Digestion Coefficients with Sheep

This work in determining Digestion Coefficients with South Dakota grown forage plants and feeding stuffs was commenced in the Fall of 1905. Six grade Merino wethers were secured for this purpose. They were taken up and handled daily until they were perfectly accustomed to their attendant before the feeding trial were started they were kept in a box stall during each trial and were so tied that no one of them could reach the feed box of another. Harnesses were provided by means of which sacks were attached to each sheep to receive the faeces. [sic] The arrangement is shown by the cut on the title page. The sheep soon became accustomed to the harnesses and care was taken that they should be perfectly contented with their surroundings before the actual experiments commenced. In the case of hays and fodders the feed was run through a cutting machine reducing it to half inch lengths. Any refuse was carefully saved, weighed back and analyzed. Each feeding stuff was analyzed and the faeces were also analyzed. Careful moisture determinations were made on the feeding stuff as fed and on the faeces. From these data the digestion coefficients have been determined

Evidence for LineLike Vortex Liquid Phase in Tl2_2Ba2_2CaCu2_2O8_8 Probed by the Josephson Plasma Resonance

We measured the Josephson plasma resonance (JPR) in optimally doped Tl$_2$Ba$_2$CaCu$_2$O$_{8+\delta}$ thin films using terahertz time-domain spectroscopy in transmission. The temperature and magnetic field dependence of the JPR frequency shows that the c-axis correlations of pancake vortices remain intact at the transition from the vortex solid to the liquid phase. In this respect Tl$_2$Ba$_2$CaCu$_2$O$_{8+\delta}$ films, withanisotropy parameter $\gamma\approx 150$, are similar to the less anisotropic YBa$_2$Cu$_3$O$_{7-\delta}$ $(\gamma\approx 8)$ rather than to the most anisotropic Bi$_2$Sr$_2$CaCu$_2$O$_{8+\delta}$ single crystals $\gamma\geq 500$).Comment: Submitted to Physical Review Letter

Pregnancy related pharmacokinetics and antimicrobial prophylaxis during fetal surgery, cefazolin and clindamycin as examples

Antimicrobial prophylaxis during surgery aims to prevent post-operative site infections. For fetal surgery, this includes the fetal and amniotic compartments. Both are deep compartments as drug equilibrium with maternal blood is achieved relatively late. Despite prophylaxis, chorio-amnionitis or endometritis following ex utero intrapartum treatment or fetoscopy occur in 4.13% and 1.45% respectively of the interventions. This review summarizes the observations on two commonly administered antimicrobials (cefazolin, clindamycin) for surgical prophylaxis during pregnancy, with emphasis on the deep compartments. For both compounds, antimicrobial exposure is on target when we consider the maternal and fetal plasma compartment. In contrast, amniotic fluid concentrations-time profiles display a delayed and much more blunted pattern, behaving as deep compartment. For cefazolin, there are data that document further dilution in the setting of polyhydramnios. Along this deep compartment concept, there is some accumulation during repeated administration, modeled for cefazolin and observed for clindamycin. The relative underexposure to antimicrobials in amniotic fluid may be reflected in the pattern of maternal-fetal complications after fetal surgery, and suggest that antimicrobial prophylaxis practices for fetal surgery should be reconsidered. Further studies should be designed by a multidisciplinary team (fetal surgeons, clinical pharmacologists and microbiologists) to facilitate efficient evaluation of antimicrobial prophylaxis

Reduced contextually induced muscle thermogenesis in rats with calorie restriction and lower aerobic fitness but not monogenic obesity

We have previously identified predator odor as a potent stimulus activating thermogenesis in skeletal muscle in rats. As this may prove relevant for energy balance and weight loss, the current study investigated whether skeletal muscle thermogenesis was altered with negative energy balance, obesity propensity seen in association with low intrinsic aerobic fitness, and monogenic obesity. First, weight loss subsequent to three weeks of 50% calorie restriction suppressed the muscle thermogenic response to predator odor. Next, we compared rats bred based on artificial selection for intrinsic aerobic fitness—high- and low-capacity runners (HCR, LCR)—that display robust leanness and obesity propensity, respectively. Aerobically fit HCR showed enhanced predator odor-induced muscle thermogenesis relative to the less-fit LCR. This contrasted with the profound monogenic obesity displayed by rats homozygous for a loss of function mutation in Melanocortin 4 receptor (Mc4rK314X/K314X rats), which showed no discernable deficit in thermogenesis. Taken together, these data imply that body size or obesity per se are not associated with deficient muscle thermogenesis. Rather, the physiological phenotype associated with polygenic obesity propensity may encompass pleiotropic mechanisms in the thermogenic pathway. Adaptive thermogenesis associated with weight loss also likely alters muscle thermogenic mechanisms.</p

Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: a two-center prospective study (EXPAT)

Background: Early and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic dosing is not suitable in critically ill patients, since these patients undergo physiological alterations that strongly affect antibiotic exposure. For betalactam antibiotics, the unbound plasma concentrations above at least one to four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval (100%ƒT>1–4×MIC) have been proposed as pharmacodynamic targets (PDTs) to maximize bacteriological and clinical responses. The objectives of this study are to describe the PDT attainment in critically ill patients and to identify risk factors for target non-attainment. Methods: This prospective observational study was performed in two ICUs in the Netherlands. We enrolled adult patients treated with the following beta-lactam antibiotics: amoxicillin (with or without clavulanic acid), cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and meropenem. Based on five samples within a dosing interval at day 2 of therapy, the time unbound concentrations above the epidemiological cut-off (ƒT > MICECOFF and ƒT > 4×MICECOFF) were determined. Secondary endpoints were estimated multivariate binomial and binary logistic regression models, for examining the association of PDT attainment with patient characteristics and clinical outcomes. Results: A total of 147 patients were included, of whom 63.3% achieved PDT of 100%ƒT > MICECOFF and 36.7% achieved 100%ƒT > 4×MICECOFF. Regression analysis identified male gender, estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m2 , and high body mass index (BMI) as risk factors for target non-attainment. Use of continuous renal replacement therapy (CRRT) and high serum urea significantly increased the probability of target attainment. In addition, we found a significant association between the 100%ƒT > MICECOFF target attainment and ICU length of stay (LOS), but no significant correlation was found for the 30-day survival. Conclusions: Traditional beta-lactam dosing results in low target attainment in the majority of critically ill patients. Male gender, high BMI, and high eGFR were significant risk factors for target non-attainment. These predictors, together with therapeutic drug monitoring, may help ICU clinicians in optimizing beta-lactam dosing in critically ill patients

Application of time-dependent density functional theory to optical activity

As part of a general study of the time-dependent local density approximation (TDLDA), we here report calculations of optical activity of chiral molecules. The theory automatically satisfies sum rules and the Kramers-Kronig relation between circular dichroism and optical rotatory power. We find that the theory describes the measured circular dichroism of the lowest states in methyloxirane with an accuracy of about a factor of two. In the chiral fullerene C_76 the TDLDA provides a consistent description of the optical absorption spectrum, the circular dichroism spectrum, and the optical rotatory power, except for an overall shift of the theoretical spectrum.Comment: 17 pages and 13 PostScript figure

Entropy of near-extremal black holes in AdS_5

We construct the microstates of near-extremal black holes in AdS_5 x S^5 as gases of defects distributed in heavy BPS operators in the dual SU(N) Yang-Mills theory. These defects describe open strings on spherical D3-branes in the S^5, and we show that they dominate the entropy by directly enumerating them and comparing the results with a partition sum calculation. We display new decoupling limits in which the field theory of the lightest open strings on the D-branes becomes dual to a near-horizon region of the black hole geometry. In the single-charge black hole we find evidence for an infrared duality between SU(N) Yang-Mills theories that exchanges the rank of the gauge group with an R-charge. In the two-charge case (where pairs of branes intersect on a line), the decoupled geometry includes an AdS_3 factor with a two-dimensional CFT dual. The degeneracy in this CFT accounts for the black hole entropy. In the three-charge case (where triples of branes intersect at a point), the decoupled geometry contains an AdS_2 factor. Below a certain critical mass, the two-charge system displays solutions with naked timelike singularities even though they do not violate a BPS bound. We suggest a string theoretic resolution of these singularities.Comment: LaTeX; v2: references and a few additional comments adde

