Rome III Criteria Capture Higher Irritable Bowel Syndrome SNP-Heritability and Highlight a Novel Genetic Link with Cardiovascular Traits.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) shows genetic predisposition, and large-scale genome-wide association studies (GWAS) are emerging, based on heterogeneous disease definitions. We investigated the genetic architecture of IBS defined according to gold standard Rome Criteria. METHODS: We conducted GWAS meta-analyses of Rome III IBS and its subtypes in 24,735 IBS cases and 77,149 asymptomatic control subjects from 2 independent European cohorts (UK Biobank and Lifelines). Single-nucleotide polymorphism (SNP)-based heritability (h2SNP) and genetic correlations (rg) with other traits were calculated. IBS risk loci were functionally annotated to identify candidate genes. Sensitivity and conditional analyses were conducted to assess impact of confounders. Polygenic risk scores were computed and tested in independent datasets. RESULTS: Rome III IBS showed significant SNP-heritability (up to 13%) and similar genetic architecture across subtypes, including those with manifestations at the opposite ends of the symptom spectrum (rg = 0.48 between IBS-D and IBS-C). Genetic correlations with other traits highlighted commonalities with family history of heart disease and hypertension, coronary artery disease, and angina pectoris (rg = 0.20-0.45), among others. Four independent GWAS signals (P < 5×10-8) were detected, including 2 novel loci for IBS (rs2035380) and IBS-mixed (rs2048419) that had been previously associated with hypertension and coronary artery disease. Functional annotation of GWAS risk loci revealed genes implicated in circadian rhythm (BMAL1), intestinal barrier (CLDN23), immunomodulation (MFHAS1), and the cyclic adenosine monophosphate pathway (ADCY2). Polygenic risk scores allowed the identification of individuals at increased risk of IBS (odds ratio, 1.34; P = 1.1×10-3). CONCLUSIONS: Rome III Criteria capture higher SNP-heritability than previously estimated for IBS. The identified link between IBS and cardiovascular traits may contribute to the delineation of alternative therapeutic strategies, warranting further investigation.

Food environment of bus terminals in the Rio de Janeiro metropolitan region.

PURPOSE: To describe and analyze the healthiness of formal and informal food establishments in bus terminals of the metropolitan region of the state of Rio de Janeiro. METHOD: An audit was conducted in 156 formal and 127 informal food establishments located in 14 bus terminals of the five most populous cities of the metropolitan region of Rio de Janeiro. Proportions of types of establishments and means (95%CI) of food availability indicators in formal and informal settings were calculated. For the formal setting, prices, proportions of accepted payment methods, days and hours of operation, and food categories with displayed advertising were described. RESULTS: The healthiness of food establishments in bus terminals was low (less than 36%). On average, ultra-processed food subgroups were 250% more available for purchase than fresh or minimally processed food. Purchasing food at these places was convenient because several forms of payment were available, and the opening hours of the establishments followed the peaks of movement. In addition, 73.3% of the advertising referred to ultra-processed drinks, and the cost-benefit of buying ultra-processed food was better than fresh or minimally processed food. CONCLUSION: The food environment of bus terminals in the metropolitan region of Rio de Janeiro promotes unhealthy eating. Regulatory public policies should focus on initiatives to limit the wide availability and advertising of ultra-processed food in spaces of great circulation of people.

Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes.

BACKGROUND AND AIMS: Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies. METHODS: We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied. RESULTS: We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC. CONCLUSION: Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.

Food environment of bus terminals in the Rio de Janeiro metropolitan region / Ambiente alimentar de terminais rodoviários da região metropolitana do Rio de Janeiro

