Impact of Ct-measured Sarcopenic Obesity on Postoperative Outcomes Following Colon Cancer Surgery

doi:10.21203/rs.3.rs-3402982/v1

Purpose

to investigate the impact of sarcopenic obesity on anastomotic leak. Secondary outcomes included overall morbidity, mortality and length of hospital stay.

Methods

This was a unicenter, retrospective observational study conducted from January 1, 2015 to January 1, 2020. Conducted in a colorectal surgery referral center. A total of 544 consecutive patients who underwent elective colonic resection for non-metastatic colon cancer. Exclusion criteria included rectal cancer, urgent surgery, lack of anastomosis, lack of imaging, multivisceral resections and synchronic tumors.

Results

A total of 544 patients were included in the analysis with a mean age of 72.6 ± 10.8 years. Complications were noted in 177 (32.3%) patients, of which 51 (9.31%) were severe (Clavien Dindo > II). Sarcopenic obesity was seen in 24.8% of the sample, which was an independent indicator of increased overall morbidity (OR = 1.71, 95% CI: 1.14–2.56, p 0.009), a predictor of 30-day mortality (OR = 6.29, 95% CI: 1.55–25.53, p 0.010) and was significantly associated with development of anastomotic leak (OR = 1.42, 95% CI: 1.05–1.92, p 0.024). Additionally, it increased the risk of reoperation and was related to a prolonged length of hospital stay.

Conclusions

CT-measured sarcopenic obesity is associated with an increased risk of postoperative morbidity and mortality in colon cancer surgery.

Sarcopenic obesity

sarcopenia

obesity

colon cancer surgery

surgical outcomes

CT measured body parameters

Sarcopenic Obesity is currently defined as decreased muscle mass and function in obese individuals ¹. There is a bidirectional association between sarcopenia and obesity in the pathogenesis of SO. On the one hand, low skeletal muscle mass can lead to a reduction in resting and total metabolic output, which promotes fat gain. On the other hand, obesity may favor the development and progression of sarcopenia through a multifactorial network of abnormalities that involve the general proinflammatory state produced by visceral adipose tissue ². Both sarcopenia and obesity may independently present an increased risk of adverse health outcomes. When these two conditions are combined, these risks can be synergistically amplified.

CT is considered the “Gold standard” for non-invasive evaluation of muscle quantity and quality due to its excellent reproducibility ^3,4. It also has the advantage of being part of the preoperative evaluation in the majority of patients with colon cancer.

SO is associated with a higher rate of postoperative complications, longer hospital stays, and higher hospitalization costs ^3–6. In the current study, we sought to examine the association between preoperative CT measures of SO with short-term surgical outcomes in a relatively homogeneous group of non-metastatic colon cancer patients. We hypothesized that radiologic measures of SO would help in predicting adverse short-term outcomes.

A retrospective observational study carried out on 544 patients who underwent elective colonic resection (left and right, simple and extended, hemicolectomy and sigmoidectomy) for non-metastatic colon cancer, for this cause, at a tertiary level hospital in Madrid/Spain, between January 2015 to January 2020.

The study was carried out following the ethical standards of retrospective studies. Approval was granted by the Ethics Committee of the Ramón y Cajal University Hospital (No. 374/20) to carry out the study using the information obtained from the medical records.

All surgical specimens with the result of colorectal cancer were retrieved from the aforementioned period, with a total of 1192 samples and after applying the exclusion criteria, the study was conducted upon a sample number of 544 patients.

The exclusion criteria were the following: metastatic colon cancer, urgent surgery, rectal carcinoma, absence of adequate preoperative imaging, absence of bowel anastomosis, multivisceral resection and patients with synchronous tumors.

Short-Term Post-surgery Morbidity

The Clavien-Dindo complication grading system was utilized to further classify documented outcomes prior to statistical analysis. Patients who had more than one complication were classified using the highest grade of reported complication ^(7,8).

Body composition parameters measurements

Radiological measurements were made using diagnostic imaging software (Synapse PACS®). Imaging modality used was computerized tomography scan and the analysis was obtained from two-dimensional (2D) and three-dimensional (3D) images. Image slice thickness was of 3mm without gap, low noise and axial cuts. Anatomical region included the upper border of the liver to the upper border of the pubic symphysis in supine position. The diagnosis was established in the pre-surgical CT scan at the level of the third lumbar vertebra (L3).

