Surgical repair of endoscopy-induced colonic perforations: a case-matched study of short-term morbidity and mortality.

BACKGROUND: Our aim was to describe the clinical outcomes of surgical interventions performed for the management of colonoscopy-related perforations and to compare these outcomes with those of matched colorectal surgeries performed in elective and emergency settings. METHODS: We included patients with endoscopic colonic perforation who underwent surgical intervention from the 2014-2017 National Surgery Quality Improvement Program participant use data colorectal targeted procedure file. The primary outcome in this study was short term surgical morbidity and mortality. Patients (group 1) were matched with 1:2 ratio to control patients undergoing same surgical interventions for other indications on an elective (group 2) or emergency basis (group 3). Bivariate analysis was conducted to compare categorical variables between the three groups, and multivariate logistic regression was used to evaluate the association between the surgical indication and 30-day postoperative outcomes. RESULTS: A total of 590 patients were included. The average age of the patients was 66.5±13.6 with female gender predominance (381, 64.6%) The majority of patients underwent open colectomy (365, 61.9%) while the rest had suturing (140, 23.7%) and laparoscopic colectomy (85, 14.4%). Overall mortality occurred in 4.1% and no statistically significant difference in mortality was found between the three techniques (P=0.468). Composite morbidity occurred in 163 patients (27.6%). It was significantly lower in laparoscopic colectomy (14.1%) compared to 30.2% and 29.4% in open colectomy and suturing approaches (P=0.014). Patients undergoing colectomy for iatrogenic colonic perforation had less mortality, infection rates and sepsis, as well as bleeding episodes compared to those who had colectomy on an emergent basis. Outcomes were comparable between the former group and patients undergoing elective colectomy for other indications. CONCLUSIONS: Surgical management of colonoscopy related perforations is safe and effective with outcomes that are similar to that of patients undergoing elective colectomy.

Prevalence of Laryngopharyngeal Symptoms in Patients With Gastroesophageal Reflux Disease Refractory to Medical Therapy Undergoing Esophagogastroduodenoscopy.

OBJECTIVE: Casting more information on the link between GERD and LPR by investigating the prevalence of laryngopharyngeal symptoms in patients with severe GERD refractory to medical treatment. DESIGN: Prospective Study METHODS: Fifty patients with typical GERD symptoms presenting for EGD were recruited. All patients filled the GERD-Health-Related Quality of Life (HRQL) questionnaire and were screened for LPR using the Reflux Symptom Score questionnaire. All patients were also evaluated for the presence of hiatal hernia, esophagitis, inlet patch, gastritis (erosive vs. non erosive), polyps, intestinal metaplasia and or Helicobacter pylori infection. Laryngeal images were taken during EGD and evaluated using the Reflux Sign Assessment (RSA). RESULTS: A total of 50 patients were recruited for this study. The prevalence of heartburn was the highest (90%). The mean score of GERD-HRQL was 30.76±15.09. The mean RSS score was 70.96±46.08. Laryngeal examination was documented in 49 patients. the most common finding was edema (34.7%) followed by redness (28.6%). The mean RSA score for the total group was 21.15±8.04. There was a strong correlation between RSS score and GERD-HQRL score. There was no significant correlation between the RSS and any of the EGD findings (P > 0.05). There was no significant correlation between RSA and GERD-HRQL scores or any of the EGD findings (P > 0.05). However, there was a significant correlation between total RSA and RSS scores (rho=0.287, P = 0.04). CONCLUSION: The suggested high prevalence of LPRD should alarm the treating physician to the need for a thorough otolaryngologic examination in patients presenting with severe GERD, particularly those in whom the LPR symptoms may be masked by the typical symptoms of GERD.

Impact of sedation type on adenoma detection rate by colonoscopy.

