Benzene at 1GHz. Magnetic field-induced fine structure

The deuterium NMR spectrum of benzene-d6 in a high field spectrometer (1 GHz protons) exhibits a magnetic field-induced deuterium quadrupolar splitting ??. The magnitude of ?? observed for the central resonance is smaller than that observed for the 13C satellite doublets ???. This difference, ?(??) = ??? ? ??, is due to unresolved fine structure contributions to the respective resonances. We determine the origins of and simulate this difference, and report pulse sequences that exploit the connectivity of the peaks in the 13C and 2H spectra to determine the relative signs of the indirect coupling, JCD, and ??. The positive sign found for ?? is consonant with the magnetic field biasing of an isolated benzene molecule—the magnetic energy of the aromatic ring is lowest for configurations where the C6 axis is normal to the field. In the neat liquid the magnitude of ?? is decreased by the pair correlations in this prototypical molecular liquid

Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors.

PurposeThis study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition.MethodsThis was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD.ResultsAdverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses).ConclusionsContinuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested

Homogeneous nucleation in associated vapors. I. Acetic acid

Homogeneous nucleation measurements on acetic acid vapor are reported. The presence of the relatively stable association clusters tends to stabilize the vapor with regard to homogeneous nucleation. The variation of the critical supersaturation with temperature for acetic acid vapor was found to agree well with the predictions of the Katz–Saltsburg–Reiss theory for nucleation in associated vapors

Corrected model for transport in static diffusion chamber

In present consideration for the static diffusion chamber the model of mass and heat transfer and its analytical solution are presented for the pseudo-open in one direction system

Virtual patients to explore and develop clinical case summary statement skills amongst Japanese resident physicians: a mixed methods study

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The impact of polymorphic variations in the 5p15, 6p12, 6p21 and 15q25 loci on the risk and prognosis of Portuguese patients with non-small cell lung cancer

Polymorphic variants in the 5p15, 6p12, 6p21, and 15q25 loci were demonstrated to potentially contribute to lung cancer carcinogenesis. Therefore, this study was performed to assess the role of those variants in non-small cell lung cancer (NSCLC) risk and prognosis in a Portuguese population. MATERIALS AND METHODS: Blood from patients with NSCLC was prospectively collected. To perform an association study, DNA from these patients and healthy controls were genotyped for a panel of 19 SNPs using a Sequenom® MassARRAY platform. Kaplan-Meier curves were used to assess the overall survival (OS) and progression-free survival (PFS). RESULTS: One hundred and forty-four patients with NSCLC were successfully consecutively genotyped for the 19 SNPs. One SNP was associated with NSCLC risk: rs9295740 G/A. Two SNPs were associated with non-squamous histology: rs3024994 (VEGF intron 2) T/C and rs401681 C/T. Three SNPs were associated with response rate: rs3025035 (VEGF intron 7) C/T, rs833061 (VEGF -460) C/T and rs9295740 G/A. One SNP demonstrated an influence on PFS: rs401681 C/T at 5p15, p?=?0.021. Four SNPs demonstrated an influence on OS: rs2010963 (VEGF +405 G/C), p?=?0.042; rs3025010 (VEGF intron 5 C/T), p?=?0.047; rs401681 C/T at 5p15, p?=?0.046; and rs31489 C/A at 5p15, p?=?0.029. CONCLUSIONS: Our study suggests that SNPs in the 6p12, 6p21, and 5p15 loci may serve as risk, predictive and prognostic NSCLC biomarkers. In the future, SNPs identified in the genomes of patients may improve NSCLC screening strategies and therapeutic management as well.This project was supported by Programa Doutoral em Medicina e Oncologia Molecular, University of Porto, Porto, Portugal and University of Minho, Braga, Portugal. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Transport in the static diffusion cloud chamber revisited

