Key PointsQuestion
Can dual-energy computed tomography detection of microscopically proven cardiovascular monosodium urate deposits differentiate patients with gout from controls?
Findings
In this diagnostic study of 59 patients with gout, 47 controls, and 6 cadavers, the frequency of cardiovascular monosodium urate deposits in patients with gout was higher than in controls and was associated with elevated coronary calcium score.
Meaning
A relatively new imaging modality (dual-energy computed tomography) without the need of contrast can differentiate cardiovascular monosodium urate deposits from calcium deposits that might impact the treatment of patients with gout at risk of cardiovascular diseases.
Importance
The prevalence of gout has increased in recent decades. Several clinical studies have demonstrated an association between gout and coronary heart disease, but direct cardiovascular imaging of monosodium urate (MSU) deposits by using dual-energy computed tomography (DECT) has not been reported to date.
Objective
To compare coronary calcium score and cardiovascular MSU deposits detected by DECT in patients with gout and controls.
Design, Setting, and Participants
This prospective Health Insurance Portability and Accountability Act–compliant study included patients with gout and controls who presented to a rheumatologic clinic from January 1, 2017, to November 1, 2018. All consecutive patients underwent DECT to assess coronary calcium score and MSU deposits in aorta and coronary arteries. In addition, cadavers were assessed by DECT for cardiovascular MSU deposits and verified by polarizing microscope. Analysis began in January 2017.
Main Outcomes and Measures
Detection rate of cardiovascular MSU deposits using DECT in patients with gout and control group patients without a previous history of gout or inflammatory rheumatic diseases.
Results
A total of 59 patients with gout (mean [SD] age, 59 [5.7] years; range, 47-89 years), 47 controls (mean [SD] age, 70 [10.4] years; range, 44-86 years), and 6 cadavers (mean [SD] age at death, 76 [17] years; range, 56-95 years) were analyzed. The frequency of cardiovascular MSU deposits was higher among patients with gout (51 [86.4%]) compared with controls (7 [14.9%]) (χ2 = 17.68, P < .001), as well as coronary MSU deposits among patients with gout (19 [32.2%]) vs controls (2 [4.3%]) (χ2 = 8.97, P = .003). Coronary calcium score was significantly higher among patients with gout (900 Agatston units [AU]; 95% CI, 589-1211) compared with controls (263 AU; 95% CI, 76-451; P = .001) and also significantly higher among 58 individuals with cardiovascular MSU deposits (950 AU; 95% CI, 639-1261) compared with 48 individuals without MSU deposits (217 AU; 95% CI, 37-397; P < .001). Among 6 cadavers, 3 showed cardiovascular MSU deposits, which were verified by polarizing light microscope.
Conclusion and Relevance
Dual-energy computed tomography demonstrates cardiovascular MSU deposits, as confirmed by polarized light microscopy. Cardiovascular MSU deposits were detected by DECT significantly more often in patients with gout compared with controls and were associated with higher coronary calcium score. This new modality may be of importance in gout population being at risk from cardiovascular disease.
Gout and rheumatoid arthritis are the 2 most common inflammatory arthritides.1 There has been a rise in prevalence of gout worldwide in recent decades, attributed to increased longevity and changing trends in lifestyles leading to an increase in gout-related risk factors.2 However, clinical management of gout in primary care is suboptimal,2,3 despite the high incidence of gout in the United Kingdom and the United States.2,4 The risk of cardiovascular disease in gout and hyperuricemia is well established5 and relates to persistent inflammation that promotes cardiovascular damage6-8 and increased cardiovascular morbidity and mortality.4,9
Hyperuricemia is a cardiovascular risk factor. However, the underlying mechanisms by which hyperuricemia results in cardiovascular damage are not clearly defined. Uric acid has been identified in atherosclerotic plaques of carotid endarterectomies specimens as shown by Patetsios et al.8 Clinical studies have demonstrated an association between gout and coronary heart disease; the Framingham study reported an increased incidence of coronary heart disease and angina in patients with gout.2,3,5,10-18 To our knowledge, direct cardiovascular imaging of monosodium urate (MSU) deposits by dual-energy computed tomography (DECT) has not been reported to date. However, DECT is an established method for detection of MSU deposits in peripheral joints and tendons.19-26
The aim of this study is to determine the utility of DECT in detection of cardiovascular MSU deposits in patients with gout vs controls. To determine whether vascular artifacts might mimic the appearance of MSU crystals on DECT, MSU crystal characterization was performed under polarized light microscope in fresh cadavers who were also evaluated by DECT.
