Metabolic profiling during malaria reveals the role of the aryl hydrocarbon receptor in regulating kidney injury.

Systemic metabolic reprogramming induced by infection exerts profound, pathogen-specific effects on infection outcome. Here, we detail the host immune and metabolic response during sickness and recovery in a mouse model of malaria. We describe extensive alterations in metabolism during acute infection, and identify increases in host-derived metabolites that signal through the aryl hydrocarbon receptor (AHR), a transcription factor with immunomodulatory functions. We find that Ahr-/- mice are more susceptible to malaria and develop high plasma heme and acute kidney injury. This phenotype is dependent on AHR in Tek-expressing radioresistant cells. Our findings identify a role for AHR in limiting tissue damage during malaria. Furthermore, this work demonstrates the critical role of host metabolism in surviving infection.

Ten years of experience with herpes zoster vaccine in primary care- how attitudes and practices have changed and what it may mean for a new zoster vaccine.

Zoster vaccine live (ZVL [Zostavax]) has been recommended for the prevention of herpes zoster (HZ) among immunocompetent adults ≥60 years in the United States since 2008. To examine changes in healthcare providers' perceptions and practices related to HZ disease and vaccination, we administered surveys to national networks of primary care physicians in 2005, 2008, and 2016. Ten years after ZVL was first licensed, physicians were more likely to respond that they perceived HZ as a serious disease and more strongly recommended ZVL, and were less likely to report less likely to report several major barriers to HZ vaccination such as patient cost, vaccine effectiveness and competing medical concerns. Overall, physician attitudes appear to be more favorable towards zoster vaccination after a decade of availability of a HZ vaccine. The new recombinant zoster vaccine (RZV [Shingrix]) may benefit from physician's increased perception of the importance of HZ and HZ vaccination.

Physical characteristics of capacitive carbons derived from the electrolytic reduction of alkali metal carbonate molten salts.

Carbons have been synthesized through the reduction of molten carbonate systems under varied conditions. The mechanism and kinetics of carbon electrodeposition has been investigated. Carbon morphologies include amorphous, graphite-like, and spherical aggregate phases. Increased graphitic character is observed in carbons electrodeposited at more cathodic potentials, particularly at higher temperatures. Bonding has been investigated and oxygen functionalised sp2 and sp3 structures have been identified. The level of functionalization decreases in carbons with reduced amorphous and increased graphitic character. Thermal decomposition of electrodepositied carbons has been investigated and zero order kinetics have been identified. A relationship has been identified between elevated oxygen functionalization and increased pseudo-capacitance, with carbons deposited at 0.15 A cm-2 showing capacitances of 400 F g-1 in 0.5 M H2SO4 at sweep rates of 10 mV s-1.

Primary care physicians' experience with zoster vaccine live (ZVL) and awareness and attitudes regarding the new recombinant zoster vaccine (RZV).

BACKGROUND: The Advisory Committee on Immunization Practices (ACIP) has routinely recommended zoster vaccine live (ZVL) for adults  ≥60 since 2008; only 33% of eligible adults received it by 2016. A recombinant zoster vaccine (RZV) was licensed in 2017 and ACIP recommended in January 2018. Our objectives were to assess among primary care physicians (1) practices and attitudes regarding ZVL and (2) awareness of RZV. METHODS: We administered an Internet and mail survey from July to September 2016 to national networks of 953 primary care physicians. RESULTS: Response rate was 65% (603/923). Ninety-three % of physicians recommended ZVL to adults ≥60, but fewer recommended it to adults ≥60 with a prior history of zoster (88%), adults > 85 (62%) and adults ≥60 on low-dose methotrexate (42%). Several physicians recommended ZVL in ways that are not recommended by ACIP including to adults 50-59 (50%), adults ≥60 with HIV (33%), and adults ≥60 on high dose prednisone (≥20 mg/day) (27%). Nineteen percent of physicians stocked and administered ZVL and did not refer patients elsewhere for vaccination, 37% did not stock and only referred patients to receive it, and 44% both stocked/administered and referred elsewhere. Twenty-three % (n = 115) of physicians who had ever administered ZVL in the office (n = 490) had stopped, citing primarily financial issues (90%). Only 5% were 'very aware' of RZV. CONCLUSIONS: Physicians report not recommending ZVL to certain ACIP-recommended groups, but report recommending it to some groups for which the vaccine should be avoided. Implementation of recommendations for RZV will need to consider financial barriers and the complex patchwork of office-based and pharmacy delivery ZVL has encountered.