Imaging was based on automatic detection of the psoas muscle and calculation of its area and manual detection of paraspinal and abdominal wall muscles (transversus abdominis, external and internal obliques, rectus abdominis) and calculation of their area. To identify muscle tissue, the range of -29 to + 150 in Hounsfi Units (HU) was used. The skeletal muscle mass index was calculated as the sum of the cross-sectional areas of these muscles (cm²). These values were standardized according to body surface area, according to Mosteller's formula (m²).

The radiological diagnosis of obesity was established based on the semiautomatic detection and frequency distribution of subcutaneous and visceral fat in one plane (2D) at the L3 level. To identify fatty tissue, the range between − 200 and − 50 in Hounsfi Units (HU) was used. The body fat index was calculated with the sum of the cross-sectional areas (cm²).

Subsequently, all body composition measurements were standardized using height in meters squared and expressed as cm²/m². Total skeletal muscle area (TSMA), subcutaneous fat area (SFA) and visceral fat area (VFA), were used to calculate the total skeletal muscle index (TSMI = TSMA/m²), the subcutaneous adipose tissue index (SATI = SFA/m²), the visceral adipose tissue index (VATI = VFA/m²), respectively. The visceral to subcutaneous adipose tissue area ratio (VSR = VFA / SFA) was measured to explore the distribution of abdominal adipose tissue. Finally, we evaluated the relationship between VFA and TSMA, that is, the visceral fat muscle area index (VFMAI = VFA / TSMA), which was used as a measurement of SO.

The first and fourth quartiles were estimated for each index according to gender. For analysis purposes, the body composition indices were dichotomized as follows: in TSMI the first quartile was used to express the presence of sarcopenia; in VSR, VATI, SATI and VFMAI the third quartile was used to quantify visceral and subcutaneous adiposity and SO, respectively.

Sarcopenia was established when TSMI < 86.69 in males and < 68.86 in females, visceral obesity when VATI > 186.75 in males and > 136.62 in females, subcutaneous obesity > 109.76 in males and > 165.99 in females, distribution of visceral to subcutaneous obesity was measured using VSR > 2.19 in males and VSR > 1.04 in females, and finally SO diagnosed when VFMAI > 1.03 in males and > 0.72 in females.

Statistical analysis

Normality of the variables was verified with the Shapiro-Wilk test. The description of the qualitative data was done in the form of absolute frequencies and percentages and the quantitative data by mean and standard deviation, median, minimum and maximum. Comparison between qualitative data was performed using the Chi-square test or Fisher's exact test. Quantitative data were compared using the Student's t-test or the Mann-Whitney U test for ordinal data. A univariate and multivariate analysis with logistic regression was performed to detect factors associated with a higher rate of postoperative complications in colon cancer surgery and their degree of association by estimating their corresponding OR and their 95% confidence intervals. A statistically significant result was considered at a value of p < 0.05. For variables that were statistically significant in the multivariate analysis, the analysis of the ROC curve was performed and the area under the curve (AUC) was calculated. To assess diagnostic reliability, the Swets classification was used, classifying each of the diagnostic tests according to the AUC value. The STATA® Statistics software (Version 16) was used.

Clinic-pathological characteristics for a total of 544 patients included in the final analysis according to sex are reported in Table 1. A total of 135 patients (24.5% of males and 25.2% of females) were classified as having SO.

Complications were classified according to Clavien-Dindo, these were noted in 177 (32.3%) patients, of which 51 (9.31%) were severe (Clavien-Dindo > II). This study focused on four of the most frequent abdominal postoperative adverse events, these being: Anastomotic leak, paralytic ileus, surgical site infection and hemorrhagic complications. Anastomotic leak, the most frequent complication, with a total of 53 patients (9.74%), followed by paralytic ileus (9.01%), SSI occurred in 8.46% of the sample and last but not least, there were 27 cases (5.06%) of postoperative bleeding.

Univariate and multivariate analyses for overall postoperative morbidity risk factors are shown in (Table 2), these classified male sex [OR 1.79 (1.22–2.64); P = 0.003], hypercholesterolemia [OR 1.90 (1.29–2.81); P = 0.001], hypoproteinemia [OR 1.59 (1.04–2.42); P = 0.031] and SO [OR 1.55 (1.02–2.35); P = 0.041] as independent risk factors.