This prospective, Health Insurance Portability and Accountability Act of 1996–compliant study received institutional review board approval and fulfilled the ethical standards of the national research committee and the 1964 Declaration of Helsinki.27 Written informed consent was obtained from all participants. Data from the hospital database from January 2000 to December 2018 regarding disease duration, uric acid (maximum and at time of imaging), therapy, and gout attacks per year were evaluated. A total of 106 patients were prospectively enrolled from January 1, 2017, through November 1, 2018. Analysis began in January 2017.
We enrolled patients with gout older than 35 years evaluated at our rheumatology clinic fulfilling the American Rheumatism Association classification criteria28 and who consecutively agreed to undergo DECT. All patients underwent thoracic DECT to evaluate MSU deposits in the thoracic aorta and coronary arteries. We also enrolled controls older than 35 years presenting to the rheumatology clinic without prior history or evidence of gout attacks, not fulfilling the American Rheumatism Association classification criteria28 and without any evidence of inflammatory rheumatic diseases who underwent thoracic DECT to evaluate MSU deposits in thoracic aorta and coronary arteries.
Thoracic Computed Tomography and DECT
Evaluation was performed with a 128-row dual-source computed tomography (CT) scanner (Somatom Definition Flash; Siemens Healthineers). The fundamental principle behind the use of DECT is to differentiate materials based on their relative absorption of x-rays at different photon energy levels (typically at 80 kVP and 140 kVp).
Dual-source DECT scanner is able to perform simultaneous acquisitions at 2 energy levels (80 kVP and 140 kVp) using 2 separate sets of x-ray tubes and detectors positioned 90° to 95° apart29 without the need of contrast media; coronary calcium score information is obtained from the same CT acquisition without the need for additional imaging. The standardized protocol settings is 80 kV/100 − 140 mAs of tube A and 140 kV/ 200 − 250 mAs of tube B, with a ratio of 1.36, range of 4, minimum Hounsfield units of 150, and maximum Hounsfield units of 500. Using a combination of independent tube current modulation, iterative reconstruction, and integrated circuits within the detector module, high-resolution images with excellent material separation are obtained without an increase in radiation dose.30 The acquired data sets are reconstructed in the required planes and processed with dual-energy software using a standardized 2-material decomposition algorithm designed for specific clinical applications. The gout algorithm is performed to separate MSU from calcium using soft tissue as the baseline. The 2-material decomposition algorithm is based on the principle that materials with a high atomic number such as calcium would demonstrate a higher increase in attenuation at higher photon energies than does a material composed of low atomic number materials such as MSU; this attenuation difference is independent of density or concentration of the material or tissue. A graphical representation from a screenshot from Syngovia dual-energy software (Siemens Healthineers) illustrates this concept (Figure 1). Once separated and characterized, the materials are color coded and overlaid on multiplanar reformatted cross-sectional images.30 We choose green pixels for MSU deposits demonstration when using the software of the Syngovia workstation (Siemens Healthineers).
The postprocessing software enables real-time manipulation of the images at source resolution, in any plane and in 2 and 3 dimensions, to best depict the MSU deposits. Preprocessed and processed images are transferred to the picture archiving system. Corresponding preprocessed gray-scale images are reviewed for presence of deposits.30
Scan parameters were 2 × 64 × 0.625 mm at a rotation time of 280 milliseconds, dose-length product of 219 mGycm, volume CT dose index of 11.01 L, and total mAs of 3415. Image reconstruction of 0.75-mm transverse sections with an overlap of 0.4 mm was performed in soft tissue kernel (D30) and bone kernel (B60). D30 kernel was used for the dual-energy processing and MSU detection. Calcified plaques with a CT attenuation more than 130 Hounsfield units31 and MSU deposits in the aorta and coronary arteries were graded according to Gondrie et al32 as follows: score 0 was assigned when absent; score 1, 5 or fewer foci; score 2, between 6 to 8 foci and extending over 3 section; and score 3, more than 9 foci extending over 3 sections.
