Reduced Cathartic Bowel Preparation for CT Colonography: Prospective Comparison of 2-L Polyethylene Glycol and Magnesium Citrate

There were no significant differences in amount of residual solid stool or fluid or in patient acceptance when reduced-volume polyethylene glycol was compared with magnesium citrate, with both demonstrating effective bowel cleansing for CT colonography.

Abstract

Purpose:

To prospectively compare adequacy of colonic cleansing, adequacy of solid stool and fluid tagging, and patient acceptance by using reduced-volume, 2-L polyethylene glycol (PEG) versus magnesium citrate bowel preparations for CT colonography.

Materials and Methods:

This study was approved by the institutional Committee on Human Research and was compliant with HIPAA; all patients provided written consent. In this randomized, investigator-blinded study, 50 patients underwent oral preparation with either a 2-L PEG or a magnesium citrate solution, tagging with oral contrast agents, and subsequent CT colonography and segmentally unblinded colonoscopy. The residual stool (score 0 [best] to 3 [worst]) and fluid (score 0 [best] to 4 [worst]) burden and tagging adequacy were qualitatively assessed. Residual fluid attenuation was recorded as a quantitative measure of tagging adequacy. Patients completed a tolerance questionnaire within 2 weeks of scanning. Preparations were compared for residual stool and fluid by using generalized estimating equations; the Mann-Whitney test was used to compare the qualitative tagging score, mean residual fluid attenuation, and adverse effects assessed on the patient experience questionnaire.

Results:

The mean residual stool (0.90 of three) and fluid burden (1.05 of four) scores for PEG were similar to those for magnesium citrate (0.96 [P = .58] and 0.98 [P = .48], respectively). However, the mean fecal and fluid tagging scores were significantly better for PEG (0.48 and 0.28, respectively) than for magnesium citrate (1.52 [P < .01] and 1.28 [P < .01], respectively). Mean residual fluid attenuation was higher for PEG (765 HU) than for magnesium citrate (443 HU, P = .01), and mean interpretation time was shorter for PEG (14.8 minutes) than for magnesium citrate (18.0 minutes, P = .04). Tolerance ratings were not significantly different between preparations.

Conclusion:

Reduced-volume PEG and magnesium citrate bowel preparations demonstrated adequate cleansing effectiveness for CT colonography, with better tagging and shorter interpretation time observed in the PEG group. Adequate polyp detection was maintained but requires further validation because of the small number of clinically important polyps.

© RSNA, 2011

Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11110217/-/DC1

Introduction

Colorectal cancer is the third most common cancer and the third leading cause of mortality due to cancer in the United States (1). Screening and appropriate subsequent intervention has been shown to reduce colorectal cancer mortality (2–5), but less than one-half of people older than 50 years undergo the recommended screening (6,7). A primary barrier to achieving optimal screening is patients’ aversion to bowel cleansing, which is often reported as the most negatively viewed aspect of the screening process (8,9). Computed tomography (CT) colonography has been shown to be an effective tool for colorectal cancer screening (10–12), yet this examination still requires bowel cleansing similar to that used prior to optical colonoscopy. Tagging of residual colonic material with barium and iodine has the potential to reduce the rigor of bowel catharsis that patients must achieve for an adequate examination, as residual high-density colonic material can be distinguished from colonic wall and soft-tissue lesions on CT colonographic images (13). Reducing bowel preparation volume may increase patient compliance with CT colonographic screening (14,15).

Feasibility studies involving limited bowel preparation have shown promising results (16–25). Magnesium citrate, a low-volume osmotic laxative, is an effective small-volume bowel preparation, but its use may lead to adherent residual solid stool and thereby prolong interpretation times (26). Magnesium citrate preparations also carry an increased risk for hemodynamic and electrolyte disturbances (27–30), compared with osmotically balanced lavage solutions such as polyethylene glycol (PEG). However, the use of PEG preparations often results in excess residual fluid within the colon.

Researchers in previous studies have compared reduced-volume PEG with standard 4-L PEG preparations (31–33), reduced-volume PEG with small-volume sodium phosphate preparations (26,34,35), magnesium citrate combined with sodium phosphate with magnesium citrate alone (36) or 4-L PEG (37), and magnesium citrate with sodium phosphate (25,38,39). To our knowledge, the reduced-volume PEG preparation has not been directly compared with the magnesium citrate preparation.

