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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. 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. 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). 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. ClinicalTrials.gov NCT00592124.

Background Long-term tenofovir disoproxil fumarate (TDF) treatment for chronic hepatitis B (CHB) is associated with sustained viral suppression and regression of fibrosis and cirrhosis at year 5 (240 weeks) and no TDF resistance through 6 years (288 weeks). Aim We assessed the efficacy, safety, and resistance of TDF for up to 7 years (336 weeks) in HBeAg-positive and HBeAg-negative CHB patients. Methods Patients who completed 1 year (48 weeks) of randomized treatment with TDF or adefovir dipivoxil were eligible to receive open-label TDF for a total duration of 8 years (384 weeks). Results Of 641 patients initially randomized, 585 (91.3 %) entered the open-label phase; 437/585 (74.7 %) remained on study at year 7. For patients on treatment at year 7, 99.3 % maintained viral suppression (HBV DNA < 69 IU/mL), 80.0 % achieved serum alanine aminotransferase normalization, and in HBeAg-positive patients, 84/154 (54.5 %) and 25/154 (11.8 %) achieved HBeAg and HBsAg loss, respectively. One/375 (0.3 %) HBeAg-negative patients achieved HBsAg loss. No resistance to TDF was detected through 7 years. During the open-label phase, grade 3/4 drug-related adverse events were uncommon (1.0 %); ten (1.7 %) patients had elevation of serum creatinine ≥0.5 mg/dL above baseline. No significant change in bone mineral density was observed from year 4 to year 7 (week 192 to week 336). Conclusions Long-term TDF treatment was associated with sustained virologic, biochemical, and serologic responses, without resistance. TDF treatment was well tolerated, with a low incidence of renal and bone events. These data confirm the safety and efficacy of long-term TDF for CHB.

Treatment of HIV-1 infection in sub-Saharan Africa has many challenges. In this report, the safety and efficacy of three different regimens are assessed in HIV-1–infected persons in South Africa: tenofovir alafenamide fumarate (TAF)–emtricitabine (FTC)–dolutegravir (DTG), tenofovir disoproxil fumarate (TDF)–FTC–DTG, and the local standard-of-care regimen (TDF–FTC–efavirenz).

Although natural products have been a particularly rich source of human medicines, activity-based screening results in a very high rate of rediscovery of known molecules. Based on the large number of natural product biosynthetic genes in microbial genomes, many have proposed “genome mining” as an alternative approach for discovery efforts; however, this idea has yet to be performed experimentally on a large scale. Here, we demonstrate the feasibility of large-scale, high-throughput genome mining by screening a collection of over 10,000 actinomycetes for the genetic potential to make phosphonic acids, a class of natural products with diverse and useful bioactivities. Genome sequencing identified a diverse collection of phosphonate biosynthetic gene clusters within 278 strains. These clusters were classified into 64 distinct groups, of which 55 are likely to direct the synthesis of unknown compounds. Characterization of strains within five of these groups resulted in the discovery of a new archetypical pathway for phosphonate biosynthesis, the first (to our knowledge) dedicated pathway for H-phosphinates, and 11 previously undescribed phosphonic acid natural products. Among these compounds are argolaphos, a broad-spectrum antibacterial phosphonopeptide composed of aminomethylphosphonate in peptide linkage to a rare amino acid N5-hydroxyarginine; valinophos, an N-acetyl L-Val ester of 2,3-dihydroxypropylphosphonate; and phosphonocystoximate, an unusual thiohydroximate-containing molecule representing a new chemotype of sulfur-containing phosphonate natural products. Analysis of the genome sequences from the remaining strains suggests that the majority of the phosphonate biosynthetic repertoire of Actinobacteria has been captured at the gene level. This dereplicated strain collection now provides a reservoir of numerous, as yet undiscovered, phosphonate natural products.

