Pharmacogenetic variability and the probability of site of action target attainment during tuberculosis meningitis treatment: a physiologically based pharmacokinetic modeling and simulations study

Objective and methodsOur objective was to investigate the role of patient pharmacogenetic variability in determining site of action target attainment during tuberculous meningitis (TBM) treatment. Rifampin and isoniazid PBPK model that included SLCO1B1 and NAT2 effects on exposures respectively were obtained from literature, modified, and validated using available cerebrospinal-fluid (CSF) concentrations. Population simulations of isoniazid and rifampin concentrations in brain interstitial fluid and probability of target attainment according to genotypes and M. tuberculosis MIC levels, under standard and intensified dosing, were conducted.ResultsThe rifampin and isoniazid model predicted steady-state drug concentration within brain interstitial fluid matched with the observed CSF concentrations. At MIC level of 0.25 mg/L, 57% and 23% of the patients with wild type and heterozygous SLCO1B1 genotype respectively attained the target in CNS with rifampin standard dosing, improving to 98% and 91% respectively with 35 mg/kg dosing. At MIC level of 0.25 mg/L, 33% of fast acetylators attained the target in CNS with isoniazid standard dosing, improving to 90% with 7.5 mg/kg dosing.ConclusionIn this study, the combined effects of pharmacogenetic and M. tuberculosis MIC variability were potent determinants of target attainment in CNS. The potential for genotype-guided dosing during TBM treatment should be further explored in prospective clinical studies.Pharmacolog

Electrons in an annealed environment: A special case of the interacting electron problem

The problem of noninteracting electrons in the presence of annealed magnetic disorder, in addition to nonmagnetic quenched disorder, is considered. It is shown that the proper physical interpretation of this model is one of electrons interacting via a potential that is long-ranged in time, and that its technical analysis by means of renormalization group techniques must also be done in analogy to the interacting problem. As a result, and contrary to previous claims, the model does not simply describe a metal-insulator transition in $d=2+\epsilon$ ($\epsilon\ll 1$) dimensions. Rather, it describes a transition to a ferromagnetic state that, as a function of the disorder, precedes the metal-insulator transition close to $d=2$. In $d=3$, a transition from a paramagnetic metal to a paramagnetic insulator is possible.Comment: 13 pp., LaTeX, 2 eps figs; final version as publishe

International nosocomial infection control consortium (INICC) report, data summary of 36 countries, for 2004-2009

The results of a surveillance study conducted by the International Nosocomial Infection Control Consortium (INICC) from January 2004 through December 2009 in 422 intensive care units (ICUs) of 36 countries in Latin America, Asia, Africa, and Europe are reported. During the 6-year study period, using Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN; formerly the National Nosocomial Infection Surveillance system [NNIS]) definitions for device-associated health care-associated infections, we gathered prospective data from 313,008 patients hospitalized in the consortium's ICUs for an aggregate of 2,194,897 ICU bed-days. Despite the fact that the use of devices in the developing countries' ICUs was remarkably similar to that reported in US ICUs in the CDC's NHSN, rates of device-associated nosocomial infection were significantly higher in the ICUs of the INICC hospitals; the pooled rate of central line-associated bloodstream infection in the INICC ICUs of 6.8 per 1,000 central line-days was more than 3-fold higher than the 2.0 per 1,000 central line-days reported in comparable US ICUs. The overall rate of ventilator-associated pneumonia also was far higher (15.8 vs 3.3 per 1,000 ventilator-days), as was the rate of catheter-associated urinary tract infection (6.3 vs. 3.3 per 1,000 catheter-days). Notably, the frequencies of resistance of Pseudomonas aeruginosa isolates to imipenem (47.2% vs 23.0%), Klebsiella pneumoniae isolates to ceftazidime (76.3% vs 27.1%), Escherichia coli isolates to ceftazidime (66.7% vs 8.1%), Staphylococcus aureus isolates to methicillin (84.4% vs 56.8%), were also higher in the consortium's ICUs, and the crude unadjusted excess mortalities of device-related infections ranged from 7.3% (for catheter-associated urinary tract infection) to 15.2% (for ventilator-associated pneumonia). Copyright © 2012 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

