Impact on defecatory, urinary and sexual function after high-tie sigmoidectomy: a post-hoc analysis of a multicenter randomized controlled trial comparing extended versus standard complete mesocolon excision.

OBJECTIVE: To assess the effect of high inferior mesenteric artery tie on defecatory, urinary, and sexual function after surgery for sigmoid colon cancer. Performing a sigmoidectomy poses a notable risk of causing injury to the preaortic sympathetic nerves during the high ligation of the inferior mesenteric artery, as well as to the superior hypogastric plexus during dissection at the level of the sacral promontory. Postoperative defecatory and genitourinary dysfunction after sigmoid colon resection are often underestimated and underreported. METHODS: This study is a secondary research of a multicenter, single-blind, randomized clinical trial. The trial involved patients with sigmoid cancer who underwent either extended complete mesocolic excision (e-CME) or standard CME (s-CME). Patients completed questionnaires to assess defecatory, urinary, and sexual function before, 1 month after surgery, and 1 year after surgery. Multivariate analysis was conducted to identify factors associated with functional dysfunction. RESULTS: Seventy-nine patients completed functional assessments before and 1 year after surgery. One year after sigmoidectomy with a high tie of the inferior mesenteric artery, 15.2% of patients had minor low anterior resection syndrome (LARS) and 12.7% had major LARS; 22.2% of males and 29.4% of females had urinary dysfunction; and 43.8% of males and 27.3% of females had sexual dysfunction. After multivariate analysis, no significant associations were found between clinical and surgical factors and gastrointestinal or urinary dysfunction after 1 year of surgery. Age was identified as the only factor linked to sexual dysfunction in both sexes (women, ß = - 0.54, p = 0.002; men ß = - 0.38, p = 0.010). Regarding recovery outcomes, diabetes mellitus was identified as a contributing factor to suboptimal gastrointestinal recovery (p = 0.033) and urinary recovery in women (p = 0.039). Furthermore, the treatment arm was found to be significantly associated with the recovery of erectile function after 1 year of surgery (p = 0.046). CONCLUSIONS: A high tie of the inferior mesenteric artery during sigmoidectomy is associated with a high incidence of defecatory and genitourinary dysfunction. Age was identified as a significant factor associated with sexual dysfunction 1 year after sigmoid colon resection in both sexes. TRIAL REGISTRATION: Clinical trials NCT03083951 HIGHLIGHTS: • One year after high-tie sigmoidectomy, 27.9% of patients had LARS; 22.2% of the men and 29.4% of the women had urinary dysfunction; and 43.8% of the men and 27.3% of the women had sexual dysfunction. • e-CME is associated with a high rate of urinary dysfunction in men 1 year after surgery. However, after multivariate analysis, no association was found between e-CME and urinary dysfunction in men. • Age was correlated with the recovery of sexual function in both sexes 1 year after surgery. Furthermore, diabetes mellitus was identified as the factor associated with poorer recovery of urinary function in females.

Extended Versus Standard Complete Mesocolon Excision in Sigmoid Colon Cancer: A Multicenter Randomized Controlled Trial.

OBJECTIVE: The aim of this study was to evaluate whether extended complete mesocolic excision (e-CME) for sigmoid colon cancer improves oncological outcomes without compromising morbidity or functional results. BACKGROUND: In surgery for cancer of the sigmoid colon and upper rectum, s-CME removes the lymphofatty tissue surrounding the inferior mesenteric artery (IMA), but not the lymphofatty tissue surrounding the portion of the inferior mesenteric vein that does not run parallel to the IMA. Evidence about the safety and efficacy of extending CME to include this tissue is lacking. METHODS: This single-blind study randomized sigmoid cancer patients at 4 centers to undergo e-CME or s-CME. The primary outcome was the total number of lymph nodes harvested. Secondary outcomes included disease-free and overall survival at 2 years, morbidity, and bowel and genitourinary function. Clinicaltrials.gov: NCT03107650. RESULTS: We analyzed 93 patients (46 e-CME and 47 s-CME). Perioperative outcomes were similar between groups. No differences between groups were found in the total number of lymph nodes harvested [21 (interquartile range, IQR, 14-29) in e-CME vs 20 (IQR, 15-27) in s-CME, P = 0.873], morbidity (P = 0.829), disease-free survival (P = 0.926), or overall survival (P = 0.564). The extended specimen yielded a median of 1 lymph node (range, 0-6), none of which were positive.Bowel function recovery was similar between arms at all timepoints. Males undergoing e-CME had worse recovery of urinary function (P = 0.026). CONCLUSION: Extending lymphadenectomy to include the IMV territory did not increase the number of lymph nodes or improve local recurrence or survival rates.

