MTN-001: Randomized Pharmacokinetic Cross-Over Study Comparing Tenofovir Vaginal Gel and Oral Tablets in Vaginal Tissue and Other Compartments

Background: Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development. Objective: MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design. Methods and Findings: We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03). Conclusions: Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir's antiviral effect substantially influence PrEP efficacy. Trial Registration: ClinicalTrials.gov NCT00592124

Biochar Enhances Plant Growth, Fruit Yield, and Antioxidant Content of Cherry Tomato (Solanum lycopersicum L.) in a Soilless Substrate

Biochar soil amendment can improve growing medium water and nutrient status and crop productivity. A pot experiment was conducted using Solanum lycopersicum var. cerasiforme plants to investigate the effects of biochar amendment (20% application rate) on a soilless substrate, as well as on plant growth, fruit yield, and quality. During the experiment, substrate characteristics, plant morphological traits, and root and leaf C/N content were analyzed at three sampling points defined as early stage (36 days after germination), vegetative stage (84 days a. g.), and fruit stage (140 days a. g.). Fruit morphological traits, titratable acidity, lycopene, and solid soluble content were measured at the end of the experiment. Biochar ameliorated substrate characteristics (Nav increase of 17% and Ctot increase of 13% at the beginning of the study), resulting in a promotion effect on plant root, shoot, and leaf morphology mainly at the vegetative and fruit stages. Indeed, at these two sampling points, the biochar-treated plants had a greater number of leaves (38 and 68 at the vegetative and fruit stages, respectively) than the untreated plants (32 and 49, respectively). The biochar also increased leaf area with a rise of 26% and 36% compared with the values measured in the untreated plants. Moreover, the amendment increased twofold root length, root surface area, and root, stem, and leaf biomasses in comparison with untreated plants. Regarding plant productivity, although fruit morphology remained unchanged, biochar increased flower and fruit numbers (six times and two times, respectively), acidity (75%), lycopene (28%), and solid soluble content (16%). By unveiling promoting changes in morphological traits, fruit number, and antioxidant content occurring in cherry tomato plants growing in a biochar-treated soilless substrate, it could be possible to highlight the importance of biochar for future applications in the field for enhancing plant production and fruit quality in a sustainable agriculture framework

Feasibility of Quantitative Diffusion-Weighted Imaging During Intra-Procedural MRI-Guided Brachytherapy of Locally Advanced Cervical and Vaginal Cancers

Purpose: To determine the feasibility of quantitative apparent diffusion coefficient (ADC) acquisition during magnetic resonance imaging-guided brachytherapy (MRgBT) using reduced field-of-view (rFOV) diffusion-weighted imaging (DWI). Methods and materials: T2-weighted (T2w) MR and full-FOV single-shot echo planar (ssEPI) DWI were acquired in 7 patients with cervical or vaginal malignancy at baseline and prior to brachytherapy, while rFOV-DWI was acquired during MRgBT following brachytherapy applicator placement. The gross target volume (GTV) was contoured on the T2w images and registered to the ADC map. Voxels at the GTV\u27s maximum Maurer distance comprised a central sub-volume (GTVcenter). Contour ADC mean and standard deviation were compared between timepoints using repeated measures ANOVA. Results: ssEPI-DWI mean ADC increased between baseline and prebrachytherapy from 1.03 ± 0.18 10-3 mm2/s to 1.34 ± 0.28 10-3 mm2/s for the GTV (p = 0.06) and from 0.84 ± 0.13 10-3 mm2/s to 1.26 ± 0.25 10-3 mm2/s at the level of the GTVcenter (p = 0.03), consistent with early treatment response. rFOV-DWI during MRgBT demonstrated mean ADC values of 1.28 ± 0.14 10-3 mm2/s and 1.28 ± 0.19 10-3 mm2/s for the GTV and GTVcenter, respectively (p = 0.02 and p = 0.03 relative to baseline). No significant differences were observed between ssEPI-DWI and rFOV-DWI ADC measurements. Conclusions: Quantitative ADC measurement in the setting of MRI guided brachytherapy implant placement for cervical and vaginal cancers is feasible using rFOV-DWI, with comparable mean ADC comparable to prebrachytherapy ssEPI-DWI, and may enable MRI-guided radiotherapy targeting of low ADC, radiation resistant sub-volumes of tumor