ABSTRACT PURPOSE To describe and analyze the healthiness of formal and informal food establishments in bus terminals of the metropolitan region of the state of Rio de Janeiro. METHOD An audit was conducted in 156 formal and 127 informal food establishments located in 14 bus terminals of the five most populous cities of the metropolitan region of Rio de Janeiro. Proportions of types of establishments and means (95%CI) of food availability indicators in formal and informal settings were calculated. For the formal setting, prices, proportions of accepted payment methods, days and hours of operation, and food categories with displayed advertising were described. RESULTS The healthiness of food establishments in bus terminals was low (less than 36%). On average, ultra-processed food subgroups were 250% more available for purchase than fresh or minimally processed food. Purchasing food at these places was convenient because several forms of payment were available, and the opening hours of the establishments followed the peaks of movement. In addition, 73.3% of the advertising referred to ultra-processed drinks, and the cost-benefit of buying ultra-processed food was better than fresh or minimally processed food. CONCLUSION The food environment of bus terminals in the metropolitan region of Rio de Janeiro promotes unhealthy eating. Regulatory public policies should focus on initiatives to limit the wide availability and advertising of ultra-processed food in spaces of great circulation of people.

RESUMO OBJETIVO Descrever e analisar a saudabilidade dos estabelecimentos com venda formal e informal de alimentos em terminais rodoviários da região metropolitana do Rio de Janeiro. MÉTODOS Realizou-se auditoria em 156 estabelecimentos formais e 127 pontos informais de venda de alimentos localizados em 14 terminais rodoviários das cinco cidades mais populosas da região metropolitana do Rio de Janeiro. Foram calculadas proporções de tipos de estabelecimentos e médias (IC95%) de indicadores de disponibilidade de alimentos nos ambientes formal e informal. Para o ambiente formal, foram descritos preços, proporções das formas de pagamento aceitas, dias e horários de funcionamento e categorias de alimentos com propaganda exposta. RESULTADOS A saudabilidade dos pontos de venda de alimentos nos terminais rodoviários era baixa (inferior a 36%). Em média, estavam disponíveis para compra 250% mais subgrupos de alimentos ultraprocessados do que in natura ou minimamente processados. Adquirir comida nesses locais era conveniente porque diversas formas de pagamento estavam disponíveis e os horários de funcionamento dos estabelecimentos acompanhavam os picos de movimentação. Além disso, 73,3% das propagandas se referiam a bebidas ultraprocessadas e o custo-benefício da compra de alimentos ultraprocessados era melhor que o de alimentos in natura ou minimamente processados. CONCLUSÃO O ambiente alimentar dos terminais rodoviários da região metropolitana do Rio de Janeiro promove uma alimentação não saudável. Políticas públicas de regulação devem se concentrar em iniciativas que limitem a ampla disponibilidade e publicidade de alimentos ultraprocessados nesses espaços de grande circulação de pessoas.

A pilot genome-wide association study meta-analysis of gastroparesis.

BACKGROUND: Gastroparesis (GP) is characterized by delayed gastric emptying in the absence of mechanical obstruction. OBJECTIVE: Genetic predisposition may play a role; however, investigation at the genome-wide level has not been performed. METHODS: We carried out a genome-wide association study (GWAS) meta-analysis on (i) 478 GP patients from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) compared to 9931 population-based controls from the University of Michigan Health and Retirement Study; and (ii) 402 GP cases compared to 48,340 non-gastroparesis controls from the Michigan Genomics Initiative. Associations for 5,811,784 high-quality SNPs were tested on a total of 880 GP patients and 58,271 controls, using logistic mixed models adjusted for age, sex, and principal components. Gene mapping was obtained based on genomic position and expression quantitative trait loci, and a gene-set network enrichment analysis was performed. Genetic associations with clinical data were tested in GpCRC patients. Protein expression of selected candidate genes was determined in full thickness gastric biopsies from GpCRC patients and controls. RESULTS: While no SNP associations were detected at strict significance (p ≤ 5 × 10-8 ), nine independent genomic loci were associated at suggestive significance (p ≤ 1 × 10-5 ), with the strongest signal (rs9273363, odds ratio = 1.4, p = 1 × 10-7 ) mapped to the human leukocyte antigen region. Computational annotation of suggestive risk loci identified 14 protein-coding candidate genes. Gene-set network enrichment analysis revealed pathways potentially involved in immune and motor dysregulation (pFDR ≤ 0.05). The GP risk allele rs6984536A (Peroxidasin-Like; PXDNL) was associated with increased abdominal pain severity scores (Beta = 0.13, p = 0.03). Gastric muscularis expression of PXDNL also positively correlated with abdominal pain in GP patients (r = 0.8, p = 0.02). Dickkopf WNT Signaling Pathway Inhibitor 1 showed decreased expression in diabetic GP patients (p = 0.005 vs. controls). CONCLUSION: We report preliminary GWAS findings for GP, which highlight candidate genes and pathways related to immune and sensory-motor dysregulation. Larger studies are needed to validate and expand these findings in independent datasets.

