Xist RNA is a potent suppressor of hematologic cancer in mice.

X chromosome aneuploidies have long been associated with human cancers, but causality has not been established. In mammals, X chromosome inactivation (XCI) is triggered by Xist RNA to equalize gene expression between the sexes. Here we delete Xist in the blood compartment of mice and demonstrate that mutant females develop a highly aggressive myeloproliferative neoplasm and myelodysplastic syndrome (mixed MPN/MDS) with 100% penetrance. Significant disease components include primary myelofibrosis, leukemia, histiocytic sarcoma, and vasculitis. Xist-deficient hematopoietic stem cells (HSCs) show aberrant maturation and age-dependent loss. Reconstitution experiments indicate that MPN/MDS and myelofibrosis are of hematopoietic rather than stromal origin. We propose that Xist loss results in X reactivation and consequent genome-wide changes that lead to cancer, thereby causally linking the X chromosome to cancer in mice. Thus, Xist RNA not only is required to maintain XCI but also suppresses cancer in vivo.

Early Impressions and Adoption of the AtriAmp for Managing Arrhythmias Following Congenital Heart Surgery.

AtriAmp is a new medical device that displays a continuous real-time atrial electrogram on telemetry using temporary atrial pacing leads. Our objective was to evaluate early adoption of this device into patient care within our pediatric intensive care unit (PICU). This is a qualitative study using inductive analysis of semi-structured interviews to identify dominant themes. The study was conducted in a single-center, tertiary, academic 21-bed mixed PICU. The subjects were PICU multidisciplinary team members (Pediatric Cardiac Intensivists, PICU Nurse Practitioners, PICU nurses and Pediatric Cardiologists) who were early adopters of the AtriAmp (n = 14). Three prominent themes emerged: (1) Accelerated time from arrhythmia event to diagnosis and treatment; (2) Increased confidence in the accuracy of providers' arrhythmia diagnosis; and (3) Improvement in the ability to educate providers about post-operative arrhythmias. Providers also noted some learning curves, but none compromised medical care or clinical workflow. Insights from early adopters of AtriAmp signal the need for simplicity and fidelity in new PICU technologies. Our research suggests that such technologies can be pivotal to the support and growth of multi-disciplinary teams, even among those who do not participate in early implementation. Further research is needed to understand when and why novel technology adoption becomes widespread in high-stakes settings.

Persistent SARS-CoV-2-specific immune defects in kidney transplant recipients following third mRNA vaccine dose.

Kidney transplant recipients (KTRs) show poorer response to SARS-CoV-2 mRNA vaccination, yet response patterns and mechanistic drivers following third doses are ill-defined. We administered third monovalent mRNA vaccines to n = 81 KTRs with negative or low-titer anti-receptor binding domain (RBD) antibody (n = 39 anti-RBDNEG; n = 42 anti-RBDLO), compared with healthy controls (HCs, n = 19), measuring anti-RBD, Omicron neutralization, spike-specific CD8+%, and SARS-CoV-2-reactive T cell receptor (TCR) repertoires. By day 30, 44% anti-RBDNEG remained seronegative; 5% KTRs developed BA.5 neutralization (vs 68% HCs, P < .001). Day 30 spike-specific CD8+% was negative in 91% KTRs (vs 20% HCs; P = .07), without correlation to anti-RBD (rs = 0.17). Day 30 SARS-CoV-2-reactive TCR repertoires were detected in 52% KTRs vs 74% HCs (P = .11). Spike-specific CD4+ TCR expansion was similar between KTRs and HCs, yet KTR CD8+ TCR depth was 7.6-fold lower (P = .001). Global negative response was seen in 7% KTRs, associated with high-dose MMF (P = .037); 44% showed global positive response. Of the KTRs, 16% experienced breakthrough infections, with 2 hospitalizations; prebreakthrough variant neutralization was poor. Absent neutralizing and CD8+ responses in KTRs indicate vulnerability to COVID-19 despite 3-dose mRNA vaccination. Lack of neutralization despite CD4+ expansion suggests B cell dysfunction and/or ineffective T cell help. Development of more effective KTR vaccine strategies is critical. (NCT04969263).

Improvements in Accuracy and Confidence in Rhythm Identification After Cardiac Surgery Using the AtriAmp Signals.

