Treatment of Tuberculous Meningitis and Its Complications in Adults.

PURPOSE OF REVIEW: Tuberculous meningitis (TBM) is a global health problem. In this review, we systematically evaluate the evidence for current and emerging antimicrobials, host-directed therapies and supportive managements. RECENT FINDINGS: Current antimicrobial regimes do not factor the differing ability of drugs to cross the blood-brain barrier. Rifampicin may be more effective at higher doses yet the most recent clinical trial failed to demonstrate survival benefit at 15 mg/kg/day. Dose finding studies suggest that higher doses still may be safe and more effective. Fluoroquinolones are currently listed as important second-line agents in drug-resistant TBM; however, a survival benefit as a first-line agent has yet to be shown. Linezolid may be a promising antimicrobial with good central nervous system penetrance. Dexamethasone reduces mortality in HIV-uninfected individuals yet evidence for its use in HIV co-infection is lacking. Aspirin has anti-inflammatory and anti-thrombotic properties. Small studies have demonstrated efficacy in reducing stroke but further research is required to better understand its effect on controlling the host inflammatory response. Discovery of genetic polymorphisms may direct individualized immune therapies and mediators of the innate immune response may provide targets for the development of novel therapies. There is at present no significant evidence base to guide management of hydrocephalus in HIV co-infection. Further clinical trial data is required to improve treatment outcomes in TBM in particularly in regard to the value of high-dose rifampicin, newer antimicrobials with improved central nervous system penetration and host-directed therapies. Supportive measures in particular the management of hydrocephalus in HIV co-infection should be an area for future research

Ion Pair-Directed Regiocontrol in Transition-Metal Catalysis: A Meta-Selective C-H Borylation of Aromatic Quaternary Ammonium Salts

The use of noncovalent interactions to direct transition-metal catalysis is a potentially powerful yet relatively underexplored strategy, with most investigations thus far focusing on using hydrogen bonds as the controlling element. We have developed an ion pair-directed approach to controlling regioselectivity in the iridium-catalyzed borylation of two classes of aromatic quaternary ammonium salts, leading to versatile meta-borylated products. By examining a range of substituted substrates, this provides complex, functionalized aromatic scaffolds amenable to rapid diversification and more broadly demonstrates the viability of ion-pairing for control of regiochemistry in transition-metal catalysis.Engineering and Physical Sciences Research Council and Pfizer (CASE studentship), AstraZeneca (AZ-Cambridge Ph.D. Program studentship), Royal Society (University Research Fellowship), Engineering and Physical Sciences Research Council and Engineering and Physical Sciences Research Council U.K. National Mass Spectrometry Facility (Swansea University

Palladium-Catalyzed Cross Coupling of Benzylammonium Salts with Boronic Acids under Mild Conditions

Herein, we give a full account of the development of the palladium­-catalysed cross-coupling of benzylammonium salts with boronic acids. A range of benzylamine-derived quaternary ammonium salts can be coupled with boronic acids under relatively mild conditions. Our optimization has identified ligands that can be used to chemoselectively cross-couple at the ammonium in the presence of chlorides. We demonstrate that intramolecular palladium-catalysed C–H activation is also a viable pathway for the putative benzyl-Pd(II) intermediate obtained upon oxidative addition and have optimised this to obtain fluorene in good yield.We are grateful to the Engineering and Physical Sciences Research Council (EPSRC, Grant Number EP/N005422/1) and Pfizer for a CASE studentship (H.J.D.), the EPSRC and the Royal Society for a University Research Fellowship (R.J.P.). P.L.T. thanks the Swiss-European Mobility Programme for Traineeships for funding his stay in Cambridge

meta-Selective C−H Borylation of Benzylamine-, Phenethylamine-, and Phenylpropylamine-Derived Amides Enabled by a Single Anionic Ligand

Selective functionalization at the meta position of arenes remains a significant challenge. In this work, we demonstrate that a single anionic bipyridine ligand bearing a remote sulfonate group enables selective iridium-catalyzed borylation of a range of common amine-containing aromatic molecules at the arene meta position. We propose that this selectivity is the result of a key hydrogen bonding interaction between the substrate and catalyst. The scope of this meta-selective borylation is demonstrated on amides derived from benzylamines, phenethylamines and phenylpropylamines; amine-containing building blocks of great utility in many applications.We are grateful to the EPSRC and Pfizer for a CASE studentship (H.J.D.), the EPSRC (EP/N005422/1, G.R.G.) and the Royal Society for a University Research Fellowship (R.J.P.)

Further variability of the compact radio nebula of P Cygni

Skinner et al. presented two high-resolution 6-cm (5 GHz) images of the B-supergiant star P Cygni. These show the observed morphology and flux densities to have changed over the intervening month. Following on from this, we present a series of seven high-resolution 6-cm images (including re-reductions of the two from Skinner et al.). These confirm that radio emission from the inner 400 mas of the wind is inhomogeneous, consisting usually of several separated bright spots, and that the total and peak flux densities and the observed morphology vary over all time-scales sampled. We suggest that recombination in cooling clumps of gas which will decrease the radio emission, followed by the appearance of other ionized clumps, could explain such rapid changes, but detailed models must await further observations

Ion Pair-Directed C-H Activation on Flexible Ammonium Salts: Meta-Selective Borylation of Quaternized Phenethylamines and Phenylpropylamines

Ion pairing has unexplored potential as a key catalyst-substrate interaction for controlling regioselectivity and site-selectivity in transition metal catalysis, particularly in the area of C-H activation. However, there is a significant perceived challenge that has meant that few have investigated this approach to date – that of the low directionality, which could present an insurmountable challenge if seeking positional selectivity on flexible substrates. Herein, we demonstrate that even flexible substrates with several freely rotatable bonds undergo ion pair-directed CH borylation with good to excellent levels of regiocontrol for the arene meta position. Furthermore, we demonstrate that in specially designed competition substrates, ion pair direction prevails over competing hydrogen bond direction. We anticipate that these findings will inspire the greater incorporation of ion-pairing into site-selective catalytic strategies

A compact, variable radio nebula around P Cygni

We present high spatial resolution images, at a wavelength of 6 cm, of the luminous blue variable star P Cygni. The images fully resolve the core of the stellar wind, and show that it is very clumpy. Two images were taken, separated in time by approximately a month, during which the structure in the wind has changed radically. The total flux observed has also changed significantly. We show that the clump sizes and electron densities are consistent with the radio variability being due to recombination of the ionized gas within the clumps, after key cooling lines become optically thin, causing the free-free emission to disappear. This is the first time that resolved radio images of a hot star wind have been obtained. It also represents important confirmation of a previous observation that thermal free-free wind emission can vary rapidly in a hot stellar wind