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Background: The interactive media-based approach to community consultation and public disclosure (CC/PD), a key step when conducting exception from informed consent (EFIC) clinical trials, is intended to be completed in 4 months. This analysis characterizes the process, from initiation of CC/PD activities to institutional review board approval, to better understand the barriers and how these can be mitigated., Methods: This is a retrospective post hoc analysis of data collected as part of the CC/PD campaigns conducted for a large trial involving up to 90 trauma centers in the United States. Each site was provided with templated materials that had been reviewed and approved by a central institutional review board (cIRB). We collected the dates of milestones, including the study "kickoff call," start of the social media campaign, dates of online community meetings, date of submission of site report to the cIRB, and cIRB approval date., Results: Sixty-two sites were cIRB approved at the time of this analysis. The median time from the kickoff call to the start of the social media campaign was 79 days, with an interquartile range of 33 to 126 days (range, 0-285 days). All social media campaigns ran for the prescribed period of at least 2 months. All sites conducted at least four online community meetings. The median number of days from the kickoff call to cIRB approval was 216 days (interquartile range, 168-281 days; range, 116-459 days). There was no significant difference between sites that had previous experience of EFIC trials., Conclusion: Using the interactive media-based approach, CC/PD can be completed quickly; however, there are barriers that can incur substantial delays. Greater harmonization of local administrative processes would shorten the time to conduct CC/PD activities and facilitate the timely commencement and execution of EFIC trials., Level of Evidence: Prognostic and Epidemiological; Level IV., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Surgery of Trauma.)

Importance: Exception From Informed Consent (EFIC) research requires community consultation (CC) and public disclosure (PD). Traditional methods of conducting CC and PD are slow, expensive, and labor intensive., Objective: To describe the feasibility and reach of a novel interactive, media-based approach to CC and PD and to identify the similarities and differences between trial sites in website views, survey responses, online community forum attendance, and opt-out requests., Design, Setting, and Participants: This survey study analyzed the CC and PD campaigns conducted for the TAP trial (Evaluation of BE1116 in Patients With Traumatic Injury and Acute Major Bleeding to Improve Survival), an EFIC trial of the early administration of prothrombin complex concentrate in patients with trauma. The CC and PD campaigns consisted of social media advertisements, linked websites, community surveys, and online community forums. These activities were coordinated from a central site and approved by a central institutional review board. This study focused on the first 52 of 91 TAP trial sites (level I trauma centers) in the US to have completed their CC and PD campaigns. Community members in the catchment areas of the participating trauma centers were targeted. Data analysis was conducted between October 2023 and February 2024., Exposure: Social media advertisements, surveys, and online community meetings conducted as part of the CC and PD campaign for the TAP trial., Main Outcomes and Measures: Social media campaign reach and engagement, web page views, survey results, online community forum attendance, and opt-out requests., Results: Fifty-two trial sites were approved for participant enrollment. Social media advertisements were displayed 92 million times, reaching 11.8 million individuals. The median (IQR) number of people reached in each location was 210 317 (172 068-276 968). Site-specific websites were viewed 144 197 times (median [IQR] viewings per site, 2984 [1267-4038]). A total of 17 206 fully or partly completed surveys were received, and survey respondents had a median (IQR) age of 40.1 (15-65) years and included 10 444 females (60.7%). Overall, 60.6% survey respondents said they would want to be entered into the trial even if they could not give consent, 87.7% agreed that emergency care research was necessary, and 88.0% agreed that the TAP trial should be conducted in their community. Online community forums were attended by a median (IQR) number of 38 (20-63) people. Four opt-out requests were received., Conclusions and Relevance: The interactive media-based approach to CC and PD for the ongoing TAP trial showed the feasibility and benefits of executing an efficient, coordinated, centrally run series of locally branded and geographically targeted CC and PD campaigns for a large EFIC study.

