Prioritization of HCV treatment in the direct-acting antiviral era: an economic evaluation

BACKGROUND & AIMS: We determined the optimal HCV treatment prioritization strategy for interferon-free (IFN-free) HCV direct-acting antivirals (DAAs) by disease stage and risk status incorporating treatment of people who inject drugs (PWID). METHODS: A dynamic HCV transmission and progression model compared the cost-effectiveness of treating patients early vs. delaying until cirrhosis for patients with mild or moderate fibrosis, where PWID chronic HCV prevalence was 20, 40 or 60%. Treatment duration was 12weeks at £3300/wk, to achieve a 95% sustained viral response and was varied by genotype/stage in alternative scenarios. We estimated long-term health costs (in £UK=€1.3=$1.5) and outcomes as quality adjusted life-years (QALYs) gained using a £20,000 willingness to pay per QALY threshold. We ranked strategies with net monetary benefit (NMB); negative NMB implies delay treatment. RESULTS: The most cost-effective group to treat were PWID with moderate fibrosis (mean NMB per early treatment £60,640/£23,968 at 20/40% chronic prevalence, respectively), followed by PWID with mild fibrosis (NMB £59,258 and £19,421, respectively) then ex-PWID/non-PWID with moderate fibrosis (NMB £9,404). Treatment of ex-PWID/non-PWID with mild fibrosis could be delayed (NMB -£3,650). In populations with 60% chronic HCV among PWID it was only cost-effective to prioritize DAAs to ex-PWID/non-PWID with moderate fibrosis. For every one PWID in the 20% chronic HCV setting, 2 new HCV infections were averted. One extra HCV-related death was averted per 13 people with moderate disease treated. Rankings were unchanged with reduced drug costs or varied sustained virological response/duration by genotype/fibrosis stage. CONCLUSIONS: Treating PWID with moderate or mild HCV with IFN-free DAAs is cost-effective compared to delay until cirrhosis, except when chronic HCV prevalence and reinfection risk is very high

Novos compostos sintéticos no tratamento antineoplásico : uma avaliação em tumores pediátricos