Pure Laparoscopic Anatomic Resection of the Segment 8 Dorsal Area Using the Dorsal Approach of the Right Hepatic Vein.

BACKGROUND: Anatomical resection of segment 8 (s8) is a challenging procedure. S8 can be subdivided into two areas: ventral (s8v) and dorsal (s8d). In the last years, different approaches for performing laparoscopic resection of s8 or any of its subsegments have been described, i.e. the hilar extrafascial approach, transfissural approach for s8v, transparenchymal approach for s8d, and the intrahepatic Glissonean approach. We recently described the dorsal approach of the right hepatic vein (RHV) for anatomical segment 7 resection. This video report describes the approach to a dorsal s8 pedicle using the RHV dorsal approach. METHODS: A 50-year-old woman with a history of morbid obesity and sleep apnea was diagnosed after episodes of hematochezia sigmoid cancer and a 2-cm liver metastases in the s8d, according to vascular reconstruction (Cella Medical Solutions, Murcia, Spain). The surgical technique started with mobilization of the right liver until the root of the RHV was identified and exposed in a craniocaudal fashion and until the s8d Glissonean pedicle was identified and clamped. Indocyanine green counterstaining depicted an intersegmental plane between the s8d and segment 5 and s8v. Transection continued until the anterior fissural vein was exposed at its root, as a landmark of the medial plane. RESULTS: Operative time lasted 265 min. Transection was carried out using the intermittent Pringle maneuver over a period of 81 min. Estimated blood loss was 252 cc. There were no postoperative complications and the patient was discharged on postoperative day 2. CONCLUSIONS: In some cases, the RHV dorsal approach can be used as the landmark for the s8d Glissonean pedicle, allowing anatomical resection of this particular area.

Is Metformin Associated With Improved Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer?

BACKGROUND: Efforts to determine whether metformin can increase the effectiveness of neoadjuvant chemoradiotherapy in rectal cancer have increased in recent years. However, retrospective studies have yielded inconclusive results. OBJECTIVES: The aim of this study was to compare oncological outcomes and survival after neoadjuvant chemoradiotherapy in patients with rectal cancer taking metformin versus in those not taking metformin. METHODS: This study analyzed 423 consecutive patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy and curative surgery between January 2010 and May 2020; of these, 59 were taking metformin and 364 were not taking metformin. RESULTS: Patients taking metformin had a lower proportion of tumor regression (6.8% versus 22.0%, P = 0.012) as well as a lower proportion of patients achieving a pathological complete response (6.8% versus 20.6%, P = 0.011). In the multivariate analysis, independent predictors of pathologic complete response were not taking metformin (OR: 5.26, 95% CI: 1.12-24.85, P= 0.035) and cT2 stage (OR: 3.49, 95% CI: 1.10-11.07, P= 0.034); the interval was also an independent predictor of tumor regression (OR: 1.78, 95% CI: 1.06-2.96, P= 0.028). No differences were observed in survival between groups. CONCLUSION: Metformin was not associated with better tumor responses or survival after neoadjuvant treatment.

Comparison of Outcomes between Obese and Nonobese Patients in Laparoscopic Adrenalectomy: A Cohort Study.

