Acute lymphoblastic leukemia (ALL) is the most prevalent cancer in children, and despite considerable progress in treatment outcomes, relapses still pose significant risks of mortality and long-term ...complications. To address this challenge, we employed a supervised machine learning technique, specifically random survival forests, to predict the risk of relapse and mortality using array-based DNA methylation data from a cohort of 763 pediatric ALL patients treated in Nordic countries. The relapse risk predictor (RRP) was constructed based on 16 CpG sites, demonstrating c-indexes of 0.667 and 0.677 in the training and test sets, respectively. The mortality risk predictor (MRP), comprising 53 CpG sites, exhibited c-indexes of 0.751 and 0.754 in the training and test sets, respectively. To validate the prognostic value of the predictors, we further analyzed two independent cohorts of Canadian (n = 42) and Nordic (n = 384) ALL patients. The external validation confirmed our findings, with the RRP achieving a c-index of 0.667 in the Canadian cohort, and the RRP and MRP achieving c-indexes of 0.529 and 0.621, respectively, in an independent Nordic cohort. The precision of the RRP and MRP models improved when incorporating traditional risk group data, underscoring the potential for synergistic integration of clinical prognostic factors. The MRP model also enabled the definition of a risk group with high rates of relapse and mortality. Our results demonstrate the potential of DNA methylation as a prognostic factor and a tool to refine risk stratification in pediatric ALL. This may lead to personalized treatment strategies based on epigenetic profiling.
Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been ...evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome.
Introdução/Objetivo: Os antimicrobianos amplamente utilizados no âmbito hospitalar representam grande impacto financeiro à instituição, e seu uso inadequado pode propiciar o desenvolvimento de ...bactérias multirresistentes. A partir disso, foi implantado o Programa de Gerenciamento do Uso de Antimicrobianos (ASP) que envolve conjunto de ações destinadas ao controle e uso racional dos antimicrobianos nos serviços de saúde, sendo um dos objetivos secundários a redução de custos financeiros com medicamentos (farmacoeconomia), contribuindo para a otimização de cuidados, tomada de decisão e melhor uso dos recursos financeiros. O objetivo é avaliar o impacto da implantação de um Programa de Gerenciamento do Uso de Antimicrobianos na farmacoeconomia hospitalar. Métodos: Estudo retrospectivo quase-experimental, com intervenção, realizado em um hospital público oncológico, universitário, quaternário. Os períodos do estudo foram: pré-implantação–2018, pós-implantação–2022. A implantação do ASP ocorreu em 2019, com o início do gerenciamento do consumo de 18 antimicrobianos, sendo ampliado o escopo para 35 antimicrobianos em 2020. Esta seleção foi baseada em maior valor financeiro, medicamentos de amplo espectro e/ou uso restrito, e aqueles gerenciados pela COVISA. O ASP implantado avalia o consumo de antimicrobianos a partir de 5 indicadores: 1. Densidade de Prescrição (DP); 2. Dose Diária Definida (DDD); 3. Dias de Terapia (DOT); 4. Duração da Terapia (LOT); 5. Razão DOT/LOT. Além de realizar auditorias prospectivas beira-leito, avaliação de prescrição, e reunião mensal entre a equipe do Serviço de Controle de Infecção Hospitalar, membros do ASP e equipe multidisciplinar das Unidades de Terapia Intensiva (UTI), setor de maior consumo de antimicrobianos, a fim de fornecer devolutivas. Compararam-se os custos financeiros com os 35 antimicrobianos monitorados entre os dois períodos. Resultados: Foram analisados os setores: Unidades de Internação, Hematologia e UTI. No ano de 2022 (pós) a Unidade de Internação apresentou 52,54%, Onco-hematologia 25,19% e UTI 59,87% de diminuição de custo financeiro quando comparado com o ano de 2018 (pré). Conclusão: O estudo mostrou uma diminuição do custo com antimicrobianos em todos os setores em 4 anos de implantação do ASP, reforçando sua importância, principalmente em unidade de saúde pública onde os recursos financeiros são limitados.