Ecological study of the association between socioeconomic inequality and food deserts and swamps around schools in Rio de Janeiro, Brazil.

BACKGROUND: Previous research suggests that unhealthy community food environments around schools contribute to unhealthy eating habits and negative health outcomes among the youth. However, little is known about how socioeconomic inequalities in those community food environments are associated with food deserts and food swamps across schools' neighborhoods. METHODS: An ecological study was carried out in all 3,159 public and private schools in Rio de Janeiro, Brazil. Three measures of socioeconomic inequality were evaluated: per capita income, segregation index and deprivation index. The community school food environment was analyzed by metrics of food swamps and food deserts. RESULTS: Food deserts and food swamps were simultaneously more prevalent in neighborhoods of the lowest income, high deprivation, and high segregation. Spatial socioeconomic disparities at the neighborhoods of schools were associated with food deserts and food swamps in Rio de Janeiro. CONCLUSIONS: Our results point to a spatial socioeconomic inequality of establishments that sell food around schools in a Brazilian metropolis, indicating that the areas of greatest deprivation of food services are also the areas with the worst socioeconomic characteristics.

Content validity and reliability of a university food environment assessment instrument. / Validade de conteúdo e confiabilidade de instrumento de avaliação do ambiente alimentar universitário.

This study aimed to evaluate the content validity and reliability of an instrument for evaluating the university food environment. A checklist was developed to assess establishments that sell food and beverages in the university environment. The content validation encompassed the development of the instrument, expert evaluation and pretest performance. Reliability was evaluated using a convenience sample (n=64) of establishments distributed across seven campuses of three public universities and was carried out using interobserver (IO) and test-retest (TR) evaluations. Categorical and count variables were analyzed by calculating the percentage agreement (PA), kappa coefficient (k) and prevalence-adjusted, bias-adjusted kappa (ka), and continuous variables were analyzed by the intraclass correlation coefficient (ICC). The checklist consisted of 204 items distributed in seven domains. The instrument's performance was considered excellent or very good for 91.3% (PA) of the items when evaluated. For IO, 68.3% (k) and 96.5% (ka) had excellent, very good or good agreement, while for TR, 65% (k) and 96.5% (ka) had excellent agreement. The instrument showed satisfactory content validity and reliability for characterizing the food environment at Brazilian universities.

O objetivo foi avaliar a validade de conteúdo e a confiabilidade de um instrumento de auditoria para avaliação do ambiente alimentar universitário. Foi desenvolvido checklist para a avaliação de estabelecimentos que comercializavam alimentos e bebidas neste ambiente. A validação de conteúdo abarcou o desenvolvimento do instrumento, a análise por especialistas e a realização do pré-teste. A confiabilidade foi avaliada em uma amostra de conveniência (n=64) de estabelecimentos distribuídos em sete campi de três universidades públicas e foi realizada pelos testes interobservador (TIO) e teste-reteste (TR). Variáveis categóricas e de contagem foram analisadas pelo cálculo da concordância percentual (CP) e dos índices kappa (k) e kappa ajustado pela prevalência e pelo viés (ka) e variáveis contínuas, pelo Coeficiente de Correlação Intraclasse (CCI). O checklist foi composto por 204 itens distribuídos em sete domínios. O desempenho do instrumento foi considerado excelente ou muito bom para 91,3% (CP) dos itens quando avaliados. No TIO 68,3% (k) e 96,5% (ka) tiveram concordância excelente, muito boa ou boa, enquanto no TR 65% tiveram concordância excelente para o k e 96,5% para o ka. O instrumento apresentou validade de conteúdo e confiabilidade satisfatórias.

