Data sources for drug utilization research in Latin American countries-A cross-national study: DASDUR-LATAM study.

PURPOSE: Drug utilization research (DUR) contributes to inform policymaking and to strengthen health systems. The availability of data sources is the first step for conducting DUR. However, documents that systematize these data sources in Latin American (LatAm) countries are not known. We compiled the potential data sources for DUR in the LatAm region. METHODS: A network of DUR experts from nine LatAm countries was assembled and experts conducted: (i) a website search of the government, academic, and private health institutions; (ii) screening of eligible data sources, and (iii) liaising with national experts in pharmacoepidemiology (via an online survey). The data sources were characterized by accessibility, geographic granularity, setting, sector of the data, sources and type of the data. Descriptive analyses were performed. RESULTS: We identified 125 data sources for DUR in nine LatAm countries. Thirty-eight (30%) of them were publicly and conveniently available; 89 (71%) were accessible with limitations, and 18 (14%) were not accessible or lacked clear rules for data access. From the 125 data sources, 76 (61%) were from the public sector only; 46 (37%) were from pharmacy records; 43 (34%) came from ambulatory settings and; 85 (68%) gave access to individual patient-level data. CONCLUSIONS: Although multiple sources for DUR are available in LatAm countries, the accessibility is a major challenge. The procedures for accessing DUR data should be transparent, feasible, affordable, and protocol-driven. This inventory could permit a comparison of drug utilization between countries identifying potential medication-related problems that need further exploration.

Cost-effectiveness of a Digital Health Intervention for Acute Myocardial Infarction Recovery.

BACKGROUND: Acute myocardial infarction (AMI) is a common cause of hospital admissions, readmissions, and mortality worldwide. Digital health interventions (DHIs) that promote self-management, adherence to guideline-directed therapy, and cardiovascular risk reduction may improve health outcomes in this population. The "Corrie" DHI consists of a smartphone application, smartwatch, and wireless blood pressure monitor to support medication tracking, education, vital signs monitoring, and care coordination. We aimed to assess the cost-effectiveness of this DHI plus standard of care in reducing 30-day readmissions among AMI patients in comparison to standard of care alone. METHODS: A Markov model was used to explore cost-effectiveness from the hospital perspective. The time horizon of the analysis was 1 year, with 30-day cycles, using inflation-adjusted cost data with no discount rate. Currencies were quantified in US dollars, and effectiveness was measured in quality-adjusted life-years (QALYs). The results were interpreted as an incremental cost-effectiveness ratio at a threshold of $100,000 per QALY. Univariate sensitivity and multivariate probabilistic sensitivity analyses tested model uncertainty. RESULTS: The DHI reduced costs and increased QALYs on average, dominating standard of care in 99.7% of simulations in the probabilistic analysis. Based on the assumption that the DHI costs $2750 per patient, use of the DHI leads to a cost-savings of $7274 per patient compared with standard of care alone. CONCLUSIONS: Our results demonstrate that this DHI is cost-saving through the reduction of risk for all-cause readmission following AMI. DHIs that promote improved adherence with guideline-based health care can reduce hospital readmissions and associated costs.

Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance.

We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the Plasmodium falciparum proteasome (Pf20S) ß5 subunit that spare all active subunits of human constitutive and immuno-proteasomes. The compounds are active against erythrocytic, sexual, and liver-stage parasites, against parasites resistant to current antimalarials, and against P. falciparum strains from patients in Africa. The ß5 inhibitors synergize with a ß2 inhibitor in vitro and in mice and with artemisinin. P. falciparum selected for resistance to an AsnEDA ß5 inhibitor surprisingly harbored a point mutation in the noncatalytic ß6 subunit. The ß6 mutant was resistant to the species-selective Pf20S ß5 inhibitor but remained sensitive to the species-nonselective ß5 inhibitors bortezomib and carfilzomib. Moreover, resistance to the Pf20S ß5 inhibitor was accompanied by increased sensitivity to a Pf20S ß2 inhibitor. Finally, the ß5 inhibitor-resistant mutant had a fitness cost that was exacerbated by irradiation. Thus, used in combination, multistage-active inhibitors of the Pf20S ß5 and ß2 subunits afford synergistic antimalarial activity with a potential to delay the emergence of resistance to artemisinins and each other.

Modeling Prevention of Malaria and Selection of Drug Resistance with Different Dosing Schedules of Dihydroartemisinin-Piperaquine Preventive Therapy during Pregnancy in Uganda.

