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The COVID-19 pandemic provided an ideal scenario for studying the care of the elderly population, we implemented a tool named the Geriatric Measure (GM) tool to determine the severity and need for hospitalization. The objective of the study is to evaluate if the results of a brief Geriatric Measure tool are associated with mortality and other outcomes among older adults with COVID-19 treated in the emergency department. Retrospective observational cohort study. Participants were older adults (65 years and over) who required hospitalization for SARS CoV2 pneumonia. Patients were evaluated with the GM tool and were followed-up until death or discharge and associations between GM tool scores and mortality and other outcomes were assessed. A total of 275 patients were included. The proportion of patients who died increased with every category of the GM tool. Patients in category 1 (fit with good functional status) had a mortality of 24.7% versus those in category 4 (frail with poor functional status) who had a mortality of 51%. Our results show an association between our GM tool and mortality among older adults with pneumonia caused by SARS CoV2 and treated in the emergency department, and highlight the need of individualizing care for older patients., Competing Interests: Declarations. Conflict of interest: No conflict of interest exists for any of the authors. Ethical statements: This project was approved by the ethical and investigations committee of the National Institute of Medical Sciences and Nutrition Salvador Zubiran, Mexico City. The authors declare that they have not used any type of generative artificial intelligence for the writing of this manuscript, nor for the creation of table captions and/or figure legends. Informed consent: For this type of study formal consent is not required., (© 2025. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Acute heart failure is characterized by neurohormonal activation, which leads to sodium and water retention and causes alterations in body composition, such as increased body fluid congestion or systemic congestion. This condition is one of the most common reasons for hospital admission and has been associated with poor outcomes. The phase angle indirectly measures intracellular status, cellular integrity, vitality, and the distribution of spaces between intracellular and extracellular body water. This parameter has been found to be a predictor of health status and an indicator of survival and other clinical outcomes. In addition, phase angle values of <4.8° upon admission were associated with higher mortality in patients with acute heart failure. However, low phase angle values may be due to alterations-such as the shifting of fluids from an intracellular body water (ICW) compartment to an ECW (extracellular body water) compartment and a concurrent decrease in body-cell mass (which can reflect malnutrition)-that are present in heart failure. Thus, a low phase angle may be due to overhydration and/or malnutrition. BIVA provides additional information about the body-cell mass and congestion status with a graphical vector (R-Xc graph). In addition, a BIVA Z-score analysis (the number of standard deviations from the mean value of the reference group) that has the same pattern as that of the ellipses for the percentiles on the original R-Xc graph can be used to detect changes in soft-tissue mass or tissue hydration and can help researchers compare changes in different study populations. This protocol explains how to obtain and interpret phase angle values and BIVA Z-score analyses, their clinical applicability, and their usefulness as a predictive marker for the prognosis of a 90-day event in patients admitted to an emergency department with acute heart failure.

Early detection and management of fluid overload are critically important in acute illness, as the impact of therapeutic intervention can result in decreased or increased mortality rates. Accurate fluid status assessment entails appropriate therapy. Unfortunately, as the gold standard method of radioisotopic fluid measurement is costly, time-consuming, and lacks sensitivity in the acute care clinical setting, other less-accurate methods are typically used, such as clinical examination or 24 h output. Bioelectrical impedance vectorial analysis (BIVA) is an alternative impedance-based approach, where the raw parameter resistance and reactance of a subject are plotted to produce a vector, the position of which can be evaluated relative to tolerance intervals in an R-Xc graph. The fluid status is then interpreted as normal or abnormal, based on the distance from the mean vector derived from a healthy reference population. The objective of the present study is to demonstrate how to evaluate the presence of fluid overload through bioelectrical impedance vectorial analysis and the impedance ratio measured with tetrapolar multi-frequency equipment in patients admitted to the emergency department.