INTRODUCTION: Obesity is usually considered a risk factor for surgical complications. Laparoscopic adrenalectomy has replaced open adrenalectomy as the standard operation for adrenal tumors. OBJECTIVE: To compare the safety of laparoscopic adrenalectomy to treat adrenal tumors in obese versus nonobese patients. METHODS: This observational cohort study analyzed consecutive patients who underwent laparoscopic adrenalectomy with a lateral transperitoneal approach at a single center (2003-2020). Data and outcomes of obese (body mass index ≥30 kg/m2) and nonobese patients were compared. To analyze the association between operative time and other variables, we used simple and multivariate linear regression. RESULTS: N = 160 (90 obese/70 nonobese) patients underwent laparoscopic adrenalectomy. Cushing syndrome and pheochromocytoma were the most frequent indications. Obese patients were older (58 vs. 52 years, p < 0.001). A greater proportion of obese patients were ASA grade III + IV (71.1 vs. 48.6%, p = 0.004). Obesity was associated with a longer operative time (72.5 vs. 60 min, p < 0.001) and greater blood loss (40 vs. 20 mL, p = 0.022). There were no differences in conversion, morbidity, or hospital stay. After adjustment for confounding factors, operative time was positively correlated with BMI ≥30 kg/m2, learning curve, estimated blood loss, 2D laparoscopy, and specimen size. CONCLUSION: Lateral transperitoneal laparoscopic adrenalectomy is safe in patients with a BMI 30-35 kg/m2, so these patients also benefit from this minimally invasive surgery.

Risk factors for suboptimal laparoscopic surgery in rectal cancer patients.

PURPOSE: Laparoscopic surgery for rectal cancer is technically complex. This study aimed to identify risk factors for suboptimal laparoscopic surgery (involved margins, incomplete mesorectal excision, and/or conversion to open surgery) in patients with rectal cancer. METHODS: We included patients undergoing laparoscopic anterior resection for rectal cancer between June 2009 and June 2018. We defined the outcome variable suboptimal laparoscopic surgery as conversion to open surgery or inadequate histopathological specimens (margins < 1 mm or involved and/or poor-quality mesorectal excision). To identify independent predictors of suboptimal laparoscopic surgery, we analyzed 15 prospectively recorded demographic, clinical, and anthropometric variables obtained from our rectal cancer unit's database. Subanalyses examined the same variables with respect to conversion and to inadequate histopathological specimens. RESULTS: Of the 323 patients included, 91 (28.2%) had suboptimal laparoscopic surgery. In the multivariate analysis, the independent factors associated with all suboptimal laparoscopic surgery were tumor location ≤ 5 cm from the anal verge (OR = 2.95, 0.95% CI 1.32-6.60; p = 0.008) and the intertuberous distance (OR = 0.79, 0.95% CI 0.65-0.96; p = 0.019). In the subanalyses, the promontorium-retropubic axis was an independent predictor of conversion (OR 0.70, 0.95% CI 0.51-0.96; p = 0.026), and tumor location ≤ 5 cm from the anal verge (OR 3.71, 0.95% 1.51-9.15; p = 0.004) was an independent predictor of inadequate histopathological specimens. CONCLUSIONS: Predictive factors for suboptimal laparoscopic anterior resection for rectal cancer were tumor location and the intertuberous distance. These results could help surgeons decide whether to use other surgical approaches in complex cases. TRIAL REGISTRATION: The study was registered at Clinicaltrials.org (No. NCT03107650).

[Impact of SARS-COV-2 pandemic on elective and emergency surgery in a university hospital]. / Estudio del impacto de la pandemia por SARS-CoV-2 en la práctica quirúrgica urgente y electiva en un hospital de tercer nivel.

Introduction: SARS-CoV-2 pandemic has caused an important impact in our country and elective surgery has been postponed in most cases. There's not known information about the decreasing and impact on surgery. Mortality of surgical patients with SARS-CoV-2 infection is estimated to be around 20%. Methods: We conducted prospective data recruitment of people inpatient in our Digestive and General Surgery section of Girona's University Hospital Dr. Josep Trueta from 03/14 to 05/11. Our objective is to analyze the impact that SARS-CoV-2 pandemic over elective and urgent surgery. Results: During the peak occupation of our center Intensive Care Unit (303.8%) there was a reduction on elective (93.8%) and urgent (72.7%) surgery. Mortality of patients with SARS-CoV-2 infection who underwent surgery (n = 10) is estimated to be a 10%. An 80% of these patients suffer complications (sever complications in 30%). Conclusions: The actual study shows a global reduction of the surgical activity (elective and urgent) during de SARS-CoV-2 pandemic. Global mortality of patients with SARS-CoV-2 infection are low, but the severe complications have been over the usual.

Three-dimensional (3D) system versus two-dimensional (2D) system for laparoscopic resection of adrenal tumors: a case-control study.

