Serum C-reactive protein as an adjunct for identifying complicated parapneumonic effusions.

INTRODUCTION: Distinguishing non-purulent complicated parapneumonic pleural effusions (CPPE) from uncomplicated parapneumonic pleural effusions (UPPE) is challenging. We aimed to determine whether serum C-reactive protein (sCRP), alone or in combination with classical pleural fluid parameters, is useful in making such discrimination. METHODS: The study was composed of a total of 104 consecutive patients, of whom 47 had UPPE and 57 had CPPE. Standard biochemical pleural fluid data along with sCRP were measured. RESULTS: sCRP at the time of thoracentesis or chest tube insertion was significantly higher in CPPE (238 mg/L) than UPPE (147 mg/L). At the optimum cutoff value of 200 mg/L, sCRP had a sensitivity, specificity, likelihood ratio positive, likelihood ratio negative, and area under the receiver-operating characteristic curve for diagnosing CPPE of 58 %, 81 %, 3.1, 0.52, and 0.67, respectively. The combination of sCRP >200 mg/L with pleural fluid glucose <60 mg/dL using an "and" rule achieved a specificity of 98 %, whereas both parameters combined in an "or" rule had a sensitivity of 81 %, which was higher than that of pleural fluid pH (57 %) or glucose (54 %). CONCLUSIONS: sCRP, when combined with classical pleural fluid biochemistries, improves the diagnostic accuracy in identifying those patients with non-purulent parapneumonic effusions who need chest drainage.

A Simple Scoring System to Differentiate Bacterial from Viral Infections in Acute Exacerbations of COPD Requiring Hospitalization.

Objective: Both bacteria and viruses may cause acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The objective of this study was to identify readily available clinical parameters to discriminate between them. Methods: During a winter period all consecutive patients with an AECOP who were hospitalized in a non-ICU general ward were prospectively enrolled. In addition to blood tests, cultures of spontaneous or induced sputum samples, and genome detection of respiratory viruses in nasopharyngeal swab samples using multiplex RT-PCR assays were obtained. Only patients with positive microbiological results (bacteria, virus, or both) were eventually included. Mixed infections (bacteria plus viruses) were categorized into the bacterial group due to therapeutic implications (ie, need for antibiotics). Demographic and routine clinical and analytical information was collected. Results: A total of 127 AECOPD patients out of 213 initially evaluated met inclusion criteria and were classified as having bacterial (70, 55.1%) or viral (57, 44.9%) infection. Although no single variable was useful to identify bacteria, the combination of serum C-reactive protein >70 mg/L (2 points), >1 day of symptoms (1.5 points), and a blood neutrophil count >9,500 x109/L (1 point) into a scoring system reached an AUC of 0.80 (95% CI=0.73-0.88) for bacterial etiologies. With this model, scoring 0 or 1 point significantly reduced the probability of a bacterial infection (likelihood ratio negative of 0.2), whereas summing up 2.5 points or more increased it sufficiently to be clinically meaningful (likelihood ratio positive >3.7). Viral infections resulted in fewer hospitalization days (78.9% of patients spent ≥3 days in hospital vs 95.7% of those with bacterial infections; P=0.008). Conclusion: A simple and easy to obtain score system can help clinicians in the decision of prescribing antibiotics in AECOPD patients.

Triggering receptor (TREM-1) expressed on myeloid cells predicts bacteremia better than clinical variables in community-acquired pneumonia.

BACKGROUND AND OBJECTIVE: Some clinical variables are associated with bacteremia in patients with community-acquired pneumonia (CAP). The aim of this study was to analyse the accuracy of the soluble form of triggering receptor expressed on myeloid cells-1 (sTREM-1) to predict positive blood cultures in comparison with established clinical prognostic variables. METHODS: In addition to collecting clinical and laboratory information, a commercially available immunoassay kit was used to measure the serum sTREM-1 levels on the first day of admit ion in patients with CAP. Receiver operating characteristic (ROC) curves were used to compare the ability of sTREM-1 and commonly used clinical variables to identify bacteremia. RESULTS: Blood cultures yielded a pathogen in 13 (10.4%) out of 124 patient samples. The microorganisms isolated were Streptococcus pneumoniae (11 patients) and Klebsiella pneumoniae (2 patients). The presence of pleuritic chest pain, tachycardia and extreme white cell count (WCC) were associated with bacteremia. However, ROC curve analysis showed an accuracy of sTREM-1 (area under the receiver operating characteristic curve (AUC) 0.84, 95% CI: 0.72-0.95), which was higher than pleuritic chest pain (AUC 0.71, 95% CI: 0.57-0.84), tachycardia (AUC 0.73, 95% CI: 0.58-0.88) and extreme WCC (AUC 0.70, 95% CI: 0.55-0.85) for predicting positive blood cultures. Low admission sTREM-1 serum values had a high negative predictive value for excluding bacteremia (sTREM-1 <120 pg/mL = 98.8%). CONCLUSIONS: This preliminary study suggests that the determination of sTREM-1 serum levels on admission may be more accurate than clinical variables for identifying bacteremic patients.

