2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

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Lipids assist the membrane insertion of a BAM-independent outer membrane protein

Like several other large, multimeric bacterial outer membrane proteins (OMPs), the assembly of the Klebsiella oxytoca OMP PulD does not rely on the universally conserved β-barrel assembly machinery (BAM) that catalyses outer membrane insertion. The only other factor known to interact with PulD prior to or during outer membrane targeting and assembly is the cognate chaperone PulS. Here, in vitro translation-transcription coupled PulD folding demonstrated that PulS does not act during the membrane insertion of PulD, and engineered in vivo site-specific cross-linking between PulD and PulS showed that PulS binding does not prevent membrane insertion. In vitro folding kinetics revealed that PulD is atypical compared to BAM-dependent OMPs by inserting more rapidly into membranes containing E. coli phospholipids than into membranes containing lecithin. PulD folding was fast in diC(14:0)-phosphatidylethanolamine liposomes but not diC(14:0)-phosphatidylglycerol liposomes, and in diC(18:1)-phosphatidylcholine liposomes but not in diC(14:1)-phosphatidylcholine liposomes. These results suggest that PulD efficiently exploits the membrane composition to complete final steps in insertion and explain how PulD can assemble independently of any protein-assembly machinery. Lipid-assisted assembly in this manner might apply to other large OMPs whose assembly is BAM-independent

Pharmacokinetics and Pharmacodynamics of Antibacterials, Antifungals, and Antivirals Used Most Frequently in Neonates and Infants

Antimicrobials and antivirals are widely used in young infants and neonates. These patients have historically been largely excluded from clinical trials and, as a consequence, the pharmacokinetics and pharmacodynamics of commonly used antibacterials, antifungals, and antivirals are incompletely understood in this population. This review summarizes the current literature specific to neonates and infants regarding pharmacokinetic parameters and changes in neonatal development that affect antimicrobial and antiviral pharmacodynamics. Specific drug classes addressed include aminoglycosides, aminopenicillins, cephalosporins, glycopeptides, azole antifungals, echinocandins, polyenes, and guanosine analogs. Within each drug class, the pharmacodynamics, pharmacokinetics, and clinical implications and future directions for prototypical agents are discussed. β-Lactam antibacterial activity is maximized when the plasma concentration exceeds the minimum inhibitory concentration for a prolonged period, suggesting that more frequent dosing may optimize β-lactam therapy. Aminoglycosides are typically administered at longer intervals with larger doses in order to maximize exposure (i.e., area under the plasma concentration–time curve) with gestational age and weight strongly influencing the pharmacokinetic profile. Nonetheless, safety concerns necessitate therapeutic drug monitoring across the entire neonatal and young infant spectrum. Vancomycin, representing the glycopeptide class of antibacterials, has a long history of clinical utility, yet there is still uncertainty about the optimal pharmacodynamic index in neonates and young infants. The high degree of pharmacokinetic variability in this population makes therapeutic drug monitoring essential to ensure adequate therapeutic exposure. Among neonates treated with the triazole agent fluconazole, it has been speculated that loading doses may improve pharmacodynamic target attainment rates. The use of voriconazole necessitates therapeutic drug monitoring and dose adjustments for patients with hepatic dysfunction. Neonates treated with lipid-based formulations of the polyene amphotericin B may be at an increased risk of death, such that alternative antifungal agents should be considered for neonates with invasive fungal infections. Alternative antifungal agents such as micafungin and caspofungin also exhibit unique pharmacokinetic considerations in this population. Neonates rapidly eliminate micafungin and require nearly three times the normal adult dose to achieve comparable levels of systemic exposure. Conversely, peak caspofungin concentrations have been reported to be similar among neonates and adults. However, both of these drugs feature favorable safety profiles. Recent studies with acyclovir have suggested that current dosing regimens may not result in therapeutic central nervous system concentrations and more frequent dosing may be required for neonates at later postmenstrual ages. Though ganciclovir and valganciclovir demonstrate excellent activity against cytomegalovirus, they are associated with significant neutropenia. In summary, many pharmacokinetic and pharmacodynamic studies have been conducted in this vulnerable population; however, there are also substantial gaps in our knowledge that require further investigation. These studies will be invaluable in determining optimal neonatal dosing regimens that have the potential to improve clinical outcomes and decrease adverse effects associated with antimicrobial and antiviral treatments