Objectives: Following cardiac surgery, 50% to 60% of patients with congenital heart disease will experience an arrhythmia. These arrhythmias are associated with increased morbidity and mortality. Therefore, rapid and accurate identification is paramount to the improvement of patient outcome. We hypothesize that the AtriAmp, a device which allows atrial electrogram (AEG) display on the bedside monitors, will increase provider accuracy and confidence in arrhythmia diagnosis. Design: A prospective observational study. Electrograms were collected from post-operative patients from the bedside monitors surface ECG and an AEG using the AtriAmp. A 12-question online survey was given to critical care and cardiology providers at 9 different programs across the country as well as being posted to the AAP SOCC fall newsletter. Six questions displayed signals from only the surface leads, while the other 6 showed the same arrhythmias with an AEG obtained from the AtriAmp. Answers were then evaluated for confidence and accuracy. A paired t-test along with mixed method modeling was used to assess the data. Setting: Cardiac pediatric ICU. Subjects: Providers in pediatric cardiology and pediatric critical care were evaluated on their ability to diagnose arrhythmias on surface ECG and AEG obtained from bedside monitor. Interventions: The accuracy and confidence of diagnosis of both surface and AEG signals were evaluated through an on-line survey. Results: Eighty-eight providers completed the survey. The study showed that interpreting with the AtriAmp signal, compared to the surface ECG only, significantly increased the accuracy (P = .002) and confidence in provider rhythm diagnosis (P < .001). Junctional ectopic tachycardia, sinus tachycardia, and complete heart block had the most significant increase in accuracy of diagnose when using the AtriAmp signal (P < .001, P = .002, P = .010, respectively). Conclusion: Use of the AtriAmp increased provider accuracy and confidence in post-operative rhythm diagnosis when compared to diagnosis using the surface electrograms only.

Hypokalemia/Hyperkalemia and Hyponatremia/Hypernatremia.

Electrolyte disorders are very common in the pediatric population. Derangements in serum sodium and potassium concentrations are among the most frequently seen given the risk factors and comorbidities unique to children. Pediatricians, in both outpatient and inpatient settings, should be comfortable with the evaluation and initial treatment of disturbances in these electrolyte concentrations. However, to evaluate and treat a child with abnormal serum concentrations of sodium or potassium, it is critical to understand the regulatory physiology that governs osmotic homeostasis and potassium regulation in the body. Comprehension of these basic physiologic processes will allow the provider to uncover the underlying pathology of these electrolyte disturbances and devise an appropriate and safe treatment plan.

A multi-step education model for advancing competencies in geriatrics and interprofessional collaboration for health students.

At a time when the older adult population is increasing exponentially and health care agencies are fraught with crisis-level short-handedness and burnout, addressing the Quadruple Aim of enhancing patient experience, improving population health, reducing costs, and improving the work life of health care providers is more crucial than ever. A multi-step education model was designed to advance competencies in geriatrics and Interprofessional Collaborative Practice (IPCP) for health profession students focused on each element of the Quadruple Aim. The goals of this education were to equip students with knowledge and experience to provide team-based care for older adults and achieve satisfaction with the education program. The education steps consisted of online didactics, team icebreaker, skills practice, professional huddles, and interprofessional simulation with debriefing. Over 2,300 students and 87 facilitators from 16 professions completed the training over three years. A positive statistically significant increase was found between pre- and post-measures of IPCP competency, knowledge, and attitudes. Additionally, high satisfaction with the education was reported by students and facilitators. By providing positive geriatric education and experiences for health students to work in interprofessional teams, it can translate into future improvements in older adult population health, health care provider job satisfaction, and reduced health care costs.

National Landscape of Human Immunodeficiency Virus-Positive Deceased Organ Donors in the United States.