[Incidence of hyponatremia and its causes in neurological patients]. / Incidencia de la hiponatremia y de sus causas en pacientes neurológicos.

INTRODUCTION: Hyponatremia is considered the most frequent electrolyte disorder found in hospitalized patients and seems to be a prognostic factor during hospitalization. METHODS: A prospective observational study was carried out in consecutive neurological patients admitted to our hospital over a 3-month period. Blood and urinary ionogram and osmolality were determined at entry and 3-5 days after admission in all patients with hyponatremia. RESULTS: Of the 130 patients admitted, 19 (14.6%) had hyponatremia. The causes of hyponatremia were as follows: inappropriate fluid replacement in 4 patients (21%), antihypertensive drugs in 4 (21%), syndrome of inappropriate secretion of antidiuretic hormone in 4 (21%), cerebral salt wasting syndrome in 2 (10%), and edematous status caused by liver disease in one and digestive loss in one (5%) each. Mortality was one (5%) and 0 (0%) among patients with and without hyponatremia, respectively. CONCLUSION: Hyponatremia is common in hospitalized neurological patients and can be misdiagnosed as a worsening of the main illness.

A prediction rule for estimating the risk of bacteremia in patients with community-acquired pneumonia.

BACKGROUND: We endeavored to construct a simple score based entirely on epidemiological and clinical variables that would stratify patients who require hospital admission because of community-acquired pneumonia into groups with a low or high risk of developing bacteremia. METHODS: Derivation and internal validation cohorts were obtained by retrospective analysis of a database that included 3116 consecutive patients with community-acquired pneumonia from 2 university hospitals. Potential predictive factors were determined by means of a multivariate logistic regression equation applied to a cohort consisting of 60% of the patients. Points were assigned to significant parameters to generate the score. It was then internally validated with the remaining 40% of patients and was externally validated using an independent multicenter cohort of 1369 patients. RESULTS: The overall rates of bacteremia were 12%-16% in the cohorts. The clinical probability estimate of developing bacteremia was based on 6 variables: liver disease, pleuritic pain, tachycardia, tachypnea, systolic hypotension, and absence of prior antibiotic treatment. For the score, 1 point was assigned to each predictive factor. In the derivation cohort, a cutoff score of 2 best identified the risk of bacteremia. In the validation cohorts, rates of bacteremia were <8% for patients with a score 1 (43%-49% of patients), whereas blood culture results were positive in 14%-63% of cases for patients with a score 2. CONCLUSIONS: This clinical score, based on readily available and objective variables, provides a useful tool to predict bacteremia. The score has been internally and externally validated and may be useful to guide diagnostic decisions for community-acquired pneumonia.

Risk factors and outcome of community-acquired pneumonia due to Gram-negative bacilli.