Background: The Sequential Organ Failure Assessment (SOFA) is a scoring system used for the evaluation of disease severity and prognosis of critically ill patients. The impedance ratio (Imp-R) is a novel mortality predictor., Aims: This study aimed to evaluate the combination of the SOFA + Imp-R in the prediction of mortality in critically ill patients admitted to the Emergency Department (ED)., Methods: A retrospective cohort study was performed in adult patients with acute illness admitted to the ED of a tertiary-care referral center. Baseline SOFA score and bioelectrical impedance analysis to obtain the Imp-R were performed within the first 24 h after admission to the ED. A Cox regression analysis was performed to evaluate the mortality risk of the initial SOFA score plus the Imp-R. Harrell's C-statistic and decision curve analyses (DCA) were performed., Results: Out of 325 patients, 240 were included for analysis. Overall mortality was 31.3%. Only 21.3% of non-surviving patients died after hospital discharge, and 78.4% died during their hospital stay. Of the latter, 40.6% died in the ED. The SOFA and Imp-R values were higher in non-survivors and were significantly associated with mortality in all models. The combination of the SOFA + Imp-R significantly predicted 30-day mortality, in-hospital mortality, and ED mortality with an area under the curve (AUC) of 0.80 (95% CI: 74-0.86), 0.79 (95% CI: 0.74-0.86) and 0.75 (95% CI: 0.66-0.84), respectively. The DCA showed that combining the SOFA + Imp-R improved the prediction of mortality through the lower risk thresholds., Conclusions: The addition of the Imp-R to the baseline SOFA score on admission to the ED improves mortality prediction in severely acutely ill patients admitted to the ED.

The coronavirus disease 2019 (COVID-19) is related to enhanced production of NETs, and autoimmune/autoinflammatory phenomena. We evaluated the proportion of low-density granulocytes (LDG) by flow cytometry, and their capacity to produce NETs was compared with that of conventional neutrophils. NETs and their protein cargo were quantified by confocal microscopy and ELISA. Antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA) and the degradation capacity of NETs were addressed in serum. MILLIPLEX assay was used to assess the cytokine levels in macrophages' supernatant and serum. We found a higher proportion of LDG in severe and critical COVID-19 which correlated with severity and inflammatory markers. Severe/critical COVID-19 patients had higher plasmatic NE, LL-37 and HMGB1-DNA complexes, whilst ISG-15-DNA complexes were lower in severe patients. Sera from severe/critical COVID-19 patients had lower degradation capacity of NETs, which was reverted after adding hrDNase. Anti-NET antibodies were found in COVID-19, which correlated with ANA and ANCA positivity. NET stimuli enhanced the secretion of cytokines in macrophages. This study unveils the role of COVID-19 NETs as inducers of pro-inflammatory and autoimmune responses. The deficient degradation capacity of NETs may contribute to the accumulation of these structures and anti-NET antibodies are related to the presence of autoantibodies.

Background: Most of the explanatory and prognostic models of COVID-19 lack of a comprehensive assessment of the wide COVID-19 spectrum of abnormalities. The aim of this study was to unveil novel biological features to explain COVID-19 severity and prognosis (death and disease progression)., Methods: A predictive model for COVID-19 severity in 121 patients was constructed by ordinal logistic regression calculating odds ratio (OR) with 95% confidence intervals (95% CI) for a set of clinical, immunological, metabolomic, and other biological traits. The accuracy and calibration of the model was tested with the area under the curve (AUC), Somer's D, and calibration plot. Hazard ratios with 95% CI for adverse outcomes were calculated with a Cox proportional-hazards model., Results: The explanatory variables for COVID-19 severity were the body mass index (BMI), hemoglobin, albumin, 3-Hydroxyisovaleric acid, CD8+ effector memory T cells, Th1 cells, low-density granulocytes, monocyte chemoattractant protein-1, plasma TRIM63, and circulating neutrophil extracellular traps. The model showed an outstanding performance with an optimism-adjusted AUC of 0.999, and Somer's D of 0.999. The predictive variables for adverse outcomes in COVID-19 were severe and critical disease diagnosis, BMI, lactate dehydrogenase, Troponin I, neutrophil/lymphocyte ratio, serum levels of IP-10, malic acid, 3, 4 di-hydroxybutanoic acid, citric acid, myoinositol, and cystine., Conclusions: Herein, we unveil novel immunological and metabolomic features associated with COVID-19 severity and prognosis. Our models encompass the interplay among innate and adaptive immunity, inflammation-induced muscle atrophy and hypoxia as the main drivers of COVID-19 severity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Torres-Ruiz, Pérez-Fragoso, Maravillas-Montero, Llorente, Mejía-Domínguez, Páez-Franco, Romero-Ramírez, Sosa-Hernández, Cervantes-Díaz, Absalón-Aguilar, Nuñez-Aguirre, Juárez-Vega, Meza-Sánchez, Kleinberg-Bid, Hernández-Gilsoul, Ponce-de-León and Gómez-Martín.)