The purpose of this study was to prospectively compare the adequacy of colonic cleansing, the adequacy of solid stool and fluid tagging, and patient acceptance with the use of the reduced-volume, 2-L PEG preparation versus those with the use of the magnesium citrate bowel preparation for CT colonography.

Materials and Methods

Patients

This was a single-center prospective, randomized, investigator-blinded study, in which we compared two forms of bowel preparation prior to CT colonography, which was approved by our institutional Committee on Human Research. All patients provided written informed consent, and this study was compliant with the Health Insurance Portability and Accountability Act. No industry support was provided for this study.

All patients referred for outpatient colonoscopy were considered for participation. Exclusion criteria were as follows: age younger than 18 years; personal history of diabetes mellitus, inflammatory bowel disease, familial polyposis syndrome, gastroparesis or other gastrointestinal motility disorders, or end-stage renal disease; and women of child-bearing age. Three patients who provided consent were subsequently excluded because of diabetes mellitus. No other exclusion criteria were relevant in this study. All enrolled patients underwent a CT colonographic examination, followed by same-day optical colonoscopy. In all, 50 patients were included in the study.

Bowel Preparation

Patients were instructed to avoid solid food on the day prior to the colonic examinations, with no food or liquid after midnight. Fecal tagging was achieved by using barium sulfate suspension (Tagitol V; E-Z-Em, Westbury, NY), and residual fluid tagging was achieved with diatrizoate meglumine (Gastrografin; Mallinckrodt, St Louis, Mo) with a protocol identical to that used in the American College of Radiology Imaging Network 6664 National CT Colonography Trial (10).

Patients were randomized to receive one of two bowel preparations: a 2-L PEG solution or a magnesium citrate solution. After a patient was enrolled in the study, he or she was assigned to a bowel preparation on the basis of a computer-generated random number. Each liter of the PEG solution consisted of 100 g PEG-3350, 7.5 g sodium sulfate, 2.7 g sodium chloride, 1.0 g potassium chloride, 5.9 g sodium ascorbate, and 4.7 g ascorbic acid (MoviPrep; Salix Pharmaceuticals, Morrisville, NC). The PEG solution was ingested in eight 16-oz (473 mL) aliquots, taken over 2 hours on the evening before the examination. Each liter of PEG solution was followed by 16 oz (473 mL) of clear liquid. The PEG solution used is one of only two 2-L PEG solutions approved for bowel cleansing prior to colonic examination.

The 8-oz (237 mL) magnesium citrate solution consisted of magnesium carbonate (31%), citric acid (65%), and potassium citrate (3%), yielding 18.0 g of magnesium citrate (LoSo Prep; E-Z-Em), ingested the evening before the examinations. A total of 72 oz (2129 mL) of water was taken in nine doses on the day prior to the colonic examinations. Four 5-mg enteric-coated bisacodyl tablets (E-Z-Em) were taken 2 hours after the ingestion of the magnesium citrate solution. A 10-mg bisacodyl suppository was administered 2 hours before the CT colonographic examination. All patients evacuated the rectal vault prior to CT colonographic examination to eliminate the potential for dilution of tagging in the rectum associated with bisacodyl suppositories.

CT Colonographic Technique

All CT colonographic examinations were performed with use of a 64–detector row scanner (LightSpeed VCT; GE Medical Systems, Milwaukee, Wis), with a gantry rotation period of 500 msec. During a single breath hold, CT images were obtained with the following scanning parameters: 120 kVp, 70 mAs, 64 detector rows, 0.625-mm section thickness, and pitch of 1.375. Patients were scanned in the supine and prone positions, and an automatic insufflator (ProtocO₂l; E-Z-Em) was used to distend the colon with carbon dioxide up to maximum patient tolerance prior to scanning.

