Neonatal Host Defense against Staphylococcal Infections

Preterm infants are especially susceptible to late-onset sepsis that is often due to Gram-positive bacterial infections resulting in substantial morbidity and mortality. Herein, we will describe neonatal innate immunity to Staphylococcus spp. comparing differences between preterm and full-term newborns with adults. Newborn innate immunity is distinct demonstrating diminished skin integrity, impaired Th1-polarizing responses, low complement levels, and diminished expression of plasma antimicrobial proteins and peptides, especially in preterm newborns. Characterization of distinct aspects of the neonatal immune response is defining novel approaches to enhance host defense to prevent and/or treat staphylococcal infection in this vulnerable population

Tuning coordination in s-block carbazol-9-yl complexes

1,3,6,8-Tetra-tert-butylcarbazol-9-yl and 1,8-diaryl-3,6-di(tert-butyl)carbazol-9-yl ligands have been utilized in the synthesis of potassium and magnesium complexes. The potassium complexes (1,3,6,8-tBu4carb)K(THF)4 (1; carb=C12H4N), [(1,8-Xyl2-3,6-tBu2carb)K(THF)]2 (2; Xyl=3,5-Me2C6H3) and (1,8-Mes2-3,6-tBu2carb)K(THF)2 (3; Mes=2,4,6-Me3C6H2) were reacted with MgI2 to give the Hauser bases 1,3,6,8-tBu4carbMgI(THF)2 (4) and 1,8-Ar2-3,6-tBu2carbMgI(THF) (Ar=Xyl 5, Ar=Mes 6). Structural investigations of the potassium and magnesium derivatives highlight significant differences in the coordination motifs, which depend on the nature of the 1- and 8-substituents: 1,8-di(tert-butyl)-substituted ligands gave π-type compounds (1 and 4), in which the carbazolyl ligand acts as a multi-hapto donor, with the metal cations positioned below the coordination plane in a half-sandwich conformation, whereas the use of 1,8-diaryl substituted ligands gave σ-type complexes (2 and 6). Space-filling diagrams and percent buried volume calculations indicated that aryl-substituted carbazolyl ligands offer a steric cleft better suited to stabilization of low-coordinate magnesium complexes

A Neonatal Model of Intravenous Staphylococcus epidermidis Infection in Mice <24 h Old Enables Characterization of Early Innate Immune Responses

Staphylococcus epidermidis (SE) causes late onset sepsis and significant morbidity in catheterized preterm newborns. Animal models of SE infection are useful in characterizing disease mechanisms and are an important approach to developing improved diagnostics and therapeutics. Current murine models of neonatal bacterial infection employ intraperitoneal or subcutaneous routes at several days of age, and may, therefore, not accurately reflect distinct features of innate immune responses to bacteremia. In this study we developed, validated, and characterized a murine model of intravenous (IV) infection in neonatal mice <24 hours (h) old to describe the early innate immune response to SE. C57BL/6 mice <24 h old were injected IV with 106, 107, 108 colony-forming units (CFU) of SE 1457, a clinical isolate from a central catheter infection. A prospective injection scoring system was developed and validated, with only high quality injections analyzed. Newborn mice were euthanized between 2 and 48 h post-injection and spleen, liver, and blood collected to assess bacterial viability, gene expression, and cytokine production. High quality IV injections demonstrated inoculum-dependent infection of spleen, liver and blood. Within 2 h of injection, SE induced selective transcription of TLR2 and MyD88 in the liver, and increased systemic production of plasma IL-6 and TNF-α. Despite clearance of bacteremia and solid organ infection within 48 h, inoculum-dependent impairment in weight gain was noted. We conclude that a model of IV SE infection in neonatal mice <24 h old is feasible, demonstrating inoculum-dependent infection of solid organs and a pattern of bacteremia, rapid and selective innate immune activation, and impairment of weight gain typical of infected human neonates. This novel model can now be used to characterize immune ontogeny, evaluate infection biomarkers, and assess preventative and therapeutic modalities

TLR2 Mediates Recognition of Live Staphylococcus epidermidis and Clearance of Bacteremia

Background: Staphylococcus epidermidis (SE) is a nosocomial pathogen that causes catheter-associated bacteremia in the immunocompromised, including those at the extremes of age, motivating study of host clearance mechanisms. SE-derived soluble components engage TLR2; but additional signaling pathways have also been implicated, and TLR2 can play complex, at times detrimental, roles in host defense against other Staphylococcal spp. The role of TLR2 in responses of primary blood leukocytes to live SE and in clearance of SE bacteremia, the most common clinical manifestation of SE infection, is unknown. Methodology/Principal Findings: We studied TLR2-mediated recognition of live clinical SE strain 1457 employing TLR2- transfected cells, neutralizing anti-TLR antibodies and TLR2-deficient mice. TLR2 mediated SE-induced cytokine production in human embryonic kidney cells, human whole blood and murine primary macrophages, in part via recognition of a soluble TLR2 agonist. After i.v. challenge with SE, early (1 h) cytokine/chemokine production and subsequent clearance of bacteremia (24-48 h) were markedly impaired in TLR2-deficient mice. Conclusions/Significance: TLR2 mediates recognition of live SE and clearance of SE bacteremia in vivo

