by 13.6%, and transfused plasma units (2,374,000; 95% CI, 2,262,000-2,487,000) declined by 12.9%. The 2017 NBCUS suggests a continued but slowing decline in demand for RBCs. The decline in blood collection and use will likely continue. Despite decreasing demand and increasing manufacturing costs of blood products, the US blood industry has met the regular and emergent needs of the country.

The evanescence and persistence of RBC alloantibodies in blood donors.

Blood donors represent a healthy population, whose red blood cell (RBC) alloantibody persistence or evanescence kinetics may differ from those of immunocompromised patients. A better understanding of the biologic factors impacting antibody persistence is warranted, as the presence of alloantibodies may impact donor health and the fate of the donated blood product. Donor/donation data collected from four US blood centers from 2012 to 2016 as part of the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) were analyzed. Clinically significant antibodies from blood donors with more than one donation who underwent at least one follow-up antibody screen after the initial antibody identification were included. Of 632,378 blood donors, 481 (128 males and 353 females) fit inclusion criteria. Antibody screens detected 562 alloantibodies, with 368 of 562 (65%) of antibodies being persistently detected and with 194 of 562 (35%) becoming evanescent. Factors associated with antibody persistence included antibody specificity, detection at the first donation, reported history of transfusion, and detection of multiple antibodies concurrently. Anti-D, C, and Fya were most likely to persist, while anti-M, Jka , and S were most frequently evanescent. These data provide insight into variables impacting the duration of antibody detection, and they may also influence blood donor center policies regarding donor recruitment/acceptance.

Update on the NAEPPCC Asthma Guidelines: The wait is over, or is it?

As an asthma specialist, one is often asked to discuss the asthma guidelines. The challenge that one faces is deciding which guidelines to use as a resource for discussion or presentation. It often comes down to the following questions: What is the question? What message does one want to deliver? Where is the most current information? and Who is the target audience? This commentary will help answer those questions as it guides the reader through the new update of the National Heart, Lung and Blood Institute/National Asthma Education and Prevention Program guidelines and then outlines differences between 2 widely used strategies for the management of asthma: the Global Initiative for Asthma and the National Heart, Lung and Blood Institute/National Asthma Education and Prevention Program Guidelines for the Diagnosis and Management of Asthma.

Optimizing the Use of Platelets in a Single Oncology Center during Critical Shortages: Can Current Platelet Donations from Volunteer Donors be Sustained to Provide Adequate Platelet Inventories Long Term?