Background & Aims: The accuracy of estimating body composition compartments is critical in the clinical setting. Currently, there are different bioelectrical impedance analysis (BIA) devices available for obtaining raw BIA parameters. The aim of this study was to determine the level of agreement between multiple frequency (MF)-BIA and single frequency (SF)-BIA devices in obtaining raw BIA measurements (resistance (R), reactance (Xc), and phase angle (PhA)), as well as the agreement on the classification of hydration status and body cell mass by the bioelectrical impedance vector analysis (BIVA) method., Methods: This cross-sectional study included 406 outpatients with stable chronic heart failure (HF). The raw BIA measurements at 50 kHz obtained by tetrapolar MF-BIA (Bodystat QuadScan 4000) were compared with those obtained by tetrapolar SF-BIA (RJL Quantum X). In addition, the patients were classified by their hydration status and body cell mass according to the BIVA method., Results: Strong and significant correlations were observed between the two methods in all raw BIA variables (r ≥ 0.90). Lin's concordance correlation coefficient (CCC) values were almost perfect for R (CCC = 0.99; 95% CI 0.997 to 0.998), moderate for Xc (CCC = 0.93; 95% CI 0.92 to 0.94), and poor for PhA (CCC = 0.88; 95% CI 0.85 to 0.90). The agreement obtained in the two classifications (quadrants and hydration status) was >0.81., Conclusions: MF-BIA and SF-BIA demonstrated good agreement for measurement of the R parameter; however, the Xc and PhA parameters must be used carefully due to the previously reported variability. Likewise, the agreement in all classifications by the BIVA method was almost perfect., Competing Interests: Declaration of competing interest None declared., (Copyright © 2021 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Healthcare-associated infections (HAIs) are important adverse events that must be prevented., Objective: The objective of the study was to report and study possible changes in HAI rates as well as their causes after the COVID-19 hospital surge capacity response (HSCR) in an academic referral center., Methods: This was a before-after observational study. The Infection Prevention and Control (IPC) program (prospective surveillance, prevention bundles, antibiotic stewardship, continuing education, and feedback) was transiently disrupted after the start of HSCR (March 2020). HAI rates were compared before (January 2019-February 2020) and after (April-July 2020) HSCR, and plausible predisposing factors in affected patients were compared., Results: An increase in the HAI rate from 6.2 to 11.8 cases/1000 patient-days was noted between periods due to increases in ventilator-associated pneumonia and bloodstream infection (BSI) rates. More critically ill patients were admitted during HSCR, and use of invasive devices increased. Prone positioning and infusion of muscle relaxants became commonplace. The nurse-to-patient ratio in the intensive care unit decreased, and 4 h shifts were introduced to avoid fatigue. The BSI rate decreased after the IPC program with additional measures was reintroduced in May 2020., Conclusions: The strain on the workforce and modifications to the IPC program very possibly underlay the findings. IPC programs continue to be essential during the pandemic.

Background: Fluid overload (FO) in critically ill patients is associated with increased adverse events. This study aims to compare different bioelectrical impedance analysis (BIA) parameters that demonstrate FO and their association with 30-day mortality in critical patients admitted to the emergency department (ED)., Methods: Five components of the BIA were obtained by multifrequency device-total body water (TBW), extracellular water (ECW), intracellular water (ICW), resistance (R), and reactance (Xc)-to calculate parameters (impedance vectors, impedance ratio, and the ratios of ECW to TBW, ECW to ICW, ECW to body surface area, TBW to height 2 , ICW to height 2 , Xc to height, and R to height) that have been used for the detection of FO. A concordance analysis (κ) was performed comparing every parameter with each other. Furthermore, different regression models (Cox regression) were created associating the FO for each parameter with 30-day mortality, adjusted for age, body mass index, sex, Sequential Organ Failure Assessment score, and serum albumin level., Results: A total of 142 patients were included in the study. Only FO by impedance vector analysis (relative risk [RR] = 6.4; 95% CI, 1.5-27.9; P = .01), impedance ratio (RR = 2.7; 95% CI, 1.1-7.1; P = .04), and R (RR = 2.6; 95% CI, 1.2-5.5; P = .02) increased the probability of 30-day mortality., Conclusions: Different parameters that determine FO by BIA were associated with the mortality of patients admitted to the ED, but the impedance vector analysis was superior to any other parameter of the BIA., (© 2020 American Society for Parenteral and Enteral Nutrition.)