BACKGROUND AND OBJECTIVE: Several sets of guidelines have advocated initial antibiotic treatment for community-acquired pneumonia due to Gram-negative bacilli in patients with specific risk factors. However, evidence to support this recommendation is scarce. We sought to identify risk factors for community-acquired pneumonia due to Gram-negative bacilli, including Pseudomonas aeruginosa, and to assess outcomes. METHODS: An observational analysis was carried out on prospectively collected data for immunocompetent adults hospitalized for community-acquired pneumonia in two acute-care hospitals. Cases of pneumonia due to Gram-negative bacilli were compared with those of non-Gram-negative bacilli causes. RESULTS: Sixty-one (2%) of 3272 episodes of community-acquired pneumonia were due to Gram-negative bacilli. COPD (odds ratio (OR) 2.4, 95% confidence interval (CI): 1.2-5.1), current use of corticosteroids (OR 2.8, 95% CI: 1.2-6.3), prior antibiotic therapy (OR 2.6, 95% CI: 1.4-4.8), tachypnoea >or=30 cycles/min (OR 2.1, 95% CI: 1.1-4.2) and septic shock at presentation (OR 6.1, 95% CI: 2.5-14.6) were independently associated with Gram-negative bacilli pneumonia. Initial antibiotic therapy in patients with pneumonia due to Gram-negative bacilli was often inappropriate. These patients were also more likely to require admission to the intensive care unit, had longer hospital stays, and higher early (<48 h) (21% vs 2%; P < 0.001) and overall mortality (36% vs 7%; P < 0.001). CONCLUSIONS: These results suggest that community-acquired pneumonia due to Gram-negative bacilli is uncommon, but is associated with a poor outcome. The risk factors identified in this study should be considered when selecting initial antibiotic therapy for patients with community-acquired pneumonia.

C-reactive protein and other predictors of poor outcome in patients hospitalized with exacerbations of chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: CRP is elevated in patients with acute exacerbations of COPD (AECOPD), but there is little information on whether this biomarker can help to identify adverse short-term clinical outcomes. METHODS: A 6-month prospective study of all patients with AECOPD requiring hospital admission. Clinical, laboratory (including plasma CRP levels at admission) and functional data were recorded. The outcome variable (the adverse outcome) consisted of: (i) death in hospital or within 15 days of discharge, (ii) transfer to the intensive care unit, or (iii) development of acute heart failure during hospitalization. RESULTS: Data from 147 patients with a total of 160 admissions were recorded. During follow up, 38 (23.7%) adverse outcomes were observed, including 13 (8.8%) and 8 (5.4%) patients who died during hospitalization or within 15 days of discharge, respectively. CRP at a level of 50 mg/L was related to an adverse outcome (OR 4.9, 95% CI: 1.92-12.6, P < 0.01), although by itself it was neither sensitive nor specific (area under the receiver operating characteristic curve (AUC) 0.69, 95% CI: 0.60-0.77). However, a risk score derived from the combination of CRP with other variables, such as 'current smoker', 'at least two comorbidities' and 'confusion,' at admission showed good predictive ability to identify an adverse outcome (AUC of 0.80, 95% CI: 0.72-0.88). CONCLUSIONS: Plasma CRP in combination with other variables obtained at admission may assist identification of high-risk patients with AECOPD.

Pleural fluid interleukin-8 and C-reactive protein for discriminating complicated non-purulent from uncomplicated parapneumonic effusions.

BACKGROUND AND OBJECTIVE: This study was designed to test the hypothesis that measurement of IL-8 and CRP in pleural fluid could improve the identification of patients with non-purulent parapneumonic effusions that ultimately require chest tube drainage. METHODS: We assessed IL-8, CRP and three classical parameters (pH, glucose and LDH) in the pleural fluid of 100 patients with parapneumonic effusions. Forty-nine of these patients had non-purulent complicated effusions (complicated parapneumonic pleural effusion, CPPE), and 51 had uncomplicated parapneumonic pleural effusions (UPPE). Receiver-operating characteristic curves were used to assess the sensitivity and specificity of pleural fluid biochemical parameters for differentiating among the two patient groups. IL-8 production was determined using a commercially available ELISA kit, and CRP was measured by immunoassay. RESULTS: At a cutoff value of 1000 pg/mL, IL-8 differentiated CPPE from UPPE with a sensitivity of 84% and a specificity of 82%. Likewise, CRP levels were higher in CPPE than in UPPE, and showed 72% sensitivity and 71% specificity at a cutoff value of 80 mg/L. We found that all five pleural fluid tests showed similar diagnostic accuracies when evaluated by receiver-operating characteristic analysis. However, multivariate analysis indicated that the size of the effusion, as well as pleural fluid pH and IL-8 concentration, were the best discriminatory parameters, with likelihood ratios of 6.4, 4.4 and 3.9, respectively. CONCLUSIONS: Pleural fluid IL-8 is an accurate marker for the identification of non-purulent CPPE.

