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Higher Urine Nitric Oxide Is Associated with Improved Outcomes in Patients with Acute Lung Injury

Cardiovascular Research Institute and Division of Occupational and Environmental Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, California; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee; and Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Dana McClintock, M.D., Cardiovascular Research Institute, 505 Parnassus Avenue, San Francisco, CA 94143-0130. E-mail: dana.mcclintock{at}ucsf.edu

	ABSTRACT

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Rationale: Nitrogen oxide (NO) species are markers for oxidative stress that may be pathogenic in acute lung injury (ALI).

Objectives: We tested two hypotheses in patients with ALI: (1) higher levels of urine NO would be associated with worse clinical outcomes, and (2) ventilation with lower VT would reduce urine NO as a result of less stretch injury.

Methods: Urine NO levels were measured by chemiluminescence in 566 patients enrolled in the National Heart Lung and Blood Institute Acute Respiratory Distress Syndrome Network trial of 6 ml/kg versus 12 ml/kg VT ventilation. The data were expressed corrected and uncorrected for urine creatinine (Cr).

Results: Higher baseline levels of urine NO to Cr were associated with lower mortality (odds ratio, 0.43 per log(10) increase in the ratio), more ventilator-free days (mean increase, 1.9 d), and more organ-failure–free days (mean increase, 2.3 d) on multivariate analysis (p < 0.05 for all analyses). Similar results were obtained using urine NO alone. NO to Cr levels were higher on Day 3 in the 6 ml/kg than in the 12 ml/kg VT group (p = 0.04).

Conclusions: Contrary to our hypothesis, higher urine NO was associated with improved outcomes in ALI at baseline and after treatment with the 6 ml/kg VT strategy. Higher endogenous NO may reflect less severe lung injury and better preservation of the pulmonary and systemic endothelium or may serve a protective function in patients with ALI.

Key Words: acute respiratory distress syndrome • nitrogen oxide species • pulmonary endothelium • tidal volume • pulmonary edema

AT A GLANCE COMMENTARY TOP ABSTRACT AT A GLANCE COMMENTARY METHODS RESULTS DISCUSSION REFERENCES   Scientific Knowledge on the Subject Higher levels of nitrogen oxide species in lavage and pulmonary edema fluid correlated with worse outcomes in human and animal studies of acute lung injury. What This Study Adds to the Field In a large-scale, multicenter trial of patients with the acute respiratory distress syndrome, higher urine nitric oxide levels correlated with better outcomes. This may reflect better preservation of the endothelium or a protective effect of nitric oxide.

 
Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) define a clinical disorder that causes acute respiratory failure in critically ill patients. There is evidence for lung endothelial damage and alveolar epithelial damage in ALI/ARDS that may be the result of oxidative injury (1–6). Important markers of oxidative injury in the lung include nitrogen oxide species (NOx), particularly nitric oxide (NO), nitrite , and nitrate (7). NO readily reacts with superoxide ion to form a highly reactive intermediate known as peroxynitrite (4, 7, 8). Peroxynitrite rapidly oxidizes and nitrates proteins such as ₁-antitrypsin and surfactant protein A, respectively, thereby inhibiting their function (6). Inhibition of these proteins may contribute to the proinflammatory environment believed to be pathogenic in ALI (3, 9). Peroxynitrite cannot be measured directly because of its short half-life, but its presence can be inferred by measuring metabolites such as and (6).

Prior research in ALI has demonstrated the importance of NOx. Rats that underwent a ventilator-induced lung injury protocol demonstrated elevations in whole-lung lavage NOx levels (10). Similarly, sheep that underwent combined burn and smoke inhalation injury to model ARDS had higher plasma NOx levels than control sheep (11). In a single-center clinical study, higher NOx levels in bronchoalveolar lavage (BAL) samples from patients with ALI were associated with increased mortality on Days 3 and 7 of the study, leading to the conclusion that NOx elevation occurs early and is associated with worse outcomes (12). In another observational clinical study, patients with ALI had higher NOx levels in pulmonary edema samples than control patients with hydrostatic pulmonary edema (13). In summary, some observational studies have shown that higher levels of NOx are associated with more severe illness, but a definitive evaluation in a multicenter study with large numbers of patients has not been done.