BACKGROUND: Organ transplantation from donors with human immunodeficiency virus (HIV) to recipients with HIV (HIV D+/R+) presents risks of donor-derived infections. Understanding clinical, immunologic, and virologic characteristics of HIV-positive donors is critical for safety. METHODS: We performed a prospective study of donors with HIV-positive and HIV false-positive (FP) test results within the HIV Organ Policy Equity (HOPE) Act in Action studies of HIV D+/R+ transplantation (ClinicalTrials.gov NCT02602262, NCT03500315, and NCT03734393). We compared clinical characteristics in HIV-positive versus FP donors. We measured CD4 T cells, HIV viral load (VL), drug resistance mutations (DRMs), coreceptor tropism, and serum antiretroviral therapy (ART) detection, using mass spectrometry in HIV-positive donors. RESULTS: Between March 2016 and March 2020, 92 donors (58 HIV positive, 34 FP), representing 98.9% of all US HOPE donors during this period, donated 177 organs (131 kidneys and 46 livers). Each year the number of donors increased. The prevalence of hepatitis B (16% vs 0%), syphilis (16% vs 0%), and cytomegalovirus (CMV; 91% vs 58%) was higher in HIV-positive versus FP donors; the prevalences of hepatitis C viremia were similar (2% vs 6%). Most HIV-positive donors (71%) had a known HIV diagnosis, of whom 90% were prescribed ART and 68% had a VL <400 copies/mL. The median CD4 T-cell count (interquartile range) was 194/µL (77-331/µL), and the median CD4 T-cell percentage was 27.0% (16.8%-36.1%). Major HIV DRMs were detected in 42%, including nonnucleoside reverse-transcriptase inhibitors (33%), integrase strand transfer inhibitors (4%), and multiclass (13%). Serum ART was detected in 46% and matched ART by history. CONCLUSION: The use of HIV-positive donor organs is increasing. HIV DRMs are common, yet resistance that would compromise integrase strand transfer inhibitor-based regimens is rare, which is reassuring regarding safety.

HOPE in action: A prospective multicenter pilot study of liver transplantation from donors with HIV to recipients with HIV.

Liver transplantation (LT) from donors-with-HIV to recipients-with-HIV (HIV D+/R+) is permitted under the HOPE Act. There are only three international single-case reports of HIV D+/R+ LT, each with limited follow-up. We performed a prospective multicenter pilot study comparing HIV D+/R+ to donors-without-HIV to recipients-with-HIV (HIV D-/R+) LT. We quantified patient survival, graft survival, rejection, serious adverse events (SAEs), human immunodeficiency virus (HIV) breakthrough, infections, and malignancies, using Cox and negative binomial regression with inverse probability of treatment weighting. Between March 2016-July 2019, there were 45 LTs (8 simultaneous liver-kidney) at 9 centers: 24 HIV D+/R+, 21 HIV D-/R+ (10 D- were false-positive). The median follow-up time was 23 months. Median recipient CD4 was 287 cells/µL with 100% on antiretroviral therapy; 56% were hepatitis C virus (HCV)-seropositive, 13% HCV-viremic. Weighted 1-year survival was 83.3% versus 100.0% in D+ versus D- groups (p = .04). There were no differences in one-year graft survival (96.0% vs. 100.0%), rejection (10.8% vs. 18.2%), HIV breakthrough (8% vs. 10%), or SAEs (all p > .05). HIV D+/R+ had more opportunistic infections, infectious hospitalizations, and cancer. In this multicenter pilot study of HIV D+/R+ LT, patient and graft survival were better than historical cohorts, however, a potential increase in infections and cancer merits further investigation.

A prospective multicenter pilot study of HIV-positive deceased donor to HIV-positive recipient kidney transplantation: HOPE in action.

HIV-positive donor to HIV-positive recipient (HIV D+/R+) transplantation is permitted in the United States under the HIV Organ Policy Equity Act. To explore safety and the risk attributable to an HIV+ donor, we performed a prospective multicenter pilot study comparing HIV D+/R+ vs HIV-negative donor to HIV+ recipient (HIV D-/R+) kidney transplantation (KT). From 3/2016 to 7/2019 at 14 centers, there were 75 HIV+ KTs: 25 D+ and 50 D- (22 recipients from D- with false positive HIV tests). Median follow-up was 1.7 years. There were no deaths nor differences in 1-year graft survival (91% D+ vs 92% D-, P = .9), 1-year mean estimated glomerular filtration rate (63 mL/min D+ vs 57 mL/min D-, P = .31), HIV breakthrough (4% D+ vs 6% D-, P > .99), infectious hospitalizations (28% vs 26%, P = .85), or opportunistic infections (16% vs 12%, P = .72). One-year rejection was higher for D+ recipients (50% vs 29%, HR: 1.83, 95% CI 0.84-3.95, P = .13) but did not reach statistical significance; rejection was lower with lymphocyte-depleting induction (21% vs 44%, HR: 0.33, 95% CI 0.21-0.87, P = .03). In this multicenter pilot study directly comparing HIV D+/R+ with HIV D-/R+ KT, overall transplant and HIV outcomes were excellent; a trend toward higher rejection with D+ raises concerns that merit further investigation.

