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Context: AML represents a broad and complex group of diseases characterized by involvement of the myeloid lineage on hematopoiesis. Objective: To explore the frequency and impact of mutated genes on clinical outcomes in a cohort of Peruvian patients. Design: In this report, we showed 32 AML cases treated at 3 medical centers in Lima (Clinica Delgado, Anglo Americana, and INEN) from January 2016 until May 2021. Setting: Information at diagnosis was clinical, karyotype, molecular PCR panel, myeloid NGS panel, therapy regimen, response to treatment, DFS, and OS Patients or Other Participants: A total of 32 cases were studied. F/M=0.6 (12/20), median age 55 years (32–87). Interventions: Among the 24 available karyotypes, the abnormal vs diploid karyotype ratio was 0.26 (5/19). Number of pathogenic mutated genes was 2.5 (range 0–10). Most common (≥15%) pathogenic mutated genes were BCOR (n=7, 21.9%), CUX1 (n=5, 15.6%), DNMT3 (n=8, 25.0%), and NRAS (n=5, 15.6%). Main Outcome Measures: Response rates were as follows: 71.9% complete (23/32), 18.8% non-response (6/32), and 9.3% non-evaluable (3/32). The estimated median OS was 26.01 months for the entire cohort, the 1- and 2-year OS were 72.1% and 51.1%, respectively. The estimated median DFS was 15.79 months for the entire cohort, the 1- and 2-year DFS were 77.6% and 31.5%, respectively. Mutated TP53 was detected in 3 cases, with no therapeutic response in 2 of them. Results: No significant difference in OS was observed in cases with ≥3 pathogenic mutated genes (log-rank 0.10, p=0.920) or ≥3 pathogenic mutated genes + TP53 cases (log-rank 0.11 p=0.739). No significant difference in DFS was observed in cases ≥3 pathogenic mutated genes + TP53 cases (log-rank 0.775 p=0.379). Conclusions: Of 53 genes, four genes were detected in ≥ 15% of cases: BCOR, CUX1, DNMT3, and NRAS. TP53 was related to a high degree of therapeutic failure response and short OS. Number of pathogenic mutated genes ≥3 or ≥4 by NGS showed no significant tendency toward shorter OS. A composite analysis of patients with 4 mutated genes with or without mutated-TP53 showed no significantly shorter OS and DFS. Further studies with mature data and more cases are warranted to propose risk stratification by NGS.

Aims To assess the haemodynamic effects of organic vs. inorganic nitrate administration among patients with heart failure with preserved ejection fraction (HFpEF). Methods and results We assessed carotid and aortic pressure–flow relations non-invasively before and after the administration of 0.4 mg of sublingual nitroglycerin (n = 26), and in a separate sub-study, in response to 12.9 mmoL of inorganic nitrate (n = 16). Nitroglycerin did not consistently reduce wave reflections arriving at the proximal aorta (change in real part of reflection coefficient, 1st harmonic: −0.09; P = 0.01; 2nd harmonic: −0.045, P = 0.16; 3rd harmonic: +0.087; P = 0.05), but produced profound vasodilatation in the carotid territory, with a significant reduction in systolic blood pressure (133.6 vs. 120.5 mmHg; P = 0.011) and a marked reduction in carotid bed vascular resistance (19 580 vs. 13 078 dynes · s/cm5; P = 0.001) and carotid characteristic impedance (3440 vs. 1923 dynes · s/cm5; P = 0.002). Inorganic nitrate, in contrast, consistently reduced wave reflections across the first three harmonics (change in real part of reflection coefficient, 1st harmonic: −0.12; P = 0.03; 2nd harmonic: −0.11, P = 0.01; 3rd harmonic: −0.087; P = 0.09) and did not reduce blood pressure, carotid bed vascular resistance, or carotid characteristic impedance (P = NS). Conclusions Nitroglycerin produces marked vasodilatation in the carotid circulation, with a pronounced reduction in blood pressure and inconsistent effects on central wave reflections. Inorganic nitrate, in contrast, produces consistent reductions in wave reflections, and unlike nitroglycerin, it does so without significant hypotension or cerebrovascular dilatation. These haemodynamic differences may underlie the different effects on exercise capacity and side effect profile of inorganic vs. organic nitrate in HFpEF.