Objectives: To derive systematic-review informed, modified Delphi consensus regarding prophylactic transfusions in neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE., Data Sources: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2020, with an update in May 2021., Study Selection: Included studies assessed use of prophylactic blood product transfusion in pediatric ECMO., Data Extraction: Two authors reviewed all citations independently, with a third independent reviewer resolving conflicts. Thirty-three references were used for data extraction and informed recommendations. Evidence tables were constructed using a standardized data extraction form., Measurements and Main Results: The evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. Forty-eight experts met over 2 years to develop evidence-informed recommendations and, when evidence was lacking, expert-based consensus statements or good practice statements for prophylactic transfusion strategies for children supported with ECMO. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was based on a modified Delphi process with agreement defined as greater than 80%. We developed two good practice statements, 4 weak recommendations, and three expert consensus statements., Conclusions: Despite the frequency with which pediatric ECMO patients are transfused, there is insufficient evidence to formulate evidence-based prophylactic transfusion strategies., Competing Interests: The Executive Committee (Drs. Alexander, Muszynski, Bembea, Cheifetz, Steiner, and Barbaro) served as arbitrators for conflict of interest management. Dr. Alexander’s institution received funding from Novartis (consultant on the end-point adjudication committee for Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF [PANORAMA-HF] clinical trial). Dr. Sloan commenced employment with CSL Behring after the consensus process was complete. Dr. Kneyber received funding from Metran. Drs. Alexander and Muszynski’s institutions received funding from the National Institutes of Health (NIH); they received support for article research from the NIH. Dr. Alexander’s institution received funding from the Extracorporeal Life Support Organization and Novartis. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objectives: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference., Data Sources: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children., Study Selection: The management of ECMO anticoagulation for critically ill children., Data Extraction: Within each of eight subgroup, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts., Data Synthesis: A systematic review was conducted using MEDLINE, Embase, and Cochrane Library databases, from January 1988 to May 2021. Each panel developed evidence-based and, when evidence was insufficient, expert-based statements for the clinical management of anticoagulation for children supported with ECMO. These statements were reviewed and ratified by 48 PEACE experts. Consensus was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 23 recommendations, 52 expert consensus statements, and 16 good practice statements covering the management of ECMO anticoagulation in three broad categories: general care and monitoring; perioperative care; and nonprocedural bleeding or thrombosis. Gaps in knowledge and research priorities were identified, along with three research focused good practice statements., Conclusions: The 91 statements focused on clinical care will form the basis for standardization and future clinical trials., Competing Interests: Drs. Alexander’s and Muszynski’s institutions received funding from the National Institutes of Health (NIH). Drs. Alexander, Bembea, Himebauch, Barbaro, and Muszynski received support for article research from the NIH. Drs. Alexander’s and Bembea’s institutions received funding from the Extracorporeal Life Support Organization (ELSO). Dr. Alexander’s institution received funding from Novartis (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF [PANORAMA-HF]). Dr. Alexander disclosed that she is Treasurer of the Board of Directors of ELSO, past Co-Chair of Pediatric Extracorporeal Membrane Oxygenation (Pedi-ECMO). Dr. Bembea’s institution received funding from the National Institute of Neurologic Disorders and Stroke and a Grifols Investigator Sponsored Research Grant. Dr. Cheifetz received funding from UptoDate. Dr. Dalton received funding from Innovative Extracorporeal Membrane Oxygenation (ECMO) Concepts, Medtronic, Entegrion, and Hemocue. Drs. Dalton, Ozment, Barbaro, Almond, Brandão, Baumann Kreuziger, Paden, and Ryerson disclosed the off-label product use of pediatric ECMO-related medications for anticoagulation. Dr. Himebauch’s institution received funding from the National Heart, Lung, and Blood Institute (NHLBI) (K23HL153759). Drs. Karam’s and Nellis’s institutions received funding from the NHBLI (R34HL159119). Dr. Ozment received funding from Kaufman & Canoles, Social Cascade, and Wiseman Ashworth Law Group. Dr. Steiner’s institution received funding from the Department of Defense (DoD); she received funding from Medtronic and Octapharma; she disclosed that she is a Pumps for Kids, Infantsand Neonates (PumpKIN) trial Data Safety and Monitoring Board member. Dr. Alexander’s and Thiagarajan’s institution received funding from the DoD Clinical Trial Award for Trial of Indication-Based Transfusion of RBCs in ECMO trial (W81XWH2210301). Dr. Thiagarajan received funding from Society of Critical Care Medicine and ELSO. Dr. Zantek disclosed that she is a Board Member and Vice President of the North American Specialized Coagulation Laboratory Association and Board Member of the American Society for Apheresis, the External Quality Assurance in Thrombosis and Hemostasis, and Blood Network subgroup of Pediatric Acute Lung Injury and Sepsis Investigators groups; she disclosed that her spouse is an employee of Boston Scientific and owns stock in Endo International PLC. Dr. Barbaro’s institution received funding from the NHLBI (R01 HL153519 and K12 HL138039); he disclosed that he is ELSO Board of Directors and Pedi-ECMO Co-Chair. Dr. Emani received funding from Chiesi Pharma. Dr. Hyslop disclosed he is Co-Chair of ELSO Registry Database Development Committee and Coordinator Liaison to ELSO Steering Committee. Dr. Baumann Kreuziger received funding from the Health Resources and Services Administration Vaccine Injury Compensation Program. Dr. Paden disclosed that he is past president and board member of ELSO. Dr. Ryerson received an honorarium from Instrumentation Laboratory for consultation work. Dr. Sloan commenced employment with CSL Behring after the consensus process was complete. Dr. Patregnani received funding from Mallinckrodt; he discloses consultation payments from MNK pharmaceuticals and Pfizer. The Executive Committee (Drs. Alexander, Muszynski, Bembea, Cheifetz, Steiner, and Barbaro) served as arbitrators for conflict-of-interest management. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

BACKGROUNDRBC transfusion effectiveness varies due to donor, component, and recipient factors. Prior studies identified characteristics associated with variation in hemoglobin increments following transfusion. We extended these observations, examining donor genetic and nongenetic factors affecting transfusion effectiveness.METHODSThis is a multicenter retrospective study of 46,705 patients and 102,043 evaluable RBC transfusions from 2013 to 2016 across 12 hospitals. Transfusion effectiveness was defined as hemoglobin, bilirubin, or creatinine increments following single RBC unit transfusion. Models incorporated a subset of donors with data on single nucleotide polymorphisms associated with osmotic and oxidative hemolysis in vitro. Mixed modeling accounting for repeated transfusion episodes identified predictors of transfusion effectiveness.RESULTSBlood donor (sex, Rh status, fingerstick hemoglobin, smoking), component (storage duration, γ irradiation, leukoreduction, apheresis collection, storage solution), and recipient (sex, BMI, race and ethnicity, age) characteristics were associated with hemoglobin and bilirubin, but not creatinine, increments following RBC transfusions. Increased storage duration was associated with increased bilirubin and decreased hemoglobin increments, suggestive of in vivo hemolysis following transfusion. Donor G6PD deficiency and polymorphisms in SEC14L4, HBA2, and MYO9B genes were associated with decreased hemoglobin increments. Donor G6PD deficiency and polymorphisms in SEC14L4 were associated with increased transfusion requirements in the subsequent 48 hours.CONCLUSIONDonor genetic and other factors, such as RBC storage duration, affect transfusion effectiveness as defined by decreased hemoglobin or increased bilirubin increments. Addressing these factors will provide a precision medicine approach to improve patient outcomes, particularly for chronically transfused RBC recipients, who would most benefit from more effective transfusion products.FUNDINGFunding was provided by HHSN 75N92019D00032, HHSN 75N92019D00034, 75N92019D00035, HHSN 75N92019D00036, and HHSN 75N92019D00037; R01HL126130; and the National Institute of Child Health and Human Development (NICHD).

Background: We hypothesized that variability in practice exists for newborn immunohematology testing due to lack of consensus guidelines. We report the results of a survey assessing that variability at hospitals in the United States and Canada., Study Design and Methods: An AABB Pediatric Subsection working party developed and validated a survey of newborn immunohematology testing practice. The survey was sent electronically to transfusion service leadership at teaching institutions., Results: The response rate was 67% (61/91); 56 surveys meeting inclusion criteria were analyzed. Approximately 90% (50/56) were from birth hospitals and 16.1% (9/56) were from pediatric hospitals. Newborn immunohematology testing is ordered as a panel by 66.0% (33/50) of birth hospitals. ABO group and DAT is mandated before discharge in 14/56 (25.0%) and 13/56 (23.2%), respectively. About 76.8% (43/56) selectively perform a DAT according to blood blank or clinical parameters. The most common DAT practices include anti-IgG only testing by 73.2% (41/56) and use of umbilical cord specimen type by 67.9% (38/56). A positive DAT is a critical value for 26.8% (15/56) and followed with eluate testing when a maternal antibody screen is positive for 48.2% (27/56). In the setting of a non-ABO maternal red cell antibody, 55.4% (31/56), phenotype neonatal red cells when the DAT is positive. Group O RBC are transfused irrespective of the DAT result for 82.1%, (46/56)., Conclusion: There is variability in newborn immunohematology testing and transfusion practice and potential overutilization of the DAT. Evidence-based consensus guidelines should be developed to standardize practice and to improve safety., (© 2021 AABB.)

