332 research outputs found
Scaling laws in bacterial genomes: A side-effect of selection of mutational robustness?
In the past few years, numerous research projects have focused on identifying and understanding scaling properties in the gene content of prokaryote genomes and the intricacy of their regulation networks. Yet, and despite the increasing amount of data available, the origins of these scalings remain an open question. The RAevol model, a digital genetics model, provides us with an insight into the mechanisms involved in an evolutionary process. The results we present here show that (i) our model reproduces qualitatively these scaling laws and that (ii) these laws are not due to differences in lifestyles but to differences in the spontaneous rates of mutations and rearrangements. We argue that this is due to an indirect selective pressure for robustness that constrains the genome size
Reduction of computing time for least-squares migration based on the Helmholtz equation by graphics processing units
In geophysical applications, the interest in leastsquares
migration (LSM) as an imaging algorithm is
increasing due to the demand for more accurate solutions
and the development of high-performance computing. The
computational engine of LSM in this work is the numerical
solution of the 3D Helmholtz equation in the frequency
domain. The Helmholtz solver is Bi-CGSTAB preconditioned
with the shifted Laplace matrix-dependent multigrid
method. In this paper, an efficient LSM algorithm is presented
using several enhancements. First of all, a frequency
decimation approach is introduced that makes use of redundant
information present in the data. It leads to a speedup of
LSM, whereas the impact on accuracy is kept minimal. Secondly,
a new matrix storage format Very Compressed Row
Storage (VCRS) is presented. It not only reduces the size of
the stored matrix by a certain factor but also increases the
efficiency of the matrix-vector computations. The effects of
lossless and lossy compression with a proper choice of the
compression parameters are positive. Thirdly, we accelerate
the LSM engine by graphics cards (GPUs). A GPU is used
as an accelerator, where the data is partially transferred to
a GPU to execute a set of operations or as a replacement,
where the complete data is stored in the GPU memory. We
demonstrate that using the GPU as a replacement leads to
higher speedups and allows us to solve larger problem sizes.
Summarizing the effects of each improvement, the resulting
speedup can be at least an order of magnitude compared to
the original LSM method
Tobramycin Clearance Is Best Described by Renal Function Estimates in Obese and Non-obese Individuals: Results of a Prospective Rich Sampling Pharmacokinetic Study
Item does not contain fulltextPURPOSE: Tobramycin is an aminoglycoside antibiotic of which the 24 h exposure correlates with efficacy. Recently, we found that clearance of the aminoglycoside gentamicin correlates with total body weight (TBW). In this study, we investigate the full pharmacokinetic profile of tobramycin in obese and non-obese individuals with normal renal function. METHODS: Morbidly obese individuals (n = 20) undergoing bariatric surgery and non-obese healthy volunteers (n = 8), with TBW ranging 57-194 kg, received an IV dose of tobramycin with plasma concentrations measured over 24 h (n = 10 per individual). Statistical analysis, modelling and simulations were performed using NONMEM. RESULTS: In a two-compartment model, TBW was the best predictor for central volume of distribution (p < 0.001). For clearance, MDRD (de-indexed for body surface area) was identified as best covariate (p < 0.001), and was superior over TBW ((p < 0.05). Other renal function estimates (24 h urine GFR and de-indexed CKD-EPI) led to similar results as MDRD (all p < 0.001)). CONCLUSIONS: In obese and non-obese individuals with normal renal function, renal function estimates such as MDRD were identified as best predictors for tobramycin clearance, which may imply that other processes are involved in clearance of tobramycin versus gentamicin. To ensure similar exposure across body weights, we propose a MDRD-based dosing nomogram for obese patients
Dosing Recommendations for Vancomycin in Children and Adolescents with Varying Levels of Obesity and Renal Dysfunction: a Population Pharmacokinetic Study in 1892 Children Aged 1–18 Years
Vancomycin is an effective but potentially nephrotoxic antibiotic commonly used for severe infections. Dosing guidelines for vancomycin in obese children and adolescents with or without renal impairment are currently lacking. This study describes the pharmacokinetics of vancomycin in a large pediatric cohort with varying degrees of obesity and renal function to design practical dosing guidelines for this population. A multi-center retrospective population pharmacokinetic study was conducted using data from patients aged 1−18 years who received \u3e1 dose of vancomycin and had ≥1 vancomycin concentration measured between January 2006 and December 2012. Besides pharmacokinetic data, age, gender, body weight, creatinine clearance (CLcr, bedside Schwartz equation), ward, race, and neutropenic status were collected. Population pharmacokinetic analysis and simulations were performed using NONMEM7.4. A total of 1892 patients (5524 samples) were included, with total body weight (TBW) ranging 6−188 kg (1344 normal weight, 247 overweight, and 301 obese patients) and CLcr down to 8.6 mL/min/1.73 m2. The two-compartment model, with clearance (CL) significantly increasing with TBW and CLcr, central and peripheral volume of distribution and inter-compartmental clearance increasing with TBW, performed well for all age, weight, and renal function ranges. A dosing guideline is proposed that integrates body weight and CLcr resulting in effective and safe exposures across all ages, body weight, and renal functions in the pediatric population. We have characterized the full pharmacokinetic profile of vancomycin in obese children and adolescents aged 1−18 years and propose a practical dosing guideline that integrates both body weight and renal function
Photometric Light Curves and Polarization of Close-in Extrasolar Giant Planets
The close-in extrasolar giant planets [CEGPs], \ltorder 0.05 AU from their
parent stars, may have a large component of optically reflected light. We
present theoretical optical photometric light curves and polarization curves
for the CEGP systems, from reflected planetary light. Different particle sizes