Introduction: The single largest use of platelets transfusions (PLT) are for patients with hematologic malignancies receiving Myeloablative chemotherapy or undergoing hematopoietic stem cell transplantation (HSCT). Patients routinely get prophylactically platelet transfusions at platelet counts ≤ 20 × 109/L at our institution per institutional guidelines. For this review we analyzed a two day period when a critical shortage of platelets occurred to illustrate how we managed the transfusion needs of our patients. Method All daily platelet orders are triaged. The orders are inclusive of patient demographics, indication(s) for transfusion and pertinent lab results (most recent H/H, PLT count, PT/INR/PTT, fibrinogen, D-Dimer, Creatinine and BUN). The location of the patient and indications (ICH Hemorrhage/coagulation abnormalities) further allows the Blood Bank to prioritize the release of platelets. The orders are sorted by counts ≤5K, 6-10K, 11-20K, 21-30K, 31-40K, 51-60K and &amp;gt;61K and then categorized by location (EC, Surgery/Outpatients and disease (Hematologic malignancies/HSCT/other neoplasms). A reduction of the Random Donor Platelet (RDP) inventory by 50% is considered critical especially when daily shipments from our contracted blood suppliers are delayed or reduced. Our regular platelet inventory consist mainly of RDPs with 5-10% of Single Donor Apheresis platelets (SDPs). Our daily transfusion needs consists of 400 to 700 RDPs with a reduction on weekends. Due to the volume of our daily platelet transfusion our needs cannot be met by SDPs only. Results: We received 269 platelet transfusion orders within the two day critical shortage period. The bulk of the orders were received between 4-10 am. The majority (93%) were from patients undergoing treatment for hematologic malignancies of which 18% were from HSCT patients. A total of 474 RDP were transfused to 176 (66%) patients, median of 3 (range 2-4 pooled RDPs), 57 (32%) received 2 pooled RDPs, 116 (66%) received 3 pooled RDPs and 3 (2%) patients received 4 pooled RDPs. Of the 269 patients 82 (30%) were transfused with SDPs. There were 2 duplicate orders and 9 (3.3%) patients did not receive platelets on the requested day. The majority of the platelet orders (85.5%) were for platelet counts =&amp;lt;20 K/uL, followed by Intracranial hemorrhage (4%), active bleeding (3.4%) and bone marrow biopsy (2.6%) and LP/Solid Organ biopsy/Spinal Surgery/Others (each &amp;lt;1%). The reduction in the number of pooled RDPs did not lead to adverse events. Discussion: When the platelet inventory is at par, patients receive 4 pooled RDP units as prophylactic transfusion for counts ≤ 20K. When the inventory falls to below 50% of par, the number of pooled RDPs is decreased to 3 for actively bleeding patients and for those with counts ≤10 K/L. The pools are further decreased to 2-3 RDP units for counts 11-20 K based on inventory. Electronic notification is sent to primary providers to call the Transfusion Medicine Physician when the reason for transfusion does not meet institutional guidelines. The current platelet stock management is heavily dependent on whole blood donations from which RDPs are processed. High school students currently contribute 10% of the US blood supply which may increase up to 20% during the spring/fall months. The most important question that needs to be discussed and addressed before it leads to a crisis is the sustainability of Platelets donations from volunteer donors. Donor Centers around the United States have seen a gradual decline in volunteer donors with aging of the volunteer donor pool. Only 4-6% of eligible donors in the US currently donate blood and this is projected to decrease in the next five years. The TRALI mitigation strategy eliminated many eligible females from donating whole blood/platelets and now the Iron mitigation strategy will also impact the volunteer donor pool. One avenue that could be explored for platelet acquisition would be to accumulate a dedicated pedigreed/trusted pre-screened repeat pool of paid donors similar to the concept used by US plasma centers. This will be a major paradigm shift, be problematic in the beginning as the model is not being used currently in the US for platelet donations. However, with the ever increasing need for platelet transfusion, altruistic appeals alone may be insufficient to meet the demands of blood and platelets. This concept may not be too farfetched in the near future and begs to be considered. Disclosures No relevant conflicts of interest to declare.

The Presence and Persistence of Pregnancy-Associated Red Blood Cell Alloantibodies in Blood Donors

