Heterogeneous chemical cycles of pyrogenic nitrogen and halides influence tropospheric ozone and affect the stratosphere during extreme Pyrocumulonimbus (PyroCB) events. We report field‐derived N2O5 ...uptake coefficients, γ(N2O5), and ClNO2 yields, φ(ClNO2), from two aircraft campaigns observing fresh smoke in the lower and mid troposphere and processed/aged smoke in the upper troposphere and lower stratosphere (UTLS). Derived φ(ClNO2) varied across the full 0–1 range but was typically <0.5 and smallest in a PyroCB (<0.05). Derived γ(N2O5) was low in agricultural smoke (0.2–3.6 × 10−3), extremely low in mid‐tropospheric wildfire smoke (0.1 × 10−3), but larger in PyroCB processed smoke (0.7–5.0 × 10−3). Aged biomass burning aerosol in the UTLS had a higher γ(N2O5) of 17 × 10−3 that increased with sulfate and liquid water, but that was 1–2 orders of magnitude lower than values for aqueous sulfuric aerosol used in stratospheric models.
Plain Language Summary
The injection of reactive material into Earth's atmosphere from fires affects atmospheric composition at regional and hemispheric scales. Reported stratospheric ozone depletion during extreme events, such as the 2020 Australian wildfires, illustrates one example of fire impacts and the role of heterogeneous (gas‐particle) processes. We report field quantification of rates and product yields from airborne observations of smoke. Extremely slow heterogeneous reaction rates on young smoke increase with transport and aging, but upper atmospheric values are still a factor of 10 slower than parameterizations used in stratospheric models. Heterogeneous production of ClNO2, a major lower atmospheric chlorine activation pathway, may be active on biomass burning aerosol in the upper atmosphere.
Key Points
ClNO2 formation is active on biomass burning (BB) particles but decreases with transport to the upper troposphere and lower stratosphere (UTLS)
N2O5 uptake coefficients are low on young BB smoke and increase with transport through a PyroCB and UTLS aging
N2O5 uptake coefficients on aged BB particles in the UTLS are significantly lower than those used in model parameterizations
In this article we consider the a posteriori error estimation and adaptive mesh refinement of discontinuous Galerkin finite element approximations of the hydrodynamic stability problem associated ...with the incompressible Navier-Stokes equations. Particular attention is given to the reliable error estimation of the eigenvalue problem in channel and pipe geometries. Here, computable a posteriori error bounds are derived based on employing the generalization of the standard dual-weighted-residual approach, originally developed for the estimation of target functionals of the solution, to eigenvalue/stability problems. The underlying analysis consists of constructing both a dual eigenvalue problem and a dual problem for the original base solution. In this way, errors stemming from both the numerical approximation of the original nonlinear flow problem and the underlying linear eigenvalue problem are correctly controlled. Numerical experiments highlighting the practical performance of the proposed a posteriori error indicator on adaptively refined computational meshes are presented.
Physiological Fontan Procedure Corno, Antonio F; Owen, Matt J; Cangiani, Andrea ...
Frontiers in pediatrics,
05/2019, Letnik:
7
Journal Article
Recenzirano
Odprti dostop
The conventional Fontan circulation deviates the superior vena cava (SVC = 1/3 of the systemic venous return) toward the right lung (3/5 of total lung volume) and the inferior vena cava (IVC = 2/3 of ...the systemic venous return) toward the left lung (2/5 of total lung volume). A "physiological" Fontan deviating the SVC toward the left lung and the IVC toward the right lung was compared with the conventional setting by computational fluid dynamics, studying whether this setting achieves a more favorable hemodynamics than the conventional Fontan circulation.
An
3D parametric model of the Fontan procedure was developed using idealized vascular geometries with invariant sizes of SVC, IVC, right pulmonary artery (RPA), and left pulmonary artery (LPA), steady inflow velocities at IVC and SVC, and constant equal outflow pressures at RPA and LPA. These parameters were set to perform finite-volume incompressible steady flow simulations, assuming a single-phase, Newtonian, isothermal, laminar blood flow. Numerically converged finite-volume mass and momentum flow balances determined the inlet pressures and the outflow rates. Numerical closed-path integration of energy fluxes across domain boundaries determined the flow energy loss rate through the Fontan circulation. The comparison evaluated: (1) mean IVC pressure; (2) energy loss rate; (3) kinetic energy maximum value throughout the domain volume.
