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Gastrointestinal Imaging |
1 From Johns Hopkins Univ School of Med, 600 N Wolfe St, Baltimore, MD 21287 (D.A.B.); Univ of Alabama at Birmingham (T.M.W.); Good Samaritan Hosp, San Jose, Calif (D.R.); Univ of Virginia Health Sciences System, Charlottesville (E.E.d.L.); Scatliff MRI, UNC Hosp, Chapel Hill (R.S.); Emory Univ Hosp, Atlanta, Ga (R.D.R., J.C.); Thomas Jefferson Univ Hosp, Philadelphia, Pa (E.O.); Univ of Michigan, Ann Arbor (R.C.); Massachusetts Gen Hosp, Boston (S.S.); Med Coll of Pennsylvania-Tenet, Philadelphia (G.A.H.); Cooper Hosp/Univ Med Ctr, Camden, NJ (J.F.M.); Mallinckrodt Inst of Radiology, Washington Univ School of Med, St Louis, Mo (J.J.B.); Temple Univ Hosp, Philadelphia, Pa (B.M.); George Washington Univ Med Ctr, Washington, DC (M.C.J.); and Advanced Magnetics, Cambridge, Mass (P.J.). Received Dec 18, 2001; revision requested Feb 26, 2002; final revision received Oct 29; accepted Nov 27. Supported by Advanced Magnetics. Address correspondence to D.A.B. (e-mail: dbluemke@jhmi.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Two hundred thirty-three patients at 16 institutions were randomized to receive either an undiluted direct injection of 0.56 mg of iron per kilogram of body weight of ferumoxides administered during 2 minutes (2 mL/min) or a diluted slow infusion administered during 30 minutes. Safety was assessed with monitoring for adverse events and laboratory tests. For sensitivity, specificity, and accuracy analysis, two independent blinded observers identified and classified lesions as benign or malignant with precontrast images and with pre- and postcontrast images combined.
RESULTS: There was no statistically significant difference in adverse events in the group with direct injection compared with those in the group with infusion (21 [18%] of 114 patients vs 19 [17%] of 112 patients, respectively). No serious adverse events were observed. The most common adverse events in the group with direct injection versus the group with infusion were headache (five [4%] of 114 vs three [3%] of 112, respectively) and back pain (five [4%] of 114 vs three [3%] of 112, respectively). Overall, in 68 (62%) of 109 patients with direct injection and 71 (66%) of 108 patients with infusion, additional magnetic resonance (MR) imaging information was obtained after ferumoxides administration (P = .67). Sensitivity, specificity, and accuracy for the diagnosis of malignancy were significantly improved by adding images obtained after ferumoxides administration to the images obtained before contrast agent administration (P < .05 for all comparisons).
CONCLUSION: Direct injection of ferumoxides has safety and effectiveness profiles similar to those of slow infusion of the agent. Further findings indicate that the addition of ferumoxides increases the sensitivity and specificity of hepatic MR evaluation when compared with unenhanced MR imaging.
© RSNA, 2003
Index terms: Contrast media • Iron • Liver neoplasms, diagnosis, 76.31, 76.32 • Liver neoplasms, MR, 76.121411, 76.12143
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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In the United States, ferumoxides is approved for administration with dilution of the dose (0.56 mg of iron per kilogram of body weight) in 100 mL of 5% dextrose. The solution is then slowly infused intravenously during 30 minutes. The purpose of this study was to compare the safety and effectiveness of an undiluted direct injection of ferumoxides at 2 mL/sec with those of a diluted slow infusion of ferumoxides during 30 minutes in patients with known liver lesions or in those suspected of having them.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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Patient Population
Patients who were included in the study were 18 years of age or older, had confirmed focal liver lesions or were suspected of having them, and had no contraindications to MR imaging (ie, aneurysm clip, pacemaker, severe claustrophobia). Both inpatients and outpatients were eligible for inclusion. Patients were excluded from the study if they were women who were pregnant or who were lactating, if they had a known allergic or hypersensitivity reaction to iron preparations, if they had known iron overload or were suspected of having it, or if they had medical conditions deemed by the investigators at each site to preclude participation. These medical conditions included known multiple drug sensitivities, history of reactions to other radiologic contrast media, or known multiple allergies or immunodeficiencies that predispose a patient to specific or nonspecific mediator release. Patients who had received ferumoxides within 3 months of enrollment were also excluded. One patient was enrolled who received ferumoxides on two occasions 3
months apart. The investigational review board at each institution approved the protocol, and all patients provided written informed consent.
