Applicability of the acute leukemia (AL) - EBMT score as a prognostic model for allogeneic hematopoietic stem cell transplantation: a single-center, prospective, cohort study at a reference transplant center in Brazil

Abstract Introduction The Acute Leukemia-European Society for Blood and Marrow Transplantation (AL-EBMT) risk score was recently developed and validated by Shouval et al. Objective To assess the ability of this score in predicting the 2-year overall survival (OS-2), leukemia-free survival (LFS-2) and transplant-related mortality (TRM) in acute leukemia (AL) adult patients undergoing a first allogeneic hematopoietic stem cell transplant (HSCT) at a transplant center in Brazil. Methods In this prospective, cohort study, we used the formula published by Shouval et al. to calculate the AL-EBMT score and stratify patients into three risk categories. Results A total of 79 patients transplanted between 2008 and 2018 were analyzed. The median age was 38 years. Acute myeloid leukemia was the most common diagnosis (68%). Almost a quarter of the cases were at an advanced stage. All hematopoietic stem cell transplantations (HSCTs) were human leukocyte antigen-matched (HLA-matched) and the majority used familial donors (77%). Myeloablative conditioning was used in 92% of the cases. Stratification according to the AL-EBMT score into low-, intermediate- and high-risk groups yielded the following results: 40%, 12% and 47% of the cases, respectively. The high scoring group was associated with a hazard ratio of 2.1 (p= 0.007), 2.1 (p= 0.009) and 2.47 (p= 0.01) for the 2-year OS, LFS and TRM, respectively. Conclusion This study supports the ability of the AL-EBMT score to reasonably predict the 2-year post-transplant OS, LFS and TRM and to discriminate between risk categories in adult patients with AL, thus confirming its usefulness in clinical decision-making in this setting. Larger, multicenter studies may further help confirm these findings.

Applicability of the acute leukemia (AL) - EBMT score as a prognostic model for allogeneic hematopoietic stem cell transplantation: a single-center, prospective, cohort study at a reference transplant center in Brazil.

INTRODUCTION: The Acute Leukemia-European Society for Blood and Marrow Transplantation (AL-EBMT) risk score was recently developed and validated by Shouval et al. OBJECTIVE: To assess the ability of this score in predicting the 2-year overall survival (OS-2), leukemia-free survival (LFS-2) and transplant-related mortality (TRM) in acute leukemia (AL) adult patients undergoing a first allogeneic hematopoietic stem cell transplant (HSCT) at a transplant center in Brazil. METHODS: In this prospective, cohort study, we used the formula published by Shouval et al. to calculate the AL-EBMT score and stratify patients into three risk categories. RESULTS: A total of 79 patients transplanted between 2008 and 2018 were analyzed. The median age was 38 years. Acute myeloid leukemia was the most common diagnosis (68%). Almost a quarter of the cases were at an advanced stage. All hematopoietic stem cell transplantations (HSCTs) were human leukocyte antigen-matched (HLA-matched) and the majority used familial donors (77%). Myeloablative conditioning was used in 92% of the cases. Stratification according to the AL-EBMT score into low-, intermediate- and high-risk groups yielded the following results: 40%, 12% and 47% of the cases, respectively. The high scoring group was associated with a hazard ratio of 2.1 (p = 0.007), 2.1 (p = 0.009) and 2.47 (p = 0.01) for the 2-year OS, LFS and TRM, respectively. CONCLUSION: This study supports the ability of the AL-EBMT score to reasonably predict the 2-year post-transplant OS, LFS and TRM and to discriminate between risk categories in adult patients with AL, thus confirming its usefulness in clinical decision-making in this setting. Larger, multicenter studies may further help confirm these findings.

CYP2D6 activity and the risk of recurrence of Plasmodium vivax malaria in the Brazilian Amazon: a prospective cohort study.

