Clinical Pharmacokinetics of Triazoles in Pediatric Patients

Triazoles represent an important class of antifungal drugs in the prophylaxis and treatment of invasive fungal disease in pediatric patients. Understanding the pharmacokinetics of triazoles in children is crucial to providing optimal care for this vulnerable population. While the pharmacokinetics is extensively studied in adult populations, knowledge on pharmacokinetics of triazoles in children is limited. New data are still emerging despite drugs already going off patent. This review aims to provide readers with the most current knowledge on the pharmacokinetics of the triazoles: fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole. In addition, factors that have to be taken into account to select the optimal dose are summarized and knowledge gaps are identified that require further research. We hope it will provide clinicians guidance to optimally deploy these drugs in the setting of a life-threatening disease in pediatric patients

Obstetric care models in the Southern Region of Brazil and associated factors

The study sought to identify obstetric care models for low-risk pregnancies in the Southern Region of Brazil and to estimate factors associated with these models and maternal and neonatal outcomes. This is a cross-sectional, hospital-based study using data from the Birth in Brazil survey regarding puerperae and newborns. We identified 2,668 low-risk pregnant women. We carried out an exploratory analysis using the proportion of practices per hospital, among them inducing labor, presence of a companion, cesarean section and skin-to-skin contact, in order to obtain the care models we called Best Practice, Interventionist I and Interventionist II. We then carried out an inferential analysis of the associated characteristics. Results show that access to public or private funding, cultural factors and actions taken by health professional are associated with the care models. Public care had different contexts, one based on public policies and evidence-based practices; and another, that suggests the intentionality of vaginal delivery without considering humanization principles. Private care, on the other hand, is standardized and centered on the medical professional, with higher intervention levels. We conclude there is a predominance of interventionist obstetric care models in the Southern Region of Brazil, a type of care that goes against the best evidence, and that women who receive care in public hospitals have greater chances of benefiting from good practices

Splanchnic metabolism of nutrients and hormones in steers fed alfalfa under conditions of increased absorption of ammonia and L-arginine supply across the portal-drained viscera

Effects of increased ammonia and/or arginine absorption on net splanchnic (portal-drained viscera [PDV] plus liver) metabolism of nonnitrogenous nutrients and hormones in cattle were examined. Six Hereford × Angus steers (501 ± 1 kg BW) prepared with vascular catheters for measurements of net flux across the splanchnic bed were fed a 75% alfalfa:25% (as-fed basis) corn and soybean meal diet (0.523 MJ of ME/[kg BW0.75.d]) every 2 h without (27.0 g of N/kg of DM) and with 20 g of urea/kg of DM (35.7 g of N/kg of DM) in a split-plot design. Net flux measurements were made immediately before and after a 72-h mesenteric vein infusion of L-arginine (15 mmol/h). There were no treatment effects onPDVor hepaticO2 consumption. Dietary urea had no effect on splanchnic metabolism of glucose or L-lactate, but arginine infusion decreased net hepatic removal of L-lactate when urea was fed (P < 0.01). Net PDV appearance of n-butyrate was increased by arginine infusion (P < 0.07), and both dietary urea (P < 0.09) and arginine infusion (P < 0.05) increased net hepatic removal of n-butyrate. Dietary urea also increased total splanchnic acetate output (P < 0.06), tended to increase arterial glucagon concentration (P < 0.11), and decreased arterial ST concentration (P < 0.03). Arginine infusion increased arterial concentration (P < 0.07) and net PDV release (P < 0.10) and tended to increase hepatic removal (P < 0.11) of insulin, as well as arterial concentration (P < 0.01) and total splanchnic output (P < 0.01) of glucagon. Despite changes in splanchnic N metabolism, increased ammonia and arginine absorption had little measurable effect on splanchnic metabolism of glucose and other nonnitrogenous components of splanchnic energy metabolism

Denitrifying pathways dominate nitrous oxide emissions from managed grassland during drought and rewetting

Nitrous oxide is a powerful greenhouse gas whose atmospheric growth rate has accelerated over the past decade. Most anthropogenic N2O emissions result from soil N fertilization, which is converted to N2O via oxic nitrification and anoxic denitrification pathways. Drought-affected soils are expected to be well oxygenated; however, using high-resolution isotopic measurements, we found that denitrifying pathways dominated N2O emissions during a severe drought applied to managed grassland. This was due to a reversible, drought-induced enrichment in nitrogen-bearing organic matter on soil microaggregates and suggested a strong role for chemo- or codenitrification. Throughout rewetting, denitrification dominated emissions, despite high variability in fluxes. Total N2O flux and denitrification contribution were significantly higher during rewetting than for control plots at the same soil moisture range. The observed feedbacks between precipitation changes induced by climate change and N2O emission pathways are sufficient to account for the accelerating N2O growth rate observed over the past decade

