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Inconsistencies have been reported on the effect of sex on aldosterone (ALDO) levels leading to clinical confusion. The reasons for these inconsistencies are uncertain but include estrogen and/or its receptor modulating target gene responses to mineralocorticoid receptor activation and ALDO secretagogues’ levels. This study’s goal was to determine whether ALDO’s biosynthesis also differed by sex. Two approaches were used. First, plasma renin activity and aldosterone were measured in rats. Both were significantly higher in males. Secondly, using rat zona glomerulosa (ZG) cells, we assessed three ex vivo areas: (1) activity/levels of early steps in ALDO’s biosynthesis (StAR and CYP11A1); (2) activity/levels of a late step (CYP11B2); and (3) the status of the mineralocorticoid receptor (MR)-mediated, ultrashort feedback loop. Females had higher expression of CYP11A1 and StAR and increased CYP11A1 activity (increased pregnenolone/corticosterone levels) but did not differ in CYP11B2 expression or activity (ALDO levels). Activating the ZG’s MR (thereby activating the ultrashort feedback loop) reduced CYP11B2’s activity similarly in both sexes. Exvivo, these molecular effects were accompanied, in females, by lower ALDO basally but higher ALDO with angiotensin II stimulation. In conclusion, we documented that not only was there a sex-mediated difference in the activity of ALDO’s biosynthesis but also these differences at the molecular level help explain the variable reports on ALDO’s circulating levels. Basally, both in vivo and ex vivo, males had higher ALDO levels, likely secondary to higher ALDO secretagogue levels. However, in response to acute stimulation, ALDO levels are higher in females because of the greater levels and/or activity of their StAR/CYP11A1.

Multidrug resistance (MDR) is one of the major factors in the failure of many chemotherapy approaches. In cancer cells, MDR is mainly associated with the expression of ABC transporters such as P‐glycoprotein, MRP1 and ABCG2. Despite major efforts to develop new selective and potent inhibitors of ABC drug transporters, no ABCG2‐specific inhibitors for clinical use are yet available. Here, we report the evaluation of sixteen tetrahydroquinoline/4,5‐dihydroisoxazole derivatives as a new class of ABCG2 inhibitors. The affinity of the five best inhibitors was further investigated by the vanadate‐sensitive ATPase assay. Molecular modelling data, proposing a potential binding mode, suggest that they can inhibit the ABCG2 activity by binding on site S1, previously reported as inhibitors binding region, as well targeting site S2, a selective region for substrates, and by specifically interacting with residues Asn436, Gln398, and Leu555. Altogether, this study provided new insights into THQ/4,5‐dihydroisoxazole molecular hybrids, generating great potential for the development of novel most potent ABCG2 inhibitors., Tetrahydroquinoline/4,5‐dihydroisoxazole hybrids can inhibit the ABCG2 transporter activity and increase the ATP hydrolysis in cells overexpressing ABCG2. Molecular docking and molecular dynamics simulation results suggest that molecular hybrids inhibit ABCG2 activity by binding at the inhibitor binding region, as well as the substrate binding regions.

In this work, fluorinated and platinized TiO2 was evaluated in the glycerol oxidation. Fluorination led to increase the specific surface area of titania, and platinization treatment led to obtain the highest absorption in the visible region of the electromagnetic spectrum; thus, 0.5 wt.% Pt-F-TiO2 was the best catalyst in the obtention of highest yield and selectivity to glyceraldehyde (GAL). It was also found that 2wt.% of Pt content had a detrimental effect in the glycerol conversion. Fluorination and platinum addition led to modify the reaction mechanism and selectivity.

A Na-P zeolite was synthesized and subjected to ion exchange with Ca2+, Cu2+, Al3+, and In3+, and supported with H+/NH4Cl (NH4-P) by in situ reaction of EtOH and NH4Cl. All the exchanged zeolites showed catalytic activity in the ABB’ Povarov reaction. However, zeolite NH4-P promoted a better yield. In all reactions two products were obtained, 2,6-dimethyl-4-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydroquinoline and 1-(1-(4-methylphenylamino)ethyl)pyrrolidin 2-one. Synthesis using zeolite P as catalyst proves to be a simple method with high yields, short reaction times and easy preparation. The catalyst can be recovered by filtration and reused up to three times in good yields.

Cotton (Gossypium hirsutum L.) is an important fibre crop of global significance. It is mainly utilised for the textile industry, and its seeds as cattle feed and to re-harvest fields. However, an important amount of the cottonseed obtained during processing is discarded. Some reports indicate that cottonseed contains high-quality protein and important lipid content. The aim of the present study was to compare different extraction methods (Soxhlet, mechanical and ultrasound-assisted) in order to achieve the highest extraction yield of cottonseed oil (CSO). The extraction efficiency was measured based on the effects of temperature, organic solvent (OS), extraction time and solvent:seed (s:s) ratio, using a Box-Behnken 34 experimental design. From our results, ultrasound-assisted extraction had the highest extraction yield (38.25%) at 45 oC, after 1 h for a 10:1 ratio using Folch mixture as OS. Palmitic, oleic and linoleic acids were the main residues in the characterised CSO, and this oil can be utilized for biodiesel production. This research intends to promote the use of this agroindustrial by-product to add value to cottonseed.

Aldosterone modulates the activity of both epithelial (specifically renal) and non-epithelial cells. Binding to the mineralocorticoid receptor (MR), activates two pathways: the classical genomic and the rapidly activated non-genomic that is substantially modulated by the level of striatin. We hypothesized that disruption of MR’s non-genomic pathway would alter aldosterone-induced cardiovascular/renal damage. To test this hypothesis, wild type (WT) and striatin heterozygous knockout (Strn+/−) littermate male mice were fed a liberal sodium (1.6% Na+) diet and randomized to either protocol one: 3 weeks of treatment with either vehicle or aldosterone plus/minus MR antagonists, eplerenone or esaxerenone or protocol two: 2 weeks of treatment with either vehicle or L-NAME/AngII plus/minus MR antagonists, spironolactone or esaxerenone. Compared to the WT mice, basally, the Strn+/− mice had greater (~26%) estimated renal glomeruli volume and reduced non-genomic second messenger signaling (pAkt/Akt ratio) in kidney tissue. In response to active treatment, the striatin-associated-cardiovascular/renal damage was limited to volume effects induced by aldosterone infusion: significantly increased blood pressure (BP) and albuminuria. In contrast, with aldosterone or L-NAME/AngII treatment, striatin deficiency did not modify aldosterone-mediated damage: in the heart and kidney, macrophage infiltration, and increases in aldosterone-induced biomarkers of injury. All changes were near-normalized following MR blockade with spironolactone or esaxerenone, except increased BP in the L-NAME/AngII model. In conclusion, the loss of striatin amplified aldosterone-induced damage suggesting that aldosterone’s non-genomic pathway is protective but only related to effects likely mediated via epithelial, but not non-epithelial cells.

