Xpert MTB/XDR implementation in South Africa: cost outcomes of centralised vs. decentralised approaches.

INTRODUCTION: In South Africa, Xpert® MTB/RIF Ultra (Ultra) is the recommended diagnostic assay for TB with line-probe assays for first- (LPAfl) and second-line drugs (LPAsl) providing additional drug susceptibility testing (DST) for samples that were rifampicin-resistant (RR-TB). To guide implementation of the recently launched Xpert® MTB/XDR (MTB/XDR) assay, a cost-outcomes analysis was conducted comparing total costs for genotypic DST (gDST) for persons diagnosed with RR-TB considering three strategies: replacing LPAfl/LPAsl (centralised level) with MTB/XDR vs. Ultra reflex testing (decentralised level). Further, DST was performed using residual specimen following RR-TB diagnosis. METHODS: The total cost of gDST was determined for three strategies, considering loss to follow-up (LTFU), unsuccessful test rates, and specimen volume. RESULTS: For 2019, 9,415 persons were diagnosed with RR-TB. A 35% LTFU rate between RR-TB diagnosis and LPAfl/LPAsl-DST was estimated. Unsuccessful test rates of 37% and 23.3% were reported for LPAfl and LPAsl, respectively. The estimated total costs were $191,472 for the conventional strategy, $122,352 for the centralised strategy, and $126,838 for the decentralised strategy. However, it was found that sufficient residual volume for reflex MTB/XDR testing is a limiting factor at the decentralised level. CONCLUSION: Centralising the implementation of XDR testing, as compared to LPAfl/LPAsl, leads to significant cost savings.

INTRODUCTION: En Afrique du Sud, Xpert® MTB/RIF Ultra (Ultra) est le test de diagnostic recommandé pour la TB avec des tests par sonde de ligne pour les médicaments de première (LPAfl) et de deuxième ligne (LPAsl) fournissant des tests de sensibilité aux médicaments (DST) supplémentaires pour les échantillons résistants à la rifampicine (RR-TB). Afin d'orienter la mise en œuvre du test Xpert® MTB/XDR (MTB/XDR) récemment lancé, une analyse coûts-résultats a été réalisée en comparant les coûts totaux de la DST génotypique (gDST) pour les personnes diagnostiquées avec une RR-TB en tenant compte de trois stratégies : remplacer le LPAfl/LPAsl (niveau centralisé) par le MTB/XDR par rapport au test Ultra reflex (niveau décentralisé). De plus, l'heure d'été a été réalisée à l'aide d'un échantillon résiduel après le diagnostic de RR-TB. MÉTHODES: Le coût total de la gDST a été déterminé pour trois stratégies, en tenant compte de la perte de suivi (LTFU), des taux d'échec des tests et du volume d'échantillons. RÉSULTATS: En 2019, 9 415 personnes ont reçu un diagnostic de RR-TB. Un taux de LTFU de 35% entre le diagnostic de RR-TB et le diagnostic de LPAfl/LPAsl-DST a été estimé. Des taux d'échec de 37% et de 23,3% ont été signalés pour LPAfl et LPAsl, respectivement. Les coûts totaux estimés étaient de 191 472 dollars pour la stratégie conventionnelle, de 122 352 dollars pour la stratégie centralisée et de 126 838 dollars pour la stratégie décentralisée. Cependant, il a été constaté qu'un volume résiduel suffisant pour les tests réflexes MTB/XDR est un facteur limitant au niveau décentralisé. CONCLUSION: La centralisation de la mise en œuvre des tests XDR, par rapport à LPAfl/LPAsl, permet de réaliser d'importantes économies.

Vicia sativa subsp. sativa native to the Middle East comprises Pea Albumin1 b-like homologs: A promising natural biopesticide.