Molecular Characterization of a Novel Staphylococcus Aureus Surface Protein (SasC) Involved in Cell Aggregation and Biofilm Accumulation

BACKGROUND:Staphylococci belong to the most important pathogens causing implant-associated infections. Colonization of the implanted medical devices by the formation of a three-dimensional structure made of bacteria and host material called biofilm is considered the most critical factor in these infections. To form a biofilm, bacteria first attach to the surface of the medical device, and then proliferate and accumulate into multilayered cell clusters. Biofilm accumulation may be mediated by polysaccharide and protein factors. METHODOLOGY/PRINCIPAL FINDINGS:The information on Staphylococcus aureus protein factors involved in biofilm accumulation is limited, therefore, we searched the S. aureus Col genome for LPXTG-motif containing potential surface proteins and chose the so far uncharacterized S. aureus surface protein C (SasC) for further investigation. The deduced SasC sequence consists of 2186 amino acids with a molecular mass of 238 kDa and has features typical of gram-positive surface proteins, such as an N-terminal signal peptide, a C-terminal LPXTG cell wall anchorage motif, and a repeat region consisting of 17 repeats similar to the domain of unknown function 1542 (DUF1542). We heterologously expressed sasC in Staphylococcus carnosus, which led to the formation of huge cell aggregates indicative of intercellular adhesion and biofilm accumulation. To localize the domain conferring cell aggregation, we expressed two subclones of sasC encoding either the N-terminal domain including a motif that is found in various architectures (FIVAR) or 8 of the DUF1542 repeats. SasC or its N-terminal domain, but not the DUF1542 repeat region conferred production of huge cell aggregates, higher attachment to polystyrene, and enhanced biofilm formation to S. carnosus and S. aureus. SasC does not mediate binding to fibrinogen, thrombospondin-1, von Willebrand factor, or platelets as determined by flow cytometry. CONCLUSIONS/SIGNIFICANCE:Thus, SasC represents a novel S. aureus protein factor involved in cell aggregation and biofilm formation, which may play an important role in colonization during infection with this important pathogen

Wicked social–ecological problems forcing unprecedented change on the latitudinal margins of coral reefs: the case of southwest Madagascar

High-latitude coral reefs may be a refuge and area of reef expansion under climate change. As these locations are expected to become dryer and as livestock and agricultural yields decline, coastal populations may become increasingly dependent on marine resources. To evaluate this social–ecological conundrum, we examined the Grand Récif of Toliara (GRT), southwest Madagascar, which was intensively studied in the 1960s and has been highly degraded since the 1980s. We analyzed the social and ecological published and unpublished literature on this region and provide new data to assess the magnitude of the changes and evaluate the causes of reef degradation. Top-down controls were identified as the major drivers: human population growth and migrations, overfishing, and climate change, specifically decreased rainfall and rising temperature. Water quality has not changed since originally studied, and bottom-up control was ruled out. The identified network of social–ecological processes acting at different scales implies that decision makers will face complex problems that are linked to broader social, economic, and policy issues. This characterizes wicked problems, which are often dealt with by partial solutions that are exploratory and include inputs from various stakeholders along with information sharing, knowledge synthesis, and trust building. A hybrid approach based on classical fishery management options and preferences, along with monitoring, feedback and forums for searching solutions, could move the process of adaptation forward once an adaptive and appropriately scaled governance system is functioning. This approach has broad implications for resources management given the emerging climate change and multiple social and environmental stresses

Vaccination Targeting a Surface Sialidase of P. acnes: Implication for New Treatment of Acne Vulgaris

BACKGROUND: Acne vulgaris afflicts more than fifty million people in the United State and the severity of this disorder is associated with the immune response to Propionibacterium acnes (P. acnes). Systemic therapies for acne target P. acnes using antibiotics, or target the follicle with retinoids such as isotretinoin. The latter systemic treatment is highly effective but also carries a risk of side effects including immune imbalance, hyperlipidemia, and teratogenicity. Despite substantial research into potential new therapies for this common disease, vaccines against acne vulgaris are not yet available. METHODS AND FINDINGS: Here we create an acne vaccine targeting a cell wall-anchored sialidase of P. acnes. The importance of sialidase to disease pathogenesis is shown by treatment of a human sebocyte cell line with recombinant sialidase that increased susceptibility to P. acnes cytotoxicity and adhesion. Mice immunized with sialidase elicit a detectable antibody; the anti-sialidase serum effectively neutralized the cytotoxicity of P. acnes in vitro and P. acnes-induced interleukin-8 (IL-8) production in human sebocytes. Furthermore, the sialidase-immunized mice provided protective immunity against P. acnes in vivo as this treatment blocked an increase in ear thickness and release of pro-inflammatory macrophage inflammatory protein (MIP-2) cytokine. CONCLUSIONS: Results indicated that acne vaccines open novel therapeutic avenues for acne vulgaris and other P. acnes-associated diseases