Ferumoxides Administration
Patients were randomly assigned to receive 0.56 mg of iron per kilogram of ferumoxides (Feridex I.V.; Advanced Magnetics, Cambridge, Mass) either as a direct undiluted injection administered at 2 mL/min (supplied as 11.2 mg of iron per milliliter) or as an infusion diluted in 100 mL of 5% dextrose solution administered at 2–4 mL/min. The direct injection duration was approximately 2 minutes. The infusion duration was approximately 30 minutes. The direct injection was performed while the patient was in the MR imaging suite. For the slow infusion, the patient was removed from the MR imaging suite during the 30-minute infusion. The time from the completion of ferumoxides injection to the start of MR imaging was recorded. All doses were administered through a 5-µm filter. If the dose was incomplete, the total volume of the injected dose was recorded.
Monitoring of Patients
Physical examination of the patient was performed within 24 hours before ferumoxides administration and within 24 hours after its administration. Vital signs were assessed immediately before and after administration of the dose; at 10, 20, 30, and 45 minutes after administration of the dose; and at 1, 3, and 24 hours after administration of the dose. Complete blood cell count and serum assay were performed within 24 hours before and at 24 hours after ferumoxides administration. Monitoring of the injection site for signs of irritation or inflammation was performed immediately before and after injection of the contrast agent.
Adverse Events
Adverse events were defined as illnesses, signs, or symptoms that appeared or worsened after the implementation of the study procedures. Adverse events were recorded by the principal investigator or designated nurse coordinator at each site. Adverse events were recorded beginning at 24 hours prior to ferumoxides administration and ending at 24 hours after administration of the dose. Adverse events were classified as either nonserious or serious, and the intensity of the event was rated as mild, moderate, or severe. Serious events were those that were life threatening or permanently disabling, that caused death, or that required hospitalization or extended inpatient hospitalization for 1 or more days.
Laboratory Testing
In addition to a complete blood cell count, serum assay was performed and included measurement of glucose, creatinine, uric acid, urea nitrogen, calcium, phosphorus, total protein, albumin, total bilirubin, alkaline phosphatase, sodium, potassium, chloride, and lactate dehydrogenase levels. Evaluation of clotting function included prothrombin time and activated partial thromboplastin time. Hepatic function was assessed with 
-glutamyl transpeptidase, aspartate aminotransferase, and alanine aminotransferase levels. Iron metabolism was assessed with transferrin levels, serum iron levels, total iron binding capacity, and serum ferritin levels. Total complement was also measured. Clinical laboratory analyses were performed at a central laboratory (Covance Central Laboratories, Indianapolis, Ind).
MR Imaging
Patients were scheduled to undergo MR imaging during two sessions. MR imaging before ferumoxides administration was performed within 24 hours before dose administration. MR imaging after ferumoxides administration was performed after completion of administration of the iron dose in as many as 3 hours after administration of the dose. Commercially approved 1.5-T MR devices and pulse sequences were used in the study. MR imaging performed before and after ferumoxides administration included transverse T2-weighted spin-echo and/or fast spin-echo sequences and transverse T1-weighted spin-echo and/or fast T1-weighted spoiled gradient-echo sequences, according to each institution’s standard imaging protocol. For T2-weighted fast spin-echo sequences, repetition time msec/echo time msec was 2,000–6,000/75–180. For fast T1-weighted spoiled gradient-echo sequences, the parameters were 9–220/2–7. For T1-weighted spin-echo sequences, the parameters were 300–700/9–17. The most common section thickness was 8 mm. Imaging sequences performed before and after administration of the dose in each patient were the same.
MR Image Analysis
Patients who received at least 80% of their dose of ferumoxides and who underwent imaging with at least one technically adequate T2-weighted sequence were included in the imaging evaluation.
Principal investigators at each center conducted unblinded image review. The objective of this review was to determine if the method of ferumoxides administration resulted in additional lesion detection or provided additional information compared with findings on precontrast images. Investigators recorded the number of lesions and the size and the diagnosis of each lesion; they also compared pre- and postcontrast images to determine whether any additional information was provided with ferumoxides-enhanced images.
