Early and sustained Lactobacillus plantarum probiotic therapy in critical illness: the randomised, placebo-controlled, restoration of gut microflora in critical illness trial (ROCIT).

PURPOSE: In adults requiring treatment in an intensive care unit, probiotic therapy using Lactobacillus plantarum 299v may reduce nosocomial infection. The aim of this study was to determine whether early and sustained L. plantarum 299v therapy administered to adult ICU patients increased days alive and at home. METHODS: A multicentre, parallel group, placebo-controlled, randomised clinical trial was conducted. Adult patients within 48 h of intensive care admission and expected to require intensive care beyond the day after recruitment were eligible to participate. L plantarum 299v or placebo were administered immediately after enrolment and continued for 60 days. The primary outcome was days alive and out of hospital to Day 60 (DAOH60). Secondary outcomes included nosocomial infections. RESULTS: The median [interquartile range (IQR)] number of DAOH60 in the probiotic (n = 110) and placebo group (n = 108) was 49.5 (IQR 37.0-53.0) and 49.0 (IQR 43.8-53.0) respectively, between-group difference of 0.0 [95% confidence interval (CI) - 6.10 to 7.1, P = 0.55]. Nosocomial infection occurred in 8 (7.3%) and 5 (4.6%) of the probiotic and placebo group participants, respectively, odds ratio 1.62 (95% CI 0.51-5.10), P = 0.57. There were no serious, or probiotic-associated adverse events. CONCLUSION: Early and sustained untargeted administration of probiotic therapy with Lactobacillus plantarum 299v to adult patients admitted to the ICU is safe, but not associated with improved patient outcomes.

Study protocol for the safety and efficacy of probiotic therapy on days alive and out of hospital in adult ICU patients: the multicentre, randomised, placebo-controlled Restoration Of gut microflora in Critical Illness Trial (ROCIT).

INTRODUCTION: The effect of early and sustained administration of daily probiotic therapy on patients admitted to the intensive care unit (ICU) remains uncertain. METHODS AND ANALYSIS: The Restoration Of gut microflora in Critical Illness Trial (ROCIT) study is a multicentre, randomised, placebo-controlled, parallel-group, two-sided superiority trial that will enrol 220 patients in five ICUs. Adult patients who are within 48 hours of admission to an ICU and are expected to require intensive care beyond the next calendar day will be randomised in a 1:1 ratio to receive early and sustained Lactobacillus plantarum 299v probiotic therapy in addition to usual care or placebo in addition to usual care. The primary endpoint is days alive and out of hospital to day 60. ETHICS AND DISSEMINATION: ROCIT has been approved by the South Metropolitan Health Service Human Research Ethics Committee (ref: RGS00000004) and the St John of God Health Care Human Research Ethics Committee (ref: 1183). The trial results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ANZCTR12617000783325); Pre-results.

Polyurethanes and Polyallophanates via Sequence-Selective Copolymerization of Epoxides and Isocyanates.

Aryl isocyanates are introduced as comonomers for ring-opening copolymerization (ROCOP) with epoxides. Informed by studies of reaction kinetics, we show that divergent sequence selectivity for AB- and ABB-type copolymers can be achieved with a single dimagnesium catalyst. The resulting materials respectively constitute a new class of polyurethanes (PUs) and a new class of materials featuring an unprecedented backbone structure, the polyallophanates (PAs). The successful use of isocyanate comonomers in this way marks a new direction for the field of ROCOP while providing distinct opportunities for expansion of PU structural diversity. Specifically, the methodology reported herein delivers PUs featuring fully substituted (tertiary) carbamyl nitrogen atoms, a structural motif that is almost inaccessible via extant polymerization strategies. Thus, in one step from commercially available comonomers, our methodology expands the scope of ROCOP and gives access to diverse materials featuring both privileged (PU) and unexplored (PA) microstructures.

Selective glucose sensing in complex media using a biomimetic receptor.

Glucose is a key biomedical analyte, especially relevant to the management of diabetes. Current methods for glucose determination rely on the enzyme glucose oxidase, requiring specialist instrumentation and suffering from redox-active interferents. In a new approach, a powerful and highly selective achiral glucose receptor is mixed with a sample, l-glucose is added, and the induced CD spectrum is measured. The CD signal results from competition between the enantiomers, and is used to determine the d-glucose content. The involvement of l-glucose doubles the signal range from the CD spectrometer and allows sensitivity to be adjusted over a wide dynamic range. It also negates medium effects, which must be equal for both enantiomers. The method has been demonstrated with human serum, pre-filtered to remove proteins, giving results which closely match the standard biochemical procedures, as well as a cell culture medium and a beer sample containing high (70 mM) and low (0.4 mM) glucose concentrations respectively.