Contribution of a pleural antigen assay (Binax NOW) to the diagnosis of pneumococcal pneumonia.

STUDY OBJECTIVES: To determine whether the detection of pneumococcal antigen in pleural fluid augments conventional microbiological methods used for the etiologic diagnosis of pneumonia. METHODS: In this retrospective study, a rapid immunochromatographic test (ICT) [NOW Streptococcus pneumoniae assay; Binax; Scarborough, ME] was performed on pleural fluid samples from 34 patients with pneumonia due to S pneumoniae, 89 patients with effusions of nonpneumococcal origin, and 17 patients with pneumonia of unknown etiology. Data on blood cultures, pleural fluid cultures, and urinary antigen tests were recorded. RESULTS: The ICT test result was positive in 24 of 34 patients (70.6%) with pneumococcal pneumonia and negative in 83 of 89 patients (93.3%) without pneumococcal pneumonia. The sensitivity of the pleural ICT test was higher than that obtained for blood (37.5%) and pleural fluid cultures (32.3%), but lower than the detection of pneumococcal antigen in urine samples (82.1%). However, three patients with pneumococcal pneumonia and a negative ICT urine test result had a positive pleural fluid antigen detection result test. Previous antibiotic exposure did not influence pneumococcal antigen detection in either pleural fluid or urine specimens. Six additional patients with empyema due to anaerobes (three patients), Streptococcus viridans (two patients), and Enterococcus faecalis (one patient) had false-positive pleural ICT test results. Finally, the ICT assay finding was also positive in 5 of 17 patients (29.4%) with pneumonia without a definite microbiological cause. CONCLUSIONS: The ICT test performed on pleural fluid samples augments the standard diagnostic methods of blood and pleural fluid cultures, even in the case of prior antibiotic therapy, and enhances the ICT urinary antigen assay.

The Diagnostic Value of Serum C-Reactive Protein for Identifying Pneumonia in Hospitalized Patients with Acute Respiratory Symptoms.

Background. The clinical diagnosis of pneumonia is sometimes difficult since chest radiographs are often indeterminate. In this study, we aimed to assess whether serum C-reactive protein (CRP) could assist in identifying patients with pneumonia. Methods. For one winter, all consecutive patients with acute respiratory symptoms admitted to the emergency ward of a single center were prospectively enrolled. In addition to chest radiographs, basic laboratory tests, and microbiology, serum levels of CRP were measured at entry. Results. A total of 923 (62.3%) of 1473 patients hospitalized for acute respiratory symptoms were included. Subjects with a final diagnosis of pneumonia had higher serum CRP levels (median 187 mg/L) than those with exacerbations of chronic obstructive pulmonary disease (63 mg/L) or acute bronchitis (54 mg/L, p < 0.01). CRP was accurate in identifying pneumonia (area under the curve 0.84, 95% CI 0.82-0.87). The multilevel likelihood ratio (LR) for intervals of CRP provided useful information on the posttest probability of having pneumonia. CRP intervals above 200 mg/L were associated with LR+ > 5, for which pneumonia is likely, whereas CRP intervals below 75 mg/L were associated with LR < 0.2, for which pneumonia is unlikely. Conclusion. Serum CRP may be a useful addition for diagnosing pneumonia in hospitalized patients with acute respiratory symptoms.

Community-acquired pneumonia as the initial manifestation of serious underlying diseases.

PURPOSE: Community-acquired pneumonia is common among patients with coexisting illnesses and it can be the initial manifestation of these comorbid diseases. The objectives of our study were to evaluate the frequency of this association and to analyze whether certain characteristics could predict the presence of unknown comorbid conditions. SUBJECTS AND METHODS: Over a 5-year period, we prospectively studied 660 consecutive patients with community-acquired pneumonia seen at our institution. In a subgroup of these patients, diagnosis of previously unknown comorbid conditions was established during follow-up. Characteristics of these patients were compared with data from the remaining sample of patients. RESULTS: Prior underlying diseases were present in 298 (45%) patients. One or more new comorbid conditions were found in 41 (6%), of which diabetes (14 cases), malignancies (12 cases), chronic obstructive pulmonary disease (8 cases), and human immunodeficiency virus (HIV) infection (5 cases) were the most common. In the comparative study, a bacterial etiology, positive blood cultures, and hospitalization were more frequently found (P < 0.05) in patients with new comorbid conditions than atypical microorganisms or viruses, negative blood cultures, or outpatient care. CONCLUSION: In the initial diagnostic workup of patients with community-acquired pneumonia, the possibility of unknown comorbid conditions should be carefully evaluated.