Alterations to the biochemical composition of the intervertebral disc (IVD) are hallmarks of aging and degeneration. Methods to assess biochemical content, such as histology, immunohistochemistry, and spectrophotometric assays, are limited in their ability to quantitatively analyze the spatial distribution of biochemical components. Fourier transform infrared (FTIR) microscopy is a biochemical analysis method that can yield both quantitative and high-resolution data about the spatial distribution of biochemical components. This technique has been largely unexplored for use with the IVD, and existing methods use complex analytical techniques that make results difficult to interpret. The objective of the present study is to describe an FTIR microscopy method that has been optimized for imaging the collagen and proteoglycan content of the IVD. The method was performed on intact and discectomized IVDs from the sheep lumbar spine after 6 weeks in vivo in order to validate FTIR microscopy in healthy and degenerated IVDs. FTIR microscopy quantified collagen and proteoglycan content across the entire IVD and showed local changes in biochemical content after discectomy that were not observed with traditional histological methods. Changes in collagen and proteoglycans content were found to have strong correlations with Pfirrmann grades of degeneration. This study demonstrates how FTIR microscopy is a valuable research tool that can be used to quantitatively assess the local biochemical composition of IVDs in development, degeneration, and repair., Competing Interests: Roger Härtl is a consultant for AO Spine, Brainlab, Depuy‐Synthes and Lanx, and received research funding from Baxter. Lawrence J. Bonassar is a consultant for Fidia Pharmaceuticals and 3DBio Corp., (© 2020 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Tissue-engineered approaches for the treatment of early-stage intervertebral disc degeneration have shown promise in preclinical studies. However, none of these therapies has been approved for clinical use, in part because each therapy targets only one aspect of the intervertebral disc's composite structure. At present, there is no reliable method to prevent intervertebral disc degeneration after herniation and subsequent discectomy. Here, we demonstrate the prevention of degeneration and maintenance of mechanical function in the ovine lumbar spine after discectomy by combining strategies for nucleus pulposus augmentation using hyaluronic acid injection and repair of the annulus fibrosus using a photocrosslinked collagen patch. This combined approach healed annulus fibrosus defects, restored nucleus pulposus hydration, and maintained native torsional and compressive stiffness up to 6 weeks after injury. These data demonstrate the necessity of a combined strategy for arresting intervertebral disc degeneration and support further translation of combinatorial interventions to treat herniations in the human spine., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Intervertebral disc (IVD) herniations are currently treated with interventions that leave the IVD with persistent lesions prone to further herniations. Annulus fibrosus (AF) repair has become of interest as a method to seal defects in the IVD and prevent reherniation, but this requires strong adhesion of the implanted biomaterial to the native AF tissue. Our group has previously developed a high-density collagen (HDC) gel for AF repair and tested its efficacy in vivo, but its adhesion to the AF could be improved. Increased cell adhesion to cartilage has previously been reported through chondroitinase ABC (ChABC) digestion, which removes proteoglycans and increases access to cell binding motifs. Such approaches could also increase biomaterial adhesion to tissue, but the effects of ChABC digestion on AF have yet to be investigated. In this study, ovine AF tissue was digested with either 10 U/mL ChABC or saline for up to 10 min and the effect of this treatment on collagen adhesion between AF tissue samples was investigated by histology and mechanical testing in a lap-shear configuration. ChABC digestion removed proteoglycans within the AF in a time-dependent fashion and enhanced adhesion of the HDC gel to the AF. ChABC digestion increased the elastic toughness and total shear energy of the HDC gel-AF interface by 88% and 46% respectively. ChABC treatment enhanced the adhesion of the HDC gel to the AF without significantly decreasing native AF cell viability. Thus, ChABC digestion is a viable method to improve adhesion of biomaterials for AF repair. STATEMENT OF SIGNIFICANCE: Intervertebral disc herniations are currently treated with interventions that leave persistent lesions in the annulus fibrosus that are prone to further herniations. Annular repair is a promising method to seal lesions and prevent reherniation, but requires strong adhesion of the implanted biomaterial to native annulus fibrosus. Since large proteoglycans like aggrecan occupy regions of the extracellular matrix between collagen fibers in the annulus fibrosus, we hypothesized that removing proteoglycans via chondroitinase digestion would increase the adhesion of annular repair hydrogels. This investigation demonstrated that chondroitinase removed proteoglycans within annulus fibrosus tissue, enhanced the interaction of an injected collagen gel with the native tissue, and mechanically improved adhesion between the collagen gel and annulus fibrosus. This is the first study of its kind to evaluate the biochemical and mechanical effects of short-term chondroitinase digestion on annulus fibrosus tissue., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Our group has previously demonstrated in vivo annulus fibrosus repair in animal models using an acellular, riboflavin crosslinked, high-density collagen (HDC) gel., Objective: To assess if seeding allogenic mesenchymal stem cells (MSCs) into this gel yields improved histological and radiographic benefits in an in vivo sheep model of annular injury., Methods: Fifteen lumbar intervertebral discs (IVDs) were randomized into 4 groups: intact, injury only, injury + acellular gel treatment, or injury + MSC-seeded gel treatment. Sheep were sacrificed at 6 wk. Disc height index (DHI), Pfirrmann grade, nucleus pulposus area, and T2 relaxation time (T2-RT) were calculated for each IVD and standardized to healthy controls from the same sheep. Quantitative histological assessment was also performed using the Han scoring system., Results: All treated IVDs retained gel plugs on gross assessment and there were no adverse perioperative complications. The MSC-seeded gel treatment group demonstrated statistically significant improvement over other experimental groups in DHI (P = .002), Pfirrmann grade (P < .001), and T2-RT (P = .015). There was a trend for greater Han scores in the MSC-seeded gel-treated discs compared with injury only and acellular gel-treated IVDs (P = .246)., Conclusion: MSC-seeded HDC gel can be delivered into injured IVDs and maintained safely in live sheep to 6 wk. Compared with no treatment and acellular HDC gel, our data show that MSC-seeded HDC gel improves outcomes in DHI, Pfirrmann grade, and T2-RT. Histological analysis shows improved annulus fibrosus and nucleus pulposus reconstitution and organization over other experimental groups as well., (Copyright © 2018 by the Congress of Neurological Surgeons.)