Localization of calcified plaques and MSU deposits was determined as follows: calcified plaques within the aorta were assigned to ascending aorta, descending aorta, aortic arch and aortic root, and supraaortal vessels. For the coronary arteries, calcified plaques were assigned to the right coronary artery, left main artery, circumflex artery, and left anterior descending artery. In addition, the tricuspid valve and mitral valve were assessed for calcifications. Calcified plaques and Agatston units (AU) were calculated in the native CT scan images, while MSU deposits were identified on the color-coded DECT images.
Interoversver and intraobserver variability was not quantified in our study. Two radiologists (A.S.K. and S.S.) with experience in cardiovascular imaging and gout imaging by DECT of 5 and 7 years, respectively, evaluated the DECT images in consensus. They were blinded to clinical and medical history. Because of the potential for artifacts masquerading as MSU deposits, we have defined small (<2 mm) green pixels adjacent to calcifications as artifactual and did not score them.
According to American College of Radiology/European League Against Rheumatism guidelines, nail bed deposits, submillimeter deposits, skin deposits, and deposits obscured by motion, beam hardening, vascular artifact, artifacts on rib cartilage, and bronchial calcifications33 were not classified as positive findings in our study.21
Serum Uric Acid Level and Clinical Parameter
Serum uric acid, maximum uric acid at imaging time, disease duration, and the number of gout attacks of per year were evaluated. According to American College of Radiology/European League Against Rheumatism guidelines, serum uric acid was considered elevated above 6 mg/dL (to convert to µmol/L, multiply by 59.485).34
Fresh cadavers were examined by DECT to verify the presence of MSU deposits in the thoracic aorta and coronary arteries. Informed consent was provided according to the last wills of the donors, who had dedicated their cadavers to human research studies. All cadavers were referred to DECT within 48 hours after death and were in legal custody of the anatomical institution. No information was available on medical disorders in these patients or regarding whether they had gouty arthritis or hyperuricemia.
According to standardized landmarks, a detailed localization of cardiovascular MSU deposits was determined to localize the MSU deposits for gross anatomical resection. Monosodium urate deposits within the aorta were localized according their presence at thoracic vertebral level (eg, thoracic vertebra 6) and clock position (eg, 19:00). Monosodium urate presence in supra-aortic vessels were determined according to the distance from aortic arch. For coronary arteries, MSU deposits were localized according to their presence in the right coronary artery, left main artery, left circumflex artery, and left anterior descending artery.
Polarizing Microscopic Evaluation
In DECT-positive MSU cardiovascular specimens, gross anatomic sections were obtained at the positive levels defined by anatomic landmarks. Specimens were cut unfixed to into 5 × 5-mm sections, embedded using Tissue-Tek OCT (Miles Inc) compound medium and sectioned at 5 μm using a Leica CM1950 cryostat (Leica Biosystems). After mounting on microscope slides and covering using glycerol/glycerol-phosphate buffer solution, cryostat sections examination was performed with compensated polarized light microscopy at magnification ×400. First-order red compensation performed to identify MSU crystals by their needlelike appearance and strong negative birefringence.
Statistical calculations for this study were performed with Stata version 15.1 (StataCorp). The continuous variable of calcium score was summarized by mean (SD). Comparison of calcium score between patients with gout and controls, as well as comparison of calcium score between DECT-positive and DECT-negative patients, was performed with a 2-tailed t test, using P < .05 as the cutoff for statistical significance. Frequency data for the presence of MSU deposits on DECT in patients vs controls and for the frequency of gout attacks in MSU-positive vs MSU-negative patients were compared with a χ2 statistic based on a 2 × 2 tabulation, using P < .05 as the cutoff for statistical significance.
Among 59 patients with gout, 46 (78.0%) were men, and the mean (SD) age was 59 (5.7) years (range 47-89). This group of patients presented with a maximum uric acid over 15 years of 9.33 mg/dL (range, 4.83-11.37), a maximum uric acid at imaging time of 6.35 mg/dL (range, 1.7-12.28), a mean (SD) disease duration of 3 (3.5) years, and a mean (SD) of 2 (0.6) gout attacks per year. Clinical characteristics of the patients are presented in Table 1. Of 59 patients, 55 (93.2%) demonstrated calcified coronary plaques with a mean coronary calcium score of 900 AU. Cardiovascular MSU deposits were detected in 51 of 59 (86.4%) patients with mean (SD) disease duration of 3 (3.5) years (range, 1-13), mean (SD) serum uric acid at imaging time of 7.4 (3.26) mg/dL (median, 7.04), and mean (SD) serum uric acid level over 15 years hospital records of 9.5 (4.5) mg/dL (median, 9.22).
