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OBJECTIVES: To identify children at risk for in-hospital mortality following tracheotomy. DESIGN: Retrospective cohort study. SETTING: 25 746 876 US hospitalisations for children within the Kids'' Inpatient Database 1997, 2000, 2003 and 2006. PARTICIPANTS: 18 806 hospitalisations of children ages 0–18 years undergoing tracheotomy, identified from ICD-9-CM tracheotomy procedure codes. MAIN OUTCOME MEASURE: Mortality during the initial hospitalisation when tracheotomy was performed in relation to patient demographic and clinical characteristics (neuromuscular impairment (NI), chronic lung disease, upper airway anomaly, prematurity, congenital heart disease, upper airway infection and trauma) identified with ICD-9-CM codes. RESULTS: Between 1997 and 2006, mortality following tracheotomy ranged from 7.7% to 8.5%. In each year, higher mortality was observed in children undergoing tracheotomy who were aged <1 year compared with children aged 1–4 years (mortality range: 10.2–13.1% vs 1.1–4.2%); in children with congenital heart disease, compared with children without congenital heart disease (13.1–18.7% vs 6.2–7.1%) and in children with prematurity, compared with children who were not premature (13.0–19.4% vs 6.8–7.3%). Lower mortality was observed in children with an upper airway anomaly compared with children without an upper airway anomaly (1.5–5.1% vs 9.1–10.3%). In 2006, the highest mortality (40.0%) was observed in premature children with NI and congenital heart disease, who did not have an upper airway anomaly. CONCLUSIONS: Congenital heart disease, prematurity, the absence of an upper airway anomaly and age <1 year were characteristics associated with higher mortality in children following tracheotomy. These findings may assist provider communication with children and families regarding early prognosis following tracheotomy. [ABSTRACT FROM AUTHOR]

Screeningof the GSK corporate collection, some 1.9 million compounds,against Plasmodium falciparum(Pf), revealed almost 14000 active hits that are now knownas the Tres Cantos Antimalarial Set (TCAMS). Followup work by Calderonet al. clustered and computationally filtered the TCAMS through avariety of criteria and reported 47 series containing a total of 522compounds. From this enhanced set, we identified the carbamoyl triazoleTCMDC-134379 (1), a known serine protease inhibitor,as an excellent starting point for SAR profiling. Lead optimizationof 1led to several molecules with improved antimalarialpotency, metabolic stabilities in mouse and human liver microsomes,along with acceptable cytotoxicity profiles. Analogue 44displayed potent in vitro activity (IC50= 10 nM) andoral activity in a SCID mouse model of Pfinfectionwith an ED50of 100 and ED90of between 100and 150 mg kg−1, respectively. The results presentedencourage further investigations to identify the target of these highlyactive compounds. [ABSTRACT FROM AUTHOR]

We report the activities of a number of thiazolides [2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis C virus (HCV)genotypes IA and IB, using replicon assays. The structure–activityrelationships (SARs) of thiazolides against HCV are less predictablethan against hepatitis B virus (HBV), though an electron-withdrawinggroup at C(5′) generally correlates with potency. Among therelated salicyloylanilides, the m-fluorophenyl analoguewas most promising; niclosamide and close analogues suffered fromvery low solubility and bioavailability. Nitazoxanide (NTZ) 1has performed well in clinical trials against HCV. We showhere that the 5′-Cl analogue 4has closely comparablein vitro activity and a good cell safety index. By use of supportvector analysis, a quantitative structure–activity relationship(QSAR) model was obtained, showing good predictive models for cellsafety. We conclude by updating the mode of action of the thiazolidesand explain the candidate selection that has led to compound 4entering preclinical development. [ABSTRACT FROM AUTHOR]

Four new layered phases have been synthesized by the hydrothermal reactions of zinc and magnesium salts with fenbufen (γ-oxo-(1,1′-biphenyl)-4-butanoic acid) as a result of the oxidation of fenbufen at the ketone forming biphenylcarboxylate. Reactions with zinc nitrate give different degrees of oxidation, yielding Zn(C16H13O3)(C13H9O2)(H2O) (1) and Zn5(OH)6(C13H9O2)4(2), depending on the reaction temperature. Compound 2has an unusual zinc hydroxide layer structure which contains hydroxide-centered Zn4OH(OH)4units where the central hydroxide has two long and two short bonds to the Zn atoms. The mechanism for the ketone oxidation has been investigated by a series of DFT calculations which indicate that a concerted, metal-mediated pathway is lower in energy than a two-step process. The importance of the metal cation in this oxidation reaction has been shown by demonstrating that oxidation of fenbufen also occurs during reactions with magnesium nitrate and zinc chloride. These reactions yielded fully oxidized Mg(C13H9O2)2(H2O)2(3) and half-oxidized Zn(C16H13O3)(C13H9O2)(H2O) (4), a polymorph of 1. Reactions with ammonium salts gave only recrystallized fenbufen, providing further evidence for the role of the metal cation in these oxidation reactions. [ABSTRACT FROM AUTHOR]