Early or deferred initiation of efavirenz during rifampicin‐based TB therapy has no significant effect on CYP3A induction in TB‐HIV infected patients

Background and Purpose: In TB‐HIV co‐infection, prompt initiation of TB therapy is recommended but anti‐retroviral treatment (ART) is often delayed due to potential drug–drug interactions between rifampicin and efavirenz. In a longitudinal cohort study, we evaluated the effects of efavirenz/rifampicin co‐treatment and time of ART initiation on CYP3A induction. / Experimental Approach: Treatment‐naïve TB‐HIV co‐infected patients (n = 102) were randomized to efavirenz‐based‐ART after 4 (n = 69) or 8 weeks (n = 33) of commencing rifampicin‐based anti‐TB therapy. HIV patients without TB (n = 94) receiving efavirenz‐based‐ART only were enrolled as control. Plasma 4β‐hydroxycholesterol/cholesterol (4β‐OHC/Chol) ratio, an endogenous biomarker for CYP3A activity, was determined at baseline, at 4 and 16 weeks of ART. / Key Results: In patients treated with efavirenz only, median 4β‐OHC/Chol ratios increased from baseline by 269% and 275% after 4 and 16 weeks of ART, respectively. In TB‐HIV patients, rifampicin only therapy for 4 and 8 weeks increased median 4β‐OHC/Chol ratios from baseline by 378% and 576% respectively. After efavirenz/rifampicin co‐treatment, 4β‐OHC/Chol ratios increased by 560% of baseline (4 weeks) and 456% of baseline (16 weeks). Neither time of ART initiation, sex, genotype nor efavirenz plasma concentration were significant predictors of 4β‐OHC/Chol ratios after 4 weeks of efavirenz/rifampicin co‐treatment. / Conclusion and Implications: Rifampicin induced CYP3A more potently than efavirenz, with maximum induction occurring within the first 4 weeks of rifampicin therapy. We provide pharmacological evidence that early (4 weeks) or deferred (8 weeks) ART initiation during anti‐TB therapy has no significant effect on CYP3A induction

Importance of Ethnicity, CYP2B6 and ABCB1 Genotype for Efavirenz Pharmacokinetics and Treatment Outcomes: A Parallel-group Prospective Cohort Study in two sub-Saharan Africa Populations.

We evaluated the importance of ethnicity and pharmacogenetic variations in determining efavirenz pharmacokinetics, auto-induction and immunological outcomes in two African populations. ART naïve HIV patients from Ethiopia (n = 285) and Tanzania (n = 209) were prospectively enrolled in parallel to start efavirenz based HAART. CD4+ cell counts were determined at baseline, 12, 24 and 48 weeks. Plasma and intracellular efavirenz and 8-hydroxyefvairenz concentrations were determined at week 4 and 16. Genotyping for common functional CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 variant alleles were done. Patient country, CYP2B6*6 and ABCB1 c.4036A>G (rs3842A>G) genotype were significant predictors of plasma and intracellular efavirenz concentration. CYP2B6*6 and ABCB1 c.4036A>G (rs3842) genotype were significantly associated with higher plasma efavirenz concentration and their allele frequencies were significantly higher in Tanzanians than Ethiopians. Tanzanians displayed significantly higher efavirenz plasma concentration at week 4 (p<0.0002) and week 16 (p = 0.006) compared to Ethiopians. Efavirenz plasma concentrations remained significantly higher in Tanzanians even after controlling for the effect of CYP2B6*6 and ABCB1 c.4036A>G genotype. Within country analyses indicated a significant decrease in the mean plasma efavirenz concentration by week 16 compared to week 4 in Tanzanians (p = 0.006), whereas no significant differences in plasma concentration over time was observed in Ethiopians (p = 0.84). Intracellular efavirenz concentration and patient country were significant predictors of CD4 gain during HAART. We report substantial differences in efavirenz pharmacokinetics, extent of auto-induction and immunologic recovery between Ethiopian and Tanzanian HIV patients, partly but not solely, due to pharmacogenetic variations. The observed inter-ethnic variations in efavirenz plasma exposure may possibly result in varying clinical treatment outcome or adverse event profiles between populations

Computer-assisted mammographic imaging

Computer-assisted mammography imaging comprises computer-based analysis of digitized images resulting in prompts aiding mammographic interpretation and computerized stereotactic localization devices which improve location accuracy. The commercial prompting systems available are designed to draw attention to mammographic abnormalities detected by algorithms based on symptomatic practise in North America. High sensitivity rates are important commercially but result in increased false prompt rates, which are known to distract radiologists. A national shortage of breast radiologists in the UK necessitates evaluation of such systems in a population breast screening programme to determine effectiveness in increasing cancer detection and feasibility of implementation

Conventional and microwave-assisted pyrolysis of biomass under different heating rates

Biomass was subjected to conventional and microwave pyrolysis, to determine the influence of each process on the yield and composition of the derived gas, oil and char products. The influence of pyrolysis temperature and heating rate for the conventional pyrolysis and the microwave power was investigated. Two major stages of gas release were observed during biomass pyrolysis, the first being CO/CO and the second one CH/H. This two-stage gas release was much more obvious for the conventional pyrolysis. While similar yield of liquid was obtained for both cases of conventional and microwave pyrolysis (∼46 wt.%), higher gas yield was produced for the conventional pyrolysis; it is suggested that microwave pyrolysis is much faster. When the heating rate was increased, the peak release of CO and CO was moved to higher reaction temperature for both conventional (500 °C) and microwave pyrolysis (200 °C). The production of CH and H were very low at a conventional pyrolysis temperature of 310 °C and microwave pyrolysis temperature of 200 °C (600 and 900 W). However, at higher heating rate of microwave pyrolysis, clear release of CH was observed. This work tentatively demonstrates possible connections and difference for biomass pyrolysis using two different heating resources (conventional and microwave heating)

