Antibiotic De-Escalation Practices in the Intensive Care Unit: A Multicenter Observational Study.

BACKGROUND: There is little known about antibiotic de-escalation (ADE) practices in the intensive care unit (ICU). OBJECTIVE: The objective was to determine the proportion of patients who received ADE within 24 hours of actionable cultures and identify predictors of timely ADE. METHODS: Multicenter cohort study in ICUs of 15 hospitals in Australia and New Zealand. Adult patients were included if they were started on broad-spectrum antibiotics within 24 hours of ICU admission. The ADE was defined as switching from a broad-spectrum agent to a narrower-spectrum agent or antibiotic cessation. The primary outcome was ADE within 24 hours of an actionable culture, where ADE was possible. RESULTS: The 446 patients included in the study had a mean age of 63 ± 16 years, 60% were male, 32% were mechanically ventilated, and 19% were immunocompromised. Of these, 161 (36.1%) were not eligible for ADE and 37 (8.3%) for whom ADE within 24 hours of actionable culture could not be determined. In the remaining 248 patients, ADE occurred ≤24 hours in 60.5% (n = 150/248) after actionable cultures. In the multivariable logistic regression analysis, ADE was less likely to occur within 24 hours for patients with negative cultures (odds ratio [OR] = 0.48, 95% confidence interval [CI] = 0.25-0.92, P = 0.03). CONCLUSION AND RELEVANCE: Timely ADE may not occur in 40% of patients in the ICU and is less likely to occur in patients with negative cultures. Timely ADE can be improved, and patients with negative cultures should be targeted as part of antimicrobial stewardship efforts.

Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.

The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. We describe a mitochondrial protein, aspartyl-tRNA synthetase (DARS2), which is released in circulation during bacterial pneumonia in humans and displays intrinsic innate immune properties and cellular repair properties. DARS2 interacts with a bacterial-induced ubiquitin E3 ligase subunit, FBXO24, which targets the synthetase for ubiquitylation and degradation, a process that is inhibited by DARS2 acetylation. During experimental pneumonia, Fbxo24 knockout mice exhibit elevated DARS2 levels with an increase in pulmonary cellular and cytokine levels. In silico modeling identified an FBXO24 inhibitory compound with immunostimulatory properties which extended DARS2 lifespan in cells. Here, we show a unique biological role for an extracellular, mitochondrially derived enzyme and its molecular control by the ubiquitin apparatus, which may serve as a mechanistic platform to enhance protective host immunity through small molecule discovery.

Predictors and pregnancy outcomes associated with a newborn birth weight of 4000 g or more in Lusaka, Zambia.

OBJECTIVE: To identify predictors and outcomes associated with a birth weight of 4000g or more in Lusaka, Zambia. METHODS: Data from women who delivered between February 2006 and August 2011 were obtained from electronic perinatal records at 25 public sector facilities in Lusaka. Macrosomia was defined as a birth weight of 4000g or more and normal birth weight as 2500-3999g. Maternal and newborn characteristics were analyzed for association with macrosomia. RESULTS: There were 4717 macrosomic and 187 117 normal birth weight newborns. The strongest predictors of macrosomia were high BMI (adjusted odds ratio [AOR], 2.88; 95% confidence interval [CI], 1.95-4.24), prior macrosomic newborn (AOR, 7.60; 95% CI, 6.81-8.49), and history of diabetes (AOR, 3.09; 95% CI, 1.36-6.98). Macrosomic newborns were at increased risk for cesarean delivery (AOR, 1.63; 95% CI, 1.35-1.96), fresh stillbirth (AOR, 2.24; 95% CI, 1.56-3.21), Apgar score of under 7 at 5minutes (AOR, 2.03; 95% CI, 1.33-3.11), and neonatal intensive care admission (AOR, 2.07; 95% CI, 1.32-3.23). CONCLUSION: Screening for macrosomia should be considered for high-risk patients in Sub-Saharan Africa. Institutional delivery at facilities with operating rooms and neonatal intensive care services should be encouraged.

POT1 proteins in green algae and land plants: DNA-binding properties and evidence of co-evolution with telomeric DNA.

Telomeric DNA terminates with a single-stranded 3' G-overhang that in vertebrates and fission yeast is bound by POT1 (Protection Of Telomeres). However, no in vitro telomeric DNA binding is associated with Arabidopsis POT1 paralogs. To further investigate POT1-DNA interaction in plants, we cloned POT1 genes from 11 plant species representing major branches of plant kingdom. Telomeric DNA binding was associated with POT1 proteins from the green alga Ostreococcus lucimarinus and two flowering plants, maize and Asparagus. Site-directed mutagenesis revealed that several residues critical for telomeric DNA recognition in vertebrates are functionally conserved in plant POT1 proteins. However, the plant proteins varied in their minimal DNA-binding sites and nucleotide recognition properties. Green alga POT1 exhibited a strong preference for the canonical plant telomere repeat sequence TTTAGGG with no detectable binding to hexanucleotide telomere repeat TTAGGG found in vertebrates and some plants, including Asparagus. In contrast, POT1 proteins from maize and Asparagus bound TTAGGG repeats with only slightly reduced affinity relative to the TTTAGGG sequence. We conclude that the nucleic acid binding site in plant POT1 proteins is evolving rapidly, and that the recent acquisition of TTAGGG telomere repeats in Asparagus appears to have co-evolved with changes in POT1 DNA sequence recognition.