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Author(s): Gottschall, Jerome; Wu, YanYun; Triulzi, Darrell; Kleinman, Steven; Strauss, Ronald; Zimrin, Ann Butler; McClure, Christopher; Tan, Sylvia; Bialkowski, Walter; Murphy, Edward; Ness, Paul; NHLBI Recipient Epidemiology and Donor Evaluation (REDS-III) Study | Abstract: BackgroundUsing the Recipient and Donor Epidemiology Study-III (REDS-III) recipient and donor databases, we performed a retrospective analysis of platelet use in 12 US hospitals that were participants in REDS-III.Study design and methodsData were electronically extracted from participating transfusion service and blood center computer systems and from medical records of the 12 REDS-III hospitals. All platelet transfusions from 2013 to 2016 given to patients aged 18 years and older were included in the analysis.ResultsThere were 28,843 inpatients and 2987 outpatients who were transfused with 163,719 platelet products (103,371 apheresis, 60,348 whole blood derived); 93.5% of platelets were leukoreduced and 72.5% were irradiated. Forty-six percent were transfused to patients with an International Classification of Diseases, 9th/10th Revision (ICD-9/10) diagnosis of leukemia, myelodysplastic syndrome (MDS), or lymphoma. The general ward and the intensive care unit (ICU) were the most common issue locations. Only 54% of platelet transfusions were ABO identical; and 60.6% of platelet transfusions given to Rh-negative patients were Rh positive. The most common pretransfusion platelet count range for inpatients was 20,000 to 50,000/μL, for outpatients it was 10,000 to 20,000/μL. Among ICU patients, 35% of platelet transfusion episodes had a platelet count of greater than 50,000/μL; this was only 8% for general ward and 2% for outpatients. The median posttransfusion increment, not corrected for platelet dose and/or patient size, ranged from 12,000 to 20,000/μL for inpatients, and from 17,000 to 27,000/μL for outpatients.ConclusionsThese data from one of the largest reviews of platelet transfusion practice to date provide guidance for where to focus future clinical research studies and platelet blood management programs.

Background Although the subject of many previous studies, the importance of white blood cell (WBC) alloimmunization in granulocyte transfusion therapy has not been settled. In this study, we report the results of the effects of WBC antibodies in the RING (Resolving Infection in Neutropenia with Granulocytes) study, a randomized controlled trial comparing the efficacy of daily granulocyte transfusion therapy plus antimicrobials versus antimicrobials alone; the primary outcome results have been published previously. Study design and methods One hundred fourteen subjects were enrolled in the study. Serum samples for WBC antibody determination were obtained from each subject at baseline and at 2 and 6 weeks. One hundred subjects had at least one antibody test result. Samples were tested for human leukocyte antigen (HLA) Class I and Class II antibodies as well as for granulocyte-specific antibodies using granulocyte agglutination and immunofluorescence techniques. All testing was performed at a central laboratory. Results Baseline WBC alloimmunization was modest, depending somewhat on the assay. Seroconversion during the study was slightly higher in the granulocyte transfusion arm, but the differences were not statistically significant. There was no demonstrable effect of the presence of alloimmunization on the primary outcome (survival and microbial response at 42 days), the occurrence of transfusion reactions (either overall or pulmonary), or posttransfusion neutrophil increments. Conclusion The presence or development of WBC antibodies had no demonstrable effect on any clinical aspect of granulocyte transfusion therapy. It appears that, at least in the patient population studied, there is no evidence suggesting need for concern about recipient WBC alloimmunization when prescribing granulocyte transfusions.

Background Sites of entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly expressed in nasal epithelial cells; however, little is known about the impact of intranasal corticosteroids (INCS) on coronavirus disease 2019 (COVID-19)-related outcomes. Objective To determine the association between baseline INCS use and COVID-19-related outcomes. Methods Using the Cleveland Clinic COVID-19 Research Registry, we performed a propensity score matching for treatment with INCS before SARS-CoV-2 infection (April 1, 2020, to March 31, 2021). Of the 82,096 individuals who tested positive, 72,147 met inclusion criteria. Our endpoints included the need for hospitalization, admission to the intensive care unit (ICU), or in-hospital mortality. Results Of the 12,608 (17.5%) who were hospitalized, 2935 (4.1%) required ICU admission and 1880 (2.6%) died during hospitalization. A significant proportion (n = 10,187; 14.1%) were using INCS before SARS-CoV-2 infection. Compared with nonusers, INCS users demonstrated lower risk for hospitalization (adjusted odds ratio [OR] [95% confidence interval (CI)]: 0.78 [0.72; 0.85]), ICU admission (adjusted OR [95% CI]: 0.77 [0.65; 0.92]), and in-hospital mortality (adjusted OR [95% CI]: 0.76 [0.61; 0.94]). These findings were replicated in sensitivity analyses where patients on inhaled corticosteroids and those with allergic rhinitis were excluded. The beneficial effect of INCS was significant after adjustment for baseline blood eosinophil count (measured before SARS-CoV-2 testing) in a subset of 30,289 individuals. Conclusion INCS therapy is associated with a lower risk for COVID-19-related hospitalization, ICU admission, or death. Future randomized control trials are needed to determine if INCS reduces the risk for severe outcomes related to COVID-19.

BACKGROUND Prevalence estimates of the serious hazards of transfusion vary widely. We hypothesized that the current reporting infrastructure in the United States fails to capture many transfusion reactions and undertook a multicenter study using active surveillance, data review, and adjudication to test this hypothesis. STUDY DESIGN AND METHODS A retrospective record review was completed for a random sample of 17% of all inpatient transfusion episodes over 6 months at four academic tertiary care hospitals, with an episode defined as all blood products released to a patient in 6 hours. Data were recorded by trained clinical research nurses, and serious reactions were adjudicated by a panel of transfusion medicine experts. RESULTS Of 4857 transfusion episodes investigated, 1.1% were associated with a serious reaction. Transfusion-associated circulatory overload was the most frequent serious reaction noted, being identified in 1% of transfusion episodes. Despite clinical notes describing a potential transfusion association in 59% of these cases, only 5.1% were reported to the transfusion service. Suspected transfusion-related acute lung injury/possible transfusion-related acute lung injury, anaphylactic, and hypotensive reactions were noted in 0.08, 0.02, and 0.02% of transfusion episodes, respectively. Minor reactions, including febrile nonhemolytic and allergic, were noted in 0.62 and 0.29% of transfusion episodes, respectively, with 30 and 50% reported to the transfusion service. CONCLUSION Underreporting of cardiopulmonary transfusion reactions is striking among academic, tertiary care hospitals. Complete and accurate reporting is essential to identify, define, establish pathogenesis, and mitigate/treat transfusion reactions. A better understanding of the failure to report may improve the accuracy of passive reporting systems.

