Horio Y, Uchino M, Tomoo Y, Nomura K, Nagano K, Kusunoki K, Kuwahara R, Kimura K, Sato T, Kataoka K, Igeta M, Shinzaki S, Ikeda M, Ikeuchi H. Preoperative performance status was associated with postoperative fatal complications in elderly patients with refractory ulcerative colitis. World J Gastrointest Surg 2025; 17(8): 109326 [DOI: 10.4240/wjgs.v17.i8.109326]
Corresponding Author of This Article
Yuki Horio, MD, PhD, Lecturer, Department of Gastroenterological Surgery, Hyogo Medical University, 1-1, Mukogawa-cho, Nishinomiya 663-8501, Hyogo, Japan. yu-horio@hyo-med.ac.jp
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Retrospective Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Author contributions: Horio Y was responsible for conception and design of the study; acquisition, analysis, and interpretation of data; and drafting of the article; Igeta M was responsible for analysis and interpretation of data; Tomoo Y, Nomura K, Nagano K, Kusunoki K, Kuwahara R, Kimura K, Kataoka K, and Sato T were responsible for conception and design of the study; acquisition, analysis, and interpretation of data; Uchino M, Shinzaki S, Ikeda M, and Ikeuchi H were responsible for acquisition of data, drafting or critical revision of the article for important intellectual content, and final approval.
Institutional review board statement: All human studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All study protocols were approved by the institutional review board of Hyogo Medical University (No. 3811).
Informed consent statement: Informed consent and agreement for the use of patient data were obtained before surgery was commenced. Written informed consent was obtained using the opt-out method. An opt-out informed consent protocol was used for the use or collection of participant data for research purposes. This consent procedure was reviewed and approved by the institutional review board of Hyogo Medical University (approval number: 3811; date of decision: June 18, 2021).
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement:sharing statement: All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yuki Horio, MD, PhD, Lecturer, Department of Gastroenterological Surgery, Hyogo Medical University, 1-1, Mukogawa-cho, Nishinomiya 663-8501, Hyogo, Japan. yu-horio@hyo-med.ac.jp
Received: May 8, 2025 Revised: May 19, 2025 Accepted: June 12, 2025 Published online: August 27, 2025 Processing time: 110 Days and 6.6 Hours
Abstract
BACKGROUND
Elderly patients with refractory ulcerative colitis (UC) have a poor prognosis, and timely surgical intervention should not be delayed. However, with the advent of biologics, therapy has become more complex, and there are no clear criteria for the timing of surgical conversion.
AIM
To investigate the risk factors for postoperative complications in elderly patients with UC.
METHODS
Elderly patients (≥ 60 years old) with refractory UC who underwent colectomy at Hyogo Medical University between April 2012 and March 2024 were included in this study. Fatal complications included life-threatening complications requiring intensive care unit management and death. The primary outcome was defined by possible risk factors for fatal complications in older patients with refractory UC.
RESULTS
A total of 191 elderly patients with UC were analyzed in this series. The rate of fatal complications was 18/191 (9.4%), and the most common complication was pneumonia due to disuse syndrome. Body mass index (BMI) < 17 kg/m2 [odds ratio (OR) = 4.08, 95% confidence interval (95%CI): 1.19-13.97, P = 0.02] and Eastern Cooperative Oncology Group performance status (ECOG-PS) ≥ 3 (OR = 14.5, 95%CI: 3.43-61.64, P < 0.01) were identified as independent risk factors for fatal complications.
CONCLUSION
Among the elderly patients with refractory UC, the risk factors for fatal complications were low BMI and ECOG-PS score. Prompt surgical intervention is recommended before the patient loses weight or has difficulty walking. These factors may allow for early surgical decision-making before patients become debilitated.