Predicting position along a looping immune response trajectory.

When we get sick, we want to be resilient and recover our original health. To measure resilience, we need to quantify a host's position along its disease trajectory. Here we present Looper, a computational method to analyze longitudinally gathered datasets and identify gene pairs that form looping trajectories when plotted in the space described by these phases. These loops enable us to track where patients lie on a typical trajectory back to health. We analyzed two publicly available, longitudinal human microarray datasets that describe self-resolving immune responses. Looper identified looping gene pairs expressed by human donor monocytes stimulated by immune elicitors, and in YF17D-vaccinated individuals. Using loops derived from training data, we found that we could predict the time of perturbation in withheld test samples with accuracies of 94% in the human monocyte data, and 65-83% within the same cohort and in two independent cohorts of YF17D vaccinated individuals. We suggest that Looper will be useful in building maps of resilient immune processes across organisms.

Five-Year Progress Update on the Surgeon General's Call to Action to Support Breastfeeding, 2011.

In 2011, Surgeon General Regina Benjamin issued a Call to Action to Support Breastfeeding (Call to Action) in an effort to mobilize families, communities, clinicians, healthcare systems, and employers to take action to improve support for breastfeeding. The Call to Action identified 20 key action steps to address society-wide breastfeeding barriers in six areas: mothers and families, communities, healthcare, employment, research, and public health infrastructure. This report highlights major federal activities that show progress toward answering the Call to Action in the first 5 years since its launch.

Breastfeeding Supportive Hospital Practices in the US Differ by County Urbanization Level.

BACKGROUND: Breastfeeding rates are lower among infants living in rural areas of the United States, yet there are limited data on whether hospital breastfeeding support differs between rural and urban areas. OBJECTIVE: This study aimed to describe whether maternity care practices supportive of breastfeeding vary by level of urbanization. METHODS: We linked data from the 2007, 2009, and 2011 Maternity Practices in Infant Nutrition and Care (mPINC) surveys with Rural-Urban Continuum Codes to categorize hospital counties as metropolitan urbanized, nonmetropolitan urbanized, less urbanized, and thinly populated. RESULTS: From 2007 to 2011, the average hospital mPINC score, a composite quality score ranging from 0 to 100, increased from 64 to 71 in metropolitan urbanized counties and from 54 to 65 in thinly populated areas. Scores were lowest in thinly populated counties in 2007 and 2009 and in less urbanized counties in 2011. Examination of 2011 mPINC scores by 7 domains of care revealed that hospitals in less urbanized counties had lower scores than those in metropolitan urbanized counties for feeding of breastfed infants, breastfeeding assistance, staff training, and structural and organizational aspects of care delivery; for 3 of these practices, scores were 10 or more points lower-breastfeeding assistance, structural and organizational aspects of care, and staff training. In contrast, hospitals in thinly populated areas had higher scores than in metropolitan areas for mother-infant contact and facility discharge care; differences were less than 10 points. CONCLUSION: Interventions that specifically target rural hospitals may reduce the gap in access to hospital maternity care practices supportive of breastfeeding by population density.

Using mPINC data to measure breastfeeding support for hospital employees.