PURPOSE: Laparoscopy is the standard technique for resecting adrenal tumors worldwide. The main drawbacks of conventional 2D laparoscopy are limited depth perception and tactile feedback. Currently available high-quality 3D laparoscopy systems might improve surgical outcomes for adrenalectomy. We compare the safety and efficacy of 3D versus 2D laparoscopy in the treatment of adrenal tumors. METHODS: This case-control study analyzed prospectively collected data from patients with benign or malignant adrenal tumors treated laparoscopically at a single academic medical center between April 2003 and March 2020. We collected demographic, diagnostic, preoperative, and operative variables, and used multiple linear and logistic regression to analyze differences in various short-term outcomes between the two approaches while adjusting for potential confounders. RESULTS: We included 150 patients: 128 with benign tumors and 22 with malignant tumors; 95 treated with 3D laparoscopy (case group); and 55 with 2D laparoscopy (control group). After adjustment for patient, surgical, and tumor characteristics, a 2D vision was associated with a longer operative time (ß = 0.26, p = 0.002) and greater blood loss (ß = 0.20, p = 0.047). There was no significant difference in rates of conversion to open surgery (odds ratio [OR] = 1.47 (95% CI 0.90-22.31); p = 0.549) or complications (3.6% vs. 2.1%; p = 0.624). CONCLUSIONS: With experienced surgeons, laparoscopic adrenalectomy was safer and more feasible with the 3D system than with the 2D system, resulting in less operative blood loss and shorter operative time with no differences in rates of conversion to open surgery or postoperative complications. For adrenal tumors, 3D laparoscopy offers advantages over 2D laparoscopy.

Urethral Injury in Rectal Cancer Surgery: A Comprehensive Study Using Cadaveric Dissection, Imaging Analyses, and Clinical Series.

Male urethral injury during rectal cancer surgery is rare but significant. Scant information is available about the distances between the rectourethral space and neighboring structures. The aim of this study is to describe the anatomical relations of the male urethra. This three-pronged study included cadaveric dissection, retrospective MRI analysis, and clinical cases. Measurements included the R-Mu distance (shortest distance between the rectum and the membranous urethra), R-Am distance (distance from the anterior rectal wall to anal margin nearest to the membranous urethra), and the anal canal-rectum axis angle. The clinical study analyzed the incidence of urethral injury and associated factors among 244 consecutive men from January 2016 to January 2023. The overall incidence of urethral injury in our series was low (0.73%), but in men with tumors < 10 cm from the anal margin, it was 4% in abdominoperineal resection and 3.2% in TaTME. On preoperative MRI, the median R-Mu distance was 1 cm (IQR, range, 0.2-2.3), the median R-Am distance was 4.3 cm (range, 2-7.3), and the median anorectal angle was 128° (range, 87-160). In the cadaveric study (nine adult male pelvises), the mean R-Mu distance was 1.18 cm (range 0.8-2), and the mean R-Am distance was 2.64 cm (range 2.1-3). Avoiding urethral injury is crucial. The critical point for injury lies 2-7.3 cm from the anal margin, with a 0.2-2.3 cm distance between the rectum and the membranous urethra. Collaborating with anatomists and radiologists improves surgeons' anatomy knowledge.

[Is body mass index a prognostic factor of survival in colonic cancer? A multivariate analysis]. / ¿Es el índice de masa corporal un factor pronóstico de supervivencia en el cáncer de colon? Análisis multivariable.

INTRODUCTION: The long-term survival of patients operated on for colonic cancer depends on many factors. Obesity decreases the life expectancy of the general population who suffer from it, but it is not clear whether obesity, measured by the Body Mass Index (BMI), is a prognostic factor of survival for patients operated on for colonic cancer. MATERIAL AND METHODS: The patients included in this study had TNM stage I, II y III, and were subjected to elective surgery for cancer of the colon in the Girona University Hospital between 1990 and 2001. The BMI was classified according to the WHO classification. A total of 38 different variables were studied using a bivariate analysis with BMI. A Cox model was subsequently constructed with the most clinically relevant parameters, and with those most strongly associated with survival in the bivariate analysis. RESULTS: BMI was not associated with survival in the bivariate analysis. Neither did the multivariate analysis show that BMI was an independent prognostic factor of long-term survival in cancer of the colon without metastasis, but it did show that the TNM stage, ASA score, surgical technique, age at surgery, and the immune cell response were prognostic factors. CONCLUSIONS: The body mass index is not a prognostic factor of the long-term survival of patients with colonic cancer.