CT Colonographic Interpretation

CT colonographic scans were interpreted by one of three radiologists who specialized in abdominal imaging (J.Y., R.A., L.A.L., with > 1500, > 300, and > 100 CT colonographic scans interpreted, respectively). Data were evaluated on a dedicated CT colonographic workstation with commercially available software (Vitrea, Vital Images, Minnetonka, Minn; or Aquarius, TeraRecon, Foster City, Calif). A primary two-dimensional approach with three-dimensional problem solving was used. Electronic stool subtraction was not used. Residual stool and fluid and colonic distention were assessed in each colonic segment by scoring residual stool on a scale from a score of 0 for best to a score of 3 for worst and by scoring fluid and distention on a scale from a score of 0 for best to a score of 4 for worst. Tagging was assessed qualitatively on a scale from a score of 0 for best to a score of 4 for worst and quantitatively by measuring the CT attenuation of the largest residual colonic fluid collection. Appendix E1 (online) includes further details of scoring and representative examples of residual solid stool (Fig E1 [online]) and fluid (Fig E2 [online]) scores. The time for data interpretation was recorded for each study. Readers were blinded to patient history and bowel preparation used.

Optical Colonoscopy

Following CT colonographic data acquisition, patients underwent optical colonoscopy. Segmental unblinding was performed, whereby after the initial endoscopic findings were recorded for each segment, the endoscopist (K.R.M. and J.N.S., with 23 and 11 years of experience, respectively) was unblinded to the CT colonographic findings for that segment. If there were discrepant findings between CT colonography and endoscopy, the segment was reassessed by the endoscopist. The final, unblinded endoscopic findings served as the reference standard for polyp detection. For CT colonography, a polyp was considered to be a true-positive lesion if it was detected in the same or an adjacent colonic segment as the reference standard and the size was within 50% of that measured at colonoscopy.

Patient Experience

Patients were mailed a questionnaire to assess their experience with CT colonography and optical colonoscopy. The questionnaire included experience with adverse effects of bowel preparation, comfort during the bowel preparation and the CT and fiberoptic examinations, and attitude toward future colon cancer screening. Appendix E1 (online) gives further details.

Statistical Analysis

Statistical analysis was performed by using software (SAS, version 9.1; SAS Institute, Cary, NC). Because multiple observations from the same subject are likely to be correlated, significant differences were tested with the use of generalized estimating equations (40) for residual solid stool and fluid, distention, and quantitative tagging. The Mann-Whitney test was used to compare the two preparations on qualitative tagging score, mean residual fluid attenuation according to segment, and adverse effects assessed on the patient experience questionnaire. The t test was used to compare preparation groups on interpretation times and mean age. The Fisher’s exact test was used to compare preparation groups on preferences for colorectal cancer screening, male-female ratios, race distribution, and indication for colonoscopy. A difference with a P value of .05 or less was considered to indicate a significant result.

Results

Patients

Fifty consecutive patients were enrolled in the study, with randomization of 25 patients into the PEG group and 25 patients into the magnesium citrate group. The cohort consisted of 48 men (mean age, 60 years; range, 43–78 years) and two women (mean age, 63 years; range, 53–73 years); for the entire cohort, the mean age was 60 years, and the age range was 43–78 years. The indication for colonoscopy was routine screening (n = 25), surveillance (n = 17), heme-positive stool (n = 4), iron deficiency anemia (n = 2), and diarrhea (n = 2). There were no significant differences in baseline demographic characteristics between preparation groups (Table 1).

Table 1.

Patient Demographic Information according to Preparation Group

Note.—Each preparation group included 25 patients. MC = magnesium citrate, PEG = 2-L PEG.

^*Numbers in parentheses are ranges.

^†Comparisons were performed with the t test.

^‡Comparisons were performed with the Fisher exact test.

^§Numbers in parentheses are percentages.

Bowel Preparation

Three hundred bowel segments were evaluated in both the supine and prone positions. For overall evaluation considering all bowel segments and patient positions, the PEG preparation group had a mean residual solid stool score on a scale from 0 to 3 of 0.90 ± 0.62 (standard deviation) versus 0.96 ± 0.58 for the magnesium citrate preparation group (Table 2). Neither preparation type (estimate = 0.06; 95% confidence interval: −0.18, 0.31; P = .58), nor patient position (P = .67) showed a significant association with residual solid stool in the generalized estimating equation analysis. The amount of residual stool was significantly related to colonic segment (P = .003), with the more proximal segments demonstrating increased stool (Fig 1). There was no significant difference in this observation between preparation groups (P = .18).

Table 2.

Preparation and Distention Grading

Note.—Data are number of segments, with percentages calculated on the basis of 50 scans per preparation group in parentheses. The total number of scans included those obtained in both the supine and prone positions, such that each colonic segment was evaluated twice (50 scans) in each patient (25 patients). Differences between preparation groups were not significant (P = .58 for stool, .48 for fluid, and .61 for distention). MC = magnesium citrate, PEG = 2-L PEG.