Dihydroartemisinin-piperaquine (DHA-PQ) is under study for intermittent preventive treatment during pregnancy (IPTp), but it may accelerate selection for drug resistance. Understanding the relationships between piperaquine concentration, prevention of parasitemia, and selection for decreased drug sensitivity can inform control policies and optimization of DHA-PQ dosing. Piperaquine concentrations, measures of parasitemia, and Plasmodium falciparum genotypes associated with decreased aminoquinoline sensitivity in Africa (pfmdr1 86Y, pfcrt 76T) were obtained from pregnant Ugandan women randomized to IPTp with sulfadoxine-pyrimethamine (SP) or DHA-PQ. Joint pharmacokinetic/pharmacodynamic models described relationships between piperaquine concentration and the probability of genotypes of interest using nonlinear mixed effects modeling. An increase in the piperaquine plasma concentration was associated with a log-linear decrease in risk of parasitemia. Our models predicted that higher median piperaquine concentrations would be required to provide 99% protection against mutant infections than against wild-type infections (pfmdr1: N86, 9.6 ng/ml; 86Y, 19.6 ng/ml; pfcrt: K76, 6.5 ng/ml; 76T, 19.6 ng/ml). Comparing monthly, weekly, and daily dosing, daily low-dose DHA-PQ was predicted to result in the fewest infections and the fewest mutant infections per 1,000 pregnancies (predicted mutant infections for pfmdr1 86Y: SP monthly, 607; DHA-PQ monthly, 198; DHA-PQ daily, 1; for pfcrt 76T: SP monthly, 1,564; DHA-PQ monthly, 283; DHA-PQ daily, 1). Our models predict that higher piperaquine concentrations are needed to prevent infections with the pfmdr1/pfcrt mutant compared to those with wild-type parasites and that, despite selection for mutants by DHA-PQ, the overall burden of mutant infections is lower for IPTp with DHA-PQ than for IPTp with SP. (This study has been registered at ClinicalTrials.gov under identifier NCT02282293.).

Impact of Intermittent Preventive Treatment During Pregnancy on Plasmodium falciparum Drug Resistance-Mediating Polymorphisms in Uganda.

Background: In a recent trial of intermittent preventive treatment in pregnancy (IPTp) in Uganda, dihydroartemisinin-piperaquine (DP) was superior to sulfadoxine-pyrimethamine (SP) in preventing maternal and placental malaria. Methods: We compared genotypes using sequencing, fluorescent microsphere, and quantitative polymerase chain reaction assays at loci associated with drug resistance in Plasmodium falciparum isolated from subjects receiving DP or SP. Results: Considering aminoquinoline resistance, DP was associated with increased prevalences of mutations at pfmdr1 N86Y, pfmdr1 Y184F, and pfcrt K76T compared to SP (64.6% vs 27.4%, P < .001; 93.9% vs 59.2%, P < .001; and 87.7% vs 75.4%, P = .03, respectively). Increasing plasma piperaquine concentration at the time of parasitemia was associated with increasing pfmdr1 86Y prevalence; no infections with the N86 genotype occurred with piperaquine >2.75 ng/mL. pfkelch13 propeller domain polymorphisms previously associated with artemisinin resistance were not identified. Recently identified markers of piperaquine resistance were uncommon and not associated with DP. Considering antifolate resistance, SP was associated with increased prevalence of a 5-mutation haplotype (pfdhfr 51I, 59R, and 108N; pfdhps 437G and 581G) compared to DP (90.8% vs 60.0%, P = .001). Conclusions: IPTp selected for genotypes associated with decreased sensitivity to treatment regimens, but genotypes associated with clinically relevant DP resistance in Asia have not emerged in Uganda.

Miracle drug: Brazil approves never-tested cancer medicine.

Background Brazil recently approved synthetic phosphoetanolamine, a popularly dubbed 'cancer pill', a substance that has been shown to kill cancer cells in lab animal models but was not yet formally accessed in humans, and thus despite the existence of any evidence of its efficacy and safety. Methods The authors describe the recent decision of Brazil to aprove phosphoetanolamine in the context of growing 'judicialization' to promote access to medicines and thus reinforcing a growing sense of legal uncertainty. Results The approval of phosphoetanolamine despite the existence of any evidence of its efficacy and safety represents to the authors one of the saddest and surrealistic episodes in Brazil's recent public health history. Brazil's current economic crisis is fueling the 'judicialization' to promote access to medicines and thus reinforcing a growing sense of legal uncertainty in the context of rising economic constrains and a progressive failing state. The authors state that the Phosphoetanolamine's approval bill violates current legal prohibition of commercialisation of drugs without the Brazilian national drug regulatory agency's approval and thus may represent a potential menace to Brazil's pharmacogovernance and the country's governance to health technology assessment at the Brazilian national health systems. Conclusion Phosphoetanolamine's approval illustrates that the combination of flawed decision making, economic crisis and political interference may threaten weak governance mechanisms for drug regulation and health technology assessment and thus representing an extra burden in the sustainability of universal access-based national health systems.

