Antiviral activity and pharmacokinetics of 1-(2,3-dideoxy-2-fluoro-beta-L-glyceropent-2-enofuranosyl)cytosine

1-(2,3-Dideoxy-2-fluoro-beta-L-glyceropent-2-enofuranosyl)cytosine (L-2'-Fd4C) is an L-nucleoside analogue with both anti-human immunodeficiency virus (HIV) and anti-hepatitis B virus (HBV) activity with median effective concentrations of 0.12 microM in peripheral blood mononuclear cells and 0.002 microM in HepG2-2.2.15 cells, respectively. The purpose of this study was to examine the antihepadnavirus potency and pharmacokinetics of L-2'-Fd4C in vivo. HBV-transgenic mice treated intraperitoneally with L-2'-Fd4C showed a reduction of HBV levels in their blood comparable to that produced by lamivudine. The pharmacokinetics of L-2'-Fd4C in rhesus monkeys was evaluated after intravenous and oral administration. The concentrations in plasma declined in a biexponential manner after intravenous administration, with a long terminal-phase half-life of 5.02 h. The steady-state volumes of distribution and systemic clearance were 1.09 liter x kg(-1) and 0.25 liter x h(-1) x kg(-1), respectively, with a renal clearance of 0.16 liter x h(-1) x kg(-1). The oral bioavailability was approximately 44%. About 53% of the compound administered intravenously and 19% of that administered orally were recovered unchanged in the urine within the 24-h urine collection period, and no other metabolite was detected. The compound penetrated the central nervous system at concentrations that exceeded the median effective antiviral concentration against HIV in cell cultures. Based upon these observations, further testing to develop this agent for treatment of HIV and HBV infections is warranted.     

Health Information Seeking and Cancer Screening Adherence Rates

Effective screening tools are available for many of the top cancer killers in the USA. Searching for health information has previously been found to be associated with adhering to cancer screening guidelines, but Internet information seeking has not been examined separately. The current study examines the relationship between health and cancer Internet information seeking and adherence to cancer screening guidelines for breast, cervical, and colorectal cancer in a large nationally representative dataset. The current study was conducted using data from the Health Information National Trends Survey from 2003 and 2007. The study examined age-stratified models which correlated health and cancer information seeking with getting breast, cervical, and colorectal cancer screening on schedule, while controlling for several key variables. Internet health and cancer information seeking was positively associated with getting Pap screening on schedule, while information seeking from any sources was positively associated with getting colorectal screening on schedule. People who look for health or cancer information are more likely to get screened on schedule. Some groups of people, however, do not exhibit this relationship and, thus, may be more vulnerable to under-screening. These groups may benefit more from targeted interventions that attempt to engage people in their health care more actively.     

An evaluation of constrained randomization for the design and analysis of group‐randomized trials

In group‐randomized trials, a frequent practical limitation to adopting rigorous research designs is that only a small number of groups may be available, and therefore, simple randomization cannot be relied upon to balance key group‐level prognostic factors across the comparison arms. Constrained randomization is an allocation technique proposed for ensuring balance and can be used together with a permutation test for randomization‐based inference. However, several statistical issues have not been thoroughly studied when constrained randomization is considered. Therefore, we used simulations to evaluate key issues including the following: the impact of the choice of the candidate set size and the balance metric used to guide randomization; the choice of adjusted versus unadjusted analysis; and the use of model‐based versus randomization‐based tests. We conducted a simulation study to compare the type I error and power of the F‐test and the permutation test in the presence of group‐level potential confounders. Our results indicate that the adjusted F‐test and the permutation test perform similarly and slightly better for constrained randomization relative to simple randomization in terms of power, and the candidate set size does not substantially affect their power. Under constrained randomization, however, the unadjusted F‐test is conservative, while the unadjusted permutation test carries the desired type I error rate as long as the candidate set size is not too small; the unadjusted permutation test is consistently more powerful than the unadjusted F‐test and gains power as candidate set size changes. Finally, we caution against the inappropriate specification of permutation distribution under constrained randomization. An ongoing group‐randomized trial is used as an illustrative example for the constrained randomization design. Copyright © 2015 John Wiley & Sons, Ltd.     

