Apart from new anti-tuberculosis drug development, another approach for tuberculosis (TB) treatment optimization is to derive maximum benefit from current agents. However, the dosage of current ...anti-TB drug regimens has never been optimized according to the exposure-effect relationships of each drug. The objective of this article is to review the latest pharmacokinetic, pharmacodynamic, experimental, and clinical data concerning the use of higher doses of first-line anti-TB drugs to improve the efficacy of pulmonary tuberculosis treatment. Exposure-effect relationships have been described for all first-line anti-TB agents. There is convincing evidence that patients would benefit from higher rifamycin exposure. This could be achieved by using higher daily doses of rifampin, or more frequent dosing of rifapentine. The dose-dependent activity of pyrazinamide observed in hollow-fiber and animal models suggests that higher doses of pyrazimamide might be more efficacious, but the tolerability of such higher doses needs to be investigated in humans. It is likely that higher doses of ethambutol would be associated with higher antibacterial effect, but the dose-related ocular toxicity of the drug precludes such practice. For isoniazid, dose individualization is required to optimize patient care. The use of higher than standard doses of isoniazid in fast acetylators should result in greater early bactericidal activity. To conclude, the use of higher doses for some of the firstline anti-TB agents has definite potential for shortening or improving TB treatment.
The last decade has witnessed dramatic improvements in whole-genome sequencing capabilities coupled to drastically decreased costs, leading to an inundation of high-quality de novo genomes. For this ...reason, the continued development of genome quality metrics is imperative. Using the 2016 Atlantic bottlenose dolphin NCBI RefSeq annotation and mass spectrometry-based proteomic analysis of six tissues, we confirmed 10,402 proteins from 4711 protein groups, constituting nearly one-third of the possible predicted proteins. Since the identification of larger proteins with more identified peptides implies reduced database fragmentation and improved gene annotation accuracy, we propose the metric NP10, which attempts to capture this quality improvement. The NP10 metric is calculated by first stratifying proteomic results by identifying the top decile (or 10th 10-quantile) of identified proteins based on the number of peptides per protein and then returns the median molecular weight of the resulting proteins. When using the 2016 versus 2012 Tursiops truncatus genome annotation to search this proteomic data set, there was a 21% improvement in NP10. This metric was further demonstrated by using a publicly available proteomic data set to compare human genome annotations from 2004, 2013 and 2016, which showed a 33% improvement in NP10. These results demonstrate that proteomics may be a useful metrological tool to benchmark genome accuracy, though there is a need for reference proteomic datasets across species to facilitate the evaluation of new de novo and existing genome.
We present the redshift lower limit of z > or =, slanted 0.6035 for the very high energy (VHE; E > or =, slanted 100 GeV) emitting blazar PKS 1424+240 (PG 1424+240). This limit is inferred from Ly ...beta and Ly gamma absorption observed in the far-ultraviolet spectra from the Hubble Space Telescope/Cosmic Origins Spectrograph. No VHE-detected blazar has shown solid spectroscopic evidence of being more distant. At this distance, VHE observations by VERITAS are shown to sample historically large gamma-ray opacity values at 500 GeV, extending beyond tau = 4 for low-level models of the extragalactic background light (EBL) and beyond tau = 5 for high levels. The majority of the z = 0.6035 absorption-corrected VHE spectrum appears to exhibit a lower flux than an extrapolation of the contemporaneous Large Area Telescope power-law fit beyond 100 GeV. However, the highest energy VERITAS point is the only point showing agreement with this extrapolation, possibly implying the overestimation of the gamma-ray opacity or the onset of an unexpected VHE spectral feature. A curved log parabola is favored when fitting the full range of gamma-ray data (0.5-500 GeV). While fitting the absorption-corrected VHE data alone results in a harder differential power law than that from the full range, the indices derived using three EBL models are consistent with the physically motivated limit set by Fermi acceleration processes.