A pilot study on the diagnostic accuracy of proadrenomedullin and proatrial natriuretic Peptide in lower respiratory tract infections.

BACKGROUND: Pneumonia is the leading cause of death among infectious diseases in developed countries. However, the severity of pneumonia requiring hospitalization often makes the initial diagnosis difficult because of an equivocal clinical picture or interpretation of the chest film. The objective of the present study was to assess the usefulness of the plasma levels of mid-regional proadrenomedullin (MR-proADM) and mid-regional proatrial natriuretic peptide (MR-proANP) in differentiating pneumonia from other lower respiratory tract infections (LRTIs). METHODS: A retrospective study was conducted. The plasma levels of MR-proADM and MR-proANP were measured in 85 patients hospitalized for LRTIs, 56 of whom with diagnosis of pneumonia and 29 with other LRTIs. RESULTS: The patients with pneumonia had increased MR-proADM levels (median 1.46 nmol/L [IQR 25-75, 0.82-2.02 nmol/L]) compared with the patients with other LRTIs (median 0.88 nmol/mL [0.71-1.39 nmol/L]) (p= 0.04). However, the MR-proANP levels did not show differences between the groups. The optimal threshold of MR-proADM to predict pneumonia was 1.5 nmol/L, which yielded a sensitivity of 51.7% (95% CI, 38.0-65.3), a 79.3% specificity (95% CI, 60.3-92.0), and an odds ratio of 6.64 (95% CI, 1.32-32.85). The combination of this parameter with C-reactive protein in an "and" rule increased the specificity for detecting pneumonia significantly. CONCLUSION: MR-proADM levels (but not MR-proANP levels) are increased in patients with pneumonia although its discriminatory power is moderate.

Pleural fluid C-reactive protein contributes to the diagnosis and assessment of severity of parapneumonic effusions.

BACKGROUND AND AIMS: Prompt identification of parapneumonic effusions has immediate therapeutic benefits. We aimed to assess whether C-reactive protein (CRP) and routine biochemistries in pleural fluid are accurate markers of parapneumonic effusions, and to evaluate their properties as indicators for drainage (complicated parapneumonic effusion). METHODS: A retrospective review of 340 non-purulent parapneumonic effusions and 1,659 non-parapneumonic exudates from a single center was performed and the discriminative properties of pleural fluid routine biochemistries and, when available, CRP were evaluated. CRP, along with classical fluid parameters, was also applied to classify patients as having complicated or uncomplicated parapneumonic effusions. ROC analysis established the threshold of CRP for discriminating between groups. RESULTS: Pleural fluids with neutrophilic predominance and CRP levels >45 mg/dL were most likely to be parapneumonic in origin (likelihood ratio=7.7). When attempting to differentiate non-purulent complicated from uncomplicated effusions, a CRP >100mg/L had the same performance characteristics (area under the curve=0.81) as the widely accepted biochemistries pH and glucose. Combinations of CRP with pH or glucose resulted in incrementally discriminating values, pertaining to either sensitivity (75-80%) or specificity (97%), for complicated effusions. CONCLUSION: Pleural fluid CRP may be a useful adjunctive test in pleural effusions, both as a marker of parapneumonics and, particularly, as a differentiator between complicated and uncomplicated effusions.

C-reactive protein for discriminating treatment failure from slow responding pneumonia.