Electrochemical Production of Bismuth in the KCl–PbCl2 Melt

An anode dissolution of binary metallic lead–bismuth alloys with different concentrations of components has been studied in the KCl–PbCl₂ molten eutectic. The dissolution of lead is found to be a basic process for the alloys of Pb–Bi (59.3–40.7), Pb–Bi (32.5–67.5), Pb–Bi (7.0–93.0) compositions in the whole interval of studied anode current densities. A limiting diffusion current of lead dissolution was observed at 2 A/cm² and 0.1 A/cm² for the alloys of Pb–Bi (5.0–95.0) and Pb–Bi (3.0–97.0) compositions, respectively. The dissolution of bismuth takes place at the anode current densities exceeding the mentioned values. The number of electrons participating in the electrode reactions is detected for each mechanism. Based on the theoretical analysis, the experimental electrolysis of bismuth was performed in the laboratory-scale electrolytic cell with a porous ceramic diaphragm. The final product contained pure bismuth with a lead concentration of 3.5 wt.%.     

Retrospective diagnosis of lymphatic tuberculosis in frozen samples using two genetic amplification methods,Xpert® MTB/RIF ULTRA and Abbott RealTime MTB Assay

ObjectivesThe main objective of the present study is to assess the sensitivity and specificity of a retrospective diagnostic of lymphatic tuberculosis (LTB), testing frozen samples using gene amplification PCR methods. The secondary objective was to compare the results of two different commercial tuberculosis gene amplification methods for this purpose.Material and methodsWe retrospectively studied 38 frozen samples, previously processed for mycobacterial culture between January 2014 and August 2019. The results of the previous cultures were: 21 samples positive for Mycobacterium tuberculosis complex (MTB) (5 being smear positive), 7 samples culture positive for Mycobacterium avium-intracellulare complex and 10 samples which were mycobacterial culture negative and discarded for LTB diagnosis, used as controls. The samples were processed using two gene amplification methods: Xpert® MTB/RIF Ultra (Cepheid) and Abbott RealTime MTB Assay (Abbott).ResultsCompared to initial culture results the sensitivity and specificity of Xpert® MTB/RIF Ultra were 57.1% and 100% and 52.3 % and 92.5%, respectively for the Abbott RealTime MTB assay. The differences were not statistically significant. In addition, there were no differences according to the period of freezing.ConclusionsGene amplification of frozen samples confirmed the diagnosis of lymphatic TB in almost 60% of cases, allowing retrospective diagnosis in initially non suspected cases. Both gene amplification techniques tested were equally useful.     

Challenges in urine bioanalytical assays: overcoming nonspecific binding

Dr Allena Ji is the Director of Bioanalytical Services, XenoBiotic Laboratories, Inc., NJ, USA. She has worked in the bioanalytical field for many years and accumulated rich experience in LC-MS/MS method development, method validation and sample analysis under GLP compliance in large pharmaceutical company and contract laboratory settings. In the past 10 years, Allena worked at Pfizer (Legacy of Wyeth) and investigated many small-molecule drug candidates for their nonspecific binding in urine assays. Nonspecific binding of compounds results in a severe underestimation of the compounds' concentrations and poor precision and accuracy in urine bioanalytical assays. To overcome nonspecific binding in urine assays, Allena and her colleagues developed a series of practical approaches for urine method development. By adding an appropriate anti-adsorptive agent at its optimum concentration to the urine collection containers, the nonspecific binding can be blocked. Urine assays have much higher hurdles than plasma assays due to nonspecific binding and variability of urine pH, salt concentration, volume and solubility of drug(s) in urine. A simple and systematic approach for urine method development is emphasized in this paper. Nonspecific binding is a very serious issue in bioanalytical urine assays where a compound(s) adsorbs to the container wall. The adsorption happens frequently in urine assays because urine lacks proteins and lipids that can bind to the analytes or solubilize lipophilic analytes. Therefore, urine bioanalytical assays tend to suffer from analyte losses more often than plasma assays. In the past decade, there have been many methods described to overcome nonspecific adsorption in urine assays based on individual analyte characteristics. However, a common and simple method development approach for various analytes has not been discussed and summarized. In this article we demonstrate, discuss and summarize a common approach to urine method development with a focus on overcoming adsorption issues. The advantages and limitations of commonly used anti-adsorptive agents, such as bovine serum albumin, zwitterionic detergents such as CHAPS, sodium dodecyl benzene sulfonate, β-cyclodextrin, Tween 80 and Tween 20 are discussed.