Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear un derstanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5–7 vast areas of the tropics remain understudied.8–11 In the American tropics, Amazonia stands out as the world’s most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepre sented in biodiversity databases.13–15 To worsen this situation, human-induced modifications16,17 may elim inate pieces of the Amazon’s biodiversity puzzle before we can use them to understand how ecological com munities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple or ganism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region’s vulnerability to environmental change. 15%–18% of the most ne glected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lostinfo:eu-repo/semantics/publishedVersio

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear understanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5,6,7 vast areas of the tropics remain understudied.8,9,10,11 In the American tropics, Amazonia stands out as the world's most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepresented in biodiversity databases.13,14,15 To worsen this situation, human-induced modifications16,17 may eliminate pieces of the Amazon's biodiversity puzzle before we can use them to understand how ecological communities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple organism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region's vulnerability to environmental change. 15%–18% of the most neglected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lost

Sementes cerâmicas radioativas com Ho-166 E Sm-153 com perspectiva de uso em braquiterapia

Exportado OPUSMade available in DSpace on 2019-08-12T17:18:56Z (GMT). No. of bitstreams: 1 tese_eduardo_sarmento_valente.pdf: 20016693 bytes, checksum: 962592c86c4eb957cc290ff8920104b2 (MD5) Previous issue date: 29Este trabalho teve como objetivo apresentar a caracterização física, química e nuclear das sementes cerâmicas com hólmio e samário incorporados em matriz cerâmica, produzidas pela rota sol-gel. Foi investigada a resposta biológica in vitro, macroscópica, com célulastumorais de linhagem HeLa, em função da exposição à radiação do Ho-166 e do Sm-153. Foi também avaliada a dispersão do material radioativo em fluido corpóreo simulado (SBF) e foi feito o cálculo da taxa de dose e da dose total depositada no volume delimitado peloalcance das partículas na água. A metodologia utilizada na caracterização físico-química e nuclear baseou-se nas seguintes técnicas: espectrometria por emissão atômica, análise por ativação neutrônica, espectrometria das radiações gama, espectrometria por fluorescência de raios-X e difratometria de raios-X. Em adição à solubilidade em SBF, um estudo piloto avaliou in vivo a dispersão de material radioativo de sementes implantadas em tecido muscular de coelho. Para a investigação da resposta biológica in vitro, foram preparados quatro experimentos nos quais as sementes radioativas foram colocadas diretamente em contato com as células em frascos de cultura confluente. Os dois primeiros foram realizados com atividade das sementes em torno de 3,7 MBq (0,1 mCi) para o Sm-153 e 11,1 MBq (0,3mCi) para o Ho-166. Não houve posicionamento espacial definido para as sementes nesses primeiros experimentos. Os experimentos subsequentes foram realizados com atividade que variaram entre 37 MBq (1 mCi) e 111 MBq (3 mCi) com posição definida das sementes nofrasco de cultura. Os resultados mostraram a formação de halos com diâmetro máximo de 8 mm em torno das sementes onde houve drástica redução no número de células viáveis, em consequência dos efeitos da radiação . O cálculo das doses depositadas em água seguiu ametodologia estabelecida pelo MIRD bem como o cálculo da taxa de exposição durante a manipulação das sementes durante um implante. Esses cálculos encontraram taxas de dose que variaram entre7 e 19 Gy/h e doses integradas entre 93 e 730 Gy, devidas à radiação , noperíodo de 6 meias-vidas dos radioisótopos Sm-153 e Ho-166. As taxas de dose calculadas a uma distância de um metro variaram entre 0,081 e 0,159 h semente Sv × . Os resultados mostraram que as sementes cerâmicas produzidas possuem características físico-químicas adequadas ao uso proposto em braquiterapia como: dimensões reduzidas, concentração adequada de átomos alvo de samário ou hólmio e nenhuma dispersão de material radioativo em fluido corpóreo no período de até dez dias. Mostraram também que a concentração desses elementos na matriz cerâmica é suficiente para que as sementes sejam ativadas em reatores de baixo fluxo neutrônico, gerando radioatividade suficiente para a braquiterapia em altas taxasde dose. Os resultados obtidos nos experimentos in vitro foram encorajadores e demonstraram a capacidade que as sementes, com emissores de radiação , têm para eliminar células tumorais. O alcance da radiação , nos experimentos biológicos in vitro, foi compatível com ovalor teórico e poderá ser usado como referência para o espaçamento entre sementes quando forem implantadas in vivo. Foram determinadas as características de solubilidade dos nuclídeos radioativos em fluido corpóreo simulado a curto e a longo prazo, e ficou demonstrado que, nos primeiros dias, não há solubilização mensurável. Foram obtidasindicações que a semente se dissolve de forma mensurável após alguns meses imersa em fluido corpóreo simulado. Concluiu-se que as sementes cerâmicas radioativas com emissores tem perspectivas favoráveis para uso em braquiterapia de altas taxas de dose.This work aimed to characterize physically, chemically and radioactively ceramics seeds with holmium and samarium embedded in ceramic matrix produced by sol-gel route. Biological response of HeLa cells was investigated macroscopically in vitro under the exposure to radiation of Ho-166 and Sm-153. The dispersal of radioactive material in simulated body fluid (SBF) was made and the dose rate and total dose deposited in the volume delimited by the range of particles in the water was calculated. The methodology used in physical, chemical and nuclear characterization was based on the following techniques: atomic emission spectrometry, neutron activation analysis, gamma spectrometry,X-ray fluorescence spectrometry and X-rays diffraction. In addition to the solubility in SBF, an in vivo pilot study assessed the dispersion of radioactive seeds implanted in rabbit muscle tissue. Four experiments were prepared to investigate the biological response in vitro, inwhich radioactive seeds were placed directly in contact with the cells in confluent culture flasks. The first two were done with seeds activity of 3.7 MBq (0.1 mCi) for the Sm-153 and 11.1 MBq (0.3 mCi) for Ho-166. There were no concerns with spatial positioning for seeds inthose early experiments. The subsequent experiments were performed with activity ranging from 37 MBq (1 mCi) and 111 MBq (3 mCi) and with defined position of the seeds in the flask. The results showed the presence of halos with maximum diameter of 8 mm around theseeds where there was a drastic reduction in the number of viable cells as a result of the effects of radiation. The calculation of dose deposited in water as well as the dose rate calculation of during handling of the seeds for an implant followed the methodology established by MIRD. These calculations found dose rates ranging from 7 to 19 Gy/h an

