A phase 1 randomized, open label, rectal safety, acceptability, pharmacokinetic, and pharmacodynamic study of three formulations of tenofovir 1% Gel (the CHARM-01 study)

Objectives: The CHARM-01 study characterized the safety, acceptability, pharmacokinetics (PK), and pharmacodynamics (PD) of three tenofovir (TFV) gels for rectal application. The vaginal formulation (VF) gel was previously used in the CAPRISA 004 and VOICE vaginal microbicide Phase 2B trials and the RMP-02/MTN-006 Phase 1 rectal safety study. The reduced glycerin VF (RGVF) gel was used in the MTN-007 Phase 1 rectal microbicide trial and is currently being evaluated in the MTN-017 Phase 2 rectal microbicide trial. A third rectal specific formulation (RF) gel was also evaluated in the CHARM-01 study. Methods: Participants received 4 mL of the three TFV gels in a blinded, crossover design: seven daily doses of RGVF, seven daily doses of RF, and six daily doses of placebo followed by one dose of VF, in a randomized sequence. Safety, acceptability, compartmental PK, and explant PD were monitored throughout the trial. Results: All three gels were found to be safe and acceptable. RF and RGVF PK were not significantly different. Median mucosal mononuclear cell (MMC) TFV-DP trended toward higher values for RF compared to RGVF (1136 and 320 fmol/106 cells respectively). Use of each gel in vivo was associated with significant inhibition of ex vivo colorectal tissue HIV infection. There was also a significant negative correlation between the tissue levels of TFV, tissue TFV-DP, MMC TFV-DP, rectal fluid TFV, and explant HIV-1 infection. Conclusions: All three formulations were found to be safe and acceptable. However, the safety profile of the VF gel was only based on exposure to one dose whereas participants received seven doses of the RGVF and RF gels. There was a trend towards higher tissue MMC levels of TFV-DP associated with use of the RF gel. Use of all gels was associated with significant inhibition of ex vivo tissue HIV infection. Trial Registration: ClinicalTrials.gov NCT01575405

Seasonal patterns of tuberculosis case notification in the tropics of Africa: A six-year trend analysis in Ethiopia.

OBJECTIVE:Seasonal variations affect the health system's functioning, including tuberculosis (TB) services, but there is little evidence about seasonal variations in TB case notification in tropical countries, including Ethiopia. This study sought to fill this gap in knowledge using TB data reported from 10 zones, 5 each from Amhara and Oromia regions. METHODS:Notified TB cases for 2010-2016 were analyzed using SPSS version 20. We calculated the quarterly and annual average TB case notification rates and the proportion of seasonal amplitudes. We applied Winters' multiplicative method of exponential smoothing to break down the original time series into seasonal, trend, and irregular components and to build a suitable model for forecasting. RESULTS:A total of 205,575 TB cases were identified (47.8% from Amhara, 52.2% from Oromia), with a male-to-female ratio of 1.2:1. The means of 8,200 (24%), 7,992 (23%), 8,849 (26%), and 9,222 (27%) TB cases were reported during July-September, October-December, January-March, and April-June, respectively. The seasonal component of our model indicated a peak in April-June and a trough in October-December. The seasonal amplitude in Amhara region is 10% greater than that of Oromia (p < 0.05). CONCLUSIONS:TB is shown to be a seasonal disease in Ethiopia, with a peak in quarter four and a low in quarter two of the fiscal year. The peak TB case notification rate corresponds with the end of the dry season in the two agrarian regions of Ethiopia. TB prevention and control interventions, such as efforts to increase community TB awareness about TB transmission and contact tracing, should consider seasonal variation. Regional variations in TB seasonality may require consideration of geographic-specific TB case-finding strategies. The mechanisms underlying the seasonal variation of TB are complex, and further study is needed

The yield of community-based tuberculosis and HIV among key populations in hotspot settings of Ethiopia: A cross-sectional implementation study.