A new series of tetrahydroquinoline-isoxazoline hybrid derivatives (3a–p) were efficiently synthesized involving 1,3-dipolar cycloaddition reaction according to click chemistry approach, from the corresponding N-allyl-4-(2-oxopyrrolinidyl-1)-tetrahydroquinolines preformed, with moderate to good yields (63–77%). To establish new candidates with anticancer activity, the antiproliferative effect of these compounds was measured by the MTT assay on different cancer cell lines such as human breast adenocarcinoma (MCF-7), human liver carcinoma (HepG2), human lung adenocarcinoma (A549), cervical cancer (HeLa), and murine melanoma (B16F10). Compounds 3a (CC50 = 11.37 μM, SI = 5.1) and 3i (CC50 = 25.59 μM, SI > 4.6) showed the best anticancer activities against murine melanoma cells with considerable selectivity compared with VERO cells. Compound 3h showed the best anticancer activity on cervical cancer (HeLa) cells (CC50 = 10.21 μM, SI = 4.1), and it was also slightly more active than the reference drug oxaliplatin. In addition, the compounds 3a and 3m decrease the mitochondrial membrane potential and induce apoptosis, suggesting that their cytotoxic effects may be based on mitochondrial parameter modulation.

The accumulation of cyanobacteria produced due to eutrophication processes and the increment of different pollutants in water as a result of industrial processes affects aquatic environments such as the ocean, rivers, and swamps. In this work, cyanobacterial biomass was used as a biosorbent for the removal of a commercial dye, methylene blue (MB). Thus, MB was removed from biomass obtained from cyanobacterial samples collected from the swamp located in the Colombian Caribbean. Spectroscopical techniques such as FTIR, SEM, EDX measurements were used for the physico-chemical characterization of the bio-adsorbent material. Furthermore, we present the effect of various adsorption parameters such as pH, MB dose, time, and adsorbent concentration on the adsorbent equilibrium process. Three different isotherm models were used to model the MB adsorption on biomass. The functional groups identified on biomass suggest that these models are suitable for the characterization of the sorption of cationic dyes on the surfaces of the biomass, in addition, an SEM assay showed the heterogeneous surface of the biomass’ morphology. The equilibrium tests suggested a multilayer type adsorption of MB on the biomass surface. The kinetics results show that a pseudo-second order kinetic model was suitable to describe the MB adsorption on the biomass surface. Finally, the herein obtained results give an alternative to resolve the eutrophication problems generated by cyanobacterial growth in the swamp “Ciénaga de Malambo”.

Metastatic melanoma, unlike early-stage melanomas, requires significant interventions with a poor prognosis. In consequence, we evaluated the effect of three tetrahydroquinoline/4,5-dihydroisoxazole hybrids (CB35, CB46, and CB50) on cellular respiration in murine melanoma cells (B16F10). Additionally, the impact of these compounds against the main antioxidant enzymes and the electron transport on the mitochondrial respiratory chain also was determined. The effect on cellular respiration indicates that compound CB35 (10 µM) inhibits the electron transport through the mitochondrial respiratory chain after 24 h of treatment. This inhibition could be related to the transport of electrons to cytochrome c due to the decreasing activity in the NADH cytochrome c reductase at 1 µM in disrupted mitochondria. On the other hand, compounds CB46 and CB50 generate an uncoupling effect on oxidative phosphorylation by increasing oxygen consumption in the LEAK state (10 µM, 24 h), as well as the increase in state 4 in the mitochondrial bioenergetics. In all cases, molecular hybrids increase ATPase activity in coupled mitochondria, suggesting an uncoupled effect. All hybrids disrupt the redox system in B16F10, and the glycolytic pathway by inhibiting hexokinase and pyruvate kinase activities.

The clinical characteristics of patients with postoperative hypoparathyroidism who recover parathyroid function more than 12 months after surgery have not been studied. We aimed to evaluate whether the intensity of replacement therapy with calcium and calcitriol is related to the late recovery of parathyroid function. We compared the demographic, surgical, pathological, and analytical features of two groups of patients: cases, i. e., late recovery patients (those who recover parathyroid function>1 year after thyroidectomy, n=40), and controls, i. e., patients with permanent hypoparathyroidism (n=260). Replacement therapy with calcium and calcitriol was evaluated at discharge of surgery, 3–6 months, 12 months, and last visit. No significant differences were found in clinical, surgical, pathological, or analytical characteristics between cases and controls. The proportion of cases who required treatment with calcium plus calcitriol at 12 months was significantly lower than that found in controls (p

SummaryMaintenance of energy balance is essential for the overall health of an organism. In mammals, both negative and positive energy balance are associated with disease states. To maintain their energy balance within a defined homeostatic setpoint, mammals have evolved complex regulatory mechanisms that control energy intake and expenditure. Traditionally, studies have focused on understanding the role of macronutrient physiology in energy balance. In the present study, we examined the role of the essential micronutrient iron in regulating energy balance. Using a dietary model, we found that a short course of excess dietary iron caused a negative energy balance resulting in a severe whole body wasting phenotype. This disruption in energy balance was due to an iron dependent increase in energy expenditure caused by a heightened basal metabolic rate and activity level. Using a transgenic mouse model lacking adipose triglyceride lipase (ATGL) specifically in fat tissue, we found that to meet the increased energetic demands, dietary iron caused increased lipid utilization that required fat specific ATGL-mediated lipid mobilization and wasting of subcutaneous white adipose tissue deposits. When fed dietary iron, mice lacking fat-specific ATGL activity were protected from fat wasting, and developed a severe cachectic response that is necessary to meet the increased energetic demands caused by the dietary regimen. Our work highlights the multi-faceted role of iron regulation of organismal metabolism and provides a novel in vivo mechanism for micronutrient control of lipolysis that is necessary for regulating mammalian energy balance.

Cynodon dactylon (bermudagrass) is the most important weed in sugarcane crops in Tucuman. The aim of this study was to evaluate the weed control efficacy (CE) of topramezone alone and in a tank-mix with atrazine on bermudagrass plants obtained from a single-node stem cutting, simulating the condition of the weeds after a mechanical control. The effect of different doses used in a sugarcane crop was also evaluated. Topramezone (33.6 g a.i./ha) + atrazine (0.9 kg a.i./ha) was the treatment with the best CE on bermudagrass, lower aboveground dry weight of the weed at 43 days after treatment, and absence of shoots. This treatment did not decrease crop yield when compared to the control. The efficient control of bermudagrass, as well as the absence of crop injury, permits the use of topramezone, in combination with atrazine, as a new chemical alternative for the post-emergent control for this and other weeds.

