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Introdução: A trazodona é um antidepressivo atípico derivado da triazolopiridina, indicado para o tratamento da depressão com ou sem episódios de ansiedade, dor associada à neuropatia diabética e outros tipos de dor crônica. Objetivo: Este estudo teve como objetivo avaliar a bioequivalência entre a formulação teste de Trazodona 100 mg (Sanofi Medley Farmacêutica Ltda) e o produto de referência, Donaren (Apsen Farmacêutica S/A) de acordo com a legislação vigente. Método: Foi realizado um estudo cruzado, aberto, randomizado, de dose única com indivíduos saudáveis ​​de ambos os sexos. A fase clínica foi realizada com 48 indivíduos que receberam os medicamentos em condições de alimentação. A fármaco foi quantificado no plasma por cromatografia líquida acoplada a espectrometria de massas (LC-MS/MS). A avaliação da bioequivalência foi baseada em critérios de aceitação pré-definidos de 80,00 – 125,00% para o intervalo de confiança de 90% para a razão dos produtos teste e referência para os dados log-transformados da área sob a curva (ASC) e da concentração plasmática máxima (Cmax), conforme recomendação da Anvisa. Resultados: As razões geométricas médias (intervalos de confiança de 90%) para Cmax e ASC0-t foram 103,22% (96,13 – 110,84) e 99,06% (94,80 – 103,150), respectivamente. Não houve eventos adversos durante o estudo. Conclusão: As formulações teste e de referência foram consideradas estatisticamente bioequivalentes de acordo com os requisitos regulatórios. A formulação do teste tem sido disponibilizada no mercado local, contribuindo para o acesso da população a medicamentos genéricos de qualidade para o tratamento de transtornos depressivos.

The agri-food and forestry sectors are in transition towards more sustainable, green, and innovative systems tackling several challenges posed by globalization, governance, and consumers’ demands. This transition to novel processes, markets, and businesses requires skills and competences to prepare the new generations and upskill the actual workforce. The purpose of this paper was to assess the skills and knowledge needs of future professionals in the agri-food and forestry sectors, from European stakeholders’ perspectives, by using a European questionnaire. Overall, respondents highlighted the importance of improving sustainability and soft and digital skills. In particular, food safety management and control; quality management and assurance of processes and product; efficient use of resources and organization; and planning, visioning, and strategic thinking skills ranked higher. In almost all countries, respondents had the perception that neither formal nor non-formal training covered training needs, though formal training was more suited to address education requirements. Both for organizations and individuals, it is far more relevant to have skills to perform than to have training recognition. The outcomes also provide findings that can be used to help develop updated curricula that meet the sector’s needs.

We investigated the magnetic effect of Mn2+ ions on an exciton of Mn-doped CsPbI3 quantum dots (QDs), where we looked for the signatures of an exciton magnetic polaron known to produce a large effective magnetic field in Mn-doped CdSe QDs. In contrast to Mn-doped CdSe QDs that can produce ∼100 T of magnetic field upon photoexcitation, manifested as a large change in the energy and relaxation dynamics of a bright exciton, Mn-doped CsPbI3 QDs exhibited little influence of a magnetic dopant on the behavior of a bright exciton. However, a μs-lived dark exciton in CsPbI3 QDs showed 40% faster decay in the presence of Mn2+, equivalent to the effect of ∼3 T of an external magnetic field. While further study is necessary to fully understand the origin of the large difference in the magneto-optic property of an exciton in two systems, we consider that the difference in antiferromagnetic coupling of the dopants is an important contributing factor.

2D reactions on surfaces/interfaces are important but difficult to study. In this issue of Chem, Seki et al. report the use of sum-frequency generation vibrational spectroscopy to elucidate that molecular mechanisms of surfactants facilitated "on-water" 2D polymerization reactions by identifying the key reaction intermediate.

