Use of apixaban in children awaiting heart transplantation.

BACKGROUND: The use of apixaban in the pediatric cardiac population is expanding. We describe our apixaban dosing and monitoring strategy in children and young adults awaiting heart transplantation, along with outcomes related to bleeding and thrombosis during wait-list and early post-transplant periods. METHODS: This study is a retrospective, single-center analysis of all patients receiving apixaban while awaiting cardiac transplantation. Weight-based dosing was monitored with peak drug-specific anti-Xa chromogenic analysis. Significant post-operative bleeding defined by chest tube output or need for surgical intervention. RESULTS: From September 2020 to December 2022, 19 patients, median age 13.5 years (6.1, 15.8 years), weighing 48.9 kg (15.4, 67.6) received apixaban while awaiting transplant. Indication for apixaban was prophylaxis (n = 18, 3 with ventricular assist devices) and treatment of thrombus (n = 1). There were no clinically relevant non-major or major bleeding, nor thrombotic events while awaiting transplant. The median time from last apixaban dose to arrival in the operating room was 23.2 h (15.6-33.8), with median random apixaban level of 37 ng/mL (28.3, 59), 6.3 h (4.8, 8.4) prior to arrival in the operating room. In this study, 32% of patients had significant post-operative bleeding based on chest tube output post-transplant or need for intervention. No patients meeting criteria for significant post-operative bleeding were thought to be attributable to apixaban. CONCLUSIONS: Careful use of apixaban can be safe and effective while awaiting heart transplant. There was no appreciable increase in peri-operative bleeding. The use of apixaban is promising in providing safe, predictable and efficacious anticoagulation while avoiding additional patient stressors.

Lessons Learned From Applying a Monitoring and Evaluation Framework to Economic, Social, and Other Health Impacts of the COVID-19 Pandemic.

Individual and community-level COVID-19 mitigation policies can have effects beyond direct COVID-19 health outcomes, including social, behavioral, and economic outcomes. These social, behavioral, and economic outcomes can extend beyond the pandemic period and have disparate effects on populations. Public Health-Seattle & King County (PHSKC) built on the Centers for Disease Control and Prevention's community mitigation strategy framework to create a local project tracking near-real-time data to understand factors affected by mitigation approaches, inform decision-making, and monitor and evaluate community-level disparities during the pandemic. This case study describes the framework and lessons learned from PHSKC's collation, use, and dissemination of local data from 20 data sources to guide community and public health decision-making. Social, behavioral, economic, and health indicators were regularly updated and disseminated through interactive dashboards and products that examined data in the context of applicable policies. Data disaggregated by demographic characteristics and geography highlighted inequities, but not all datasets contained the same details; local surveys or qualitative data were used to fill gaps. Project outcomes included informing city and county emergency response planning related to implementation of financial and food assistance programs. Key lessons learned included the need to (1) build on existing processes and use automated processes and (2) partner with other sectors to use nontraditional public health data for active dissemination and data disaggregation and for real-time data contextualized by policy changes. This project provided programs and communities with timely, reliable data to understand where to invest recovery funding. A similar framework could position other health departments to examine social and economic effects during future public health emergencies.

Evaluation of Centers for Disease Control and Prevention's Evaluation Fellowship Program.

OBJECTIVE: The Centers for Disease Control and Prevention's (CDC's) Evaluation Fellowship Program is a 2-year fellowship that includes training, placement with a CDC program, and professional development funds. We evaluated whether the program contributed to CDC's evaluation capacity, prepared fellows for evaluation work, and contributed to their career advancement during its first 10 years. METHODS: We used a mixed-methods approach, including conducting an online survey and telephone interviews. External evaluators sent surveys to all 152 alumni and all 123 mentors who participated in the program from 2011 through 2020 (first 8 cohorts) and interviewed 9 mentors and 15 alumni. RESULTS: A total of 110 alumni (72.4%) and 44 mentors (35.8%) completed surveys. Of 44 mentors, most agreed their fellow(s) contributed to their program's overall evaluation capacity (90.9%) and its ability to do more evaluation (88.6%). Most (84.2%-88.1%) alumni agreed that the Evaluation Fellowship Program prepared them to apply the 6 skill sets that aligned with CDC's Framework for Program Evaluation in Public Health. Support from the Fellowship office was significantly and positively correlated with performing evaluation tasks (ß = 0.25; P = .004) and alumni obtaining their first job (ß = 0.36; P < .001). Host program mentoring was significantly correlated with performing evaluation tasks (ß = 0.27; P = .02) and alumni obtaining their first job (ß = 0.34; P = .007). CONCLUSION: CDC's Evaluation Fellowship Program has made progress toward building CDC's evaluation capacity and preparing a public health workforce to use evaluation skills in various settings. A service-learning model that provides training and applied experiences could prepare a workforce to build evaluation capacity.

