Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771): Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7.

A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective NaV1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.

Developing a practical suicide risk prediction model for targeting high-risk patients in the Veterans health Administration.

OBJECTIVES: The US Veterans Health Administration (VHA) has begun using predictive modeling to identify Veterans at high suicide risk to target care. Initial analyses are reported here. METHODS: A penalized logistic regression model was compared with an earlier proof-of-concept logistic model. Exploratory analyses then considered commonly-used machine learning algorithms. Analyses were based on electronic medical records for all 6,360 individuals classified in the National Death Index as having died by suicide in fiscal years 2009-2011 who used VHA services the year of their death or prior year and a 1% probability sample of time-matched VHA service users alive at the index date (n = 2,112,008). RESULTS: A penalized logistic model with 61 predictors had sensitivity comparable to the proof-of-concept model (which had 381 predictors) at target thresholds. The machine learning algorithms had relatively similar sensitivities, the highest being for Bayesian additive regression trees, with 10.7% of suicides occurred among the 1.0% of Veterans with highest predicted risk and 28.1% among the 5.0% of with highest predicted risk. CONCLUSIONS: Based on these results, VHA is using penalized logistic regression in initial intervention implementation. The paper concludes with a discussion of other practical issues that might be explored to increase model performance.

Laser-plasmas in the relativistic-transparency regime: Science and applications.

Laser-plasma interactions in the novel regime of relativistically induced transparency (RIT) have been harnessed to generate intense ion beams efficiently with average energies exceeding 10 MeV/nucleon (>100 MeV for protons) at "table-top" scales in experiments at the LANL Trident Laser. By further optimization of the laser and target, the RIT regime has been extended into a self-organized plasma mode. This mode yields an ion beam with much narrower energy spread while maintaining high ion energy and conversion efficiency. This mode involves self-generation of persistent high magnetic fields (∼104 T, according to particle-in-cell simulations of the experiments) at the rear-side of the plasma. These magnetic fields trap the laser-heated multi-MeV electrons, which generate a high localized electrostatic field (∼0.1 T V/m). After the laser exits the plasma, this electric field acts on a highly structured ion-beam distribution in phase space to reduce the energy spread, thus separating acceleration and energy-spread reduction. Thus, ion beams with narrow energy peaks at up to 18 MeV/nucleon are generated reproducibly with high efficiency (≈5%). The experimental demonstration has been done with 0.12 PW, high-contrast, 0.6 ps Gaussian 1.053 µm laser pulses irradiating planar foils up to 250 nm thick at 2-8 × 1020 W/cm2. These ion beams with co-propagating electrons have been used on Trident for uniform volumetric isochoric heating to generate and study warm-dense matter at high densities. These beam plasmas have been directed also at a thick Ta disk to generate a directed, intense point-like Bremsstrahlung source of photons peaked at ∼2 MeV and used it for point projection radiography of thick high density objects. In addition, prior work on the intense neutron beam driven by an intense deuterium beam generated in the RIT regime has been extended. Neutron spectral control by means of a flexible converter-disk design has been demonstrated, and the neutron beam has been used for point-projection imaging of thick objects. The plans and prospects for further improvements and applications are also discussed.

Acidic triazoles as soluble guanylate cyclase stimulators.

A series of acidic triazoles with activity as soluble guanylate cyclase stimulators is described. Incorporation of the CF(3) triazole improved the overall physicochemical and drug-like properties of the molecule and is exemplified by compound 25.

Reductive cyclization cascades of lactones using SmI2-H2O.

Lactones bearing two alkenes or an alkene and an alkyne undergo reductive cyclization cascades upon treatment with SmI(2)-H(2)O, giving decorated azulene motifs in excellent yields with good diastereocontrol.

Optimisation of a pyrazole series of progesterone antagonists; Part 1.

The design and synthesis of a novel series of non-steroidal progesterone receptor antagonists is described. Ligand-lipophilicity efficiency (LLE) was used in the selection of a prototype agent for in vivo pharmacology studies.