Core Tip: This study identified low body mass index (< 17 kg/m²) and poor Eastern Cooperative Oncology Group performance status (≥ 3) as independent risk factors for fatal postoperative complications in elderly patients with refractory ulcerative colitis. The most common fatal complication was pneumonia due to disuse syndrome. These findings emphasize the importance of early surgical intervention before significant functional decline or weight loss occurs. In the era of complex biologic therapies, these simple, clinically assessable markers offer practical guidance for timely surgical decision-making in high-risk elderly patients.
Citation: Horio Y, Uchino M, Tomoo Y, Nomura K, Nagano K, Kusunoki K, Kuwahara R, Kimura K, Sato T, Kataoka K, Igeta M, Shinzaki S, Ikeda M, Ikeuchi H. Preoperative performance status was associated with postoperative fatal complications in elderly patients with refractory ulcerative colitis. World J Gastrointest Surg 2025; 17(8): 109326
Japan currently has the highest percentage of elderly people in the world; however, other Western countries are expected to face aging issues in the future. In addition, it has been predicted that one-third of patients with inflammatory bowel disease (IBD) will be those over the age of 60 years by 2030[1]. Elderly patients with ulcerative colitis (UC) are at an increased risk of infectious complications and mortality during medical therapy[2,3]. Although it is established that aging affects postoperative complications in surgical care, the turnaround time for elderly patients with UC is less well reported and controversial[4]. While some studies have reported that the postoperative complication rate in elderly patients with UC who underwent surgery was similar to that in younger patients, others have reported higher rates of postoperative complications and mortality[5-8]. We previously reported that being elderly was a risk factor for postoperative complications when compared with younger age[9]. We also reported that emergency surgery had a particularly poor prognosis and high mortality rate in elderly patients with UC[10]. It has been reported that the prognosis of emergency surgery for UC is poor and that elective surgery is preferable[11,12]. Delayed surgery is also a risk factor for postoperative complications in elderly patients with UC[13]. However, in the biologic era, medical treatment options have rapidly increased in number and complexity, making the decision to opt for surgery more difficult in patients with refractory diseases than in those with cancer. Additionally, no clear criteria for relative surgical indications is present. It can be very complex and difficult to accurately assess the condition of elderly patients because of age-related changes, lack of symptoms such as fever, and comorbidities that make physical assessment difficult[14]. Therefore, this leads to unnecessary continuation of medical treatment and the referral of some patients with disuse syndrome for surgery. From the above, it is important to consider the risk factors for postoperative complications in elderly patients with refractory UC, timing of surgical decisions, and optimization of medical management to avoid emergency surgery and improve prognosis. The aims of our study were to retrospectively investigate the patient characteristics, the operative parameters, and the postoperative complications in elderly patients with UC who underwent colectomy. We also analyzed possible risk factors for postoperative complications limited to refractory diseases.
MATERIALS AND METHODS
Patient selection
Patients with UC who underwent colectomy at Hyogo Medical University between April 2012 and March 2024 were included in this study. Elderly patients were defined as those aged ≥ 60 years at the time of surgery. To examine the risk factors for postoperative complications in older patients with refractory UC, patients with cancer were excluded. Sex, age at onset, age at initial surgery, elderly onset, disease duration, disease severity, serum albumin (Alb) level, C-reactive protein level, total lymphocyte count, body mass index (BMI), Eastern Cooperative Oncology Group performance status (ECOG-PS), smoker status, American Society of Anesthesiologists score, Carlson risk index, total administered prednisolone dose, preoperative prednisolone administration, immunomodulator (thiopurines, including azathioprine and 6-mercaptopurine) administration, calcineurin inhibitor (tacrolimus and cyclosporine A) administration, Janus kinase inhibitor (tofacitinib) administration, biologic (infliximab, adalimumab, golimumab, and vedolizumab) administration, urgent/emergent or elective surgery, laparoscopic surgery or laparotomy, surgical procedure [total colectomy (TC), abdominal perineal resection, or pouch surgery], operative time, amount of blood loss, and intraoperative blood transfusion were retrospectively determined using clinical records. Severe disease was assessed primarily according to clinical features using the criteria of Truelove and Witts: Six or more stools with blood and one or more of the following: Hemoglobin level < 105 g/L, ESR > 30 mm/hour, body temperature > 37.8 °C, or pulse rate > 90/minute[15]. The total amount of corticosteroids administered was converted into the prednisolone dose and calculated based on the administered corticosteroid dose since the initial onset of UC. Patients who received immunomodulators, calcineurin inhibitors, or Janus kinase inhibitors within 72 hours before surgery, regardless of the dosage, were included. All infusions administered within 12 weeks before surgery were considered biologically administered.