The new compound (4R)-methyl-3-(1-(4-chlorophenyl)-1H-1,2,3-triazole-4-carbonyl)thiazolidin-4-carboxylate was synthesized by the 1,3-dipolar cycloaddition reaction between (4R)-methyl-3-propionyl-thiazolidin-4-carboxylate (1) and 4-chlorophenylazide using the click chemistry approach. Molecular characterization was carried out by infrared spectroscopy and mass spectrometry. The X-ray powder diffraction study determined that the title compound crystallized in an orthorhombic system with unit-cell parameters a = 20.876 (2) Å, b = 12.111 (1) Å, and c = 6.288 (9) Å. The volume of the unit cell is V = 1589.7 (2) Å3. All measured diffraction maxima were indexed and are consistent with the P2221 space group (No. 17). No detectable impurities were observed.

The knowledge of the mechanical properties of any material subjected to loads is necessary for its use in structural applications. Silicon nitride (Si3N4) ceramics are well-known materials used in engineering applications due to their outstanding combination of high strength and fracture toughness. The most studied mechanical properties of Si3N4 are hardness, fracture toughness and mechanical resistance. Recent advances in the production processes that incorporate high purity rare earth elements as sintering additives have improved these mechanical properties. Using Vickers indentation method, the elastic module and fracture toughness of Si3N4 based materials modified with La2O3, Y2O3 and Al2O3 were determined as a function of the cracking system type that prevails under the effect of load. The results indicate that adding rare earth to the matrix increased the fracture toughness the Si3N4 base ceramic Samples containing La2O3+Y2O3 showed higher values of fracture toughness than the ones with Al2O3+La2O3, regardless of the equation used in the calculations. Meanwhile the elastic module decrease approximately 100 GPa for both types of nitrides by the effect of the temperature.

Mid-infrared analysis of reconstituted milk is proposed as a feasible solution for the detection of milk powder adulteration regardless of the blending practice. To challenge the concept, skim milk powders were spiked with three of the most reactive/unstable of potential milk adulterants: semicarbazide hydrochloride, ammonium sulfate and cornstarch. To create the wet-blended set, a fraction of each sample was reconstituted and re-spray dried at laboratory scale with a benchtop spray dryer. Dry and wet-blended adulterated samples were reconstituted prior to mid-infrared measurement and projected onto a one-class classifier SIMCA model for reconstituted skim milk. Quantitative sensitivities, determined from the normalized orthogonal distances, were compared. Although the non-industrial spray drying introduced a spectroscopic bias, as revealed by the control samples, the non-targeted mid-infrared model showed comparable sensitivities for both blending practices once the main bias-rich spectral regions were removed, validating thereby the proposed concept.

Different α-Fe2O3 porous architectures were obtained by electrospinning (nanotubes) or without electrospinning (flakes), and heating treatments using Fe(NO3)2/PVP (Polyvinylpyrrolidone) as a precursor. The particles constituting the nanotubes and flakes samples exhibited similar wall porosity and crystal size, while the existence of the micropore area was also a characteristic. The chemical identity was confirmed as hematite by XRD, Raman and XPS studies. The prepared samples were studied as photocatalytic materials in the removal of NOX gases from air, their De-NOX ability being superior to that previously reported for hematite photocatalysts. These porous hematite samples exhibited a high NO conversion efficiency and similar to that of TiO2 P25, this being the first report for α-Fe2O3 oxide. Additionally, the calculated De-NOX selectivity values were higher than that of TiO2 P25. The adsorption of NO2 molecules is facilitated on these porous architectures, assisting in the enhancement of the of the photochemical process selectivity.

A series of isoxazole linked to 4-(2-oxopyrrolinidyl-1)-tetrahydroquinoline derivatives was efficiently synthesized. The synthetic route started with the formation of the corresponding N-propargyl tetrahydroquinoline derivatives via cationic Povarov reaction. Tetrahydroquinoline-isoxazole hybrid systems (3a–p) were obtained with good yields (42–88%) through a 1,3-dipolar cycloaddition reaction with a click chemistry approach. These compounds have been tested for their in vitro cytotoxic activity against four different human cancer cell lines, lung (A549), liver (HepG2), and melanoma murine (B16F10) using the conventional MTT assay. Among all tetrahydroquinoline-isoxazole hybrids synthesized, compounds 3a, 3e, 3j, and 3m showed promising in vitro activity against HepG2 cancer cell line with considerable selectivity. Compounds 3a (IC50 = 6.80 µM, SI = 14.7) and 3j (IC50 = 5.20 µM, SI > 16.1) exhibited the highest cytotoxic effect. The death pathway related to cytotoxicity of the compound 3j showed necrotic characteristics selectively on the tumor cell line, also showed an improved in vitro activity against the tested reference drug (oxaliplatin), without significant affectation on the viability of hepatocytes. In general, results suggested that these type of hybrid compounds might have therapeutic potential in future investigations on hepatocellular carcinoma.

A novel family of porphyrins based on 5,10,15,20-Tetrakis(4-ethylphenyl)porphyrin (1) and six metallo-derivatives (Zn2+(2), Sn2+(3), Mn2+ (4), Ni2+ (5), Al3+ (6) and V3+ (7)) were synthesized via the Alder-cols method (synthesis yield between 59%-75%) and characterized through 1H- and 13C- NMR, MALDI-TOF mass spectrometry and FT-IR assay. Photophysical study was carried out by UV-Vis and fluorescence spectrophotometry with the aim of assessing their potential as dye sensitizers for photodynamic therapy (PDT). In this regard, fluorescence quantum yield values are between 0.002-0.38, being the macrocycle 3, the porphyrin with the highest fluorescence quantum yield while the derivative 7 showed the lowest value. Quantum chemical calculations were carried out to study the molecular structure of the porphyrins and to get insight of the luminescent process for 1, which is the free metal system and 3 which includes Sn2+ as metal center. Results indicated that the emissive states involve the transitions with LLCT character for 1, while for 3 it is ML–LCT. This fact evidenced the metal effects on their photophysical properties. Finally, optical and spectroscopic properties and besides, DFT study suggest that 3 could be used as sensitizer in photodynamic therapy applications. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Both mechanistic target of rapamycin (mTOR) pathway and aldosterone are implicated in the development of cardiovascular and renal disease. However, the interaction between aldosterone and the mTOR pathway is unknown. We hypothesized the following: that (i) increased aldosterone will modulate the activity of the mTORC1 and mTORC2 molecular pathways in the heart and kidney; (ii) a physiologic increase in aldosterone will affect these pathways differently than a pathophysiologic one; and (iii) the changes in the mTOR level/activity will differ between the heart and kidney. In both kidney and heart tissues, phosphorylation of mTOR is significantly decreased when aldosterone levels are physiologically increased (by dietary sodium restriction), followed by a decrease in phosphorylated p70S6K1 in cardiac, but not renal, tissue. Sirtuin 1, an epigenetic modulator, is decreased in the heart but increased in the kidney. Conversely, pathophysiologic aldosterone levels (an infusion for 3 weeks) had divergent effects on phosphorylated mTOR and the downstream substrates of mTORC1 and mTORC2 in cardiac and renal tissues. Increased aldosterone levels significantly alter mTOR activity in the heart and kidney. In the kidney, substantial differences were noted if the increase was produced physiologically vs pathophysiologically, suggesting that mTOR activity, in part, may mediate aldosterone-induced renal damage. Thus, modulating mTOR activity may reduce aldosterone-dependent renal damage similar to mineralocorticoid receptor blockade but potentially with less adverse side effects.