The comparison of the physiological vs. conventional Fontan provided these results: (1) mean IVC pressure 13.9 vs. 14.1 mmHg (= 0.2 mmHg reduction); (2) energy loss rate 5.55 vs. 6.61 mW (= 16% reduction); (3) maximum kinetic energy 283 vs. 396 J/m
(= 29% reduction).
A more physiological flow distribution is accompanied by a reduction of mean IVC pressure and by substantial reductions of energy loss rate and of peak kinetic energy. The potential clinical impact of these hemodynamic changes in reducing the incidence and severity of the adverse long-term effects of the Fontan circulation, in particular liver failure and protein-losing enteropathy, still remains to be assessed and will be the subject of future work.
Pseudomonas aeruginosa is a highly versatile, antibiotic-resistant Gram-negative bacterium known for causing opportunistic infections and contamination of industrial products. Despite extensive ...genomic analysis of clinical P. aeruginosa strains, no genomes exist for preservative-tolerant industrial strains. A unique collection of 69 industrial isolates was assembled and compared to clinical and environmental strains; 16 genetically distinct industrial strains were subjected to array tube genotyping, multilocus sequence typing and whole-genome sequencing. The industrial strains possessed high preservative tolerance and were dispersed widely across P. aeruginosa as a species, but recurrence of strains from the same lineage within specific industrial products and locations was identified. The industrial P. aeruginosa genomes (mean=7.0 Mb) were significantly larger than those of previously sequenced environmental (mean=6.5 Mb; n=19) and clinical (mean=6.6 Mb; n=66) strains. Complete sequencing of the P. aeruginosa industrial strain RW109, which encoded the largest genome (7.75 Mb), revealed a multireplicon structure including a megaplasmid (555 265 bp) and large plasmid (151 612 bp). The RW109 megaplasmid represented an emerging plasmid family conserved in seven industrial and two clinical P. aeruginosa strains, and associated with extremely stress-resilient phenotypes, including antimicrobial resistance and solvent tolerance. Here, by defining the detailed phylogenomics of P. aeruginosa industrial strains, we show that they uniquely possess multireplicon, megaplasmid-bearing genomes, and significantly greater genomic content worthy of further study.
Objective
To assess the relative contribution of intestinal and hepatic CYP3A inhibition to the interaction between the prototypic CYP3A substrates midazolam and clarithromycin.
Methods
On day 1, 16 ...volunteers (eight men and eight women; age range, 20 to 40 years; weight range, 45 to 100 kg) received simultaneous doses of midazolam intravenously (0.05 mg/kg over 30 minutes) and orally (4 mg of a stable isotope, 15N3‐midazolam). Starting on day 2, 500 mg clarithromycin was administered orally twice daily for 7 days. On day 8, intravenous and oral doses of midazolam were administered 2 hours after the final clarithromycin dose. Blood and urine samples were assayed for midazolam, 15N3‐midazolam, and metabolites by gas chromatography‐mass spectrometry.
Results
There was no significant (p > 0.05) difference in the urinary excretion of 1′‐hydroxymidazolam after intravenous and oral dosing on day 1 or day 8, indicating that the oral dose was completely absorbed into the gut wall. The oral clearance of midazolam was found to be significantly greater in female subjects (1.9 ± 1.0 versus 1.0 ± 0.3 L/hr/kg; p < 0.05) than in male subjects but not systemic clearance (0.35 ± 0.1 versus 0.44 ± 0.1 L/hr/kg). For women not receiving oral contraceptives (n = 6) a significant gender‐related difference was observed for systemic and oral clearance and for area under the curve and elimination half‐life after oral administration. A significant (p < 0.05) reduction in the systemic clearance of midazolam from 28 ± 9 L/hr to 10 ± 3 L/hr occurred after clarithromycin administration. Oral midazolam availability was significantly increased from 0.31 ± 0.1 to 0.75 +‐ 0.2 after clarithromycin dosing. Likewise, intestinal and oral availability were significantly increased from 0.42 ± 0.2 to 0.83 ± 0.2 and from 0.74 ± 0.1 to 0.90 ± 0.04, respectively. A significant correlation was observed between intestinal and oral availability (n = 32, r = 0.98, p < 0.05). After clarithromycin administration, a significant correlation was observed between the initial hepatic or intestinal availability and the relative increase in hepatic or intestinal availability, respectively. Female subjects exhibited a greater extent of interaction after oral and intravenous dosing than male subjects (p < 0.05).