Pregnancy alters interleukin-1 beta expression and antiviral antibody responses during severe acute respiratory syndrome coronavirus 2 infection.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2, the disease-causing pathogen of the coronavirus disease 2019 pandemic, has resulted in morbidity and mortality worldwide. Pregnant women are more susceptible to severe coronavirus disease 2019 and are at higher risk of preterm birth than uninfected pregnant women. Despite this evidence, the immunologic effects of severe acute respiratory syndrome coronavirus 2 infection during pregnancy remain understudied. OBJECTIVE: This study aimed to assess the impact of severe acute respiratory syndrome coronavirus 2 infection during pregnancy on inflammatory and humoral responses in maternal and fetal samples and compare antibody responses to severe acute respiratory syndrome coronavirus 2 among pregnant and nonpregnant women. STUDY DESIGN: Immune responses to severe acute respiratory syndrome coronavirus 2 were analyzed using samples from pregnant (n=33) and nonpregnant (n=17) women who tested either positive (pregnant, 22; nonpregnant, 17) or negative for severe acute respiratory syndrome coronavirus 2 (pregnant, 11) at Johns Hopkins Hospital. We measured proinflammatory and placental cytokine messenger RNAs, neonatal Fc receptor expression, and tetanus antibody transfer in maternal and cord blood samples. In addition, we evaluated antispike immunoglobulin G, antispike receptor-binding domain immunoglobulin G, and neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 in serum or plasma collected from nonpregnant women, pregnant women, and cord blood. RESULTS: Pregnant women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection expressed more interleukin-1 beta, but not interleukin 6, in blood samples collected within 14 days vs >14 days after performing severe acute respiratory syndrome coronavirus 2 test. Pregnant women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection also had reduced antispike receptor-binding domain immunoglobulin G titers and were less likely to have detectable neutralizing antibody than nonpregnant women. Although severe acute respiratory syndrome coronavirus 2 infection did not disrupt neonatal Fc receptor expression in the placenta, maternal transfer of severe acute respiratory syndrome coronavirus 2 neutralizing antibody was inhibited by infection during pregnancy. CONCLUSION: Severe acute respiratory syndrome coronavirus 2 infection during pregnancy was characterized by placental inflammation and reduced antiviral antibody responses, which may impact the efficacy of coronavirus disease 2019 treatment in pregnancy. In addition, the long-term implications of placental inflammation for neonatal health require greater consideration.

Early experiences of independent advocates for potential HIV+ recipients of HIV+ donor organ transplants.

BACKGROUND: HIV+ to HIV+ solid organ transplants in the United States are now legally permitted. Currently, these transplants must adhere to the HIV Organ Policy Equity (HOPE) Act Safeguards and Research Criteria that require the provision of an independent recipient advocate, a novel requirement for solid organ transplant programs. The objective of this study was to understand the experiences of the first advocates serving in this role. METHODS: We conducted semi-structured interviews with 15 HOPE independent recipient advocates (HIRAs) from 12 institutions. RESULTS: All HIRAs had a professional degree and experience in transplantation or infectious diseases. HIRAs' encounters with potential recipients varied in length, modality, and timing. The newness of the role and the lack of guidance were associated with unease among some HIRAs. Some questioned whether their role was redundant to others involved in transplantation and research since some potential recipients experienced informational fatigue. CONCLUSIONS: HOPE independent recipient advocates are ensuring the voluntariness of potential participants' decision to accept an HIV-infected organ. Many suggested additional guidance would be helpful and alleviate unease. Concerns about potential role redundancy raise the question of whether the HIRA requirement may be inadvertently increasing burden for potential recipients. Future work that captures the experiences of potential recipients is warranted.

Dissemination of healthy kids out of school principles for obesity prevention: A RE-AIM analysis.

Health-promoting behaviors for childhood obesity prevention are needed across multiple environments where children spend time, including out-of-school time (OST). Therefore Healthy Kids Out of School (HKOS) developed intervention strategies to promote three evidence-based principles (Drink Right, Move More, Snack Smart) for obesity prevention in OST. The strategies were developed with stakeholder input, disseminated, and evaluated (2012-2015) in two volunteer-led OST organizations, Boy Scouts of America (BSA) and 4-H, across three US states using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. Mixed methods were used involving surveys, key informant interviews, and organizational-level data collection. Sixty out of 81 (74.1%) BSA districts and 4-H counties reaching 84,590 children (72% of children participating in BSA and 4-H in three states) adopted the strategies. 530 surveys completed by local OST leaders at baseline and 294 at follow-up showed the percentage of programs offering healthy beverages and opportunities for physical activity increased from baseline to follow-up (beverages 26% baseline, 35% follow-up, odds ratio (OR) 1.53; physical activity 31% baseline, 45% follow-up, OR 1.79; all p < 0.05). The increasing trend for healthy snacks was statistically non-significant (p = 0.09). Leaders interviewed reported the strategies were easy to implement, a good fit with their program, facilitated success, and they expected to maintain the changes. Integration of HKOS customized materials (BSA patch and 4-H pin) on BSA and 4-H national websites is a broader indicator of maintenance. Intervention strategies developed with stakeholder input and disseminated with training can effectively facilitate healthy environments for children, and have potential for national scale.