BACKGROUND: Employer support is important for mothers, as returning to work is a common reason for discontinuing breastfeeding. This article explores support available to breastfeeding employees of hospitals that provide maternity care. OBJECTIVES: This study aimed to describe the prevalence of 7 different types of worksite support and changes in these supports available to breastfeeding employees at hospitals that provide maternity care from 2007 to 2011. METHODS: Hospital data from the 2007, 2009, and 2011 Centers for Disease Control and Prevention Survey on Maternity Practices in Infant Nutrition and Care (mPINC) were analyzed. Survey respondents were asked if the hospital provides any of the following supports to hospital staff: (1) a designated room to express milk, (2) on-site child care, (3) an electric breast pump, (4) permission to use existing work breaks to express milk, (5) a breastfeeding support group, (6) lactation consultant/specialist available for consult, and (7) paid maternity leave other than accrued vacation or sick leave. This study was exempt from ethical approval because it was a secondary analysis of a publicly available dataset. RESULTS: Of the 7 worksite supports in hospitals measured, 6 increased and 1 decreased from 2007 to 2011. Across all survey years, more than 70% of hospitals provided supports for expressing breast milk, whereas less than 15% provided direct access to the breastfeeding child through on-site child care, and less than 35% offered paid maternity leave. Results differed by region and hospital size and type. In 2011, only 2% of maternity hospitals provided all 7 worksite supports; 40% provided 5 or more. CONCLUSION: The majority of maternity care hospitals (> 70%) offer breastfeeding supports that allow employees to express breast milk. Supports that provide direct access to the breastfeeding child, which would allow employees to breastfeed at the breast, and access to breastfeeding support groups are much less frequent than other supports, suggesting opportunities for improvement.

Baby-friendly hospital practices and birth costs.

BACKGROUND: Hospital practices supportive of breastfeeding can improve breastfeeding rates. There are limited data available on how improved hospital practices are associated with hospital costs. We describe the association between the number of breastfeeding supportive practices a hospital has in place and the cost of an uncomplicated birth. METHODS: Data from hospitals in 20 states that participated in the 2007 Maternity Practices in Infant Nutrition and Care (mPINC) survey and Healthcare Cost and Utilization Project's (HCUP) State Inpatient Databases (SID) were merged to calculate the average median hospital cost of uncomplicated vaginal and cesarean section births by number of ideal practices from the Ten Steps to Successful Breastfeeding. Linear regression analyses were conducted to estimate change in birth cost for each additional ideal practice in place. RESULTS: Sixty-one percent of hospitals had ideal practice on 3-5 of the 10 steps, whereas 29 percent of hospitals had ideal practice on 6-8. Adjusted analyses of uncomplicated births revealed a higher but nonsignificant increase in any of the birth categories (all births, $19; vaginal, $15; cesarean section, $39) with each additional breastfeeding supportive maternity care practice in place. CONCLUSIONS: Our results revealed that the number of breastfeeding supportive practices a hospital has in place is not significantly associated with higher birth costs. Concern for higher birth costs should not be a barrier for improving maternity care practices that support women who choose to breastfeed.

Purified hematopoietic stem cell allografts reconstitute immunity superior to bone marrow.

Antigen-specific immune responses are impaired after allogeneic hematopoietic cell transplantation (HCT). The events contributing to this impairment include host hematolymphoid ablation and donor cell regeneration, which is altered by pharmacologic immune suppression to prevent graft-versus-host disease (GVHD). A generally accepted concept is that graft T cell depletion performed to avoid GVHD yields poorer immune recovery because mature donor T cells are thought to be the major mediators of protective immunity early post-HCT. Our findings contradict the idea that removal of mature donor cells worsens immune recovery post-HCT. By transplantation of purified hematopoietic stem cells (HSC) compared with bone marrow (BM) across donor and recipient pairs of increasing genetic disparity, we show that grafts composed of the purified progenitor population give uniformly superior lymphoid reconstitution, both qualitatively and quantitatively. Subclinical GVHD by T cells in donor BM likely caused this lympho-depleting GVHD. We further determined in the major histocompatibility complex (MHC)-mismatched pairs, that T cell restricted proliferative responses were dictated by donor rather than host elements. We interpret these latter findings to show the importance of peripheral antigen presentation in the selection and maintenance of the T cell repertoire.