BACKGROUND: CYP2D6 pathway mediates the activation of primaquine into active metabolite(s) in hepatocytes. CYP2D6 is highly polymorphic, encoding CYP2D6 isoforms with normal, reduced, null or increased activity. It is hypothesized that Plasmodium vivax malaria patients with defective CYP2D6 function would be at increased risk for primaquine failure to prevent recurrence. The aim of this study was to investigate the association of CYP2D6 polymorphisms and inferred CYP2D6 phenotypes with malaria recurrence in patients from the Western Brazilian Amazon, following chloroquine/primaquine combined therapy. METHODS: The prospective cohort consisted of P. vivax malaria patients who were followed for 6 months after completion of the chloroquine/primaquine therapy. Recurrence was defined as one or more malaria episodes, 28-180 days after the initial episode. Genotyping for nine CYP2D6 SNPs and copy number variation was performed using TaqMan assays in a Fast 7500 Real-Time System. CYP2D6 star alleles (haplotypes), diplotypes and CYP2D6 phenotypes were inferred, and the activity score system was used to define the functionality of the CYP2D6 diplotypes. CYP2D6 activity scores (AS) were dichotomized at ≤ 1 (gPM, gIM and gNM-S phenotypes) and ≥ 1.5 (gNM-F and gUM phenotypes). RESULTS: Genotyping was successfully performed in 190 patients (44 with recurrence and 146 without recurrences). Recurrence incidence was higher in individuals presenting reduced activity CYP2D6 phenotypes (adjusted relative risk = 1.89, 95% CI 1.01-3.70; p = 0.049). Attributable risk and population attributable fraction were 11.5 and 9.9%, respectively. The time elapsed from the first P. vivax malaria episode until the recurrence did not differ between patients with AS of ≤ 1 versus ≥ 1.5 (p = 0.917). CONCLUSIONS: The results suggest that CYP2D6 polymorphisms are associated with increased risk of recurrence of vivax malaria, following chloroquine-primaquine combined therapy. This association is interpreted as the result of reduced conversion of primaquine into its active metabolites in patients with reduced CYP2D6 enzymatic activity.

Influence of pharmacogenetic polymorphisms and demographic variables on metformin pharmacokinetics in an admixed Brazilian cohort.

AIMS: To identify pharmacogenetic and demographic variables that influence the systemic exposure to metformin in an admixed Brazilian cohort. METHODS: The extreme discordant phenotype was used to select 106 data sets from nine metformin bioequivalence trials, comprising 256 healthy adults. Eleven single-nucleotide polymorphisms in SLC22A1, SLC22A2, SLC47A1 SLC47A2 and in transcription factor SP1 were genotyped and a validated panel of ancestry informative markers was used to estimate the individual proportions of biogeographical ancestry. Two-step (univariate followed by multivariate) regression modelling was developed to identify covariates associated with systemic exposure to metformin, accessed by the area under the plasma concentration-time curve, between 0 and 48 h (AUC0-48h ), after single oral doses of metformin (500 or 1000 mg). RESULTS: The individual proportions of African, Amerindian and European ancestry varied widely, as anticipated from the structure of the Brazilian population The dose-adjusted, log-transformed AUC0-48h 's (ng h ml-1  mg-1 ) differed largely in the two groups at the opposite ends of the distribution histogram, namely 0.82, 0.79-0.85 and 1.08, 1.06-1.11 (mean, 95% confidence interval; P = 6.10-26 , t test). Multivariate modelling revealed that metformin AUC0-48h increased with age, food and carriage of rs12208357 in SLC22A1 but was inversely associated with body surface area and individual proportions of African ancestry. CONCLUSIONS: A pharmacogenetic marker in OCT1 (SLC22A1 rs12208357), combined with demographic covariates (age, body surface area and individual proportion of African ancestry) and a food effect explained 29.7% of the variability in metformin AUC0-48h .

Limited sampling strategy for determining metformin area under the plasma concentration-time curve.

AIM: The aim was to develop and validate limited sampling strategy (LSS) models to predict the area under the plasma concentration-time curve (AUC) for metformin. METHODS: Metformin plasma concentrations (n = 627) at 0-24 h after a single 500 mg dose were used for LSS development, based on all subsets linear regression analysis. The LSS-derived AUC(0,24 h) was compared with the parameter 'best estimate' obtained by non-compartmental analysis using all plasma concentration data points. Correlation between the LSS-derived and the best estimated AUC(0,24 h) (r(2) ), bias and precision of the LSS estimates were quantified. The LSS models were validated in independent cohorts. RESULTS: A two-point (3 h and 10 h) regression equation with no intercept estimated accurately the individual AUC(0,24 h) in the development cohort: r(2)  = 0.927, bias (mean, 95% CI) -0.5, -2.7-1.8% and precision 6.3, 4.9-7.7%. The accuracy of the two point LSS model was verified in study cohorts of individuals receiving single 500 or 1000 mg (r(2)  = -0.933-0.934) or seven 1000 mg daily doses (r(2)  = 0.918), as well as using data from 16 published studies covering a wide range of metformin doses, demographics, clinical and experimental conditions (r(2)  = 0.976). The LSS model reproduced previously reported results for effects of polymorphisms in OCT2 and MATE1 genes on AUC(0,24 h) and renal clearance of metformin. CONCLUSIONS: The two point LSS algorithm may be used to assess the systemic exposure to metformin under diverse conditions, with reduced costs of sampling and analysis, and saving time for both subjects and investigators.