Factors associated with prolonged hospital stay after laparoscopic adrenalectomy.

Laparoscopy is the standard technique for resecting adrenal tumors, but short-term outcomes such as length of stay (LOS) vary widely between centers. We aimed to identify factors associated with LOS after lateral transperitoneal laparoscopic adrenalectomy (LTLA). We analyzed consecutive patients undergoing unilateral LTLA between April 2003 and April 2020. Prolonged LOS was defined as a stay longer than the 75th percentile of the overall cohort. To identify potential factors associated with prolonged LOS, we compared collected data from patients with LOS ≤ 2 days versus LOS > 2 days and elaborated multivariate logistic regression models. We included 150 patients (73 men and 77 women, median age 54 years), with benign (n = 128) and malignant tumors (n = 22). The median LOS after LTLA was 2 days; 64 (42.7%) patients had prolonged hospitalization. Variables significantly associated with prolonged LOS in the univariate analysis included ASA III + IV (p = 0.016), pheochromocytoma (p < 0.001), learning curve (p = 0.032), surgery on Thursday or Friday (p < 0.001), 2D laparoscopy (p = 0.003), operative time (p < 0.001), estimated blood loss (p < 0.001), drainage (p < 0.001), specimen size (p = 0.011), conversions (p = 0.002), complications (p = 0.019), and hospital stay (p < 0.001). After adjustment for patient, surgical, and tumor characteristics, risk factors associated with prolonged LOS in the multivariate analysis were specimen size > 9 cm (OR:13.03, p = 0.005), surgery on Thursday or Friday (OR:6.92, p = 0.001), estimated blood loss ≥ 60 ml (OR:6.22, p = 0.021), and drainage (OR:5.29, p = 0.005). Prolonged length of stay after LTLA was associated with specimen size > 9 cm, operating on Thursday or Friday, estimated blood loss ≥ 60 mL, and drainage.

Impact of SARS-COV-2 pandemic on elective and emergency surgery in a university hospital. / Estudio del impacto de la pandemia por SARS-CoV-2 en la práctica quirúrgica urgente y electiva en un hospital de tercer nivel.

INTRODUCTION: SARS-CoV-2 pandemic has caused an important impact in our country and elective surgery has been postponed in most cases. There's not known information about the decreasing and impact on surgery. Mortality of surgical patients with SARS-CoV-2 infection is estimated to be around 20%. METHODS: We conducted prospective data recruitment of people inpatient in our Digestive and General Surgery section of Girona's University Hospital Dr. Josep Trueta from 03/14 to 05/11. Our objective is to analyze the impact that SARS-CoV-2 pandemic over elective and urgent surgery. RESULTS: During the peak occupation of our center Intensive Care Unit (303.8%) there was a reduction on elective (93.8%) and urgent (72.7%) surgery. Mortality of patients with SARS-CoV-2 infection who underwent surgery (n=10) is estimated to be a 10%. An 80% of these patients suffer complications (sever complications in 30%). CONCLUSIONS: The actual study shows a global reduction of the surgical activity (elective and urgent) during de SARS-CoV-2 pandemic. Global mortality of patients with SARS-CoV-2 infection are low, but the severe complications have been over the usual.

Randomized clinical trial comparing side to end vs end to end techniques for colorectal anastomosis.

BACKGROUND: Low anterior resection syndrome affects 60%-90% of patients with anastomoses after colorectal resection. Consensus regarding the best anastomosis is lacking. OBJECTIVE: To compare outcomes after end-to-end versus side-to-end anastomoses. DESIGN: Randomized clinical trial. SETTINGS: University hospital (April 2016-October 2017). PATIENTS: Patients aged ≥18 years with rectal or sigmoid adenocarcinoma. INTERVENTIONS: Patients were randomized to undergo mechanical end-to-end or side-to-end (n = 33) anastomosis after laparoscopic resection. MAIN OUTCOME MEASURES: Primary outcome was to assess intestinal function (COREFO and LARS questionnaires) 12 months after surgery or ileostomy closure. Secondary outcomes were postoperative complications and intestinal function and quality of life (SF-36® questionnaire) at different time points after surgery or ileostomy closure. RESULTS: No significant differences in intestinal function were observed between the two groups 12 months after surgery. Subanalysis of low-mid rectum tumors with end-to-end anastomosis yielded better function at 12 months. Postoperative complications did not differ between the two groups (p = 0.070), but reinterventions were more common in the side-to-end group (p = 0.040). Multivariate analysis found neoadjuvant treatment was independently associated with intestinal dysfunction at 12 months (ß = 0.41, p = 0.033, COREFO; ß = 0.41, p = 0.024, LARS). CONCLUSIONS: End-to-end anastomosis yielded low rates of severe complications and reintervention, as well as better intestinal function at 12 months in the subgroup with tumors in the low-mid rectum. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT02746224.