Chemerin activation by serine proteases of the coagulation, fibrinolytic, and inflammatory cascades.

Proteases function at every level in host defense, from regulating vascular hemostasis and inflammation to mobilizing the "rapid responder" leukocytes of the immune system by regulating the activities of various chemoattractants. Recent studies implicate proteolysis in the activation of a ubiquitous plasma chemoattractant, chemerin, a ligand for the G-protein-coupled receptor CMKLR1 present on plasmacytoid dendritic cells and macrophages. To define the pathophysiologic triggers of chemerin activity, we evaluated the ability of serum- and inflammation-associated proteases to cleave chemerin and stimulate CMKLR1-mediated chemotaxis. We showed that serine proteases factor XIIa and plasmin of the coagulation and fibrinolytic cascades, elastase and cathepsin G released from activated neutrophil granules and mast cell tryptase are all potent activators of chemerin. Activation results from cleavage of the labile carboxyl terminus of the chemoattractant at any of several different sites. Activation of chemerin by the serine protease cascades that trigger rapid defenses in the body may direct CMKLR1-positive plasmacytoid dendritic cell and tissue macrophage recruitment to sterile sites of tissue damage, as well as trafficking to sites of infectious and allergic inflammation.

Neutrophils sustain pathogenic CD8+ T cell responses in the heart.

This study explores the influence of innate immunity on CD8(+) T-cell responses against heart tissue. Adoptive transfer of ovalbumin-specific CD8(+) effector T cells into CMy-mOva mice, which express ovalbumin in cardiac myocytes, results in a lethal acute myocarditis. The inflammatory infiltrate in the heart includes neutrophils as well as T cells. We used anti-Ly6G antibody to transiently deplete neutrophils at the time of onset of disease. By day 7 after receiving 5 x 10(5) CD8(+) effector T cells, 100% of control Ig-treated CMy-mOva mice had died, while 85% of anti-Ly6G-treated mice survived indefinitely. CD8(+) T-cell infiltration and tissue damage were present in both groups, but the disease was limited in the anti-Ly6G-treated mice, with a rapid disappearance of the adoptively transferred CD8(+) T cells within 11 days. Recovery occurred even though blood neutrophil counts began to rise 48 hours after the last anti-Ly6G treatment. Recovery was associated with a chronic CD4(+) cell infiltrate, and a rapid decline in expression of IFN-gamma and IP-10 mRNA in the myocardium. Neutrophil depletion did not effect survival of CMy-mOva mice that received 3 x 10(6) CD8(+) T cells. These data show that granulocytic inflammation sustains CD8(+) T-cell-mediated heart disease, which has important implications for the pathogenesis and treatment of acute myocarditis and allograft rejection.

Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis.

Interactions between CD8+ T cells and endothelial cells are important in both protective and pathologic immune responses. Endothelial cells regulate the recruitment of CD8+ T cells into tissues, and the activation of CD8+ T cells by antigen presentation and costimulatory signals. PD-L1 and PD-L2 are recently described B7-family molecules which bind to PD-1 on activated lymphocytes and down-regulate T cell activation. We found that PD-L1 is expressed on interferon-gamma stimulated cultured human and mouse endothelial cells, while PD-L2 was found on stimulated human but not mouse endothelial cells. Expression was further up-regulated by TNF-alpha. Antibody blockade of endothelial cell PD-L1 and PD-L2 enhanced endothelial cell costimulation of PHA-activated human CD8+ T cells. Antibody blockade of mouse endothelial cell PD-L1 enhanced both IFN-gamma secretion and cytolytic activity of CD8+ T cells in response to endothelial cell antigen presentation. These results show that IFN-gamma activated endothelial cells can inhibit T cell activation via expression of the immunoinhibitory PD-L1 and PD-L2 molecules. Endothelial expression of PD-ligands would allow activation and extravasation of T cells without excessive vessel damage. Our findings highlight a potentially important pathway by which endothelial cells down-regulate CD8+ T cell-mediated immune responses.