More than 1 million apheresis platelet collections are performed annually in the United States. After 2 healthy plateletpheresis donors were incidentally found to have low CD4 + T-lymphocyte counts, we investigated whether plateletpheresis causes lymphopenia. We conducted a cross-sectional single-center study of platelet donors undergoing plateletpheresis with the Trima Accel, which removes leukocytes continuously with its leukoreduction system chamber. We recruited 3 groups of platelet donors based on the total number of plateletpheresis sessions in the prior 365 days: 1 or 2, 3 to 19, or 20 to 24. CD4 + T-lymphocyte counts were <200 cells per microliter in 0/20, 2/20, and 6/20 donors, respectively ( P = .019), and CD8 + T-lymphocyte counts were low in 0/20, 4/20, and 11/20 donors, respectively ( P < .001). The leukoreduction system chamber's lymphocyte-extraction efficiency was ∼15% to 20% for all groups. Immunophenotyping showed decreases in naive CD4 + T-lymphocyte and T helper 17 (Th17) cell percentages, increases in CD4 + and CD8 + effector memory, Th1, and regulatory T cell percentages, and stable naive CD8 + and Th2 percentages across groups. T-cell receptor repertoire analyses showed similar clonal diversity in all groups. Donor screening questionnaires supported the good health of the donors, who tested negative at each donation for multiple pathogens, including HIV. Frequent plateletpheresis utilizing a leukoreduction system chamber is associated with CD4 + and CD8 + T-cell lymphopenia in healthy platelet donors. The mechanism may be repeated extraction of these cells during plateletpheresis. The cytopenias do not appear to be harmful., (© 2019 by The American Society of Hematology.)

Objective: The aim is assessing the in vivo efficacy of annulus fibrosus (AF) cells seeded into collagen by enhancing the reparative process around annular defects and preventing further degeneration in a rat-tail model., Summary of Background Data: Treating disc herniation with discectomy may relieve the related symptoms but does not address the underlying pathology. The persistent annular defect may lead to re-herniation and further degeneration. We recently demonstrated that riboflavin crosslinked high-density collagen gels (HDC) can facilitate annular repair in vivo., Methods: 42 rats, tail disc punctured with an 18-gauge needle, were divided into 3 groups: untreated (n = 6), injected with crosslinked HDC (n = 18), and injected with AF cell-laden crosslinked HDC (n = 18). Ovine AF cells were mixed with HDC gels prior to injection. X-rays and MRIs were conducted over 5 weeks, determining disc height index (DHI), nucleus pulposus (NP) size, and hydration. Histological assessments evaluated the viability of implanted cells and degree of annular repair., Results: Although average DHIs of both HDC gel groups were higher than those of the puncture control group at 5 weeks, the retention of disc height, NP size and hydration at 1 and 5 weeks was significant for the cellular group compared to the punctured, and at 5 weeks to the acellular group. Histological assessment indicated that AF cell-laden HDC gels have accelerated reparative sealing compared to acellular HDC gels., Conclusions: AF cell-laden HDC gels have the ability of better repairing annular defects than acellular gels after needle puncture., Statement of Significance: This project addresses the compelling demand of a sufficient treatment strategy for degenerative disc disease (DDD) perpetuated by annulus fibrosus (AF) injury, a major cause of morbidity and burden to health care systems. Our study is designed to answer the question of whether injectable, photo-crosslinked, high density collagen gels can seal defects in the annulus fibrosus of rats and prevent disc degeneration. Furthermore, we investigated whether the healing of AF defects will be enhanced by the delivery of AF cells (fibrochondrocytes) to these defects. The use of cell-laden collagen gels in spine surgery holds promise for a wide array of applications, from current discectomy procedures to future nucleus pulposus reparative therapies, and our group is excited about this potential., (Copyright © 2018. Published by Elsevier Ltd.)

Lower back pain, the leading cause of workplace absences and disability, is often attributed to intervertebral disc degeneration, in which nucleus pulposus (NP) herniates through lesions in the annulus fibrosus (AF) and impinges on the spinal cord and surrounding nerves. Surgeons remove extruded NP via discectomy when indicated by local/radicular pain supported by radiographic evidence; however, current interventions do not alter the underlying disease or seal the AF. The reported rates of recurrent herniation or pain following discectomy cases range from 5% to 25%, which has pushed spine research in recent years toward annular repair and closure strategies. Synthetic implants designed to mechanically seal the AF have been subject to large animal and clinical trials, with limited success in preventing recurrent herniation. Like gold standard interventions, purely mechanical devices fail to promote tissue integration, long-term healing, or restore native biomechanical function to the spine. Biological repair strategies utilizing principles of tissue engineering have demonstrated success in overcoming the inadequacies of current interventions and mechanical implants, yet, none has reached clinical or proof-of-concept trials in humans. In this review, we will discuss annular repair strategies promoting biological healing that have been implemented in small and large animal models in vivo, and ways to enhance the efficacy of these treatments.

Purpose/Aim: Despite their importance in accurate mechanical modeling of the cornea, the depth-dependent material properties of the cornea have only been partially elucidated. In this work, we characterized the depth-dependent out-of-plane Young's modulus of the central and peripheral human cornea with high spatial resolution., Materials and Methods: Central and peripheral corneal buttons from human donors were subjected to unconfined axial compression followed by stress relaxation for 30 min. Sequences of fluorescent micrographs of full-thickness corneal buttons were acquired throughout the experiment to enable tracking of fluorescently labeled stromal keratocyte nuclei and measurements of depth-dependent infinitesimal strains. The nominal (gross) out-of-plane Young's modulus and drained Poisson's ratio for each whole specimen was computed from the equilibrium stress and overall tissue deformation. The depth-dependent (local) out-of-plane Young's modulus was computed from the equilibrium stress and local tissue strain based on an anisotropic model (transverse isotropy)., Results: The out-of-plane Young's modulus of the cornea exhibited a strong dependence on in-plane location (peripheral versus central cornea), but not depth. The depth-dependent out-of-plane Young's modulus of central and peripheral specimens ranged between 72.4-102.4 kPa and 38.3-58.9 kPa. The nominal out-of-plane Young's modulus was 87 ± 41.51 kPa and 39.9 ± 15.28 kPa in the central and peripheral cornea, while the drained Poisson's ratio was 0.05 ± 0.02 and 0.07 ± 0.04., Conclusions: The out-of-plane Young's modulus of the cornea is mostly independent of depth, but not in-plane location (i.e. central vs. peripheral). These results may help inform more accurate finite element computer models of the cornea.

