Background: Among diabetics, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality, and progression of their underlying disease. Finerenone is a novel, non-steroidal, selective mineralocorticoid-receptor antagonist which has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD), while revealing only a low risk of hyperkalemia. However, the effect of finerenone on renal and CV outcomes has not been investigated in long-term trials yet. Methods: The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease ­(FIDELIO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important renal and CV outcomes in T2D patients with CKD. FIDELIO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 5.5 years. FIDELIO-DKD randomized 5,734 patients with an estimated glomerular filtration rate (eGFR) ≥25–<75 mL/min/1.73 m2 and albuminuria (urinary albumin-to-creatinine ratio ≥30–≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of kidney failure, a sustained decrease of eGFR ≥40% from baseline over at least 4 weeks, or renal death. Conclusion: FIDELIO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of renal and CV events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen.

OBJECTIVE: To describe the rates of cure, treatment failure, and treatment abandonment obtained with the basic regimen recommended by the Brazilian National Ministry of Health-rifampin, isoniazid, pyrazinamide, and ethambutol for two months, followed by isoniazid and rifampin for four months-involving the use of fixed-dose combination tablets (self-administered treatment), as well as to describe adverse events and their potential impact on treatment outcomes. METHODS: This was a descriptive study based on prospective data obtained from the medical records of tuberculosis patients (≥ 18 years of age) treated with the basic regimen at either of two primary health care facilities in the greater metropolitan area of Goiânia, Brazil. RESULTS: The study sample comprised 40 tuberculosis patients. The rate of cure was 67.5%, the rate of treatment abandonment was 17.5%, and there were no cases of treatment failure. Of the 40 patients in the sample, 19 (47%) reported adverse reactions, which were mild and moderate, respectively, in 87% and 13% of the cases. It was not necessary to alter the regimen or discontinue the treatment in any of the cases evaluated. CONCLUSIONS: The rate of cure obtained with the self-administered, fixed-dose combination tablet form of the new basic regimen was similar to the historical rates of cure obtained with the previous basic regimen. The rate of treatment abandonment in our sample was much higher than that considered appropriate (up to 5%).

Rationale: Frailty in chronic obstructive pulmonary disease (COPD) patients has been associated with a higher rate of incidents, longer duration of hospitalization, poorer quality of life, and higher mortality. Objective: To measure the prevalence of frailty among COPD patients and to evaluate associated variables. Methods: A cross-sectional study. Subjects who visited a State Center for High-Cost Medicines to obtain free monthly COPD medicines were considered eligible. Individuals ≥40 years old who had a FEV 1 /FVC ratio of <0.7 post-bronchodilation were enrolled. The Fatigue, Resistance, Ambulation, Illnesses, and Loss of weight (FRAIL) scale, Medical Research Council dyspnea scale (MRC), COPD Assessment Test (CAT), a combination of CAT/MRC [(CAT/8)+MRC], and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity scale were used to evaluate the enrolled subjects. Variables associated with frailty were analyzed using an ordered logistic regression and a multivariate logistic regression. Results: The prevalence of frailty and pre-frailty among the 153 COPD subjects enrolled was 50.3% (77/153) and 35.3% (54/153), respectively. Frailty scores were correlated with CAT (correlation coefficient [cc]: 0.52, p <0.001) and MRC (cc: 0.48, p <0.001). Ordinal regression models showed that MRC and CAT were associated with fragility (p <0.0001 for both models). Higher odds of frailty were observed in GOLD groups B (p = 0.04) and D (p = 0.02). Multiple logistic regression revealed that the combination CAT/MRC≥5.5 was associated with frailty (OR 6.73; p <0.0001) and had a specificity of 80.3%, sensitivity of 62.3%, and positive and negative predictive values of 76.2% and67.8%, respectively. Conclusion: Frailty prevalence was high and was correlated with higher MRC and CAT scores. The CAT/MRC combination [(CAT/8)+MRC] ≥5.5 was highly associated with frailty, suggesting that an additional specific evaluation for the presence of frailty is indicated.