High-dose granulocyte transfusion therapy has been available for 20 years, yet its clinical efficacy has never been conclusively demonstrated. We report here the results of RING (Resolving Infection in Neutropenia with Granulocytes), a multicenter randomized controlled trial designed to address this question. Eligible subjects were those with neutropenia (absolute neutrophil count500/μL) and proven/probable/presumed infection. Subjects were randomized to receive either (1) standard antimicrobial therapy or (2) standard antimicrobial therapy plus daily granulocyte transfusions from donors stimulated with granulocyte colony-stimulating factor (G-CSF) and dexamethasone. The primary end point was a composite of survival plus microbial response, at 42 days after randomization. Microbial response was determined by a blinded adjudication panel. Fifty-six subjects were randomized to the granulocyte arm and 58 to the control arm. Transfused subjects received a median of 5 transfusions. Mean transfusion dose was 54.9 × 10(9) granulocytes. Overall success rates were 42% and 43% for the granulocyte and control groups, respectively (P.99), and 49% and 41%, respectively, for subjects who received their assigned treatments (P = .64). Success rates for granulocyte and control arms did not differ within any infection type. In a post hoc analysis, subjects who received an average dose per transfusion of ≥0.6 × 10(9) granulocytes per kilogram tended to have better outcomes than those receiving a lower dose. In conclusion, there was no overall effect of granulocyte transfusion on the primary outcome, but because enrollment was half that planned, power to detect a true beneficial effect was low. RING was registered at www.clinicaltrials.gov as #NCT00627393.

Background: Epidemiologic studies involving birth defects are extremely sensitive to phenotype accuracy and precision. We devised a case review and classification protocol for a project to study school achievement in children with idiopathic, nonsyndromic orofacial clefts to improve the reliability of phenotypic classification from the statewide birth defects registry. Methods: Surveillance-program abstraction data and medical records at the birth or treating hospitals were used when available. Exclusion criteria included: median cleft lip; Tessier cleft; premaxillary agenesis; presence of a recognizable syndrome, phenotype, association, or sequence (other than Robin sequence); clefts with other malformations not considered to be normal or common variants in the newborn; and cases with documented or suspected genetic or teratogenic causes. Results: Of 712 children identified with orofacial clefts, 153 were excluded, leaving 559 nonsyndromic orofacial cleft cases of unknown cause in the final study. These cases were grouped into the following clinically meaningful types: cleft lip with or without cleft alveolus; cleft lip and cleft palate; and cleft palate only. This review and classification process resulted in the elimination of 21.5% of the original cohort of identified cases, with most exclusions being due to suspected syndromic associations. Conclusion: Verbatim descriptions of the clinical findings are critical for accurate classification of diagnoses. This review process improved the precision of orofacial cleft phenotype classification for our study. Precision would have been further improved if all of the cases had verbatim descriptions of diagnoses and all medical records could have been reviewed by the classification team. Birth Defects Research (Part A) 103:899–903, 2015. © 2015 Wiley Periodicals, Inc.

Background and objectives Many hospitals require transfusions to be discontinued when vital signs stray from predetermined ranges, regardless of clinical symptoms. Variations in vital signs may be unrelated to transfusion, however, and needlessly stopping a transfusion may delay medical care while increasing donor exposures and healthcare costs. We hypothesized that a detailed study of vital sign changes associated with transfusion of blood product by component, including those associated with potential reactions (complicated) and those deemed to be uncomplicated, would establish a useful framework of reference for treating clinicians and transfusion services alike. Materials and methods A retrospective electronic record review of transfusion service and transfusion recipient data was completed on 3852 inpatient transfusion episodes over a 6-month period at four academic tertiary care hospitals across the United States. Vital signs pre- and post-transfusion were recorded by trained clinical research nurses. Serious reactions were adjudicated by a panel of transfusion medicine experts. Results In both uncomplicated transfusions (n = 3765) and those including an adverse reaction (n = 87), vital sign fluctuations were generally modest. Compared to uncomplicated transfusions, transfusions complicated by febrile reactions were associated with higher pretransfusion temperature and higher pretransfusion pulse rates. Episodes of transfusion circulatory overload were associated with higher pretransfusion respiration rates compared to uncomplicated transfusions. Conclusion Most transfusions are associated with only modest changes in vital signs. Pretransfusion vital signs may be an important yet previously understudied predictor of vital sign changes during transfusion. The optimal role of vital sign assessment during blood transfusion deserves further study.

Background Little is known about the barriers faced by families of children with birth defects in obtaining healthcare. We examined reported perceived barriers to care and satisfaction with care among mothers of children with orofacial clefts.

BACKGROUND How platelet (PLT) product characteristics such as dose, source (whole blood-derived (WBD) vs. apheresis), storage duration, and ABO matching status affect the risks of transfusion-related adverse events (TRAEs) is unclear. Similarly, more information is needed to define how recipient characteristics affect the frequency of TRAEs following PLT transfusion.

The purpose of this review is to report a recently completed multicenter randomized controlled trial of neutrophil/granulocyte transfusions collected from G-CSF + dexamethasone donors to treat neutropenic infections in oncology and transplant patients, within the context of other historic and current clinical trials.The multicenter trial (RING Study) was funded by the NHLBI transfusion medicine/hemostasis clinical trials network.There was no significant benefit of therapeutic neutrophil/granulocyte transfusions versus antibiotics per intention to treat analysis, but 32% of patients received substandard neutrophil doses. Separate analysis suggested patients given a higher neutrophil doses had better outcomes.Efficacy of 'high-dose' therapeutic neutrophil/granulocyte transfusions remains unproven, but promising.