Evaluation of hela cell lineage response to &#946; radiation from Holmium-166 embedded in ceramic seeds

This work studied the effects of &#946; radiation of Ho-166 embedded in ceramic seeds on HeLa cells. Methodology consisted in the production of ceramic seeds with holmium-165 by sol-gel route. Chemical and physical characterizations of the seeds were performed. Subsequently, nuclear characterization was performed by gamma spectrometry. Experimental and theoretical activities were defined and initial dose rate were evaluated by MIRD (Medical Internal Radiation Dose Committee) methodology. The seeds were placed in confluent culture flasks and remained for six radionuclide half-lives. Biological results were represented by a clean 6 mm diameter area around the seed where the tumour cells were killed. The initial dose rate was 15.5 Gy. h-1. The maximum absorbed dose was 591.3 Gy. The features of the Ho-166 seeds suggested that such ceramic seeds were suitable for high dose rate brachytherapy

Characterization of ceramic seeds with samarium-153 for use in brachytherapy

Ceramic seeds were synthesized by the sol-gel technique with Si:Sm:Ca. One sample was irradiated in the TRIGA nuclear reactor IPR-R1. After irradiation, the seeds were submitted to instrumental neutron activation analysis to determine the 153Sm concentration in weight. The same irradiated seed sample was submitted to gamma spectrometry analysis to determine all existing radionuclides as well as its individual activities. A second sample was submitted to ICP-AES atomic emission spectrometry. A third sample was submitted to X-ray fluorescence spectrometry to determine qualitative chemical composition. The measured activity was due to 153Sm with a well-characterized gamma spectrum. The X-ray fluorescence spectrum demonstrates that there is no discrepancy in seed composition. Maximum range of beta particles from 153Sm were evaluated, as well as the total dose and dose rate on its range´s volume. The results are relevant for investigation of the viability of producing 153Sm radioactive seeds for use in brachytherapy

Synthesis, quality control and dosimetry of the radiopharmaceutical 18F-sodium fluoride produced at the Center for Development of Nuclear Technology - CDTN

18F-Sodium fluoride (Na18F) is a radiopharmaceutical used for diagnosis in nuclear medicine by positron emission tomography (PET) imaging. Bone scintigraphy is normally performed using 99mTc-MDP. However, 18F PET scans promise high quality imaging with increased resolution and improved sensitivity and specificity. In order to make available a tool for more specific studies of tumors and non-oncological diseases of bone tissue, the UPPR/CDTN team undertook the production and quality control of Na18F injectable solution with the physical-chemical, microbiological and biological characteristics recommended in the U.S. Pharmacopeia. Na18F radiochemical purity was 96.7 ± 1.3 %, with Rf= 0.026 ± 0.006. The product presented a pH of 5.3 ± 0.6, half life of 109.0 ± 0.8 minutes, endotoxin limit < 5.0 EU.mL-1 and no microbial contaminants. The biodistribution of Na18F was similar to that described in the literature, with a clearance of 0.19 mL.min-1 and distribution volume of 18.76 mL. The highest bone concentration (5.0 ± 0.5 %ID.g-1) was observed 20 minutes after injection. Na18F produced at the UPPR presented all the quality assurance requirements of the U.S. Pharmacopeia and can be safely used for clinical bone imaging.<br>O Fluoreto de sódio 18F (Na18F) é um radiofármaco empregado para diagnóstico através da Tomografia por Emissão de Pósitrons (PET). Cintilografias ósseas são normalmente obtidas utilizando-se 99mTc-MDP. Entretanto, o interesse pelo Na18F é crescente, principalmente devido à obtanção de imagens de elevada resolução. Com o objetivo de tornar disponível uma ferramenta mais específica para estudos de tumores e doenças não-oncológicas do tecido ósseo, o grupo da UPPR/CDTN implementou a produção e o controle de qualidade da solução injetável de Na18F com as características físico-química, microbiológica e biológica preconizadas pela farmacopéia. Sua pureza radioquímica foi de 96,7 ± 1,3 %, com Rf= 0,026 ± 0,006. O produto apresentou pH igual a 5,3 ± 0,6, tempo de meia-vida de 109,0 ± 0,8 minutos, limite de endotoxinas < 5,0 EU.mL-1 e ausência de microrganismos. O perfil de biodistribuição em camundongos foi semelhante ao disponível na literatura, com depuração igual a 0,19 mL.min-1 e volume de distribuição igual a 18,76 mL. A concentração máxima (5,0 ± 0,5 % DI.g-1) foi observada no osso 20 minutos após a injeção. O Na18F produzido na UPPR do CDTN apresentou os parâmetros de qualidade definidos na farmacopéia americana e pode ser usado com segurança para uso clínico em cintilografia óssea

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

Background: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. Methods: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. Results: SVR24 rates were 46.1 % (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1,2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced ≥1 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with ≥1 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not ≥5. Conclusions: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginter-feron alfa-2a/ribavirin