Don't want to show fellow students my naughty bits: medical students' anxieties about peer examination of intimate body regions at six schools across UK, Australasia and Far-East Asia.

BACKGROUND: Although recent quantitative research suggests that medical students are reluctant to engage in peer physical examination (PPE) of intimate body regions, we do not know why. AIM: This article explores first-year medical students' anxieties about PPE of intimate body regions at six schools. METHODS: Using the Examining Fellow Students (EFS) questionnaire, we collected qualitative data from students in five countries (UK; Australia; New Zealand; Japan; Hong Kong) between 2005 and 2007. RESULTS: Our framework analysis of 617 (78.7%) students' qualitative comments yielded three themes: present and future benefits of PPE; possible barriers to PPE; and student stipulations for successful PPE. This article focuses on several sub-themes relating to students' anxieties about PPE of intimate body regions and their associated sexual, gender, cultural and religious concerns. By exploring students' euphemisms about intimate areas, our findings reveal further insights into the relationship between students' anxieties, gender and culture. CONCLUSION: First-year students are anxious about examining intimate body regions, so a staged approach starting with manikins is recommended. Further qualitative research is needed employing interviews to explore in depth students' anxieties about examinations of intimate body regions and how their views are shaped by interactions with peers, patients and doctors.

Studies on the mechanism, selectivity, and synthetic utility of lactone reduction using SmI(2) and H(2)O.

Although simple aliphatic esters and lactones have long been thought to lie outside the reducing range of SmI(2), activation of the lanthanide reagent by H(2)O allows some of these substrates to be manipulated in an unprecedented fashion. For example, the SmI(2)-H(2)O reducing system shows complete selectivity for the reduction of 6-membered lactones over other classes of lactones and esters. The kinetics of reduction has been studied using stopped-flow spectrophotometry. Experimental and computational studies suggest that the origin of the selectivity lies in the initial electron-transfer to the lactone carbonyl. The radical intermediates formed during lactone reduction with SmI(2)-H(2)O can be exploited in cyclizations to give cyclic ketone (or ketal) products with high diastereoselectivity. The cyclizations constitute the first examples of ester-alkene radical cyclizations in which the ester carbonyl acts as an acyl radical equivalent.

The National Ignition Facility neutron imaging system.

The National Ignition Facility (NIF) is scheduled to begin deuterium-tritium (DT) shots possibly in the next several years. One of the important diagnostics in understanding capsule behavior and to guide changes in Hohlraum illumination, capsule design, and geometry will be neutron imaging of both the primary 14 MeV neutrons and the lower-energy downscattered neutrons in the 6-13 MeV range. The neutron imaging system (NIS) described here, which we are currently building for use on NIF, uses a precisely aligned set of apertures near the target to form the neutron images on a segmented scintillator. The images are recorded on a gated, intensified charge coupled device. Although the aperture set may be as close as 20 cm to the target, the imaging camera system will be located at a distance of 28 m from the target. At 28 m the camera system is outside the NIF building. Because of the distance and shielding, the imager will be able to obtain images with little background noise. The imager will be capable of imaging downscattered neutrons from failed capsules with yields Y(n)>10(14) neutrons. The shielding will also permit the NIS to function at neutron yields >10(18), which is in contrast to most other diagnostics that may not work at high neutron yields. The following describes the current NIF NIS design and compares the predicted performance with the NIF specifications that must be satisfied to generate images that can be interpreted to understand results of a particular shot. The current design, including the aperture, scintillator, camera system, and reconstruction methods, is briefly described. System modeling of the existing Omega NIS and comparison with the Omega data that guided the NIF design based on our Omega results is described. We will show NIS model calculations of the expected NIF images based on component evaluations at Omega. We will also compare the calculated NIF input images with those unfolded from the NIS images generated from our NIS numerical modeling code.