Background: Females have higher RBC alloantibody prevalence than males, presumably due to exposure to non-self RBC antigens through pregnancy as well as transfusion. Given the lack of routinely available and longitudinal data on lifelong pregnancy and transfusion histories, few studies have been able to distinguish pregnancy versus transfusion as contributing risk factors for RBC alloantibody induction or for the persistence of RBC alloantibody detectability. We hypothesized that pregnancy would be an important source of persistently detected RBC alloantibodies and investigated this in a longitudinal blood donor database. Study Design and Methods: Donor/donation data were obtained from 4 US blood centers from 2012-2016. RBC antibody screen results and antibody identification (using tube, gel, or solid phase), donor demographics, pregnancy history, and transfusion history were evaluated. Blood donors were included in this analysis if they had an RBC alloantibody detected at any given donation as long as they had at least one subsequent blood donation and antibody screen. Anti-D antibodies detected, but present for &lt; 6 months in females &lt;50 years old were presumed due to passive RhIg and were excluded from this analysis. RBC alloantibody persistence was defined as an RBC alloantibody detected at each subsequent donation following its initial identification and RBC alloantibody evanescence was defined as one or more subsequent donations without re-detection of the alloantibody. Rates of donor alloantibody persistence were calculated as blood donors with persistent alloantibodies divided by blood donors with any alloantibody, and patterns of persistence were characterized by donor sex and presumed alloantibody source exposure. Results: 503 blood donors had a detectable RBC alloantibody and a follow-up antibody screen; 374 (74%) were female and 130 (26%) were male. Of the 374 alloimmunized females, 210 (56%) reported prior pregnancy and no transfusion, 124 (33%) reported prior pregnancy and transfusion, 26 (7%) reported no pregnancy or transfusion, and 12 (3%) reported prior transfusion and no pregnancy. 215/334 (64%) of previously pregnant females had RBC alloantibodies that remained detectable throughout the duration of the study. The mean duration of detectability for persistent antibodies in previously pregnant females was 640 days, compared to a mean time to disappearance of 183 days for evanescent antibodies. In contrast, males and all never-pregnant females were less likely to have persistently detectable antibodies, with 52% (87/167) being in this category (chi square p = 0.008). The mean duration of detectability for persistent antibodies in males and never-pregnant females was 576 days, compared to a mean time to disappearance of 290 days for evanescent antibodies. Previously pregnant females with a reported history of prior transfusion (n=124) had the highest rate (77%) of RBC alloantibody persistence. The alloantibody specificities of previously pregnant females included E (96), D (81), K (78), Fy (21), C (47), MNS (38), and Jk (18). Of these, Fy and non-passive D were most likely to be persistent (each 86%), followed by C (79%), K (74%), E (59%), Jk (55%), and MNS (34%). Conclusion: Data from this multi-center blood donor database, with documented life-long pregnancy and transfusion histories, highlight the role that pregnancy plays in RBC alloimmunization. Importantly, pregnancy was an exposure source in almost all studied RBC alloimmunized female healthy blood donors and was the sole reported exposure in the majority of donors. Although these data cannot definitively identify the source of non-self blood group antigen exposure in blood donors with both pregnancy and transfusion histories, they show that antibodies in previously pregnant females are long lasting. It is possible that length of exposure to non-self RBC antigens, the relatively young age of females during childbearing, long standing fetal white blood cell microchimerism in the maternal circulation, or other variables may impact plasma cell longevity and/or antibody production, and thus the persistence of pregnancy (versus transfusion) associated RBC alloantibodies. Given the numbers and persistence of such RBC alloantibodies, we recommend that pregnancy history be taken into consideration in all RBC alloimmunization studies involving females at or beyond childbearing age. Disclosures Spencer: HemaStrat, LLC: Membership on an entity's Board of Directors or advisory committees.

Iron status and risk factors for iron depletion in a racially/ethnically diverse blood donor population.

The optimal approach for reducing iron depletion (ID) in blood donors may vary depending on biologic or behavioral differences across donors. More than 12,600 successful whole blood donors were enrolled from four US blood centers for ferritin testing. The study population was enriched for racial/ethnic minorities (1605 African American, 1616 Asian, 1023 Hispanic). Subjects completed questionnaires on ID risk factors. Logistic regression identified predictors of absent iron stores (AIS; ferritin <12 ng/mL) and low ferritin (LF; ferritin <26 ng/mL). Across all subjects, 19% had AIS and 42% had LF, with a sharp increase in risk observed with increasing donation intensity and among women a large decrease in risk in those more than 50 years old. When other factors were controlled for, African American and Asian donors showed 20% to 25% decreased risk for AIS compared to non-Hispanic Caucasian donors, while Hispanic donors had 25% higher risk. Daily iron supplementation reduced risk for LF and AIS by 30% to 40%, respectively, while the benefit from less frequent use was lower (7%-19% protection). Regular antacid use was associated with at least 20% increment to risk. Use of oral contraceptives or estrogen in females reduced risk by 16% to 22%, while males who reported supplemental testosterone use had a 50% to 125% greater risk for LF and AIS. This study confirms high prevalence of LF and AIS in US donors and the principal risk factors of age, sex, and donation frequency. Additional demographic and behavioral risk factors of secondary importance might allow for refinement of ID mitigation strategies.