[Judicialization of cannabidiol-based products in Brazil: an analysis from 2019 to 2022]. / Judicialização de produtos à base de canabidiol no Brasil: uma análise de 2019 a 2022.

The study analyzed the lawsuits of patients who requested cannabidiol (CBD)-based products from the Brazilian Unified National Health System during the period from 2019 to 2022, describing sociodemographic, clinical, and legal characteristics. This is a cross-sectional study composed of the evaluation of the technical notes issued by the Center for Technical Support of the Judiciary (NatJus), which supports judicial decisions. The data were obtained from the e-NatJus system, of the Brazilian Ministry of Justice, using web scraping techniques. Logistic regression was used to estimate odds ratios with 95% confidence intervals. We analyzed 1,115 technical notes of the CBD plaintiffs, of which 54.7% of the male patients, with a mean age of 18.4 years, mostly from the South Region of the country (38.8%), and 49.6% sought treatment for epilepsy. Regarding the actions with favorable opinions, 28.8% had no scientific evidence, 26.5% pleaded for products without registration with the Brazilian Health Regulatory Agency, and 25.3% of those that had registration were not in compliance with the therapeutic indication. Patients from the Northeast Region had a chance of a favorable opinion increased by 3.0 times and those diagnosed with epilepsy by 2.3. The expert opinions that supported the magistrates for the judicial decisions regarding the demands of patients for cannabidiol-based products in Brazil were mostly in accordance with scientific evidence, denoting the importance of NatJus in the qualification of access to medicinal products in the country.

Este estudo analisou as ações judiciais de pacientes que solicitaram ao Sistema Único de Saúde produtos à base de canabidiol (CBD) durante o período de 2019 a 2022, descrevendo características sociodemográficas, clínicas e jurídicas. Trata-se de um estudo transversal composto pela avaliação das notas técnicas emitidas pelos Núcleos de Apoio Técnico do Judiciário (NatJus), que embasaram as decisões judiciais. Os dados foram obtidos do sistema e-NatJus, do Ministério da Justiça, utilizando técnicas de web scraping. Regressão logística foi empregada para estimar razões de chances com intervalos de 95% de confiança. Foram analisadas 1.115 notas técnicas das ações demandantes de CBD, das quais 54,7% dos pacientes eram do sexo masculino, com idade média de 18,4 anos, em sua maioria da Região Sul do país (38,8%), e 49,6% buscavam tratamento para epilepsia. Das ações com pareceres favoráveis, 28,8% não tinham evidências científicas, 26,5% pleitearam produtos sem registro na Agência Nacional de Vigilância Sanitária e 25,3% dos que tinham registro não estavam em conformidade com a indicação terapêutica. Os pacientes da Região Nordeste tiveram a chance de parecer favorável aumentada em 3 vezes; e os que tinham diagnóstico de epilepsia, em 2,3 vezes. Os pareceres técnicos que deram suporte aos magistrados para as decisões judiciais das demandas de pacientes por produtos à base de canabidiol no Brasil estavam, em sua maioria, em conformidade com evidências científicas, denotando a importância dos NatJus na qualificação do acesso a produtos medicinais no país.

El estudio analizó las acciones legales de pacientes que solicitaron al Sistema Único de Salud brasileño productos a base de cannabidiol (CBD) durante el período de 2019 a 2022, describiendo características sociodemográficas, clínicas y legales. Se trata de un estudio transversal compuesto por la evaluación de las notas técnicas emitidas por los Núcleos de Apoyo Técnico del Poder Judicial (NatJus) que basaron las decisiones judiciales. Los datos se obtuvieron del sistema e-NatJus, del Ministerio de Justicia brasileño, mediante técnicas de web scraping. La regresión logística se empleó para estimar los odds ratios con intervalos del 95% de confianza. Fueron analizadas 1.115 notas técnicas de las acciones demandantes de CBD que tenían 54,7 % de los pacientes del género masculino, con una edad media de 18,4 años, en su mayoría de la Región Sur del país (38,8%) y 49,6% buscaban tratamiento para la epilepsia. De las acciones con opiniones favorables, el 28,8% no tenían evidencias científicas, el 26,5% pleitearon productos sin registro en la Agencia Nacional de Vigilancia Sanitaria y el 25,3% de los que tenían registro, no estaban en conformidad con la indicación terapéutica. Los pacientes de la Región Nordeste tuvieron la posibilidad de opiniones favorables aumentada en 3,0 veces y los que tenían diagnóstico de epilepsia en 2,3. Los dictámenes técnicos que dieron apoyo a los magistrados para las decisiones judiciales de las demandas de los pacientes por productos a base de cannabidiol en Brasil estaban en su mayoría en conformidad con las evidencias científicas, denotando la importancia de NatJus en la calificación del acceso a productos medicinales en el país.

Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington's Disease.

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. We report the design of a series of HTT pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of HTT mRNA transcripts and protein levels. The starting benzamide core was modified to pyrazine amide and further optimized to give a potent, CNS-penetrant, and orally bioavailable HTT-splicing modulator 27. This compound reduced canonical splicing of the HTT RNA exon 49-50 and demonstrated significant HTT-lowering in both human HD stem cells and mouse BACHD models. Compound 27 is a structurally diverse HTT-splicing modulator that may help understand the mechanism of adverse effects such as peripheral neuropathy associated with branaplam.

The Use of the Target Trial Approach in Perinatal Pharmacoepidemiology: A Scoping Review Protocol.

Background: Pregnant and postpartum women have been historically excluded from clinical trials, with data on the safety of drugs relying on observational research. Methodological concerns regarding the timing and dosing of medications, data sources, study designs, and methods used for estimating associations are still problematic in observational studies. Answering causal questions is even more complex. Despite the increased interest in emulating target trials using observational data, little is known about this approach in perinatal pharmacoepidemiology. Objective: This scoping review protocol aims to describe the methodology for assessing the available literature concerning emulating target trials for studying outcomes in women exposed to medications in the preconception, perinatal, or postpartum periods. Methods and Analysis: We will follow the methods detailed in the Joanna Briggs Institute reviewer's manual. We will adopt the six-stage framework recommended by Arksey and O'Malley and Levac and others. Web scraping techniques will be used for identifying relevant studies. Two authors will select articles based on the title and abstract, with discrepancies resolved by consensus, by a third reviewer. Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews flow diagram will be presented to reflect the search process. We will use existing statements to identify quality gaps in the current literature. Variables related to the content for perinatal pharmacoepidemiologic research will be included. The Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) will guide the assessment of the target trial emulation (i.e., treatment strategies compared, assignment procedures, follow-up period, outcome, and causal contrasts). Discussion: Data regarding the safety of drugs taken, prior to and during pregnancy and while lactating are lacking and it is necessary to understand how we can answer these questions using rigorous methods in observational research. Through this scoping review, we intend to understand to what extent the target trial approach is being used in perinatal pharmacoepidemiology and provide recommendations to improve its use in this field. Ethics and Dissemination: Secondary data from published scientific articles will be used, not requiring approval by the Research Ethics Committee with human beings. Findings will be submitted to a peer-reviewed journal.

Autonomic dysfunction is common in liver cirrhosis and is associated with cardiac dysfunction and mortality: prospective observational study.

BACKGROUND: Although autonomic dysfunction has been shown to be associated with liver cirrhosis, the prevalence and prognostic implications are unclear. Abnormal heart rate variability (HRV), a measure of autonomic function, has not been well investigated in cirrhosis. OBJECTIVE: To evaluate the prevalence of high-risk HRV parameters in a cohort of cirrhotic patients and their association with cardiac dysfunction and mortality. DESIGN AND SETTING: Prospective observational study conducted in the Federal University of São Paulo. METHOD: A cohort of 120 patients, comprising 17 healthy controls and 103 cirrhotic outpatients, was evaluated and followed for 10 months. HRV analysis was based on 24-hour Holter monitoring and defined using time-domain and frequency-domain parameters. RESULTS: The HRV parameters were statistically lower in cirrhotic patients than in healthy subjects. High-risk HRV parameters were prevalent, such that 64% had at least one high-risk parameter. Time-domain parameters correlated with Child scores (P < 0.0001). In regression models, HRV parameters were independent predictors of diastolic dysfunction and mortality. During 10 months of follow-up, there were 11 deaths, all of patients with at least one high-risk HRV parameter. Kaplan-Meier analysis estimated low survival rates among patients with standard deviation of normal-to-normal RR intervals (SDNN) < 100. CONCLUSION: Reduced HRV is prevalent in liver cirrhosis and is related to cardiac dysfunction, severity of liver disease and mortality. Abnormal high-risk HRV parameters are prevalent among cirrhotic patients and are also predictors of mortality. Our findings highlight the need for a more careful cardiac evaluation of cirrhotic patients.

[Adverse drug reaction notification forms of the pharmacovigilance systems in Brazil and twelve other Latin-American countries: a comparative analysis]. / Formulários de notificação de reações adversas a medicamento nos sistemas de farmacovigilância do Brasil e outros doze países latino-americanos: análise comparativa.