Direct-Acting Antiviral Prophylaxis in Kidney Transplantation From Hepatitis C Virus-Infected Donors to Noninfected Recipients: An Open-Label Nonrandomized Trial.

Background: Given the high mortality rate for patients with end-stage kidney disease receiving dialysis and the efficacy and safety of hepatitis C virus (HCV) treatments, discarded kidneys from HCV-infected donors may be a neglected public health resource. Objective: To determine the tolerability and feasibility of using direct-acting antivirals (DAAs) as prophylaxis before and after kidney transplantation from HCV-infected donors to non-HCV-infected recipients (that is, HCV D+/R- transplantation). Design: Open-label nonrandomized trial. (ClinicalTrials.gov: NCT02781649). Setting: Single center. Participants: 10 HCV D+/R- kidney transplant candidates older than 50 years with no available living donors. Intervention: Transplantation of kidneys from deceased donors aged 13 to 50 years with positive HCV RNA and HCV antibody test results. All recipients received a dose of grazoprevir (GZR), 100 mg, and elbasvir (EBR), 50 mg, immediately before transplantation. Recipients of kidneys from donors with genotype 1 infection continued receiving GZR-EBR for 12 weeks after transplantation; those receiving organs from donors with genotype 2 or 3 infection had sofosbuvir, 400 mg, added to GZR-EBR for 12 weeks of triple therapy. Measurements: The primary safety outcome was the incidence of adverse events related to GZR-EBR treatment. The primary efficacy outcome was the proportion of recipients with an HCV RNA level below the lower limit of quantification 12 weeks after prophylaxis. Results: Among 10 HCV D+/R- transplant recipients, no treatment-related adverse events occurred, and HCV RNA was not detected in any recipient 12 weeks after treatment. Limitation: Nonrandomized study design and a small number of patients. Conclusion: Pre- and posttransplantation HCV treatment was safe and prevented chronic HCV infection in HCV D+/R- kidney transplant recipients. If confirmed in larger studies, this strategy should markedly expand organ options and reduce mortality for kidney transplant candidates without HCV infection. Primary Funding Source: Merck Sharp & Dohme.

Perceptions, motivations, and concerns about living organ donation among people living with HIV.

Recent changes to United States law now permit people living with HIV (PLWH) to donate organs to HIV-infected (HIV+) recipients under research protocols. PLWH may have unique motivations for and concerns about living donation and understanding them is critical to ensuring the integrity of this novel approach to organ transplantation. We conducted in-depth interviews with PLWH from an urban HIV clinic who had previously indicated their willingness to be a living donor. Interviews elicited information on their motivations, perceived benefits, and concerns regarding living donation. Codes were identified inductively and then organized into themes and subthemes. Two coders independently analyzed the interviews and reconciled differences in coding by consensus. Thematic saturation was reached after 20 interviews. Motivations for living donation among PLWH included an altruistic desire to help others as well as HIV-specific motivations including solidarity with potential recipients and a desire to overcome HIV-related stigma. Perceived benefits of living donation included gratification from saving or improving the recipient's life and conferring a sense of normalcy for the HIV+ donor. Concerns about donation included the possibility of a prolonged recovery period, organ failure, and transmission of another strain of the virus to the recipients. PLWH had unique motivations, perceived benefits, and concerns about living donation in addition to those previously identified in the general population. These unique factors should be addressed in research protocols, informed consent processes, and the education and training of independent living donor advocates so that these endeavors are ethically sound.

Evaluation of simulation debriefing methods with interprofessional learning.