Two independent blinded readers who had not participated in MR imaging conducted blinded image review. These two reviewers were radiologists with 9 and 10 years of experience in reading abdominal MR images. Reviewers were from sites at which patient studies had not been conducted. Blinded readers did not have information concerning the patient’s diagnosis. The blinded readers evaluated the images obtained before and after administration of the dose without access to clinical information about the method of ferumoxides administration, the laboratory values, the medical history, or the clinical findings. Image review was conducted with images that were obtained before and after administration of the dose and that were randomized across all patients so that no patient’s images that were obtained before and after administration of ferumoxides were evaluated sequentially. At a separate reading session, the blinded readers performed a side-by-side evaluation of the images obtained before and after ferumoxides administration.
For each patient, the blinded readers recorded the number of focal lesions (up to a maximum of 10 lesions), as well as their confidence for lesion detection. Their confidence was rated with the following scale: grade 1, very low confidence; grade 2, low confidence; grade 3, intermediate confidence; grade 4, high confidence; grade 5, very high confidence. The segmental location of liver lesions was also recorded. For paired readings performed before and after administration of ferumoxides, each reader also indicated if more lesions were seen before or after the administration of the dose and in which segment these lesions were identified. The type of lesion present on MR images obtained before and after administration of the dose was assessed by each reader as benign, malignant, or indeterminate, and the confidence of the diagnosis was recorded according to the scale just mentioned. Cysts were defined as lesions with sharp margins that had very low signal intensity on T1-weighted MR images and very high signal intensity on T2-weighted MR images obtained both before and after administration of ferumoxides. Hemangiomas were defined as lesions with sharp margins with very low signal intensity on T1-weighted MR images and with very high signal intensity on unenhanced T2-weighted MR images that decreased after ferumoxides administration. Malignant liver tumors were defined as lesions with low signal intensity on T1-weighted MR images obtained before administration of ferumoxides and intermediate to high signal intensity on T2-weighted MR images that increased relative to liver signal after ferumoxides administration. Lesions that are suspected of being hepatocellular lesions (eg, focal nodular hyperplasia, adenoma, hepatocellular carcinoma) in some cases are known to undergo signal change after ferumoxides administration (7–9). In these cases, the readers additionally used well-established features of each tumor (eg, central vascular scar for focal nodular hyperplasia, tumor capsule for hepatocellular carcinoma) to classify tumors considered as benign or malignant.
Standard of Reference
The standard of reference for the final diagnosis was confirmed by using all available information, including findings of one or more of the following: surgery or biopsy, contrast material–enhanced computed tomography (CT), MR imaging performed prior to MR imaging performed as part of this study, ultrasonography for detection of cysts, autopsy, or radionuclide imaging for hemangiomas. The investigator at each site determined the final diagnosis on the basis of these standards of reference.
Statistical Analysis
For sensitivity and specificity analysis, the blinded readers had to detect and correctly classify a lesion as benign or malignant to categorize a lesion as a correct interpretation. True-positive lesions were lesions that were determined to be malignant at final diagnosis and that were correctly characterized at MR imaging. True-negative lesions were lesions that were determined to be benign at final diagnosis and that were correctly characterized as benign at MR imaging or that were not detected. Malignant lesions that were not detected were false-negative lesions. False-positive lesions were those lesions that the readers classified as malignant but were actually benign at final diagnosis.
The primary outcome variable was the overall incidence of adverse events. The adverse event rate was compared between the group that received the direct injection and the group that received the infusion. The site investigators included reports of adverse events whether or not they were likely related to administration of ferumoxides. Adverse events were considered to be related to ferumoxides administration if the site investigator indicated that the relationship to drug administration was at least possibly or remotely related to the drug. The two groups were considered equivalent if the 95% CI of the difference in adverse event rate between the two groups was no greater than 10%. To determine the 95% CI of the difference in adverse events between the groups as no greater than 10% with at least 80% power, a minimum of 111 patients in each group was required.
For clinical laboratory evaluations and vital signs, differences from baseline values were evaluated by using the Wilcoxon matched-pair signed rank test. Differences between the administration methods were analyzed by using the Wilcoxon rank sum test. Sensitivity and specificity were calculated for the blinded MR image readers, and statistical significance was tested with two-tailed levels of significance at a P value of .05 by using the McNemar test. All computations were performed by using software (SAS for Windows, version 6.11; SAS Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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Three patients received less than 80% of the ferumoxides dose and were excluded from the evaluation of the MR images. One of these three patients had an adverse event. In another patient, the intravenous line infiltrated. In still another patient, MR imaging was discontinued when the patient became uncooperative.