Wine lees are rich in anthocyanins (AC), natural colorants with health promoting properties. The extraction kinetics of AC from different wine lees in conventional solid-liquid extraction were studied for the first time. The influence of parameters such as temperature, solid-liquid ratio (RS-L) and type of solvent (hydro-alcoholic mixtures) was also studied. Furthermore, microwaves (MW) and ultrasounds (US) were used as pre-treatments (a prior step to the conventional extraction) in order to increase AC yield. Maximum extraction yield (2.78 mgMALVIDIN-EQUIVALENTS/gDRY-LEES) was achieved after 15 minutes at 25ºC, with a RS-L of 1/10 (g/mL) and with a 50%vol. ethanol mixture. When MW were used AC extraction yield was doubled (6.20 mgMALVIDIN-EQUIVALENTS/gDRY-LEES) and the required time to achieve a constant yield was reduced (from 15 min to 90s). Meanwhile, US only shortened extraction time in less proportion (from 15 to 5 min). Putative identification of main extract compounds was performed by LC/MS-MS., 2019-09-01

BackgroundBehavioural research is needed to inform a ban on sales of filtered cigarettes that could reduce plastic waste due to discarded filters. This study reports on differences in perceptions, nicotine dependence and behaviour among participants in a cross-over randomised trial of filtered compared with unfiltered cigarettes.MethodThis proof-of-concept study involved 43 people who smoke filtered cigarettes (41.9% women, mean age 36.7 years). Participants were provided 2 weeks’ supply of filtered cigarettes, 2 weeks of the same brand of unfiltered cigarettes and randomly assigned to starting conditions. Measures included the Modified Cigarette Evaluation Questionnaire; single-item cigarette perception questions; Fagerström Test of Nicotine Dependence; 7-day cigarette consumption, urinary cotinine and intention to quit. Analyses included linear and ordinal repeated measures mixed-effects models and paired t-tests.ResultsFiltered cigarettes were perceived as better tasting, more satisfying, more enjoyable, less aversive, less harsh, less potent and less negatively reinforcing than unfiltered cigarettes. Filtered cigarettes were smoked at a higher rate during the trial than unfiltered cigarettes (p<0.05). There was no difference in cotinine, dependence or intention to quit between filtered versus unfiltered cigarette conditions (p>0.05).ConclusionPeople who smoke perceived unfiltered cigarettes as having greater nicotine effects and less desirable sensory effects than filtered cigarettes, and they smoked fewer of these during the trial. Although cotinine, dependence and intention to quit were similar for smoking unfiltered and filtered cigarettes in this small trial, results suggest that banning the sale of filtered cigarettes might make smoking less attractive overall to people who smoke.Trial registration numberNCT03749876.

In this work, we synthesized the meso-(aryl) porphyrin derivative 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) and two meso-(aryl) metalloporphyrins, TCPP-Zn(II) and TCPP-Sn(IV), with reaction yields between 33.91 and 80.4%. The photophysical properties were determined, and the in vitro photodynamic properties were evaluated against Leishmania spp in the promastigote stage. The TCPP-Zn(II) reduced the viability of the parasites as shown by the lowest IC50, which is even lower than the reference drug glucantime. In general, our results indicate that the beneficial effect related to the lethal capacity of porphyrins was greater in the presence of light irradiation. Furthermore, the inclusion of a diamagnetic metal such as Zn(II) is essential for the biological properties shown by this type of compounds, as it substantially improves their photodynamic activity. The Jablonsky diagrams were proposed using DFT computations, where the decay channels through the ground and excited states were assessed and the feasible generation of singlet oxygen was established, being TCPP-Zn(II) the one that shows a slightly more exothermic process than TCPP-Sn(IV).

Partially Hydrolyzed Polyacrylamide (HPAM) is the polymer most used in chemical enhanced oil recovery (cEOR) processes and it has been implemented in several field projects worldwide. Polymer injection has shown to be an effective EOR process. However, it has not been implemented massively due to HPAM polymer's limitations, mostly related to thermal and chemical degradation caused by exposure at high temperatures and salinities (HTHS). As an alternative, a new generation of chemically stable monomers to improve the properties of HPAM has been assessed at laboratory and field conditions. However, the use of enhanced polymers is limited due to its larger molecular size, large-scale production, and higher costs. One of the alternatives proposed in the last decade to improve polymer properties is the use of nanoparticles, which due to their ultra-small size, large surface area, and highly reactive capacity, can contribute to reduce or avoid the degrading processes of HPAM polymers. Nanoparticles (NPs) can be integrated with the polymer in several ways, it being worth to highlight mixing with the polymer in aqueous solution or inclusion by grafting or chemical functionalization on the nanoparticle surface. This review focuses on hybrid nanomaterials based on SiO2 NPs and synthetic polymers with great EOR potential. The synthesis process, characterization, and the main properties for application in EOR processes, were reviewed and analyzed. Nanohybrids based on polymers and silica nanoparticles show promising results in improving viscosity and thermal stability compared to the HPAM polymer precursor. Furthermore, based on recent findings, there are great opportunities to implement polymer nanofluids in cEOR projects. This approach could be of value to optimize the technical-economic feasibility of projects by reducing the polymer concentration of using reasonable amounts of nanoparticles. However, more significant efforts are required to understand the impact of nanoparticle concentrations and injection rates to support the upscaling of this cEOR technology. RESUMEN La poliacrilamida parcialmente hidrolizada (HPAM) es el polímero más usado en procesos de recuperación mejorada de petróleo por métodos químicos (cEOR) y ha sido implementado a escala piloto y comercial alrededor del mundo. La inyección de polímero muestra ser efectiva en la recuperación de petróleo, pero esta técnica no se ha implementado masivamente debido a limitaciones de los polímeros de tipo HPAM que incluyen la degradación térmica y química causada principalmente por su exposición a altas temperaturas y salinidades (HTHS). Como alternativa, una nueva generación de polímeros que incluyen monómeros químicamente estables para mejorar las propiedades del HPAM han sido evaluados en condiciones de laboratorio y campo. Sin embargo, el uso de estos polímeros está limitado por tratarse de moléculas de mayor tamaño, producción a gran escala y sus altos costos. Una de las alternativas propuestas en la última década para mejorar las propiedades del polímero es el uso de nanopartículas, que, debido a sus propiedades de ultra bajo tamaño, gran área superficial y capacidad reactiva podrían ayudar a mitigar o evitar los procesos de degradación que presentan los polímeros de tipo HPAM. Las nanopartículas (NPs) se pueden incluir en la matriz polimérica de varias maneras, destacando el mezclado con el polímero en solución acuosa o la inclusión mediante injerto o funcionalización química del polímero en la superficie de la nanopartícula. Esta revisión se enfoca en nanomateriales híbridos basados en NP de SiO2 y polímeros sintéticos con gran potencial para aplicaciones EOR. Los procesos de síntesis, caracterización y las principales propiedades para su aplicación en procesos de EOR fueron revisados y analizados. Nanohibridos basados en polímeros y nanopartículas de sílice muestran resultados prometedores en la estabilidad térmica y la viscosidad comparados con los polímeros precursores. Además, basados en hallazgos recientes, hay grandes oportunidades para implementar nanofluidos base polímero en proyectos de recobro mejorado de petróleo. Este enfoque podría ser de gran valor para optimizar la factibilidad técnico económica de los proyectos reduciendo la concentración de polímero requerida usando una cantidad razonable de nanopartículas. Sin embargo, mayores esfuerzos son requeridos para entender el impacto de la concentración de nanopartículas y las tasas de inyección como soporte al escalado como tecnología de recobro mejorado.