BACKGROUND Information on travel distance and time to care for children with birth defects is lacking. We examined factors associated with travel distance and time to cleft care among children with orofacial clefts. METHODS In 2006, a mail/phone survey was administered in English and Spanish to all resident mothers of children with orofacial clefts born 2001 to 2004 and identified by the North Carolina birth defects registry. We analyzed one-way travel distance and time and the extent to which taking a child to care was a problem. We used multivariable logistic regression to examine the association between selected sociodemographic factors and travel distance (≤60 miles and >60 miles) and time (≤60 min and >60 min) to cleft care. RESULTS Of 475 eligible participants, 51.6% (n = 245) responded. Of the respondents, 97.1% (n = 238) were the child's biological mother. Approximately 83% (n = 204) of respondents were non-Hispanic White; 33.3% (n = 81) were college educated; and 50.0% (n = 115) had private health insurance. One-way mean and median travel distances were 80 and 50 miles, respectively (range, 0–1058 miles). One-way mean and median travel times were 92 and 60 min, respectively (range, 5 min to 8 hr). After adjusting for selected sociodemographics, travel distance varied significantly by maternal education, child's age, and cleft type. Travel time varied significantly by child's age. Approximately 67% (n = 162) reported taking their child to receive care was not a problem. CONCLUSION Approximately 48% of respondents traveled > 1 hr to receive cleft care. Increasing access to care may be important for improving health outcomes among this population Birth Defects Research (Part A) 97:685–695, 2013. © 2013 Wiley Periodicals, Inc.

Study of the pathophysiology and treatment of anemia of prematurity is facilitated by direct measurement of red cell volume (RCV) utilizing microliter quantities of blood samples. Our objective was to compare concurrent measurements of multiple direct RCV methods in infants.Eighteen preterm infants receiving clinically indicated transfusions had concurrent flow cytometric determinations of RCV and 24-h red blood cell (RBC) recovery based on donor-recipient differences of biotin-labeled RBCs (BioRBCs), Kidd antigen mismatched RBCs, and fetal hemoglobin-positive (HbF(+)) RBCs. High-performance liquid chromatography (HPLC) was also used for measuring HbF and adult hemoglobin protein concentrations for the determination of RCV.Concurrent RCV measurements using BioRBCs (18 and 54 µg/ml), Kidd antigen, and HbF flow cytometry were not statistically different compared with RCVs measured using the reference BioRBC density (6 µg/ml). By contrast, the HbF-HPLC method overestimated RCV by 45% compared with the reference method. All the methods demonstrated 100% 24-h posttransfusion RBC recovery (PTR24).Because BioRBC, Kidd antigen, and fetal hemoglobin (HbF) flow cytometry are safe and accurate methods requiring10 µl of patient blood for determining RCV and PTR24 in preterm infants, they can be useful in clinical and research studies of anemia and other conditions.

S. Panzer, S. Engelbrecht, M. F. Cole-Sinclair, E. M. Wood, S. Wendel, S. Biagini, Z. Zhu, J.-J. Lefrere, G. Andreu, T. Zunino, J.-J. Cabaud, P. Rouger, O. Garraud, K. Janetzko, M. Muller-Steinhardt, P. van der Burg, A. Brand, P. Agarwal, T. Triyono, A. Gharehbaghian, N. Manny, O. Zelig, A. Takeshita, Y. Yonemura, H. Fujihara, K. E. Nollet, H. Ohto, K.-S. Han, V. S. Nadarajan, G. Berlin, S. G. Sandler, R. G. Strauss & H. W. Reesink

Background Prevention of red blood cell (RBC) alloimmunization in patients with sickle cell disease (SCD) focuses on phenotypic RBC matching. We assessed alloimmunization among transfused patients with SCD after implementing leukoreduction and prophylactic antigen matching (PAM). Study design and methods Retrospective review of transfusion and medical records for SCD patients 18 months to 81 years of age was performed covering two 5-year periods: Period 1, no PAM, occasional leukoreduction, and Period 2, consistent leukoreduction and extended PAM (Rh, Kell, S, Fy, Jk) for patients already alloimmunized. Patients transfused in Period 1 were excluded from Period 2. Results A total of 293 patients were transfused in Period 1 and 183 in Period 2. Median time between first sample and last type and screen after transfusion was 2.12 years in Period 1 and 1.03 years in Period 2. Initial alloimmunization prevalence was lower in Period 2 (26.2%) versus Period 1 (37.5%) and after subsequent transfusions in Period 2 (23.8%) versus Period 1 (45.7%), although without significant difference after adjusting for number of units transfused, percentage of leukoreduced RBCs, sex, and age. Alloimmunized patients received more nonleukoreduced RBCs in Period 1 than nonalloimmunized. Patients transfused during inflammatory conditions were not significantly more likely to become alloimmunized. Conclusions The prevalence of initial and subsequent RBC alloimmunization in Period 2 was lower than that in Period 1; however, overall prevalence remained high. We recommend leukoreduced, hemoglobin S-negative Rh and Kell PAM RBCs for transfusion of patients with SCD. Component and recipient factors affecting alloimmunization should be studied further.

Age-group analyses were conducted of patients in the prophylactic platelet dose trial (PLADO), which evaluated the relation between platelet dose per transfusion and bleeding. Hospitalized patients with treatment-induced hypoproliferative thrombocytopenia were randomly assigned to 1 of 3 platelet doses: 1.1 × 1011, 2.2 × 1011, or 4.4 × 1011 platelets/m2 per transfusion, given for morning counts of ≤ 10 000 platelets/μL. Daily hemostatic assessments were performed. The primary end point (percentage of patients who developed grade 2 or higher World Health Organization bleeding) was evaluated in 198 children (0-18 years) and 1044 adults. Although platelet dose did not predict bleeding for any age group, children overall had a significantly higher risk of grade 2 or higher bleeding than adults (86%, 88%, 77% vs 67% of patients aged 0-5 years, 6-12 years, 13-18 years, vs adults, respectively) and more days with grade 2 or higher bleeding (median, 3 days in each pediatric group vs 1 day in adults; P < .001). The effect of age on bleeding differed by disease treatment category and was most pronounced among autologous transplant recipients. Pediatric subjects were at higher risk of bleeding over a wide range of platelet counts, indicating that their excess bleeding risk may be because of factors other than platelet counts. This trial was registered at www.clinicaltrials.gov as #NCT00128713.