The extensive and indiscriminate use of chemical pesticides in agriculture has led to adverse effects on human health, environmental pollution, and the emergence of pesticide-resistant pests. To mitigate these challenges, the development of environmentally friendly alternatives is crucial, with biopesticides emerging as promising solutions such as peptides. Legume seeds naturally contain diverse insecticidal peptides or proteins to combat pest attacks. One such peptide is PA1b (Pea Albumin 1, subunit b), a 37 amino acid extracted from pea seeds (Pisum sativum). PA1b has shown significant potential in controlling cereal weevils (Sitophilus spp.), a major pest of stored cereals. Here, we screened PA1b-like peptides in five wild seeds of vetches (Vicia sativa subsp. sativa) from the Middle East. Using a comprehensive set of biochemical, biological, and molecular techniques, we characterized different PA1b homologs and assessed their toxicity and expression profiles. Our results reveal that PA1b homolog from Vicia sativa subsp. sativa originating from turkey displays outstanding insecticidal activity against Sitophilus oryzae through binding to the receptor site found in the midgut of the insect. Moreover, it exhibits a strong cytotoxic effect against Sf9 cells. This cysteine-rich peptide shows sequence identity and the same hydrophobic pole as AG41, a tenfold more toxic isoform of PA1b from Medicago truncatula. Such observations pave the way for the development of bioinsecticides, with PA1b-like peptides as lead compounds.

Advanced spectroscopic investigation of colour centres in LiF crystals irradiated with monochromatic hard x-rays.

Nominally-pure lithium fluoride (LiF) crystals were irradiated with monochromatic hard x-rays of energy 5, 7, 9 and 12 keV at the METROLOGIE beamline of the SOLEIL synchrotron facility, in order to understand the role of the selected x-ray energy on their visible photoluminescence (PL) response, which is used for high spatial resolution 2D x-ray imaging detectors characterized by a wide dynamic range. At the energies of 7 and 12 keV the irradiations were performed at five different doses corresponding to five uniformly irradiated areas, while at 5 and 9 keV only two irradiations at two different doses were carried out. The doses were planned in a range between 4 and 1.4 × 103Gy (10.5 mJ cm-3to 3.7 J cm-3), depending on the x-ray energy. After irradiation at the energies of 7 and 12 keV, the spectrally-integrated visible PL intensity of the F2and F3+colour centres (CCs) generated in the LiF crystals, carefully measured by fluorescence microscopy under blue excitation, exhibits a linear dependence on the irradiation dose in the investigated dose range. This linear behaviour was confirmed by the optical absorption spectra of the irradiated spots, which shows a similar linear behaviour for both the F2and F3+CCs, as derived from their overlapping absorption band at around 450 nm. At the highest x-ray energy, the average concentrations of the radiation-induced F, F2and F3+CCs were also estimated. The volume distributions of F2defects in the crystals irradiated with 5 and 9 keV x-rays were reconstructed in 3D by measuring their PL signal using a confocal laser scanning microscope operating in fluorescence mode. On-going investigations are focusing on the results obtained through thisz-scanning technique to explore the potential impact of absorption effects at the excitation laser wavelength.

Over-blending effect of lubricants on capsules manufacturing: a simple and fast wettability technique to predict batch dissolution performance.

Mixing/blending is a crucial operation in the manufacturing of solid drug products in the pharmaceutical industry. Although usually described and controlled in specific steps, blending is also inherent to other operations such as the transference of materials and equipment feeding systems. This study aimed to investigate a simple and fast wettability testing procedure capable to foresee the potential over-blending effects of lubricants occurring during the manufacturing of solid dosage forms. An industrial batch blend was submitted to two mixing mechanisms studies (diffusion and shear) during increasing time periods, and the developed wettability testing procedure was applied to assess their impact on blend water uptake. Capsules filled with these blends were tested for dissolution and disintegration. The method was applied to capsules with known dissolution results manufactured at an industrial scale. Results demonstrated that processes inducing shear stress led to less permeable blends with consequent retardation on capsules dissolution of at least 35% in the tested timepoints and obtained study metrics above 500 s. Moreover, disintegration testing was not able to detect non-compliant dissolutions, while the proposed wettability testing procedure proved to be able to identify performance failures. Wettability results correlate the effect of mixing mechanisms to capsules dissolution performance, evidencing that this technique can be applied in the pharmaceutical industry to evaluate possible over-blending effects.