Monosodium urate deposits were identified in the aorta in 10 of 59 patients (16.9%), while 19 patients (32.2%) had coronary MSU deposits. Both aortic and coronary MSU deposits were identified in 22 patients (37.3%) (Table 2 and Figure 2). Thus, only 8 of 59 patients with gout (13.6%) did not demonstrate vascular MSU deposits.
Among 59 patients, 2 (3.4%) presented with 1 gout attack per year, 18 patients (30.5%) had 2 or more gout attacks per year, and 7 patients (11.9%) had no gout attacks. Regarding medical therapy for gout, 24 of 59 patients (40.7%) did not receive medical therapy, whereas 18 (30.5%) were treated with allopurinol, 8 (13.6%) with febuxostat, and 1 (1.6%) with other new medications. In 8 patients (13.6%), data on medical therapy were not available.
Of 47 controls, 28 (59.6%) were men, and the mean (SD) age was 70 (10.4) years (range, 44-86). The control group presented with a mean (SD) uric acid at imaging time of 6.63 (2.5) mg/dL (range, 4.02-8.18). Among control individuals, 40 of 47 (85.1%) did not demonstrate cardiovascular MSU deposits, while 7 (14.9%) were positive for cardiovascular MSU deposits with a mean (SD) uric acid at imaging time of 6.8 (3.3) mg/dL (median, 6.3). The maximum uric acid during 15 years hospital record was only available in 5 patients, with a mean (SD) of 6.94 (3.6) mg/dL (median, 6.9). No control individual had a history of gout attacks.
Two of the control individuals (4.3%) showed aortic MSU deposits, 2 (4.3%) showed coronary artery MSU deposits, and 3 (6.4%) showed both (Table 2). Compared with patients with gout, the frequency of cardiovascular MSU deposits was lower in controls (χ2 = 17.68, P < .001) as was the frequency of coronary MSU deposits (χ2 = 8.97, P = .003) (Table 2).
Only a small difference between patients with gout and controls was found for MSU deposits on the mitral or tricuspid valve. We identified MSU deposits on the tricuspid valve in only 1 patient (1.7%) and in no control individuals and on the mitral valve in 8 of 59 patients (13.6%) vs 2 of 47 controls (4.3%). The mean coronary calcium score among controls of 263 AU (95% CI, 76-451) was significantly lower than the calcium score among patients with gout (P = .001).
Gout attacks were more common among MSU-positive individuals (χ2 = 35.96, P < .001). Among 58 MSU-positive individuals, 14 (24.1%) had no gout attacks, 28 (48.3%) had 1 gout attack, and 16 (27.6%) had 2 or more gout attacks. Among 48 individuals without MSU deposits, 39 (81.3%) had no gout attacks, 6 (12.5%) had 1 gout attack, and 2 (4.2%) had 2 or more gout attacks.
The coronary calcium score was significantly higher among the 58 individuals with cardiovascular MSU deposits (950 AU; 95% CI, 639-1261) compared with the 48 individuals without MSU deposits (217 AU; 95% CI, 37-397) (P < .001). Among 48 individuals without MSU deposits, 40 (83.3%) had no gout attacks (all from the control group), 6 (12.5%) had 1 gout attack (from the gout group), and 2 (4.2%) had 2 or more gout attacks (also from the gout group). There was no significant correlation of uric acid level with the presence of MSU-positive plaque.
Six fresh cadavers (3 male and 3 female; mean [SD] age at death, 79 [17] years; range, 57-95) underwent DECT (Table 2). Three of the cadaver DECT studies demonstrated MSU deposits, including 1 cadaver with MSU deposits in the thoracic aorta, 1 cadaver with MSU deposits in the coronary arteries, and 1 cadaver with MSU deposits in the thoracic aorta, coronary arteries, and mitral valve. Eight biopsy specimens were evaluated pathologically. Monosodium urate deposits visualized by DECT were histological proven to be present by polarized light microscopy in 7 of 8 biopsies (positive predictive value of DECT = 87.5%) (Figure 3 and eTable in the Supplement).