Validade de conteúdo e confiabilidade de instrumento de avaliação do ambiente alimentar universitário / Content validity and reliability of a university food environment assessment instrument

Resumo O objetivo foi avaliar a validade de conteúdo e a confiabilidade de um instrumento de auditoria para avaliação do ambiente alimentar universitário. Foi desenvolvido checklist para a avaliação de estabelecimentos que comercializavam alimentos e bebidas neste ambiente. A validação de conteúdo abarcou o desenvolvimento do instrumento, a análise por especialistas e a realização do pré-teste. A confiabilidade foi avaliada em uma amostra de conveniência (n=64) de estabelecimentos distribuídos em sete campi de três universidades públicas e foi realizada pelos testes interobservador (TIO) e teste-reteste (TR). Variáveis categóricas e de contagem foram analisadas pelo cálculo da concordância percentual (CP) e dos índices kappa (k) e kappa ajustado pela prevalência e pelo viés (ka) e variáveis contínuas, pelo Coeficiente de Correlação Intraclasse (CCI). O checklist foi composto por 204 itens distribuídos em sete domínios. O desempenho do instrumento foi considerado excelente ou muito bom para 91,3% (CP) dos itens quando avaliados. No TIO 68,3% (k) e 96,5% (ka) tiveram concordância excelente, muito boa ou boa, enquanto no TR 65% tiveram concordância excelente para o k e 96,5% para o ka. O instrumento apresentou validade de conteúdo e confiabilidade satisfatórias.

Abstract This study aimed to evaluate the content validity and reliability of an instrument for evaluating the university food environment. A checklist was developed to assess establishments that sell food and beverages in the university environment. The content validation encompassed the development of the instrument, expert evaluation and pretest performance. Reliability was evaluated using a convenience sample (n=64) of establishments distributed across seven campuses of three public universities and was carried out using interobserver (IO) and test-retest (TR) evaluations. Categorical and count variables were analyzed by calculating the percentage agreement (PA), kappa coefficient (k) and prevalence-adjusted, bias-adjusted kappa (ka), and continuous variables were analyzed by the intraclass correlation coefficient (ICC). The checklist consisted of 204 items distributed in seven domains. The instrument's performance was considered excellent or very good for 91.3% (PA) of the items when evaluated. For IO, 68.3% (k) and 96.5% (ka) had excellent, very good or good agreement, while for TR, 65% (k) and 96.5% (ka) had excellent agreement. The instrument showed satisfactory content validity and reliability for characterizing the food environment at Brazilian universities.

Nanoencapsulated Lippia rotundifolia antimicrobial peptide: synthesis, characterization, antimicrobial activity, and cytotoxicity evaluations.

Antimicrobial peptides (AMP) are promising novel antibiotics but exhibit low stability and can be toxic. The AMP encapsulation can be used to protect the drug and control its release rates. The Lr-AMP1f encapsulated into chitosan nanoparticle (NP) by ionic gelation method reached 90% efficiency. The results indicated that the hydrodynamic particle size of NPs increased from 196.1 ± 3.14 nm (free NP) to 228.1 ± 12.22 nm (nanoencapsulated Lr-AMP1f), while the atomic force microscope showed the spherical shape. The Zeta potential of the nanoencapsulated Lr-AMP1f was high (+ 35 mV). These AMP-loaded NPs exhibited stability for up to 21 days of storage. The minimum inhibitory concentration (MIC) of free Lr-AMP1f was 8 µg/mL for E. coli and S. epidermidis. However, the nanoencapsulated Lr-AMP1f produced a bacteriostatic effect against both bacteria at 8 µg/mL. The MIC of nanoencapsulated Lr-AMP1f was 16 µg/mL for E. coli and 32 for S. epidermidis. Nanoencapsulated Lr-AMP1f was nontoxic to HEK293 cells. Promisingly, chitosan NP can be used as a vehicle for the antibacterial application of new AMP (Lr-AMP1f).

Machine Learning for Prediction of Stable Warfarin Dose in US Latinos and Latin Americans.