ObjectivesDual antiplatelet therapy (DAPT) with aspirin + a P2Y12 inhibitor is recommended for at least 12 months for patients with acute coronary syndrome (ACS), with shorter durations considered ...for patients with increased bleeding risk. However, there are no decision support tools available to predict an individual patient’s bleeding risk during DAPT treatment in the post-ACS setting.MethodsTo develop a longitudinal bleeding risk prediction model, we analy sed 9240 patients with unstable angina/non-ST segment elevation myocardial infarction (NSTEMI) from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial, who were managed without revasculari sation and treated with DAPT for a median of 14.8 months.ResultsWe identified 10 significant baseline predictors of non-coronary artery bypass grafting (CABG)-related Global Use of Strategies to Open Occluded Arteries (GUSTO) severe/life-threatening/moderate bleeding: age, sex, weight, NSTEMI (vs unstable angina), angiography performed before randomi sation, prior peptic ulcer disease, creatinine, systolic blood pressure, haemoglobin and treatment with beta-blocker. The five significant baseline predictors of Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding included age, sex, angiography performed before randomi sation, creatinine and haemoglobin. The models showed good predictive accuracy with Therneau’s C-indices: 0.78 (SE = 0.024) for the GUSTO model and 0.67 (SE = 0.023) for the TIMI model. Internal validation with bootstrapping gave similar C-indices of 0.77 and 0.65, respectively. External validation demonstrated an attenuated C-index for the GUSTO model (0.69) but not the TIMI model (0.68).ConclusionsLongitudinal bleeding risks during treatment with DAPT in patients with ACS can be reliably predicted using selected baseline characteristics. The TRILOGY ACS bleeding models can inform risk –benefit considerations regarding the duration of DAPT following ACS.Trial registrationClinicalTrials.gov identifier: https://clinicaltrials.gov/ct2/show/NCT00699998
Very preterm (VPT) infants are at-risk for altered growth, slower speed of processing (SOP), and hypertension. This study assesses the relationship between postnatal body composition (BC), ...neurodevelopment (indexed by SOP), and blood pressure (BP) in VPT infants.
Thirty-four VPT infants underwent weekly measurements and BC testing until discharge and post-discharge at 4 mos CGA and 4 yrs. At post-discharge visits, SOP was assessed using visual evoked potentials and the NIH Toolbox; BP was also measured.
In-hospital rate of weight, length and fat-free mass (FFM) gains were associated with faster SOP at 4 yrs. Higher rate of gains in weight and FFM from discharge to 4 mos CGA were associated with faster SOP at 4 mos CGA, while higher fat mass (FM) gains during the same time were positively associated with BP at 4 yrs. BC at 4 yrs nor gains beyond 4 mos CGA were associated with outcomes.
In VPT infants, early FFM gains are associated with faster SOP, whereas post-discharge FM gains are associated with higher BPs at 4 yrs. This shows birth to 4 mos CGA is a sensitive period for growth and its relation to neurodevelopmental and metabolic outcomes. Close monitoring and early nutritional adjustments to optimize quality of gains may improve outcomes.
Phase transitions are ubiquitous in nature, and can be arranged into universality classes such that systems having unrelated microscopic physics show identical scaling behaviour near the critical ...point. One prominent universal element of many continuous phase transitions is the spontaneous formation of topological defects during a quench through the critical point. The microscopic dynamics of defect formation in such transitions are generally difficult to investigate, particularly for superfluids. However, Bose-Einstein condensates (BECs) offer unique experimental and theoretical opportunities for probing these details. Here we present an experimental and theoretical study of the BEC phase transition of a trapped atomic gas, in which we observe and statistically characterize the spontaneous formation of vortices during condensation. Using microscopic theories that incorporate atomic interactions and quantum and thermal fluctuations of a finite-temperature Bose gas, we simulate condensation and observe vortex formation in close quantitative agreement with our experimental results. Our studies provide further understanding of the development of coherence in superfluids, and may allow for direct investigation of universal phase transition dynamics.
Conventional wisdom is that quantum effects will tend to disappear as the number of quanta in a system increases, and the evolution of a system will become closer to that described by mean-field ...classical equations. In this Letter we combine newly developed theoretical and experimental techniques to propose and analyze an experiment using a Bose-Hubbard trimer where the opposite is the case. We find that differences in the preparation of a centrally evacuated trimer can lead to readily observable differences in the subsequent dynamics which increase with system size. Importantly, these differences can be detected by the simple measurements of atomic number.
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