Aims Neladenoson bialanate is a partial adenosine A1 receptor agonist with demonstrated beneficial effects on cardiac function in animal models. We aimed to assess the dose–response effect of neladenoson bialanate on cardiac structure and function, clinical outcome, and safety in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Methods and results PANTHEON was a dose‐finding, phase IIb, randomized, double‐blind, placebo‐controlled trial conducted in 92 centres in 11 countries including 462 patients with chronic HFrEF, randomized to once daily oral dose of neladenoson bialanate (5, 10, 20, 30, and 40 mg) or placebo. The primary endpoints were change from baseline to 20 weeks in left ventricular ejection fraction (LVEF) (echocardiography) and in N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP). Mean age of the patients was 67 years, 17% were female, mean LVEF was 28%, mean NT‐proBNP was 2085 ng/L. After 20 weeks of treatment, there was no dose–effect of neladenoson bialanate on changes in NT‐proBNP or LVEF (primary endpoints). No effect of neladenoson bialanate was found on left ventricular volumes, high‐sensitivity troponin T, or cardiovascular mortality, HF hospitalization, and urgent visits for HF (secondary endpoints). There was a dose‐dependent increase in creatinine and cystatin C, and a dose‐dependent decrease in estimated glomerular filtration rate and heart rate. Conclusions In patients with chronic HFrEF, treatment with neladenoson bialanate was not associated with dose‐dependent favourable effects on cardiac structure and function, cardiac risk markers, or clinical outcome but was associated with a dose‐dependent decrease in renal function. Clinical Trial Registration: https://ClinicalTrials.gov Identifier NCT02992288.

Background/Aims: Finerenone decreases albuminuria in patients having heart failure with reduced ejection fraction and mild-to-moderate (stage 2-3) chronic kidney disease. The MinerAlocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy (ARTS-DN; NCT01874431) is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2b study. ARTS-DN investigated whether the mineralocorticoid receptor antagonist finerenone reduces albuminuria without causing major alterations in serum potassium levels in patients with type 2 diabetes mellitus and a clinical diagnosis of DN who were receiving a renin-angiotensin-system (RAS) inhibitor. Methods: Patients were randomized to oral finerenone 1.25-20 mg or placebo once daily. The primary objectives were to assess the ratio of the urinary albumin-to-creatinine ratio at day 90 to that at baseline in patients receiving finerenone, and to compare it with that in the placebo group. Additional exploratory analyses included evaluating changes from baseline in serum potassium levels, efficacy and safety biomarkers, and health-related quality of life. Results: Of 1,501 patients screened, 821 (the sample population) received at least one dose of finerenone/placebo. Baseline characteristics included: male, 77.8%; white, 84.2%; very high albuminuria (formerly macroalbuminuria), 38.4%; high albuminuria (formerly microalbuminuria), 60.3%; median (range) estimated glomerular filtration rate, 66.3 (24.5-130.7) ml/min/1.73 m²; and systolic blood pressure (mean ± standard deviation), 138.1 ± 14.4 mm Hg. There was a history of cardiovascular disease in 39.6%, diabetic neuropathy in 20.0%, and diabetic retinopathy in 19.9% of patients. Conclusion: ARTS-DN is the first phase 2b trial of finerenone in combination with a RAS inhibitor in patients with type 2 diabetes mellitus and a clinical diagnosis of DN.

ResumoObjetivo: Avaliar o efeito da sazonalidade climática na ocorrência de sintomas respiratórios em uma cidade de clima tropical no Brasil. Métodos: Estudo de corte transversal relacionando dados de indivíduos que procuraram assistência médica em uma Unidade Básica de Saúde na cidade de Goiânia (GO) com dados meteorológicos coletados diariamente. No intervalo de um ano, todos os pacientes que preenchiam os critérios de inclusão foram entrevistados em 44 dias distintos (11 em cada estação) escolhidos aleatoriamente. ANOVA foi usada para a comparação das médias das variáveis dependentes por estação. Correlação foi conduzida entre as variáveis dependentes e cada variável meteorológica. Os efeitos das variáveis meteorológicas foram analisados com um modelo de AutoRegressive Moving Average with eXogenous input (ARMAX, média móvel autorregressiva com entrada exógena). Resultados: Dos 3.354 participantes, 494 (14,6%) apresentavam sintomas respiratórios. A variação de temperatura não foi suficiente para provocar mudanças no número de indivíduos com sintomas respiratórios; porém, houve aumento desse número com baixos níveis de umidade no inverno, com diferença estatisticamente significativa entre as estações (p < 0,01). Foi observado que a média da umidade relativa mínima dos três dias que antecederam as observações correlacionou-se negativamente com o número de indivíduos com sintomas respiratórios (p = 0,04), e um modelo ARMAX incluindo a mesma variável apresentou um coeficiente estatisticamente significativo (p < 0,0001). Conclusões: Nesta amostra, o número de indivíduos com sintomas respiratórios aumentou significativamente com a redução da umidade relativa do ar, e esse aumento pôde ser previsto a partir de dados meteorológicos.Descritores: Estações do ano; Clima tropical/efeitos adversos; Sinais e sintomas respiratórios; Modelos logísticos. AbstractObjective: To evaluate the effect that seasonality has on the occurrence of respiratory symptoms in a Brazilian city with a tropical climate. Methods: This was a cross-sectional study, in which data related to subjects who sought outpatient treatment at a primary health care clinic in the city of Goiânia, Brazil, were correlated with daily meteorological data. Over a one-year period, all the patients who met the inclusion criteria were interviewed on 44 distinct, randomly selected days (11 days per season). We used ANOVA in order to compare the means of the dependent variables by season. Correlations were drawn between each dependent variable and each meteorological variable. The effects of the meteorological variables were analyzed with an AutoRegressive Moving Average with eXogenous input (ARMAX) model. Results: Of the 3,354 participants, 494 (14.6%) had respiratory symptoms. Although temperature variation alone had no effect on the number of individuals with respiratory symptoms, the low levels of humidity during winter resulted in a statistically significant difference among the seasons (p < 0.01). The mean minimum relative humidity on the three days prior to the i...