Effect of UGT1A1, UGT1A3, DIO1 and DIO2 polymorphisms on L-thyroxine doses required for TSH suppression in patients with differentiated thyroid cancer.

AIM: To evaluate the impact of genetic polymorphisms in uridine 5'-glucuronosylytansferases UGT1A1 and UGT1A3 and iodothyronine-deiodinases types 1 and 2 on levothyroxine (T4 ; 3,5,3',5'-triiodo-L-thyronine) dose requirement for suppression of thyrotropin (TSH) secretion in patients with differentiated thyroid cancer (DTC). METHODS: Patients (n = 268) submitted to total thyroidectomy and ablation by (131) I, under T4 therapy for at least 6 months were recruited in three public institutions in Brazil. Multivariate regression modelling was applied to assess the association of T4 dosing with polymorphisms in UGT1A1 (rs8175347), UGT1A3 (rs3806596 and rs1983023), DIO1 (rs11206244 and rs2235544) and DIO2 (rs225014 and rs12885300), demographic and clinical variables. RESULTS: A regression model including UGT1A haplotypes, age, gender, body weight and serum TSH concentration accounted for 39% of the inter-individual variation in the T4 dosage. The association of T4 dose with UGT1A haplotype is attributed to reduced UGT1A1 expression and T4 glucuronidation in liver of carriers of low expression UGT1A1 rs8175347 alleles. The DIO1 and DIO2 genotypes had no influence of T4 dosage. CONCLUSION: UGT1A haplotypes associate with T4 dosage in DTC patients, but the effect accounts for only 2% of the total variability and recommendation of pre-emptive UGT1A genotyping is not warranted.

Global pharmacogenomics: distribution of CYP3A5 polymorphisms and phenotypes in the Brazilian population.

The influence of self-reported "race/color", geographical origin and genetic ancestry on the distribution of three functional CYP3A5 polymorphisms, their imputed haplotypes and inferred phenotypes was examined in 909 healthy, adult Brazilians, self-identified as White, Brown or Black ("race/color" categories of the Brazilian census). The cohort was genotyped for CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343), CYP3A5 haplotypes were imputed and CYP3A5 metabolizer phenotypes were inferred according to the number of defective CYP3A5 alleles. Estimates of the individual proportions of Amerindian, African and European ancestry were available for the entire cohort. Multinomial log-linear regression models were applied to infer the statistical association between the distribution of CYP3A5 alleles, haplotypes and phenotypes (response variables), and self-reported Color, geographical region and ancestry (explanatory variables). We found that Color per se or in combination with geographical region associates significantly with the distribution of CYP3A5 variant alleles and CYP3A5 metabolizer phenotypes, whereas geographical region per se influences the frequency distribution of CYP3A5 variant alleles. The odds of having the default CYP3A5*3 allele and the poor metabolizer phenotype increases continuously with the increase of European ancestry and decrease of African ancestry. The opposite trend is observed in relation to CYP3A5*6, CYP3A5*7, the default CYP3A5*1 allele, and both the extensive and intermediate phenotypes. No significant effect of Amerindian ancestry on the distribution of CYP3A5 alleles or phenotypes was observed. In conclusion, this study strongly supports the notion that the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of pharmacogenomic studies, and dealt with as a continuous variable, rather than proportioned in arbitrary categories that do not capture the diversity of the population. The relevance of this work extrapolates the Brazilian borders, and extends to other admixed peoples of the Americas, with ancestral roots in Europe, Africa and the American continent.

Dark carbon fixation: an important process in lake sediments.