Computer-aided detection system for clustered microcalcifications: comparison of performance on full-field digital mammograms and digitized screen-film mammograms

We have developed a computer-aided detection (CAD) system to detect clustered microcalcifications automatically on full-field digital mammograms (FFDMs) and a CAD system for screen-film mammograms (SFMs). The two systems used the same computer vision algorithms but their false positive (FP) classifiers were trained separately with sample images of each modality. In this study, we compared the performance of the CAD systems for detection of clustered microcalcifications on pairs of FFDM and SFM obtained from the same patient. For case-based performance evaluation, the FFDM CAD system achieved detection sensitivities of 70%, 80% and 90% at an average FP cluster rate of 0.07, 0.16 and 0.63 per image, compared with an average FP cluster rate of 0.15, 0.38 and 2.02 per image for the SFM CAD system. The difference was statistically significant with the alternative free-response receiver operating characteristic (AFROC) analysis. When evaluated on data sets negative for microcalcification clusters, the average FP cluster rates of the FFDM CAD system were 0.04, 0.11 and 0.33 per image at detection sensitivity level of 70%, 80% and 90% compared with an average FP cluster rate of 0.08, 0.14 and 0.50 per image for the SFM CAD system. When evaluated for malignant cases only, the difference of the performance of the two CAD systems was not statistically significant with AFROC analysis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58099/2/pmb7_4_008.pd

Expanding the chemical scope of RNA:methyltransferases to site-specific alkynylation of RNA for click labeling

This work identifies the combination of enzymatic transfer and click labeling as an efficient method for the site-specific tagging of RNA molecules for biophysical studies. A double-activated analog of the ubiquitous co-substrate S-adenosyl-l-methionine was employed to enzymatically transfer a five carbon chain containing a terminal alkynyl moiety onto RNA. The tRNA:methyltransferase Trm1 transferred the extended alkynyl moiety to its natural target, the N2 of guanosine 26 in tRNAPhe. LC/MS and LC/MS/MS techniques were used to detect and characterize the modified nucleoside as well as its cycloaddition product with a fluorescent azide. The latter resulted from a labeling reaction via Cu(I)-catalyzed azide-alkyne 1,3-cycloaddition click chemistry, producing site-specifically labeled RNA whose suitability for single molecule fluorescence experiments was verified in fluorescence correlation spectroscopy experiments

CO2 gasification of chars prepared from wood and forest residue

The CO2 gasification of chars prepared from Norway spruce and its forest residue was investigated in a thermogravimetric analyzer (TGA) at slow heating rates. The volatile content of the samples was negligible; hence the gasification reaction step could be studied alone, without the disturbance of the devolatilization reactions. Six TGA experiments were carried out for each sample with three different temperature programs in 60 and 100% CO2. Linear, modulated, and constant-reaction rate (CRR) temperature programs were employed to increase the information content available for the modeling. The temperatures at half of the mass loss were lower in the CRR experiments than in the other experiments by around 120 degrees C. A relatively simple, well-known reaction kinetic equation described the experiments. The dependence on the reacted fraction as well as the dependence on the CO2, concentration were described by power functions (n-order reactions). The evaluations were also carried out by assuming a function of the reacted fraction that can mimic the various random pore/random capillary models. These attempts, however, did not result in an improved fit quality. Nearly identical activation energy values were obtained for the chars made from wood and forest residues (221 and 218 kJ/mol, respectively). Nevertheless, the forest residue char was more reactive; the temperatures at half of the mass loss showed 20-34 degrees C differences between the two chars at 10 degrees C/min heating rates. The assumption of a common activation energy, E, and a common reaction order, v, on the CO2, concentration for the two chars had only a negligible effect on the fit quality

Using computer-aided detection in mammography as a decision support

Contains fulltext : 87548.pdf (publisher's version ) (Closed access)OBJECTIVE: To evaluate an interactive computer-aided detection (CAD) system for reading mammograms to improve decision making. METHODS: A dedicated mammographic workstation has been developed in which readers can probe image locations for the presence of CAD information. If present, CAD findings are displayed with the computed malignancy rating. A reader study was conducted in which four screening radiologists and five non-radiologists participated to study the effect of this system on detection performance. The participants read 120 cases of which 40 cases had a malignant mass that was missed at the original screening. The readers read each mammogram both with and without CAD in separate sessions. Each reader reported localized findings and assigned a malignancy score per finding. Mean sensitivity was computed in an interval of false-positive fractions less than 10%. RESULTS: Mean sensitivity was 25.1% in the sessions without CAD and 34.8% in the CAD-assisted sessions. The increase in detection performance was significant (p = 0.012). Average reading time was 84.7 +/- 61.5 s/case in the unaided sessions and was not significantly higher when interactive CAD was used (85.9 +/- 57.8 s/case). CONCLUSION: Interactive use of CAD in mammography may be more effective than traditional CAD for improving mass detection without affecting reading time.1 oktober 201