Figure 1:

Residual solid stool assessment according to segment. Data are mean residual solid stool score for both the prone and supine positions. Data are arranged from proximal to distal colon. Differences between preparation groups were not significant (P = .58). PEG = 2-L PEG, MC = magnesium citrate, C = cecum, A = ascending colon, T = transverse colon, D = descending colon, S = sigmoid colon, R = rectum, * = segment had a significant difference in residual solid stool compared with the rectum for both preparations combined.

For overall evaluation considering all bowel segments and patient positions, the mean residual fluid score on a scale from 0 to 4 was 1.05 ± 0.67 for the PEG group and 0.98 ± 0.76 for the magnesium citrate group (Table 2). Neither preparation type (estimate = −0.07; 95% confidence interval : −0.32, 0.18, P = .48) nor patient position (P = .48) showed a significant association with residual fluid in the generalized estimating equation analysis. The amount of residual colonic fluid was related to the colonic segment (P < .001), with the more proximal segments demonstrating increased fluid (Fig 2). There was no significant difference in this observation between preparation groups (P = .38).

Figure 2:

Residual fluid assessment according to segment. Data are mean residual fluid score for both the prone and supine positions. Data are arranged from proximal to distal colon. Differences between preparation groups were not significant (P = .48). * = Segment had a significant difference in residual fluid compared with the rectum for both preparations combined. Other keys are the same as in Figure 1.

For overall evaluation considering all bowel segments and patient positions, the mean distention score on a scale from 0 to 4 was 0.51± 1.00 for the PEG group and 0.47 ± 0.97 for the magnesium citrate group (Table 2). Neither preparation type (P = .61) nor patient position (P = .16) were significantly associated with colonic distention.

Improved tagging was observed in the PEG group for both residual solid stool and fluid. The mean fecal tagging score on a scale from 0 to 4 was 0.48 ± 0.83 for the PEG group and 1.52 ± 1.42 (P = .006) for the magnesium citrate group. The qualitative mean fluid tagging score on a scale from 0 to 4 was 0.28 ± 0.68 for the PEG group and 1.28 ± 1.51 (P = .009) for the magnesium citrate group. The quantitative analysis demonstrated higher attenuation of residual fluid in the PEG group for all segments combined (765 HU ± 491 and 443 HU ± 393 for the PEG and magnesium citrate groups, P = .01), and in the cecum, descending colon, and sigmoid colon (Fig 3).

Figure 3:

Residual fluid attenuation assessment according to segment. Data are mean residual fluid attenuation (Hounsfield units) for both the prone and supine positions. Data are arranged from proximal to distal colon. * = Segment had a significant difference in residual fluid attenuation between preparation groups. Other keys are the same as in Figure 1.

The CT colonographic data sets from the PEG group required a shorter interpretation time than did the data sets from the magnesium citrate group, with a mean of 14.8 minutes ± 4.98 and 18.0 minutes ± 5.43, respectively (P = .04).

Polyp Detection

A total of 91 polypoid lesions were detected with colonoscopy in 37 of 50 patients (74%). Table 3 includes details on histopathologic findings. Of the 16 polyps that were 6 mm or larger, there were 12 true-positive lesions and four false-negative lesions depicted at CT colonography, and these false-negative lesions measured 7, 8, 9, and 10 mm. Three false-negative lesions occurred in the magnesium citrate group, and one occurred in the PEG group. The 7-mm sessile lesion of the descending colon was identified on retrospective review of the CT images. The 8-mm sessile lesion of the sigmoid colon was not identified at retrospective review, likely owing to poor distention of the sigmoid colon in both the prone and supine positions. The 9-mm flat rectal lesion was not identified on retrospective review owing to severe beam-hardening artifact from metallic hardware for bilateral total hip arthroplasty. The 10-mm pedunculated rectosigmoid polyp was not identifiable on retrospective review. This polyp demonstrated tubular adenomatous histopathologic characteristics.

Table 3.