O câncer é, atualmente, uma das principais causas de morte em todo o mundo. Segundo a Organização Mundial da Saúde (OMS), somente em 2018 haverá 18,1 milhões de novos diagnósticos de câncer e 9,6 milhões de mortes causadas por tumores em todo o mundo. O mesmo acontece na infância e na adolescência: o câncer representa a segunda maior causa de falecimento em indivíduos de 0 a 19 anos. Com o crescimento no número de casos, esse conjunto de doenças tornou-se o maior obstáculo para o aumento na expectativa de vida mundial. Mesmo com o avanço da medicina, ainda há muito a ser atingido: reincidências, resistência ao tratamento, metástases e até mesmo toxicidade e morbidade induzidas pelas abordagens terapêuticas têm sido os principais motivos da incansável busca por novas terapias antitumorais, procurando sempre por intervenções mais eficazes, menos invasivas e com maior grau de seletividade. Na procura por novos agentes antitumorais, observou-se atividade citotóxica em um composto que se tornou base para a síntese de diferentes oxazolidinas quirais 2,3,4-substituídas através da modificação de radicais, extensão da molécula inicial e modificações na estereoquímica. Neste presente estudo, analisamos o efeito citotóxico de sete diferentes compostos dessa classe de oxazolidinas (PH135, PH136, PH137, PH138, PH139, PH140 e PH141) em três linhagens de tumores pediátricos (RD-ES, SK-NBE( 2) e Daoy, representativos de sarcoma de Ewing, neuroblastoma e meduloblastoma, respectivamente). Calculamos seus respectivos IC50 com base em sua citotoxicidade bem como realizamos testes de biologia molecular para melhor entender as vias de atuação dessas moléculas. Buscamos avaliar a expressão diferencial de mRNA de p16, p21, c-Myc e Bcl-2 em células tratadas com o IC50 dos PH135, PH136 e PH138. Nossos resultados demonstraram relevante atividade citotóxica de seis dos sete compostos avaliados dessa classe de oxazolidinas e as três linhagens celulares se mostraram suscetíveis a sua ação citotóxica. Em avaliação por qPCR, observamos que as células de neuroblastoma apresentaram o maior número de alterações: elevação na expressão de c-Myc por PH136 e PH138; além da redução e do aumento na expressão de CDKN2A induzida por PH135 e PH138, respectivamente. Na linhagem de meduloblastoma observamos diminuição dos níveis de mRNA de BCL2 induzida por PH138, enquanto a linhagem de sarcoma de Ewing não demonstrou diferenças significativas. Esses resultados são de extrema importância para que a elucidação dos mecanismos de ação dos compostos candidatos seja possível. Com o potencial dessa nova classe de compostos sintéticos, é interessante que sejam realizadas outras metodologias a fim de melhor compreender a ação dessas oxazolidinas. Avaliar o efeito in vitro a longo prazo dessas moléculas e a ação in vivo desses compostos são perspectivas que podem fornecer importantes dados acerca dos candidatos.Organization (WHO), 18,1 million new cases of cancer will be diagnosed and 9,6 million deaths caused by tumors will take place in 2018. During childhood and adolescence, cancer represents the second leading death cause in individuals from 0 to 19 years. As the cases number increases, tumors become a major barrier when it comes to increasing life expectancy. Even with treatment progress, there are still many issues to be addressed: recurrence, resistance to treatment, metastasis and even toxicity and morbidity driven by medication have been the main reasons for the development of novel therapies. Attempting to develop new anti-tumor agents, a prototype compound with cytotoxic capacity which has been used as a base to the development and synthesis of different 2,3,4-substituted chiral oxazolidines through group modifications, molecule extension and stereochemistry alterations. In this present study, we analyzed the cytotoxic effect of seven different compounds (PH135, PH136, PH137, PH138, PH139, PH140 e PH141) in three different cell lineages of pediatric tumors (RD-ES, SK-N-BE(2) and Daoy representative of Ewing sarcoma, neuroblastoma and medulloblastoma, respectively). To access efficacy of each candidate compound, we calculated IC50 values based on cytotoxic effects after forty-eight hours’ incubation and we also performed molecular analysis to shed light on the mechanisms involved in their intracellular action. We aimed to evaluate the differential expression of p16, p21, c-Myc and Bcl-2 mRNA in cells treated with PH135, PH136 and PH138. Our results showed six of seven compounds presented a relevant cytotoxic response and all three lineages were susceptible to their toxic action. After qPCR evaluation, we observed that neuroblastoma cells presented the highest amount of alterations after treatment with oxazolidines: differences in expression of CDKN2A and c-Myc following PH136 and PH138 treatment were significant. In medulloblastoma, we also found downregulation of BCL2 mRNA level as a consequence of PH138 action, while the Ewing sarcoma lineage did not present any differential expression. These results are crucial to better understand how these novel compounds may act in cell death. Considering their potential cytotoxic capability, different methodologies should be performed in the future to understand the mechanism of action of these molecules. Long-term toxicity evaluation and in vivo analysis are perspectives that could shed light on the pathways involved in this drug response

The Endometrial Microbiome and Its Impact on Human Conception

Changes in the female genital tract microbiome are consistently correlated to gynecological and obstetrical pathologies, and tract dysbiosis can impact reproductive outcomes during fertility treatment. Nonetheless, a consensus regarding the physiological microbiome core inside the uterine cavity has not been reached due to a myriad of study limitations, such as sample size and experimental design variations, and the influence of endometrial bacterial communities on human reproduction remains debated. Understanding the healthy endometrial microbiota and how changes in its composition affect fertility would potentially allow personalized treatment through microbiome management during assisted reproductive therapies, ultimately leading to improvement of clinical outcomes. Here, we review current knowledge regarding the uterine microbiota and how it relates to human conception