Influence of particle size on the SARS-CoV-2 spike protein detection using IgG-capped gold nanoparticles and dynamic light scattering.

Due to the unprecedented and ongoing nature of the coronavirus outbreak, the development of rapid immunoassays to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its highly contagious variants is an important and challenging task. Here, we report the development of polyclonal antibody-functionalized spherical gold nanoparticle biosensors as well as the influence of the nanoparticle sizes on the immunoassay response to detect the SARS-CoV-2 spike protein by dynamic light scattering. By monitoring the increment in the hydrodynamic diameter (ΔDH) by dynamic light scattering measurements in the antigen-antibody interaction, SARS-CoV-2 S-protein can be detected in only 5 min. The larger the nanoparticles, the larger ΔDH in the presence of spike protein. From adsorption isotherm, the calculated binding constant (K D ) was 83 nM and the estimated limit of detection was 13 ng/mL (30 pM). The biosensor was stable up to 90 days at 4 °C. Therefore, the biosensor developed in this work could be potentially applied as a fast and sensible immunoassay to detect SARS-CoV-2 infection in patient samples.

Gender-related differences in the modulation of anthropometric, biochemical, and immune markers by physical activity in hypertensive and diabetic individuals.

Systemic arterial hypertension (SAH) and type 2 diabetes mellitus (T2DM) compose the two major noncommunicable chronic inflammatory diseases. Physical activity has been shown as a promising complementary approach to control the systemic inflammation. However, it is still unclear whether this modulation is gender-dependent. The objective of this study was evaluate the gender-related influence of physical activity on the inflammatory response and biochemical profile of individuals with SAH and T2DM. An international physical activity questionnaire was applied to 376 individuals diagnosed with SAH and T2DM in order to access their exercises routine and was evaluated the influence of physical activity in biochemical, anthropometrical, and immunological markers involved in these disorders in men and women. Even though active individuals have exhibited lower serum levels of IL-1ß, IFN-γ, TNF-α, and IL-17A, the ratios between IL-10 and all inflammatory cytokines were higher in men than in women. Physically active individuals also demonstrated increased HDL/LDL and HDL/VLDL ratios. Moreover, multiple correlations revealed that in active women both IL-10 and TNF-α serum levels positively correlate with fasting glucose levels, and were negatively associated with HDL levels. Our findings suggest that gender-related differences dictate a distinct crosstalk between inflammatory and biochemical markers in physically active individuals.

Rifampicin-resistant TB: discordance between Xpert® MTB/RIF and MTBDRplus results.

BACKGROUND: South Africa´s diagnostic algorithm for TB diagnosis from 2011 to 2017 employed the Xpert® MTB/RIF assay as the initial screening test for TB diagnosis and rifampicin (RIF) susceptibility, followed by submission of a specimen for GenoType® MTBDRplus. This study aimed to determine the concordance between the two assays in terms of RIF susceptibility and explore reasons for discordance.METHODS: This was a retrospective laboratory-based study that included all MTBDRplus results of tests performed at the Braamfontein Mycobacteriology Referral Laboratory between 1 September 2014 and 31 August 2015. The patient´s Xpert RIF result was linked with the MTBDRplus result.RESULTS: The overall concordance between RIF susceptibility results was 96.4%. There were 68 discordant RIF results. The most common reasons for discordance identified were possible false Xpert RIF-resistant results (22%), mixed infection/heteroresistance (16%), transcription errors (7%) and erroneous manual interpretation of the MTBDRplus strip (7%). Xpert RIF resistance detected using delayed hybridisation was associated with discordance.CONCLUSIONS: The overall concordance between the MTBDRplus and Xpert RIF results were very good. Management of discordance should include repeat specimens for Xpert and MTBDRplus and rpoB sequencing. All variables should then be considered before treatment regimens are altered.