Close to redox boundaries, dark carbon fixation by chemoautotrophic bacteria may be a large contributor to overall carbon fixation. Still, little is known about the relative importance of this process in lake systems, in spite the potentially high chemoautotrophic potential of lake sediments. We compared rates of dark carbon fixation, bacterial production and oxygen consumption in sediments from four Swedish boreal and seven tropical Brazilian lakes. Rates were highly variable and dark carbon fixation amounted up to 80% of the total heterotrophic bacterial production. The results indicate that non-photosynthetic carbon fixation can represent a substantial contribution to bacterial biomass production, especially in sediments with low organic matter content.

Desafios para a implantação de Sistema de Monitoramento e Avaliação da Qualidade de Bases de Dados – SUS, Município de São Paulo – MSP

O trabalho apresenta o processo de concepção, desenvolvimento e implantação do Sistema de Monitoramento e Avaliação de Qualidade de Bases de Dados do SUS – SMAQBD, implantado pela Coordenação de Epidemiologia e Informação (CEInfo) da Secretaria Municipal de Saúde de São Paulo (SMS)

Desafios para a implantação de Sistema de Monitoramento e Avaliação da Qualidade de Bases de Dados – SUS, Município de São Paulo – MSP / Challenges to the implementation of the monitoring system and quality evaluation of databases - SUS, São Paulo - MSP

O trabalho apresenta o processo de concepção, desenvolvimento e implantação do Sistema de Monitoramento e Avaliação de Qualidade de Bases de Dados do SUS – SMAQBD, implantado pela Coordenação de Epidemiologia e Informação (CEInfo) da Secretaria Municipal de Saúde de São Paulo (SMS)

Desafios para a implantação de Sistema de Monitoramento e Avaliação da Qualidade de Bases de Dados – SUS, Município de São Paulo – MSP / Challenges to the implementation of the monitoring system and quality evaluation of databases - SUS, São Paulo - MSP

O trabalho apresenta o processo de concepção, desenvolvimento e implantação do Sistema de Monitoramento e Avaliação de Qualidade de Bases de Dados do SUS – SMAQBD, implantado pela Coordenação de Epidemiologia e Informação (CEInfo) da Secretaria Municipal de Saúde de São Paulo (SMS)

Saúde materno-infantil / Maternal and child health

Nesta parte é abordada a Saúde Materno-Infantil, com questões relativas ao pré-natal, parto e acompanhamento inicial do desenvolvimento da criança, comparando os resultados desse inquérito com o realizado em 2003 e aprofundando alguns aspectos da utilização dos serviços que foram incorporados no questionário de 2008. O tema da saúde materno-infantil é muito presente em estudos e pesquisas, inclusive nos sistemas de informação do SUS e o ISA-Capital traz novos elementos como a utilização dos serviços privados nos diversos momentos que envolvem o ciclo inicial da vida.

Saúde materno-infantil / Maternal and child health

Nesta parte é abordada a Saúde Materno-Infantil, com questões relativas ao pré-natal, parto e acompanhamento inicial do desenvolvimento da criança, comparando os resultados desse inquérito com o realizado em 2003 e aprofundando alguns aspectos da utilização dos serviços que foram incorporados no questionário de 2008. O tema da saúde materno-infantil é muito presente em estudos e pesquisas, inclusive nos sistemas de informação do SUS e o ISA-Capital traz novos elementos como a utilização dos serviços privados nos diversos momentos que envolvem o ciclo inicial da vida.

Pharmacogenetics of calcineurin inhibitors in Brazilian renal transplant patients.

AIM: Polymorphisms in the CYP3A5 and ABCB1 genes have been investigated as modulators of the pharmacokinetics and clinical effects of cyclosporine (CSA) and tacrolimus (TAC) in European, North American and Asian populations, with controversial results. The extensive variation in worldwide frequency distribution of CYP3A5 and ABCB1 polymorphisms is a caveat against the extrapolation of these data to the heterogeneous and admixed Brazilian population. We investigated the effect of CYP3A5 and ABCB1 polymorphisms on CSA and TAC dose-adjusted trough concentration (C0/dose) in Brazilian renal transplant recipients, during the first 3 months post-transplantation. MATERIALS & METHODS: Patients receiving CSA (n = 150) or TAC (n = 151) were genotyped for CYP3A5*3 (rs776746, 6986A>G), *6 (rs10264272, 14690G>A) and *7 (rs41303343, 27131-27132insT) and for ABCB1 1236C>T (rs1128503), 2677G>T/A (rs2032582) and 3435C>T (rs1045642) polymorphisms. We explored the effects of CYP3A5 and ABCB1 polymorphisms, clinical and demographical characteristics on CSA and TAC C0/dose under a two-step data analysis strategy by fitting a longitudinal mixed-effects model to the data; first to select the important covariates under a univariate setting and then to fit the final multivariate model. RESULTS: C0/dose of TAC was associated with the number of CYP3A5-defective alleles, in a gene-dose manner, throughout the observation period, whereas C0/dose of CSA was associated with body surface area and prednisone dosing. No other significant associations were detected. CONCLUSION: Individual adjustment of the initial TAC dose according to the CYP3A5 haplotypes comprising the CYP3A5*3, *6 and *7 defective alleles might prove beneficial to Brazilian renal transplant recipients and should be further investigated in prospective trials.