BACKGROUND: The management of patients with community-acquired pneumonia (CAP) who fail to improve constitutes a challenge for clinicians. This study investigated the usefulness of C-reactive protein (CRP) changes in discriminating true treatment failure from slow response to treatment. METHODS: This prospective multicenter observational study investigated the behavior of plasma CRP levels on days 1 and 4 in hospitalized patients with CAP. We identified non-responding patients as those who had not reached clinical stability by day 4. Among them, true treatment failure and slow response situations were defined when initial therapy had to be changed or not after day 4 by attending clinicians, respectively. RESULTS: By day 4, 78 (27.4%) out of 285 patients had not reached clinical stability. Among them, 56 (71.8%) patients were cured without changes in initial therapy (mortality 0.0%), and in 22 (28.2%) patients, the initial empirical therapy needed to be changed (mortality 40.9%). By day 4, CRP levels fell in 52 (92.9%) slow responding and only in 7 (31.8%) late treatment failure patients (p<0.001). A model developed including CRP behavior and respiratory rate at day 4 identified treatment failure patients with an area under the Receiver Operating Characteristic curve of 0.87 (CI 95%, 0.78-0.96). CONCLUSION: Changes in CRP levels are useful to discriminate between true treatment failure and slow response to treatment and can help clinicians in management decisions when CAP patients fail to improve.

Comparing serum and pleural fluid pro-brain natriuretic peptide (NT-proBNP) levels with pleural-to-serum albumin gradient for the identification of cardiac effusions misclassified by Light's criteria.

BACKGROUND AND OBJECTIVES: To assess the diagnostic performance of the amino-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) in pleural fluid and serum for the identification of pleural effusions owing to heart failure, and to determine if these measurements allow better categorization of cardiac effusions that have been misclassified by Light's criteria, than do serum-pleural fluid albumin and protein gradients. METHODS: The study prospectively evaluated NT-proBNP in serum and pleural fluid from patients with effusions owing to heart failure (n = 53) and other causes (n = 40). Measurements were made of levels of NT-proBNP by an electrochemiluminiscence immunoassay, and serum-pleural fluid protein and albumin gradients. RESULTS: Using a cut-off value of 1500 pg/mL for serum and pleural samples, the accuracy of NT-proBNP for identifying pleural effusions from cardiac causes was 89% and 90%, respectively. The area under the receiver operating characteristic curve for the diagnosis of pleural effusions from heart failure was similar for pleural fluid (0.931, 95% CI: 0.871-0.991) and serum (0.919, 95% CI: 0.855-0.984) NT-proBNP. Six (75%) of eight patients with cardiac effusions that were misclassified as exudates by Light's criteria would have been correctly categorized by either NT-proBNP or the albumin gradient, whereas only four (50%) would have been correctly classified by the protein gradient. CONCLUSIONS: NT-proBNP is a useful marker for the diagnosis of pleural effusions from heart failure when measured in either serum or pleural fluid. At a cut-off of 1500 pg/mL, NT-proBNP is at least as accurate as the albumin gradient to correctly identify cardiac effusions misclassified as exudates by standard criteria, but at much higher cost.

Open-label, randomized comparison trial of long-term outcomes of levofloxacin versus standard antibiotic therapy in acute exacerbations of chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: This study investigated whether treating acute exacerbations of COPD (AE-COPD) with levofloxacin modifies the long-term outcome of COPD patients in comparison with standard antibiotic regimens. METHODS: A 6-month open-label clinical trial of AE-COPD patients compared the outcomes of treating with levofloxacin versus standard therapy (clarithromycin, cefuroxime, or amoxicillin/clavulanate) at recommended doses for 10 days. Several variables were analysed: pulse oximetry, FEV1, health-related quality of life, infection-free interval, number of exacerbations, hospitalizations due to an exacerbation and mortality. RESULTS: Of the 116 patients initially enrolled, completion or withdrawal information was available for 50 patients in the levofloxacin arm and 52 in the standard therapy arm. At the end of the study, there were no differences in mortality (17.8% vs. 22.9%, P = 0.53), number of exacerbations (33 vs. 41, P = 0.40), pulse oximetry (median 91.71% vs. 92.46%, P = 0.18), FEV1 (median 51.31% vs. 47.14%, P = 0.30), health-related quality of life (median 8.63 vs. 10.75, P = 0.94) and infection-free interval (median 112 vs. 101 days, P = 0.72), for the levofloxacin and standard therapy, respectively. However, 12 out of 33 (33.6%) exacerbations treated with levofloxacin required in-hospital management versus 27 out of 41 (65.8%) treated with standard therapy (P = 0.02). CONCLUSION: This preliminary study suggests that 10-day treatment of AE-COPD with levofloxacin is associated with a reduction in hospitalizations compared with standard antibiotics despite there being no significant benefit in other outcome variables.