Study Design: Ovine in vivo study., Objective: To perform lateral approach lumbar surgery in an ovine model to administer an injectable riboflavin cross-linked high-density collagen (HDC) gel and to assess its ability to mitigate intervertebral disc (IVD) degeneration after induced annulus fibrosus (AF) injury., Summary of Background Data: Biological-based injectable gels have shown efficacy in restoring biomechanical, radiographic, and histological parameters in IVD-injured animal models. Riboflavin cross-linked HDC gel has previously demonstrated retention of nucleus pulposus (NP) tissue, reduced loss of disc height, and prevention of terminal cellular degenerative changes in rat-tail spines. However, this biological therapy has never been tested in large animal models., Methods: Forty lumbar IVDs were accessed from eight sheep via lateral approach surgery. IVDs were randomly assigned to healthy control, injury and HDC treatment, or negative control with injury and no treatment. IVD injury was carried out using a drill-bit through the AF followed by needle puncture of the NP. Sheep were followed for 16 weeks and underwent qualitative/quantitative magnetic resonance imaging, x-ray, and histological analyses of collagen and proteoglycan content., Results: The lateral approach to the ovine lumbar spine to deliver HDC gel proved to be safe and reproducible. IVDs treated with the HDC gel revealed less degenerative changes at the microscopic level based on AF and NP histology. However, mean Pfirrmann grade, T2 relaxation time, NP voxel size, and disc height index were not significantly different between the two injury groups., Conclusion: Injectable HDC gel can be administered safely via lateral approach surgery in an ovine AF injury model. IVDs treated with HDC gel demonstrated less degeneration at the microscopic level though radiographic changes were slight when comparing treated to untreated IVDs. Future studies will need to elucidate the role of injury technique and time frame for follow-up in correlating histological and radiographical outcomes., Level of Evidence: N /A.

Novel tissue engineered and biomaterial approaches to treat intervertebral disc (IVD) degeneration focus on single aspects of the progressive disease and hence are insufficient repair strategies. In this study, annulus fibrosus (AF) and nucleus pulposus (NP) biomaterial repair strategies were used individually and combined to treat IVD degeneration modeled in ex vivo rat-tail motion segments by annulotomy and nucleotomy. An injectable riboflavin cross-linked high-density collagen gel patched defects in the AF, while NP repair consisted of injections of a modified hyaluronic acid (HA) hydrogel. Qualitative imaging showed the annulotomy and nucleotomy successfully herniated NP material, while the HA NP injections restored intact NP morphology and the collagen AF patches sealed AF defects. Assessed by quantitative T2 magnetic resonance imaging, combined repair treatments yielded disc hydration not significantly different than intact hydration, while AF and NP repairs alone only restored ∼1/3 of intact hydration. Mechanical testing showed NP injections alone recovered on average ∼35% and ∼40% of the effective instantaneous and equilibrium moduli. The combined treatment comprising biomaterial AF and NP repair was effective at increasing NP hydration from NP repair alone, however HA injections alone are sufficient to improve mechanical properties., Statement of Significance: Intervertebral disc degeneration affects an estimated 90% of individuals throughout their life, and is a candidate pathology for tissue engineered repair. The current standard of clinical care reduces spinal articulation and leads to further degeneration along the spine, hence great interest in a regenerative medicine therapy. Literature studies focused on biomaterial repair strategies for treating degenerated discs have partially restored native disc function, however no studies have reported the use of combined therapies to address multiple aspects of disc degeneration. This initial investigation screened injectable biomaterial repair strategies ex vivo, and through complementary outcome measures showed a combined therapy restores disc function better than individual approaches. This study is the first of its kind to address multiple aspects of disc degeneration, using clinically-oriented biomaterials in a well-established animal model., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Although many apheresis centers offer extracorporeal photopheresis (ECP), little is known about current treatment practices., Methods: An electronic survey was distributed to assess ECP practice internationally., Results: Of 251 responses, 137 met criteria for analysis. Most respondents were from North America (80%). Nurses perform ECP at most centers (84%) and the majority of centers treat adults only (52%). Most centers treat fewer than 50 patients/year (83%) and perform fewer than 300 procedures/year (70%). Closed system devices (XTS and/or Cellex) are used to perform ECP at most centers (96%). The most common indications for ECP are acute/chronic skin graft versus host disease (89%) and cutaneous T-cell lymphoma (63%). The typical wait time for ECP treatment is less than 2 weeks (91%). Most centers do not routinely perform quality control assessment of the collected product (66%). There are device-specific differences in treatment parameters. For example, XTS users more frequently have a minimum weight limit (P = 0.003) and use laboratory parameters to determine eligibility for treatment (P = 0.03). Regardless of device used, the majority of centers assess the clinical status of the patient before each procedure. Greater than 50% of respondents would defer treatment for hemodynamic instability due to active sepsis or heart failure, positive blood culture in the past 24 h or current fever., Conclusion: This survey based study describes current ECP practices. Further research to provide evidence for optimal standardization of patient qualifications, procedure parameters and product quality assessment is recommended., (© 2016 Wiley Periodicals, Inc.)