The plasma confinement of the International Tokamak Experimental Rector (ITER) is provided by the magnetic field generated by 18 toroidal field (TF) coils while 6 poloidal field (PF) and 6 central solenoid coils have the function to drive, shape and pre-heat the plasma. Fusion for Energy (F4E), the European Domestic Agency for ITER, is responsible for the supply of 10 TF coils and 5 PF coils to the ITER project. The ITER Organization (IO) team is instead responsible for the design of such coils as well for the coordination of the activities of the different Domestic Agencies (DAs) producing the different components, and their assembly into the Tokamak. The PF coils utilize NbTi Cable-in-Conduit-Conductor and have different diameters between 8 and 24 meters and weights of up to 400 tons. Regarding the PF coils produced by F4E, so far one has been completed by the Institute of Plasma Physics Chinese Academy of Sciences (ASIPP) under a collaboration agreement with F4E. The other 4 PF coils are being produced at the ITER site in Saint Paul lez Durance, France, under F4E supervision. The first of these (PF5) will be completed by July 2020 while the last coil (PF3) will be ready be the end of 2023. The TF coils utilize Nb3Sn conductor and are manufactured with the “Wind, React & Transfer” method. The first TF coil is close to completion and will be delivered to the ITER site in early 2020. Subsequent TF coils will follow at a rate of about one every 3-4 months. In this article we will report on the production status of both PF and TF coils and, in particular, the different manufacturing strategies employed. The main challenges faced so far and the results obtained are also described.

Study design We combined elements of cohort and crossover-cohort design. Objective The objective of this study was to compare long-term outcomes for Spinal Manipulative Therapy (SMT) and Opioid Analgesic Therapy (OAT) regarding escalation of care for patients with chronic low back pain (cLBP). Summary of background data Current evidence-based guidelines for clinical management of cLBP include both OAT and SMT. For long-term care of older adults, the efficiency and value of continuing either OAT or SMT are uncertain. Methods We examined Medicare claims data spanning a five-year period. We included older Medicare beneficiaries with an episode of cLBP beginning in 2013. All patients were continuously enrolled under Medicare Parts A, B, and D. We analyzed the cumulative frequency of encounters indicative of an escalation of care for cLBP, including hospitalizations, emergency department visits, advanced diagnostic imaging, specialist visits, lumbosacral surgery, interventional pain medicine techniques, and encounters for potential complications of cLBP. Results SMT was associated with lower rates of escalation of care as compared to OAT. The adjusted rate of escalated care encounters was approximately 2.5 times higher for initial choice of OAT vs. initial choice of SMT (with weighted propensity scoring: rate ratio 2.67, 95% CI 2.64-2.69, p Conclusions Among older Medicare beneficiaries who initiated long-term care for cLBP with opioid analgesic therapy, the adjusted rate of escalated care encounters was significantly higher as compared to those who initiated care with spinal manipulative therapy.Level of Evidence: 3.

Study design Retrospective observational study. Objective Opioid Analgesic Therapy (OAT) and Spinal Manipulative Therapy (SMT) are evidence-based strategies for treatment of chronic low back pain (cLBP), but the long-term safety of these therapies is uncertain. The objective of this study was to compare OAT versus SMT with regard to risk of adverse drug events (ADEs) among older adults with cLBP. Summary of background data We examined Medicare claims data spanning a 5-year period on fee-for-service beneficiaries aged 65 to 84 years, continuously enrolled under Medicare Parts A, B, and D for a 60-month study period, and with an episode of cLBP in 2013. We excluded patients with a diagnosis of cancer or use of hospice care. Methods All included patients received long-term management of cLBP with SMT or OAT. We assembled cohorts of patients who received SMT or OAT only, and cohorts of patients who crossed over from OAT to SMT or from SMT to OAT. We used Poisson regression to estimate the adjusted incidence rate ratio for outpatient ADE among patients who initially chose OAT as compared with SMT. Results With controlling for patient characteristics, health status, and propensity score, the adjusted rate of ADE was more than 42 times higher for initial choice of OAT versus initial choice of SMT (rate ratio 42.85, 95% CI 34.16-53.76, P Conclusion Among older Medicare beneficiaries who received long-term care for cLBP the adjusted rate of ADE for patients who initially chose OAT was substantially higher than those who initially chose SMT.Level of Evidence: 2.