Populations used to create warfarin dose prediction algorithms largely lacked participants reporting Hispanic or Latino ethnicity. While previous research suggests nonlinear modeling improves warfarin dose prediction, this research has mainly focused on populations with primarily European ancestry. We compare the accuracy of stable warfarin dose prediction using linear and nonlinear machine learning models in a large cohort enriched for US Latinos and Latin Americans (ULLA). Each model was tested using the same variables as published by the International Warfarin Pharmacogenetics Consortium (IWPC) and using an expanded set of variables including ethnicity and warfarin indication. We utilized a multiple linear regression model and three nonlinear regression models: Bayesian Additive Regression Trees, Multivariate Adaptive Regression Splines, and Support Vector Regression. We compared each model's ability to predict stable warfarin dose within 20% of actual stable dose, confirming trained models in a 30% testing dataset with 100 rounds of resampling. In all patients (n = 7,030), inclusion of additional predictor variables led to a small but significant improvement in prediction of dose relative to the IWPC algorithm (47.8 versus 46.7% in IWPC, p = 1.43 × 10-15). Nonlinear models using IWPC variables did not significantly improve prediction of dose over the linear IWPC algorithm. In ULLA patients alone (n = 1,734), IWPC performed similarly to all other linear and nonlinear pharmacogenetic algorithms. Our results reinforce the validity of IWPC in a large, ethnically diverse population and suggest that additional variables that capture warfarin dose variability may improve warfarin dose prediction algorithms.

Development and Application of Healthiness Indicators for Commercial Establishments That Sell Foods for Immediate Consumption.

Studies of food environments lack easy-to-apply indicators for their characterization and monitoring. This study aimed to create and assess the applicability of an a priori classification of establishments that sell foods for immediate consumption and to develop and apply indicators for assessment of the establishments' healthiness. The indicators were grouped by the types of foods sold most frequently at these establishments, according to the extent and purpose of the foods' industrial processing. Four indicators were developed, based on the availability of unprocessed/minimally processed foods (MPF) and ultra-processed foods (UPF) in the establishments. The classification and indicators were applied to commercial food establishments at two Brazilian universities. Descriptive analyses were performed to characterize the food environment for all the establishments and by university. Two proportion indicators assess the relative availability of subgroups of MPF and UPF. The UPF/MPF ratio expresses the relative advantage/disadvantage of the availability of MPF compared to that of UPF. The Healthiness Index or summary score expresses the availability of MPF and the unavailability of UPF. The classification and indicators present good discriminatory power and are easy to operationalize, interpret, and adapt.

Multi-site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos.

We conducted a multi-site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from four institutions in the United States (n = 411) and Brazil (n = 663) were genotyped for VKORC1 c.-1639G> A, common CYP2C9 variants, CYP4F2*3, and NQO1*2. Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Brazilians. In the U.S. cohort, VKORC1 and CYP2C9 variants were associated with lower warfarin dose (ß = -0.29, P < 2.0 × 10-16 ; ß = -0.21, P = 4.7 × 10-7 , respectively) whereas CYP4F2 and NQO1 variants were associated with higher dose (ß = 0.10, P = 2 × 10-4 ; ß = 0.10, P = 0.01, respectively). Associations with VKORC1 (ß = -0.14, P = 2.0 × 10-16 ), CYP2C9 (ß = -0.07, P = 5.6 × 10-10 ), and CYP4F2 (ß = 0.03, P = 3 × 10-3 ), but not NQO1*2 (ß = 0.01, P = 0.30), were replicated in the Brazilians, explaining 43-46% of warfarin dose variability among the cohorts from the U.S. and Brazil, respectively. We identified genetic associations with warfarin dose requirements in the largest cohort of ancestrally diverse, warfarin-treated Latinos from the United States and Brazil to date. We confirmed the association of variants in VKORC1, CYP2C9, and CYP4F2 with warfarin dose in Latinos from the United States and Brazil.