As is shown in Table 3, the incidence of postoperative mortality was independently related to older age [OR 1.14 (1.02–1.27); P = 0.020], dementia [OR 12.85 (2.12–77.83); P = 0.005], chronic liver disease [OR 17.36 (3.49–86.31); P = 0.000] and SO [OR 8.01 (1.77–36.34); P = 0.007].

Among specific abdominal complications (table 4), SO increased the risk of anastomotic leak [OR 1.48 (1.02–2.14); P = 0.007], but did not influence the incidence of paralytic ileus (P = 0.94), SSI (P = 0.91)or postoperative bleeding (P = 0.765). Patients with SO had longer hospital stays [OR 1.75 (1.18–2.60); P = 0.006] and a higher risk of reoperation [OR 1.48 (1.01–2.17); P = 0.047], this said, no effects on readmission (P = 0.54) or operative time (P = 0.08) could be demonstrated.

The current study has proven SO to be a risk factor of postoperative morbidity and mortality, with a noticeable effect on anastomotic leak. Numerous studies have shown a clear cause-effect between obesity and the incidence of colon cancer, especially in men ^9–13. The most accepted definition of obesity is high BMI. Although this has deficiencies when it comes to classifying patients, since it only takes into account weight and height, without considering other factors with defined metabolic effects ^14,15. In our study, BMI data were collected with the aim of demonstrating the difference with other factors that we consider more accurate when measuring obesity. Certain differences can be observed in the distribution of BMI between men and women. These gender weight disparities are likely influenced by sociocultural factors, diet, and alcohol consumption, among others ¹⁶.

A meta-analysis ¹⁷, made up of four studies, 3 retrospective and 1 prospective, revealed an increase in morbidity with a significant difference in favor of the viscerally obese, since it showed an incidence of 29.6% in visceral obese patients, compared to a 17.8% in non-obese patients [OR 2.33 (1.56–3.48); P < 0.0001]. On the contrary, in our cohort we have not been able to demonstrate differences in complications in obese versus non-obese patients.

Lieffers et al. ¹⁸ showed an overall prevalence of sarcopenia of 38.9% in a cohort of 234 patients with stage II-IV CRC. Miyamoto et al. ¹⁹ reported a 25% sarcopenia in 220 patients with stage I-III CRC. Vashi et al. ²⁰ described 41.1% sarcopenia in a series of 112 patients with CRC in stages I-IV. Our data is similar to that of Miyamoto et al. ¹⁹ with 25.18% of sarcopenia in our cohort of 545 patients with colon cancer (stages I-III). The differences with the other cohorts can be explained with the inclusion of patients in stage IV; since it is to be expected that patients with a more advanced oncological stage are more vulnerable to suffering from sarcopenia.

Several previously conducted studies have shown that preoperative sarcopenia is a predictor of postoperative complications in colon cancer surgery ^3,19–27, but our study failed to prove this, possibly due to the different cut-off points when defining radiological sarcopenia.

Regarding the association between obesity and sarcopenia, or SO in our sample it has an incidence of 25%, somewhat higher than the results published in the literature, which range from 6–18% according to the most recent series ^2,6.

It is of special interest that the analysis carried out could not demonstrate an association between sarcopenia, visceral obesity and postoperative abdominal complications when considering each factor as a stand-alone. However, the sum of the two factors, in the form of SO, increases this risk by more than 70%, [OR 1.71 (1.14–2.56); P = 0.009]. This suggests that SO could be a more accurate indicator of morbidity.

Other authors have investigated the relationship between SO and postoperative complications with similar results. For example, Chen et al. ³ reflect a surgical complication rate of 6.7% in the non-SO group compared to 31.7% in the SO group, with a significant difference (P < 0.001). Pedrazzani et al. ²⁷, when analyzing preoperative CT studies of 261 patients who underwent laparoscopic resection for CRC, found that SO was a risk factor for developing medical and surgical complications. Another study that reports the effect of SO is that of Malietzis et al. ⁴, with a higher risk of major complications (22 Vs 13.0%; P = 0.019).

Our model for the prediction of postoperative morbidity, built based on the factors resulting from the multivariate analysis: sex, dyslipidemia, hypoproteinemia, SO, demonstrated with the curve ROC with an AUC of 0.6311 providing satisfactory discrimination.