OBJECTIVE:To determine the yield of tuberculosis (TB) and the prevalence of Human Immuno-deficiency virus (HIV) among key populations in the selected hotspot towns of Ethiopia. METHODS:We undertook a cross-sectional implementation research during August 2017-January 2018. Trained TB focal persons and health extension workers (HEWs) identified female sex workers (FSWs), health care workers (HCWs), prison inmates, homeless, internally displaced people (IDPs), internal migratory workers (IMWs) and residents in missionary charities as key and vulnerable popuaiton. They carried out health education on the importance of TB screening and HIV testing prior to recruitment of the study participants. Symptomatic TB screening and HIV testing was done. The yield of TB was computed per 100,000 background key population. RESULTS:A total of 1878 vulnerable people were screened, out of which 726 (38.7%) presumptive TB cases and 87 (4.6%) TB cases were identified. The yield of TB was 1519 (95% CI: 1218.1-1869.9). The highest proportion (19.5%) and yield of TB case (6,286 (95% CI: 3980.8-9362.3)) was among HCWs. The prevalence of HIV infection was 6%, 67 out of 1,111 tested. IMWs and FSWs represented 49.3% (33) and 28.4% (13) of the HIV infections, respectively. There was a statistically significant association of active TB cases with previous history of TB (Adjusted Odds Ratio (AOR): 11 95% CI, 4.06-29.81), HIV infection (AOR: 7.7 95% CI, 2.24-26.40), and being a HCW (AOR: 2.42 95% CI, 1.09-5.34). CONCLUSIONS:The prevalence of TB in key populations was nine times higher than 164/100,000 national estimated prevalence rate. The prevalence of HIV was five times higher than 1.15% of the national survey. The highest yield of TB was among the HCWs and the high HIV burden was detected among the FSWs and IMWs. These suggest a community and health facility based integrated and enhanced case finding approaches for TB and HIV in hotspot settings

Estimation of soil clay content from hygroscopic water content measurements

Soil texture and the soil water characteristic are key properties used to estimate flow and transport parameters. Determination of clay content is therefore critical for understanding of plot-scale soil heterogeneity. With increasing interest in proximal soil sensing, there is the need to relate obtained signals to soil properties of interest. Inference of soil texture, especially clay mineral content, from instrument response from electromagnetic induction and radiometric methods is of substantial interest. However, the cost of soil sampling and analysis required to link proximal measurements and soil properties, for example, clay mineral content, can sometimes outweigh the benefits of using a fast proximal technique. In this paper, we propose that determination of a soil's hygroscopic water content at 50% atmospheric relative humidity (RH50), which is time and cost efficient, and particularly suitable for developing countries, can act as a useful surrogate for clay content in interpreting soil spatial patterns based on proximal signals. We used standard clays such as kaolinite, illite, and montmorillonite to determine the water release characteristic as a function of hygroscopic water content. We also determined clay content of soils from temperate (Arizona, United States) and tropical (Trinidad) regions using the hydrometer method and hygroscopic water content for soils equilibrated at RH50. We found linear dependence of clay percentage and RH50 for a range of soil mineralogies. Hygroscopic water measurements offer an inexpensive and simple way to estimate site-specific clay mineral content that in turn can be used to interpret geophysical signal data in reconnaissance surveys

Beta-Lactamase Repressor BlaI Modulates Staphylococcus aureus Cathelicidin Antimicrobial Peptide Resistance and Virulence

BlaI is a repressor of BlaZ, the beta-lactamase responsible for penicillin resistance in Staphylococcus aureus. Through screening a transposon library in S. aureus Newman for susceptibility to cathelicidin antimicrobial peptide, we discovered BlaI as a novel cathelicidin resistance factor. Additionally, through integrational mutagenesis in S. aureus Newman and MRSA Sanger 252 strains, we confirmed the role of BlaI in resistance to human and murine cathelidicin and showed that it contributes to virulence in human whole blood and murine infection models. We further demonstrated that BlaI could be a target for innate immune-based antimicrobial therapies; by removing BlaI through subinhibitory concentrations of 6-aminopenicillanic acid, we were able to sensitize S. aureus to LL-37 killing