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Not AvailableWe investigated the effect of dietary fish oil supplementation on the development of the ovarian follicles, corpus luteum (CL), conceptus and certain reproductive events in Marwari mares, since it is reported to improve reproduction in cows. Accordingly, non-lactating mares (n = 20) were randomly assigned into two groups (10 per group) and fed either the control diet (CTR) or a diet enriched with fish oil (FOS) to supplement n-3 polyunsaturated fatty acids (PUFA) at the rate of 64 mg/kg body weight/day for 70 days or until 45 days postovulation in the mares that became pregnant. Estrus was detected using a teaser and insemination was performed using frozen thawed semen in the experimental mares. Development of the ovarian follicle, CL and conceptus were recorded using trans-rectal ultrasonography. Plasma concentrations of progesterone and estradiol were estimated by radioimmunoassay. In the FOS group, the diameter of the largest follicle from day 4 of estrus until ovulation, and the diameter of the CL on day 7 post-ovulation (D7PO) were greater (P<0.05). However, on day 15 post-ovulation (D15PO), the CL diameter increased significantly in the pregnant mares. Dietary fish oil significantly improved the development of the embryo as evidenced by an increase in the diameter of the embryonic vesicle on day 15 post-ovulation (D15PO), and the embryo proper on day 28 post ovulation (D28PO). Further, the mean plasma estradiol concentration was higher on the day of estrus onset (P<0.05) and day 4 of estrus (P<0.01) in the FOS group. Similarly, dietary fish oil significantly increased the plasma progesterone on D15PO in the pregnant mares (P<0.01). Although the duration of estrus was shorter by 19 hours (P<0.05), the length of the estrous cycle did not vary in the FOS group. A non-significant increase in the pregnancy rate was observed in the mares that received fish oil. It was concluded that dietary fish oil supplementation improved ovarian function and embryonic development in the Marwari mares. © 2018, University of Zagreb, Facultty of Veterinary Medicine. All rights reservedNot Availabl

Carbon monoxide-induced reduction and healing of graphene oxide

Graphene oxide holds promise as a carbon-based nanomaterial that can be produced inexpensively in large quantities. However, its structural and electrical properties remain far from those of the graphene sheets obtained by mechanical exfoliation or by chemical vapor deposition unless efficient reduction methods that preserve the integrity of the parent carbon-network structure are found. Here, the authors use molecular dynamics and density functional theory calculations to show that the oxygen from the main functional groups present on graphene oxide sheets is removed by the reducing action of carbon monoxide; the energy barriers for reduction by CO are very small and easily overcome at low temperatures. Infrared and Raman spectroscopy experiments confirm the reduction in CO atmosphere and also reveal a strong tendency for CO to heal vacancies in the carbon network. Our results show that reduced graphene oxide with superior properties can be obtained through reduction in CO atmosphere

Dendritic and Axonal Architecture of Individual Pyramidal Neurons across Layers of Adult Human Neocortex.

The size and shape of dendrites and axons are strong determinants of neuronal information processing. Our knowledge on neuronal structure and function is primarily based on brains of laboratory animals. Whether it translates to human is not known since quantitative data on "full" human neuronal morphologies are lacking. Here, we obtained human brain tissue during resection surgery and reconstructed basal and apical dendrites and axons of individual neurons across all cortical layers in temporal cortex (Brodmann area 21). Importantly, morphologies did not correlate to etiology, disease severity, or disease duration. Next, we show that human L(ayer) 2 and L3 pyramidal neurons have 3-fold larger dendritic length and increased branch complexity with longer segments compared with temporal cortex neurons from macaque and mouse. Unsupervised cluster analysis classified 88% of human L2 and L3 neurons into human-specific clusters distinct from mouse and macaque neurons. Computational modeling of passive electrical properties to assess the functional impact of large dendrites indicates stronger signal attenuation of electrical inputs compared with mouse.We thus provide a quantitative analysis of "full" human neuron morphologies and present direct evidence that human neurons are not "scaled-up" versions of rodent or macaque neurons, but have unique structural and functional properties