Urine samples were chosen for the current study as a novel medium in which to assess NOx levels in patients with ALI. Two prior studies have demonstrated the utility of studying urine biomarkers in ALI. Mathru and colleagues (14) demonstrated that higher urine H₂O₂ levels in patients with ALI were associated with worse clinical outcomes, perhaps reflecting greater oxidative injury in these patients. Parikh and colleagues (15) recently showed that higher urine IL-18 levels predicted which patients with ALI would develop acute kidney injury.

The current study investigated urine NO levels in a subgroup of 566 of the 861 patients included in the NHLBI ARDS Network study of lower VT ventilation (16). We tested two hypotheses. First, we hypothesized that baseline urine NO levels would be elevated in patients with more severe clinical indices and worse clinical outcomes. Second, we hypothesized that urine NO levels would be lower in patients who received lower VT ventilation because this intervention reduced mortality in the lower VT ventilation study. Some of the results from this study have been previously reported in the form of abstracts (17, 18).

	METHODS

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Subjects
The ARDS network trial of lower VT ventilation (16) included 861 patients, but only 590 had urine samples available for analysis. Most of the excluded patients (235 of 271) were in a lisofylline versus placebo arm of the trial, and these patients did not have urine collected per protocol (19). Fourteen of the 590 patient samples were grossly contaminated on visual inspection or did not have enough urine available for analysis. Therefore, 576 patients underwent assay of urine NO and urine creatinine (Cr) levels. For this study, Day 0 and Day 3 urine samples were analyzed. Clinical data were obtained from the ARDS Network Clinical Coordinating Center. Risk factors predisposing to ALI (sepsis, pneumonia, aspiration, trauma, and other) were determined by investigators at study enrollment. Study protocols with informed consent to participate in the ARDS Network trial of lower VT ventilation were approved by the institutional review board at each hospital before enrolling patients into the clinical trial. Permission for collection and analysis of biological samples was granted as part of the original Institutional Review Board approval of this study for all participating medical centers.

NO and Cr Measurements
Urine samples were obtained from the National Heart Lung and Blood Institute repository, thawed, and aliquotted into 0.5-ml vials. The aliquots were relabeled using sequential integer values to maintain blinding of the individuals performing the laboratory analysis. One 0.5-ml aliquot of each urine sample was used to measure NO. The urine aliquots were heated at 90°C in an acidic environment (1 M HCl) in the presence of vanadium (III) chloride to catalyze the reduction of to and then to NO (20–26). NO levels were measured with a chemiluminescent analyzer (Sievers Nitric Oxide Analyzer, model 280i; Sievers, Boulder, CO). These measurements were repeated in duplicate and compared with a standard curve. None of the NO levels were above or below the limit of detection for the NO analyzer. Urine Cr was measured in a second set of urine aliquots from the same patients as previously described (27). Ten patients had urine Cr levels below the lower limit of detection for this competitive assay. These patient samples were excluded from the analysis to avoid the hazards of imputing an arbitrary value to a sample that was not reliable for evaluation. The Cr results obtained were also used to evaluate urine desmosine in these patients; those results have been reported elsewhere (27). The ratio of urine NO to urine Cr (NO/Cr) was used in the statistical analyses to control for urine dilution, a standard method when evaluating urine biomarkers (28–31). Analyses using urine NO without Cr correction were performed for comparison.

Statistics
Statistical analyses were done using SAS software. The data were logarithmically (log₁₀) transformed before statistical analysis because the urine NO (corrected and uncorrected for urine Cr) was not normally distributed. Ventilator-free days (VFD) and organ failure–free days (OFFD) to Day 28 were calculated as previously described (16). Spearman correlation coefficients were used to compare markers of disease severity with urine NO levels. Direct comparisons between groups were made using unpaired t tests. Analysis of covariance was used to analyze the impact of ventilator group on change in urine NO from baseline to Day 3 of the study. Statistical significance was defined as p < 0.05.