Area-wide insecticide resistance and endosymbiont incidence in the whitefly Bemisia tabaci MEAM1 (B biotype): A Neotropical context.

Agriculture insecticides are used against insect pest species, but are able to change community structure in contaminated habitats, and also the genetic pool of exposed individuals. In fact, the latter effect is a relevant tool to in situ biomonitoring of pollutant contamination and impact, besides its practical economic and management concerns. This takes place because the emergence of individuals with resistance to insecticides is particularly frequent among insect pest species and usually enhances insecticide overuse and crop losses. Pest insects of global prominence such as whiteflies are a focus of attention due to problems with insecticide resistance and association with endosymbionts, as the case of the invasive putative species Bemisia tabaci MEAM1. The scenario is particularly complex in the Neotropics, where insecticide use is ubiquitous, but whose spatial scale of occurrence is usually neglected. Here we explored the spatial-dependence of both phenomena in MEAM1 whiteflies recording resistance to two widely used insecticides, lambda-cyhalothrin and spiromesifen, and endosymbiont co-occurrence. Resistance to both insecticides was frequent exhibiting low to moderate frequency of lambda-cyhalothrin resistance and moderate to high frequency of spiromesifen resistance. Among the prevailing whitefly endosymbionts, Wolbachia, Cardinium and Arsenophonus were markedly absent. In contrast, Hamiltonella and Rickettsia prevailed and their incidence was correlated. Furthermore, Rickettsia endosymbionts were particularly associated with lambda-cyhalothrin susceptibility. These traits were spatially dependent with significant variation taking place within an area of about 700 Km2. Such findings reinforce the notion of endosymbiont-associated resistance to insecticides, and also of their local incidence allowing spatial mapping and locally-targeted mitigation.

Sustainable laser-based technology for insect pest control.

Aphids damage directly or indirectly cultures by feeding and spreading diseases, leading to huge economical losses. So far, only the use of pesticides can mitigate their impact, causing severe health and environmental issues. Hence, innovative eco-friendly and low-cost solutions must be promoted apart from chemical control. Here, we have investigated the use of laser radiation as a reliable solution. We have analyzed the lethal dose required to kill 90% of a population for two major pest aphid species (Acyrthosiphon pisum and Rhopalosiphum padi). We showed that irradiating insects at an early stage (one-day old nymph) is crucial to lower the lethal dose without affecting plant growth and health. The laser is mostly lethal, but it can also cause insect stunting and a reduction of survivors' fecundity. Nevertheless, we did not notice any significant visible effect on the offspring of the surviving irradiated generation. The estimated energy cost and the harmless effect of laser radiation on host plants show that this physics-based strategy can be a promising alternative to chemical pesticides.

Management of rifampicin-resistant TB: programme indicators and care cascade analysis in South Africa.

BACKGROUND: Xpert® MTB/RIF was expected to revolutionise the management of rifampicin-resistant TB (RR-TB) by enabling rapid and decentralised diagnosis of rifampicin (RIF) resistance.METHODS: We performed a care cascade analysis for a cohort of RR-TB patients managed under programmatic conditions. Cumulative incidences of time to completion of the RR-TB care cascade steps were estimated, reasons for delay or attrition from the cascade investigated and WHO programme indicators for monitoring of RR-TB programmes calculated.RESULTS: Of 502 patients diagnosed with RR-TB using Xpert, 64% initiated multidrug-resistant TB (MDR-TB) treatment immediately, 20% after some first-line treatment, 16% never initiated MDR-TB treatment, mainly because of death (44%) or loss to follow-up (26%) soon after diagnosis. A supplementary sputum sample was collected within 14 days of treatment in 58.8% of cases. Only 63% of RR-TB cases were assessed for isoniazid resistance, and only 65% of MDR-TB cases were evaluated for pre-XDR-TB (extensively drug-resistant TB). Treatment was individualised in 57% of pre-XDR and 68% of XDR-TB patients. Only 8% completed the entire RR-TB care cascade as intended.CONCLUSION: Fidelity to the RR-TB algorithm was poor, with substantial losses at each step of the cascade, highlighting the fact that implementation of novel technologies needs to be accompanied by health system strengthening to maximise impact.

