Pioneer Venus polarimetry and haze optical thickness

The Pioneer Venus mission provided us with high-resolution measurements at four wavelengths of the linear polarization of sunlight reflected by the Venus atmosphere. These measurements span the complete phase angle range and cover a period of more than a decade. A first analysis of these data by Kawabata et al. confirmed earlier suggestions of a haze layer above and partially mixed with the cloud layer. They found that the haze exhibits large spatial and temporal variations. The haze optical thickness at a wavelength of 365 nm was about 0.06 at low latitudes, but approximately 0.8 at latitudes from 55 deg poleward. Differences between morning and evening terminator have also been reported by the same authors. Using an existing cloud/haze model of Venus, we study the relationship between the haze optical thickness and the degree of linear polarization. Variations over the visible disk and phase angle dependence are investigated. For that purpose, exact multiple scattering computations are compared with Pioneer Venus measurements. To get an impression of the variations over the visible disk, we have first studied scans of the polarization parallel to the intensity equator. After investigating a small subset of the available data we have the following results. Adopting the haze particle characteristics given by Kawabata et al., we find a thickening of the haze at increasing latitudes. Further, we see a difference in haze optical thickness between the northern and southern hemispheres that is of the same order of magnitude as the longitudinal variation of haze thickness along a scan line. These effects are most pronounced at a wavelength of 935 nm. We must emphasize the tentative nature of the results, because there is still an enormous amount of data to be analyzed. We intend to combine further polarimetric research of Venus with constraints on the haze parameters imposed by physical and chemical processes in the atmosphere

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 $\approx 100$ 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

Novel model-based dosing guidelines for gentamicin and tobramycin in preterm and term neonates

Objectives In the heterogeneous group of preterm and term neonates, gentamicin and tobramycin are mainly dosed according to empirical guidelines, after which therapeutic drug monitoring and subsequent dose adaptation are applied. In view of the variety of neonatal guidelines available, the purpose of this study was to evaluate target concentration attainment of these guidelines, and to propose a new model-based dosing guideline for these drugs in neonates. Methods Demographic characteristics of 1854 neonates (birth weight 390-5200 g, post-natal age 0-27 days) were extracted from earlier studies and sampled to obtain a test dataset of 5000 virtual patients. Monte Carlo simulations on the basis of validated models were undertaken to evaluate the attainment of target peak (5-12 mg/L) and trough (<0.5 mg/L) concentrations, and cumulative AUC, with the existing and proposed guidelines. Results Across the entire neonatal age and weight range, the Dutch National Formulary for Children, the British National Formulary for Children, Neofax and the Red Book resulted in adequate peak but elevated trough concentrations (63%-90% above target). The proposed dosing guideline (4.5 mg/kg gentamicin or 5.5 mg/kg tobramycin) with a dosing interval based on birth weight and post-natal age leads to adequate peak concentrations with only 33%-38% of the trough concentrations above target, and a constant AUC across weight and post-natal age. Conclusions The proposed neonatal dosing guideline for gentamicin and tobramycin results in improved attainment of target concentrations and should be prospectively evaluated in clinical studies to evaluate the efficacy and safety of this treatmen

Daily interruption of sedation in critically ill children:study protocol for a randomized controlled trial

BACKGROUND: In adult patients who are critically ill and mechanically ventilated, daily interruption of sedation (DSI) is an effective method of improving sedation management, resulting in a decrease of the duration of mechanical ventilation, the length of stay in the intensive care unit (ICU) and the length of stay in the hospital. It is a safe and effective approach and is common practice in adult ICUs. For critically ill children it is unknown if DSI is effective and feasible. The aim of this multicenter randomized controlled trial is to evaluate the safety and efficacy of daily sedation interruption in critically ill children. METHODS/DESIGN: Children between 0 and 18 years of age who require mechanical ventilation, with an expected duration of at least 48 h and need for sedative infusion, will be included. After enrollment patients will be randomly assigned to DSI in combination with protocolized sedation (intervention group) or protocolized continuous sedation (control group). A sedation protocol that contains an algorithm for increasing and weaning of sedatives and analgesics will be used. The sedative infusion will be restarted if the patient becomes uncomfortable or agitated according to the sedation protocol. The primary endpoint is the number of ventilator-free days at 28 days. TRIAL REGISTRATION: NTR203

Psychostimulants: Influence on Body Mass Index and Height in a Pediatric Population with Attention-Deficit/Hyperactivity Disorder?

OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is often treated with psychostimulants. Psychostimulants' adverse effects on body mass index standard deviation score (BMI-sds) and height in children/adolescents with ADHD have been reported. However, literature is inconsistent, and it is unclear whether the observed effects are dosage- and/or BMI-dependent. Therefore, the aim of this retrospective observational study is to evaluate the influence of psychostimulants on BMI-sds and height-sds in a pediatric cohort with ADHD from an outpatient clinic, and to study the correlation between psychostimulant dosage and BMI-sds and height-sds change. METHOD: Participants ≤18 years of age diagnosed with ADHD who started with psychostimulants (methylphenidate) were studied. Changes in BMI-sds and height-sds over an 18-month treatment period were assessed in subgroups according to baseline BMI-sds, gender, and age. Furthermore, correlations between BMI-sds, height-sds, and psychostimulant dose were studied. RESULTS: In total, 298 participants [median age 9.8 years, height-sds 0.0, BMI-sds 0.5, psychostimulant dosage 0.5 (0.2-1.4) mg/kg/day] were analyzed, with an underweight, overweight, and obesity prevalence of 5%, 21%, and 7%, respectively. After 18 months of treatment a significant decline in BMI-sds (-0.4) and height-sds (-0.2) was observed. These effects were consistent in all subgroups except for no change in BMI-sds in the underweight subgroup and no change in height-sds in the overweight subgroup. Medication dosage was weakly correlated with change in BMI-sds [r = -0.3 (-0.9 to +0.5); p < 0.01] and height-sds [r = -0.2 (-0.4 to -0.1); p = 0.01]. CONCLUSION: After 18 months of psychostimulant treatment, a significant decline in BMI-sds and height-sds was observed. However, the correlation with psychostimulant dosage was weak, and the decline was not observed in all subgroups. Therefore, further studies on the etiology of BMI-change are warranted, particularly with regard to the ADHD symptoms

Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen

Introduction: Acetaminophen (paracetamol) is mainly metabolized via glucuronidation and sulphation, while the minor pathway through cytochrome P450 (CYP) 2E1 is held responsible for hepatotoxicity. In obese patients, CYP2E1 activity is reported to be induced, thereby potentially worsening the safety profile of acetaminophen. The aim of this study was to determine the pharmacokinetics of acetaminophen and its metabolites (glucuronide, sulphate, cysteine and mercapturate) in morbidly obese and non-obese patients. Methods: Twenty morbidly obese patients (with a median total body weight [TBW] of 140.1 kg [range 106–193.1 kg] and body mass index [BMI] of 45.1 kg/m2 [40–55.2 kg/m2]) and eight non-obese patients (with a TBW of 69.4 kg [53.4–91.7] and BMI of 21.8 kg/m2 [19.4–27.4]) received 2 g of intravenous acetaminophen. Fifteen blood samples were collected per patient. Population pharmacokinetic modelling was performed using NONMEM. Results: In morbidly obese patients, the median area under the plasma concentration–time curve from 0 to 8 h (AUC0–8h) of acetaminophen was significantly smaller (P = 0.009), while the AUC0–8h ratios of the glucuronide, sulphate and cysteine metabolites to acetaminophen were significantly higher (P = 0.043, 0.004 and 0.010, respectively). In the model, acetaminophen CYP2E1-mediated clearance (cysteine and mercapturate) increased with lean body weight [LBW] (population mean [relative standard error] 0.0185 L/min [15 %], P < 0.01). Moreover, accelerated formation of the cysteine and mercapturate metabolites was found with increasing LBW (P < 0.001). Glucuronidation clearance (0.219 L/min [5 %]) and sulphation clearance (0.0646 L/min [6 %]) also increased with LBW (P < 0.001). Conclusion: Obesity leads to lower acetaminophen concentrations and earlier and higher peak concentrations of acetaminophen cysteine and mercapturate. While a higher dose may be anticipated to achieve adequate acetaminophen concentrations, the increased CYP2E1-mediated pathway may preclude this dose adjustment

The role of population PK-PD modelling in paediatric clinical research

Children differ from adults in their response to drugs. While this may be the result of changes in dose exposure (pharmacokinetics [PK]) and/or exposure response (pharmacodynamics [PD]) relationships, the magnitude of these changes may not be solely reflected by differences in body weight. As a consequence, dosing recommendations empirically derived from adults dosing regimens using linear extrapolations based on body weight, can result in therapeutic failure, occurrence of adverse effect or even fatalities. In order to define rational, patient-tailored dosing schemes, population PK-PD studies in children are needed. For the analysis of the data, population modelling using non-linear mixed effect modelling is the preferred tool since this approach allows for the analysis of sparse and unbalanced datasets. Additionally, it permits the exploration of the influence of different covariates such as body weight and age to explain the variability in drug response. Finally, using this approach, these PK-PD studies can be designed in the most efficient manner in order to obtain the maximum information on the PK-PD parameters with the highest precision. Once a population PK-PD model is developed, internal and external validations should be performed. If the model performs well in these validation procedures, model simulations can be used to define a dosing regimen, which in turn needs to be tested and challenged in a prospective clinical trial. This methodology will improve the efficacy/safety balance of dosing guidelines, which will be of benefit to the individual child