Surgical indications and timing of surgery
The absolute indications for emergent surgery include massive bleeding, toxic megacolon, and perforation at our institution. The indications for urgent surgery to be performed within the first 24 hours of hospitalization include: (1) Severe colitis that is unresponsive to aggressive pharmacotherapies; and (2) Less severe colitis with medically intolerable adverse drug reactions in a patient with a declining general condition. The indications for elective surgery are refractory diseases or extraintestinal manifestations in patients without a declining general condition. Our standard surgical procedures for UC include restorative proctocolectomy with IPAA. Even among elderly individuals, IPAA was performed in those who desired anal preservation if they had favorable preoperative physical condition, good sphincter function, and understanding of expected postoperative functional outcomes. Abdominoperineal resection was performed in patients with poor sphincter function and a history of perianal disease (e.g., fissure, fistula, or abscess). TC with end ileostomy (mucous fistula or Hartmann procedure) was primarily performed as an urgent or emergent surgery. These procedures were performed in patients with free perforation, toxic megacolon, or fulminant colitis that was progressing to severe sepsis or septic shock.
Laparoscopic surgery is indicated for elective surgery and a stable preoperative general condition in either young or old people. We did not perform laparoscopic surgery in emergency cases involving fulminant disease, perforation, toxic megacolon, or massive bleeding.
Definition of postoperative complications
Postoperative complications were defined as unexpected medical events that occurred between the end of surgery and hospital discharge. The following were included: (1) Incisional surgical site infection (SSI) was identified by signs such as erythema, induration, purulent drainage, or dehiscence at the wound site. Cases in which the wound infection was managed by bedside opening were included in this category; (2) Organ/space SSI referred to abdominal or pelvic abscesses, including anastomotic leakage. These were diagnosed using gastrografin enema, abdominal ultrasonography, or computed tomography (CT), and cases that required medical therapy were included; (3) Bloodstream infections were confirmed by positive blood cultures. Complications were included if they required medical therapy; (4) Pneumonia was diagnosed based on findings from plain radiography or CT scans, and cases that necessitated pharmacological intervention were considered postoperative complications; (5) Other infections comprised urinary tract infections and fevers exceeding 38 °C from either known or unknown sources. Urinary tract infections were confirmed by urine culture. Fever of unknown origin was diagnosed when no causative organism or antigen was detected in blood or urine cultures, and no evident infection was present in the wound, abdomen, or pelvis, nor was any other clear cause identified; (6) Obstruction and ileus were diagnosed using plain radiography or CT. Complications were counted when intravenous nutritional support was needed; (7) Postoperative bleeding included both intra-abdominal and gastrointestinal hemorrhages, such as those from gastric, duodenal, or small intestinal ulcers, as well as anastomotic bleeding. These were identified using endoscopy or CT, and included if treatment such as proton pump inhibitors or blood transfusions was administered; (8) Thrombosis was detected using echocardiography or CT imaging. Inclusion required that the patient underwent anticoagulant therapy; (9) Urinary retention was defined by the necessity of urinary catheterization and administration of medications (e.g., cholinergic agonists) based on urologist evaluation; and (10) High-output stoma was characterized by stoma output of ≥ 2000 mL per day for at least two consecutive days. Complications were included when intravenous fluid replacement was needed due to resulting electrolyte imbalance.