Introdução/Objetivo: Os Programas de Gerenciamento do Uso de Antimicrobianos (ASP) visam garantir o uso adequado de antimicrobianos (ATM) e obter melhores desfechos clínicos e microbiológicos. Nosso ...objetivo foi descrever a implantação do ASP em hospital público oncológico, desafios enfrentados e resultados obtidos. Métodos: Estudo descritivo, retrospectivo, realizado em hospital oncológico, universitário, com 499 leitos. O ASP foi estruturado em 2018, com descrição de estrutura, divisão dos times (gestor/operacional), atribuições, atividades programáticas, indicadores monitorados e divulgações. Em 2019, o programa iniciou as atividades: A. Avaliação do consumo de 18 ATM em unidades de internação e de terapia intensiva (UTI) com 5 indicadores: Densidade de Prescrição, Dose Diária Definida (DDD), Dias de Terapia, Duração da Terapia e Razão DOT/LOT. B. Avaliação da adesão à Profilaxia Antimicrobiana Cirúrgica (PAC) – aprimoramento do indicador de escolha correta e implementação do indicador do tempo certo. C. Visitas médicas regulares às unidades. D. Auditoria prospectiva diária dos ATM de maior impacto financeiro e implantação de indicador de custos. Em 2020 foi ampliada a avaliação do consumo para 35 ATM, e implantado o indicador de PAC na duração adequada e iniciada em 2021 intervenção farmacêutica com as especialidades da Urologia e Coluna nos casos de profilaxia mantida além do previsto. A divulgação de indicadores foi realizada por meio de reuniões sistemáticas e relatórios encaminhados às áreas e chefias correspondentes. Resultados: Na implantação do ASP o maior desafio foi obter a equipe necessária (time gestor e operacional com 1 médico, 1 farmacêutico e 1 enfermeiro). As UTIs eram os setores com maior consumo de ATM, com intensificação das medidas de controle e educação e consequente queda progressiva do consumo– proporção de ATM com DDD acima do p90 da Covisa era de 33% em 2019, e de 17% em 2022. Observou-se 56,2% de queda de custos com ATM na instituição comparando 2018 e 2022. Quanto à administração da PAC no Tempo Certo, a adesão era de 88% em 2019 e após intervenções entre ASP, Anestesia e Qualidade, obteve-se adesão sustentada de 92% a partir do final de 2021. Conclusão: O estudo demonstrou que uma implantação estruturada de ASP pode gerar resultados assistenciais e financeiros favoráveis, com diminuição do consumo de ATM, maior adesão ao Protocolo de PAC e diminuição dos custos com ATM, auxiliando na otimização da gestão institucional.
As the changes on the mechanical properties with depth of indentation provide valuable information that may be suitable for design purposes, nanoindentation is an adequate technique for investigating ...the nanomechanical changes in the surface and in the inner polymers. This research focuses on the study of the nanomechanical properties of two grades of polypropylene (PP) after the long term exposure to an organic fluid, such as paraffin wax used as a phase change materials (PCM). PCM are used for thermal energy storage (TES) in buildings applications for passive systems or heating and cooling usages. In any of these uses PCM must be encapsulated and PP is a possibility within the container materials used. Four different samples of the polypropylene were evaluated: PP, filled polypropylene with 60% Mg(OH)2 (PP-60Mg), PP-60Mg with PCM (RT-25), and PP-60Mg with PCM (RT-42). It was studied the thermal stability by Thermogravimetrical analysis of these samples, and also it was evaluated the Hardness (H), Elastic modulus (E) and Loss modulus (Eloss) for the unfilled PP and PP-60Mg in contact with two different PCM at different temperatures (30 °C, 45 °C and 60 °C for RT-25 and 45 °C for RT-42) for 32 days. Results show that the mechanical properties H, E, and Eloss are higher for PP-60Mg than for PP. Nevertheless, these properties decrease significantly when the PP and the PP-60Mg are in contact with PCM, because it acts as a plasticizer, softening the polymer. Besides, the higher PCM's melting point, the lowest mechanical properties were observed.
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•H and E at nanometric scale.•Polymer materials.•Oliver and Pharr and Loubet methods.
Mechanical data (hardness and elastic modulus) from instrumented indentation testing are often ...extracted assuming linear elasticity in the initial portion of the unloading. The method is nowadays widely accepted as a convenient tool to interpret depth-sensing data, however it is a matter of controversy when applied to polymer materials due to their time-dependent behavior. More recently, Loubet and co-workers applied continuous stiffness measurements (CSM), consisting of superimposing a small oscillation to the quasi-static component of loading, to the study of the mechanical properties of polymers and proposed a new model to account for the apparent increase in the contact area detected at the first stages of contact. The present work offers a comparative study between the Loubet’s model using CSM and the procedure yielding a single reading from the onset of unloading. A wide range of thermoplastic polymer materials including glassy and semicrystalline polymers have been investigated. The most important equations employed for each method are summarized and the advantages and disadvantages of employing one procedure or the other are discussed. The differences found between the results obtained from both approaches are discussed in relation to the nature of the polymer material. A comparison between mechanical data extracted from indentation measurements and from classical dynamic mechanical analysis is offered.
As the changes on the mechanical properties with depth of indentation provide valuable information that may be suitable for design purposes, nanoindentation is an adequate technique for investigating ...the nanomechanical changes in the surface and in the inner polymers. This research focuses on the study of the nanomechanical properties of two
grades of polypropylene (PP) after the long term exposure to an organic fluid, such as paraffin wax used as a phase change materials (PCM). PCM are used for thermal energy storage (TES) in buildings applications for passive systems or heating and cooling usages. In any of these uses PCM must be encapsulated and PP is a possibility within the container materials used. Four different samples of the polypropylene were evaluated: PP, filled polypropylene
with 60% Mg(OH)2 (PP-60Mg), PP-60Mg with PCM (RT-25), and PP-60Mg with PCM (RT-42). It was studied the thermal stability by Thermogravimetrical analysis of these samples, and also it was evaluated the Hardness (H), Elastic modulus (E) and Loss modulus (Eloss) for the unfilled PP and PP-60Mg in contact with two different PCM at different temperatures (30 C, 45 C and 60 C for RT-25 and 45 C for RT-42) for 32 days. Results show that the
mechanical properties H, E, and Eloss are higher for PP-60Mg than for PP. Nevertheless, these properties decrease significantly when the PP and the PP-60Mg are in contact with PCM, because it acts as a plasticizer, softening the polymer. Besides, the higher PCM’s melting
point, the lowest mechanical properties were observed.
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