The scope of this study was to assess the forms used to report suspected adverse drug reactions (ADR) to the pharmacovigilance system in Brazil and twelve other Latin-American countries. The study comprised three stages. In the first stage, the forms were attributed a score relating to the presence of critical items to generate ADR notification. In the second stage, the variables of the forms were quantified and classified regarding feasibility to contribute to an appropriate assessment of causality. In the last stage, hierarchical clustering was used to identify similar forms. The Venezuelan form achieved the highest score (18 points). The median number of variables in the forms of each country was 41 [26 (Guatemala) to 95 (Brazil)]. Most of the variables of the form were classified as life-critical and the majority contribute as an alternative explanation to causality assessment. Four clusters were identified (1, 2, 3 and 4). The forms of Brazil and Bolivia formed two distinct groups, 1 and 3 respectively. The results of this study indicate the need to change the forms of the different countries studied or even delete some variables, making them more appropriate for the process of assessment of ADR causality.

Avaliou-se os formulários de notificação de suspeitas de reações adversas a medicamentos (RAM) do sistema de farmacovigilância do Brasil e outros doze países latino-americanos. O estudo foi composto por três etapas. Na primeira, os formulários foram pontuados em relação à presença de itens essenciais para compor uma notificação de RAM. Na segunda, as variáveis dos formulários foram quantificadas e classificadas, quanto à razoabilidade em contribuírem para a avaliação de causalidade. Na última etapa, recorreu-se à análise de agrupamento hierárquico para identificar os formulários similares. O formulário da Venezuela obteve a maior pontuação (18 pontos). A mediana das variáveis nos formulários dos países foi de 41 [26 (Guatemala) a 95 (Brasil)]. A maioria das variáveis dos formulários foram classificadas como vitais e a maior parte contribui como fator de explicação alternativo para a avaliação de causalidade. Quatro agrupamentos foram identificados (1, 2, 3 e 4). Os formulários do Brasil e da Bolívia formaram dois grupos distintos, 1 e 3 respectivamente. Há necessidade de modificação dos formulários dos países ou até mesmo exclusão de variáveis, tornando-os mais adequados ao processo de avaliação da causalidade das RAM.

Six-minute walking test performance is associated with survival in cirrhotic patients.

BACKGROUND: Patients with cirrhosis are at risk of cirrhotic cardiomyopathy, with resulting cardiac dysfunction and exercise limitations. Six minute walking test (6MWT) assesses functional status and predicts morbidity and mortality in cardiopulmonary diseases. AIM: To determine if it associates with mortality by analyzing 6MWT performance in patients with liver cirrhosis. METHODS: A cohort of 106 cirrhotic patients was evaluated in the outpatient setting with echocardiogram and 6MWT and follow up for one year to document hepatic decompensation and mortality. The distance in meters was recorded at the end of 6 min (6MWD). RESULTS: This cohort had a mean age of 51 years and 56% male; patients were staged as Child A in 21.7%, B 66% and C 12.3%. Walk distance inversely correlated with Child scores, and was significantly reduced as Child stages progresses. Patients who died (10.4%) showed shorter mean 6MWD (P = 0.006). Low 6MWD was an independent predictor of mortality (P = 0.01). CONCLUSION: 6MWT is a noninvasive inexpensive test whose result is related to Child scores and mortality. It is useful to identify patients with liver cirrhosis at high risk of mortality for closer monitoring and potential early intervention.

Data Sources for Drug Utilization Research in Brazil-DUR-BRA Study.

Background: In Brazil, studies that map electronic healthcare databases in order to assess their suitability for use in pharmacoepidemiologic research are lacking. We aimed to identify, catalogue, and characterize Brazilian data sources for Drug Utilization Research (DUR). Methods: The present study is part of the project entitled, "Publicly Available Data Sources for Drug Utilization Research in Latin American (LatAm) Countries." A network of Brazilian health experts was assembled to map secondary administrative data from healthcare organizations that might provide information related to medication use. A multi-phase approach including internet search of institutional government websites, traditional bibliographic databases, and experts' input was used for mapping the data sources. The reviewers searched, screened and selected the data sources independently; disagreements were resolved by consensus. Data sources were grouped into the following categories: 1) automated databases; 2) Electronic Medical Records (EMR); 3) national surveys or datasets; 4) adverse event reporting systems; and 5) others. Each data source was characterized by accessibility, geographic granularity, setting, type of data (aggregate or individual-level), and years of coverage. We also searched for publications related to each data source. Results: A total of 62 data sources were identified and screened; 38 met the eligibility criteria for inclusion and were fully characterized. We grouped 23 (60%) as automated databases, four (11%) as adverse event reporting systems, four (11%) as EMRs, three (8%) as national surveys or datasets, and four (11%) as other types. Eighteen (47%) were classified as publicly and conveniently accessible online; providing information at national level. Most of them offered more than 5 years of comprehensive data coverage, and presented data at both the individual and aggregated levels. No information about population coverage was found. Drug coding is not uniform; each data source has its own coding system, depending on the purpose of the data. At least one scientific publication was found for each publicly available data source. Conclusions: There are several types of data sources for DUR in Brazil, but a uniform system for drug classification and data quality evaluation does not exist. The extent of population covered by year is unknown. Our comprehensive and structured inventory reveals a need for full characterization of these data sources.