	RESULTS

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Demographics
Table 1 shows the baseline demographics and clinical variables for the included and excluded subjects. Baseline demographics were not significantly different between the groups, although there was a trend for more women in the included group. APACHE (Acute Physiology and Chronic Health Evaluation) III and serum Cr levels were significantly higher, and platelet count showed a trend toward being lower in the patients who were excluded from the current study.

In separate analyses, urine NO/Cr levels were compared in patients with and without vasopressor use as a surrogate for the presence or absence of shock, respectively. There was no difference in urine NO/Cr levels when comparing patients who required vasopressors with those who did not (p = 0.48; unpaired t test analysis). Although there was no significant difference between groups, this analysis may have missed a more subtle interaction between urine NO/Cr levels and shock. Therefore, we included vasopressor use in our multivariate models as a surrogate for shock.

Urine NO and Conditions Predisposing to ALI
The conditions predisposing to ALI recorded in the original trial of lower VT ventilation were aspiration, pneumonia, sepsis, trauma, and other (16). The urine NO/Cr level was compared between different conditions predisposing to ALI using analysis of variance. Only patients with sepsis showed a significant difference in urine NO/Cr when compared with each of the alternate predisposing conditions (p = 0.006). Patients with sepsis as a primary risk factor for ALI had significantly higher levels of urine NO/Cr (p = 0.0008), a finding that would be expected based on prior studies (33, 34). Because sepsis was the only predisposing condition with significantly different urine NO/Cr levels, only sepsis was included in the multivariate models.

Multivariate Analysis of NO and Clinical Outcomes
The association between higher levels of urine NO (corrected and uncorrected for urine Cr) and better clinical outcomes was assessed in a multivariate model that included other clinical variables known to have predictive value in ALI or suspected to contribute to urine NO levels. The multivariate analyses included age, sex, ventilator group assignment, estimated glomerular filtration rate (GFR) (35, 36), APACHE III score, vasopressor use, and sepsis as a primary risk factor for ALI. GFR was estimated using the modified MDRD equation (Modified Diet in Renal Disease) because this equation provides a more accurate estimate of GFR for patients with normal renal function and patients with mild, moderate, or end-stage renal disease than older methods, such as the Cockcroft-Gault equation for creatinine clearance (35, 36–38). Even when controlling for multiple potential contributing factors, higher urine NO (corrected and uncorrected for urine creatinine) was independently predictive of lower mortality. Specifically, for each log₁₀ increase in urine NO (corrected and uncorrected for urine Cr), the risk of death decreased by more than half. The OR for death when NO was corrected for Cr was 0.43 per log₁₀ increase in urine NO/Cr; the OR for death without correcting for urine Cr was 0.33 per log₁₀ increase in urine NO (Table 6).

Effect of Lower VT Ventilation on Each Study Day
Lower VT ventilation reduced mortality in the ARDS network trial of lower VT ventilation (16). Therefore, urine NO/Cr levels were assessed by ventilator group assignment. Median values of untransformed urine NO/Cr levels by ventilator group and study day are shown in Table 7. Statistical analysis using unpaired t test of the log-transformed data showed no significant difference in values on Day 0 between the 6 ml/kg VT group and the 12 ml/kg VT group (p = 0.58). However, the NO/Cr levels were higher in the 6 ml/kg than in the 12 ml/kg groups by Day 3 (p = 0.05).

View larger version (24K): [in this window] [in a new window]   Figure 1. Median of the change in urine NO/Cr from Day 0 to Day 3 by ventilator group. The median change from Day 0 to Day 3 was higher in the 6 ml/kg VT group than the 12 ml/kg VT group. This was analyzed statistically using analysis of covariance of the log-transformed urine NO/Cr data, which showed that the mean increase from Day 0 to Day 3 was significantly higher in the 6 ml/kg group than the 12 ml/kg group. Values are given in µmol/mg creatinine. **p = 0.04.

	DISCUSSION

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Why might NO be associated with better outcomes in patients with ALI? It is possible that NO or NOx are protective during ALI. NO scavenges oxygen free radicals that are generated during oxidative stress (4, 33). NO vasodilates the microcirculation, which allows for increased perfusion of tissue beds (33). Prior research has demonstrated an elevation in pulmonary dead space in patients with ALI, in part because some alveoli are being ventilated but not perfused (39). By increasing flow to the microcirculation, particularly to the alveoli that are well ventilated, higher levels of NO would allow for better ventilation to perfusion matching. Regarding the alveolar epithelium, NO has been shown to protect type II alveolar cells from stretch injury (40).