Outcome measures
All complications were ranked according to the Clavien-Dindo classification[16]. Fatal complications included life-threatening complications requiring ICU management (grade IV) and death (grade V)[17]. The patients were divided into a fatal complication group or a non-fatal complication group. The primary outcome was the identification of risk factors associated with fatal complications in elderly patients with UC.
Statistical analysis
Categorical variables were compared using the chi-squared test or Fisher’s exact test. Continuous variables were expressed as medians (quartile ranges) or means (SD). Continuous variables were compared using the Mann-Whitney U test or ANOVA. The level of statistical significance was set at P < 0.05. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated for all variables in the univariate analysis. Multivariate logistic regression analysis was performed to evaluate the risk factors for fatal complications in elderly patients with UC, with P values < 0.10. JMP version 17 (SAS Institute, Inc., Cary, NC, United States) was used for all analyses.
RESULTS
Patient characteristics
We performed 294 colectomies in elderly patients preoperatively diagnosed with UC. Ninety-two patients had cancer, three were diagnosed with Crohn’s disease after surgery, and eight had insufficient data or underwent the initial surgery at another hospital. A total of 191 patients with UC were analyzed in this series (Figure 1).
Figure 1 Flow chart of patients with ulcerative colitis.
UC: Ulcerative colitis.
Postoperative complications are presented in Table 1. The complication rate (from grade I) was 118/191 (61.7%), the rate of fatal complications was 18/191 (9.4%), and the rate of complications of Clavien-Dindo classification grade IV was 4/191 (2%) patients with a median length of stay of 87.5 days (37-142 days). The complications were caused by sepsis due to organ/space infection in one case, sepsis due to meningitis in one case, and pneumonia due to disuse syndrome in two cases. The rate of complications of Clavien-Dindo classification grade V was 14/191 (7.3%) patients, with a median length of stay of 49.5 days (2–155 days). The complications were caused by pneumonia due to disuse syndrome in eight cases, bleeding due to digestive ulcers in four cases, sepsis due to organ/space infection in one case, and sepsis due to bloodstream infection and infective endocarditis in one case.
The clinical characteristics of the patients classified into a fatal complication or non-fatal complication group are presented in Table 2. The rate of severe disease was significantly higher (P = 0.03), BMI was significantly lower (P = 0.02), and the rate of ECOG-PS ≥ 3 was significantly higher (P < 0.01) among patients in the fatal complication group than among those in the non-fatal complication group. Regarding pharmacotherapy, the rate of immunomodulator administration was significantly lower (P = 0.02) among patients in the fatal complication group than among those in the non-fatal complication group. Regarding surgical factors, the rate of urgent/emergent surgery was significantly higher (P < 0.01) among patients in the fatal complication group than among those in the non-fatal complication group. This tended to result in a higher TC rate in the fatal complication group than in the non-fatal complication group. Conversely, a significantly lower rate of abdominal perineal resection (P = 0.04) and a lower rate of pouch surgery resulted in a significantly shorter operative time (P < 0.01).
Univariate and multivariate analyses were performed to identify independent risk factors for fatal complications. The results of the analyses of risk factors potentially associated with fatal complications are presented in Table 3. The nine clinically significant factors, including age at surgery, severe disease, BMI < 17 kg/m2 (low BMI: Moderate and severe thinness by World Health Organization), preoperative prednisolone, immunomodulator administration, urgent/emergent surgery, ECOG-PS ≥ 3, lymphocyte count, and Charlson risk index ≥ 3, were entered into the multivariate logistic regression model. BMI < 17 kg/m2 (OR = 4.08, 95%CI: 1.19-13.97, P = 0.02) and ECOG-PS ≥ 3 (OR = 14.5, 95%CI: 3.43-61.64, P < 0.01) were identified as independent risk factors for fatal complications.
Table 3 Logistic regression analysis of risk factors for fatal complications1.