Summary Infections continue to be a serious problem for severely neutropenic oncology and haematopoietic progenitor cell (HPC) transplant patients. Although it is now possible to collect much larger numbers of neutrophils (PMNs) from donors stimulated with granulocyte colony-stimulating factor + corticosteroids, the efficacy of these ‘modern’ granulocyte/PMN transfusions, with higher doses of PMNs, has not been established by convincing randomized control trials. Accordingly, they cannot be recommended for standard therapy at this time.

Platelet characteristics, such as platelet dose, platelet source (apheresis vs pooled), platelet donor-recipient ABO compatibility, and duration of platelet storage, can affect posttransfusion platelet increments, but it is unclear whether these factors impact platelet transfusion efficacy on clinical bleeding. We performed secondary analyses of platelet transfusions given in the prospective randomized Platelet Dose Study, which included 1272 platelet-transfused hematology-oncology patients who received 6031 prophylactic platelet transfusions. The primary outcome of these analyses was time from first transfusion to first World Health Organization ≥ grade 2 bleeding. Platelet transfusion increments were assessed at 0.25 to 4 hours and 16 to 32 hours after platelet transfusion. There were 778 patients evaluable for analysis of time to bleeding. Adjusted models showed that randomized dose strategy, platelet source, ABO compatibility, and duration of storage did not predict this outcome. Platelet increments were generally higher for transfusions of apheresis platelets, ABO-identical platelets, and platelets stored 3 days versus 4 to 5 days. Thus, although platelet source, ABO compatibility, and duration of storage exert a modest impact on both absolute and corrected posttransfusion platelet increments, they have no measurable impact on prevention of clinical bleeding. This trial was registered at www.clinicaltrials.gov as #NCT00128713.

Objective To examine maternal perceptions of barriers to care of children with orofacial clefts (OFC) in a population-based survey that solicited open-ended qualitative responses. Design and Setting In 2006, a combination mail/phone survey was sent to all mothers of children with OFC. The questionnaire included 76 items. A final open-ended question was included for additional information about cleft-related care. The analysis included responses to the open-ended question and sociodemographic characteristics of the respondents. Qualitative responses were transcribed and entered into a qualitative software package for analysis, and common themes were elucidated. Participants/Patients The North Carolina Birth Defects Monitoring Program was used to identify all resident infants born with OFC from 2001 to 2004. Of 478 eligible mothers, 52.9% (n = 248) responded to the survey, and 39.5% (n = 98) responded to the final open-ended question. Main Outcome Measures Percentage reporting problems accessing care, frequency of positive and negative comments, and indicators of financial, personal, and structural barriers to care. Results Of the 98 respondents, the majority (n = 95, 96.99%) were the biological mother. Almost 40% of mothers indicated that accessing primary craniofacial care was a problem. Of those citing perceived barriers to care, the major issues cited were financial, structural, and personal barriers. Conclusions Collaborative efforts between craniofacial centers and teams, health care systems, and birth defects registries are warranted to reduce perceived barriers to care among families of children with OFC. Further exploration of the themes and factors associated with barriers to care and services is needed.

Characterization of the behavior of red blood cells (RBCs) in the bloodstream after transfusion (i.e., posttransfusion RBC kinetics) generally consists of measurement of RBC volume (RCV) and RBC survival (RCS) assessed by posttransfusion recovery at 24 hours (PTR24) and at later times, that is, to 50% survival (T50) and to the mean potential life span (MPL). Posttransfusion RBC kinetic studies provide information valuable in establishing the diagnosis and defining the pathogenesis of hematologic conditions and in determining optimal RBC transfusion and blood banking practices.1 Ideally, techniques for measuring posttransfusion RBC kinetics should be precise, safe, and easily applied. They should also be broadly applicable to diverse study populations and require minimal blood volumes for sampling, labeling, and analysis—particularly for infants. Methods utilizing chromium-51 (51Cr) radionuclide RBC labeling have been adopted by the International Committee for Standardization in Hematology as the reference method for determining posttransfusion RCS in humans.2 Unfortunately, because some species experience excessive rates of loss of 51Cr from RBCs (3%–4% per day in sheep, horses, cattle, goats, cats, and rats, compared to approx. 1% in humans),3 the 51Cr labeling method is not reliable for all mammalian species. Moreover, the costs for radiation containment and disposal are substantial and increasing. Recently, a method based on biotin-labeled RBCs (BioRBC) that does not require radiation exposure has been developed and validated for use in posttransfusion kinetic studies in a broad spectrum of mammalian species. In addition to overcoming the aforementioned limitations of the 51Cr method, the BioRBC method achieves similar sensitivity while requiring analytic blood volumes as small as 3 μL4,5 compared to the 1 to 2 mL recommended for the 51Cr method.3 The focus of this study was on validating the BioRBC labeling method in sheep. This is important because ovine fetal and newborn cardiovascular, pulmonary, and of relevance for this report, hematologic development and physiology resemble those of humans.6 In particular, ovine erythropoiesis in the fetus, neonate, and adult is similar to the human, and regulation of erythropoiesis and RBC kinetics in the ovine model are currently active areas of study.7–10 Accordingly, lambs and sheep are logical animal models for preclinical testing of this method for measuring RCV and RCS. We recently demonstrated that autologous sheep RBCs labeled at four discrete, low biotin densities yielded RCV results that are equivalent to one another and are within 10% of values determined simultaneously using [14C]cyanate-labeled RBCs.11 Further, we have applied the multidensity method to measurement of RCV in human adults with similar success. We were able to extend these human studies to survival of the BioRBCs and determine short-term and long-term RCS in eight participants. However, use of a radioactive-labeled marker such as 51Cr was not included because of the technical and financial demands. In this study, we extend these preclinical animal studies to assess the validity of RCS determined in the same animals using RBCs labeled with the same four biotin densities and with [14C]cyanate. Because of the additional complexities of dealing with an animal with a large spleen that sequesters up to 30% of RBCs, of the difficulties of measuring radiolabeled RBCs, and the need to fit a mathematical curve to accurately determine the proportion of each of the BioRBC peaks, we have only recently completed this analysis for the current report. To do so, we assessed short-term RCS by PTR24 and long-term RCS by T50 and by MPL. For long-term RCS, we hypothesized that these two variables would agree closely when determined using RBCs labeled with the lower BioRBC densities and that they would agree with RCS determined using [14C]cyanate.12