Bacterial Contamination of Platelet Units is an Under-Recognized Contributor to Healthcare-associated infections (HAIs)

BACKGROUND HAIs create a major logistical, financial and patient safety concerns within the healthcare system. Bacterial contamination of platelet components (PCs) is the most common, under recognized, infectious risk of transfusion and contributor to HAIs. Contaminated PCs can lead to central line-associated bloodstream infections, bacteremia, and sepsis, with major long term complications and/or death. While US blood centers employ primary bacterial culture screening (pBCS) today, FDA's Draft Guidance and Blood Products Advisory Committee recommend additional approaches to reduce continued risk including FDA-approved pathogen reduction technology (PRT). Our objective is to determine whether PRT is an effective means to reduce the infectious risk of PCs. METHODS We compiled national hemovigilance (HV) data (2006-2016) from the UK, France, Switzerland, Belgium and the US to examine use of pBCS and PRT with amotosalen/UVA and their associated reports of PC bacterial contamination and sepsis. RESULTS Introduction of pBCS decreased HV reports of PC bacterial contamination in the US by 72.5% (p 700,000 PRT PCs over the same time period. CONCLUSIONS pBCS does not eliminate the risk of bacterial contamination; In its Draft Guidance, FDA acknowledges this shortcoming and recommends further measures. In contrast, PRT inactivates a broad spectrum of pathogens present in PCs, regardless of low level contamination, eliminating the need for pBCS. PRT provides clinicians and patients with transfusion-ready PCs, mitigating the risk of transfusion-transmitted infections and representing an approach to increase hospital safety while reducing the financial challenges of transfusion-related HAIs.

Is rescue based treatment or early conservative treatment superior in managing patent ductus arteriosus?

Commentary on: Clyman RI, Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Håkansson S, Lindqvist J, Farooqi A, Katheria A, Sauberan J, Singh J, Nelson K, Wickremasinghe A, Dong L, Hassinger DC, Aucott SW, Hayashi M, Heuchan AM, Carey WA, Derrick M, Fernandez E, Sankar M, Leone T, Perez J, Serize A, the PDA-TOLERATE (PDA: TO LEave it alone or Respond And Treat Early) Trial Investigators. PDA-TOLERATE trial: an exploratory randomized controlled trial of treatment of moderate-to-large patent ductus arteriosus at one week of age. J Pediatr 2018; 205: 41–48.e6. PMID: 30340932. Numerous poor outcomes in premature neonates are attributed to the persistent left-to-right shunt of a PDA, such as pulmonary haemorrhage, bronchopulmonary dysplasia and death. There is also concern that PDAs cause ‘systemic steal’, leading to intraventricular haemorrhage (IVH), hypotension and delay of time to full feeds 1, 2. The PDA is particularly problematic in the extremely premature neonate: Clyman et al. 3 showed spontaneous closure at seven days of life in 98% of those infants born at ≥30 weeks compared to just 13% of infants born at 24 weeks. No trial, however, has definitively shown reduced incidence of BPD or death with either prophylactic indomethacin or closure of the PDA regardless of timing 4. Thus, optimal management of the PDA in premature infants has long been a source of controversy among neonatologists. According to the authors, this study, which they describe as a pilot exploratory trial, had two goals – to evaluate whether there is a difference between presumptive and rescue-based treatment of the PDA on ligation and presence of PDA at discharge, and to obtain data on several secondary outcomes to appropriately power future investigations. This trial addressed the current knowledge gap by focusing solely on infants with moderate-to-large PDAs present after the first week of life and evaluating PDA exposure to assess for long-term outcomes throughout hospitalisation. There was no statistically significant difference, however, in the primary outcome or in many of the pre-specified secondary outcomes. The authors note many limitations of their trial, which can make this paper difficult for clinicians to generalise to their populations. The primary outcome is difficult to apply to clinical practice, as most clinicians are less interested in the presence of PDA as they are in preventing its long-term consequences. The small size of the study and high rate (almost 50%) of rescue treatment in the CT arm could have contributed to the lack of difference in the outcomes of the two groups. Further, the multiple comparisons required for the statistical analysis of groups and subgroups impedes our ability to draw conclusions from the appearance of statistical significance. What the results of this study do suggest is that clinicians should not feel obligated to automatically treat every PDA. Based on the data presented, a reasonable strategy is to follow the infant's clinical status, treating when necessary. With this strategy, about 50% of infants with a persistent PDA may avoid exposure to the harms of NSAIDs and ligation by the time of discharge. This study also highlights the need for larger trials to assess the long-term consequences of prolonged PDA exposure in lower gestational age infants. This study also helps inform future trials about specific sub-populations of infants to include, and about required sample sizes. https://ebneo.org/2019/04/pda-tolerate-trial/ None. This study was funded by grants from the Gerber Foundation, US Public Health Service, National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, and National Institutes of Health and a gift from the Jamie and Bobby Gates Foundation.