In the case of anastomotic leak specifically, preoperative detection of SO is useful in predicting the occurrence of gastric leaks after sleeve gastrectomy ²⁸ and increased the risk of pancreatic fistula after pancreaticoduodenectomy ²⁹. In addition, SO was considered a risk factor for severe postoperative complications and poorer long-term survival after gastrectomy for gastric cancer ³⁰. Regarding colon cancer surgery, there are contradictory results. In our study, a 1.5 times higher rate of anastomosis dehiscence can be observed in the group of patients with SO. Other authors found no relationship between OS and the leak rate ³¹. Berkel et al. ³² investigated the effect of SO on complications after neoadjuvant chemoradiation and surgery in rectal cancer, patients with SO had a 3-fold increased risk of developing a postoperative complication (OR between 3.2 and 3.8).

Malietzis et al. ⁴ showed a median 1-day increase in hospital stay in patients with SO. A statistically significant difference could not be demonstrated in terms of the other complications, nor in the conversion rate.

With regard to postoperative mortality we used detailed preoperative clinical data, collected according to standardized definitions, to assess risk factors for mortality in this patient population. Accurate risk stratification of the individual patient helps make safer treatment decisions.

SO as a predictor of mortality in colon cancer surgery is a relatively new concept, although it has already been described as a good predictor of postoperative mortality after pancreaticoduodenectomy for cancer ²⁹. In addition, it was described as a predictor of serious postoperative complications after open resection of the colon for cancer ³³. Although several studies have shown an association between OS and worse 5-year survival rates in colon cancer ^34,35, to date, a very limited number of studies show as clearly the association between OS and immediate postoperative mortality in the setting of colon cancer surgery [OR 6.29 (1.55–25.53); P = 0.010]. This is not surprising given its association with abdominal complications and more specifically anastomotic leak, which is the leading cause of direct or indirect postoperative mortality in our cohort.

What we can see from the results is that the most important thing in the case of postoperative complications is the preoperative condition of the patient, which opens up a horizon of possibilities when it comes to preoperative rehabilitation. This is consistent with other previous studies on risk factors for postoperative complications ^{5, 36,37}.

The clinical utility, population specificity, and good predictive capacity of this model are its advantages, which simplify and speed up the consent process for patients and provide another tool in pre-surgical rehabilitation protocols. This is of interest because patients who complete surgical prehabilitation experience a number of benefits compared to patients who undergo elective abdominal surgery without prehabilitation. These benefits include improved physiology during surgery, reduced complication rate, and lower costs ³⁸. A few studies have investigated the effectiveness of short term preoperative prehabilitation for sarcopenia through exercise and nutritional supplements with diverse outcomes ^39,40. However, studies demonstrating both the tools needed to improve preoperative SO and whether these changes can influence postoperative outcomes, are still lacking.

SO measured by CT is an easy tool to implement since it does not cause greater monetary expenditure for the institution or physical or psychological suffering for the patient, since it is an essential tool in the staging of all colon tumors and the calculations are easy to master for non radiologist personnel.

CT measured SO is associated with an increased risk of postoperative morbidity and mortality in colon cancer surgery. Specifically, it contributes to an increased risk of anastomotic leak. It can also be considered an easy to implement tool in surgical prehabilitation programs, although more prospective clinical trials are needed to determine which measures should be undertaken to improve preoperative SO, taking in consideration that colon cancer surgery is time sensitive.

There were some limitations in this study. First, this was a single-center study. In addition, this study was retrospective. Second, the procedures are carried out by a heterogeneous group of surgeons.

There were no conflicts of interest

There was no funding or financial support of any kind

The manuscript has not been a podium or poster meeting presentation

Author contributions:

Mariam Bajawi: conceived and designed the study, acquired and analyzed the data, and drafted the manuscript

Sara Corral: project development, manuscript revision

Javier Blázquez: provided expertise in the field of radiology and contributed to the interpretation of the results

Javier Die: project development

Paula Muñoz: project development

Alberto G Barranquero: project development

Luz Juez: data collection and analysis

Francisca García-Moreno Nisa: provided critical feedback, and ensured the accuracy and integrity of the research.

All authors have read and approved the final version of the manuscript.