To our best knowledge, there are no reports on the risk factors for postoperative complications in elderly patients with refractory UC. The study’s findings suggest that low BMI and ECOG-PS are risk factors for fatal complications in elderly patients with refractory UC. The most common fatal complication was pneumonia due to disuse syndrome. These findings provide valuable indicators for supporting surgical decision-making when managing elderly patients with UC who have diverse medical therapy options.
In the era of biologics, reports have indicated that postoperative complications and mortality rates have increased despite a decrease in surgical rates in patients with UC[18]. Risk factors for postoperative complications include corticosteroid use, biologics use, severe disease, low Alb levels, and preoperative comorbidities, while risk factors for postoperative mortality include age, emergency surgery, and comorbidities[12-22]. Therefore, we investigated whether these known risk factors were also relevant in the UC cohort. In the present study, univariate analysis showed significant differences between severe disease and emergency surgery; however, these were not identified as independent factors in the multivariate analysis. This finding may be explained by the reduced physiological reserve, malnutrition, and multiple comorbidities often present in elderly patients, which may have confounded the association between disease severity, emergency surgery, and fatal outcomes in our study[23]. Regarding BMI, obesity has been reported as a risk factor for surgical complications in patients with IBD, mainly manifesting as infectious complications, as reported in a systematic review[24]. Conversely, a low BMI has been reported to be associated with postoperative complications, as well as a high activity index and low Alb level, both of which predict more severe disease after hospitalization and the need for colectomy[25-27]. A high BMI is less frequently observed in elderly patients than in younger populations, possibly because of age-related changes in body composition and baseline nutritional status. As a result, obesity-related surgical risks may be less relevant in this population.
The ECOG-PS is a clinically reported functional status score in oncology practice and has long been used as a simple scale for assessing decline in muscle strength and physical performance[28]. The ECOG-PS scale can be applied daily in a simplified manner and has been reported to exhibit fewer inter-observer differences than Karnofsky Performance Status[29]. In our cohort, patients classified as ECOG-PS ≥ 3 were non-ambulatory and spent more than 50% of their day in bed or on a seat, strongly suggesting an underlying decline in physical function and muscle strength. Sarcopenia, as an indicator of skeletal muscle loss, is also important for predicting the development of UC in elderly patients, the need for medical rescue therapy, and future colectomy. Sarcopenia has been reported to be associated with increased postoperative complications[30-33]. As sarcopenia is also observed in overweight patients, it is useful as an objective marker that does not correlate with BMI. In other words, because BMI and muscle weakness are associated with exacerbation of disease activity, increased risk of surgery, and even risk of postoperative complications, they are expected to serve as decision indicators for surgical conversion and the basis for persuading patients against surgery. Sarcopenia can be diagnosed using objective methods such as dual X-ray absorptiometry, bioelectrical impedance analysis, and CT[34]. However, these techniques are not always feasible in acute care settings, and most frailty assessment tools are too complex for routine use[35]. Although ECOG-PS does not directly measure muscle mass or strength, it remains a simple and practical screening tool for detecting functional decline, particularly in elderly patients.
Based on the results of this study, low BMI and muscle weakness should be assessed during the medical treatment phase as a countermeasure for elderly patients with UC. Future prospective studies should determine whether early introduction of nutritional therapy and rehabilitation improves outcomes in high-risk patients. The reason for mentioning intervention at the early stage is that few studies have recommended the administration of enteral nutrition or total parenteral nutrition (TPN) immediately before surgery in UC surgery cases, which is considered too late for intervention. In a comparative study of 56 patients with UC undergoing surgery who received TPN for at least 7 days before surgery and 179 controls, there was no difference in postoperative complications, and preoperative TPN had no significant effect on postoperative outcomes[36]. However, randomized controlled trials that compared complete enteral nutrition to standard therapy for hospitalized patients with UC have reported promising results[37].
