Superficial malignant peripheral nerve sheath tumor from recurrent neurofibroma in the abdominal wall of a patient without neurofibromatosis type 1 / 영남의대학술지

Malignant peripheral nerve sheath tumor (MPNST) is rare, accounting for 5-10% of all soft tissue sarcomas. MPNST is characteristically aggressive and has a poor prognosis. Fifty percent of patients with MPNST have neurofibromatosis type 1 (NF1). NF-associated MPNST occurs more often at younger ages than sporadic MPNST, but the survival difference is controversial. Superficial MPNST from a recurrent neurofibroma is extremely rare and only a limited number of cases have been reported in the literature. Herein, we report an unusual case of superficial MPNST from a recurrent neurofibroma in a patient without NF1.

Superficial malignant peripheral nerve sheath tumor from recurrent neurofibroma in the abdominal wall of a patient without neurofibromatosis type 1 / 영남의대학술지

Malignant peripheral nerve sheath tumor (MPNST) is rare, accounting for 5-10% of all soft tissue sarcomas. MPNST is characteristically aggressive and has a poor prognosis. Fifty percent of patients with MPNST have neurofibromatosis type 1 (NF1). NF-associated MPNST occurs more often at younger ages than sporadic MPNST, but the survival difference is controversial. Superficial MPNST from a recurrent neurofibroma is extremely rare and only a limited number of cases have been reported in the literature. Herein, we report an unusual case of superficial MPNST from a recurrent neurofibroma in a patient without NF1.

Comparison of Clinical Characteristics between Single Incision Laparoscopic Appendectomy

PURPOSE: Conventional laparoscopic appendectomy (LA) is a widely used treatment for appendicitis. Nowadays, single incision laparoscopic appendectomy (SILA) is increasingly used as an alternative treatment for appendicitis. The purpose of this study is to evaluate the clinical significance and differences between LA and SILA. METHODS: A total of 519 patients undergoing LA or SILA between January 2011 and December 2012 were identified in a retrospectively collected database. Patients' characteristics and peri-operative variables were analyzed. RESULTS: LA was performed in 485 patients and SILA was performed in 34 patients. Mean operation time for the LA group was 62.7 minutes (range 23.3~68.1) and that for the SILA group was 62.7 minutes (range 50.9~74.5). This difference of operation time was statistically significant. In the learning curve of SILA, operation time was gradually decreased. No significant differences in hospital stay and peri-operative complications were observed between groups. CONCLUSION: Although operation time for SILA was longer than that for LA, SILA was safe. Therefore, a prospective study should be conducted in order to confirm the possibility of application to most appendicitis patients.

Prostaglandin E2 and Interleukin-1beta Reduce E-cadherin Expression by Enhancing Snail Expression in Gastric Cancer Cells

Inflammation is closely related to the progression of cancer as well as tumorigenesis. Here, we investigated the effect of prostaglandin E2 (PGE2) and interleukin-1beta (IL-1beta) on E-cadherin expression in SNU719 gastric cancer cells. E-cadherin expression decreased as the dose or exposure time of PGE2 and IL-1beta increased, whereas Snail expression increased with dose or time of PGE2 and IL-1beta. E-cadherin expression reduced by PGE2 treatment increased after the transfection of Snail siRNA. Neutralization of IL-1beta using anti-IL-1beta antibody blocked the expression pattern of E-cadherin and Snail occurred by IL-1beta treatment. However, there was no synergic effect of IL-1beta and PGE2 on the expression pattern of E-cadherin and Snail. In conclusion, inflammatory mediators reduced E-cadherin expression by enhancing Snail expression in gastric cancer cells. Inflammation-induced transcriptional regulation of E-cadherin in gastric cancer has implications for targeted chemoprevention and therapy.