Background: We compared outcomes up to 24 months after treatment initiation for rifampicin-resistant tuberculosis (RR-TB) patients in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable group). Methods: RR-TB patients eligible for a short regimen starting treatment between 1 January and 31 December 2017 with a bedaquiline-containing or WHO recommended injectable-containing treatment regimen of 9 to 12 months, registered with their national ID in the drug-resistant TB database and with known age, sex, and HIV status were eligible for study inclusion. To compare regimens, we exactly matched patients on HIV-infection, previous TB treatment history, baseline acid-fast bacilli smear and culture result, and propensity score matched patients on age, sex, and isoniazid susceptibility status, using logistic regression with generalized linear mixed models to estimate adjusted odds ratios (aOR) and 95% confidence intervals (95%CI). Results: Overall, 1,387 of the 10,152 RR-TB patients treated during 2017 met inclusion criteria, of whom 688 received the bedaquiline-containing regimen and 699 patients received the injectable-containing regimen. Four patients (0.6%) had treatment failure and/or recurrence, 44 (6.4%) were lost to follow-up, and 162 (23.5%) died in the bedaquiline group, compared to 17 (2.4%), 87 (12.4%), and 199 (28.5%), respectively, in the injectable group. Patients in the bedaquiline group had 1.8 (95%CI 1.4 to 2.4) times higher odds of treatment success at 24 months and 0.6 (0.4 to 0.8) times lower odds of loss to follow-up. This was consistent in stratified analyses on HIV-status, AFB smear positivity, and previous treatment history. The bedaquiline group had lower odds of mortality during treatment (0.5, 95%CI 0.4 to 0.7), but not post treatment (1.1, 95%CI 0.7 to 1.7). Conclusion: Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months compared to the injectable group. The analysis supports the use of short bedaquiline-containing regimens in eligible patients. Funding: WHO Global TB Programme. Declaration of Interest: We declare no competing interests. Ethical Approval: This analysis was approved by Human Research Ethics Committee, Medical of University of Witwatersrand (#M150340, March 2015).

A patient with a history of UTI acquired an isolate of Staphylococcus saprophyticus that was resistant to clindamycin, streptogramin A, pleuromutilins (LSPs), and oxacillin. A plasmid-located vga variant was identified in this pathogen, and the encoded protein showed a 39% to 67% identity to other previously characterized vga.

Background Plastic filters on cigarette butts are a widespread source of nonbiodegradable, toxic environmental waste. State and local legislation to ban the sale of single-use cigarettes may be considered to prevent this waste, but scientific evidence on the impact of switching smokers to unfiltered cigarettes on smoking behavior and toxicant exposures is needed to inform this policy. We have designed an open-label, randomized, 9-week, crossover clinical trial of adult filtered-cigarette smokers who switch to unfiltered cigarettes. Objective Our objective is to understand the impact of switching smokers of filtered cigarettes to unfiltered cigarettes on smoking behavior and toxic exposures. Methods This trial involves a 1-week baseline period; a 2-week period of smoking filtered or unfiltered cigarettes, where groups are randomly assigned; a 3-week washout period; another 1-week baseline period; and a 2-week crossover period of smoking the opposite condition (ie, filtered or unfiltered cigarettes) for a sufficient sample size of 40 participants. We will determine changes in (1) observed topography (ie, puff count, interpuff interval, and puff volume) and cigarettes smoked per day, via butt counts and self-report, (2) expired carbon monoxide and excretion of urinary cotinine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and volatile organic compounds, and (3) participants’ knowledge and attitudes toward unfiltered cigarettes, satisfaction with smoking, and intention to quit if they were not able to smoke filtered cigarettes. Results This study was funded in June 2018 and approved by the relevant Institutional Review Boards in July 2018. This study has enrolled 37 participants as of October 2020. Data analysis is currently underway, and trial results are expected to be published in spring 2021. Conclusions This pilot proof-of-principle study will inform the design of a larger, future research project that can provide robust scientific evidence on our research question. Such a large study could inform possible state or local legislation to ban the sale of single-use filtered cigarettes in order to mitigate the environmental impact of discarded single-use plastic filters. Trial Registration ClinicalTrials.gov NCT03749876; https://clinicaltrials.gov/ct2/show/NCT03749876 International Registered Report Identifier (IRRID) DERR1-10.2196/19603

Worldwide uptake of new drugs in the treatment of rifampicin-resistant tuberculosis (RR-TB) has been extremely low. In June 2018, ahead of the release of the updated WHO guidelines for the management of RR-TB, South Africa announced that bedaquiline (BDQ) would be provided to virtually all RR-TB patients on shorter or longer regimens. South Africa has been the global leader in accessing BDQ for patients with RR-TB, who now represent 60% of the global BDQ cohort. The use of BDQ within a shorter modified regimen has generated the programmatic data underpinning the most recent change in WHO guidelines endorsing a shorter, injectable-free regimen. Progressive policies on access to new drugs have resulted in improved favourable outcomes and a reduction in mortality among RR-TB patients in South Africa. This supported global policy change. The strategies underpinning these bold actions include close collaboration between the South African National TB Programme and partners, introduction of new TB diagnostic tools in closely monitored conditions and the use of locally generated programmatic evidence to inform country policy changes. In this paper, we summarise a decade´s work that led to the bold decision to use a modified, short, injectable-free regimen with BDQ and linezolid under carefully monitored programmatic conditions.