The Antiangiogenic Activity of Naturally Occurring and Synthetic Homoisoflavonoids from the Hyacinthaceae ( sensu APGII).

Excessive blood vessel formation in the eye is implicated in wet age-related macular degeneration, proliferative diabetic retinopathy, neovascular glaucoma, and retinopathy of prematurity, which are major causes of blindness. Small molecule antiangiogenic drugs are strongly needed to supplement existing biologics. Homoisoflavonoids have been previously shown to have potent antiproliferative activities in endothelial cells over other cell types. Moreover, they demonstrated a strong antiangiogenic potential in vitro and in vivo in animal models of ocular neovascularization. Here, we tested the antiangiogenic activity of a group of naturally occurring homoisoflavonoids isolated from the family Hyacinthaceae and related synthetic compounds, chosen for synthesis based on structure-activity relationship observations. Several compounds showed interesting antiproliferative and antiangiogenic activities in vitro on retinal microvascular endothelial cells, a disease-relevant cell type, with the synthetic chromane, 46, showing the best activity (GI50 of 2.3 × 10-4 µM).

Unexpected Formation of Early Late Heterobimetallic Complexes from Transition Metal Frustrated Lewis Pairs.

Reaction of transition metal "frustrated" Lewis pair compounds of the type [Cp2Zr(Me)(OC(CF3)2CH2P(t)Bu2)] with the low valent platinum species [Pt(norbornene)3] leads to the unexpected formation of a heterobimetallic species [Cp2Zr{ Pt(Me)}(OC(CF3)2CH2 P(t)Bu2)]. Single crystal X-ray analysis reveals an unusual T-shaped geometry at the platinum center, with a relevant C-Pt-P angle of 163.3(3)°. Treatment of this compound with PMe3 yields [Pt(PMe3)4] and regenerates the zirconium precursor. Treatment with [(Et2O)2H][B(C6F5)4] protonates off the methyl ligand to give an ether adduct at platinum. Analogous observations are made with titanium-platinum species. We propose the chemistry is best rationalized as a formal insertion of Pt(0) into a Zr-C or Ti-Cl bond.

A one-step, modular route to optically-active diphos ligands.

A chlorosilane elimination reaction has been developed that allows the efficient synthesis of optically pure C1-symmetric, C1-backboned diphosphines with a wide variety of stereoelectronic characteristics.

The effect of prognostic data presentation format on perceived risk among surrogate decision makers of critically ill patients: a randomized comparative trial.

PURPOSE: The purpose of this study is to determine whether varying the format used to present prognostic data alters the perception of risk among surrogate decision makers in the intensive care unit (ICU). METHODS: This was a prospective randomized comparative trial conducted in a 23-bed adult tertiary ICU. Enrolled surrogate decision makers were randomized to 1 of 2 questionnaires, which presented hypothetical ICU scenarios, identical other than the format in which prognostic data were presented (eg, frequencies vs percentages). Participants were asked to rate the risk associated with each prognostic statement. RESULTS: We enrolled 141 surrogate decision makers. The perception of risk varied significantly dependent on the presentation format. For "quantitative data," risks were consistently perceived as higher, when presented as frequencies (eg, 1 in 50) compared with equivalent percentages (eg, 2%). Framing "qualitative data" in terms of chance of "death" rather than "survival" led to a statistically significant increase in perceived risks. Framing "quantitative" data in this way did not significantly affect risk perception. CONCLUSION: Data format had a significant effect on how surrogate decision makers interpreted risk. Qualitative statements are interpreted widely and affected by framing. Where possible, multiple quantitative formats should be used for presenting prognostic information.

Generation of aminoborane monomers RR'N=BH2 from amine-boronium cations [RR'NH-BH2L](+): metal catalyst-free formation of polyaminoboranes at ambient temperature.

Protonation of MeRNH·BH3 (R = Me or H) with HX (X = B(C6F5)4, OTf, or Cl), followed by immediate, spontaneous H2 elimination, yielded the amine-boronium cation salt [MeRNH·BH2(OEt2)][B(C6F5)4] and related polar covalent analogs, MeRNH·BH2X (X = OTf or Cl). These species can be deprotonated to conveniently generate reactive aminoborane monomers MeRN=BH2 which oligomerize or polymerize; in the case of MeNH2·BH3, the two step process gave poly(N-methylaminoborane), [MeNH-BH2]n.

Frustrated Lewis pairs beyond the main group: transition metal-containing systems.

