CDC Program Evaluation Framework, 2024.

Program evaluation is a critical tool for understanding and improving organizational activities and systems. This report updates the 1999 CDC Framework for Program Evaluation in Public Health (CDC. Framework for program evaluation in public health. MMWR Recomm Rep 1999;48[No. RR-11];1-40) by integrating major advancements in the fields of evaluation and public health, lessons learned from practical applications of the original framework, and current Federal agency policies and practices. A practical, nonprescriptive tool, the updated 2024 framework is designed to summarize and organize essential elements of program evaluation, and can be applied at any level from individual programs to broader systems by novices and experts for planning and implementing an evaluation. Although many of the key aspects from the 1999 framework remain, certain key differences exist. For example, this updated framework also includes six steps that describe the general process of evaluation planning and implementation, but some content and step names have changed (e.g., the first step has been renamed Assess context). The standards for high-quality evaluation remain central to the framework, although they have been updated to the five Federal evaluation standards. The most substantial change from the 1999 framework is the addition of three cross-cutting actions that are core tenets to incorporate within each evaluation step: engage collaboratively, advance equity, and learn from and use insights. The 2024 framework provides a guide for designing and conducting evaluation across many topics within and outside of public health that anyone involved in program evaluation efforts can use alone or in conjunction with other evaluation approaches, tools, or methods to build evidence, understand programs, and refine evidence-based decision-making to improve all program outcomes.

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.

Regulation of embryonic haematopoietic multipotency by EZH1.

All haematopoietic cell lineages that circulate in the blood of adult mammals derive from multipotent haematopoietic stem cells (HSCs). By contrast, in the blood of mammalian embryos, lineage-restricted progenitors arise first, independently of HSCs, which only emerge later in gestation. As best defined in the mouse, 'primitive' progenitors first appear in the yolk sac at 7.5 days post-coitum. Subsequently, erythroid-myeloid progenitors that express fetal haemoglobin, as well as fetal lymphoid progenitors, develop in the yolk sac and the embryo proper, but these cells lack HSC potential. Ultimately, 'definitive' HSCs with long-term, multilineage potential and the ability to engraft irradiated adults emerge at 10.5 days post-coitum from arterial endothelium in the aorta-gonad-mesonephros and other haemogenic vasculature. The molecular mechanisms of this reverse progression of haematopoietic ontogeny remain unexplained. We hypothesized that the definitive haematopoietic program might be actively repressed in early embryogenesis through epigenetic silencing, and that alleviating this repression would elicit multipotency in otherwise lineage-restricted haematopoietic progenitors. Here we show that reduced expression of the Polycomb group protein EZH1 enhances multi-lymphoid output from human pluripotent stem cells. In addition, Ezh1 deficiency in mouse embryos results in precocious emergence of functional definitive HSCs in vivo. Thus, we identify EZH1 as a repressor of haematopoietic multipotency in the early mammalian embryo.

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.

Changes in Self-Reported Mask Use After the Lifting of State-Issued Mask Mandates in 20 US States, February-June 2021.

OBJECTIVE: In April 2020, the US Centers for Disease Control and Prevention (CDC) recommended community masking to prevent the transmission of SARS-CoV-2. Since then, a total of 39 US states and DC issued mask mandates. Despite CDC recommendations and supporting evidence that masking reduces COVID-19 community transmission, from January to June 20, 2021 states lifted their mask mandates for all individuals. This study examined the association between lifting state-issued mask mandates and mask-wearing behavior in 2021. DESIGN: We estimated a difference-in-difference model, comparing changes in the likelihood for individuals to wear a mask in states that lifted their mask mandate relative to states that kept their mandates in place between February and June of 2021. SETTING: Individuals were surveyed from across the United States. PARTICIPANTS: We used masking behavior data collected by the Porter Novelli View 360 + national surveys (N = 3459), and data from state-issued mask mandates obtained by CDC and the University of Nevada, Las Vegas. MAIN OUTCOMES: The outcome variable of interest was self-reported mask use during the 30 days prior to the survey data collection. RESULTS: In the overall population, lifting mask mandates did not significantly influence mask-wearing behavior. Mask wearing did significantly decrease in response to the lifting of mask mandates among individuals living in rural counties and individuals who had not yet decided whether they would receive a COVID-19 vaccine. CONCLUSION: Policies around COVID-19 behavioral mitigation, specifically amongst those unsure about vaccination and in rural areas, may help reduce the transmission of COVID-19 and other respiratory viruses, especially in communities with low vaccination rates.

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.

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.

De novo generation of HSCs from somatic and pluripotent stem cell sources.