A Extensão Universitária no Instituto de Nutrição Josué de Castro da Universidade Federal do Rio de Janeiro / University outreach at Instituto de Nutrição Josué de Castro of the Universidade Federal do Rio de Janeiro

A extensão universitária é um processo educativo, científico e cultural que aproxima a universidade da sociedade. Este trabalho, apresentado na modalidade "Perspectivas", busca relatar a inserção da extensão universitária nos cursos de graduação do Instituto de Nutrição Josué de Castro (INJC), da Universidade Federal do Rio de Janeiro (UFRJ), ressaltando a análise das ações extensionistas para a formação de estudantes. As principais áreas contempladas nas ações guardam forte relação com os cursos de Gastronomia e de Nutrição do Instituto. Em junho de 2021, o INJC contava com 39 ações ativas registradas no sistema de gestão acadêmica da UFRJ, distribuídas em 30 projetos, seis eventos e três cursos, contemplando, assim, as áreas temáticas de Saúde, Cultura, Educação, Meio Ambiente e Trabalho, Tecnologia e Comunicação. Essas ações disponibilizam 288 vagas para alunos de graduação da UFRJ, acolhendo estudantes do INJC e de outros centros universitários, em especial das Ciências Humanas e Sociais, tendo como público-alvo diferentes faixas etárias, grupos populacionais e territórios. Apesar da diversidade dos objetos de trabalho, a alimentação apresenta-se como tema transversal nas três modalidades de ações realizadas. Nota-se uma firme tendência de fortalecimento das atividades universitárias de extensão, seja pela obrigatoriedade da creditação de carga horária para o corpo discente ou pelo compromisso da universidade em responder às demandas sociais, equiparando-as efetivamente à pesquisa no que tange à valorização acadêmica e institucional.

University outreach is an educational, scientific and cultural process that brings the university closer to society. This work, presented in the "Perspectives" modality, seeks to report the inclusion of university outreach in the undergraduate degree programs of the Instituto de Nutrição Josué de Castro (INJC) (Josué de Castro Nutrition Institute), at the Universidade Federal do Rio de Janeiro (UFRJ) (Federal University of Rio de Janeiro). It emphasizes the analysis of outreach activities for students' education. The main areas covered by the actions are strongly related to the Institute's Gastronomy and Nutrition courses. In June 2021, INJC presented 39 ongoing activities registered in UFRJ's academic management system, namely 30 projects, 6 events and 3 courses, covering the thematic areas of Health, Culture, Education, Environment and Work, Technology and Communication. These activities offer 288 vacancies for undergraduate students at UFRJ, not only from INJC but also from other colleges, especially in the human and social sciences. They are targeted at different ages, populational groups and territories. Despite the diversity of the objects of work, food is a theme present in all the 3 types of activities carried out. There is a firm tendency to strengthen university outreach activities, either through the mandatory credit completion by students or through the university's commitment to respond to social demands. This way, it receives at the same level of importance as novice research, when considering academic and institutional quality recognition

Guazuma ulmifolia: an environmentally friendly coagulant aid for water treatment.

In the present work the use of a promising novel coagulant aid, Guazuma ulmifolia, was optimized to treat synthetic water using central composite being highly efficient at rotatable design (CCRD). The factors evaluated for the coagulation-flocculation process were coagulants dosages and pH. A model to describe the coagulation-flocculation process was successfully obtained. The model was validated using 5 mg L-1 aluminum sulfate, 2.5 mg L-1 G. ulmifolia and pH 9, achieving excellent agreement with observed values.

Evaluation of the Long-Term Impact on Quality After the End of Pharmacist-Driven Warfarin Therapy Management in Patients With Poor Quality of Anticoagulation Therapy.