Histopathologic Findings in Polypoid Lesions Detected at Colonoscopy according to Size

In addition, there were four false-positive lesions that were 6 mm or larger identified at CT colonography, and these false-positive lesions measured 6, 8, 8, and 9 mm. Three false-positive lesions occurred in the magnesium citrate group, and one occurred in the PEG group. For all false-positive lesions, a polyp was identified at optical colonoscopy in the same bowel segment, but the measurement was less than 50% of that measured at CT colonoscopy.

Patient Experience

Forty of 50 patients (80%) returned the patient experience questionnaire within 2 weeks of colonic examination. The most common complaints relating to the bowel preparation were bloating (n = 24), sleep disturbance (n = 24), and hunger (n = 32). Table 4 provides additional details of patient side effects. There were no significant differences between preparation groups in the patient experience survey (P > .05). Nineteen patients stated a preference for CT colonoscopy over optical colonoscopy (48%) versus only three patients preferring optical colonoscopy (8%), while 18 patients had no preference for either test (45%, P < .001). The preference for CT colonoscopy was not significantly different between preparation groups (P = .23).

Table 4.

Discomforts Experienced by Patients during Bowel Preparation

Note.—Data are the numbers of patients. MC = magnesium citrate, PEG = 2-L PEG. Twenty-one patients from the PEG group and 19 patients from the MC group returned the questionnaire. One patient declined to comment on whether bloating was experienced.

^*Grade 1 = did not experience discomfort, grade 2 = experienced discomfort but was not bothersome, grade 3 = experienced discomfort and was somewhat bothersome, and grade 4 = experienced discomfort and was very bothersome.

^†Comparisons were performed with the Mann-Whitney test. There were no significant differences between preparation groups (P > .05 for all comparisons).

Discussion

CT colonography is a validated diagnostic and screening technique for examination of the colon (10–12), but standard preimaging preparation still requires cleansing of the bowel: one of the primary barriers to achieving optimal colorectal cancer screening (8,9). The ability to tag residual colonic material at CT colonography potentially allows a less rigorous bowel cleansing compared with that for optical colonoscopy because the radiologist is able to distinguish high-density stool and fluid from the colonic wall. In our study, we compared two tagged, limited bowel preparations: a 2-L PEG electrolyte lavage and a low-volume magnesium citrate solution. The PEG solution is half the volume of the standard 4-L PEG solution. The smaller volume is easier for patients to ingest but maintains the advantages of an osmotically neutral electrolyte lavage solution, which has fewer deleterious effects on serum electrolytes than do osmotically active preparations (30). In addition, the PEG solution used in our study includes high doses of ascorbic acid (21.2 g), used to improve taste and provide an extra laxative effect. The magnesium citrate solution has a lower volume than does the 2-L PEG solution but is an osmotic laxative that can potentially cause electrolyte disturbances (27–30). The magnesium citrate preparation uses citric acid to help improve taste but does not provide the laxative effect of ascorbic acid.

In our study, we found no significant differences between the PEG and magnesium citrate preparations in regard to cleansing effectiveness or patient experience. There were several advantages for the PEG preparation, which required a shorter study interpretation time and promoted improved tagging of residual solid stool and fluid.

Less residual fluid is generally preferable for CT colonographic data interpretation; however, this factor may result in longer interpretation times, presumably caused by increased residual solid stool obscuring the colonic wall (26,36). Although no significant differences were observed in the amount of residual solid stool or fluid, there was a trend toward more solid stool in the magnesium citrate group. Our study demonstrated that very few colonic segments had a score of 3 or 4 for residual solid stool or fluid, respectively, indicating that both preparations provide adequate cleansing. The shorter interpretation time and trend toward less residual solid stool in the PEG group suggest that it may be preferable to magnesium citrate for CT colonographic bowel preparation.

When one uses limited bowel preparations, adequate tagging of residual contents becomes increasingly important, as more residual solid stool and fluid is expected. Interestingly, we observed improved tagging of both residual solid stool and fluid in the PEG group. In addition to demonstrating subjectively better tagging, the PEG group demonstrated higher attenuation of residual fluid; the higher the attenuation of residual fluid, the easier the process of distinguishing the fluid–soft tissue interface. One possible explanation for this finding is that the osmotic laxative or the stimulant laxative (bisacodyl) used in the magnesium citrate preparation interferes with the mixing process required for homogeneous tagging. Our study was not designed to address this question; therefore, additional validation is needed.