Genome editing in the mouse brain with minimally immunogenic Cas9 RNPs.

Transient delivery of CRISPR-Cas9 ribonucleoproteins (RNPs) into the central nervous system (CNS) for therapeutic genome editing could avoid limitations of viral vector-based delivery including cargo capacity, immunogenicity, and cost. Here, we tested the ability of cell-penetrant Cas9 RNPs to edit the mouse striatum when introduced using a convection-enhanced delivery system. These transient Cas9 RNPs showed comparable editing of neurons and reduced adaptive immune responses relative to one formulation of Cas9 delivered using AAV serotype 9. The production of ultra-low endotoxin Cas9 protein manufactured at scale further improved innate immunity. We conclude that injection-based delivery of minimally immunogenic CRISPR genome editing RNPs into the CNS provides a valuable alternative to virus-mediated genome editing.

Duration of Behavioral Policy Interventions and Incidence of COVID-19 by Social Vulnerability of US Counties, April-December 2020.

OBJECTIVE: State-issued behavioral policy interventions (BPIs) can limit community spread of COVID-19, but their effects on COVID-19 transmission may vary by level of social vulnerability in the community. We examined the association between the duration of BPIs and the incidence of COVID-19 across levels of social vulnerability in US counties. METHODS: We used COVID-19 case counts from USAFacts and policy data on BPIs (face mask mandates, stay-at-home orders, gathering bans) in place from April through December 2020 and the 2018 Social Vulnerability Index (SVI) from the Centers for Disease Control and Prevention. We conducted multilevel linear regression to estimate the associations between duration of each BPI and monthly incidence of COVID-19 (cases per 100 000 population) by SVI quartiles (grouped as low, moderate low, moderate high, and high social vulnerability) for 3141 US counties. RESULTS: Having a BPI in place for longer durations (ie, ≥2 months) was associated with lower incidence of COVID-19 compared with having a BPI in place for <1 month. Compared with having no BPI in place or a BPI in place for <1 month, differences in marginal mean monthly incidence of COVID-19 per 100 000 population for a BPI in place for ≥2 months ranged from -4 cases in counties with low SVI to -401 cases in counties with high SVI for face mask mandates, from -31 cases in counties with low SVI to -208 cases in counties with high SVI for stay-at-home orders, and from -227 cases in counties with low SVI to -628 cases in counties with high SVI for gathering bans. CONCLUSIONS: Establishing COVID-19 prevention measures for longer durations may help reduce COVID-19 transmission, especially in communities with high levels of social vulnerability.

Stem cell-based multi-tissue platforms to model human autoimmune diabetes.

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic insulin-producing ß cells are specifically destroyed by the immune system. Understanding the initiation and progression of human T1D has been hampered by the lack of appropriate models that can reproduce the complexity and heterogeneity of the disease. The development of platforms combining multiple human pluripotent stem cell (hPSC) derived tissues to model distinct aspects of T1D has the potential to provide critical novel insights into the etiology and pathogenesis of the human disease. SCOPE OF REVIEW: In this review, we summarize the state of hPSC differentiation approaches to generate cell types and tissues relevant to T1D, with a particular focus on pancreatic islet cells, T cells, and thymic epithelium. We present current applications as well as limitations of using these hPSC-derived cells for disease modeling and discuss efforts to optimize platforms combining multiple cell types to model human T1D. Finally, we outline remaining challenges and emphasize future improvements needed to accelerate progress in this emerging field of research. MAJOR CONCLUSIONS: Recent advances in reprogramming approaches to create patient-specific induced pluripotent stem cell lines (iPSCs), genome engineering technologies to efficiently modify DNA of hPSCs, and protocols to direct their differentiation into mature cell types have empowered the use of stem cell derivatives to accurately model human disease. While challenges remain before complex interactions occurring in human T1D can be modeled with these derivatives, experiments combining hPSC-derived ß cells and immune cells are already providing exciting insight into how these cells interact in the context of T1D, supporting the viability of this approach.