Simple Summary Colorectal cancer (CRC) causes a high number (more than 800,000) of deaths worldwide each year. Better methods for early diagnosis and the development of strategies to enhance the efficacy of the therapeutic approaches used to complement or substitute surgical removal of the tumor are urgently needed. Currently available pharmacological armamentarium provides very moderate benefits to patients due to the high resistance of tumor cells to respond to anticancer drugs. The present review summarizes and classifies into seven groups the cellular and molecular mechanisms of chemoresistance (MOC) accounting for the failure of CRC response to the pharmacological treatment. Abstract The unsatisfactory response of colorectal cancer (CRC) to pharmacological treatment contributes to the substantial global health burden caused by this disease. Over the last few decades, CRC has become the cause of more than 800,000 deaths per year. The reason is a combination of two factors: (i) the late cancer detection, which is being partially solved by the implementation of mass screening of adults over age 50, permitting earlier diagnosis and treatment; (ii) the inadequate response of advanced unresectable tumors (i.e., stages III and IV) to pharmacological therapy. The latter is due to the existence of complex mechanisms of chemoresistance (MOCs) that interact and synergize with each other, rendering CRC cells strongly refractory to the available pharmacological regimens based on conventional chemotherapy, such as pyrimidine analogs (5-fluorouracil, capecitabine, trifluridine, and tipiracil), oxaliplatin, and irinotecan, as well as drugs targeted toward tyrosine kinase receptors (regorafenib, aflibercept, bevacizumab, cetuximab, panitumumab, and ramucirumab), and, more recently, immune checkpoint inhibitors (nivolumab, ipilimumab, and pembrolizumab). In the present review, we have inventoried the genes involved in the lack of CRC response to pharmacological treatment, classifying them into seven groups (from MOC-1 to MOC-7) according to functional criteria to identify cancer cell weaknesses. This classification will be useful to pave the way for developing sensitizing tools consisting of (i) new agents to be co-administered with the active drug; (ii) pharmacological approaches, such as drug encapsulation (e.g., into labeled liposomes or exosomes); (iii) gene therapy interventions aimed at restoring the impaired function of some proteins (e.g., uptake transporters and tumor suppressors) or abolishing that of others (such as export pumps and oncogenes).

In industry, silica nanoparticles (NPs) are obtained by the fuming and the precipitation method. Fumed silica NPs are commonly used in the preparation of nanocomposites because they have an extremely low bulk density (160&ndash, 190 kg/m3), large surface area (50&ndash, 600 m2/g), and nonporous surface, which promotes strong physical contact between the NPs and the organic phase. Fumed silica has fewer silanol groups (Si&ndash, OH) on its surface than the silica prepared by the St&ouml, ber method. However, the number of &ndash, OH groups on the fumed silica surface can be increased by pretreating them with sodium hydroxide (NaOH) before further surface modification. In this study, the effectiveness of the NaOH pretreatment was evaluated on commercial fumed silica NPs with a surface area of 200 m2/g. The number of surface &ndash, OH groups was estimated by potentiometric titration. The pretreated fumed NPs, and the precipitated NPs (prepared by the St&ouml, ber method) were modified with 3-aminopropyltriethoxysilane (APTES) to obtain A200S and nSiO2-APTES, respectively. The NPs were characterized using electron dispersive scanning (EDS), scanning electron microscopy (SEM), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), X-ray diffraction (XRD), BET (Brunauer&ndash, Emmett&ndash, Teller) analysis, and &zeta, potential. XRD confirmed the presence of the organo-functional group on the surface of both NPs. After the amino-functionalization, the &zeta, potential values of the nSiO2 and A200 changed from &minus, 35.5 mV and &minus, 14.4 mV to +26.2 mV and +11.76 mV, respectively. Consequently, we have successfully synthesized functionalized NPs with interesting, specific surface area and porosity (pore volume and size), which can be attractive materials for chemical and energy industries.

The poor outcome of patients with non-surgically removable advanced hepatocellular carcinoma (HCC), the most frequent type of primary liver cancer, is mainly due to the high refractoriness of this aggressive tumor to classical chemotherapy. Novel pharmacological approaches based on the use of inhibitors of tyrosine kinases (TKIs), mainly sorafenib and regorafenib, have provided only a modest prolongation of the overall survival in these HCC patients. The present review is an update of the available information regarding our understanding of the molecular bases of mechanisms of chemoresistance (MOC) with a significant impact on the response of HCC to existing pharmacological tools, which include classical chemotherapeutic agents, TKIs and novel immune-sensitizing strategies. Many of the more than one hundred genes involved in seven MOC have been identified as potential biomarkers to predict the failure of treatment, as well as druggable targets to develop novel strategies aimed at increasing the sensitivity of HCC to pharmacological treatments.

In this study, a set of advanced characterization techniques were used to evaluate the morphological, structural, and thermal properties of a novel molecular hybrid based on silica nanoparticles/hydrolyzed polyacrylamide (CSNH-PC1), which was efficiently obtained using a two-step synthetic pathway. The morphology of the nanohybrid CSNH-PC1 was determined using scanning electron microscopy (SEM), dynamic light scattering (DLS), and nanotracking analysis (NTA) techniques. The presence of C, N, O, and Si atoms in the nanohybrid structure was verified using electron dispersive scanning (EDS). Moreover, the corresponding structural analysis was complemented using powder X-ray diffraction (XRD) and attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FT-IR). The covalent bond between APTES-functionalized SiO2 nanoparticles (nSiO2-APTES), and the hydrolyzed polyacrylamide (HPAM) chain (MW &asymp, 20.106 Da) was confirmed with high-resolution X-ray spectroscopy (XPS). Finally, the thermal properties of the nanohybrid were evaluated by using thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The results showed that the CSNH-PC1 has a spherical morphology, with sizes between 420&ndash, 480 nm and higher thermal resistance compared to HPAM polymers without modification, with a glass transition temperature of 360 &deg, C. The integration of these advanced characterization techniques implemented here shows promising results for the study and evaluation of new nanomaterials with multiple applications.