BACKGROUND: Adherence to tuberculosis (TB) treatment is important for TB control. The effect of stigma on adherence has not been well quantified. OBJECTIVE: To identify the effects of TB and acquired immune-deficiency syndrome (AIDS) stigma on missed doses during TB treatment. DESIGN: Validated TB and AIDS stigma scales assessing perceived and experienced/felt stigma were administered in a prospective cohort of 459 TB patients at TB treatment initiation and after 2 months. Repeated measures and multivariable models estimated the effects of stigma on the rate of missed doses. RESULTS: Fifty-six per cent of patients missed no doses and associations between stigma and missed doses were minimal. Heterogeneity of effects was observed how- ever with higher experienced and felt TB stigma increasing missed doses among women (adjusted RR 1.22 95%CI 1.10-1.34) and human immunodeficiency virus (HIV) co-infected patients (aRR 1.39 95%CI 1.13-1.72). Experienced and felt AIDS stigma also increased missed doses among HIV co-infected patients (aRR 1.43 95%CI 1.31-1.56). CONCLUSION: Stigma has a minimal effect in this population with good adherence. Among women and HIV co-infected patients however experienced and felt stigma and not perceived stigma increased the rate of missed doses. Further research is needed to determine if stigma or coping interventions among these subgroups would improve adherence.

A previous International Forum (IF) addressed collection modalities of granulocytes (i.e. neutrophils) for supportive therapy (Vox Sang 2010; 88:567–575). Contributions to this IF came only from European centres because physicians representing centres from the United States of America (USA) elected not to participate. However, after publication of the IF, it was suggested by Professor Strauss that other centres from the USA be invited to describe their collection modalities, because it was anticipated that there might be noteworthy differences in practices between centres in Europe and the USA. Indeed, some differences have now become apparent, based on responses from four different centres in the USA. Question 1 Donor selection Do you collect granulocytes exclusively from your pool of healthy blood donors or do you also include the patients’ relatives as donors? When selecting the donor, do you predominantly select CMV-negative donors for CMV-negative recepients? Question 2 Mobilization regimen Does your national law allow the administration of G-CSF to unrelated donors Does your national law allow the administration of G-CSF to related donors Which dose of G-CSF is administered to the donors and at how many hours before donation? Do you combine G-CSF with steroids? If yes, at which dose and which kind of steroids – prednisolone or dexamethason (DXM)? If steroids are given alone, at how many hours before collection? prednisolone (dosage)? DXM (dosage)? Question 3 Frequency of donations Do you restrict the frequency of donations if the donor has been primed with G-CSF, steroids or both? What are your regulations concerning the accumulation of HES in the donor? Question 4 Sedimentation agents High- (Hetastarch, HS) and low molecular weight hydroxyethyl starch (Pentastarch PS) are used as sedimentation agents to enhance granulocyte collection. Which kind of hydroxyethyl starch is used at your institution for granulocyte collection? Question 5 Compatibility tests Do you respect or ignore the ABO and Rhesus match between donor and recipient? Do D-negative women younger than 50 years receive granulocytes only from D-negative donors? Question 6 Screening for leucocyte antibodies Because of the risk of TRALI, the ISBT working party has recommended to screen donor and recipient for the leucocyte antibodies. In case of positivity of either donor or recipient, a crossmatch between the plasma/serum of the positive individual and the leucocytes of the negative individual was recommended [4]. Do you screen or crossmatch the donor and recipient for leucocyte antibodies (HLA and HNA)? If positive, which consequences are drawn? Do you routinely reduce the plasma donations from female donors? In the USA, G-CSF is not approved by the FDA to be given to apheresis donors for mobilizing granulocytes. Furthermore, ‘granulocytes apheresis’ are not listed as an FDA-licensed product. In three of the four responding USA centres, the dose of G-CSF given to all donors before each collection is a standard one of 480 μg, whereas it is 600 μg in the fourth centre. In all centres, G-CSF is combined with oral dexamethasone (8 mg). In contrast, six European centres give varying doses of G-CSF according to the donors’ body weight, and only two apply a standardized dose of 300 μg G-CSF to all donors. Further, some European centres use only steroids for donor stimulation, while others use G-CSF alone. Although steroids alone are used by some of the other centres in the USA, they are not used alone by the four responding centres because granulocyte yields are substantially lower than those when donors are stimulated with combined G-CSF + dexamethasone. Moreover, the frequency of donations per donor is significantly less frequent in Europe than in the USA. Another difference is that in the USA, high molecular weight HES is used in three of the four centres because granulocyte yields are superior when compared to lower molecular weight HES, whereas this higher molecular weight HES is applied in only three European centres because of preference in Europe for the lower molecular weight formulation of HES. In two of the three USA centres that answered the question concerning ABO and Rh-D compatibility, ABO compatibility is required – similarly to Europe, where it is required in all but one centre. In two of the four USA centres, Rh-D compatibility is required. Screening donors for HLA and/or HNA antibodies is rarely performed, either in the USA or Europe. The apparent variation in methods for collecting granulocyte concentrates by apheresis requires interested readers to study all available reports and then to select the procedure that best suits their practice. This challenging field is certainly open for further research, and this IF may serve as a stimulating basis for further investigations. Guest Editor Ronald G. Strauss Professor Emeritus of Pathology & Pediatrics University Of Iowa College of Medicine Tel.: 1-319-338-8071 Fax: 1-319-356-0331 E-mail: ude.awoiu@ssuarts-dlanor International Forum Editors Simon Panzer University of Vienna Department Blood Group Serology and Transfusion Medicine Waahringer Gurtel 18-20 A-1090 Vienna, Austria E-mails: ta.ca.neiwinudem@reznap.nomis; ln.tenalpnpk@muroflanoitanretni and Henk W. Reesink Academic Medical Center Department Gastroenterology and Hepatology Amsterdam The Netherlands E-mails: ln.tenalpnpk@muroflanoitanretni; ln.cma@kniseer.w.h