Background: Cardiac surgery is the most common setting for massive transfusion in medically advanced countries. Studies of massive transfusion after injury suggest that the ratios of administered plasma and platelets (PLT) to red blood cells (RBCs) affect mortality. Data from the Red Cell Storage Duration Study (RECESS), a large randomized trial of the effect of RBC storage duration in patients undergoing complex cardiac surgery, were analyzed retrospectively to investigate the association between blood component ratios used in massively transfused patients and subsequent clinical outcomes., Methods: Massive transfusion was defined as those who had ≥6 RBC units or ≥8 total blood components. For plasma, high ratio was defined as ≥1 plasma unit:1 RBC unit. For PLT transfusion, high ratio was defined as ≥0.2 PLT doses:1 RBC unit; PLT dose was defined as 1 apheresis PLT or 5 whole blood PLT equivalents. The clinical outcomes analyzed were mortality and the change in the Multiple Organ Dysfunction Score (ΔMODS) comparing the preoperative score with the highest composite score through the earliest of death, discharge, or day 7. Outcomes were compared between patients transfused with high and low ratios. Linear and Cox regression were used to explore relationships between predictors and continuous outcomes and time to event outcomes., Results: A total of 324 subjects met the definition of massive transfusion. In those receiving high plasma:RBC ratio, the mean (SE) 7- and 28-day ΔMODS was 1.24 (0.45) and 1.26 (0.56) points lower, (P = .007 and P = .024), respectively, than in patients receiving lower ratios. In patients receiving high PLT:RBC ratio, the mean (SE) 7- and 28-day ΔMODS were 1.55 (0.53) and 1.49 (0.65) points lower (P = .004 and P = .022), respectively. Subjects who received low-ratio plasma:RBC transfusion had excess 7-day mortality compared with those who received high ratio (7.2% vs 1.7%, respectively, P = .0318), which remained significant at 28 days (P = .035). The ratio of PLT:RBCs was not associated with differences in mortality., Conclusions: This analysis found that in complex cardiac surgery patients who received massive transfusion, there was an association between the composition of blood products used and clinical outcomes. Specifically, there was less organ dysfunction in those who received high-ratio transfusions (plasma:RBCs and PLT:RBCs), and lower mortality in those who received high-ratio plasma:RBC transfusions.

Outside the neonatal period, most platelets that are transfused to pediatric patients are given to those who are thrombocytopenic secondary to malignancy and associated therapy and/or hematopoietic progenitor cell transplant, or to those with significant bleeding associated with surgery, especially cardiac surgery. Indications for platelet transfusion, doses, and other practices for children largely mimic adult platelet transfusion protocols because there are few pediatric-specific studies in this area. Pediatric platelet transfusion practices would benefit from focused pediatric research. The appropriate indications and doses for platelet transfusions in oncology, hematopoietic progenitor cell transplant, and cardiac surgery patients need to be determined., (Copyright © 2016. Published by Elsevier Inc.)

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 count <500/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., (© 2015 by The American Society of Hematology.)

Apheresis can remove pathogens and mediators that contribute to pathogenic inflammatory responses in diseases not generally considered to be "Hematologic." Erythrocytapheresis can remove intracellular pathogens such as Babesiosis. Plasmapheresis can remove mediators of the inflammatory response in conditions such as sepsis, chronic autoimmune urticaria and malignant pertussis. Leukapheresis can remove potentially harmful leukocytes in Crohn's Disease and malignant pertussis. While apheresis can remove all of these substances, the clinical efficacy and pathophysiologic changes that occur during apheresis in these conditions are largely unknown. Hence, the clinical utility of apheresis in these conditions is largely unknown and research in these areas has the potential to benefit many patients with a variety of diseases., (© 2014 Wiley Periodicals, Inc.)

Background: Some observational studies have reported that transfusion of red-cell units that have been stored for more than 2 to 3 weeks is associated with serious, even fatal, adverse events. Patients undergoing cardiac surgery may be especially vulnerable to the adverse effects of transfusion., Methods: We conducted a randomized trial at multiple sites from 2010 to 2014. Participants 12 years of age or older who were undergoing complex cardiac surgery and were likely to undergo transfusion of red cells were randomly assigned to receive leukocyte-reduced red cells stored for 10 days or less (shorter-term storage group) or for 21 days or more (longer-term storage group) for all intraoperative and postoperative transfusions. The primary outcome was the change in Multiple Organ Dysfunction Score (MODS; range, 0 to 24, with higher scores indicating more severe organ dysfunction) from the preoperative score to the highest composite score through day 7 or the time of death or discharge., Results: The median storage time of red-cell units provided to the 1098 participants who received red-cell transfusion was 7 days in the shorter-term storage group and 28 days in the longer-term storage group. The mean change in MODS was an increase of 8.5 and 8.7 points, respectively (95% confidence interval for the difference, -0.6 to 0.3; P=0.44). The 7-day mortality was 2.8% in the shorter-term storage group and 2.0% in the longer-term storage group (P=0.43); 28-day mortality was 4.4% and 5.3%, respectively (P=0.57). Adverse events did not differ significantly between groups except that hyperbilirubinemia was more common in the longer-term storage group., Conclusions: The duration of red-cell storage was not associated with significant differences in the change in MODS. We did not find that the transfusion of red cells stored for 10 days or less was superior to the transfusion of red cells stored for 21 days or more among patients 12 years of age or older who were undergoing complex cardiac surgery. (Funded by the National Heart, Lung, and Blood Institute; RECESS ClinicalTrials.gov number, NCT00991341.).

There is concern at the National Heart, Lung, and Blood Institute (NHLBI) and among transfusion medicine specialists regarding the small number of investigators and studies in the field of pediatric transfusion medicine (PTM). Accordingly, the objective of this article is to provide a snapshot of the clinical and translational PTM research considered to be of high priority by pediatricians, neonatologists, and transfusion medicine specialists. Included is a targeted review of three research areas of importance: (i) transfusion strategies, (ii) short- and long-term clinical consequences, and (iii) transfusion-transmitted infectious diseases. The recommendations by PTM and transfusion medicine specialists represent opportunities and innovative strategies to execute translational research, observational studies, and clinical trials of high relevance to PTM. With the explosion of new biomedical knowledge and increasingly sophisticated methodologies over the past decade, this is an exciting time to consider transfusion medicine as a paradigm for addressing questions related to fields such as cell biology, immunology, neurodevelopment, outcomes research, and many others. Increased awareness of PTM as an important, fertile field and the promotion of accompanying opportunities will help establish PTM as a viable career option and advance basic and clinical investigation to improve the health and wellbeing of children.