Monitoring of Vital Signs
For vital signs, only changes in heart rate and respiration rate showed differences between baseline values and values obtained after ferumoxides administration (Table 1). Statistically significant decreases in heart rate were seen in the group that received the infusion immediately after dose administration; at 10, 20, and 30 minutes after dose administration; and at 1 hour after dose administration. The magnitude of these differences was small (0.5–2.0 beats per minute) and not of clinical significance. There was a small but significant difference in heart rate between the group that received the direct injection and the group that received the infusion immediately after ferumoxides administration (73 beats per minute versus 71 beats per minute, respectively, P < .05).
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Adverse Events
There were no serious adverse events. Overall, 21 (18%) patients in the group that received the direct injection reported 50 adverse events, and 19 (17%) patients in the group that received the infusion reported 26 adverse events (Table 2). The overall difference in the adverse event rate between the groups was not statistically significant. Adverse events were also subclassified as shown in Table 2. With consideration of adverse events for the body as a whole (as defined in Table 2), there were statistically more adverse events for the group that received direct injection (P < .05); however, there was no significant difference with regard to individual adverse events within this category. In 114 patients in the group that received direct injection, the most commonly occurring events were headache (five [4%]), back pain (five [4%]), vasodilation (five [4%]), and nausea (six [5%]). In 112 patients in the group that received the infusion, the most commonly occurring events were headache (three [3%]), back pain (three [3%]), and general pain (three [3%]). The largest difference between the groups was in regard to vasodilation, with five patients in the group that received the direct injection and one patient in the group that received the infusion. Adverse events in the majority (25 of 40) of patients occurred in the first 2 hours after direct injection (14 of 21 patients) or infusion (11 of 19 patients).
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No significant difference was present in the adverse event rate between the two groups for patients with a history of allergy (excluding allergies to contrast agents), for patients with a history of allergy to contrast agents, or for patients with a history of cirrhosis.
In one patient, direct injection of ferumoxides was discontinued because of adverse events. After 2 minutes of the injection, the patient experienced vasodilation. Ten minutes later, the patient experienced severe back pain, which resolved within 20 minutes without further treatment.
Clinical Laboratory Evaluation
Overall, laboratory evaluation revealed no statistically significant effect of ferumoxides between treatment groups with respect to blood chemistry, hepatic function, electrolyte, and immunologic (total complement) measurements. For clotting function parameters, there was no statistically significant change between the groups. No consistent effect of the method of ferumoxides administration was present for hematologic parameters.
As expected for a drug containing bioavailable iron, changes in serum ferritin and serum iron were statistically significant 24 hours after ferumoxides administration. However, there was no significant difference in these values between the group that received the direct injection and the group that received the infusion.
Monitoring of Injection Site
Two patients had mild skin discoloration at the injection site because of ferumoxides infusion. Overall, five patients in the group that received the direct injection and three patients in the group that received the infusion had abnormalities at the injection site. These abnormalities were generally related to bruising and needle insertion.
MR Imaging Effectiveness: Unblinded Readers
Of 226 patients who received ferumoxides infusion, three were excluded from imaging analysis since they received less than 80% of their intended dose. Four additional patients were excluded because no T2-weighted MR images were obtained before administration of the dose, and in two additional patients, technically inadequate T2-weighted MR images were obtained. Thus, in 217 patients (109 patients who received the direct injection, 108 patients who received the infusion), evaluable MR images were obtained. The mean time to the start of MR imaging after completion of ferumoxides administration was 13.6 minutes ± 18.5 (SD) for the group that received the direct injection and 28.1 minutes ± 26.6 for the group that received the infusion (P < .05).
Unblinded investigators at each site evaluated images for the presence of additional information after ferumoxides administration. Overall, in 68 (62%) of 109 patients who received the direct injection and in 71 (66%) of 108 patients who received the infusion, additional information was present on MR images after ferumoxides administration (P = .67, Fisher exact test). Thus, in 139 (64%) of 217 patients overall, additional information was present on ferumoxides-enhanced MR images. Investigators reported additional information in 139 patients for the following features: lesion characterization (63 [45%]), confidence in MR imaging findings (62 [45%]), definition of lesion borders (48 [35%]), detection of additional lesions (40 [29%]), confidence in exclusion of additional lesions (38 [27%]), and differentiation of lesions from blood vessels (18 [13%]). There was no significant difference in the type of additional information obtained for the patients who received the direct injection versus the patients who received the infusion.