Objective: To develop a score to predict the need for ICU admission in COVID-19., Methods: We assessed patients admitted to a COVID-19 center in Mexico. Patients were segregated into a group that required ICU admission, and a group that never required ICU admission. By logistic regression, we derived predictive models including clinical, laboratory, and imaging findings. The ABC-GOALS was constructed and compared to other scores., Results: We included 329 and 240 patients in the development and validation cohorts, respectively. One-hundred-fifteen patients from each cohort required ICU admission. The clinical (ABC-GOALSc), clinical+laboratory (ABC-GOALScl), clinical+laboratory+image (ABC-GOALSclx) models area under the curve were 0.79 (95%CI=0.74-0.83) and 0.77 (95%CI=0.71-0.83), 0.86 (95%CI=0.82-0.90) and 0.87 (95%CI=0.83-0.92), 0.88 (95%CI=0.84-0.92) and 0.86 (95%CI=0.81-0.90), in the development and validation cohorts, respectively. The ABC-GOALScl and ABC-GOALSclx outperformed other COVID-19 and pneumonia predictive scores., Conclusion: ABC-GOALS is a tool to timely predict the need for admission to ICU in COVID-19.

The use of continuous positive airway pressure (CPAP) in asthma has been a point of debate over the past several years. Various studies, including those on animals and humans have attempted to understand the role and pathophysiology of CPAP in patients with either well controlled or poorly controlled asthma. The aim of this manuscript is to review the currently available literature on the physiologic and clinical effects of CPAP in animal models of asthma and on humans with stable asthma.

A multimodal preventive strategy consisting of a ventilator-associated pneumonia (VAP) preventive bundle plus 3 additional sequential interventions (noninvasive ventilation, reeducation of health care workers, and early weaning) was associated with a marked reduction in VAP rates in a Latin American hospital, including 6 consecutive months without VAP cases. A positive association between the percentage of intubated patients and VAP rates was observed., (Copyright © 2019. Published by Elsevier Inc.)

Background: Regional information regarding the characteristics of patients with coronavirus disease (COVID)-19 is needed for a better understanding of the pandemic., Objective: The objective of the study to describe the clinical features of COVID-19 patients diagnosed in a tertiary-care center in Mexico City and to assess differences according to the treatment setting (ambulatory vs. hospital) and to the need of intensive care (IC)., Methods: We conducted a prospective cohort, including consecutive patients with COVID-19 from February 26, 2020 to April 11, 2020., Results: We identified 309 patients (140 inpatients and 169 outpatients). The median age was 43 years (interquartile range, 33-54), 59.2% men, and 18.6% healthcare workers (12.3% from our center). The median body mass index (BMI) was 29.00 kg/m 2 and 39.6% had obesity. Compared to outpatients, inpatients were older, had comorbidities, cough, and dyspnea more frequently. Twenty-nine (20.7%) inpatients required treatment in the IC unit (ICU). History of diabetes (type 1 or 2) and abdominal pain were more common in ICU patients compared to non-ICU patients. ICU patients had higher BMIs, higher respiratory rates, and lower room-air capillary oxygen saturations. ICU patients showed a more severe inflammatory response as assessed by white blood cell count, neutrophil and platelet count, C-reactive protein, ferritin, procalcitonin, and albumin levels. By the end of the study period, 65 inpatients had been discharged because of improvement, 70 continued hospitalized, and five had died., Conclusions: Patients with comorbidities, either middle-age obese or elderly complaining of fever, cough, or dyspnea, were more likely to be admitted. At admission, patients with diabetes, high BMI, and clinical or laboratory findings consistent with a severe inflammatory state were more likely to require IC., (Copyright: © 2020 Permanyer.)