We investigated the magnetic effect of Mn

O presente artigo tem como intuito elucidar a distincao entre sofistica e retorica no dialogo Gorgias de Platao, a partir da assercao enigmatica de Socrates de que "sofistas e retores se diluem em uma mesma coisa e com relacao as mesmas coisas devido a sua contiguidade" (465c4-5). Para tal fim, abordaremos, no primeiro momento, a genealogia dos termos gregos sophistike e rhetorike na literatura grega superstite, buscando mostrar que as nocoes de "sofistica" e "retorica", tal como as entendemos de um modo geral hoje, sao frutos da operacao platonica-aristotelica de delimitacao de um tipo de pensamento e pratica pedagogica em oposicao a "filosofia". No segundo momento, passaremos a analise dos dialogos platonicos, mais especificamente o Gorgias e o Protagoras, em que essas duas nocoes se encontram em processo de delineamento teorico.

Anisotropic semiconductor nanocrystals with controlled quantum confinement are important in many applications for the directionality of the flow of photons and charge carriers combined with the pro...

Orientador: Jose Pedrazzoli Junior Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas Resumo: O objetivo do presente estudo foi comparar o comportamento in vivo e in vitro de duas formulações de pantoprazol. Além disso, foi proposta a classificação biofarmacêutica provisional do fármaco, bem como uma correlação in vitro - in vivo não linear (IVIVR). Os estudos in vivo foram conduzidos em dose única em jejum (n=28) e pós-prandial (n=62) com desenho cruzado e randomizado. As concentrações plasmáticas de pantoprazol foram determinadas por LC-MS/MS. Os parâmetros farmacocinéticos e a deconvolução dos dados de concentração plasmática versus tempo foram obtidos empregando-se o programa WinNonlin 5.2 - IVIVC toolkit (Pharsight, EUA). Os perfis de dissolução foram avaliados em meios biorelevantes (FaSSIF e FeSSIF) nos aparatos USP 2 e 3 e as curvas de dissolução foram comparadas considerando os cálculos de f2 ou modelos dependentes. Os valores da solubilidade, Log P e cLog P do pantoprazol foram obtidos do Merck Index (Whitehouse Station, EUA) e do programa ChemDraw Ultra 10.0 (Cambridgesoft, EUA). Os dados de permeabilidade do pantoprazol forma obtidos do programa ADMET Predictor (Simulations Plus, EUA). A classificação biofarmacêutica provisional do pantoprazol foi proposta considerando o fármaco metoprolol como referência. A IVIVR foi estabelecida entre as frações dissolvidas (Fd), dos ensaios no aparato 2, com as frações absorvidas dos estudos in vivo. Para o estudo em jejum os valores dos intervalos de confiança 90% para os parâmetros Cmax (0.94-1.03) e ASC0-t (0.89-0.99) apresentaram-se dentro dos limites de confiança (0.8-1.25). Entretanto, os intervalos de confiança do estudo pós-prandial não se apresentaram dentro dos limites de confiança. Os perfis de dissolução nos aparatos USP 2 e 3 demonstraram a mesma disposição das formulações nos meios FaSSIF e FeSSIF, considerando o modelos de f2 e Weibull. Os valores de solubilidade, Log P e permeabilidade para o fármaco pantoprazol obtidos in silico permitiram a classificação do fármaco como de alta solubilidade e baixa permeabilidade. A IVIVR não linear obtida para as formulações de pantoprazol indicaram que a permeabilidade é fator limitante para a absorção. Enfim, os perfis de dissolução no meio biorelevante FaSSIF, nos aparatos USP 2 e 3, puderam ser empregados para prever o comportamento in vivo das formulações. O pantoprazol foi classificado como um fármaco classe III e a IVIVR não-linear obtida confirma a classificação biofarmacêutica provisional. Além disso, pôde-se sugerir a bioisenção para formulações de pantoprazol com base nos resultados dos estudos de dissolução em meios biorelevantes e na conhecida segurança e tolerabilidade desse fármaco. Abstract: The purpose of the study was to compare the in vivo and in vitro behaviour of pantoprazole formulations. Moreover, a provisional biopharmaceutical classification of the drug (BCS) was proposed as well as a non-linear in vitro - in vivo relationship (IVIVR). The in vivo studies were conducted under single dose in fasting (n=28) and fed conditions (n=62) and randomized crossover design. Plasma concentrations of pantoprazole were determined by LC-MS/MS. Pharmacokinetic parameters and deconvolution data were calculated from the observed plasma-concentration time profiles by WinNonlin 5.2 - IVIVC toolkit (Pharsight, USA). Dissolution profiles were evaluated in biorelevant media (FaSSIF and FeSSIF) in USP apparatus 2 and 3 and the dissolution curves were compared to either f2 values or model-independent approach. The solubility, Log P and cLogP data of pantoprazole were obtained from Merck Index (Whitehouse Station, USA) and ChemDraw Ultra 10.0 (Cambridgesoft, USA). The permeability data of pantoprazole were calculated by ADMET Predictor (Simulations Plus, USA). The provisional biopharmaceutical classification of pantoprazole was proposed considering metoprolol as a reference drug. The IVIVR analysis was evaluated considering the dissolved drug fraction (Fd) from apparatus 2 and the absorved drug fraction (Fa) from the in vivo studies. Under fasting condition the 90% C.I for Cmax (0.94-1.03) and AUC0-t (0.89-0.99) were within the range of bioequivalence (0.8-1.25). However, the results of the fed study were not within the BE range. The dissolution profiles in USP apparatus 2 and 3 demonstrated a similar disposition of both formulations in FaSSIF and FeSSIF media considering f2 and Weibull's models. The solubility, Log P and permeability values of pantoprazole obtained by in silico evaluation allowed the classification of pantoprazole as a highly soluble and low permeability drug. The non-linear IVIVR obtained for the pantoprazole formulations indicated that absorption of pantoprazole is limited by permeability. In conclusion, the dissolution profiles in the biorelevant medium (FaSSIF) on both USP apparatus 2 and 3 may be used as a tool to predict the in vivo disposition of the formulations. Pantoprazole was classified as a class III drug (BCS) corroborated by the non-linear IVIVR study to support this provisional classification. Furthermore, biowaiver may be granted for pantoprazole formulations on the basis of in vitro dissolution results in biorelevant media and the data available in the literature concerning high tolerability and safety of the drug. Doutorado Doutor em Farmacologia