MR Imaging Effectiveness: Blinded Readers
Because the method of ferumoxides administration resulted in no difference in imaging effectiveness of ferumoxides, images from both the group that received the direct injection and the group that received the infusion were combined for the blinded-reader analysis. The two blinded readers reported additional information after ferumoxides administration in 130 (60%) and 138 (64%) of 217 patients. The most common reasons stated were improved lesion visualization and improved confidence in MR imaging findings (Table 3).
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Blinded reader 1 observed more lesions on the images obtained after ferumoxides administration compared with the number of lesions on images obtained before the administration of the dose in 39 (18%) of 217 patients. The additional lesions were seen after administration of ferumoxides in a different segment of the liver in 17 of those patients. Blinded reader 2 observed more lesions on the images obtained after ferumoxides administration compared with the number of lesions observed on the images obtained before the dose was administered in 19 (9%) of 217 patients. The additional lesions were seen after ferumoxides was administered in a different segment of the liver in 11 of those patients.
For readers 1 and 2, 583 and 599 lesions were identified, respectively. In 40 patients, the diagnosis in 112 of 583 and 113 of 599 of these lesions was confirmed at either surgery or biopsy. For both readers, sensitivity and specificity for confirmed lesions were significantly higher with the paired evaluation (MR images obtained before and after ferumoxides administration) compared with the MR images obtained before ferumoxides administration (P < .05 for both readers, Table 4). Accuracy was also significantly higher for both readers on the basis of the paired evaluation (P < .001 for both readers, Table 4). Average sensitivity improved from 56% to 71%; accuracy, from 50% to 68%; and specificity, from 31% to 57%.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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In this study, we found that the overall adverse event rate was not statistically different in the group that received the injection compared with that in the group that received the slow infusion. The largest difference in events in the two patient groups was with vasodilation (ie, five patients in the group that received the direct injection and one patient in the group that received the infusion). Ros et al (5) reported an overall incidence of adverse effects of 15% in the administration of 213 doses of ferumoxides compared with an overall incidence of adverse effects of 18% in the administration of 220 doses in this study. Low back pain was associated with ferumoxides administration in 4% of patients in the U.S. phase III clinical trial (5). In this study, back pain showed a similar overall frequency of eight (4%) of 220 patients. The cause of back pain is unknown but has been postulated to be related to the particulate nature of ferumoxides.
There were more adverse events rated as severe in the group that received the direct injection (ie, nine events in four patients) compared with those in the group that received the infusion (ie, one event). In one patient who received a direct injection, administration of ferumoxides was discontinued because of adverse events (ie, vasodilation followed by severe back pain). No injections were discontinued in the group that received the infusion. Discontinuation of infusion has been reported in 2.5% of patients as a whole and in 12.5% of patients with cirrhosis (5). Importantly, no significant difference was found between groups for any blood chemistry, hepatic function, electrolyte, or hematologic parameter.
According to unblinded site investigators, no differences were found between the groups that received the direct injection and the infusion for additional liver lesion detection after ferumoxides administration. This indicates that ferumoxides uptake by the reticuloendothelial system is rapid and not affected by the duration of the injection. With a combination of all patients’ results, blinded readers evaluated the overall effectiveness of ferumoxides. The average sensitivity of the blinded readers was 71% (in 112 patients) for pathologically confirmed lesions for enhanced images versus 56% for unenhanced images. We compared the findings in other series in which pathologic confirmation was used. The sensitivity calculated for results achieved after versus before ferumoxides administration, respectively, was as follows: in the study of Bluemke et al (2), 68% versus 62% in 24 patients; in that of Oudkerk et al (15), 83% versus 71% in 22 patients; in that of Seneterre et al (13), 95% versus 91% in 17 patients; and in that of Raman et al (16), 93% versus 74% in 24 patients. The wide variation in reported sensitivity and specificity between studies is likely caused by differences in study methods and in statistical analysis. In the current study, blinded reviewers evaluated all MR images from the imaging examination. Also, a lesion was defined as a true-positive lesion only if the lesion was correctly identified as present and correctly characterized as benign versus malignant. In this sense, the methods are most comparable to those used in the study of Bluemke et al (2). In that study, the sensitivity of dual-phase CT, unenhanced MR imaging, and ferumoxides-enhanced MR imaging was 60.4%, 62.0%, and 68.2%, respectively.