BACKGROUND & AIMS: Endoscopic detection of polyps and adenomas decreases the incidence and mortality of colorectal cancer. The available data concerning the relationship between the sedation type and adenoma detection rate (ADR) or polyp detection rate (PDR) is inconclusive. The aim of our study was to evaluate the impact of conscious vs. deep (propofol) sedation on the ADR/PDR in diagnostic and screening colonoscopies. METHODS: This was a retrospective cohort study. Patients aged 50-75 years old presenting for a first screening or diagnostic colonoscopy were included. Baseline demographic characteristics were collected, as well as PDR and ADR. Endoscopic withdrawal time and quality of bowel preparation rated in a binary fashion were also collected. Two multivariate logistic regression models were used to evaluate the independent predictors of endoscopic detection of polyps and adenomas. RESULTS: 574 patients met our inclusion criteria. Mean age was 59.26 ± 7.21 with 52.4% females and an average BMI of 28.08 ± 4.89. 374 patients (65.2%) underwent screening colonoscopies, and deep sedation was performed in 200 patients (34.8%). Only 4.7% had bad bowel preparation. PDR was 70% and ADR was 52%. On bivariate analysis, no significant difference was shown in PDR and ADR between conscious and deep sedation groups (0.70, 0.71; p = 0.712 and 0.50, 0.54; p = 0.394, respectively). On multivariate analysis for PDR, age and withdrawal time were independent predictors. For ADR, age, female sex, and withdrawal time were independent predictors. Sedation type and the indication did not reach statistical significance in both models. CONCLUSION: The use of deep sedation didn't influence the ADR/PDR quality metrics in our mixed cohort of screening and diagnostic colonoscopies.

Timing of cholecystectomy for acute cholecystitis impacts surgical morbidity and mortality: an NSQIP database analysis.

The aim of this study is to identify the optimal timing for cholecystectomy for acute cholecystitis. Patients undergoing cholecystectomy for acute cholecystitis from the National Surgery Quality Improvement Program database between 2014 and 2016 were included. The patients were divided into 4 groups, those who underwent surgery at days 0, 1, 2, or 3+ days. The primary outcome was short-term surgical morbidity and mortality. A total of 21,392 patients were included. After adjusting for confounders, compared to day 0 patients, those who underwent surgery at day 1 and day 2 had lower composite morbidity rate, while day 3+ patients had significantly higher bleeding and mortality rate. Subgroup analysis shows this trend to be more significant in the elderly and in diabetic patients who were delayed. Delay in cholecystectomy for over 72 h from admission is associated with statistically significant increase in bleeding and mortality.

Bowel wall thickening on computed tomography scan: Inter-observer agreement and correlation with endoscopic findings.

BACKGROUND AND STUDY AIMS: Bowel wall thickening (BWT) on computed tomography (CT) has been frequently reported by radiologists. There are no clear guidelines regarding the level of thickening that is correlated with definite pathology. Radiologists usually rely on their overall subjective impression, and studies on inter-observer agreement (IOA) are lacking. This study evaluated IOA concerning BWT found on abdominal CT and identified the corresponding findings on endoscopy. PATIENTS AND METHODS: Reports of abdominal CTs performed between January 2000 and December 2015 containing the term 'thickening' were retrieved from the radiology department database. Corresponding patients who later underwent endoscopy were included. IOA concerning BWT was evaluated using a randomly mixed sample of 80 patients with normal findings or pathological BWT on endoscopy. A search for predictive factors for the subsequent finding of malignancy on endoscopy was performed using multivariate analysis. RESULTS: During the study period, 6142 CT scans described thickening, equivalent to a BWT prevalence of 13.7%. Ninety-one patients (mean age, 58 years) were included in the analysis. Thickening was found most commonly in the stomach (38.5%), followed by the rectum (22%) and small intestine (14%). Twenty-seven patients (29.7%) exhibited diffuse BWT, whereas 64 patients showed localised BWT (70.3%). Biopsy was performed for 64 of 91 patients with endoscopies. Among these patients, 8.8% exhibited normal findings, whereas inflammation and malignancy were discovered in 25 and 51.6% of patients, respectively, with a positive predictive value for malignancy of 0.36. The IOA concerning CT for predicting significantly pathological BWT was moderate (mean κ = 0.6). A strong association was evident between the presence of lymph nodes on CT and the presence of neoplastic lesions. CONCLUSION: Our study strongly recommends endoscopic follow-up of patients exhibiting BWT irrespective of the thickening location, especially if it is associated with lymphadenopathy. IOA between radiologists was moderate.

Short-term surgical morbidity and mortality of distal pancreatectomy performed for benign versus malignant diseases: a NSQIP analysis.