Endothelin-1/nitric oxide balance and HOMA index in children with excess weight and hypertension: a pathophysiological model of hypertension.

The aim of this study was to investigate the relationship between endothelin-1, nitric oxide, insulin resistance, and blood pressure in young subjects with a high prevalence of excess weight and/or elevated blood pressure. In a cohort of 238 children (mean age = 11.1 years), height, weight, waist circumference, and blood pressure were assessed. Body mass index, waist-to-height ratio, and blood pressure percentiles were calculated, and the children were classified as having excess weight and elevated blood pressure according to the International Obesity Task Force and the US blood pressure nomograms specific for gender, age and height, respectively. Endothelin-1 and nitric oxide production were assessed, and the homeostatic model assessment index was calculated. Forty-three percent of children were male, 71% had excess weight, and 37% had systolic and/or diastolic values above the ninetieth percentile. Plasma endothelin-1 and nitric oxide production were independently correlated (p < 0.05). In multivariate analyses, the HOMA index was associated with systolic and diastolic blood pressure (p = 0.01), and nitric oxide was independently related to diastolic blood pressure (p = 0.04), even after adjustment for measures of body composition. By using the waist-to-height ratio instead of BMI in the statistical model, the association between the homeostatic model assessment index and blood pressure was attenuated, while the results remained similar for nitric oxide. No correlation was found between endothelin-1 and blood pressure. In our study population, the correlation between nitric oxide and blood pressure and the lack of a relationship between endothelin-1 and blood pressure could be explained by an increase in the vasodilator effect of local and systemic nitric oxide, which counteracts the possible hypertensive effect of endothelin-1.

Sex differences in cytokine production following West Nile virus infection: Implications for symptom manifestation.

West Nile virus (WNV) infection outcomes vary among individuals, with most infections resulting in asymptomatic or mild flu-like symptoms. We previously reported an association between early cytokine production and symptom outcome following WNV infection in US blood donors. In this meta-analysis, we found that WNV-infected females reported more symptoms than WNV-infected males, despite similar initial viremia and type I interferon responses. As the infection progressed, males exhibited a protracted cytokine response-marked by sustained CCL2 (MCP-1), CCL11 (eotaxin-1), CXCL10 (IP-10) and IL-15-that was absent in females. Our results suggest that sex differences may be a factor in sustaining WNV immunity.

Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203)

Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial. In this prospective multicentre phase 2 trial, adult patients aged 18-75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1·3 mg/m2 intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day -3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m2 intravenous bolus on day 1 and 10 mg/m2 intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0·05 mg/kg twice daily (or oral equivalent) starting on day -3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5-15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3-4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037. Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0·72 (90% CI 0·54-0·94; p=0·044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0·98 (0·76-1·27; p=0·92) for tacrolimus, methotrexate, and bortezomib, and 1·10 (0·86-1·41; p=0·49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13%) had grade 3 and 67 (73%) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11%) had grade 3 and 68 (76%) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20%) had grade 3 and 63 (68%) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84%] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82%] for tacrolimus, methotrexate, and bortezomib; and 78 [85%] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47%], 44 [49%], and 43 [47%], respectively). Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial. US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.