Delaying surgery by more than 10 weeks after long-course neoadjuvant radiotherapy in locally advanced rectal cancer patients improves pathologic complete response.

BACKGROUND: We currently do not know the optimal time interval between the end of chemoradiotherapy and surgery. Longer intervals have been associated with a higher pathological response rate, worse pathological outcomes and more morbidity. The aim of this study was to evaluate the effect and safety of the current trend of increasing time interval between the end of chemoradiotherapy and surgery (< 10 weeks vs. ≥ 10 weeks) on postoperative morbidity and pathological outcomes. This study analyzed 232 consecutive patients with locally advanced rectal cancer treated with long-course neoadjuvant chemoradiotherapy from January 2012 to August 2018. 125 patients underwent surgery before 10 weeks from the end of chemoradiotherapy (Group 1) and 107 patients underwent surgery after 10 or more weeks after the end of chemoradiotherapy (Group 2). Results have shown that wait for ≥ 10 weeks did not compromise surgical safety. Pathological complete response and tumor stage was statistically significant among groups. The effect of wait for ≥ 10 weeks before surgery shown higher tumor regression than the first group (Group 1, 12.8% vs Group 2, 31.8%; p < 0.001). On multivariate analysis, wait for ≥ 10 weeks was associated with pathological compete response. Patients from the second group were four time more likely to achieve pathologic complete response than patients from the first group (OR, 4.27 95%CI 1.60-11.40; p = 0.004). Patients who undergo surgery after ≥ 10 weeks of the end of chemoradiotherapy are four time more likely to achieve complete tumor remission without compromise surgical safety or postoperative morbidity.

Lethal intestinal perforation after foreign body ingestion in a superobese patient.

Accidental ingestion of foreign bodies is common in the general population. Most foreign bodies pass through the entire digestive tract without incidents. However, in some cases, the ingested foreign body can cause complications such as acute abdomen due to intestinal perforation and even death. Bowel perforation may not be more common in the massively obese than in the normal-weight population but may be more problematic. We describe a super-obese female (body mass index, 52.3 kg/m2) who underwent emergency surgery for small-bowel perforation caused by an ingested foreign body (fish bone); the patient died despite segmental intestinal resection and intensive care.

Transanal surgery: A tool in the colorectal anastomotic leakage. / La cirugía transanal como herramienta en la dehiscencia de la anastomosis colorrectal.

The treatment of anastomotic leakage after oncological surgery for rectal cancer is a surgical challenge. The goal of this study is to show how transanal surgery combined with the abdominal approach is a very useful tool to decide on individualized treatment depending on the degree of dehiscence and to assist us in its local management. We present three cases of patients with colorectal anastomotic dehiscence. In two, we demonstrate the treatment of acute colorectal leakage and how transanal surgery allows us to confirm its viability and rule out any underlying ischemia. Furthermore, it facilitates good drainage of the adjacent collection as well as the placement of a vacuum system, if necessary, and its subsequent replacements. The last case is a delayed dehiscence with chronic presacral sinus, and its treatment by transanal access for fenestration.

Incarcerated umbilical hernia in a super-super-obese patient.

Abdominal wall hernias are more prevalent in the morbidly obese. Incarceration of external hernias is a relatively common process in adults and is associated to a high rate of complications and mortality. We present the case of a morbidly super-super-obese patient (body mass index, 80 kg/m(2)) who underwent emergency surgery for an incarcerated umbilical hernia; the patient died despite segmental intestinal resection, hernia repair using mesh, and intensive care.