Angiotensin II (AngII) is the principal effector molecule of the renin-angiotensin system (RAS). It’s effects on the cardiovascular and renal system are well-documented. AngII acts mainly via interaction with the AngII type-1 receptor (AT1R). Disordered levels of AngII lead to hypertension and cardiovascular disease. Increasing evidence suggests that AngII may also play a role in the pathophysiology of neurodegenerative diseases through unclear mechanisms. We investigated AngII, AT1R and AT2R levels in a mouse model of neurodegenerative disease, the experimentally induced autoimmune encephalomyelitis (EAE) mouse. In EAE mice, AngII and AT1R gene expression in brain tissue were significantly increased when compared to control mice (3.2 folds ±1.9, p

Background: Plastic filters on cigarette butts are a widespread source of non-biodegradable, toxic environmental waste. State and local legislation to ban the sale of single-use cigarettes may be considered to prevent this waste, but scientific evidence on the impact of switching smokers to unfiltered cigarettes on smoking behavior and toxicant exposures is needed to inform this policy. We have designed an open-label, randomized, 9-week, cross-over clinical trial of adult filtered cigarette smokers who switch to unfiltered cigarettes.Methods: The trial involves a 1-week baseline period, 2 weeks of smoking filtered or unfiltered cigarettes (groups randomly assignd), a 3-week washout period, another 1-week baseline period, and a crossover to 2-weeks of smoking the opposite condition (filtered or unfiltered cigarettes). We will determine changes in: 1) observed topography (i.e., puff count, puff volume) and cigarettes smoked per day (via butt counts and self-report); 2) expired carbon monoxide (CO), urinary cotinine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and volatile organic compound (VOC) excretion; and 3) knowledge and attitudes toward unfiltered cigarettes, satisfaction with smoking, and intention to quit if they were not able to smoke filtered cigarettes.Discussion: This comprehensive proof-of-principle study will provide preliminary evidence to develop a research project with a larger sample size. Study results will inform proposed state or local legislation to ban the sale of single-use filtered cigarettes in order to eliminate the environmental impact of cigarette butt waste stemming from the single-use plastic filter. Trial Registration: NCT03749876

The mechanistic target of the rapamycin (mTOR) pathway plays a role in features common to both excess salt/aldosterone and cardiovascular/renal diseases. Dietary sodium can upregulate mTORC1 signaling in cardiac and renal tissue, and the inhibition of mTOR can prevent aldosterone-associated, salt-induced hypertension. The impact of sex and age on mTOR’s role in volume homeostasis and the regulation of aldosterone secretion is largely unknown. We hypothesize that both age and sex modify mTOR’s interaction with volume homeostatic mechanisms. The activity of 3 volume homeostatic mechanisms—cardiovascular, renal, and hormonal (aldosterone [sodium retaining] and brain natriuretic peptide [BNP; sodium losing])—were assessed in mTORC1 deficient (Raptor +/-) and wild-type male and female littermates at 2 different ages. The mice were volume stressed by being given a liberal salt (LibS) diet. Raptor +/-mice of both sexes when they aged: (1) reduced their blood pressure, (2) increased left ventricular internal diameter during diastole, (3) decreased renal blood flow, and (4) increased mineralocorticoid receptor expression. Aldosterone levels did not differ by sex in young Raptor +/- mice. However, as they aged, compared to their littermates, aldosterone decreased in males but increased in females. Finally, given the level of Na+ intake, BNP was inappropriately suppressed, but only in Raptor +/- males. These data indicate that Raptor +/- mice, when stressed with a LibS diet, display inappropriate volume homeostatic responses, particularly with aging, and the mechanisms altered, differing by sex.

The Biological Magnetic Resonance Data Bank (BioMagResBank or BMRB), founded in 1988, serves as the archive for data generated by nuclear magnetic resonance (NMR) spectroscopy of biological systems. NMR spectroscopy is unique among biophysical approaches in its ability to provide a broad range of atomic and higher-level information relevant to the structural, dynamic, and chemical properties of biological macromolecules, as well as report on metabolite and natural product concentrations in complex mixtures and their chemical structures. BMRB became a core member of the Worldwide Protein Data Bank (wwPDB) in 2007, and the BMRB archive is now a core archive of the wwPDB. Currently, about 10% of the structures deposited into the PDB archive are based on NMR spectroscopy. BMRB stores experimental and derived data from biomolecular NMR studies. Newer BMRB biopolymer depositions are divided about evenly between those associated with structure determinations (atomic coordinates and supporting information archived in the PDB) and those reporting experimental information on molecular dynamics, conformational transitions, ligand binding, assigned chemical shifts, or other results from NMR spectroscopy. BMRB also provides resources for NMR studies of metabolites and other small molecules that are often macromolecular ligands and/or nonstandard residues. This chapter is directed to the structural biology community rather than the metabolomics and natural products community. Our goal is to describe various BMRB services offered to structural biology researchers and how they can be accessed and utilized. These services can be classified into four main groups: (1) data deposition, (2) data retrieval, (3) data analysis, and (4) services for NMR spectroscopists and software developers. The chapter also describes the NMR-STAR data format used by BMRB and the tools provided to facilitate its use. For programmers, BMRB offers an application programming interface (API) and libraries in the Python and R languages that enable users to develop their own BMRB-based tools for data analysis, visualization, and manipulation of NMR-STAR formatted files. BMRB also provides users with direct access tools through the NMRbox platform.

The essential oils obtained by hydrodistillation from fresh leaves of Vitex agnus-castus and Ocimum campechianum, and from fresh inflorescences of Ocimum carnosum were analysed by GC-FID and GC-MS. The major components of V. agnus-castus essential oil were identified as 1,8-cineole (47.9%), terpinyl α-acetate (11.6%), sabinene (11.2%) and caryophyllene oxide (9.7%), while in the O. campechianum essential oil were eugenol (72.1%), β-elemene (6.8%), (E)-caryophyllene (6.4%) and bicyclogermacrene (5.2%). Linalool (79.0%), α-epi-cadinol (5.4%), terpinen-4-ol (3.2%) and 1,8-cineole (2.8%) were the major constituents in the O. carnosum essential oil. The essential oils were subsequently evaluated for their larvicidal and cytotoxic activities. Larval bioassay against Aedes aegypti of V. agnus-castus, O. campechianum and O. carnosum essential oils showed LC50 values of 97.55 ± 0.35, 81.45 ± 0.35 and 109.49 ± 0.35 μg/mL, respectively. The in vitro cytotoxic activities of the essential oils has been evaluated on breast adenocarcinoma (MCF-7), lung carcinoma (NCI-H292), pro-myelocytic leukemia (HL-60), and cervical adenocarcinoma (HEP-2) human cell lines, and pro-myelocytic leukemia cells lines (HL-60) were found to be the most sensitive to all the essential oils tested than the others. This is the first report on larvicidal and cytotoxic activities of these essential oils.

The growth of the biological nuclear magnetic resonance (NMR) field and the development of new experimental technology have mandated the revision and enlargement of the NMR-STAR ontology used to represent experiments, spectral and derived data, and supporting metadata. We present here a brief description of the NMR-STAR ontology and software tools for manipulating NMR-STAR data files, editing the files, extracting selected data, and creating data visualizations. Detailed information on these is accessible from the links provided.