An alternate hypothesis to explain our findings is that endogenous NO has a beneficial effect in organs other than the lung during ALI. Higher NO levels could help prevent further tissue damage by improving oxygen and nutrient delivery to the tissues while helping decrease the amount of toxic oxygen species. NO may also protect endothelial tissue by decreasing platelet and leukocyte adhesion to the endothelium (33). NO would thereby decrease multiorgan failure, which contributes to mortality in ALI. Finally, NO and NOx have antibacterial effects that may be important in infectious conditions that predispose patients to ALI (33). Based on this evidence, NO species may be protective by several different mechanisms in patients with ALI.

A third interpretation of the findings is that higher NO levels are biologic markers of less severe injury. NO is produced by alveolar epithelial cells, alveolar macrophages, and endothelial cells of the lung (41–44). The presence of higher levels of NO could reflect a greater percentage of intact lung endothelium and epithelium as a result of a less severe initial insult. This explanation does not exclude the possibility that endogenous NO production is also protective during ALI. Both explanations may be valid in patients with ALI.

The finding of an association between higher urine NO (corrected and uncorrected for urine Cr levels) and better clinical outcomes was initially unexpected, given the prior experimental and clinical work that had correlated higher levels of NOx with adverse outcomes in ALI (10, 12, 13). Prior work on exhaled breath condensate showed that higher levels of correlated with higher VT (40), in contrast to our results. There are several possible explanations for the differences between the current study and prior studies. Animal models of ALI may differ significantly from human physiology. Also, most of the earlier human studies included small numbers of patients and were done at single research centers, perhaps limiting the statistical power to detect a protective effect. Some of these studies also used intermediate outcomes as a surrogate for important clinical outcomes, which is often not an effective strategy. For instance, better oxygenation was not a surrogate for better clinical outcomes in the ARDS Network trial of lower VT ventilation (16). Finally, a phase III study of a NO synthase inhibitor in patients with sepsis showed that patients who received the study drug had a lower incidence of shock and vasopressor use but had a higher mortality rate, leading to premature termination of the study (45). Therefore, it is important to consider the potential pitfalls in studying intermediate outcomes as a surrogate for important outcomes such as mortality.

There are some limitations to this study. We were not able to include all of the patients from the ARDS Network trial of lower VT ventilation in the current study primarily because urine samples were not collected in the last 235 patients of the 861 patients in the original trial. A few patients from the first 626 enrolled in the original study did not have urine samples collected. It is possible that the some of these patients were not able to provide urine samples because of more severe disease, reflected by higher APACHE III scores, or because of renal failure, reflected by higher serum Cr levels. To account for these differences at baseline, a multivariate analysis was done that included the APACHE III score and GFR to estimate renal function. Urine NO, corrected and uncorrected for urine Cr, remained independently predictive for better outcomes even when taking these factors into account.

The use of urine samples limits our ability to determine the source of the NO measured in this study. Whole-body production of NO cannot be distinguished from that produced in the lung. Also, NOx produced by the body cannot be separated from dietary intake of and (7), although under conditions of low dietary intake and control of other activities such as exercise, 24-hour urine levels of NOx have been established as a qualitative marker of NO production (7). The advantage of examining urine samples is that they provide a reasonable reflection of whole-body NO levels compared with a single-organ measurement, as would be obtained by BAL. Also, even BAL may not sample all of the NOx produced in the lung. Only the NOx present in the bronchioles and alveoli is measured in a lavage sample, meaning that potentially significant levels in the lung interstitium and vasculature may be missed. Finally, there is precedent for evaluating biomarkers of oxidative lung injury in urine samples of patients with ARDS. Mathru and colleagues (14) found that urine H₂O₂ levels were significantly higher in patients with sepsis and ARDS who died than those who survived or had other predisposing conditions for ARDS. They also identified a high correlation between urine H₂O₂ levels and the lung injury score, thus providing evidence that urine markers may reflect the severity of lung injury in patients with ARDS.