The clinical role of ferumoxides is related to both characterization and identification of liver lesions. Liver tumors that contain reticuloendothelial cells (eg, focal nodular hyperplasia, hepatic adenoma, focal fat) will show decreased signal intensity on T2-weighted MR images after administration of ferumoxides. In certain cases, this can result in confident characterization of the type of tissue present. However, MR imaging signal change by itself is unlikely to be the basis for the primary liver lesion diagnosis. Since well-differentiated hepatocellular carcinoma may also contain reticuloendothelial cells, additional image features and patient history must be considered in addition to MR imaging findings.
One role of ferumoxides may be use of this contrast agent in patients prior to scheduled hepatic surgery (2). Contrast-enhanced CT routinely is used to screen patients prior to surgery. When the CT scan is inadequate or when additional presurgical information is needed, MR imaging may be appropriate. Gadolinium-based MR imaging contrast agents and iodine-based CT contrast agents are both extracellular contrast agents that rely on bolus infusion and then arterial and portal phase imaging for identification of liver lesions. Since the mechanism of action is different, ferumoxides-enhanced MR imaging provides an alternate contrast mechanism for tumor detection after iodine-enhanced CT scanning. Cholangiocarcinoma in particular is difficult to detect on CT or MR images but has been reported to be well evaluated on ferumoxides-enhanced MR images (17).
There were several limitations in this study. First, adverse events were recorded at multiple sites by several investigators, and ratings of adverse events as mild, moderate, or severe were necessarily subjective. In addition, neither intersite nor interinvestigator variations were controlled or incorporated into the analysis. Second, sample size was a factor; 114 patients were included in the group that received the direct injection and 112 patients were included in the group that received the infusion. However, in keeping with current drug labeling, this study was specifically powered to detect a difference of 10% in adverse events with 80% at the assumed rate of 10%. Although 1.5-T MR imaging units were used at all sites, the T1- and T2-weighted pulse sequences were performed according to each institution’s standard. However, sequences performed before and after administration of the dose were identical so that lesion detection before and after ferumoxides administration could be compared. In addition, the blinded readers were able to identify which images were obtained after ferumoxides administration because of decreased liver and spleen signal. This may have increased their confidence in diagnosis and led to bias.
In conclusion, in this 16-site multicenter trial, overall adverse event rates and serologic measures of safety and effectiveness for liver lesion detection were not statistically different for patients who received direct injection of undiluted ferumoxides compared with those for patients who received diluted ferumoxides infused intravenously during 30 minutes. Direct injection of the contrast agent used in this study without the need to dilute and infuse the dose during 30 minutes may provide greater ease in drug preparation and administration and require less time in the MR imaging suite.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Author contributions: Guarantor of integrity of entire study, D.A.B. Study concepts, M.C.J.; study design, M.C.J., P.J.; literature research, D.A.B.; clinical studies, D.A.B., T.M.W., E.E.d.L., E.O., S.S., G.A.H., J.F.M., J.J.B., B.M., M.C.J.; data acquisition, D.A.B., T.M.W., D.R., R.D.R., J.C., E.O., R.C., S.S., G.A.H., J.F.M., J.J.B., B.M.; data analysis/interpretation, D.A.B., D.R., R.D.R., R.C., M.C.J., P.J.; statistical analysis, P.J.; manuscript preparation, D.A.B., D.R., R.D.R.; manuscript definition of intellectual content, D.A.B.; manuscript editing, D.A.B., T.M.W., E.E.d.L., R.S., R.D.R, R.C., J.F.M., B.M., M.C.J.; manuscript revision/review, D.A.B., T.M.W., D.R., E.E.d.L., R.S., R.D.R., J.C., E.O., R.C., S.S., G.A.H., J.F.M., J.J.B., M.C.J., P.J.; manuscript final version approval, D.A.B., T.M.W., R.D.R., J.C., R.C., G.A.H., M.C.J.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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