Conclusion
These data indicate that in addition to the liver, the intestine is a major site of the interaction between oral midazolam and clarithromycin. Interindividual variability in first‐pass extraction of high‐affinity CYP3A substrates such as midazolam is primarily a function of intestinal enzyme activity.
Clinical Pharmacology & Therapeutics (1998) 64, 133–143; doi:
Unlike familial Alzheimer's disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to ...designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.
In this article we consider the
a posteriori
error estimation and adaptive mesh refinement of discontinuous Galerkin finite element approximations of the bifurcation problem associated with the ...steady incompressible Navier-Stokes equations. Particular attention is given to the reliable error estimation of the critical Reynolds number at which a steady pitchfork bifurcation occurs when the underlying physical system possesses rotational and reflectional or
O
(2) symmetry. Here, computable
a posteriori
error bounds are derived based on employing the generalization of the standard Dual Weighted Residual approach, originally developed for the estimation of target functionals of the solution, to bifurcation problems. Numerical experiments highlighting the practical performance of the proposed
a posteriori
error indicator on adaptively refined computational meshes are presented. Here, particular attention is devoted to the problem of flow through a cylindrical pipe with a sudden expansion, which represents a notoriously difficult computational problem.
Optimization of a series of N-1-cycloalkyl-4-aryl-5-(pyrimidin-4-yl)imidazole inhibitors of p38 kinase is reported. Oral administration of inhibitors possessing a cyclohexan-4-ol or piperidin-4-yl ...group at N-1 in combination with alkoxy, amino(alkyl), phenoxy and anilino substitution at the 2-position of the pyrimidine was found to potently inhibit LPS-induced TNF in mice and rats. The selectivity of these new inhibitors for p38 kinase versus eight other protein kinases is high and in all cases exceeds that of SB 203580.
A series of N-1-cycloalkyl-4-aryl-5-(pyrimidin-4-yl)imidazole p38 kinase inhibitors has been optimized for in vitro and in vivo potency. Based upon its overall profile, SB 242235 was chosen as a clinical development candidate for evaluation in the treatment of rheumatoid arthritis.
Many surgical procedures are available for women with urinary stress incontinence, yet few randomized clinical trials have been conducted to provide a basis for treatment recommendations.
We ...performed a multicenter, randomized clinical trial comparing two procedures--the pubovaginal sling, using autologous rectus fascia, and the Burch colposuspension--among women with stress incontinence. Women were eligible for the study if they had predominant symptoms associated with the condition, a positive stress test, and urethral hypermobility. The primary outcomes were success in terms of overall urinary-incontinence measures, which required a negative pad test, no urinary incontinence (as recorded in a 3-day diary), a negative cough and Valsalva stress test, no self-reported symptoms, and no retreatment for the condition, and success in terms of measures of stress incontinence specifically, which required only the latter three criteria. We also assessed postoperative urge incontinence, voiding dysfunction, and adverse events.
A total of 655 women were randomly assigned to study groups: 326 to undergo the sling procedure and 329 to undergo the Burch procedure; 520 women (79%) completed the outcome assessment. At 24 months, success rates were higher for women who underwent the sling procedure than for those who underwent the Burch procedure, for both the overall category of success (47% vs. 38%, P=0.01) and the category specific to stress incontinence (66% vs. 49%, P<0.001). However, more women who underwent the sling procedure had urinary tract infections, difficulty voiding, and postoperative urge incontinence.
The autologous fascial sling results in a higher rate of successful treatment of stress incontinence but also greater morbidity than the Burch colposuspension. (ClinicalTrials.gov number, NCT00064662 ClinicalTrials.gov .).
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