The present study had some limitations. First, it was a retrospective study conducted at a single institution. Second, although the number of elderly patients in our study was higher than that in previous reports, the sample size was limited. The number of patients analyzed for fatal complications was particularly small. Third, the ECOG-PS is susceptible to bias, possible inter-observer variability, or lack of objectivity. Furthermore, because CT was not performed in all patients, sarcopenia, an objective measure, could not be evaluated simultaneously. In the future, it would be essential to examine whether the ECOG-PS can be used as a daily supplementary index for evaluating sarcopenia.
CONCLUSION
Of all deaths due to refractory UC in the elderly, many are caused by pneumonia due to postoperative disuse syndrome. The risk factors for fatal complications are low BMI and ECOG-PS. In elderly patients who are underweight or have reduced mobility, careful perioperative management is essential to prevent postoperative complications. As more medical treatment options become available in the future and the decision to proceed with surgery is delayed, the evaluation of these risk factors may allow for early surgical decision-making before the patient becomes debilitated.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: Japan
Peer-review report’s classification
Scientific Quality: Grade A
Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade A
P-Reviewer: Yu ZK S-Editor: Lin C L-Editor: A P-Editor: Zhang XD
Cottone M, Kohn A, Daperno M, Armuzzi A, Guidi L, D'Inca R, Bossa F, Angelucci E, Biancone L, Gionchetti P, Ardizzone S, Papi C, Fries W, Danese S, Riegler G, Cappello M, Castiglione F, Annese V, Orlando A. Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease.Clin Gastroenterol Hepatol. 2011;9:30-35.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 295][Cited by in RCA: 273][Article Influence: 19.5][Reference Citation Analysis (0)]
Horio Y, Uchino M, Kusunoki K, Minagawa T, Kuwahara R, Kimura K, Kataoka K, Beppu N, Ikeda M, Ikeuchi H. Being Elderly Is Associated with Infectious and Fatal Postoperative Complications in Ulcerative Colitis Patients.Digestion. 2022;103:470-479.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 1][Reference Citation Analysis (0)]
Colombo F, Sahami S, de Buck Van Overstraeten A, Tulchinsky H, Mege D, Dotan I, Foschi D, Leo CA, Warusavitarne J, D'Hoore A, Panis Y, Bemelman W, Sampietro GM. Restorative Proctocolectomy in Elderly IBD Patients: A Multicentre Comparative Study on Safety and Efficacy.J Crohns Colitis. 2017;11:671-679.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 5][Cited by in RCA: 10][Article Influence: 1.3][Reference Citation Analysis (0)]
Hill SS, Ottaviano KE, Palange DC, Chismark AD, Valerian BT, Canete JJ, Lee EC; NSQIP-IBD Collaborative. Impact of Preoperative Factors in Patients With IBD on Postoperative Length of Stay: A National Surgical Quality Improvement Program-Inflammatory Bowel Disease Collaborative Analysis.Dis Colon Rectum. 2024;67:97-106.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 7][Reference Citation Analysis (0)]
Fernandez C, Gajic Z, Esen E, Remzi F, Hudesman D, Adhikari S, McAdams-DeMarco M, Segev DL, Chodosh J, Dodson J, Shaukat A, Faye AS. Preoperative Risk Factors for Adverse Events in Adults Undergoing Bowel Resection for Inflammatory Bowel Disease: 15-Year Assessment of the American College of Surgeons National Surgical Quality Improvement Program.Am J Gastroenterol. 2023;118:2230-2241.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 6][Cited by in RCA: 11][Article Influence: 5.5][Reference Citation Analysis (0)]
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group.Am J Clin Oncol. 1982;5:649-655.
[PubMed] [DOI]
Gilbert T, Neuburger J, Kraindler J, Keeble E, Smith P, Ariti C, Arora S, Street A, Parker S, Roberts HC, Bardsley M, Conroy S. Development and validation of a Hospital Frailty Risk Score focusing on older people in acute care settings using electronic hospital records: an observational study.Lancet. 2018;391:1775-1782.
[RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)][Cited by in Crossref: 770][Cited by in RCA: 1028][Article Influence: 146.9][Reference Citation Analysis (0)]