Interprofessional education (IPE) using simulations provides a rich environment for mastery learning and deliberate practice. The debriefing phase is identified as the most valuable by learners, yet investigation into the most effective format for debriefing interprofessional (IP) groups has largely gone unexplored. To determine the best practices in IP simulation debriefing, we compared perceived effectiveness of in-person versus teledebriefing, and single versus IP co-debriefer models according to 404 Debriefing Assessment for Simulation in Healthcare Student-Version (DASH-SV) scores from students in medicine, nursing, and respiratory therapy (n = 135) following three critical care simulations. All calculated total mean scores were in the acceptable range (above 4.0), indicating a positive experience for all methods. We found statistically significantly higher scores for in-person (M = 5.79) compared to teledebriefing (M = 4.96, p < .001). Single debriefer (M = 6.09) compared to IP co-debriefer DASH scores (M = 5.93) for all scenarios were not significantly different (p = .059). Our results suggest that teledebriefing may provide a solution for simulation programs with off-site or rural learners, and that a single in-person debriefing can be equally effective as co-debriefing for IP students.

A Clustered Randomized Trial of an Educational Intervention During Transplant Evaluation to Increase Knowledge of Living Donor Kidney Transplant.

INTRODUCTION: Maximizing education about living donor kidney transplant (LDKT) during the in-person evaluation at the transplant center may increase the numbers of kidney patients pursuing LDKT. Research Questions and Design: To test the effectiveness of a 1-time LDKT educational intervention, we performed a cluster-randomized trial among 499 patients who presented for evaluation of kidney transplant. We compared usual care education (n = 250) versus intensive LDKT education (n = 249), which was implemented only on the evaluation day and consisted of viewing a 25-minute video of information and stories about LDKT and discussion of LDKT possibilities with an educator. Our primary outcome was knowledge of LDKT, 1 week after the transplant evaluation. RESULTS: One week after evaluation, patients who received intensive education had higher knowledge than patients who received usual care (12.7 vs. 11.7; P = .0008), but there were no differences in postevaluation readiness for LDKT. Among patients who had not previously identified a potential living donor, receiving intensive education was associated with increased willingness to take steps toward LDKT. DISCUSSION: In conclusion, expansion of LDKT education within the evaluation day may be helpful, but interventions that are implemented at multiple times and for greater duration may be necessary to ensure larger and long-term behavioral changes in pursuit of LDKT.

Ambulatory Care Nurse-Sensitive Indicators Series: Reaching for the Tipping Point in Measuring Nurse-Sensitive Quality in the Ambulatory Surgical and Procedure Environments.

The value of the ambulatory care nurse remains undocumented from a quality and patient safety measurement perspective and the practice is at risk of being highly variable and of unknown quality. The American Academy of Ambulatory Care Nursing and the Collaborative Alliance for Nursing Outcomes propose nurse leaders create a tipping point to measure the value of nursing across the continuum of nursing care, moving from inpatient to ambulatory care. As care continues to shift into the ambulatory care environment, the quality imperative must also shift to assure highly reliable, safe, and effective health care.

Increased ferroportin-1 expression and rapid splenic iron loss occur with anemia caused by Salmonella enterica Serovar Typhimurium infection in mice.

The Gram-negative intracellular bacterium Salmonella enterica serovar Typhimurium causes persistent systemic inflammatory disease in immunocompetent mice. Following oral inoculation with S. Typhimurium, mice develop a hematopathological syndrome akin to typhoid fever with splenomegaly, microcytic anemia, extramedullary erythropoiesis, and increased hemophagocytic macrophages in the bone marrow, liver, and spleen. Additionally, there is marked loss of iron from the spleen, an unanticipated result, given the iron sequestration reported in anemia of inflammatory disease. To establish why tissue iron does not accumulate, we evaluated multiple measures of pathology for 4 weeks following oral infection in mice. We demonstrate a quantitative decrease in splenic iron following infection despite increased numbers of splenic phagocytes. Infected mice have increased duodenal expression of the iron exporter ferroportin-1, consistent with increased uptake of dietary iron. Liver and splenic macrophages also express high levels of ferroportin-1. These observations indicate that splenic and hepatic macrophages export iron during S. Typhimurium infection, in contrast to macrophage iron sequestration observed in anemia of inflammatory disease. Tissue macrophage export of iron occurs concurrent with high serum concentrations of interferon gamma (IFN-γ) and interleukin 12 (IL-12). In individual mice, high concentrations of both proinflammatory (tumor necrosis factor alpha [TNF-α]) and anti-inflammatory (IL-10) cytokines in serum correlate with increased tissue bacterial loads throughout 4 weeks of infection. These in vivo observations are consistent with previous cell culture studies and suggest that the relocation of iron from tissue macrophages during infection may contribute to anemia and also to host survival of acute S. Typhimurium infection.