Because tagging helps the radiologist distinguish residual contents from the colonic wall, it is expected that improved tagging will lead to improved polyp detection. The small number of clinically important polyps found in our study population precludes a meaningful statistical analysis of diagnostic test characteristics. However, it is noteworthy that there was only one false-negative lesion and one false-positive lesion in the PEG group, compared with three false-negative lesions and three false-positive lesions in the magnesium citrate group. For the four lesions classified as false-positive lesions, a polyp was found at optical colonoscopy in the same colonic segment, but the endoscopic measurement was less than 50% of the CT colonographic measurement. Given that some studies have shown CT colonographic measurements to be more accurate and reliable for colorectal polyp measurement than are measurements with open biopsy forceps, which tend to underestimate polyp size (41), the lesions classified as false-positive lesions in our study may represent actual lesions.

Both the PEG and magnesium citrate preparations were well tolerated by the patients in our study, and there were no significant differences between groups in any aspects assessed with the patient tolerance questionnaire. Investigators in previous studies have found improved patient tolerance with reduced-volume PEG preparations compared with 4-L PEG (31,32) and sodium phosphate preparations (34). However, to our knowledge, reduced-volume PEG and magnesium citrate have not been directly compared. Magnesium citrate preparations are generally very well tolerated by patients (42), so it is encouraging to find that the reduced-volume PEG was equally well tolerated in our study. Patients of both groups expressed a preference for CT colonography over optical colonoscopy as a screening examination, which has been reported previously (16,20,43). This observation supports the likelihood that CT colonography with reduced bowel preparation will increase patient compliance with colorectal cancer screening recommendations (44).

There were several limitations of this study. First, the number of subjects was relatively small and the study was likely underpowered to detect subtle differences in preparation adequacy. In addition, there were few clinically important polyps, which precluded a meaningful statistical analysis of polyp detection capability. Second, our study included both average- and increased-risk patients; it is unclear whether our results can be generalized to populations undergoing CT colonography for screening. Because our study population comprised ambulatory, nondiabetic patients, it is unclear whether our results can be extrapolated to diabetic or sedentary patients, who are known to experience difficulty in achieving adequate bowel cleansing. Furthermore, although we are not aware of any studies demonstrating that bowel preparation quality is different between men and women, it should be noted that this study was performed in 96% male subjects (48 of 50). Finally, only one radiologist interpreted each data set, and therefore reader agreement and reproducibility could not be assessed.

In conclusion, there were no significant differences in the amount of residual solid stool or fluid or patient acceptance when we compared the reduced-volume PEG and magnesium citrate preparations, with both demonstrating effective bowel cleansing for CT colonography, while maintaining adequate polyp detection. Improved solid stool and fluid tagging, as well as a shorter interpretation time, were important advantages observed in the reduced-volume PEG group.

Advances in Knowledge.

• The amount of residual solid stool (P = .58) and fluid (P = .48) was not significantly different at CT colonography with use of a 2-L polyethylene glycol (PEG) versus a magnesium citrate bowel preparation.

• Tagging of both solid stool (P = .006) and fluid (P = .009) was significantly better with the PEG than with the magnesium citrate preparation.

• Interpretation time was significantly shorter for CT colonographic examinations performed by using PEG than it was by using magnesium citrate, with mean interpretation times of 14.8 and 18.0 minutes, respectively (P = .04).

• Patients reported similar tolerance for the reduced-volume PEG and magnesium citrate preparations (P > .05 for all queried side effects and discomforts); both patient groups preferred CT colonography over optical colonoscopy for future colorectal cancer screening, with 48% of patients stating a preference for CT colonography, versus 8% stating a preference for colonoscopy, and 45% of patients having no preference for either test (P < .001).

Implication for Patient Care.

• Both reduced-volume PEG and magnesium citrate bowel preparations provide adequate bowel cleansing while maintaining adequate polyp detection; limited bowel preparations may increase patient compliance with colorectal cancer screening recommendations.

Disclosures of Potential Conflicts of Interest: A.W.K. No potential conflicts of interest to disclose. J.Y. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: received a research grant from GE Healthcare. Other relationships: none to disclose. R.A. No potential conflicts of interest to disclose. S.W. No potential conflicts of interest to disclose. L.A.L. No potential conflicts of interest to disclose. J.S. No potential conflicts of interest to disclose. K.M. No potential conflicts of interest to disclose. B.M.Y. No potential conflicts of interest to disclose.