Antibacterial activity of Barbatimão (Stryphnodendron adstringens) against Staphylococcus aureus: in vitro and in silico studies.

We evaluated the activity of the aqueous fraction and the ethyl acetate fraction of Stryphnodendron adstringens against Staphylococcus aureus and proposed their mechanism of action. The antibacterial activity of S. adstringens fractions was evaluated against S. aureus and the cell targets were rated by docking. The fractions showed moderate antibacterial activity against S. aureus without toxicity on two mammalian cell lines. They also showed synergistic antibacterial activity with tannic acid (TA). In silico assays indicated FabG, FabZ and FabI as probable targets. The metabolic pathway for fatty acid biosynthesis in S. aureus was affected by components of S. adstringens. The synergistic effect when combining TA with S. adstringens fractions suggests a natural alternative to S. aureus control. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study describing the possible targets of action of Stryphnodendron adstringens on Staphylococcus aureus. Molecular dynamics simulations showed that the components of S. adstringens affected the metabolic pathway for fatty acid biosynthesis (FAS II) in S. aureus, inhibiting the FabI, FabG and FabZ enzymes. As tannic acid (TA) is a known inhibitor of some targets identified, we showed synergistic antibacterial activity of S. adstringens in combination with TA. This combination did not show toxicity against HaCaT and Vero cells and based on all these results we suggest that S. adstringens can be a natural and sustainable alternative to S. aureus control.

Bright and fast scintillations of an inorganic halide perovskite CsPbBr3 crystal at cryogenic temperatures.

Highly efficient scintillation crystals with short decay times are indispensable for improving the performance of numerous detection and imaging instruments that use- X-rays, gamma-quanta, ionising particles or neutrons. Halide perovskites emerged recently as very promising materials for detection of ionising radiation that motivated further exploration of the materials. In this work, we report on excellent scintillation properties of CsPbBr3 crystals when cooled to cryogenic temperatures. The temperature dependence of luminescence spectra, decay kinetics and light yield under excitation with X-rays and α-particles was investigated. It is shown that the observed changes of spectral and kinetic characteristics of the crystal with temperature can be consistently explained by radiative decay of free excitons, bound and trapped excitons as well as electron-hole pairs originating from their disintegration. It has been found that the crystal exhibits a fast decay time constant of 1 ns at 7 K. The scintillation light yield of CsPbBr3 at 7 K is assessed to be 50,000 ± 10,000 ph/MeV at excitation with 12 keV X-rays and 109,000 ± 22,000 ph/MeV at excitation with α-particles of 241Am. This finding places CsPbBr3 in an excellent position for the development of a new generation of cryogenic, efficient scintillation detectors with nanosecond response time, marking a step-change in opportunities for scintillator-based applications.

Metal-based antimicrobial strategies against intramacrophage Mycobacterium tuberculosis.