BACKGROUND/AIM: Distal pancreatectomy (DP) accounts for 25% of all pancreatic resections. Complications following DP occur in around 40% of the cases. Our aim is to analyze short-term surgical outcomes of DP based on whether the indication for resection was benign or malignant pathology, as well as the effect of the surgical approach, open versus laparoscopic on morbidity and mortality. METHODS: We studied all patients undergoing DP from the National Surgery Quality Improvement Program (NSQIP) targeted pancreatectomy participant use file from 2014 to 2016. The patients were divided into 2 groups, those who underwent DP for benign diseases (DP-B) and those who underwent DP for malignant diseases (DP-M). We performed multivariate logistic regression to evaluate the association between benign or malignant distal pancreatectomies and 30-day outcomes. We included clinically and/or statistically significant confounders into the models. We also conducted the same analysis in the subgroups of open and laparoscopic DP. RESULTS: Three thousand five hundred and seventy-nine patients underwent distal pancreatectomy. The most common indication for surgery was malignant disease in 1894 (53%). Thirty-day mortality occurred in 0.4% of DP-B compared to 1.3% DP-M. On multivariate analysis, no significant difference was found in mortality or in the risk of pancreatic fistula between the 2 groups. Bleeding (p = 0.002) and composite morbidity (p = 0.01) were significantly higher in the DP-M group. Among composite morbidities, thromboembolism was significantly associated with DP-M (OR 2.1, p = 0.0004) only when performed with an open approach. CONCLUSION: DP-M is associated with a significantly higher risk of post-operative bleeding, thromboembolism, and sepsis compared to DP-B but no significant increase in mortality. When further analyzing the impact of the operative approach on morbidity, there was an increased rate of post-operative thromboembolic in the DP-M group when the surgery was performed in an open manner and this increased risk was no longer statistically significant if the DP-M was performed using a minimally invasive approach.

Fibroscan and low-density lipoprotein as determinants of severe liver fibrosis in diabetic patients with nonalcoholic fatty liver disease.

BACKGROUND: Fibroscan is an effective and noninvasive tool to quantify fibrosis and steatosis in liver diseases including nonalcoholic fatty liver disease (NAFLD). Type-2-diabetes is a known risk factor for worse prognosis in NAFLD. In this study, we compare liver status in NAFDL diabetic and nondiabetic patients, identify potential risk factors, and determine the usefulness of Fibroscan in this population. PATIENTS AND METHODS: The charts of all patients with NAFLD who underwent Fibroscan at our institution were reviewed. Fibroscan results, demographics, and clinical data were collected and analyzed using SPSS software. RESULTS: Of the 248 NAFLD patients, 73 (29.4%) were diabetic and 175 (70.6%) were nondiabetic. As detected by the NAFLD' liver stiffness measure, 35 (47.94%) diabetic patients had severe liver fibrosis (F4) in contrast to only 46 (26.3%) nondiabetics. Diabetic patients also presented more with hypertension, dyslipidemia, coronary artery disease, and chronic kidney disease. Liver steatosis, liver function tests, and noninvasive scores did not vary significantly between the two groups, except for γ-glutamyltransferase, prothrombin time-international normalized ratio, and BMI-alanine aminotransferase ratio-diabetes score. Diabetic patients had significantly lower high-density lipoproteins and low-density lipoproteins. CONCLUSION: Fibroscan results and low-density lipoprotein are potential diagnostic factors of liver fibrosis in diabetic patients with NAFLD. Further studies are necessary to verify liver fibrosis diagnostic tools and prognostic and genetic markers in diabetic patients.

Intragastric balloon treatment of obesity: Long-term results and patient satisfaction.

BACKGROUND/AIMS: Intragastric balloon (IGB) treatment of obesity is a minimally invasive outpatient procedure that has been shown to help weight loss in some patients. The aim of this study is to analyze the long-term results regarding the effectiveness, tolerability, and patient satisfaction in a cohort of patients undergoing the IGB insertion. MATERIALS AND METHODS: Using a retrospective cohort study design, patients who had their IGB inserted/removed between the years 2009 and 2016 were contacted by phone and asked to answer a short questionnaire. The baseline characteristics, pre- and post- IGB weight, as well as their current weight were recorded. Different parameters of satisfaction were noted in addition to whether patients resorted to alternative weight-reduction measures. RESULTS: Ninety-nine eligible patients were contacted, and 65 consented to the study. The average weight loss achieved at the end of the treatment period (3 to 10 months) was approximately a 12% decrease from the baseline. Only 39% of patients were satisfied with the procedure, and less than 50% were satisfied with the weight loss achieved. When assessing the long-term follow-up, years after the IGB removal (3.3±1.76 years), the vast majority of patients (78.7%) regained weight or resorted to further bariatric measures. CONCLUSION: IGB leads to weight loss among most patients, but it does not appear to fulfill patients' expectations. Further, the initial weight loss is not sustainable over time.