of three condensates are considered. In the most reflective case, the
variability is micromagnitudes, which will be easily detectable
by the upcoming satellite missions MOST, COROT, and MONS, and possibly from the
ground in the near future. The least reflective case is caused by small, highly
absorbing grains such as solid Fe, with variation of much less than one
micromagnitude. Polarization for all cases is lower than current detectability
limits. We also discuss the temperature-pressure profiles and resulting
emergent spectra of the CEGP atmospheres. We discuss the observational results
of Tau Boo b by Cameron et al. (1999) and Charbonneau et al. (1999) in context
of our model results. The predictions - the shape and magnitude of the light
curves and polarization curves - are highly dependent on the size and type of
condensates present in the planetary atmosphere.Comment: 33 pages, accepted by Ap
Impact of bariatric surgery in the short and long term: a need for time-dependent dosing of drugs
Sparse information is available on pharmacokinetic changes of drugs over time after bariatric surgery. By reviewing the literature on the short- and long-term pharmacokinetic changes of drugs, several patterns were identified for 39 drugs. No relevant pharmacokinetic changes were identified for roughly a third of the drugs. Of the remaining drugs, levels were variable and partly unpredictable shortly after the surgery. In the long term, most of the drug levels remain altered, but in some cases they returned to preoperative values. Based on the changes and the efficacy-safety balance of each drug, clinicians may need to perform additional clinical monitoring for specific drugs, including measuring drug levels. This review provides suggestions for clinicians and pharmacists for specific time-dependent drug dosing advice.Pharmacolog
Chloroquine for SARS-CoV-2: implications of its unique pharmacokinetic and safety properties
Since in vitro studies and a preliminary clinical report suggested the efficacy of chloroquine for COVID-19-associated pneumonia, there is increasing interest in this old antimalarial drug. In this article, we discuss the pharmacokinetics and safety of chloroquine that should be considered in light of use in SARS-CoV-2 infections. Chloroquine is well absorbed and distributes extensively resulting in a large volume of distribution with an apparent and terminal half-life of 1.6 days and 2 weeks, respectively. Chloroquine is metabolized by cytochrome P450 and renal clearance is responsible for one third of total clearance. The lack of reliable information on target concentrations or doses for COVID-19 implies that for both adults and children, doses that proved effective and safe in malaria should be considered, such as 'loading doses' in adults (30 mg/kg over 48 h) and children (70 mg/kg over 5 days), which reported good tolerability. Here, plasma concentrations were < 2.5 mu mol/L, which is associated with (minor) toxicity. While the influence of renal dysfunction, critical illness, or obesity seems small, in critically ill patients, reduced absorption may be anticipated. Clinical experience has shown that chloroquine has a narrow safety margin, as three times the adult therapeutic dosage for malaria can be lethal when given as a single dose. Although infrequent, poisoning in children is extremely dangerous where one to two tablets can potentially be fatal. In conclusion, the pharmacokinetic and safety properties of chloroquine suggest that chloroquine can be used safely for an acute virus infection, under corrected QT monitoring, but also that the safety margin is small, particularly in children.Pharmacolog
Vancomycin clearance in obese adults is not predictive of clearance in obese adolescents
Contradictory pharmacokinetic (PK) results have been observed between obese adults and obese adolescents, with absolute clearance (CL) reported to be either unaltered, lower, or higher in obese adolescents compared to obese adults. This study investigates the PK of vancomycin in adolescents and adults who are overweight or obese. Data from 125 overweight and obese adolescents (aged 10-18 years, weight 28.3-188 kg) and 81 overweight and obese adults (aged 29-88 years, weight 66.7-143 kg) were analysed using population PK modelling. In addition to age, sex, renal function estimates, and regular weight descriptors, we evaluated standard weight (WTstandard, defined as weight for length, age, and sex in adolescents and weight for length in adults) and excess weight (WTexcess, defined as total body weight (TBW) minus WTstandard) as covariates in order to distinguish between weight resulting from length versus weight resulting from obesity. Analyzing adolescents and adults together, vancomycin CL was found to increase with TBW and decrease with increasing age (p standard in adolescents and adults, albeit with different functions, with adolescents having a higher CL per WTstandard than adults. Moreover, in this separate model, adolescent males had 21% higher CL than adolescent females of the same WTstandard, while in adults, CL decreased with increasing age (p Pharmacolog
Population pharmacokinetics of vancomycin in obesity: Finding the optimal dose for (morbidly) obese individuals
Aims: For vancomycin treatment in obese patients, there is no consensus on the optimal dose that will lead to the pharmacodynamic target (area under the curve 400–700 mg h L−1). This prospective study quantifies vancomycin pharmacokinetics in morbidly obese and nonobese individuals, in order to guide vancomycin dosing in the obese. Methods: Morbidly obese individuals (n = 20) undergoing bariatric surgery and nonobese healthy volunteers (n = 8; total body weight [TBW] 60.0–234.6 kg) received a single vancomycin dose (obese: 12.5 mg kg−1, maximum 2500 mg; nonobese: 1000 mg) with plasma concentrations measured over 48 h (11–13 samples per individual). Modelling, internal validation, external validation using previously published data and simulations (n = 10.000 individuals, TBW 60–230 kg) were performed using NONMEM. Results: In a 3-compartment model, peripheral volume of distribution and clearance increased with TBW (both p  90% target attainment (area under the curve > 400 mg h L−1) in individuals up to 200 kg, with corresponding trough concentrations of 5.7–14.6 mg L−1 (twice daily dosing). For continuous infusion, a loading dose of 1500 mg is required for s
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