Evaluation of a Clinical Decision Support System for the most evidence-based approach to managing perioperative anticoagulation.

STUDY OBJECTIVE: We explored the feasibility of a Clinical Decision Support System (CDSS) to guide evidence-based perioperative anticoagulation. DESIGN: Prospective randomised clinical management simulation multicentre study. SETTING: Five University and 11 general hospitals in Germany. PARTICIPANTS: We enrolled physicians (anaesthesiologist (n = 73), trauma surgeons (n = 2), unknown (n = 1)) with different professional experience. INTERVENTIONS: A CDSS based on a multiple-choice test was developed and validated at the University Hospital of Frankfurt (phase-I). The CDSS comprised European guidelines for the management of anticoagulation in cardiology, cardio-thoracic, non-cardio-thoracic surgery and anaesthesiology. Phase-II compared the efficiency of physicians in identifying evidence-based approach of managing perioperative anticoagulation. In total 168 physicians were randomised to CDSS (PERI-KOAG) or CONTROL. MEASUREMENTS: Overall mean score and association of processing time and professional experience were analysed. The multiple-choice test consists of 11 cases and two correct answers per question were required to gain 100% success rate (=22 points). MAIN RESULTS: In total 76 physicians completed the questionnaire (n = 42 PERI-KOAG; n = 34 CONTROL; attrition rate 54%). Overall mean score (max. 100% = 22 points) was significantly higher in PERI-KOAG compared to CONTROL (82 ± 15% vs. 70 ± 10%; 18 ± 3 vs. 15 ± 2 points; P = 0.0003). A longer processing time is associated with significantly increased overall mean scores in PERI-KOAG (≥33 min. 89 ± 10% (20 ± 2 points) vs. <33 min. 73 ± 15% (16 ± 3 points), P = 0.0005) but not in CONTROL (≥33 min. 74 ± 13% (16 ± 3 points) vs. <33 min. 69 ± 9% (15 ± 2 points), P = 0.11). Within PERI-KOAG, there is a tendency towards higher results within the more experienced group (>5 years), but no significant difference to less (≤5 years) experienced colleagues (87 ± 10% (19 ± 2 points) vs. 78 ± 17% (17 ± 4 points), P = 0.08). However, an association between professional experience and success rate in CONTROL has not been shown (71 ± 8% vs. 70 ± 13%, 16 ± 2 vs. 15 ± 3 points; P = 0.66). CONCLUSIONS: CDSS significantly improved the identification of evidence-based treatment approaches. A precise usage of CDSS is mandatory to maximise efficiency.

The Impact of Covid-19 State Closure Orders on Consumer Spending, Employment, and Business Revenue.

CONTEXT: In response to the COVID-19 pandemic, states across the United States implemented various strategies to mitigate transmission of SARS-CoV-2 (the virus that causes COVID-19). OBJECTIVE: To examine the effect of COVID-19-related state closures on consumer spending, business revenue, and employment, while controlling for changes in COVID-19 incidence and death. DESIGN: The analysis estimated a difference-in-difference model, utilizing temporal and geographic variation in state closure orders to analyze their impact on the economy, while controlling for COVID-19 incidence and death. PARTICIPANTS: State-level data on economic outcomes from the Opportunity Insights data tracker and COVID-19 cases and death data from usafacts.org. INTERVENTIONS: The mitigation strategy analyzed within this study was COVID-19-related state closure orders. Data on these orders were obtained from state government Web sites containing executive or administrative orders. MAIN OUTCOME MEASURES: Outcomes include state-level estimates of consumer spending, business revenue, and employment levels. RESULTS: Analyses showed that although state closures led to a decrease in consumer spending, business revenue, and employment, they accounted for only a small portion of the observed decreases in these outcomes over the first wave of COVID-19. CONCLUSIONS: The impact of COVID-19 on economic activity likely reflects a combination of factors, in addition to state closures, such as individuals' perceptions of risk related to COVID-19 incidence, which may play significant roles in impacting economic activity.

Lin28 paralogs regulate lung branching morphogenesis.