Previous studies examining the association between gout and coronary heart disease have been conflicting.12,14,15 Several studies on association between gout and myocardial infarction report an increased incidence of nonfatal myocardial infarction,35 while no association between gout and myocardial infarction was found by Abbott et al.10
Disveld et al36 showed that crystal-proven gout was strongly associated with an increased prevalence of cardiovascular disease. Furthermore, among patients with gout, characteristic gout severity factors were associated with cardiovascular disease.
Pagidipati et al37 reported that in patients with acute coronary syndrome, increasing levels of serum uric acid were associated with an elevated risk of cardiovascular events, regardless of a clinical diagnosis of gout. Also, Pascart et al22 found that the extent of MSU burden in knees and feet detected by DECT and ultrasonography did not increase the estimated risk of cardiovascular events in 42 patients with gout.
The association between uric acid and atherosclerotic plaques has been suggested in clinical, epidemiologic, and basic science publications.38-40 A qualitative and quantitative measure of uric acid in atherosclerotic plaques was performed by Patetsios et al8 in which increased uric acid levels were found in plaques from carotid endarterectomy specimens along with cholesterol and xanthine oxidase but not present in nonatherosclerotic control specimens, supporting the pathophysiologic role of uric acid in atherosclerosis.8
Direct imaging by DECT of MSU deposits in vessel walls has not been previously proven but only reported as CT artifact: Mallinson et al41 noted an interesting artifact within calcified vessels in 4 cases. Three of 4 cases showed a convincing uric acid deposition in calcified arteries elsewhere in the lower limb, but the sample size was too small for a meaningful statistical correlation. Our study supports the concept that that MSU deposits in cardiovascular vessel walls are not artifacts but true MSU deposits as demonstrated by polarizing light microscope.
Because of the potential for artifacts masquerading as MSU deposits, we have defined small (<2 mm) green pixels adjacent to calcifications as artifactual and did not score them. Whether these pixels represent artifacts or true MSU deposits should be proven by further histological studies. Temporal resolution is reduced using DECT, such that 2-mm MSU deposits are at the limit of DECT resolution. We excluded areas that were identified as possible MSU deposits on postprocessing but were also associated with streak or beam hardening artifacts, motion artifacts, image noise, or costal cartilage.33
As noise within small structures may contribute to vascular artifact, we applied the scanner’s Vascular Artifact-Reduction Techniques to avoid false-positive findings by increasing minimum and range parameters for classification of MSU deposits. Generally speaking, artifacts are common in DECT gout protocols but can usually be readily recognized by the trained radiologist, hereby avoiding false-positive results. However, we acknowledge that consideration of these artifacts is essential to accurately report studies performed with this powerful new imaging modality.41
Andrés et al42 reported a significant increase in coronary calcification and MSU deposits in knees and metatarsophalangeal 1 joints in patients with asymptomatic hyperuricemia. However, these calcifications were not evaluated in terms of cardiovascular MSU deposits, as assessed in our study.
Our preliminary findings support the hypothesis of an association between gout and cardiovascular deposition of uric acid and support gout as an independent risk factor for cardiovascular atherosclerosis.43 There was greater extent of coronary calcium among patients with gout in our study. We also demonstrated a significant association between the presence of MSU deposits and coronary calcium scores. However, because most of the MSU-positive studies were found among patients with proven gout, we cannot determine whether MSU deposits are associated with the coronary calcium score independent of the presence of gout.
Very few cases of cardiac valve tophi have been described, to our knowledge. Postmortem, surgical, or echocardiographic findings of mitral, aortic, and pulmonary valve involvement in patients with chronic gout have been reported.38,39,44-46 Our study identified MSU deposits on the tricuspid valve in only 1 patient (1.7%) and in no control individuals and on the mitral valve in 8 of 59 patients (13.6%) vs 2 of 47 controls (4.3%).
Direct cardiovascular imaging of MSU deposits might address several additional gaps in knowledge, as the reasons for increased risk of myocardial infarction in patients with gout remain unclear. It is possible that prolonged exposure to hyperuricemia prior to the onset of clinical gout may play a role in the development of cardiovascular atherosclerosis; this should be addressed in further studies.