Validation of day 1 drain fluid amylase level for prediction of clinically relevant fistula after distal pancreatectomy using the NSQIP database.

BACKGROUND: The role of postoperative day 1 drain fluid amylase level in predicting clinically relevant postoperative pancreatic fistula is under investigation. In a previous multicenter study conducted on 338 patients undergoing distal pancreatectomy, day 1 drain fluid amylase level has been correlated to the development of a clinically relevant pancreatic fistula and an amylase value of 2,000 U/L was found to be most predictive of the development of clinically relevant postoperative pancreatic fistula. Our objective was to validate the previously established cutoff level for drain fluid amylase on postoperative day 1 after distal pancreatectomy as a predictor for clinically relevant postoperative pancreatic fistula using a different patient population from the National Surgery Quality Improvement Program database. METHODS: We studied all patients undergoing distal pancreatectomy from the National Surgery Quality Improvement Program pancreatectomy specific participant use file from 2014 to 2016. We applied the day 1 drain fluid amylase level of 2,000 U/L cutoff to divide patients into 2 groups and compared clinical outcomes in both groups. Among patients with a day 1 drain fluid amylase level < 2,000 U/L, we compared the patient characteristics of those who developed a clinically relevant postoperative pancreatic fistula to those who did not. Finally, to independently validate the previously defined day 1 drain fluid amylase level, we proceeded to determine the optimal cutoff value of day 1 drain fluid amylase level, which can be used as a predictor for the development of clinically relevant postoperative pancreatic fistula after distal pancreatectomy using a receiving operating characteristic curve. RESULTS: A total of 1,007 patients underwent distal pancreatectomy. The mean day 1 drain fluid amylase level was 4,290.04 ± 8,492.35 U/L. Clinically relevant postoperative pancreatic fistula occurred in 203 patients (20.2%). Using bivariate analysis, patients with day 1 drain fluid amylase level ≥ 2,000 U/L were more likely to develop clinically relevant postoperative pancreatic fistula (32.5% vs 11.25%, P < .0001), to have a higher mean number of days before drain removal (8.83 vs 5.59, P < .0001), to have a drain 30 days postoperatively (12.59% vs 3.63%, P < .0001), and to undergo percutaneous drainage (13.75% vs 9.69%, P = .04). Among patients with a day 1 drain fluid amylase level < 2,000 U/L, 11% of patients went on to develop a clinically relevant postoperative pancreatic fistula. Analysis of this subgroup of patients did not identify any discernable preoperative characteristics that were predictive of this complication. Application of maximal Youden index calculated the day 1 drain fluid amylase level value at 2,000 U/L with a sensitivity of 67.98% and a specificity of 63.81% for clinically relevant postoperative pancreatic fistula, with a positive predictive value of 32.17%, a negative predictive value of 88.75%, and a Youden index of 0.32. CONCLUSION: Using a different population of patients and a different data set as well as an independent analysis, we successfully validated a day 1 drain fluid amylase level of 2,000 U/L as striking the best balance in terms of sensitivity and specificity for the detection of clinically relevant postoperative pancreatic fistula. The identified cutoff might be employed in the design of a trial of early drain removal in patients undergoing distal pancreatectomy.

Site specific diagnostic yield of endoscopic biopsies in Gastrointestinal Graft-versus-Host Disease: A tertiary care Center experience.