For maximum effect pre-exposure prophylaxis should be targeted to the subpopulations that account for the largest proportion of infections (population-attributable fraction [PAF]) and for whom the number needed to treat (NNT) to prevent infection is lowest. We aimed to estimate the PAF and NNT of participants in the iPrEx (Pre-Exposure Prophylaxis Initiative) trial. The iPrEx study was a randomised controlled efficacy trial of pre-exposure prophylaxis with coformulated tenofovir disoproxil fumarate and emtricitabine in 2499 men who have sex with men (MSM) and transgender women. Participants aged 18 years or older who were male at birth were enrolled from 11 trial sites in Brazil, Ecuador, Peru, South Africa, Thailand, and the USA. Participants were randomly assigned (1:1) to receive either a pill with active pre-exposure prophylaxis or placebo, taken daily. We calculated the association between demographic and risk behaviour during screening and subsequent seroconversion among placebo recipients using a Poisson model, and we calculated the PAF and NNT for risk behaviour subgroups. The iPrEx trial is registered with ClinicalTrials.gov, NCT00458393. Patients were enrolled between July 10, 2007, and Dec 17, 2009, and were followed up until Nov 21, 2010. Of the 2499 MSM and transgender women in the iPrEx trial, 1251 were assigned to pre-exposure prophylaxis and 1248 to placebo. 83 of 1248 patients in the placebo group became infected with HIV during follow-up. Participants reporting receptive anal intercourse without a condom seroconverted significantly more often than those reporting no anal sex without a condom (adjusted hazard ratio [AHR] 5·11, 95% CI 1·55–16·79). The overall PAF for MSM and transgender women reporting receptive anal intercourse without a condom was 64% (prevalence 60%). Most of this risk came from receptive anal intercourse without a condom with partners with unknown serostatus (PAF 53%, prevalence 54%, AHR 4·76, 95% CI 1·44–15·71); by contrast, the PAF for receptive anal intercourse without a condom with an HIV-positive partner was 1% (prevalence 1%, AHR 7·11, 95% CI 0·70–72·75). The overall NNT per year for the cohort was 62 (95% CI 44–147). NNTs were lowest for MSM and transgender women self-reporting receptive anal intercourse without a condom (NNT 36), cocaine use (12), or a sexually transmitted infection (41). Having one partner and insertive anal sex without a condom had the highest NNTs (100 and 77, respectively). Pre-exposure prophylaxis may be most effective at a population level if targeted toward MSM and transgender women who report receptive anal intercourse without a condom, even if they perceive their partners to be HIV negative. Substance use history and testing for STIs should also inform individual decisions to start pre-exposure prophylaxis. Consideration of the PAF and NNT can aid in discussion of the benefits and risks of pre-exposure prophylaxis with MSM and transgender women. National Institute of Allergy and Infectious Diseases and the Bill & Melinda Gates Foundation.

This review discusses the history, fundamentals, and applications of different fuel cell technologies, including proton exchange membrane fuel cells (PEMFCs), direct methanol fuel cells, solid oxide fuel cells (SOFCs), phosphoric acid fuel cells (PAFCs), alkaline fuel cells (AFCs), and molten carbonate fuel cells (MCFCs). Recent advances in fuel cell technologies have led to potential applications in aerospace, transportation, and portable and stationary power generation due to high efficiency and low emissions. Fuel cell types are also compared based on efficiency, operating temperature, lifetime, energy/power density, and cost. It was noticed that PEMFCs have the highest mass power density, reaching 1,000 W/kg compared to less than 100 W/kg for SOFCs, which makes them suitable for portable applications such as aircraft. PEMFCs and AFCs are suitable for low‐temperature applications and are highly efficient. SOFCs and MCFCs are better for high‐temperature operations. SOFCs are robust and suitable for high‐power demands, while MCFCs are advantageous for high‐power output. Hydrogen fuel cells promise to decarbonize transportation and aviation sectors with the advantages of lower weight, compactness, and quick startup times. However, challenges remain around renewable hydrogen production/infrastructure and aircraft integration, besides hydrogen storage, water management inside fuel cells, and operational robustness under varying pressures. Generally, for all fuel cell types, more focus should be given to enhancing the stability and efficiency of fuel cell materials and reducing their cost.