Objective The safe lower limit of haematocrit or haemoglobin that should trigger a red blood cell (RBC) transfusion has not been defined. The objective of this study was to examine the physiological effects of anaemia and compare the acute responses to transfusion in preterm infants who were transfused at higher or lower haematocrit thresholds. Methods The authors studied 41 preterm infants with birth weights 500–1300 g, who were enrolled in a clinical trial comparing high (‘liberal’) and low (‘restrictive’) haematocrit thresholds for transfusion. Measurements were performed before and after a packed RBC transfusion of 15 ml/kg, which was administered because the infant9s haematocrit had fallen below the threshold defined by study protocol. Haemoglobin, haematocrit, RBC count, reticulocyte count, lactic acid and erythropoietin were measured before and after transfusion using standard methods. Cardiac output was measured by echocardiography. Oxygen consumption was determined using indirect calorimetry. Systemic oxygen transport and fractional oxygen extraction were calculated. Results Systemic oxygen transport rose in both groups following transfusion. Lactic acid was lower after transfusion in both groups. Oxygen consumption did not change significantly in either group. Cardiac output and fractional oxygen extraction fell after transfusion in the low haematocrit group only. Conclusions These study9s results demonstrate no acute physiological benefit of transfusion in the high haematocrit group. The fall in cardiac output with transfusion in the low haematocrit group shows that these infants had increased their cardiac output to maintain adequate tissue oxygen delivery in response to anaemia and, therefore, may have benefitted from transfusion.

Community-based dental education (CBDE) shifts a substantial portion of dental clinical education from dental school clinics to mainly public health settings. For dental students to learn effectively in community settings they need preparatory education in cultural awareness, communication skills, and the social and behavioral sciences. The effective integration of CBDE into a dental curriculum requires reflective components, evaluation, and highly organized community-based experiences. This chapter reviews organizational principles and specific strategies to ensure that CBDE is conducted in a fashion that enables student learning and community oral health service. CBDE has substantial potential for affecting the values and behaviors of dental students relative to health care access for underserved populations and for attracting diverse students to dental education. CBDE also provides dentistry with an opportunity to guide dental faculty and student values and orientation towards public service, engagement, ethics, and the health of the public.

A “benchmark” is a standard or measure by which others can be assessed and/or compared. Benchmarking is the process of gathering information (ie, data and/or expert opinions) to set the benchmark. The greater the care, precision and validation taken during the benchmarking process, the more accurately the benchmark will reflect the optimal practices/issues in question and, in turn, allow the best point of reference for comparing/judging/instructing/advising others. In this issue of Transfusion, Fung et al report results of a benchmarking survey performed by the University HealthSystem Consortium (UHC) to assess the acceptability of various RBC anticoagulant/storage solutions and to determine the existence, or lack thereof, of policies to avoid possible hyperkalemia during RBC transfusions given to infants at member institutions.(1) The authors state in the title that this is a “benchmarking study” — which by convention implies that the results will serve as a standard by which others may be measured and/or as a point of reference from which other measurements can be made. Although the need to establish benchmarks for the issues raised (ie, RBC anticoagulant/storage solutions for infant transfusions and policies to avoid potential problems with transfusion-induced hyperkalemia) are well stated in the introduction by Fung et al,(1) the limitations/shortcomings of the benchmarking survey are multiple (as pointed-out by the authors in the discussion section). Thus, the extent to which the findings, conclusions and recommendations of Fung et al should be directly applied to neonatal/infant transfusion practices can be questioned. The basis for my opinion pertaining to limitations/shortcomings, is summarized by the following critical points — many of which were mentioned by the authors themselves,(1) but warrant emphasis here. First, response to the survey by institutions surveyed was only modest (47 of 107 UHC members = 44% for the RBC anticoagulant/preservative section and 45 of 107 = 42% for the hyperkalemia section), with no explanation offered as to why nonresponders failed to reply — other than mentioning that only 77 UHC members are “benchmarking program members” and noting that “no attempt was made at increasing response rate” beyond a few modest efforts.(1) Because UHC members are academic medical centers, one might assume that their practices would be as “evidence-based” as possible. Accordingly, to avoid possible misinformation due to reporting bias, more efforts should have been made to increase response rates to get a complete and accurate picture of member practices — to establish benchmarks that most likely reflect best/optimal practices. Second, one should question whether the most knowledgeable people completed the survey. The respondents were not neonatologists/pediatricians and only 21% were transfusion/pathology physicians. The remaining 79% of respondents were supervisors/managers/administrators.(1) Although these non-physician respondents can review blood bank/laboratory policies/procedures to answer survey questions, it is likely that they will not have in depth knowledge of transfusion practice guidelines/policies of the Departments of Pediatrics and Neonatology Divisions or of the Departments of Nursing. Moreover, they likely will not be familiar with the preferences/practices of physicians prescribing RBC transfusions for infants — particularly pertaining to potassium concerns. Third, to extend the second point, collecting data for which RBC anticoagulant/preservative solutions are “acceptable” provides only limited benchmarking data. For purposes of planning educational programs and recommending evidence-based guidelines/practices, it would be much more informative to know which anticoagulant/preservative solutions are “preferred” and, in the many institutions accepting multiple solutions, what percentage of RBC transfusions are actually given with the “accepted” anticoagulant/preservative solutions. In 19 of 47 responding institutions, four or five different anticoagulant/preservative solutions were “acceptable” with no indication as to which one(s) the prescribing physicians preferred and/or to what extent RBCs stored in different solutions were transfused. Simply acknowledging a solution is “acceptable” does not mean it is preferred or even actually used at an institution. Fourth, no mention is made as to how, or even whether, the survey answers were validated for completeness or accuracy. The authors stated that although no formal validation was performed, all participating UHC members were given opportunities to review and make corrections after close of the survey.(1) It would have increased credibility to report the number/percentage of UHC members who actually did review the completed survey and made corrections — and, in particular, to document whether answers to the survey were ever reviewed by physicians and nurses actually involved in RBC transfusions given to infants. Regarding the acceptability of anticoagulant/preservative solutions, the authors state that the decision to transfuse RBCs stored in additive solutions (AS-1, AS-3, AS-5) should be made by the medical director of the transfusion service, in consultation with institutional neonatologists — a point with which all would agree. The authors then make a rather feeble case for recommending RBCs stored in additive solutions as the best practice for low volume (