The molecular mechanisms that govern the choreographed timing of organ development remain poorly understood. Our investigation of the role of the Lin28a and Lin28b paralogs during the developmental process of branching morphogenesis establishes that dysregulation of Lin28a/b leads to abnormal branching morphogenesis in the lung and other tissues. Additionally, we find that the Lin28 paralogs, which regulate post-transcriptional processing of both mRNAs and microRNAs (miRNAs), predominantly control mRNAs during the initial phases of lung organogenesis. Target mRNAs include Sox2, Sox9, and Etv5, which coordinate lung development and differentiation. Moreover, we find that functional interactions between Lin28a and Sox9 are capable of bypassing branching defects in Lin28a/b mutant lungs. Here, we identify Lin28a and Lin28b as regulators of early embryonic lung development, highlighting the importance of the timing of post-transcriptional regulation of both miRNAs and mRNAs at distinct stages of organogenesis.

Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.

The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.

The association between intraoperative cell salvage and red blood cell transfusion in cardiac surgery - an observational study in a patient blood management centre.

INTRODUCTION: Cell salvage (CS) is an integral part of patient blood management (PBM) and aims to reduce allogeneic red blood cell (RBC) transfusion. MATERIAL AND METHODS: This observational study analysed patients scheduled for elective cardiac surgery requiring cardiopulmonary bypass (CPB) between November 2015 and October 2018. Patients were divided into a CS group (patients receiving CS) and a control group (no CS). Primary endpoints were the number of patients exposed to allogeneic RBC transfusions and the number of RBC units transfused per patient. RESULTS: A total of 704 patients undergoing cardiac surgery were analysed, of whom 338 underwent surgery with CS (CS group) and 366 were without CS (control group). Intraoperatively, 152 patients (45%) were exposed to allogeneic RBC transfusions in the CS group and 93 patients (25%) in the control group (P < 0.001). Considering the amount of intraoperative blood loss, regression analysis revealed a significant association between blood loss and increased use of RBC units in patients of the control compared to the CS group (1000 mL: 1.0 vs. 0.6 RBC units; 2000 mL: 2.2 vs. 1.1 RBC units; 3000 mL: 3.4 vs. 1.6 RBC units). Thus, CS was significantly associated with a reduced number of allogeneic RBCs by 40% for 1000 mL, 49% for 2000 mL, and 52% for 3000 mL of blood loss compared to patients without CS. CONCLUSIONS: Cell salvage was significantly associated with a reduced number of allogeneic RBC transfusions. It supports the beneficial effect of CS in cardiac surgical patients as an individual measure in a comprehensive PBM program.

Calmodulin inhibitors improve erythropoiesis in Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a rare hematopoietic disease characterized by a block in red cell differentiation. Most DBA cases are caused by mutations in ribosomal proteins and characterized by higher than normal activity of the tumor suppressor p53. Higher p53 activity is thought to contribute to DBA phenotypes by inducing apoptosis during red blood cell differentiation. Currently, there are few therapies available for patients with DBA. We performed a chemical screen using zebrafish ribosomal small subunit protein 29 (rps29) mutant embryos that have a p53-dependent anemia and identified calmodulin inhibitors that rescued the phenotype. Our studies demonstrated that calmodulin inhibitors attenuated p53 protein amount and activity. Treatment with calmodulin inhibitors led to decreased p53 translation and accumulation but does not affect p53 stability. A U.S. Food and Drug Administration-approved calmodulin inhibitor, trifluoperazine, rescued hematopoietic phenotypes of DBA models in vivo in zebrafish and mouse models. In addition, trifluoperazine rescued these phenotypes in human CD34+ hematopoietic stem and progenitor cells. Erythroid differentiation was also improved in CD34+ cells isolated from a patient with DBA. This work uncovers a potential avenue of therapeutic development for patients with DBA.

Strategies for increasing impact, engagement, and accessibility in HIV prevention programs: suggestions from women in urban high HIV burden counties in the Eastern United States (HPTN 064).

BACKGROUND: Merely having the tools to end HIV is insufficient. Effectively ending the epidemic necessitates addressing barriers that impede engagement in biomedical and behavioral prevention and wide scale implementation and utilization of existing interventions. This qualitative study identifies suggestions for increasing access to, engagement in, and impact of HIV prevention among women living in cities in high HIV burden counties in the eastern US. METHODS: Data analyzed for the current study were collected via a qualitative sub-study within the HIV Prevention Trials Network Study 064 (HPTN 064), a multisite observational cohort study designed to estimate HIV incidence among women residing in communities with elevated HIV prevalence who also reported personal or partner characteristics associated with increased risk of HIV acquisition. Focus group and interview participants in the qualitative sub-study (N = 288) were from four cities in the eastern US. RESULTS: Thematic analyses revealed four themes describing women's most frequently stated ideas for improving prevention efforts: 1) Promote Multilevel Empowerment, 2) Create Engaging Program Content, 3) Build "Market Demand", and 4) Ensure Accessibility. We conducted additional analyses to identify contradictory patterns in the data, which revealed an additional three themes: 1) Address Structural Risk Factors, 2) Increase Engagement via Pleasure Promotion, 3) Expand Awareness of and Access to Prevention Resources. CONCLUSIONS: Findings may be useful for enhancing women's engagement in and uptake of behavioral and biomedical HIV prevention resources, improving policy, and addressing multilevel risk factors. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00995176 , prospectively registered.