Purpose: To characterize the depth-dependent shear modulus of the central and peripheral human cornea along the superior-inferior and nasal-temporal directions with a high spatial resolution., Methods: Cylindrical explants from the central and peripheral corneas of 10 human donors were subjected to a 5% shear strain along the superior-inferior and nasal-temporal directions using a microscope-mounted mechanical testing device. Depth-dependent shear strain and shear modulus were computed through force measurements and displacement tracking., Results: The shear modulus G of the human cornea varied continuously with depth, with a maximum occurring roughly 25% of the way from the anterior surface to the posterior surface. G also varied with direction in the superior region and (at some depths) was significantly higher for superior-inferior shear loading. In the anterior half of the cornea, the shear modulus along the nasal-temporal direction (GNT) did not vary with location; however, the superior region had significantly higher GNT in posterior cornea. In contrast, the shear modulus along the superior-inferior direction (GSI) was independent of location at all depths., Conclusions: This study demonstrates that the peak shear modulus of the human cornea occurs at a substantial distance within the corneal stroma. Depth-dependent differences between central and peripheral cornea possibly reflect the location-dependent mechanical environment of the cornea. Moreover, the cornea is not a transverse isotropic material, and must be characterized by more than a single shear modulus due to its dependence on loading direction. The material properties measured in this study are critical for developing accurate mechanical models to predict the vision-threatening morphological changes that can occur in the cornea., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Importance: Juvenile myasthenia gravis (MG) is a relatively rare autoimmune disorder. The comparative efficacy of plasmapheresis (PLEX) vs immunoglobulin as maintenance therapy is unclear for this childhood disease., Objective: To determine whether PLEX or intravenous immunoglobulin (IVIG) therapy is more effective as maintenance therapy in this disease., Design, Setting, and Participants: This retrospective analysis over a 33-year period involved 54 children and adolescents with juvenile MG at a specialized neuromuscular clinic and electromyography laboratory at a tertiary care academic pediatric hospital., Interventions: Plasmapheresis and IVIG., Main Outcomes and Measures: Response to treatment was measured by both improvement in objective physical examination findings and the patients’ reported improvement in symptoms and functional abilities., Results: Subjective and objective outcomes correlated well. Both PLEX and IVIG had high response rates. Of the 27 patients with generalized juvenile MG receiving PLEX, IVIG, or both treatments, 7 of 7 patients treated with PLEX alone responded, 5 of 10 patients treated with IVIG alone responded, and 9 of 10 patients who received both responded. There was a significant difference in response rates between patients who received PLEX vs IVIG (P = .04). The youngest age at which PLEX was initiated via peripheral venous access was 9 years, while the youngest child who received IVIG was 9 months old. Thymectomy was performed in 17 children, of whom 11 experienced significant postoperative improvement., Conclusions and Relevance: This study provides class III evidence that PLEX and IVIG both have high response rates as maintenance therapies and are reasonable therapeutic options for juvenile MG. Plasmapheresis may have a more consistent response rate than IVIG in this setting. These findings will provide some guidance regarding the approach to therapy for juvenile MG, especially as the results differ somewhat from those of studies focusing on adult MG.

Introduction: Pediatric apheresis (PA) has distinct characteristics compared to adult apheresis, and requires specialized knowledge and experience to perform safely, particularly in low-weight patients. As evidence-based medicine advances the field of therapeutic apheresis, increased attention must be paid to pediatric patients with conditions for which apheresis is indicated., Methods: An electronic survey of >5,000 potential participants throughout the world was conducted to ascertain the scope and the current state of practice., Results: The survey elicited 159 responses from 12 countries; 107 of the responses provided sufficient information for analysis. Participants performed an average of 176 PA procedures/year (range: 1-2,000). The types of PA procedures were therapeutic plasma exchange (92% of centers), red cell exchange (86%), leukocyte depletion (87%) and peripheral blood hematopoietic progenitor cell collection (72%). More than 65% of the centers had treated children older than 5 years with PA. Many centers had also performed PA on younger children; 40% have treated patients <12 months of age; 61% had treated patients 1-5 years old. 36% of centers reported that they would perform apheresis regardless of patient weight; 18% used a 5 kg threshold, 11% used 5-10 kg, and 17% used 10 kg as their weight threshold., Conclusion: This report is the largest single survey of centers performing PA. The results provide information about the scope and diversity of PA and identify areas where considerable variability in practice exists. Further exploration of these differences could establish best practices in PA through international research and collaboration., (Copyright © 2013 Wiley Periodicals, Inc.)

Objective: Results of a large multicenter randomized clinical trial published in 2007 demonstrated no benefit in using a liberal versus conservative RBC transfusion threshold in stable critically ill children. Using the conservative threshold decreased the number of RBC transfusions without increasing adverse outcomes. We aimed to determine if wide dissemination of this evidence altered the hemoglobin threshold used for RBC transfusions in our pediatric medical-surgical ICU., Design: Before-after retrospective cohort study using multiple administrative databases and chart review., Setting: PICU serving medical and surgical patients., Patients: All potentially stable children receiving a RBC transfusion in the PICU in 2006 (prepublication) and in 2009-2010 (postpublication). Children were considered unstable and excluded if they were severely hypoxic, receiving renal replacement therapy, hemodynamically unstable, or bleeding., Interventions: Physician education on evidence supporting hemoglobin transfusion thresholds in teaching conferences, staff meetings, and via e-mail., Measurements and Main Results: In 2006, 14.6% of patients (n = 285/1,940) received a RBC transfusion. In 2009-2010, 12.1% of patients (n = 551/4,542) received a RBC transfusion. We evaluated patients transfused when they were potentially clinically stable, including 145 children in 2006 (191 transfusion days) and 266 children in 2009-2010 (369 transfusion days). We found no significant differences in age, sex, race, diagnoses, postoperative status, illness severity scores, mortality, or length of stay between these two groups. The median hemoglobin transfusion threshold decreased significantly from 8.0 g/dL (interquartile range 7.3, 8.6 g/dL) in 2006 to 7.5 g/dL (interquartile range 6.9, 8.1 g/dL) in 2009-2010 (p = 0.001). The percentage of transfusion days using a hemoglobin threshold more than 7 g/dL decreased from 81% (n = 154) in 2006 to 71% (n = 261) in 2009-2010., Conclusion: Although transfusion thresholds in potentially stable critically ill children in our PICU significantly decreased after dissemination of best available evidence, 71% of patients were transfused at a hemoglobin threshold more than 7 g/dL.

Apheresis refers to the removal of a component of the blood and is performed using a group of medical technologies in which peripheral blood is processed by an instrument that separates the various components. The selected component is isolated while the remainder is returned to the patient. The rationale behind therapeutic apheresis is to remove the pathogenic components from the circulation. Apheresis is also used for peripheral hematopoietic progenitor cell collection. The procedure can be safely performed in most children with modifications to account for smaller pediatric blood volumes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Red blood cells are a scarce resource with demand outstripping supply. Use of intraoperative red cell salvage (CS) - the process of collecting shed blood during surgery and reinfusing it to patients - is often used as an effective blood conservation strategy. However, little is known about the economic impact of CS during pediatric surgery., Methods: A decision tree model was used to estimate the transfusion-related costs per patient (2010 USD) from a healthcare system perspective of four transfusion strategies among children undergoing elective orthopedic or cardiac surgery: (i) CS followed by allogeneic transfusion, (ii) CS followed by autologous transfusion, (iii) allogeneic transfusion alone, and (iv) autologous transfusion alone., Results: Cell salvage and allogeneic transfusion was the least expensive strategy (USD 883.3) followed by CS and autologous blood transfusion (USD 1,269.7), allogeneic transfusion alone (USD 1,443.0), and autologous transfusion alone (USD 1,824.7). Savings associated with CS use persisted in separate analyses of orthopedic and cardiac surgery, as well as in one-way and probabilistic sensitivity analyses., Conclusions: Use of CS, particularly along with allogeneic blood transfusion, appears cost-saving and cost-effective in pediatric surgery., (© 2013 John Wiley & Sons Ltd.)