Orientador: Trajano Augusto Ricca Vieira Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Estudos da Linguagem Resumo: O presente trabalho tem como objetivo oferecer uma interpretação sobre o problema da retórica no diálogo Górgias de Platão. O enfoque específico, todavia, não é o problema ético-político ressaltado pela crítica platônica, que certamente é central no pensamento do filósofo, mas a presença de elementos típicos dos gêneros retóricos na própria constituição do diálogo enquanto novo gênero literário. Minha proposta de leitura, portanto, é mostrar como a retórica está presente, de diversas formas, no modo de discurso e de escrita que Platão opta para expor suas idéias filosóficas. Analiso também a interface entre o diálogo e a comédia e a tragédia do ponto de vista da construção dos caracteres das personagens, tendo em vista as referências de Platão a Epicarmo e Eurípides no drama filosófico. Por fim, apresento a tradução do diálogo Górgias como complemento ao trabalho Abstract: This work intends to offer an interpretation of the problem of rhetoric in the Plato¿s Gorgias. The specific approach, however, is not the ethic and politic problem emphasized by the platonic criticism, which is certainly central in the philosopher¿s thought, but the presence of typical elements of the rhetoric genres in the constitution of the dialogue as a new literary genre. My interpretation¿s purpose, then, is to show how the rhetoric participates in different ways in the mode of discourse and writing that Plato opts to explain his philosophical ideas. I analyze too the interface between dialogue and comedy and tragedy in the point of view of the characters¿ construction, since Plato refers to Epicarmus and Euripides in the philosophical drama. Finally, I present the Gorgias¿ translation as complement of this work Doutorado Letras Clássicas Doutor em Linguística