Transcriptome Dynamics of Hematopoietic Stem Cell Formation Revealed Using a Combinatorial Runx1 and Ly6a Reporter System.

Studies of hematopoietic stem cell (HSC) development from pre-HSC-producing hemogenic endothelial cells (HECs) are hampered by the rarity of these cells and the presence of other cell types with overlapping marker expression profiles. We generated a Tg(Runx1-mKO2; Ly6a-GFP) dual reporter mouse to visualize hematopoietic commitment and study pre-HSC emergence and maturation. Runx1-mKO2 marked all intra-arterial HECs and hematopoietic cluster cells (HCCs), including pre-HSCs, myeloid- and lymphoid progenitors, and HSCs themselves. However, HSC and lymphoid potential were almost exclusively found in reporter double-positive (DP) cells. Robust HSC activity was first detected in DP cells of the placenta, reflecting the importance of this niche for (pre-)HSC maturation and expansion before the fetal liver stage. A time course analysis by single-cell RNA sequencing revealed that as pre-HSCs mature into fetal liver stage HSCs, they show signs of interferon exposure, exhibit signatures of multi-lineage differentiation gene expression, and develop a prolonged cell cycle reminiscent of quiescent adult HSCs.

Mortality and Complication Rates in Adult Trauma Patients Receiving Tranexamic Acid: A Single-center Experience in the Post-CRASH-2 Era.

OBJECTIVES: The CRASH-2 trial demonstrated that tranexamic acid (TXA) in adults with significant traumatic hemorrhage safely reduces mortality. Given that the CRASH-2 trial did not include U.S. sites, our objective was to evaluate patient characteristics, TXA dosing strategies, and the incidence of mortality and adverse events in adult trauma patients receiving TXA at a U.S. Level I trauma center in the post-CRASH-2 era. METHODS: We conducted a retrospective study that included patients aged 18 years or older who received TXA after an acute injury from July 2014 to June 2017. We excluded patients who received TXA orally, patients who received TXA for elective surgical procedures or nontrauma indications, patients who received it 8 hours or longer after the time of injury, and patients with cardiac arrest at time of emergency department arrival. Trained abstractors collected data from the trauma registry and hospital electronic medical records. Our primary outcome measures were in-hospital death and acute thromboembolic events within 28 days from injury. RESULTS: We included 273 patients with a mean (±SD) age of 43.8 (±18.7)  years. The mean (±SD) time of administration of TXA from time of injury was 1.55 (±1.2)  hours with 229 patients (83.9%) receiving TXA within 3 hours. The overall mortality within 28 days from injury was 12.8% (95% confidence interval [CI] = 8.9% to 16.7%), which was similar compared to that in the CRASH-2 trial (14.5%, 95% CI = 13.9% to 15.2%). The incidence of acute thromboembolic events was 6.6% (95% CI = 3.7% to 9.5%), which was higher than that in the CRASH-2 trial (2.0%, 95% CI = 1.73% to 2.27%). Patients in our cohort also received surgery (64.8% vs. 47.9%) and blood transfusions (74.0% vs. 50.4%) more frequently than those in the CRASH-2 cohort. CONCLUSIONS: Adult trauma patients receiving TXA had similar incidences of death but higher incidences of thromboembolic events compared to the CRASH-2 trial. Variation in patient characteristics, injury severity, TXA dosing, and surgery and transfusion rates could explain these observed differences. Further research is necessary to provide additional insight into the incidence and risk factors of thromboembolic events in TXA use.

Treg cell-based therapies: challenges and perspectives.

Cellular therapies using regulatory T (Treg) cells are currently undergoing clinical trials for the treatment of autoimmune diseases, transplant rejection and graft-versus-host disease. In this Review, we discuss the biology of Treg cells and describe new efforts in Treg cell engineering to enhance specificity, stability, functional activity and delivery. Finally, we envision that the success of Treg cell therapy in autoimmunity and transplantation will encourage the clinical use of adoptive Treg cell therapy for non-immune diseases, such as neurological disorders and tissue repair.