Background: The coronavirus disease 2019 (COVID-19) has been declared a global pandemic. Older adults have been found as a vulnerable group for developing severe forms of disease and increased mortality., Objective: The objective of the study was to propose a pathway to assist the decision-making process for hospital resource allocation for older adults with COVID-19 using simple geriatric assessment-based tools., Methods: We reviewed the available literature at this point of the COVID-19 outbreak, focusing in older adult care to extract key recommendations for those health-care professionals who will be treating older adults in the hospital emergency ward (HEW) in developing countries during the COVID-19 pandemic., Results: We listed a series of easy recommendations for non-geriatrician doctors in the HEW and suggested simple tools for hospital resource allocation during critical care evaluation of older adults with COVID-19 in low- and middle-income countries., Conclusions: Age must not be used as the sole criterion for resource allocation among older adults with COVID-19. Simple and efficient tools are available to identify components of the comprehensive geriatric assessment, which could be useful to predict outcomes and provide high-quality care that would fit the particular needs of older adults in resource-limited settings amidst this global pandemic., (Copyright: © 2020 Permanyer.)

Purpose of the Study: The aim of this study was to investigate the association of fluid overload, measured by bioelectrical impedance vector analysis (BIVA) and also by accumulated fluid balance, with 30-day mortality rates in patients admitted to the emergency department (ED)., Design: We conducted a prospective observational study of fluid overload using BIVA, taking measures using a multiple-frequency whole-body tetrapolar equipment. Accumulated fluid balances were obtained at 24, 48 and 72 hours from ED admission and its association with 30-day mortality., Patients: 109 patients admitted to the ED classified as fluid overloaded by both methods., Results: According to BIVA, 71.6% (n=78) of patients had fluid overload on ED admission. These patients were older and had higher Sequential Organ Failure Assessment scores. During a median follow-up period of 30 days, 32.1% (n=25) of patients with fluid overload evaluated by BIVA died versus none with normovolaemia (p=0.001). There was no statistically significant difference in mortality between patients with and without fluid overload as assessed by accumulated fluid balance (p=0.81)., Conclusions: Fluid overload on admission evaluated by BIVA was significantly related to mortality in patients admitted to the ED., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: The 2009-2010 influenza A (H1N1pdm09) pandemic caused substantial morbidity and mortality among young patients; however, mortality estimates have been confounded by regional differences in eligibility criteria and inclusion of selected populations. In 2013-2014, H1N1pdm09 became North America's dominant seasonal influenza strain. Our objective was to compare the baseline characteristics, resources, and treatments with outcomes among critically ill patients with influenza A (H1N1pdm09) in Mexican and Canadian hospitals in 2014 using consistent eligibility criteria., Design: Observational study and a survey of available healthcare setting resources., Setting: Twenty-one hospitals, 13 in Mexico and eight in Canada., Patients: Critically ill patients with confirmed H1N1pdm09 during 2013-2014 influenza season., Interventions: None., Measurements and Main Results: The main outcome measures were 90-day mortality and independent predictors of mortality. Among 165 adult patients with H1N1pdm09-related critical illness between September 2013 and March 2014, mean age was 48.3 years, 64% were males, and nearly all influenza was community acquired. Patients were severely hypoxic (median PaO2-to-FIO2 ratio, 83 mm Hg), 97% received mechanical ventilation, with mean positive end-expiratory pressure of 14 cm H2O at the onset of critical illness and 26.7% received rescue oxygenation therapy with prone ventilation, extracorporeal life support, high-frequency oscillatory ventilation, or inhaled nitric oxide. At 90 days, mortality was 34.6% (13.9% in Canada vs 50.5% in Mexico, p < 0.0001). Independent predictors of mortality included lower presenting PaO2-to-FIO2 ratio (odds ratio, 0.89 per 10-point increase [95% CI, 0.80-0.99]), age (odds ratio, 1.49 per 10 yr increment [95% CI, 1.10-2.02]), and requiring critical care in Mexico (odds ratio, 7.76 [95% CI, 2.02-27.35]). ICUs in Canada generally had more beds, ventilators, healthcare personnel, and rescue oxygenation therapies., Conclusions: Influenza A (H1N1pdm09)-related critical illness still predominantly affects relatively young to middle-aged patients and is associated with severe hypoxemic respiratory failure. The local critical care system and available resources may be influential determinants of patient outcome.