Yeast Double Transporter Gene Deletion Library for Identification of Xenobiotic Carriers in Low or High Throughput.

The routes of uptake and efflux should be considered when developing new drugs so that they can effectively address their intracellular targets. As a general rule, drugs appear to enter cells via protein carriers that normally carry nutrients or metabolites. A previously developed pipeline that searched for drug transporters using Saccharomyces cerevisiae mutants carrying single-gene deletions identified import routes for most compounds tested. However, due to the redundancy of transporter functions, we propose that this methodology can be improved by utilizing double mutant strains in both low- and high-throughput screens. We constructed a library of over 14,000 strains harboring double deletions of genes encoding 122 nonessential plasma membrane transporters and performed low- and high-throughput screens identifying possible drug import routes for 23 compounds. In addition, the high-throughput assay enabled the identification of putative efflux routes for 21 compounds. Focusing on azole antifungals, we were able to identify the involvement of the myo-inositol transporter, Itr1p, in the uptake of these molecules and to confirm the role of Pdr5p in their export. IMPORTANCE Our library of double transporter deletion strains is a powerful tool for rapid identification of potential drug import and export routes, which can aid in determining the chemical groups necessary for transport via specific carriers. This information may be translated into a better design of drugs for optimal absorption by target tissues and the development of drugs whose utility is less likely to be compromised by the selection of resistant mutants.

Diazepam's antifungal activity in fluconazole-resistant Candida spp. and biofilm inhibition in C. albicans: evaluation of the relationship with the proteins ALS3 and SAP5.

The genus Candida spp. has been highlighted as one of the main etiological agents causing fungal infections, with Candida albicans being the most prominent, responsible for most cases of candidemia. Due to its capacity for invasion and tissue adhesion, it is associated with the formation of biofilms, mainly in the environment and hospital devices, decreasing the effectiveness of available treatments. The repositioning of drugs, which is characterized by the use of drugs already on the market for other purposes, together with molecular-docking methods can be used aiming at the faster development of new antifungals to combat micro-organisms. This study aimed to evaluate the antifungal effect of diazepam on mature C. albicans biofilms in vitro and its action on biofilm in formation, as well as its mechanism of action and interaction with structures related to the adhesion of C. albicans, ALS3 and SAP5. To determine the MIC, the broth microdilution test was used according to protocol M27-A3 (CLSI, 2008). In vitro biofilm formation tests were performed using 96-well plates, followed by molecular-docking protocols to analyse the binding agent interaction with ALS3 and SAP5 targets. The results indicate that diazepam has antimicrobial activity against planktonic cells of Candida spp. and C. albicans biofilms, interacting with important virulence factors related to biofilm formation (ALS3 and SAP5). In addition, treatment with diazepam triggered a series of events in C. albicans cells, such as loss of membrane integrity, mitochondrial depolarization and increased production of EROs, causing DNA damage and consequent cell apoptosis.

[Evaluation of the Performance of the Brazilian Notification System for Health Surveillance: A Tool in Brazil's Pharmacovigilance System]. / Avaliação do desempenho do Sistema Nacional de Notificações para a Vigilância Sanitária: uma ferramenta do sistema de farmacovigilância no Brasil.

The scope of this paper is to assess the performance of the Brazilian Notification System for Health Surveillance, with respect to the registration of information on adverse drug-related effects on health (Notivisa/medication) based on previously selected attributes. A cross-sectional health evaluation study was conducted between 2008 and 2013 using eight attributes established by international guidelines to assess public health surveillance systems: simplicity, acceptability, representativeness, completeness, validity, consistency, positive predictive error and timeliness. In the study period, 63,512 registrations were identified in Notivisa/medication, the majority being considered severe (60.5%). The performance of Notivisa/medication was considered satisfactory with respect to two of the eight attributes (validity and positive predictive error) and deficient in six of the remaining attributes (simplicity, acceptability, representativeness, completeness, consistency and timeliness). Quality improvement strategies to remedy the system need to be discussed and implemented in order to provide complete, timely and reliable surveillance information for different segments of Brazilian society, especially health surveillance managers.