Because most extremely preterm infants with birth weight less than 1000 g need red blood cell transfusions, many attempts have been made to collect, process, and store placental blood (ie, umbilical cord blood) for autologous transfusions. Although it is feasible to do this, multiple problems in doing so including insufficient volumes collected, clotting, hemolysis, bacterial contamination, failure to significantly supplant need for allogeneic transfusions, and high costs have led many to question whether, on balance, autologous/placental red blood cell transfusion offers clinically significant benefits.

Since the 2000 Surgeon General's Report on Oral Health (SGROH), substantial areas of inquiry relative to individuals, especially children and youth, with orofacial clefts and other craniofacial conditions have emerged. These areas include access to and cost of care, stigmatization and quality of life, and social and ethical issues around prenatal diagnosis. This update on the 2000 SGROH examines what we have learned about the cost and ability to access cleft and craniofacial care, prenatal diagnosis, and how quality of life is impacted by these conditions and the burden of care. The development of new research tools to assess quality of life since 2000 will permit further study of the impact of oral and craniofacial conditions on children and families and the effect of treatment on quality of life. Despite a better understanding of the higher use of services and increased costs of care for families of children with craniofacial conditions, major gaps in research must be addressed to assist with program planning and policy development for these groups of children and their families. Further work is also needed to assess the cost-effectiveness of craniofacial team care and to better understand family experience with accessing needed care. Finally, prenatal detection and diagnosis of clefts and craniofacial conditions have advanced dramatically, and the roles of craniofacial professionals and teams have been affected. New understandings of prenatal diagnosis and genomic sciences are redefining genetic counseling, therapy, and future preventive initiatives.

Persons with unrecognized HIV infection forgo timely clinical intervention and may unknowingly transmit HIV to partners. However, in the USA, unrecognized infection and late diagnosis are common. To understand barriers and facilitators to HIV testing and care, we conducted a qualitative study of 24 HIV infected persons attending a Southeastern HIV clinic who presented with clinically advanced illness. The primary barrier to HIV testing prior to diagnosis was perception of risk; consequently, most participants were diagnosed after the onset of clinical symptoms. While most patients were anxious to initiate care rapidly after diagnosis, some felt frustrated by the passive process of connecting to specialty care. The first visit with an HIV care provider was identified as critical in the coping process for many patients. Implications for the implementation of Centers for Disease Control and Prevention HIV routine screening guidelines are discussed.

BACKGROUND: Many clinical practices in transfusion medicine are controversial and/or lack definitive guidelines established by sound clinical trials. Although recommendations based on results of clinical trials performed using infants and children may not always be applied directly to adults—and vice versa—lessons learned from pediatric trials can be useful when critically assessing the design/results/conclusions of adult trials. STUDY DESIGN AND METHODS: Four randomized clinical trials (RCTs) studying pediatric patients were critically reviewed. They addressed two red blood cell (RBC) transfusion issues: 1) transfusion guidelines by which RBC transfusions are “triggered” by liberal (LIB; high pretransfusion patient hematocrit [Hct] levels) versus being “triggered” by restricted (RES; low pretransfusion Hct levels) and 2) transfusion of fresh RBCs (≤7 days' storage) versus RBCs (up to 42 days' storage). RESULTS: Findings established by primary outcomes generally were firm (e.g., fewer RBC transfusions were given to infants/children managed by RES guidelines; transfusing small volumes of RBCs stored up to 42 days to preterm infants diminished allogeneic donor exposures and were equally efficacious and safe as fresh RBCs stored ≤7 days). Findings based on secondary outcomes, subset, and post hoc analyses were inconsistent (e.g., clinical outcomes were equivalent after LIB or RES transfusions in only two of three RCTs; in the third, more neurologic problems were found in neonates given RES transfusions). CONCLUSIONS: Clinical practices should be based on data pertaining to the primary outcomes of RCTs, because trials are designed and statistically powered to address these issues. Clinical practices suggested by analysis of secondary outcomes, subsets of patients, and post hoc analyses should be applied cautiously until studied further—ideally, as primary outcomes in subsequent RCTs.

Many aspects of hematopoiesis are either incompletely developed in preterm infants or still functioning to serve the fetus (i.e., the intrauterine counterpart to a liveborn preterm neonate). This delayed development and/or slow adaptation to extrauterine life diminishes the capacity of the neonate to produce red blood cells (RBCs), platelets (PLTs), and neutrophils—particularly during the stress of life-threatening illnesses encountered after preterm birth such as sepsis, severe pulmonary dysfunction, necrotizing enterocolitis, and immune cytopenias. The serious medical and/or surgical problems of preterm birth can be further complicated by phlebotomy blood losses, bleeding, hemolysis, and consumptive coagulopathy. To illustrate, some preterm infants, especially those with birth weight less than 1.0 kg and respiratory distress, are given numerous RBC transfusions early in life owing to several interacting factors. Neonates delivered before 28 weeks of gestation (birth weight

Two randomized clinical trials, conducted independently, have reported results of neonates transfused with red blood cells (RBCs) given per either liberal (relatively high pretransfusion blood hematocrit levels) or restrictive (relatively low pretransfusion blood hematocrit levels) transfusion programs. Both found fewer RBC transfusions given per restrictive programs and comparable outcomes for several clinical endpoints. However, the Iowa trial found significantly more problems with apnea, intraparenchymal brain hemorrhage and periventricular leukomalacia in infants transfused per the restrictive program – findings not found by the Canadian trial. A critical analysis of both trials and possible reasons for the discrepant findings are discussed. Until definitive data are reported by additional studies, it seems prudent not to severely restrict/limit allogeneic RBC transfusions to neonates – except in approved investigational settings.