BACKGROUND: Gastrointestinal (GI) graft versus host disease (GVHD) occurs in up to 40% of patients undergoing allogenic hematopoietic stem cell transplantation (HSCT). However, the optimal endoscopic approach is still unclear and the area of the GI tract with the highest diagnostic yield is still a topic of debate. OBJECTIVE: We compared the diagnostic yield of different anatomic site biopsies in the diagnosis of GI GVHD and assessed the correlation of endoscopic findings with histopathology. METHODS: All cases of biopsy proven GI GVHD were obtained from pathology database AUBMC between 1/1/2005 and 31/8/2017. We retrospectively analyzed the demographical, clinical and endoscopic data. RESULTS: Nineteen patients were diagnosed with GI GVHD over 17.6 years. The most common presenting symptom was severe diarrhea (18 patients, 94.7%). Combining upper endoscopy and sigmoidoscopy with biopsies had the highest diagnostic yield of 90% in diagnosing GI GVHD compared to 63.6%, 78.6% and 77.8% for upper endoscopy, sigmoidoscopy and colonoscopy respectively. In macroscopically normal mucosa, the recto-sigmoid and duodenal biopsies had the highest diagnostic yield (75%). As for the macroscopically abnormal mucosa, the highest yield was for the recto-sigmoid biopsies (100%) in lower endoscopy and duodenal biopsies in the upper endoscopy (60%). CONCLUSION: In a patient suspected to have GI GVHD, the best endoscopic approach is the combination of upper endoscopy and flexible sigmoidoscopy with biopsies of normal as well as abnormal mucosa. It should be emphasized that normal mucosa be biopsied especially in the duodenum and recto-sigmoid for a better diagnostic yield.

Ear Involvement in Inflammatory Bowel Disease: A Review of the Literature.

Inflammatory bowel disease (IBD) is a multisystemic disease. The ear is a rare but recognized site of extraintestinal manifestations of IBD. In external ear, the more common manifestations of IBD are pyoderma gangrenosum, metastatic Crohn's disease and relapsing polychondritis and the treatment includes corticosteroids and anti-TNF agents. Sensorineural hearing loss (SNHL) is the most common ear disease in IBD and especially in patients with ulcerative colitis. In most cases of IBD patients with SNHL, the hearing loss is attributable to autoimmune inner ear disease (AIED). Diagnosis of AIED is based on clinical presentation, the demonstration of a progressive sensorineural hearing loss in periodic audiological tests, a response to immunosuppressive drugs and exclusion of other causes of SNHL. The only diagnostic test that is available for clinical use is the Otoblot test (Western blot for antibodies against 68 kD protein-inner ear antigens). Initial therapy is usually steroids, with a step up to anti-TNF-a therapy and cochlear implantations with failure of treatment. Furthermore, Cogan's syndrome, a chronic disease characterized by deafness, vertigo keratitis and aortitis, has been associated with IBD and mainly with Crohn's disease.

Costs of Crohn's Disease According to Severity States in France: A Prospective Observational Study and Statistical Modeling over 10 Years.

BACKGROUND: To describe the medico-economic characteristics of Crohn's disease (CD), we implemented a multicenter study in France. METHODS: From 2004 to 2006, disease severity states, direct (hospital and extra hospital) and indirect costs were prospectively collected over 1 year in patients with CD naive from anti-tumor necrosis factor alpha (infliximab) at inclusion. Economic valorization was performed from the French Social Insurance perspective, and a statistical modeling over 10 years was performed. RESULTS: In 341 patients, the mean total costs of management were &OV0556;6024 per year (&OV0556;4675 for direct costs). As compared to patients in remission, costs were 4 to 6 times higher in patients in an active period and 19 times higher for patients requiring surgery (SURG). The most important expense items were medical and surgical hospitalizations (56% of total costs), including cost of infliximab (36% of hospitalization costs, i.e., 20% of total costs), indirect costs (22%), and drugs (11%). The statistical modeling over 10 years showed that most of the clinical course was spent in drug-responsive state (54%) with 26% of costs or in remission (32%) with 11% of costs; time spent in a SURG state was small (3.2%) but generated 48% of total costs. CONCLUSIONS: Before the introduction of self-injectable anti-tumor necrosis factor alpha, the most important expenses were supported by hospitalizations, explaining why the most costly states were for patients requiring SURG or dependent on inhospital administrated drugs. Projected data show that most time is spent in a stabilized state with appropriate treatments or in remission, and that costs associated with SURG are high.