Polymer-stabilized Cas9 nanoparticles and modified repair templates increase genome editing efficiency.

Versatile and precise genome modifications are needed to create a wider range of adoptive cellular therapies1-5. Here we report two improvements that increase the efficiency of CRISPR-Cas9-based genome editing in clinically relevant primary cell types. Truncated Cas9 target sequences (tCTSs) added at the ends of the homology-directed repair (HDR) template interact with Cas9 ribonucleoproteins (RNPs) to shuttle the template to the nucleus, enhancing HDR efficiency approximately two- to fourfold. Furthermore, stabilizing Cas9 RNPs into nanoparticles with polyglutamic acid further improves editing efficiency by approximately twofold, reduces toxicity, and enables lyophilized storage without loss of activity. Combining the two improvements increases gene targeting efficiency even at reduced HDR template doses, yielding approximately two to six times as many viable edited cells across multiple genomic loci in diverse cell types, such as bulk (CD3+) T cells, CD8+ T cells, CD4+ T cells, regulatory T cells (Tregs), γδ T cells, B cells, natural killer cells, and primary and induced pluripotent stem cell-derived6 hematopoietic stem progenitor cells (HSPCs).

Author Correction: A systems biology pipeline identifies regulatory networks for stem cell engineering.

In the version of this article initially published, the second NIH grant "R24-DK49216" to author George Q. Daley contained an error. The grant number should have read U54DK110805. The error has been corrected in the HTML and PDF versions of the article.

A systems biology pipeline identifies regulatory networks for stem cell engineering.

A major challenge for stem cell engineering is achieving a holistic understanding of the molecular networks and biological processes governing cell differentiation. To address this challenge, we describe a computational approach that combines gene expression analysis, previous knowledge from proteomic pathway informatics and cell signaling models to delineate key transitional states of differentiating cells at high resolution. Our network models connect sparse gene signatures with corresponding, yet disparate, biological processes to uncover molecular mechanisms governing cell fate transitions. This approach builds on our earlier CellNet and recent trajectory-defining algorithms, as illustrated by our analysis of hematopoietic specification along the erythroid lineage, which reveals a role for the EGF receptor family member, ErbB4, as an important mediator of blood development. We experimentally validate this prediction and perturb the pathway to improve erythroid maturation from human pluripotent stem cells. These results exploit an integrative systems perspective to identify new regulatory processes and nodes useful in cell engineering.

Mortality and Thrombosis in Injured Adults Receiving Tranexamic Acid in the Post-CRASH-2 Era.

INTRODUCTION: The CRASH-2 trial demonstrated that tranexamic acid (TXA) reduced mortality with no increase in adverse events in severely injured adults. TXA has since been widely used in injured adults worldwide. Our objective was to estimate mortality and adverse events in adults with trauma receiving TXA in studies published after the CRASH-2 trial. METHODS: We systematically searched PubMed, Embase, MicroMedex, and ClinicalTrials.gov for studies that included injured adults who received TXA and reported mortality and/or adverse events. Two reviewers independently assessed study eligibility, abstracted data, and assessed the risk of bias. We conducted meta-analyses using random effects models to estimate the incidence of mortality at 28 or 30 days and in-hospital thrombotic events. RESULTS: We included 19 studies and 13 studies in the systematic review and meta-analyses, respectively. The pooled incidence of mortality at 28 or 30 days (five studies, 1538 patients) was 10.1% (95% confidence interval [CI], 7.8-12.4%) (vs 14.5% [95% CI, 13.9-15.2%] in the CRASH-2 trial), and the pooled incidence of in-hospital thrombotic events (nine studies, 1656 patients) was 5.9% (95% CI, 3.3-8.5%) (vs 2.0% [95% CI, 1.8-2.3%] in the CRASH-2 trial). CONCLUSION: Compared to the CRASH-2 trial, adult trauma patients receiving TXA identified in our systematic review had a lower incidence of mortality at 28 or 30 days, but a higher incidence of in-hospital thrombotic events. Our findings neither support nor refute the findings of the CRASH-2 trial but suggest that incidence rates in adults with trauma in settings outside of the CRASH-2 trial may be different than those observed in the CRASH-2 trial.