The aim of this study was to identify factors associated with youth satisfaction with surgical procedures performed to address oral cleft or craniofacial conditions (CFCs). It was hypothesized that youth mental health, participation in decision making, perceived consequences of living with a CFC, and coping strategies would be associated with satisfaction with past surgeries. A total of 203 youth between the ages of 11 and 18 years (mean age = 14.5, standard deviation = 2.0, 61% male participants, 78% oral cleft) completed a series of questionnaires measuring depression, self-esteem, participation in decision making, condition severity, negative and positive consequences of having a CFC, coping, and satisfaction with past surgeries. Multiple regression analysis using boot-strapping techniques found that youth participation in decision making, youth perception of positive consequences of having a CFC, and coping accounted for 32% of the variance in satisfaction with past surgeries (P < 0.001). Youth age, sex, and assessment of condition severity were not significantly associated with satisfaction with surgical outcome. Depression, self-esteem, and negative consequences of having a CFC were not associated with satisfaction with past surgeries. Youth should be actively involved in the decision for craniofacial surgery. Youth who were more satisfied with their surgical outcomes also viewed themselves as having gained from the experience of living with a CFC. They felt that having a CFC made them stronger people and they believed that they were more accepting of others and more in touch with others' feelings because of what they had been through.

ObjectiveTo compare academic outcomes between children with orofacial cleft (OFC) and children without major birth defects.Design and SettingIn 2007–2008, we mailed questionnaires to a random sample of mothers of school-aged children with OFC and mothers of children without major birth defects (comparison group). The questionnaire included Likert-scale, closed-ended, and open-ended questions from validated instruments. We conducted bivariate and multivariable analyses on parent-reported educational outcomes and bivariate analyses on parent-reported presence of related medical conditions between children with isolated OFC and unaffected children.Patients/ParticipantsA random sample of 504 parents of children with OFCs born 1996–2002 (age 5–12 years) were identified by the North Carolina Birth Defects Monitoring Program. A random sample of 504 parents of children without birth defects born 1996–2002 was selected from North Carolina birth certificates. Of the 289 (28.7%) respondents, we analyzed 112 children with isolated OFC and 138 unaffected children.Main Outcome MeasuresLetter grades, school days missed, and grade retention.ResultsParents of children with isolated OFC reported more developmental disabilities and hearing and speech problems among their children than comparison parents. Children with isolated OFC were more likely to receive lower grades and miss more school days than unaffected children. Because of the low response rate, results should be interpreted cautiously.ConclusionChildren with isolated OFC may have poorer academic outcomes during elementary school than their unaffected peers. Future studies are needed to confirm these results and determine whether these differences persist in later grades.

Developing an effective vaccine remains a critical long–term approach to HIV prevention. Every efficacy trial should be responsive to the concerns of participating communities because the successful development of an HIV preventive vaccine will require long–term involvement of people who have been marginalized and who distrust the government and biomedical research. Using qualitative interviews and purposive sampling, we elicited recommendations regarding how vaccine efficacy trials should be conducted from 90 members of communities that have been disproportionately affected by HIV/AIDS: injection drug users, gay men, and African Americans. The most common recommendation was for complete disclosure of all aspects of the trial. Other themes included participant and community education, who to include in trials, preventing harm, trust, community involvement, researcher attributes, and respect for participants. Developing positive, respectful and collaborative experiences with community members will facilitate vaccine research because negative experiences and unfavorable community reactions can greatly impede success in future trials. As the HIV epidemic in the United States continues to evolve, it is increasingly evident that a cure for AIDS is not likely in the foreseeable future. The optimism that new treatments for HIV infection might eradicate HIV infection has slowly been replaced with the reality that current treatments are not the magic bullet once envisioned (Johnson & Gerber, 2000). Problems with viral resistance, short– and long–term toxicities

Objective To assess the educational preparedness of medical and dental professionals to reduce the burden of OPC through planning effective cancer control strategies such as reducing tobacco consumption, suggesting healthy lifestyle and diet, and performing early detection through screening examinations and appropriate follow-up. Methods Self-reported adequacy of training in oral and pharyngeal cancer (OPC) early intervention activities was compared among 4 health care provider groups in North Carolina. Pretested surveys were mailed to random samples of licensed professionals. Results Nearly all providers agreed that early detection improves 5-year survival rates from OPC. Compared with 567 medical providers (273 family physicians and 294 nurse practitioners), 1235 dental providers (584 dentists and 651 hygienists) were significantly less likely to feel adequately trained in tobacco and alcohol cessation and to palpate neck nodes, but were significantly more likely to feel adequately trained to perform oral cancer examinations. Among dental providers, those who felt they had adequate training in tobacco and alcohol cessation were significantly more likely to assess these risk factors on patient medical histories. Conclusions Education is needed to prepare dental providers to undertake OPC prevention activities, whereas medical providers would benefit from enhanced oral examination skills to improve their performance in early detection.

Background: Appropriately trained dental hygienists can participate in oral cancer (OC) control. Method: We assessed knowledge of risk factors, diagnostic procedures, and opinions regarding OC education among 651 dental hygienists practicing in North Carolina using a mail survey. We constructed regression models of factors influencing high knowledge levels. Results: Most correctly identified tobacco and alcohol use as OC risk factors, and 52% felt their knowledge of OC was current; however, we identified gaps. Diagnostic knowledge was highest for those who were recent graduates or received continuing education in the last 5 years; 96% were interested in future continuing education. Conclusion: Increased OC education content in dental hygiene curricula and training programs for practicing hygienists is needed to enhance early detection of OC.