We used urine Cr to control for urinary dilution. Although it is possible that this variable influenced the statistical analysis independent of NO, this is an unlikely scenario. First, the use of a ratio between a biomarker and urine Cr is a standard method to adjust for urinary dilution (28–31). Second, in multivariate analyses that included estimated GFR, baseline urine NO/Cr remained highly predictive of better outcomes. Third, urine desmosine, a marker of elastin breakdown, was studied in this group of patients with completely contrary results. Using the same urine Cr measurements as in the current study, higher urine desmosine to Cr was predictive of worse outcomes. Moreover, desmosine levels rose in patients who died compared with those who survived by Day 3 (27). If the evaluation of desmosine and NO simply reflected the inverse of Cr, then the results in both studies should be comparable rather than divergent. Finally, we repeated the important analyses using urine NO not corrected for Cr (urine NO alone) and found even stronger associations with better outcomes than the results using the urine NO/Cr data (Table 3). Alterations in renal function are thus unlikely to explain the current results.

Another potential limitation is the role of urinary tract infection. A large percentage of patients in the ARDS Network trial had sepsis, and urinary tract infection is a leading cause of sepsis. There were no culture data for patients in the current study, so we performed an additional analysis to address this issue. The urine NO levels we measured in this study were converted using the molecular weight of NO and compared with standard urine dipstick measurement of because NO can be oxidized to an equivalent concentration of . Urine dipstick measurement is used clinically to screen for the presence of bacteria in the urine. The highest level of urine NO that was measured in this study (0.02 mg/dl) was below the limits of detection for using the urine dipstick (0.06 mg/dl) (Multistix; Bayer, Pittsburgh, PA). Therefore, we do not believe that bacteria in the urine significantly contributed to the NO levels measured.

This study has a number of strengths. Patient data and samples in this study were prospectively collected in a large multicenter trial with the pre hoc design for subsequent biomarker measurements. The biomarkers were measured in duplicate in a blinded fashion and carefully decoded for evaluation. The results were in sharp contrast to our original hypotheses, but they were internally consistent with one another. Higher urine NO levels were strongly associated with better outcomes, including lower mortality, more VFD, and more OFFD, in several different evaluations. Lower VT ventilation was associated with higher levels of urine NO, which is an important internal validation because lower VT was associated with better survival in the ARDS Network trial. The results in patients with sepsis provided further validation for this study. NO has a well described role in sepsis (33, 34, 46). We anticipated and found higher urine NO/Cr levels in patients with sepsis.

In summary, higher baseline urine NO levels are strongly associated with better clinical outcomes, including increased survival, more VFD, and more OFFD. These associations remained significant even after controlling for potentially confounding factors. Furthermore, use of lower VT for ventilation resulted in higher urine NO levels in addition to a decrease in mortality. Our findings suggest that (1) endogenous NO may be protective during ALI or (2) endogenous NO may serve as a marker of less severe organ injury or both.

	Acknowledgments

 
The authors thank Barry Starcher for his contribution to this study regarding the urine creatinine results.

	FOOTNOTES

 
^* A list of National Heart, Lung, and Blood Institute ARDS Network participants appears at the end of the article.

This study was supported in part by NHLBI HL51856 and HL74005 (M.A.M.), and by HL70521 and HL81332 (L.B.W.).

Originally Published in Press as DOI: 10.1164/rccm.200607-947OC on November 2, 2006