Early Changes in Nitrate Uptake and Assimilation Under Drought in Relation to Transpiration.

Soil drying combined with nitrogen (N) deficiency poses a grave threat to agricultural crop production. The rate at which nitrate (NO3 -) is taken up depends partly on the uptake and transpiration of water. Rapid changes in nitrate assimilation, in contrast to other N forms, may serve as a component of the plant stress response to drought because nitrate assimilation may lead to changes in xylem pH. The modulation of xylem sap pH may be relevant for stomata regulation via the delivery of abscisic acid (ABA) to guard cells. In several factorial experiments, we investigated the interactions between nitrate and water availability on nitrate fate in the plant, as well as their possible implications for the early drought-stress response. We monitored the short-term response (2-6 days) of nitrate in biomass, transport to shoot and reduction in Pisum sativum, Hordeum vulgare, Vicia faba, and Nicotiana tabacum and correlated this with sap pH and transpiration rates (TRs). Cultivation on inorganic substrate ensured control over nutrient and water supply and prevented nodulation in legume species. NO3 - content in biomass decreased in most of the species under drought indicating significant decline in NO3 - uptake. Hordeum vulgare had the highest NO3 - concentrations in all organs even under drought and low NO3 - treatment. This species can likely respond much better to the combined adverse effects of low NO3 - and water scarcity. Nitrate reductase activity (NRA) was reduced in both roots and leaves of water deficient (WD) plants in all species except H. vulgare, presumably due to its high NO3 - contents. Further, transient reduction in NO3 - availability had no effect on sap pH. Therefore, it seems unlikely that NRA shifts from shoot root leading to the supposed alkalization of sap. We also did not observe any interactive effects of NO3 - and water deficiency on transpiration. Hence, as long as leaf NO3 - content remains stable, NO3 - availability in soil is not linked to short-term modulation of transpiration.

São Paulo State Liver Transplantation Supply Chain Study.

BACKGROUND: The number of liver transplantations is increasing worldwide, and Brazil ranks in the second position. It has one of the biggest public health care systems, which is responsible for the coordination and financial funding of transplantation procedures. Meeting the demands of such a large system of transplantation has become a challenge, particularly when attempting to minimize costs of scarce and expensive resources. The aim of this study was to investigate the process of donation, the retrieval of organs, and the transplantation itself using engineering methods based on logistics analyses. METHODS: Three steps were used: study planning, data gathering, and data analysis. Researchers surveyed professionals to acquire raw information based on their observations, experience, and knowledge. Then, a data analysis was conducted, putting together all the information gathered during the previous steps. Bias was removed, and conflicting perceptions were resolved in order to have a standard view on the transplantation process. RESULTS: Data was gathered between 2014 and 2018 and included 5502 liver donors and 2678 (48.7%) patients who received liver transplants organs. A total of 2824 organs were refused because of logistics issues (transport and handling). Interviews of health care professionals enabled the design of a process map in which 4 stakeholders were identified: patient, physician, organ, and information. CONCLUSIONS: The liver transplantation process is analyzed based on a supply chain methodology applying this knowledge and putting together medical and engineering sciences to promote better efficiency and outcomes for the transplantation program. Future studies should focus on the implementation of these ideas aiming to promote optimization gains in any step of the process.

Solid Organ Transplantation Activities Evolution in Brazil: Analysis of 20 Years.

BACKGROUND: From 1968 until 1997, transplantation-related activities were not properly regulated and were informally practiced. During 20 years, many legal and political changes influenced it. OBJECTIVE: To provide a historical overview of the 20 years with a descriptive data analysis of a 20-year data set. METHODOLOGY: We investigated information from Brazilian Transplantation Reports between 1997 and 2017. In this way, we classified all data into 5 Brazilian macro regions: Center-West, Northeast, North, Southeast, and South. In total, we included 27 states (including Capital District) and limited study to the heart, liver, and kidney. RESULTS: We analyzed 2835 data entries and associated population information from the Brazilian Institute of Geography and Statistics. We observed 2 distinct groups, one uniquely formed by the North region, with figures significantly lower than the remaining regions. After 2003, Southeast, South, and Northeast regions indicated a growing movement, whereas Center-West indicated certain stability in 50 and ranging between 50 and 100 cases (yearly basis) after 2011. Recently (2016 and 2017), the South region indicates another crescendo movement suggesting another detachment from the other regions, but it is something not clearly observed and, if true, should be figured in new reports of Brazilian Association of Organ Transplantation. CONCLUSION: This study identified and observed the time-spatial progress of organ transplantation in Brazil. In conclusion, after analysis of this 20-year data consolidation related to organ transplantation in Brazil, we observed a public investment in implementing quality evaluation and safety to provide figures that deliver visibility to the numbers reported in this article.