Background and Purpose— The role of dietary fat on cardiovascular health and mortality remains under debate. Because the APOE is central to the transport and metabolism of lipids, we examined associations between plasma fatty acids and the risk of stroke, coronary heart disease, and mortality by APOE-ε4 genotype. Methods— We included 943 FHS (Framingham Heart Study) and 1406 3C (Three-City) Bordeaux Study participants. Plasma docosahexaenoic, linoleic, arachidonic, and palmitic fatty acids were measured at baseline by gas chromatography. All-cause stroke, ischemic stroke, coronary heart disease, and all-cause mortality events were identified prospectively using standardized protocols. Each cohort used Cox models to separately relate fatty acid levels to the risk of developing each event during ≤10 years of follow-up adjusting for potential confounders and stratifying by APOE genotype (ε4 carriers versus noncarriers). We then meta-analyzed summary statistics using random-effects models. Results— On average, participants had a mean age of 74 years, 61% were women, and 21% (n=483) were APOE-ε4 carriers. Meta-analysis results showed that, only among APOE-ε4 carriers, every SD unit increase in linoleic acid was associated with a reduced risk of all-cause stroke (hazard ratio [HR], 0.54 [95% CI, 0.38–0.78]), ischemic stroke (HR, 0.48 [95% CI, 0.33–0.71]), and all-cause mortality (HR, 0.70 [95% CI, 0.57–0.85]). In contrast, every SD unit increase in palmitic acid was related to an increased risk of all-cause stroke (HR, 1.58 [95% CI, 1.16–2.17]), ischemic stroke (HR, 1.76 [95% CI, 1.26–2.45]), and coronary heart disease (HR, 1.48 [95% CI, 1.09–2.01]), also in APOE-ε4 carriers only. Results for docosahexaenoic acid and arachidonic acid were heterogeneous between cohorts. Conclusions— These exploratory results suggest that APOE-ε4 carriers may be more susceptible to the beneficial or adverse impact of fatty acids on cardiovascular disease and mortality. In this subgroup, higher linoleic acid was protective for stroke and mortality, whereas palmitic acid was a risk factor for stroke and coronary heart disease. The mechanisms underlying these novel findings warrant further investigation.

Summary Background Addition of bedaquiline to treatment for multidrug-resistant tuberculosis was associated with an increased risk of death in a phase 2b clinical trial, resulting in caution from WHO. Following a compassionate access programme and local regulatory approval, the South African National Tuberculosis Programme began widespread use of bedaquiline in March, 2015, especially among patients with extensively drug resistant tuberculosis for whom no other effective treatment options were available. We aimed to compare mortality in patients on standard regimens with that of patients on regimens including bedaquiline. Methods In this retrospective cohort study, we analysed patient data from the South African rifampicin-resistant tuberculosis case register (EDRweb), and identified additional mortality using the national vital statistics register. We excluded patients who started treatment before July 1, 2014, or after March 31, 2016; patients younger than 15 years or older than 75 years; patients without documented rifampicin resistance, and patients with pre-extensively drug-resistant tuberculosis (multidrug-resistant tuberculosis with further resistance to a second-line injectable or fluoroquinolone). We compared all-cause mortality between patients who received bedaquiline in treatment regimens and those who did not. Patients who did not receive bedaquiline had kanamycin or capreomycin and moxifloxacin as core medicines in their regimen. We estimated hazard ratios for mortality separately for multidrug-resistant or rifampicin-resistant tuberculosis and extensively drug-resistant tuberculosis and adjusted using propensity score quintile strata for the potential confounders of sex, age, HIV and antiretroviral therapy status, history of prior tuberculosis, valid identification number, and year and province of treatment. Findings 24 014 tuberculosis cases were registered in the EDRweb between July 1, 2014, and March 31, 2016. Of these, 19 617 patients initiated treatment and met our analysis eligibility criteria. A bedaquiline-containing regimen was given to 743 (4·0%) of 18 542 patients with multidrug-resistant or rifampicin-resistant tuberculosis and 273 (25·4%) of 1075 patients with extensively drug-resistant tuberculosis. Among 1016 patients who received bedaquiline, 128 deaths (12·6%) were reported, and there were 4612 deaths (24·8%) among 18 601 patients on the standard regimens. Bedaquiline was associated with a reduction in the risk of all-cause mortality for patients with multidrug-resistant or rifampicin-resistant tuberculosis (hazard ratio [HR] 0·35, 95% CI 0·28–0·46) and extensively drug-resistant tuberculosis (0·26, 0·18–0·38) compared with standard regimens. Interpretation Our retrospective cohort analysis of routinely reported data in the context of high HIV and extensively drug-resistant tuberculosis prevalence showed that bedaquiline-based treatment regimens were associated with a large reduction in mortality in patients with drug-resistant tuberculosis, compared with the standard regimen. Funding None.

At high doses, glucocorticoids (GC) have been associated with enhanced serum bile acids and liver injury. We have evaluated the effect of GC, in the absence of hepatotoxicity, on FXR/FGF91(Fgf15)/FGF21-mediated ileum-liver crosstalk. Rats and mice (wild type and Fxr-/-, Fgf15-/- and int-Gr-/- strains; the latter with GC receptor (Gr) knockout selective for intestinal epithelial cells), were treated (i.p.) with dexamethasone, prednisolone or budesonide. In both species, high doses of GC caused hepatotoxicity. At a non-hepatotoxic dose, GC induced ileal Fgf15 down-regulation and liver Fgf21 up-regulation, without affecting Fxr expression. Fgf21 mRNA levels correlated with those of several genes involved in glucose and bile acid metabolism. Surprisingly, liver Cyp7a1 was not up-regulated. The expression of factors involved in transcriptional modulation by Fxr and Gr (p300, Drip205, CBP and Smrt) was not affected. Pxr target genes Cyp3a11 and Mrp2 were not up-regulated in liver or intestine. In contrast, the expression of some Pparα target genes in liver (Fgf21, Cyp4a14 and Vanin-1) and intestine (Vanin-1 and Cyp3a11) was altered. In mice with experimental colitis, liver Fgf21 was up-regulated (4.4-fold). HepG2 cells transfection with FGF21 inhibited CYP7A1 promoter (prCYP7A1-Luc2). This was mimicked by pure human FGF21 protein or culture in medium previously conditioned by cells over-expressing FGF21. This response was not abolished by deletion of a putative response element for phosphorylated FGF21 effectors present in prCYP7A1. In conclusion, GC interfere with FXR/FGF19-mediated intestinal control of CYP7A1 expression by the liver and stimulate hepatic secretion of FGF21, which inhibits CYP7A1 promoter through an autocrine mechanism.