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

National Institutes of Health, National Heart, Lung, and Blood Institute ARDS Network Participants: Cleveland Clinic Foundation—Herbert P. Wiedemann, M.D.*; Alejandro C. Arroliga, M.D.; Charles J. Fisher, Jr., M.D.; John J Komara, Jr., B.A., R.R.T.; Patricia Periz-Trepichio, B.S., R.R.T. Denver Health Medical Center—Polly E. Parsons, M.D. Denver VA Medical Center—Carolyn Welsh, M.D. Duke University Medical Center—William J. Fulkerson, Jr., M.D.*; Neil MacIntyre, M.D.; Lee Mallatratt, R.N.; Mark Sebastian, M.D.; John Davies, R.R.T.; Elizabeth Van Dyne, R.N.; Joseph Govert, M.D. Johns Hopkins Bayview Medical Center—Jonathan Sevransky, M.D.; Stacey Murray, R.R.T. Johns Hopkins Hospital—Roy G. Brower, M.D.; David Thompson, M.S., R.N.; Henry E. Fessler, M.D. LDS Hospital—Alan H. Morris, M.D.*; Terry Clemmer, M.D.; Robin Davis, R.R.T.; James Orme, Jr., M.D.; Lindell Weaver, M.D.; Colin Grissom, M.D.; Frank Thomas, M.D.; Martin Gleich, M.D. (posthumous). McKay-Dee Hospital—Charles Lawton, M.D.; Janice D'Hulst, R.R.T. MetroHealth Medical Center of Cleveland—Joel R. Peerless, M.D.; Carolyn Smith, R.N. San Francisco General Hospital Medical Center—Richard Kallet, M.S., R.R.T.; John M. Luce, M.D. Thomas Jefferson University Hospital—Jonathan Gottlieb, M.D.; Pauline Park, M.D.; Aimee Girod, R.N., B.S.N.; Lisa Yannarell, R.N., B.S.N. University of California, San Francisco—Michael A. Matthay, M.D.*; Mark D. Eisner, M.D., M.P.H.; Brian Daniel, R.C.P., R.R.T. University of Colorado Health Sciences Center—Edward Abraham, M.D.*; Fran Piedalue, R.R.T.; Rebecca Jagusch, R.N.; Paul Miller, M.D.; Robert McIntyre, M.D.; Kelley E. Greene, M.D. University of Maryland—Henry J. Silverman, M.D.*; Carl Shanholtz, M.D.; Wanda Corral, B.S.N., R.N. University of Michigan—Galen B. Toews, M.D.*; Deborah Arnoldi, M.H.S.A.; Robert H. Bartlett, M.D.; Ron Dechert, R.R.T.; Charles Watts, M.D. University of Pennsylvania—Paul N. Lanken, M.D.*; Harry Anderson, III, M.D.; Barbara Finkel, M.S.N., R.N.; C. William Hanson, III, M.D. University of Utah Hospital—Richard Barton, M.D.; Mary Mone, R.N. University of Washington/Harborview Medical Center—Leonard D. Hudson, M.D.*; Greg Carter, R.R.T.; Claudette Lee Cooper, R.N.; Annemieke Hiemstra, R.N.; Ronald V. Maier, M.D.; Kenneth P. Steinberg, M.D. Utah Valley Regional Medical Center—Tracy Hill, M.D.; Phil Thaut, R.R.T. Vanderbilt University—Arthur P. Wheeler, M.D.*; Gordon Bernard, M.D.*; Brian Christman, M.D.; Susan Bozeman, R.N.; Linda Collins; Teresa Swope, R.N.; Lorraine B. Ware, M.D.

Clinical Coordinating Center: Massachusetts General Hospital, Harvard Medical School—David A. Schoenfeld, Ph.D.*; B. Taylor Thompson, M.D.; Marek Ancukiewicz, Ph.D.; Douglas Hayden, M.A.; Francine Molay, M.S.W.; Nancy Ringwood, B.S.N., R.N.; Gail Wenzlow, M.S.W., M.P.H.; Ali S. Kazeroonin, B.S.

NHLBI Staff: Dorothy B. Gail, Ph.D.; Andrea Harabin, Ph.D.*; Pamela Lew; Myron Waclawiw, Ph.D.

*Steering Committee: Gordon R. Bernard, M.D., Chair; Principal Investigators from each center are indicated by an asterisk.

Data and Safety Monitoring Board: Roger G. Spragg, M.D., Chair; James Boyett, Ph.D.; Jason Kelley, M.D.; Kenneth Leeper, M.D.; Marion Gray Secundy, Ph.D.; Arthur Slutsky, M.D.

Protocol Review Committee: Joe G. N. Garcia, M.D., Chair; Scott S. Emerson, M.D., Ph.D.; Susan K. Pingleton, M.D.; Michael D. Shasby, M.D.; William J. Sibbald, M.D.

Received in original form July 13, 2006; accepted in final form November 1, 2006

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