[Adverse drug reactions reported to the Brazilian pharmacovigilance system from 2008 to 2013: descriptive study]. / Reações adversas a medicamentos no sistema de farmacovigilância do Brasil, 2008 a 2013: estudo descritivo.

The study aimed to analyze suspected adverse drug reactions reported to Brazil's pharmacovigilance system (Notivisa-medicamento) from 2008 to 2013. This was a descriptive study whose analytical units in the database were reports and drug-adverse reactions pairs. A total of 26,554 reports were identified, for a reporting rate of 22.8/million inhabitants/year. Reports in female patients prevailed (60.5%), as did white color/race (58.1%). Age ranged from 0 to 112 years (median = 46 years). Nearly one-third (32.5%) of suspected adverse drug reactions occurred in vulnerable populations (elderly and children). A total of 54,288 drug- adverse reactions pairs were analyzed, with a prevalence of severe adverse drug reactions (59.2%), featuring those that resulted in clinically important effects (83.1%). The most frequent drugs in severe adverse drug reactions belonged to groups L, antineoplastic and immunomodulating agents (32.1%), and J, general anti-infectious agents for systemic use (27%), while the most affected system-organ-class was conditions of the skin and related disorders (23.7%). Notivisa-medicamento is an important resource for producing warning signs and hypotheses on the safety of drugs marketed in Brazil. However, the reporting rate per million inhabitants/year was far lower than that described in middle and high-income countries.

Analisam-se as suspeitas de reações adversas a medicamentos notificadas no sistema de farmacovigilância do Brasil (Notivisa-medicamento) entre 2008 e 2013. Trata-se de estudo descritivo cujas unidades de análises da base de dados foram as notificações e os pares medicamento-reação adversa. Foi identificado um total de 26.554 notificações, o que produziu uma taxa de notificação de 22,8 milhões de habitantes/ano. As notificações referentes ao sexo feminino (60,5%) prevaleceram, assim como a raça/cor branca (58,1%). A idade variou de 0 a 112 anos (mediana = 46 anos). Quase 1/3 (32,5%) das suspeitas de reações adversas a medicamentos ocorreram em populações vulneráveis (idosos e crianças). Foram avaliados 54.288 registros de pares de medicamento-reação adversa, em que prevaleceram as reações adversas graves (59,2%), com destaque para as que resultaram em efeito clinicamente importante (83,1%). Os medicamentos mais frequentes nas reações adversas a medicamentos graves pertenceram aos grupos L - agentes neoplásicos e imunomodulares (32,1%) e J - anti-infeciosos gerais para uso sistêmico (27%), ao passo que o sistema-órgão-classe mais afetado foi o relacionado a afecções da pele e distúrbios afins (23,7%). O Notivisa-medicamento é relevante recurso para a produção de sinais de alertas e hipóteses sobre a segurança de medicamentos comercializados no Brasil. No entanto, a taxa de notificação por milhão de habitantes/ano mostrou-se muito inferior àquela descrita por países de média e alta renda.

El objetivo de este estudio es analizar las sospechas de reacciones adversas a medicamentos, notificadas en el sistema de farmacovigilancia de Brasil (Notivisa-medicamento), entre 2008 y 2013. Se trata de un estudio descriptivo cuyas unidades de análisis en la base de datos fueron las notificaciones y los pares medicamento-reacción adversa. Se identificaron un total de 26.554 notificaciones, generando una tasa de notificación de 22,8/ millones de habitantes/año. Las notificaciones referentes al sexo femenino (60,5%) prevalecieron, así como, la raza/color blanco (58,1%). La edad varió de 0 a 112 años (mediana = 46 años). Casi 1/3 (32,5%) de las sospechas de reacciones adversas a medicamentos ocurrieron en poblaciones vulnerables (ancianos y niños). Se evaluaron 54.288 registros de pares de medicamento-reacción adversa, donde prevalecieron las reacciones adversas graves (59,2%), destacando las que resultaron en un efecto clínicamente importante (83,1%). Los medicamentos más frecuentes en las reacciones adversas a medicamentos graves pertenecieron a los grupos L - agentes neoplásicos e inmunomoduladores (32,1%) y J - antiinfecciosos generales para uso sistémico (27%), mientras que el sistema-órgano-clase más afectado fue afecciones de la piel y disturbios afines (23,7%). El Notivisa-medicamento es una herramienta relevante para la producción de señales de alerta e hipótesis sobre la seguridad de medicamentos comercializados en Brasil. No obstante, la tasa de notificación por millón de habitantes/año se mostró muy inferior a la que está descrita en países de media y alta renta.