BACKGROUND: Warfarin is the most common oral anticoagulant drug, especially in low-income and emerging countries, because of the high cost of direct oral anticoagulant (DOACs), or when warfarin is the only proven therapy (mechanical prosthetic valve and kidney dysfunction). The quality of warfarin therapy is directly associated with dose management. Evidence shows that pharmaceutical care achieves a better quality of therapy with warfarin. However, there are no studies showing this intervention in a specific patient group with poor quality of anticoagulation in a long period after the end of the follow-up by a pharmacist. Thus, the aim of this study was to evaluate whether the quality of warfarin therapy driven by a pharmacist remains stable in the long term after the end of follow up with a pharmacist, in AF patients with poor quality of anticoagulation. METHODS: This is a prospective study, which evaluated about 2,620 patients and selected 262 patients with AF and poor quality of anticoagulation therapy with warfarin (TTR<50% - based on the last three values of international normalized ratio). Pharmacist-driven therapy management was performed up to 12 weeks. Data from patients were evaluated 1 year after the end of the follow-up with pharmacist. RESULTS: Comparison between mean TTR after 12 weeks of pharmaceutical care (54.1%) and mean TTR one year after the end of the pharmaceutical care (56.5%; p=0.081) did not achieve statistical difference, demonstrating that the increment of quality due to intervention of 12 weeks was maintained for 1 year after intervention. CONCLUSION: The long-term impact of pharmaceutical care was beneficial for patients with AF and poor quality of warfarin anticoagulation. This design might be an important strategy to treat a subgroup of patients without proven effectiveness of warfarin.

Antimicrobial peptide selection from Lippia spp leaf transcriptomes.

Antimicrobial resistance is considered a health issue worldwide. This public health problem underscores the importance of searching for new antimicrobial molecules with different mechanisms of action. Leaf transcriptomes were used to search and develop synthetic antimicrobial peptides derived from mRNA sequences. The in silico search for new AMPs from the L. rotundifolia and L. alba transcriptomes allowed the identification of 120 putative peptide mRNA sequences. Eight of them fitted into optimal parameters and were translated and chemically synthesized antimicrobial peptides. Their biological activity was tested in both Gram-positive and Gram-negative bacteria against which they exhibited antibacterial activity. However, they showed an important hemolytic effect. Afterwards, two active peptides showing bactericidal activity isolated from each plant transcriptome tested were modified and modeled in 11 new variants to increase their antimicrobial activity and stability and to reduce or eliminate their hemolytic effect from their original peptides. The La-AMP1 (MSLLERKLLMHFLRV) the original peptide from L. alba showed a 52% hemolytic effect while the derived peptide La-AMP1a (GLMKLLRELLHMFSRVG) had its hemolytic effect reduced to 0.5% at 128 µg.mL-1. Similarly, we observed that the original peptide from L. rotundifolia, Lr-AMP1 (MRIGLRFVLM), displayed a 71.5% hemolytic effect, while its derived peptide Lr-AMP1f (GSVLRAIMRMFAKLMG) showed 0% hemolysis at 128 µg.mL-1, tested with fresh human erythrocytes. Our results indicate a promising method for the search for novel antimicrobial agents with reduced or zero hemolytic effect, as well as prediction and optimization of their activity from plant mRNA libraries.

Pharmaceutical Care Increases Time in Therapeutic Range of Patients With Poor Quality of Anticoagulation With Warfarin.

Thromboembolic events are associated with high mortality and morbidity indexes. In this context, warfarin is the most widely prescribed oral anticoagulant agent for preventing and treating these events. This medication has a narrow therapeutic range and, consequently, patients usually have difficulty in achieving and maintaining stable target therapeutics. Some studies on the literature about oral anticoagulant management showed that pharmacists could improve the efficiency of anticoagulant therapy. However, the majority of these studies included general patients retrospectively. The aim of this study was to prospectively evaluate a pharmacist's warfarin management in patients with poor quality of anticoagulation therapy (Time in the Therapeutic Range- TTR < 50%). We included 268 patients with atrial fibrillation (AF) and without stable dose of warfarin (TTR < 50%, based on the last three values of International Normalized Ratio-INR). We followed them up for 12 weeks, INR values were evaluated and, when necessary, the dose adjustments were performed. During the first four visits, patient's INR was measured every 7 days. Then, if INR was within the target therapeutic range (INR: 2-3), the patient was asked to return in 30 days. However, if INR was out the therapeutic target, the patient was asked to return in 7 days. Adherence evaluation was measured through questionnaires and by counting the pills taken. Comparison between basal TTR (which was calculated based on the three last INR values before prospective phase) and TTR of 4 weeks (calculated by considering the INR tests from visits 0 to 4, in the prospective phase of the study) and basal TTR and TTR of 12 weeks (calculated based on the INR tests from visits 0 to 12, in the prospective phase of the study) revealed significant statistical differences (0.144 ± 0.010 vs. 0.382 ± 0.016; and 0.144 ± 0.010 vs. 0.543 ± 0.014, p < 0.001, respectively). We also observed that the mean TTR of 1 year before (retrospective phase) was lower than TTR value after 12 weeks of pharmacist-driven treatment (prospective phase) (0.320 ± 0.015; 0.540 ± 0.015, p < 0.001). In conclusion, pharmaceutical care was able to improve TTR values in patients with AF and poor quality of anticoagulation with warfarin.