BACKGROUND Large artery stiffness is increased in diabetes mellitus and causes an excessive pulsatile load to the heart and to the microvasculature. The identification of pathways related to arterial stiffness may provide novel therapeutic targets to ameliorate arterial stiffness in diabetes. Matrix Gla-Protein (MGP) is an inhibitor of vascular calcification. Activation of MGP is vitamin K dependent. We hypothesized that levels of inactive MGP (dephospho-uncarboxylated MGP; dp-ucMGP) are related to arterial stiffness in type 2 diabetes. METHODS We enrolled a multiethnic cohort of 66 participants with type 2 diabetes. Carotid-femoral pulse wave velocity (CF-PWV) was measured with high-fidelity arterial tonometry (Sphygmocor Device). Dp-ucMGP was measured with ELISA (VitaK; The Netherlands). RESULTS The majority of the participants were middle-aged (62 ± 12 years), male (91%), and had a history of hypertension (82%). Average hemoglobin A1C was 7.2% (55 mmol/mol). Mean dp-ucMGP was 624 ± 638 pmol/l and mean CF-PWV was 11 ± 4 m/sec. In multivariable analyses, dp-ucMGP was independently related to African American ethnicity (β = -0.24, P = 0.005), warfarin use (β = 0.56, P < 0.001), and estimated glomerular filtration rate (eGFR, β = -0.32, P < 0.001). Dp-ucMGP predicted CF-PWV (β = 0.40, P = 0.011), even after adjustment for age, gender, ethnicity, mean arterial pressure, eGFR, and warfarin use. CONCLUSIONS In our cross-sectional analysis, circulating dp-ucMGP was independently associated with CF-PWV in type 2 diabetes. This suggests that deficient vitamin K-dependent activation of MGP may lead to large artery stiffening and could be targeted with vitamin K supplementation in the patients with diabetes.

Background Wave reflections, which are increased in patients with heart failure with preserved ejection fraction, impair diastolic function and promote pathologic myocardial remodeling. Organic nitrates reduce wave reflections acutely, but whether this is sustained chronically or affected by hydralazine coadministration is unknown. Methods and Results We randomized 44 patients with heart failure with preserved ejection fraction in a double‐blinded fashion to isosorbide dinitrate ( ISDN ; n=13), ISDN +hydralazine ( ISDN +hydral; n=15), or placebo (n=16) for 6 months. The primary end point was the change in reflection magnitude ( RM ; assessed with arterial tonometry and Doppler echocardiography). Secondary end points included change in left ventricular mass and fibrosis, measured with cardiac magnetic resonance imaging, and the 6‐minute walk distance. ISDN reduced aortic characteristic impedance (mean baseline=0.15 [95% CI , 0.14–0.17], 3 months=0.11 [95% CI , 0.10–0.13], 6 months=0.10 [95% CI , 0.08–0.12] mm Hg/mL per second; P =0.003) and forward wave amplitude (P f , mean baseline=54.8 [95% CI , 47.6–62.0], 3 months=42.2 [95% CI , 33.2–51.3]; 6 months=37.0 [95% CI , 27.2–46.8] mm Hg, P =0.04), but had no effect on RM ( P =0.64), left ventricular mass ( P =0.33), or fibrosis ( P =0.63). ISDN +hydral increased RM (mean baseline=0.39 [95% CI , 0.35–0.43]; 3 months=0.31 [95% CI , 0.25–0.36]; 6 months=0.44 [95% CI , 0.37–0.51], P =0.03), reduced 6‐minute walk distance (mean baseline=343.3 [95% CI , 319.2–367.4]; 6 months=277.0 [95% CI , 242.7–311.4] meters, P =0.022), and increased native myocardial T1 (mean baseline=1016.2 [95% CI , 1002.7–1029.7]; 6 months=1054.5 [95% CI , 1036.5–1072.3], P =0.021). A high proportion of patients experienced adverse events with active therapy ( ISDN =61.5%, ISDN +hydral=60.0%; placebo=12.5%; P =0.007). Conclusions ISDN , with or without hydralazine, does not exert beneficial effects on RM , left ventricular remodeling, or submaximal exercise and is poorly tolerated. ISDN +hydral appears to have deleterious effects on RM , myocardial remodeling, and submaximal exercise. Our findings do not support the routine use of these vasodilators in patients with heart failure with preserved ejection fraction. Clinical Trial Registration URL : www.clinicaltrials.gov . Unique identifier: NCT 01516346.

La diarrea del viajero es una de las condiciones que con mayor frecuencia afecta a los viajeros de países industrializados que visitan las zonas tropicales y subtropicales del planeta. El 20 a 50% de viajeros se van afectar por esta condición, siendo en ocasiones tan severa como para afectar los planes del viajero en la quinta parte de pacientes. El cuadro se manifiesta por la aparición de diarrea asociada a síntomas entéricos como dolor abdominal, nauseas, vómitos y en caso de diarrea inflamatoria fiebre y deposiciones con sangre. Entre los agentes etiológicos bacterianos más frecuentes están Escherichia coli enterotoxigénica, Salmonella, Shigella, entre otros agentes, aunque en cerca de la mitad de los casos no se aísla un agente etiológico. En caso de diarrea persistente debe descartarse parásitos y en zonas endémicas debe realizarse las pruebas especiales para descartar infección por Cyclospora cayetanensis. En pacientes con diarrea del viajero está indicado el manejo empírico con antibióticos, lo cual disminuye la duración de la enfermedad. En ausencia de fiebre o diarrea con sangre puede usarse loperamida. La prevención es importante en especialmente en pacientes de alto riesgo o en quienes sea importante que no se afecte el viaje. Travelers’ diarrhea is one of the most common conditions that affect travelers from industrialized countries who visit tropical and subtropical areas of the world. Twenty to fifty percent of travelers will suffer from this condition, and one fifth of these subjects will have diarrhea severe enough to affect their travel plans. Illness is characterized by the occurrence of diarrhea, associated with other gastrointestinal symptoms such as abdominal pain, nausea, vomiting and sometimes, in association of inflammatory diarrhea, fever and bloody stools. Among the most common etiologic agents Enterotoxigenic Escherichia coli, Salmonella, and Shigella are among the most common bacterial pathogens, although in close to one half of cases culture results are negative. In cases of persistent diarrhea parasites must be ruled out, and in endemic areas special stains must be ordered to rule agents like Cyclospora cayetanensis. In patients with Travelers’ diarrhea empiric treatment with antibiotics is indicated, reducing the duration of illness. In the absence of fever or bloody diarrhea loperamide can be used. Prevention is important, especially in high risk patients or those in whom the trip must not be affected by the illness.