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 × 10(11), 2.2 × 10(11), or 4.4 × 10(11) platelets/m(2) 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.

In this issue of Blood, Smith and colleagues find that an RBC transfusion can induce tolerance to the foreign antigens on the surface of transfused erythrocytes if the animal has not been given an inflammatory stimulus.

In addition to the issues concerning blood transfusions in general, special considerations apply to transfusing neonates. Young infants' plasma may contain maternal antibodies to ABO blood group antigens instead of the naturally occurring anti-ABO antibodies normally present in older patients. This facilitates the transplant of hearts across ABO boundaries but complicates blood bank testing and selection of appropriate blood components for transfusion. Conversely, blood bank testing is simplified by the fact that neonates do not make antibodies to minor erythrocyte antigens. Cellular blood components may be irradiated to prevent transfusion-associated graft-versus-host disease, a syndrome that can affect immunocompromised patients such as premature infants. However, irradiation accelerates the leakage of potassium out of stored red blood cells (RBCs), increasing the risk or transfusion-induced arrhythmias from hyperkalemia and hypocalcemia. Two other risks of transfusing neonates RBCs include dilutional coagulopathy and potential toxicities from additives used to preserve the stored RBC units., (© 2010 Blackwell Publishing Ltd.)

The question of whether storage of red blood cells (RBCs) alters their capacity to deliver oxygen and affects patient outcomes remains in a state of clinical equipoise. Studies of the changes which occur while RBCs are stored have led to several physiologically plausible hypotheses that these changes impair RBC function when the units are transfused. Although there is some evidence of this effect in vivo from animal model experiments, the results of several largely retrospective patient studies have not been consistent. Some studies have shown an association between worse clinical outcomes and transfusion of RBC which have been stored for longer periods of time, while others have found no effect. Three multicenter, randomized, controlled trials have been developed to address this important, but currently unanswered, question. Two clinical trials, one in low birth weight neonates and the other in intensive care unit patients, are enrolling subjects in Canada (the Age of Red Blood Cells in Premature Infants; the Age of Blood Study). The third trial, which is being developed in the United States, is the Red Cell Storage Duration Study (RECESS). This is a multicenter, randomized, controlled trial in which patients undergoing complex cardiac surgical procedures who are likely to require RBC transfusion will be randomized to receive RBC units stored for either 10 or fewer days or 21 or more days. Randomization will only occur if the blood bank has enough units of RBC of both storage times to meet the crossmatch request; hence, subjects randomized to the 21 day arm will receive RBC of the same storage time as they would have following standard inventory practice of "oldest units out first". The primary outcome is the change in the Multiple Organ Dysfunction Score (MODS), a composite measure of multiorgan dysfunction, by day 7. Secondary outcomes include the change in the MODS by day 28, all-cause mortality, and several composite and single measures of specific organ system function. The estimated total sample size required will be 1434 evaluable subjects (717 per arm)., ((c) 2010. Published by Elsevier Ltd. All rights reserved.)

Background: Pediatric transfusion medicine (PTM) is a subspecialty of transfusion medicine with no formal training program and few specialists. The Pediatric Transfusion Medicine Academic Awardees (PedsTMAA) group surveyed PTM content experts to identify relevant objectives for the first formal PTM curriculum., Study Design and Methods: Eight North American PTM experts were invited to participate in a two-step consensus process. PTM-related objectives compiled from a review of existing training documents were organized into a survey. Experts were asked to rate each objective for relevancy for a clinical pathology trainee. Content validity indexes (CVIs) and asymmetric confidence intervals (ACIs) of expert ratings and analysis of respondents' comments were used to identify relevant objectives., Results: Six experts participated and reviewed 117 objectives. Based on content validity criteria (CVI > or = 0.83 and lower-limit 95% ACI > or = 3), a total of 65 objectives were considered relevant. Twenty-three objectives were rated "very relevant" by all the experts while some proposed objectives were determined to be not relevant, out of date, or inappropriate for a resident trainee level., Conclusions: The PedsTMAA group identified 65 objectives for a PTM curriculum. Twenty-three represent a clear core set of objectives and should be considered for clinical pathology training. The next step is to consider the teaching strategies and evaluation methods that will be employed to best deliver this content addressing competency in medical knowledge.

Background: We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia., Methods: We randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1x10(11), 2.2x10(11), or 4.4x10(11) platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria)., Results: In the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25x10(11)) than in the medium-dose group (11.25x10(11)) or the high-dose group (19.63x10(11)) (P=0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower, as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubic millimeter (P<0.001)., Conclusions: Low doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1x10(11) and 4.4x10(11) platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number, NCT00128713.), (2010 Massachusetts Medical Society)

Many significant events have occurred in the recent past that beg a broad audience to address the question "What is pediatric transfusion medicine?" Herein, we list some of these events and their relevance below and attempt to provide an answer for this question. Indeed, several issues regarding the subspecialty of pediatric transfusion medicine (PTM) are particularly timely, and it appears that a critical mass, or a nidus capable of becoming a critical mass, is developing in PTM.

Red blood cell (RBC) transfusion is unique as a common large-scale intravenous introduction of foreign tissue and provides a valuable opportunity to study human immunologic response to intravenous foreign antigen. Patients receiving RBC transfusions are at risk of forming alloantibodies against donor RBC antigens, and valid estimates of alloimmunization risk are clinically important, but little is known about the factors governing this risk or, more generally, about determinants of human response to intravenous antigen. Here, we mine large electronic patient databases enabling us to model RBC alloimmunization as a stochastic process. We identify a subgroup of transfusion recipients that has a dramatically increased risk of alloimmunization that appears to be genetically determined because it is independent of common disease states, patient age, or the number of alloantibodies already formed, and only weakly dependent on transfusion count.