HUMAN ETHICS AND CONSENT TO PARTICIPATE DECLARATIONS: NOT APPLICABLE

Acknowledgements

We would like to thank the Radiology department at Ramón y Cajal University hospital for their technical assistance and dedication throughout the project.

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Table (1): Characteristics of the sample

	Males (n: 310 )	Females (n: 234)
Mean age, years (±SD)	71.9 ± 11	73.5 ± 11
BMI Underweight Normal Overweight Obese	1.94% 24.52% 50.97% 22.58%	4.7% 34.62% 36.32% 24.36%
ASA I II III IV	4.70% 58.97% 35.47% 0.85%	5.81% 55.16% 38.39% 0.65%
HTN	62.46%	58.55%
DM	26.77%	17.52%
Hypercholesterolemia	32.36%	35.04%
Heart disease	20.71%	14.53%
Cerebrovascular disease	8.77%	8.15%
PAD	6.13%	0.43%
Smoking Active Ex-smoker	15.81% 30.65%	11.54% 8.55 %
Chronic lung disease	13.92%	11.54%
CKD	11.61%	4.70%
Dementia	2.58%	2.56%
Chronic liver disease	5.16%	3.85%
Anemia	57%	42%
Hypoproteinemia	24.2%	26.5%
Visceral Obesity	38.1%	33.3%
Sarcopenia	27.8%	27.2%
Sarcopenic obesity	24.5%	25.2%
Previous abdominal surgery	23.6%	32.5%
Tumor location Right-sided Left-sided	42.2% 57.8%	57.5% 42.5%
TNM I II III	24.84% 40% 35.15%	29.91% 37.17% 32.91%
Approach Laparoscopic Open Conversion	54.70% 38.46% 7.10%	30.32% 62.58% 6.84%

Table (2): Univariate and multivariate analyses for postoperative morbidity risk factor

	Postoperative morbidity n= 177	No postoperative morbidity n= 366	Univariate analysis P value	Multivariate analysis
	Postoperative morbidity n= 177	No postoperative morbidity n= 366	Univariate analysis P value	Odds ratio (95% CI)	P value
Mean age, years (±SD)	74.6∓ 9.9	71.6∓ 11.1	0.002
Sex Male Female	114 (36.77 %) 63 (27.04%)	196 (63.23%) 170 (72.96%)	0.017	1.22 - 2.64	0.003
BMI <30 >=30	140 (33.57%) 37 (29.37%)	277 (66.43%) 89 (70.63%)	0.377
ASA <III =>III	93 (27.60%) 84(40.78%)	244 (72.40%) 122 (59.22%)	0.001
HTN	118 (66.67%)	211 (57.81%)	0.048
DM	77 (21.04%)	47 (26.55%)	0.151
Hypercholesterolemia	47 (26.55%)	77 (21.04%)	0.001	1.29 - 2.81	0.001
Heart disease	64 (17.53%)	34 (19.21%)	0.635
Cerebrovascular disease	16 (9.14%)	30 (8.22%)	0.719
PAD	11 (6.21%)	9 (2.46%)	0.029
Smoking Active Ex-smoker	20 (11.30%) 45 (25.42%)	56 (15.30%) 70 (19.13%)	0.158
Chronic lung disease	28 (15.82%)	42 (11.51%)	0.160
CKD	23 (12.99%)	24 (6.56%)	0.012
Dementia	5 (2.82%)	9 (2.46%)	0.801
Chronic liver disease	10 (5.65%)	15 (4.10%)	0.421
Anemia	53 (29.94%)	67 (18.31%)	0.002
Hypoproteinemia	53 (29.94%)	67 (18.31%)	0.002	1.04 - 2.42	0.031
Visceral Obesity	60 (33.9%)	84 (22.95%)	0.058
Sarcopenia	57 (32.19%)	97 (26.50%)	0.261
Sarcopenic obesity	49 (27.69%)	78 (21.31%)	0.009	1.02 - 2.35	0.041
Previous abdominal surgery	56 (31.64%)	92 (25.14%)	0.111
Tumor location Right-sided Left-sided	103 (35.3%) 74 (29.5%)	189 (64.7%) 177 (70.5%)	0.151
TNM I II III	47 (32%) 70 (33%) 60 (32%)	100 (68%) 140 (67%) 126 (68%)	0.957
Approach Laparoscopic Open Conversion	92 (51.98%) 73 (41.24%) 12 (6.78%)	192 (52.46%) 148 (40.44%) 26 (7.10%)	0.979
Table (2): Univariate and multivariate analyses for postoperative morbidity risk factors