The combinatorial chemistry has been an important tool for the development of new strategies against the Mycobacterium tuberculosis. Therefore, we evaluated the antimycobacterial activity of two coordinated metal complexes (Cu(II) and Co(II)) and a free ligand, including in the intramacrophage environment. The complexes were more active than the free ligand, indicating that the complexation favoured the antimicrobial activity. None of the compounds showed cytotoxic effect at the concentration of 200 µg ml-1 and both complexes showed intracellular antimicrobial activity, with results as effective as rifampicin. In this study, it was possible to identify complexes containing benzohydroxamate associated with transition metal ions (Cu2+ and Co2+ ), which were able to inhibit the growth of M. tuberculosis, including in persistence stage. In addition, the docking analysis allows inferring a possible interaction of the metal complexes with the enzyme urease, which has been reported as crucial for the bacillus survival in the intraphagosomal environment. Thus, these set of results demonstrate the potential of these metals in the development of new drugs against M. tuberculosis. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, it was possible to identify complexes containing benzohydroxamate associated with transition metals (Cu2+ and Co2+ ), which were able to inhibit the growth of Mycobacterium tuberculosis, including in the persistence stage. In this context, cobalt and copper can be scaffolds for new drugs against M. tuberculosis.

Dentinal microcracks on freshly extracted teeth: the impact of the extraction technique.

AIM: To evaluate the incidence of root dentinal microcracks after two extraction techniques through micro-computed tomographic (micro-CT) analysis. METHODOLOGY: Thirty pairs of premolars, extracted for orthodontic reasons, were assigned to two experimental groups, following a split-mouth design (n = 30): traumatic technique group (TTG) - teeth extracted following a conventional protocol using forceps, and an atraumatic technique group (ATG) - teeth extracted following an atraumatic technique protocol in which the root was gently detached from the periodontal ligament using a periotome. All teeth were immediately immersed in distilled water and scanned in a micro-CT device within 72 h following the extraction. The assessment of the images was completed on cross-section images by two masked evaluators. The Mann-Whitney test was used to assess the significant differences between the groups regarding the number of cross-sections displaying microcracks whilst the Fischer's exact test was used to assess differences in the frequency of specimens with defects (P < 0.05). RESULTS: A total of 52 750 micro-CT cross-sectional images were evaluated. A total of 352 cross-sections had at least one dentinal defect. Microcracks were observed in five teeth of the TTG group (n = 352 slices) and in two teeth of the ATG group (n = 103 slices). The statistical analysis used was unable to detect a significant difference between the groups in terms of the number of dentinal microcracks (P = 0.233) and in the frequency of teeth displaying microcracks (P = 0.424). CONCLUSION: A small number of sound teeth without endodontic treatment had dentinal microcracks regardless of the extraction technique applied. No difference was noticed between the traumatic and atraumatic techniques in the incidence of microcracks.

Tooth crown mesiodistal measurements for the determination of sexual dimorphism across a range of populations: A systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to determine whether the tooth crown sexual dimorphism pattern reported in previous small studies can be generalized for a broader range of populations. LITERATURE REVIEW: A systematic literature review was performed by two independent examiners. The following databases were searched from October 2015 to July 2016: PubMed, Scopus, Lilacs, ScienceDirect, Medline, and Cochrane Reviews. No language restrictions were applied to the search. SELECTION CRITERIA: The inclusion criteria comprised original studies investigating mesiodistal permanent teeth that reported the sample population and standard deviation. All right-sided teeth, except the third molars, were measured and separated by sex in the included studies. Thirty-one studies were included in the quantitative data synthesis and meta-analysis. Studies of non-human teeth, skeletal remains, or an overly specific study population were excluded. MAIN RESULTS: Thirty-one trials, involving 6481 participants, provided data for the meta-analysis of teeth. Sexual dimorphism in mesiodistal crowns was found in all teeth across a range of populations, principally in lower canines (5.73%) and maxillary canines (4.72%), followed by the lower second molars (3.54%) and upper second molars(3.20%), and finally in the lower first molars(3.14%) and upper first molars(2.64%). CONCLUSIONS: A small degree of sexual dimorphism exists in all human teeth. Second molars and canines show the greatest sexual dimorphism. Additionally, smaller racial differences are present in mesiodistal crowns among groups living in different geographic areas; however, it is not possible to establish a single value applicable for all populations.

Repurposing strategies for Chagas disease therapy: the effect of imatinib and derivatives against Trypanosoma cruzi.