A new generation of a green polymeric matrix, chitosan/alginate-polyethyleniminemethylene phosphonic acid (CHIT/ALG-PEIMPA) was examined in comparative study of adsorption and preconcentration of non-steroidal anti-inflammatory drugs (NSAIDs), diclofenac and ibuprofen. The influences of experimental parameters like pH, time reaction, initial concentration, ionic strength were investigated. The scanning electron microscopy (SEM) images showed heterogeneous morphology with different particle sizes of agglomerates from few micrometers to a hundred micrometers and irregular particles shape, before pharmaceuticals products adsorption. However, after adsorption, SEM micrograph reveals a smooth surface structure of agglomerate, and even in this smaller magnification, it was possible to observe the formation of homogenous and regular surface of CHIT/ALG-PEIMPA. Elementary analysis (EDX) reveals that the phosphonic acid (PEIMPA) was successfully cross-linked onto chitosan/alginate. The maximal adsorption capacity was found to be 222 mg.g −1 , and 122 mg.g −1 under optimum conditions for diclofenac and ibuprofen respectively. The kinetic modeling followed the pseudo-second-order rate expression for both pharmaceutical drugs. Thermodynamics data leads to an exothermic and spontaneous adsorption processes (∆ H = −34.32 KJ mol −1 ; ∆ H =−21.59 KJ mol −1 ), respectively for diclofenac and ibuprofen.

Background: The invention of efficient systems for lignocellulose conversion is essential for economically feasible production of bio-based chemicals and biofuels. One limiting step is highly selective processes to quickly decrystallize the compact cellulose structure for efficient hydrolysis. We evaluated the impact of trifluoroacetic acid (TFA) and phosphorous acid (PA)-induced swelling of crystalline cellulose on enhancement of enzymatic digestion.Results: In this study, two swelling agents, TFA and PA, are compared and found to be highly efficient for cellulose decrystallization at low temperatures within 1 h. After treatment, the microfibril structure of swollen celluloses was observed to develop distinct microscopic morphology and subsequent enzymatic hydrolysis resulted over 90% cellulose conversion within 24 h. The crystalline cellulose change was determined by reduction of loss of X-ray diffractability, and loss of resistance to enzymatic hydrolysis. NMR results suggest that both TFA and PA efficiently converted most of the crystalline cellulose regions to amorphous regions through cellulose chain relocation that inhibits recrystallization. It was found that the swelling mechanism is different between TFA and PA. To the best of our knowledge, it is the first time to compare and quantify the cellulose regions transformation by swelling agents.Conclusion: This study shows the low-temperature swelling of different celluloses in TFA and PA reduces recalcitrance of crystalline cellulose to enzymatic hydrolysis. TFA and PA are both ideal candidate swelling agents for a closed system for ease of solvent recovery by either simple distillation or filtration. This study provides potentially useful agents in large-scale deconstruction of biomass.

Due to their structural similarity with natural α-amino acids, α-aminophosphonic acid derivatives are known biologically active molecules. In view of the relevance of tetrasubstituted carbons in nature and medicine and the strong dependence of the biological activity of chiral molecules into their absolute configuration, the synthesis of α-aminophosphonates bearing tetrasubstituted carbons in an asymmetric fashion has grown in interest in the past few decades. In the following lines, the existing literatures for the synthesis of optically active tetrasubstituted α-aminophosphonates are summarized, comprising diastereoselective and enantioselective approaches.

Selective and rapid determination of procedure for Cd 2+ and Pb 2+ samples using MWCNT surfaces can be modified by loading ligands such as D2EHPA and Cyanex 272 which is described. The adsorbent was modified with D2EHPA and Cyanex 272. Effect of pH, amount of adsorbent, contact time for adsorption, and the optimum eluent for the quantitative recovery of Cd 2+ and Pb 2+ were investigated and the subsequent determination by FAAS. The adsorption was found to be mainly due to the chemical interactions between the metal ions and functional groups –COO − and –OH which were characterized by FT-IR. The adsorption of metal occurs at pH 4.5 with 500 mg of MWCNTs. The enrichment factor was 40 and 30. The detection limit was 0.03 and 0.05 μg L −1 . The quantitative recovery of metal ion used 1 mol L −1 HNO 3 . The thermodynamic parameter of Langmuir and Freundlich adsorption isotherm revealed that the adsorption of free energy (Δ G ) was spontaneous and the monolayer adsorption of Cd 2+ and Pb 2+ was mainly on the surfaces. The adsorbent performance of R 2 in the range of 0.93–0.99 and also the identified adsorption efficiency of Cd 2+ and Pb 2+ are linear or non-linear curves respectively. The proposed method was applied to heavy metals from environmental samples. Graphical Abstract