Table (3): Univariate and multivariate analyses for postoperative mortality risk factors

	Postoperative mortality n= 9 (1.65%)	No postoperative mortality n= 535 (98.35%)	Univariate analysis P value	Multivariate analysis
	Postoperative mortality n= 9 (1.65%)	No postoperative mortality n= 535 (98.35%)	Univariate analysis P value	Odds ratio (95% CI)	P value
Mean age, years (±SD)	82 ± 6.17	72 ± 10.83	0.008	1.02 - 1.27	0.02
Sex Male Female	6 (1.94%) 3 (1.28%)	304 (98.06%) 231 (98.72%)	0.557
BMI <30 >=30	7 (1.68%) 2 (1.57%)	410 (98.32%) 125 (98.43%)	0.936
ASA <III =>III	3 (0.89%) 6 (2.91%)	335 (99.11%) 200 (97.09%)	0.090
HTN	8 (2.42%)	1 (0.47%)	0.082
DM	5 (4.03%)	4 (0.95%)	0.018
Hypercholesterolemia	6 (3.30%)	3 (0.83%)	0.034
Heart disease	4 (4.08%)	5 (1.12%)	0.038
Cerebrovascular disease	0	9 (1.82%)
PAD	1 (5.00%)	8 (1.53%)	0.232
Smoking Active Ex-smoker	0 3 (33.33%)	76 (14.21%) 112 (20.93%)	0.541
Chronic lung disease	0	70 (13.11%)
CKD	2 (4.26%)	7 (1.41%)
Dementia	2 (14.29%)	7 (1.32%)	0.003	2.12 - 77.83	0.005
Chronic liver disease	3 (12.00%)	6 (1.16%)	0.001	3.49 - 86.31	0.000
Anemia	4 (3.33%)	5 (1.18%)	0.102
Hypoproteinemia	4 (2.92%)	5 (1.23%)	0.179
Visceral Obesity	3 ( 2.17%)	6 (1.48%)	0.580
Sarcopenia	2 (1.46%)	7 (1.72%)	0.836
Sarcopenic obesity	6 (4.44%)	3 (0.73%)	0.003	1.77 - 36.34	0.007
Previous abdominal surgery	4 (2.68%)	5 (1.27%)	0.247
Tumor location Right-sided Left-sided	6 (2.05%) 3 (1.2%)	286 (97.95%) 249 (98.8%)	0.431
TNM I II III	3 (2.04%) 4 (1.9%) 2 (1.08%)	144 (97.96%) 207 (98.10%) 184 (98.92%)	0.743
Approach Laparoscopic Open Conversion	6 (2.11%) 3 (1.35%) 0	278 (97.89%) 219 (98.65%) 38 (100%)	0.568

Table(4): Effect of sarcopenic obesity on colon cancer surgery and postoperative outcomes

	P Value	OR	IC 95%
Overall morbidity	0.009	0.041	1.02 - 2.35
Post Op mortality	0.003	0.007	1.77 - 36.34
Anastomotic Leak	0.218	0.024	1.05 -1.92
Postoperative bleeding	0.765	1.09	0.62 - 1.91
Ileo paralítico	0.94	1.02	0.65 - 1.60
Paralytic ileus	0.94	1.02	0.65 - 1.60
Abdominal wound dehiscence	0.69	0.73	0.17 - 3.08
Surgical site infection	0.91	0.73	0.53 - 1.56
Readmission	0.54	1.23	0.63 - 2.38
Reoperation	0.047	1.48	1.01 - 2.17
Operative time	0.08	0.77	-10.18 - 7.58
Length of hospital stay	0.006	1.75	1.18 - 2.60

No competing interests reported.

Impact of Ct-measured Sarcopenic Obesity on Postoperative Outcomes Following Colon Cancer Surgery

Status:

Journal Publication

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Abstract

Purpose

Methods

Results

Conclusions

Introduction

Materials and Methods

Short-Term Post-surgery Morbidity

Body composition parameters measurements

Statistical analysis

Results

Discussion

Conclusions

Limitations of the study

Declarations

References

Tables

Additional Declarations

Status:

Journal Publication

Version 1