A Single Mass Forming Colonic Primary Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin's lymphoma (NHL) comprising around 7% of adult NHL. It is characterized by a chromosomal translocation t(11:14) and overexpression of Cyclin D1. The incidence of secondary gastrointestinal tract involvement in MCL ranges from 10 to 28% in various series. However primary gastrointestinal MCL is very rare, accounting for only 1 to 4% of primary gastrointestinal lymphomas. The most common endoscopic feature of primary intestinal MCL is multiple lymphomatous polyposis. In rare cases it presents as protruded lesions or superficial lesions. Single colonic mass presentation is an extremely infrequent presentation. MCL has an aggressive course with quick progression, and most cases are discovered in the advanced stages. Colonic biopsies with histologic examination and specific immunohistochemical staining are the gold standard for a proper diagnosis. We report a case of a single mass forming mantle cell lymphoma of the ascending colon in a 57-year-old female patient with unusual colonoscopic and radiologic features and describe the therapy the patient received, thereby adding to the spectrum of clinical presentations of this aggressive lymphoproliferative disorder.

Prevalence of anal cytologic abnormalities in a French referral population: a prospective study with special emphasis on HIV, HPV, and smoking.

PURPOSE: Studying anal cytology to detect intraepithelial neoplasia has been demonstrated to be useful in highly selected populations. This study was designed to determine the frequency of abnormal smears in a wide sample of patients consulting for anorectal symptoms. METHODS: An anal smear was proposed during each consultation during a three-month period. RESULTS: A total of 205 patients (112 females) were included. After the consultation, visible condylomas were detected in 12 (6 percent) of the cases. Two hundred three (99 percent) smears were able to be analyzed. No case of high-grade squamous intraepithelial lesion was found. Four cases of low-grade squamous intraepithelial lesion were found, all in HIV patients with a history of condylomatous lesions. Forty smears were interpreted as atypical squamous cells of undetermined significance and 159 were normal. The prevalence in this population of low-grade squamous intraepithelial lesion was 19 percent (4/21) in HIV seropositive males, and 15 percent (4/26) in the case of a past history of condyloma. The factors associated with an abnormal smear (low-grade squamous intraepithelial lesion or atypical squamous cells of undetermined significance) were a history of anal condylomatous lesions (odd ratio, 4.9; range, 2.1-11.5), HIV seropositivity (odd ratio, 4; range, 1.6-9.9), and smoking (odd ratio, 2.1; range, 1.1-11.5). CONCLUSIONS: This work confirms that the frequency of low-grade squamous intraepithelial lesion is raised in HIV-seropositive males and also where there is a history of condyloma, which corroborates the necessity for regular monitoring and screening of these patients at risk. This study also suggests that the use of tobacco is associated with anal cytologic abnormalities.

Predictive factors of response to cyclosporine in steroid-refractory ulcerative colitis.

OBJECTIVES: Cyclosporine is an effective rescue therapy in steroid-refractory ulcerative colitis (UC) and may avoid immediate colectomy. However, the individual's response to cyclosporine is poorly predictable. The aim of this study was to identify predictive factors of the response to cyclosporine in steroid-refractory UC. METHODS: One hundred thirty-five patients with steroid-refractory UC, admitted consecutively between 1992 and 2004, were included. Data were collected on the first day of the cyclosporine therapy. Colonoscopy was performed within 2 days preceding or following the cyclosporine treatment in 118 patients for assessing the presence of severe endoscopic lesions. RESULTS: The actuarial rate of colectomy was 0.45 at 6 months. Cox analysis in the whole population selected three predictive criteria of colectomy: body temperature >37.5 degrees C (adjusted hazard ratio = 1.94, 95% confidence interval 1.51-2.49), heart rate >90 bpm (1.86, 1.45-2.38), and C-reactive protein (CRP) >45 mg/L (1.70, 1.34-2.16). In the 118 patients who underwent colonoscopy, the presence of severe endoscopic lesions was an independent predictive factor of colectomy (2.38, 1.80-3.14). Colonoscopy was decisive and changed the therapeutic decision in patients with one or two criteria: 71% of the patients with severe endoscopic lesions were colectomized versus 17% of the patients without severe endoscopic lesions (P < 0.001). Finally, the clinical, biological, and endoscopic criteria allowed the classification of the patients into two different groups (80%vs 20% colectomy at 6 months). CONCLUSION: In patients with steroid-refractory UC, the combination of simple criteria is useful to predict the response to cyclosporine. Colonoscopy is crucial in patients with intermediate clinical and biological severity.