Nascimentos na cidade de São Paulo: onde moram as mães e onde nascem seus bebês / Births in the city of São Paulo, where they live and where the mothers their babies are born

O estudo dimensiona o processo de invasão e evasão dos NV em 2009, relativo ao MSP. Utilizou-se a base de dados do SINASC municipal de 2009 para o estudo da invasão e a retroalimentada da base nacional para a análise da evasão de residentes no MSP.

Nascimentos na cidade de São Paulo: onde moram as mães e onde nascem seus bebês

O estudo dimensiona o processo de invasão e evasão dos NV em 2009, relativo ao MSP. Utilizou-se a base de dados do SINASC municipal de 2009 para o estudo da invasão e a retroalimentada da base nacional para a análise da evasão de residentes no MSP.

Glycogen synthesis in brain and astrocytes is inhibited by chronic lithium treatment.

Lithium is a drug widely used to treat bipolar disorder. It has been shown to inhibit the total activity of phosphoglucomutase (PGM) from rat brains. In this work, we show that lithium inhibits in vitro PGM activity in the cortex, hippocampus, striatum, brainstem and cerebellum. As a compensatory effect, chronic lithium treatment of Wistar rats for 6 weeks caused a 1.6-fold upregulation of cortex PGM activity. No difference was observed in the other areas tested. Another effect of chronic lithium administration was a drastic reduction of glycogen content in rat brains, as PGM activity is essential for its synthesis. In a primary culture of astrocytes, which are the main cellular components of the brain that produce glycogen, administration of 1mM lithium for 3 days markedly reduced the steady state of glycogen content. In agreement with this result, lithium did not cause insulin-like effects as previously observed in hepatocytes where lithium activated glycogen synthesis. Reduction of glycogen content was due to inhibition of glycogen synthesis, as incorporation of [(14)U(-)C]-glucose into glycogen was impaired by lithium. Consistent with these results, incubation of glucose-starved astrocytes with lithium did not stimulate dephosphorylation of glycogen synthase, which normally occurs with re-feeding of glucose. Furthermore, in a chronically treated astrocyte culture, glycogen synthase was phosphorylated constitutively. Our results indicate that chronic lithium treatment can inhibit glycogen synthesis in brain suggesting that this effect might contribute to lithium's therapeutic effect.

Methane emissions from Pantanal, South America, during the low water season: toward more comprehensive sampling.

Freshwater environments contribute 75% of the natural global methane (CH(4)) emissions. While there are indications that tropical lakes and reservoirs emit 58-400% more CH(4) per unit area than similar environments in boreal and temperate biomes, direct measurements of tropical lake emissions are scarce. We measured CH(4) emissions from 16 natural shallow lakes in the Pantanal region of South America, one of the world's largest tropical wetland areas, during the low water period using floating flux chambers. Measured fluxes ranged from 3.9 to 74.2 mmol m(-2) d(-1) with the average from all studied lakes being 8.8 mmol m(-2) d(-1) (131.8 mg CH(4) m(-2) d(-1)), of which ebullition accounted for 91% of the flux (28-98% on individual lakes). Diel cycling of emission rates was observed and therefore 24-h long measurements are recommended rather than short-term measurements not accounting for the full diel cycle. Methane emission variability within a lake may be equal to or more important than between lake variability in floodplain areas as this study identified diverse habitats within lakes having widely different flux rates. Future measurements with static floating chambers should be based on many individual chambers distributed in the various subenvironments of a lake that may differ in emissions in order to account for the within lake variability.