Rationale: Nitrate-rich beetroot juice has been shown to improve exercise capacity in heart failure with preserved ejection fraction, but studies using pharmacological preparations of inorganic nitrate are lacking. Objectives: To determine (1) the dose–response effect of potassium nitrate (KNO 3 ) on exercise capacity; (2) the population-specific pharmacokinetic and safety profile of KNO 3 in heart failure with preserved ejection fraction. Methods and Results: We randomized 12 subjects with heart failure with preserved ejection fraction to oral KNO 3 (n=9) or potassium chloride (n=3). Subjects received 6 mmol twice daily during week 1, followed by 6 mmol thrice daily during week 2. Supine cycle ergometry was performed at baseline (visit 1) and after each week (visits 2 and 3). Quality of life was assessed with the Kansas City Cardiomyopathy Questionnaire. The primary efficacy outcome, peak O 2 -uptake, did not significantly improve ( P =0.13). Exploratory outcomes included exercise duration and quality of life. Exercise duration increased significantly with KNO 3 (visit 1: 9.87, 95% confidence interval [CI] 9.31–10.43 minutes; visit 2: 10.73, 95% CI 10.13–11.33 minute; visit 3: 11.61, 95% CI 11.05–12.17 minutes; P =0.002). Improvements in the Kansas City Cardiomyopathy Questionnaire total symptom (visit 1: 58.0, 95% CI 52.5–63.5; visit 2: 66.8, 95% CI 61.3–72.3; visit 3: 70.8, 95% CI 65.3–76.3; P =0.016) and functional status scores (visit 1: 62.2, 95% CI 58.5–66.0; visit 2: 68.6, 95% CI 64.9–72.3; visit 3: 71.1, 95% CI 67.3–74.8; P =0.01) were seen after KNO 3 . Pronounced elevations in trough levels of nitric oxide metabolites occurred with KNO 3 (visit 2: 199.5, 95% CI 98.7–300.2 μmol/L; visit 3: 471.8, 95% CI 377.8–565.8 μmol/L) versus baseline (visit 1: 38.0, 95% CI 0.00–132.0 μmol/L; P 3 did not lead to clinically significant hypotension or methemoglobinemia. After 6 mmol of KNO 3 , systolic blood pressure was reduced by a maximum of 17.9 (95% CI −28.3 to −7.6) mm Hg 3.75 hours later. Peak nitric oxide metabolites concentrations were 259.3 (95% CI 176.2–342.4) μmol/L 3.5 hours after ingestion, and the median half-life was 73.0 (interquartile range 33.4–232.0) minutes. Conclusions: KNO 3 is potentially well tolerated and improves exercise duration and quality of life in heart failure with preserved ejection fraction. This study reinforces the efficacy of KNO 3 and suggests that larger randomized trials are warranted. Clinical Trial Registration : URL: http://www.clinicaltrials.gov . Unique identifier: NCT02256345

OBJECTIVE Increased penetration of pulsatile power to the brain has been implicated in the pathogenesis of age-related cognitive dysfunction and dementia, a common comorbidity in patients with heart failure and preserved ejection fraction (HFpEF). However, there is a lack of knowledge on the effects of organic and inorganic nitrates administration in this population on the power carried by pressure and flow waves traveling through the proximal aorta and penetrating the carotid artery into the brain microvasculature. APPROACH We assessed aortic and carotid hemodynamics non-invasively in two sub-studies: (1) at baseline and after administration of 0.4 mg of sublingual nitroglycerine (an organic nitrate; n = 26); and (2) in a randomized controlled trial of placebo (PB) versus inorganic nitrate administration (beetroot-juice (BR), 12.9 mmol NO3; n = 16). MAIN RESULTS Wave and hydraulic power analysis demonstrated that NTG increased total hydraulic power (from 5.68% at baseline to 8.62%, P = 0.001) and energy penetration (from 8.69% to 11.63%; P = 0.01) from the aorta to the carotid, while inorganic nitrate administration did not induce significant changes in aortic and carotid wave power (power: 5.49%PB versus 6.25%BR, P = 0.49; energy: 8.89%PB versus 10.65%BR, P = 0.27). SIGNIFICANCE Organic nitrates, but not inorganic nitrates, increase the amount of hydraulic energy transmitted into the carotid artery in subjects with HFpEF. These findings may have implications for the adverse effect profiles of these agents (such as the differential incidence of headaches) and for the pulsatile hemodynamic stress of the brain microvasculature in this patient population.