The objective of this study was to compare patients' perspectives on the use of spinal manipulative therapy (SMT) compared to prescription drug therapy (PDT) with regard to health-related quality of life (HRQoL), patient beliefs, and satisfaction with treatment.Four cohorts of Medicare beneficiaries were assembled according to previous treatment received as evidenced in claims data: SMT, PDT, and 2 crossover cohorts (where participants experienced both types of treatments). A total of 195 Medicare beneficiaries responded to the survey. Outcome measures used were a 0-to-10 numeric rating scale to measure satisfaction, the Low Back Pain Treatment Beliefs Questionnaire to measure patient beliefs, and the 12-item Short Form Health Survey to measure HRQoL.Recipients of SMT were more likely to be very satisfied with their care (84%) than recipients of PDT (50%; P = .002). The SMT cohort self-reported significantly higher HRQoL compared to the PDT cohort; mean differences in physical and mental health scores on the 12-item Short Form Health Survey were 12.85 and 9.92, respectively. The SMT cohort had a lower degree of concern regarding chiropractic care for their back pain compared to the PDT cohort's reported concern about PDT (P = .03).Among older Medicare beneficiaries with chronic low back pain, long-term recipients of SMT had higher self-reported rates of HRQoL and greater satisfaction with their modality of care than long-term recipients of PDT. Participants who had longer-term management of care were more likely to have positive attitudes and beliefs toward the mode of care they received.

Rivaroxaban is an anticoagulant (orally active direct Xa inhibitor) considered to reduce the risk of stroke and systemic embolism and treat deep vein thrombosis, pulmonary embolism, and other cardiovascular complications. Bioanalytical methods for rivaroxaban quantification in plasma are necessary for application in pharmacokinetic studies, as well as in drug therapeutic monitoring. In this work, we developed and validated a sensitive bioanalytical method using LC-MS/MS for rivaroxaban quantification in human plasma using an one-step liquid-liquid extraction. The linear concentration range was 1-600 ng/mL. The bioanalytical method was also applied to pharmacokinetic studies in healthy volunteers under fasting and fed conditions. The results demonstrated that the method is rapid, sensitive, and adequate for application in pharmacokinetic studies.

The fine structure of the band edge exciton and the dark exciton photoluminescence (PL) are topics of significant interest in the research of semiconducting metal halide perovskite nanocrystals, with several conflicting reports on the level ordering of the bright and dark states and the accessibility of the emitting dark states. Recently, we observed the intense dark exciton PL in strongly confined CsPbBr3 nanocrystals at cryogenic temperatures, in contrast to weakly confined nanocrystals lacking dark exciton PL, which was explained by the confinement enhanced bright-dark exciton splitting. In this work, we investigated the size-dependence of the dark exciton photoluminescence properties in CsPbBr3 and CsPbI3 quantum dots in the strongly confined regime, showing the clear role of confinement in determining the bright-dark energy splitting (ΔEBD) and the dark exciton lifetime (τD). We observe the increase in both ΔEBD and τD with increasing quantum confinement in CsPbBr3 and CsPbI3 QDs, consistent with the earlier predictions on the size-dependence of ΔEBD and τD. Our results show that quantum confinement plays a crucial role in determining the accessibility to the dark exciton PL and its characteristics in metal halide perovskite nanocrystals.

Lipases are one of the most used enzymes in the pharmaceutical industry due to their efficiency in organic syntheses, mainly in the production of enantiopure drugs. From an industrial viewpoint, the selection of an efficient expression system and host for recombinant lipase production is highly important. The most used hosts areEscherichia coliandKomagataella phaffii(previously known asPichia pastoris) and less often reportedBacillusandAspergillusstrains. The use of efficient expression systems to overproduce homologous or heterologous lipases often require the use of strong promoters and the co-expression of chaperones. Protein engineering techniques, including rational design and directed evolution, are the most reported strategies for improving lipase characteristics. Additionally, lipases can be immobilized in different supports that enable improved properties and enzyme reuse. Here, we review approaches for strain and protein engineering, immobilization and the application of lipases in the pharmaceutical industry.

The aim of the present study was to bring additional evidence regarding a biopredictive dissolution medium containing 1% sodium lauryl sulphate (SLS) to predict the in vivo behavior of carbamazepine (CBZ) products. Twelve healthy volunteers took one immediate release (IR) dose of either test and reference formulations in a bioequivalence study (BE). Dissolution profiles were carried-out using the medium. Level A in vitro&ndash, in vivo correlations (IVIVC) were established using both one-step and two-step approaches as well as exploring the time-scaling approach to account for the differences in dissolution rate in vitro versus in vivo. A detailed step by step calculation was provided to clearly illustrate all the procedures. The results show additional evidence that the medium containing 1% SLS can be classified as a universal biopredictive dissolution tool, and that both of the approaches used to develop the IVIVC (one and two-steps) provide good in vivo predictability. Therefore, this biopredictive medium could be a highly relevant tool in Latin-American countries to ensure and check the quality of their CBZ marketed products for which BE studies were not requested by their regulatory health authorities.