The static diffusion chamber (SDC) allows the measurement of critical supersaturation and of nucleation rates and it is a powerful instrument for the vapor nucleation study. Earlier, within the scope of the International Nucleation Workshop Group, nucleation rates of the n-pentanol–helium system have been measured using different experimental techniques. Disagreement of experimental data obtained using the static diffusion chamber and data obtained using other methods, particularly the laminar flow diffusion chamber, can be explained by re-examining the mass and energy transport analysis used to describe static diffusion chamber operation. In the present research we describe the mass and energy transport in the SDC modeled as an effectively open system with mass and energy transport in one direction with a nonzero diffusion flux at the system boundaries. Calculated values for vapor supersaturation are compared with the n-pentanol nucleation rate experimental results of the American–Czech group [M. Rudek, J. L. Katz, I. Y. Vidensky et al., J. Chem. Phys. 111, 3623 (1999)] and with a nucleation rate Reference Equation obtained from an earlier investigation involving the n-pentanol–helium system. From our results one can see that there is a significant difference in the calculated supersaturation for all of the data. The magnitude of this difference is quite large even for the relatively small vapor mass fractions at a nucleation temperature of 260 K. We also note that the calculated nucleation temperatures from our analysis are slightly larger than those reported in the work of Rudek et al.4 We performed our calculations with and without the thermal diffusion term. We observed that the effect of thermal diffusion on the transport process is relativelly small and is not particularly essential to include in this comparison that we are making the effects of the different flux boundary conditions

Evaluation of fast atmospheric dispersion models in a regular street network

The need to balance computational speed and simulation accuracy is a key challenge in designing atmospheric dispersion models that can be used in scenarios where near real-time hazard predictions are needed. This challenge is aggravated in cities, where models need to have some degree of building-awareness, alongside the ability to capture effects of dominant urban flow processes. We use a combination of high-resolution large-eddy simulation (LES) and wind-tunnel data of flow and dispersion in an idealised, equal-height urban canopy to highlight important dispersion processes and evaluate how these are reproduced by representatives of the most prevalent modelling approaches: (i) a Gaussian plume model, (ii) a Lagrangian stochastic model and (iii) street-network dispersion models. Concentration data from the LES, validated against the wind-tunnel data, were averaged over the volumes of streets in order to provide a high-fidelity reference suitable for evaluating the different models on the same footing. For the particular combination of forcing wind direction and source location studied here, the strongest deviations from the LES reference were associated with mean over-predictions of concentrations by approximately a factor of 2 and with a relative scatter larger than a factor of 4 of the mean, corresponding to cases where the mean plume centreline also deviated significantly from the LES. This was linked to low accuracy of the underlying flow models/parameters that resulted in a misrepresentation of pollutant channelling along streets and of the uneven plume branching observed in intersections. The agreement of model predictions with the LES (which explicitly resolves the turbulent flow and dispersion processes) greatly improved by increasing the accuracy of building-induced modifications of the driving flow field. When provided with a limited set of representative velocity parameters, the comparatively simple street-network models performed equally well or better compared to the Lagrangian model run on full 3D wind fields. The study showed that street-network models capture the dominant building-induced dispersion processes in the canopy layer through parametrisations of horizontal advection and vertical exchange processes at scales of practical interest. At the same time, computational costs and computing times associated with the network approach are ideally suited for emergency-response applications

Virtual patients to explore and develop clinical case summary statement skills amongst Japanese resident physicians: A mixed methods study

Background: In Western clinical training, formulation of a summary statement (SS) is a core exercise for articulation, evaluation, and improvement of clinical reasoning (CR). In Japanese clinical training, structured guidance in developing CR, including opportunity for SS practice, is uncommon, and the present status of case summarization skills is unclear. We used Virtual Patients (VPs) to explore Japanese junior residents' SS styles and the effectiveness of VPs on improving SS quality. Methods: All first-year junior resident physicians at 4 residency programs (n = 54) were assigned randomized sequences of 5 VP modules, rolled out at 6 day intervals. During each module, participants free-texted a case summary and then reviewed a model summary. Thematic analysis was used to identify SS styles and each SS was categorized accordingly. Frequency of SS styles, and SS CR quality determined by 1) an internally developed Key Feature rubric and 2) demonstration of semantic qualification, were compared across modules. Results: Four SS styles were identified: numbered features matched to differential diagnoses, differential diagnoses with supportive comments, feature listing, and narrative summarization. From module #1 to #5, significant increases in the narrative summarization SS style (p = 0.016), SS CR quality score (p = 0.021) and percentage of semantically driven SS (p = 0.003) were observed. Conclusions: Our study of Japanese junior residents identified distinct clinical case summary statement styles, and observed adoption of the narrative summarization style and improvement in the CR quality of summary statements during a series of VP cases