As long-term exposure to elevated uric acid levels may result in increasing MSU deposition with an associated inflammatory burden, our findings can have important implications for clinical practice. There is strong evidence that cardiovascular disease in patients with gout often goes unrecognized and undertreated in primary care, as only a quarter of people diagnosed as having acute gout are screened for cardiovascular risk factors within the subsequent month.4 Dual-energy CT imaging without the need of contrast media may provide a relatively simple diagnostic test to reduce the number of unrecognized and undertreated patients with gout at risk for cardiovascular disease.
Several studies reflect the suboptimal care received by patients with gout and suggest an urgent need to improve care and prevention47,48 as well as a need to change the management of cardiovascular risk factors in this population.14 Further studies are required to establish the optimum management of vascular risk factors for the long-term health of patients with gout, to clarify the nature of the relationship between gout and coronary heart disease, and to explore the potential effect of cardiac DECT on therapeutic management of these patients to allow clinicians to address the growing public health impact of gout more effectively.49
We note several limitations to this study. Although the cadaver studies demonstrate a high positive predictive value of DECT for MSU deposits, we do not have a reference standard for the true number of MSU deposits in our study population (as pathological correlation is not available for our living patients). Thus, we are able to demonstrate the association of DECT-positive studies with the clinical diagnosis of gout and with the coronary calcium score, but we are not able to calculate the true sensitivity and specificity of DECT for MSU deposits among our study population.
Our study population may be skewed toward patients with cardiovascular disease, as we did not exclude patients with previously known heart disease. We did not include patients younger than 35 years. No medical history of the cadaver patients was available. All patients with positive coronary MSU deposits showed calcified plaques, and thus further research is needed to investigate early plaque behavior, inflammation, and MSU deposition to document if there is additional value for MSU deposit detection by DECT. Computed tomography angiography was not performed in patients and controls; therefore, positive remodeling, spotty calcification, necrotic core, and fibrofatty plaques were not evaluated. The variation of frequency of MSU deposits in different territories of coronary arteries was not evaluated and should be investigated in further studies. Volume rendering of MSU deposits in coronary arteries was not performed and should also be investigated in further studies. Another limitation is that the software cannot insure that adjacent confounding tissues such as pericoronary adipose tissue are not included in the detection/quantification of MSU deposits. The temporal resolution of CT is limited in DECT imaging relative to single energy imaging modes, and this may complicate differentiation of smaller MSU pixels.
Finally, interobserver and intraobserver variability were not evaluated in our study, as DECT scans were interpreted by consensus of 2 radiologists. The cadaver correlation is limited by the detection of a limited number of cardiovascular MSU deposits in 3 of 6 cadavers; therefore, only a limited number of biopsies specimens were evaluated for pathological correlation. Furthermore, the age of cadavers in this study was significantly higher than that of our live patients and controls. Finally, further investigation is also needed to demonstrate similar, reproducible results with other CT vendors.
Our study demonstrates the feasibility of DECT to image MSU deposits in coronary arteries and the thoracic aorta. The significantly greater extent of cardiovascular MSU deposits in patients with gout compared with controls underscores the potential importance of DECT in a comprehensive cardiovascular examination of patients with gout, which may provide new insights into the cardiovascular disease burden associated with gout.
Corresponding Author: Sylvia Strobl, MD, Department of Radiology, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria (sylvia.strobl@tirol-kliniken.at).
Accepted for Publication: July 19, 2019.
Published Online: September 11, 2019. doi:10.1001/jamacardio.2019.3201
Author Contributions: Dr Klauser had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Klauser, Strobl, Gruber, Feuchtner, Bellmann-Weiler, Jaschke.
Acquisition, analysis, or interpretation of data: Klauser, Halpern, Strobl, Bellmann-Weiler, Weiss, Stofferin, Jaschke.
Drafting of the manuscript: Klauser, Strobl, Gruber, Feuchtner, Bellmann-Weiler.
Critical revision of the manuscript for important intellectual content: Klauser, Halpern, Strobl, Bellmann-Weiler, Weiss, Stofferin, Jaschke.
Statistical analysis: Halpern, Strobl.
Obtained funding: Stofferin.
Administrative, technical, or material support: Klauser, Strobl, Gruber, Bellmann-Weiler, Weiss, Stofferin, Jaschke.
Supervision: Klauser, Strobl, Gruber, Feuchtner, Bellmann-Weiler, Jaschke.
Conflict of Interest Disclosures: None reported.
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