Background: Methylation is reported to support cancer immune tolerance. We conducted a phase 1 dose-escalation trial [NCT02998567] of combination guadecitabine (G; DNA hypomethylating agent) and pembrolizumab (P) in patients (pts) with advanced cancers. We hypothesized that G can normalize the expression of epigenetically suppressed immune genes, increase interferon producing tumor-infiltrating lymphocytes (TILs), and enhance the anticancer activity of P. Methods: In dose escalation (Es), pts received G (45 mg/m2 or 30 mg/m2, administered SC on days 1-4) with P (200 mg, administered IV starting from cycle 2 onwards) as outpatient Q3W; in expansion (Ex), the RP2D of G (30 mg/m2) with P (200 mg) Q3W was administered. Pre-treatment and on-treatment tumor biopsies were evaluated for PD-L1 expression, tumor infiltrating lymphocytes, gene expression by RNAseq and methylome studies. Longitudinal analyses of peripheral blood CD3, CD4 and CD8 lymphocytes by flow cytometry were performed. Results: Overall, 34 pts (Es, n = 14; Ex, n = 20) were evaluable for safety. The most common treatment-related adverse events (TRAEs) were neutropenia (n = 21), fatigue (n = 6) and thrombocytopenia (n = 3), diarrhea (n = 2). G3+ TRAEs were neutropenia (n = 14), febrile neutropenia (n = 4), raised ALP (n = 1), raised AST (n=1), colitis (n = 1), diarrhoea (n = 1) and lung infection (n = 1). Two DLTs (neutropenia, febrile neutropenia) were reported at G 45mg/m2 with none reported at G 30mg/m2. There were no treatment-related deaths. In total, 28 pts (Es, n = 12; Ex, n = 16) were evaluable for antitumor activity studies (≥2 scans); ORR (CR+PR) and DCR (CR+PR+SD) were 3% and 57%; 10/15 pts with non-small cell lung cancer (13 pts resistant/refractory to PD-1/PD-L1 targeting agents) were evaluable, with a DCR of 80% and 5 pts having DCR &gt; 6 months with 8 pts remaining on study treatment. Overall, 25 paired biopsies were obtained. Using LINE1 sequences to study global methylation, both tumor biopsies and peripheral blood showed reduced methylation post-G treatment. Preliminary data on tumor-infiltrating lymphocytes assessed by multicolor immunofluorescence in 9 paired biopsies showed a numerical increase in median values of T-helper (CD4+FOXP3-) (10.20 to 19.70, p = 0.5469), T-regulatory (CD4+FOXP3+) (5.1 to 6.7, p=0.8438), and T-cytotoxic (CD8+) cell densities (2.7 to 7.4, p=0.6523) . Comparing with matched pre-treatment, on treatment tumor had numerical increases in interferon alpha and gamma response pathway activation in serial biopsy RNAseq analyses but did not reach significance. Conclusions: G plus P resulted in no unexpected toxicities with evidence suggestive of biological and anti-cancer activity. Citation Format: Dionysis Papadatos-Pastos, Abhijit Pal, Melek Akay, Malaka Ameratunga, Sanjena Mithra, Joo-Ern Ang, Sofia Levva, Reece Caldwell, Ruth Riisnaes, Mateus Crespo, Wei Yuan, George Seed, Bora Gurel, Ines Figueiredo, Rita Pereira, Susana Miranda, Anna Ferreira, Suzanne Carreira, Claudia Bertan, Chloe Baker, Ricardo Morilla, Robert Brown, Nahal Masrour, Toby Prout, Anna Zachariou, Alison Turner, Mona Parmar, Mark Van de Velde, Ben Jenkins, Christina Yap, Nina Tunariu, Udai Banerji, Juanita Lopez, Anna Minchom, Johann De Bono. HyPeR: A phase 1, dose escalation and expansion trial of guadecitabine (SGI-110), a second-generation hypomethylating agent in combination with pembrolizumab (MK3475) in patients with refractory solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT129.

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