Chagas disease (CD) is a neglected parasitic condition endemic in the Americas caused by Trypanosoma cruzi. Patients present an acute phase that may or not be symptomatic, followed by lifelong chronic stage, mostly indeterminate, or with cardiac and/or digestive progressive lesions. Benznidazole (BZ) and nifurtimox are the only drugs approved for treatment but not effective in the late chronic phase and many strains of the parasite are naturally resistant. New alternative therapy is required to address this serious public health issue. Repositioning and combination represent faster, and cheaper trial strategies encouraged for neglected diseases. The effect of imatinib (IMB), a tyrosine kinase inhibitor designed for use in neoplasias, was assessed in vitro on T. cruzi and mammalian host cells. In comparison with BZ, IMB was moderately active against different strains and forms of the parasite. The combination IMB + BZ in fixed-ratio proportions was additive. Novel 14 derivatives of IMB were screened and a 3,2-difluoro-2-phenylacetamide (3e) was as potent as BZ on T. cruzi but had low selectivity index. The results demonstrate the importance of phenotypic assays, encourage the improvement of IMB derivatives to reach selectivity and testify to the use of repurposing and combination in drug screening for CD.

Long-term efficacy of opicapone in fluctuating Parkinson's disease patients: a pooled analysis of data from two phase 3 clinical trials and their open-label extensions.

BACKGROUND AND PURPOSE: The aim was to evaluate the efficacy of the catechol-O-methyltransferase inhibitor opicapone (25 and 50 mg) as adjunct therapy to levodopa in a pooled population of Parkinson's disease patients who participated in the pivotal double-blind trials of opicapone and their 1-year open-label extensions. METHODS: Data (placebo, opicapone 25 mg and opicapone 50 mg) from the BIPARK-1 and BIPARK-2 double-blind and open-label studies were combined. The studies had similar designs, eligibility criteria and assessment methods. The primary efficacy variable in both double-blind studies was the change from baseline in absolute OFF time based on patient diaries. RESULTS: Double-blind treatment with opicapone (25 and 50 mg) significantly reduced absolute daily OFF time from a baseline of 6.1-6.6 h. The mean (and 95% confidence interval) treatment effect versus placebo was -35.1 (-62.1, -8.2) min (P = 0.0106) for the 25 mg dose and -58.1 (-84.5, -31.7) min (P < 0.0001) for the 50 mg dose. Reductions in OFF time were mirrored by significant increases in ON time without troublesome dyskinesia (P < 0.05 and P < 0.0001 for the 25 and 50 mg doses, respectively). No significant differences were observed for ON time with troublesome dyskinesia. Patient diary results from the open-label phase indicated a maintenance of effect for patients previously treated with opicapone 50 mg. The group previously treated with the 25 mg dose benefitted with further optimization of therapy during the open-label phase, whilst switching from placebo to opicapone led to significant reductions in OFF time and increased ON time. CONCLUSIONS: Over at least 1 year of open-label therapy, opicapone consistently reduced OFF time and increased ON time without increasing the frequency of troublesome dyskinesia.

Photochemistry and desorption induced by X-rays in water rich astrophysical ice analogs: implications for the moon Enceladus and other frozen space environments.

Soft X-rays are an important agent for chemical processing in the Solar System and in the interstellar medium. The photolysis and photodesorption processes of H2O-rich ices triggered by soft X-rays was, experimentally, addressed in this paper. The experiments were performed at the Brazilian synchrotron facility LNLS/CNPEN employing broadband radiation (from 6 to 2000 eV; mainly soft X-rays and a small fraction of VUV) in solid samples at temperatures of 20 and 80 K. The icy samples were monitored by infrared spectroscopy. We determined the effective destruction cross section (in the order 10-18 cm2) as well as the formation cross section for the new species produced after the irradiation. Among them, we list OCN-, CO, CO3, CH3OH, H2O2, HCOO-, NH4 +, HCONH2 and CH3HCO, mostly formed in the experiment at 80 K. The chemical equilibrium stage was characterized and molecular abundances were quantified. In addition, we discuss a methodology to estimate the amount of unknown species in the ice produced by photolysis. The samples reach chemical equilibrium at fluences around 2-3 × 1018 cm-2. Timescales for reaching chemical equilibrium in space environments illuminated by X-rays were given, as well as the desorption yields induced by X-rays. The astrophysical implication on the surface chemistry and desorption processes at the moon Enceladus are provided.