Alaska Volcano Observatory Alert and Forecasting Timeliness: 1989–2017

The Alaska Volcano Observatory (AVO) monitors volcanoes in Alaska and issues notifications and warnings of volcanic unrest and eruption. We evaluate the timeliness and accuracy of eruption forecasts for 53 eruptions at 20 volcanoes, beginning with Mount Redoubt's 1989–1990 eruption. Successful forecasts are defined as those where AVO issued a formal warning before eruption onset. These warning notifications are now part of AVO's Aviation Color Code and Volcanic Alert Level. This analysis considers only the start of an eruption, although many eruptions have multiple phases of activity. For the 21 eruptions at volcanoes with functioning local seismic networks, AVO has high forecasting success at volcanoes with: &gt;15 years repose intervals and magmatic eruptions (4 out of 4, 100%); or larger eruptions (Volcanic Explosivity Index (VEI) 3 or greater; 6 out of 10, 60%). Therefore, AVO successfully forecast all four monitored, longer-repose period, VEI 3+ eruptions: Redoubt 1989–1990 and 2009, Spurr 1992, and Augustine 2005–2006. For volcanoes with functioning seismic monitoring networks, success rates are lower for: volcanoes with shorter repose periods (3 out of 16, 19%); more mafic compositions (3 out of 18, 17%); or smaller eruption size (VEI 2 or less, 1 out of 11, 9%). These eruptions (Okmok, Pavlof, Veniaminof, and Shishaldin) often lack detectable precursory signals. For 32 eruptions at volcanoes without functioning local seismic networks, the forecasting success rate is much lower (2, 6%; Kasatochi 2008 and Shishaldin 2014). For remote volcanoes where the main hazard is to aviation, rapid detection is a goal in the absence of in situ monitoring. Eruption detection has improved in recent years, shown by a decrease in the time between eruption onset and notification. Even limited seismic monitoring can detect precursory activity at volcanoes with certain characteristics (intermediate composition, longer repose times, larger eruptions), but difficulty persists in detecting subtle precursory activity at frequently active volcanoes with more mafic compositions. This suggests that volcano-specific characteristics should be considered when designing monitoring programs and evaluating forecasting success. More proximally-located sensors and data types are likely needed to forecast eruptive activity at frequently-active, more mafic volcanoes that generally produce smaller eruptions

Staphylococcus aureus Bacteremia in Children of Rural Areas of The Gambia, 2008–2015

Staphylococcus aureus bacteremia is a substantial cause of childhood disease and death, but few studies have described its epidemiology in developing countries. Using a population-based surveillance system for pneumonia, sepsis, and meningitis, we estimated S. aureus bacteremia incidence and the case-fatality ratio in children <5 years of age in 2 regions in the eastern part of The Gambia during 2008–2015. Among 33,060 children with suspected pneumonia, sepsis, or meningitis, we performed blood culture for 27,851; of 1,130 patients with bacteremia, 198 (17.5%) were positive for S. aureus. S. aureus bacteremia incidence was 78 (95% CI 67–91) cases/100,000 person-years in children <5 years of age and 2,080 (95% CI 1,621–2,627) cases/100,000 person-years in neonates. Incidence did not change after introduction of the pneumococcal conjugate vaccine. The case-fatality ratio was 14.1% (95% CI 9.6%–19.8%). Interventions are needed to reduce the S. aureus bacteremia burden in The Gambia, particularly among neonates

Similarities and differences in the historical records of lava dome-building volcanoes: implications for understanding magmatic processes and eruption forecasting

A key question for volcanic hazard assessment is the extent to which information can be exchanged between volcanoes. This question is particularly pertinent to hazard forecasting for dome-building volcanoes, where effusive activity may persist for years to decades, and may be punctuated by periods of repose, and sudden explosive activity. Here we review historical eruptive activity of fifteen lava dome-building volcanoes over the past two centuries, with the goal of creating a hierarchy of exchangeable (i.e., similar) behaviours. Eruptive behaviour is classified using empirical observations that include patterns of SO2 flux, eruption style, and magma composition. We identify two eruptive regimes: (i) an episodic regime where eruptions are much shorter than intervening periods of repose, and degassing is temporally correlated with lava effusion; and (ii) a persistent regime where eruptions are comparable in length to periods of repose and gas emissions do not correlate with eruption rates. A corollary to these two eruptive regimes is that there are also two different types of repose: (i) inter-eruptive repose separates episodic eruptions, and is characterised by negligible gas emissions and (ii) intra-eruptive repose is observed in persistently active volcanoes, and is characterised by continuous gas emissions. We suggest that these different patterns of can be used to infer vertical connectivity within mush-dominated magmatic systems. We also note that our recognition of two different types of repose raises questions about traditional definitions of historical volcanism as a point process. This is important, because the ontology of eruptive activity (that is, the definition of volcanic activity in time) influences both analysis of volcanic data and, by extension, interpretations of magmatic processes. Our analysis suggests that one identifying exchangeable traits or behaviours provides a starting point for developing robust ontologies of volcanic activity. Moreover, by linking eruptive regimes to conceptual models of magmatic processes, we illustrate a path towards developing a conceptual framework not only for comparing data between different volcanoes but also for improving forecasts of eruptive activity