Impact of incorporating ABCB1 and CYP4F2 polymorphisms in a pharmacogenetics-guided warfarin dosing algorithm for the Brazilian population.

PURPOSE: Interpatient variation of warfarin dose requirements may be explained by genetic variations and general and clinical factors. In this scenario, diverse population-calibrated dosing algorithms, which incorporate the main warfarin dosing influencers, have been widely proposed for predicting supposed warfarin maintenance dose, in order to prevent and reduce adverse events. The aim of the present study was to evaluate the impact of the inclusion of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms as additional covariates in a previously developed pharmacogenetic-based warfarin dosing algorithm calibrated for the Brazilian population. METHODS: Two independent cohorts of patients treated with warfarin (n = 832 and n = 133) were included for derivation and replication of the algorithm, respectively. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms was performed by polymerase chain reaction followed by melting curve analysis and TaqMan® assay, respectively. A multiple linear regression was performed for the warfarin stable doses as a dependent variable, considering clinical, general, and genetic data as covariates. RESULTS: The inclusion of ABCB1 and CYP4F2 polymorphisms was able to improve the algorithm's coefficient of determination (R2) by 2.6%. In addition, the partial determination coefficients of these variants revealed that they explained 3.6% of the warfarin dose variability. We also observed a marginal improvement of the linear correlation between observed and predicted doses (from 59.7 to 61.4%). CONCLUSION: Although our study indicates that the contribution of the combined ABCB1 and CYP4F2 genotypes in explaining the overall variability in warfarin dose is not very large, we demonstrated that these pharmacogenomic data are statistically significant. However, the clinical relevance and cost-effective impact of incorporating additional variants in warfarin dosing algorithms should be carefully evaluated.

Association Between ABCB1 Polymorphism and Stable Warfarin Dose Requirements in Brazilian Patients.

The ideal dose of the oral anticoagulant warfarin varies widely among patients, mainly due to genetic factors. Genetic variations that impact warfarin pharmacokinetics and the vitamin K cycle are plausible candidates for being associated with warfarin dose requirements. Therefore, the aim of this study was to assess whether polymorphisms in the ABCB1 and CYP4F2 genes were associated with stable warfarin dose requirements in Brazilian patients. This retrospective study included samples from 309 individuals. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A were performed by polymerase chain reaction followed by melting curve analysis (HRM-PCR) and TaqMan® genotyping assay, respectively. Stable doses were adjusted in a linear multiple regression model for age, gender, body mass index, self-reported race, use of amiodarone, CYP2C9 (*2 and *3), VKORC1 c.1639G>A, and ABCB1 c.3435C>T or CYP4F2 c.1297G>A. By performing a univariate analysis of variance, we found that the warfarin patients who carry ABCB1 c.3435T variant alleles (CT and TT genotypes) need fewer warfarin stable doses in comparison with the individuals that are CC wild-type: 2.5 (p = 0.003) and 4.3 (p < 0.001) mg/week less, respectively, for the overall group of patients on stable anticoagulation therapeutics (n = 309); and 5.5 (p = 0.006) and 10.2 (p < 0.001) mg/week less, respectively, for the self-declared non-white stable subgroup (n = 76). No statistically significant differences in dose requirements were observed according to CYP4F2 genotypes. In conclusion, our results suggest ABCB1 c.3435C>T variant may influence warfarin dose requirements in Brazilian patients, when associated with other genotypic, demographic and clinical factors.