Introduction: Acquired von Willebrand disease is initiated by autoantibodies and hyperviscosity syndrome caused by a massive polyclonal hypergammaglobulinemia. Acquired von Willebrand disease associated with autoimmune disease in addition to pulmonary hypertension during emergency room presentation is a rare condition. To the best of our knowledge, this is the second case reported in the literature treated with success; the first one was reported in 1987., Case Presentation: A 28-year-old mestizo man with a 3-year history of inflammatory arthritis was admitted to our hospital. An overlap of rheumatoid arthritis with systemic lupus erythematosus was suspected; therefore methotrexate was initiated, and later changed to leflunomide because of liver toxicity. Prothrombin time, international normalized ratio and activated partial thromboplastin times were normal (11/10.4 seconds; 1.2; 31.1/26.9 seconds, respectively), von Willebrand factor activity was observed with low ristocetin cofactor at 33.6UI/dL, high von Willebrand factor antigen >200UI/dL, and a low von Willebrand factor: ristocetin cofactor to von Willebrand factor antigen ratio. He was admitted to the emergency room with a 24-hour evolution of progressive dyspnea, cough, thoracic pain, and palpitations, 104 beats/min, 60/40 mmHg, temperature of 38°C, pulse oximetric saturation 88% and 30 breaths/minute. Cold, pale and mottled skin was also observed. He was then transferred to the intensive care unit. The placement of a pulmonary artery catheter was made. The initial patterns showed a precapillary pulmonary hypertension; acute pulmonary embolism was the first choice for diagnosis. Pulmonary angiography was conducted, and when no clot was discovered, pulmonary artery hypertension associated with connective tissue disease was considered. Serum protein electrophoresis confirmed the presence of a massive polyclonal hypergammaglobulinemia, and no paraproteinemia or monoclonal cell population was found from the electrophoretic pattern of the patient's plasma. Hypergammaglobulinemia was the cause of hyperviscosity syndrome associated with autoantibodies. Three sessions of plasma exchange therapy were made, and clinical improvement was observed. He was then discharged from the intensive care unit and hospital, respectively. He is now attended by an external consult and has no respiratory symptomatology., Conclusions: Hyperviscosity syndrome with pulmonary arterial hypertension presentation in a patient with acquired von Willebrand disease in an autoimmune context is a rare condition that can be treated successfully with plasmapheresis and critical care support.

Background: Microalbuminuria is considered a major risk factor predisposing to cardiovascular morbidity and mortality. Microalbuminuria levels in patients with or without diabetes have been associated with a higher risk of chronic heart failure (HF). However, there are limited data regarding prevalence of microalbuminuria in chronic heart failure and its prognostic value. The aim of this study was to assess the occurrence of microalbuminuria in chronic heart failure patients as well as its association with clinical, echocardiographic, and body composition markers., Methods: In a cross-sectional study, we included 72 chronic heart failure patients (NYHA I-III) on standard HF therapy. All patients had an echocardiogram and body composition by vector bioelectric impedance analysis (measured by Body Stat Quad Scan)., Results: The studied population consisted of 64% men at mean age of 62.6 +/- 15.1 years. Patients were divided into systolic and diastolic HF groups. Microalbuminuria was observed in 40% of diastolic and 24% systolic HF patients (p = 0.04). Microalbuminuria was present in more patients with volume overload (80 vs. 21.9%, p = 0.002), with a worse phase angle and lower serum albumin (4.7 vs. 5.9 degrees and 3.5 vs. 4.0 mg/dl, p = 0.02) and higher pulmonary arterial pressure compared with patients without microalbuminuria in systolic HF patients. There was no significant association between frequency of microalbuminuria and ejection fraction. In the diastolic HF group, the presence of microalbuminuria was not associated with any known risk factor., Conclusions: Microalbuminuria was more frequent in diastolic than systolic HF patients. In systolic HF patients microalbuminuria was associated with factors known to be markers of worse prognosis.