Dislocations and the critical endpoint of the melting line of vortex line lattices

We develop a theory for dislocation-mediated structural transitions in the vortex lattice which allows for a unified description of phase transitions between the three phases, the elastic vortex glass, the amorphous vortex glass, and the vortex liquid, in terms of a free energy functional for the dislocation density. The origin of a critical endpoint of the melting line at high magnetic fields, which has been recently observed experimentally, is explained.Comment: 4 pages, 1 figur

Population pharmacokinetics and target attainment of ciprofloxacin in critically ill patients

Purpose: To develop and validate a population pharmacokinetic model of ciprofloxacin intravenously in critically ill patients, and determine target attainment to provide guidance for more effective regimens. Methods: Non-linear mixed-effects modelling was used for the model development and covariate analysis. Target attainment of an ƒAUC0–24/MIC ≥ 100 for different MICs was calculated for standard dosing regimens. Monte Carlo simulations were performed to define the probability of target attainment (PTA) of several dosing regimens. Results: A total of 204 blood samples were collected from 42 ICU patients treated with ciprofloxacin 400–1200 mg/day, with median values for age of 66 years, APACHE II score of 22, BMI of 26 kg/m2, and eGFR of 58.5 mL/min/1.73 m2. The median ƒAUC0–24 and ƒCmax were 29.9 mg•h/L and 3.1 mg/L, respectively. Ciprofloxacin pharmacokinetics were best described by a two-compartment model. We did not find any significant covariate to add to the structural model. The proportion of patients achieving the target ƒAUC0–24/MIC ≥ 100 were 61.9% and 16.7% with MICs of 0.25 and 0.5 mg/L, respectively. Results of the PTA simulations suggest that a dose of ≥ 1200 mg/day is needed to achieve sufficient ƒAUC0–24/MIC ratios. Conclusions: The model described the pharmacokinetics of ciprofloxacin in ICU patients adequately. No significant covariates were found and high inter-individual variability of ciprofloxacin pharmacokinetics in ICU patients was observed. The poor target attainment supports the use of higher doses such as 1200 mg/day in critically ill patients, while the variability of inter-individual pharmacokinetics parameters emphasizes the need for therapeutic drug monitoring to ensure optimal exposure

The effect of therapeutic drug monitoring of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients: The DOLPHIN trial protocol of a multi-centre randomised controlled trial

Background: Critically ill patients undergo extensive physiological alterations that will have impact on antibiotic pharmacokinetics. Up to 60% of intensive care unit (ICU) patients meet the pharmacodynamic targets of beta-lactam antibiotics, with only 30% in fluoroquinolones. Not reaching these targets might increase the chance of therapeutic failure, resulting in increased mortality and morbidity, and antibiotic resistance. The DOLPHIN trial was designed to demonstrate the added value of therapeutic drug monitoring (TDM) of beta-lactam and fluoroquinolones in critically ill patients in the ICU. Methods: A multi-centre, randomised controlled trial (RCT) was designed to assess the efficacy and cost-effectiveness of model-based TDM of beta-lactam and fluoroquinolones. Four hundred fifty patients will be included within 24 months after start of inclusion. Eligible patients will be randomly allocated to either study group: the intervention group (active TDM) or the control group (non-TDM). In the intervention group dose adjustment of the study antibiotics (cefotaxime, ceftazidime, ceftriaxone, cefuroxime, amoxicillin, amoxicillin with clavulanic acid, flucloxacillin, piperacillin with tazobactam, meropenem, and ciprofloxacin) on day 1, 3, and 5 is performed based upon TDM with a Bayesian model. The primary outcome will be ICU length of stay. Other outcomes amongst all survival, disease severity, safety, quality of life after ICU discharge, and cost effectiveness will be included. Discussion: No trial has investigated the effect of early TDM of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients. The findings from the DOLPHIN trial will possibly lead to new insights in clinical management of critically ill patients receiving antibiotics. In short, to TDM or not to TDM? Trial registration: EudraCT number: 2017-004677-14. Sponsor protocol name: DOLPHIN. Registered 6 March 2018. Protocol Version 6, Protocol date: 27 November 2019