We report the strong light-induced activation of forbidden exciton transition in CsPbBr3 perovskite quantum dots mediated by the symmetry-breaking polaron that modifies the optical selection rule of the confined exciton transition. The activated forbidden transition results in an intense pump-induced absorption in the transient absorption spectra above the bandgap, where the original parity-forbidden transition was located. In contrast to many other semiconductor quantum dots, photoexcitation of an exciton in CsPbBr3 quantum dots creates a sufficiently large perturbation via a lattice-distorting polaron, which turns on the formally forbidden transition. Compared to the bulk or weakly confined CsPbBr3, the activation of the forbidden transition in strongly confined quantum dots is much more prominent due to the stronger influence of the polaron on exciton transitions in the confined space. This nonlinear optical property highlights the intimate coupling of the photoexcited charge carriers with the lattice ...

Adverse local tissue reactions (ALTRs) due to tribocorrosion of head-neck taper junctions in contemporary metal-on-polyethylene (MoP) total hip arthroplasty (THA) are emerging as an important reason for failure requiring revision surgery. This study aimed at: (1) reporting early complication rates and outcome, and (2) identifying risk factors associated with complications of revision surgery for head-neck taper corrosion in patients with MoP THA.Forty consecutive revision surgeries in 39 patients (male, 16; female, 23) with MoP THA were evaluated. The follow-up period after revision was a minimum of 14 months (range, 14-45). The indication for revision surgery was the presence of symptomatic ALTR on magnetic resonance imaging (MRI) with elevated metal ion levels.The overall complication rate was 25% and the reoperation rate was 10%. The median serum level of cobalt ions decreased significantly 8.2 μg/L (1.2-56.1 μg/L) pre-revision to 3.1 μg/L (0.2-14.0 μg/L) post-revision (P.01). High fretting and corrosion grades (Goldberg score ≥ 3) were observed in 82% of retrieved implants. MRI findings of solid lesion(s) with abductor deficiency (P.01) and intraoperative tissue damage at revision (P = .02) were significantly associated with post-revision complications.A high rate of early complications (25%) and re-revisions (10%) was observed after revision of ALTR associated with head-neck taper corrosion. Pre-revision MRI findings of solid lesion(s) with abductor deficiency and intraoperative tissue damage were risk factors associated with the occurrence of a complication after revision surgery. This information provides clinically useful information for clinical decision-making and preoperative counseling of MoP THA patients undergoing revision surgery for head-neck taper corrosion.

Aim: The combination of levodopa with carbidopa has been used for treatment of Parkinson's disease being an important therapy in dopamine level control in the brain. Both are very polar compounds becoming a challenge for analysis by LC–MS/MS.Materials & methods: In this work, it was developed and validated a sensitive bioanalytical method by UHPLC–MS/MS for simultaneous levodopa and carbidopa quantification in human plasma using a fast protein precipitation method. Moreover, the bioanalytical method was applied to a pharmacokinetic study in healthy volunteers. Results/Conclusion: The results demonstrated a sensitive and adequate method for application to pharmacokinetic/bioequivalence studies.

Cesium lead halide (CsPbX3) nanocrystals have emerged as a new family of materials that can outperform the existing semiconductor nanocrystals due to their superb optical and charge-transport properties. However, the lack of a robust method for producing quantum dots with controlled size and high ensemble uniformity has been one of the major obstacles in exploring the useful properties of excitons in zero-dimensional nanostructures of CsPbX3. Here, we report a new synthesis approach that enables the precise control of the size based on the equilibrium rather than kinetics, producing CsPbX3 quantum dots nearly free of heterogeneous broadening in their exciton luminescence. The high level of size control and ensemble uniformity achieved here will open the door to harnessing the benefits of excitons in CsPbX3 quantum dots for photonic and energy-harvesting applications.