Copper(II) complex-loaded castor oil-based nanostructured lipid carriers used against Mycobacterium tuberculosis : Development, characterisation, in vitro and in vivo biological assays.

A copper(II) complex-loaded castor oil-based nanostructured lipid carrier was evaluated to enhance the poor water solubility of antimicrobial compounds, improving their biological properties and antimicrobial activity against Mycobacterium tuberculosis. Nanostructured lipid carriers were composed of the castor oil, polyoxyethylene 40 stearate and caprylic/capric triglyceride, poloxamer 407, cetyltrimethylammonium bromide and three different copper(II) complexes. The systems were ultrasonicated at an amplitude of 8% for 20 min and an ice bath was used throughout the procedure. The blank nanostructured lipid carrier (F5) and nanostructured lipid carriers loaded with copper(II) complex 1, 2 and 3 (F5.1, F5.2 and F5.3, respectively) for 45 days presented values of mean diameter, poly dispersity index and zeta potential ranging from 186 to 199 nm, 0.14 to 0.2 and 24 to 30 mV, respectively. Atomic force microscopy indicated that the nanostructured lipid carriers were distributed at the nanoscale, corroborating the mean diameter data. Differential scanning calorimetry determined the melting points of the constituents of the nanostructured lipid carriers. The antimicrobial activity of copper(II) complexloaded F5 against M. tuberculosis H37Rv showed better anti-tuberculosis activity than the free complexes. In vivo biological assays of complex-loaded F5 demonstrated reduced toxicity. Our results suggest that nanostructured lipid carriers could be a potential nanotechnological strategy to optimise tuberculosis treatment.

Climatic variables drive temporal patterns of α and ß diversities of dung beetles.

Understanding the mechanisms underpinning spatiotemporal diversity patterns of biological communities is a major goal of ecology. We aimed to test two ecological hypotheses: (i) temporal patterns of ß-diversity will mostly be driven by nestedness, with a loss of species from summer to winter, and (ii) nestedness values will correlate with climatic variables instead of turnover values, indicating either a loss of species during winter or a gain of species during summer. We sampled dung beetles using standardized sampling protocols along a year in four Atlantic forest sites: two at the northwest and two at the central region of Rio Grande do Sul state, southern Brazil. We partitioned temporal patterns of ß-diversity into turnover and nestedness in order to investigate if community changes are driven by species substitution or gain/loss across time. Our results highlighted five main findings: (i) dung beetle composition varied more with sites than site geographic position; (ii) there was almost one and a half 'true' dung beetle assemblages regarding the spatial distribution of species weighed by abundance; (iii) we found a positive influence of mean temperature and a negative influence of relative humidity on both species richness and abundance; (iv) both spatial and temporal dissimilarity among sites were dominated by species replacement, while the relative importance of nestedness was higher in temporal than spatial patterns; (v) there was an effect of precipitation and relative humidity on temporal patterns of ß-diversity components, but these effects were site-dependent. Contrary to our expectations, the ß-diversity component of turnover dominated both spatial and temporal patterns in dung beetle dissimilarity among sites and months. Distinct climatic variables affected differently the α-diversity and ß-diversity components of dung beetle assemblages. Partitioning ß-diversity into temporal components is a promising approach to unveil patterns of the community dynamics and to produce insights on mechanisms underlying such patterns.