The concept of the "frustrated" Lewis pair (FLP) offers a valuable paradigm for transition metal complexes. This chapter describes recent developments in FLP chemistry where one or both of the Lewis acidic or Lewis basic components are based on a transition metal. At the forefront of these developments have been zirconocene-phosphinoaryloxide complexes; the activation of small molecules, including H2, CO2, ethers, olefins and alkyl chlorides or fluorides, with such zirconocene (or group 4 metallocene in general) phosphine pairs is described. Nascent catalytic applications for such complexes in dehydrogenation reactions and future possibilities for catalytic reactivity are also highlighted. A wider discussion of how the FLP concept may rationalise previous examples of cooperative reactivity in transition metal complexes, such as the heterolytic cleavage of hydrogen, suggests a strong and useful analogy.

Cationic Ti(IV) and neutral Ti(III) titanocene-phosphinoaryloxide frustrated Lewis pairs: hydrogen activation and catalytic amine-borane dehydrogenation.

Titanium-phosphorus frustrated Lewis pairs (FLPs) based on titanocene-phosphinoaryloxide complexes have been synthesised. The cationic titanium(IV) complex [Cp(2)TiOC(6)H(4)P((t)Bu)(2)][B(C(6)F(5))(4)] 2 reacts with hydrogen to yield the reduced titanium(III) complex [Cp(2)TiOC(6)H(4)PH((t)Bu)(2)][B(C(6)F(5))(4)] 5. The titanium(III)-phosphorus FLP [Cp(2)TiOC(6)H(4)P((t)Bu)(2)] 6 has been synthesised either by chemical reduction of [Cp(2)Ti(Cl)OC(6)H(4)P((t)Bu)(2)] 1 with [CoCp*(2)] or by reaction of [Cp(2)Ti{N(SiMe(3))(2)}] with 2-C(6)H(4)(OH){P((t)Bu)(2)}. Both 2 and 6 catalyse the dehydrogenation of Me(2)HN·BH(3).

Frustrated Lewis pairs beyond the main group: synthesis, reactivity, and small molecule activation with cationic zirconocene-phosphinoaryloxide complexes.

The extension of the frustrated Lewis pair (FLP) concept to the transition series with cationic zirconocene-phosphinoaryloxide complexes is demonstrated. Such complexes mimic the reactivity of main group FLPs in reactions such as heterolytic hydrogen cleavage, CO(2) activation, olefin and alkyne addition, and ring-opening of tetrahydrofuran. The interplay between sterics and electronics is shown to have an important role in determining the reactivity of these compounds with hydrogen in particular. The Zr-H species generated from the heterolytic activation of hydrogen is shown to undergo insertion reactions with both CO(2) and CO. Crucially, these transition metal FLPs are markedly more reactive than main group systems in many cases, and in addition to the usual array of reactions they demonstrate unprecedented reactivity in the activation of small molecules. This includes S(N)2 and E2 reactions with alkyl chlorides and fluorides, enolate formation from acetone, and the cleavage of C-O bonds to facilitate S(N)2 type reactions with noncyclic dialkyl ethers.

Frustrated Lewis pairs beyond the main group: cationic zirconocene-phosphinoaryloxide complexes and their application in catalytic dehydrogenation of amine boranes.

The cationic zirconocene-phosphinoaryloxide complexes [Cp(2)ZrOC(6)H(4)P(t-Bu)(2)][B(C(6)F(5))(4)] (3) and [Cp*(2)ZrOC(6)H(4)P(t-Bu)(2)][B(C(6)F(5))(4)] (4) were synthesized by the reaction of Cp(2)ZrMe(2) or Cp*(2)ZrMe(2) with 2-(diphenylphosphino)phenol followed by protonation with [2,6-di-tert-butylpyridinium][B(C(6)F(5))(4)]. Compound 3 exhibits a Zr-P bond, whereas the bulkier Cp* derivative 4 was isolated as a chlorobenzene adduct without this Zr-P interaction. These compounds can be described as transition-metal-containing versions of linked frustrated Lewis pairs (FLPs), and treatment of 4 with H(2) under mild conditions cleaved H(2) in a fashion analogous to that for main-group FLPs. Their reactivity in amine borane dehydrogenation also mimics that of main-group FLPs, and they dehydrogenate a range of amine borane adducts. However, in contrast to main-group FLPs, 3 and 4 achieve this transformation in a catalytic rather than stoichiometric sense, with rates superior to those for previous high-valent catalysts.

Facile dihydrogen release from phosphino-borinate ester Lewis pairs.

New phosphino-borinate ester Lewis pairs of the type (t)Bu(2)PCH(2)C(R)(2)OB(C(6)F(5))(2) (R = Me or CF(3)) are synthesised from the corresponding phosphino-alcohol and HB(C(6)F(5))(2). Dihydrogen release from the zwitterionic (t)Bu(2)PHCH(2)C(R)(2)OBH(C(6)F(5))(2) is facile.