Generating human hematopoietic stem cells (HSCs) from autologous tissues, when coupled with genome editing technologies, is a promising approach for cellular transplantation therapy and for in vitro disease modeling, drug discovery, and toxicology studies. Human pluripotent stem cells (hPSCs) represent a potentially inexhaustible supply of autologous tissue; however, to date, directed differentiation from hPSCs has yielded hematopoietic cells that lack robust and sustained multilineage potential. Cellular reprogramming technologies represent an alternative platform for the de novo generation of HSCs via direct conversion from heterologous cell types. In this review, we discuss the latest advancements in HSC generation by directed differentiation from hPSCs or direct conversion from somatic cells, and highlight their applications in research and prospects for therapy.

Public Health Detailing-A Successful Strategy to Promote Judicious Opioid Analgesic Prescribing.

OBJECTIVES: To evaluate knowledge and prescribing changes following a 2-month public health detailing campaign (one-to-one educational visits) about judicious opioid analgesic prescribing conducted among health care providers in Staten Island, New York City, in 2013. METHODS: Three detailing campaign recommendations were (1) a 3-day supply of opioids is usually sufficient for acute pain, (2) avoid prescribing opioids for chronic noncancer pain, and (3) avoid high-dose opioid prescriptions. Evaluation consisted of a knowledge survey, and assessing prescribing rates and median day supply per prescription. Prescribing data from the 3-month period before the campaign were compared with 2 sequential 3-month periods after the campaign. RESULTS: Among 866 health care providers visited, knowledge increased for all 3 recommendations (P < .01). After the campaign, the overall prescribing rate decreased similarly in Staten Island and other New York City counties (boroughs), but the high-dose prescribing rate decreased more in Staten Island than in other boroughs (P < .01). Median day supply remained stable in Staten Island and increased in other boroughs. CONCLUSIONS: The public health detailing campaign improved knowledge and likely prescribing practices and could be considered by other jurisdictions to promote judicious opioid prescribing.

Socioecological factors influencing women's HIV risk in the United States: qualitative findings from the women's HIV SeroIncidence study (HPTN 064).

BACKGROUND: We sought to understand the multilevel syndemic factors that are concurrently contributing to the HIV epidemic among women living in the US. We specifically examined community, network, dyadic, and individual factors to explain HIV vulnerability within a socioecological framework. METHODS: We gathered qualitative data (120 interviews and 31 focus groups) from a subset of women ages 18-44 years (N = 2,099) enrolled in the HPTN 064 HIV seroincidence estimation study across 10 US communities. We analyzed data from 4 diverse locations: Atlanta, New York City (the Bronx), Raleigh, and Washington, DC. Data were thematically coded using grounded theory methodology. Intercoder reliability was assessed to evaluate consistency of team-based coding practices. RESULTS: The following themes were identified at 4 levels including 1) exosystem (community): poverty prevalence, discrimination, gender imbalances, community violence, and housing challenges; 2) mesosystem (network): organizational social support and sexual concurrency; 3) microsystem (dyadic): sex exchange, interpersonal social support, intimate partner violence; and 4) individual: HIV/STI awareness, risk taking, and substance use. A strong theme emerged with over 80 % of responses linked to the fundamental role of financial insecurity underlying risk-taking behavioral pathways. CONCLUSIONS: Multilevel syndemic factors contribute to women's vulnerability to HIV in the US. Financial insecurity is a predominant theme, suggesting the need for tailored programming for women to reduce HIV risk. TRIAL REGISTRATION: Clinicaltrials.gov, NCT00995176.

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.

Public e-learning opportunities in anesthesia on YouTube.

Background: The increasing knowledge in medicine makes continuous education for clinicians necessary more than ever. The range of skills to be covered in anesthesia is constantly growing. How to optimize complex training in practical skills in an increasingly economized environment remains unclear. The extent and suitability to which video platforms assist in learning basic skills in anesthesia has not been investigated yet. Methods: To identify appropriate videos on YouTube, we conducted a search (May 1st 2023), including common combinations of synonymous terms, and checked up to the 50th result for relevance. Videos initially deemed suitable were archived and evaluated to exclude duplicates. All included videos were subsequently scrutinized for content. For this purpose, a validated checklist to assess procedural and didactic content was used. Data analysis involved assessing interrater reliability, Spearman's rho test, and linear regression analysis. Results: We were able to include 222 videos related to 16 basic skills. The low number of videos found on specific skills was striking. The level of fulfillment illustrating a practical skill was repeatedly found <60%. The consistency of the questionnaire was moderate (Fleiss kappa 0.59). Video runtime displayed a significant correlation (p < 0.001) with the number of items accomplished on procedural (|ρ| = 0.442, R 2 = 0.196) and didactic items (|ρ| = 0.452, R 2 = 0.153). The professional context of the content creators showed no influence. Conclusion: The quantity of available material on specific basic anesthesiologic skills varied drastically. In addition, the videos available often revealed significant shortcomings, making it challenging to easily assess the quality of the content. The vast majority of evaluated videos did not reflect the intended approach in a scientifically correct manner or were entirely unsuitable for displaying the procedural requirements.

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.

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 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.

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.

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.