Advantage of Laparoscopic Appendectomy for Perforated Appendicitis / 대한내시경복강경외과학회지

PURPOSE: Laparoscopic appendectomy (LA) is currently more popular than an open appendectomy (OA), because of its advantages, such as a decrease in postoperative pain, short hospitalization and quick recovery. On the other hand, the efficacy and safety of a laparoscopic appendectomy for complicated appendicitis is controversial. Therefore, this study compared the efficacy and safety of LA and OA. METHODS: This study reviewed retrospectively 262 patients with perforated appendicitis who underwent ether open or laparoscoic appendectomy between January 2001 and December 2010. The medical record and video were used to collect data. The operative time, length of hospital stay, time to diet, time to remove drain and complications were assessed. RESULTS: There were 207 and 55 patients in the OA and LA group, respectively. The operation times were significantly longer in the LA group than the OA group (OA group 68.25+/-33.08 vs. LA group 90.80+/-47.64 min) (p<0.05). The length of hospital stay was longer in the OA group than the LA group (OA group 10.96+/-5.24 vs. LA group 8.86+/-5.18 days) (p<0.05). The time to diet and time to remove the drain was longer in the OA group than the LA group (p<0.05). The postoperative complication rate was similar in the two groups. CONCLUSION: The operative time was longer in the LA group but the length of hospital stay, time to diet, and time to remove drain was longer in the OA group. Such merits show that laparoscopic appendectomy is a good surgical option for perforated appendicitis.

50 Cases of Laparoscopic Appendectomy by One Surgical Resident: The Learning Curve and Safety / 대한내시경복강경외과학회지

PURPOSE: The frequency of performing laparoscopic appendectomy (LA) has increased compared to that of open appendectomy because of its advantages such as decreased postoperative pain, shorter hospitalization and quicker recovery. The advantages of minimally invasive surgery are well known to the general public, so we recognized the importance of a laparoscopic training course. We analyzed the results of LA performed by one resident and we determined the learning curve and the safety. METHODS: We retrospectively studied 50 consecutive patients with a preoperative diagnosis of acute appendectomy and who underwent LA by one surgical resident. We used the medical and video records and compared the patients' age, gender, BMI, the location of the appendix tip, the pathologic findings, the state of drainage insertion, intraoperative bleeding, conversion to open surgery, the operation time and the complicating factor affecting the operating time. RESULTS: The mean operation time was 79.9 minutes and the operation time was effectively shortened when the surgeon had many experiences, the patients had a low BMI and there was no perforation, periappendiceal abscess or insertion of drains. After 25 cases of surgery experience (LA), the surgeon had enough expertise for the operations. Two cases of wound infection around the umbilical area and 1 case of intraperitoneal fluid collection occurred after the surgery. Yet this was all soon cured by wound dressing and the use of antibiotics. CONCLUSION: Fifty cases of LA were safely performed by one surgical resident. Thus, LA is a suitable procedure for surgical residents and it helpful for learning the basic technique of other advanced laparoscopic surgeries.

Cyclooxygenase-2 Expression Is Related to the Epithelial-to-Mesenchymal Transition in Human Colon Cancers

PURPOSE: Down-regulation of E-cadherin is a hallmark of the epithelial-to-mesenchymal transition (EMT). EMT progression in cancer cells is associated with the loss of certain epithelial markers and the acquisition of a mesenchymal phenotype, as well as migratory activities. Cyclooxygenase-2 (COX-2) expression is associated with tumor invasion and metastasis in colon cancer. This study investigated the relationship between E-cadherin and COX-2 in colon cancer cells and human colon tumors. MATERIALS AND METHODS: Colon cancer cell lines and immunohistochemistry were used. RESULTS: E-cadherin expression was inversely related to the expressions of COX-2 and Snail in colon cancer cells. Ectopic expression of COX-2 or Snail reduced E-cadherin and induced a scattered, flattened phenotype with few intercellular contacts in colon cancer cells. Treatment of cancer cells with phorbol 12-myristate 13-acetate increased the expressions of COX-2 and Snail, decreased 15-hydroxyprostaglandin dehydrogenase expression, and increased the cells' motility. In addition, exposure to prostaglandin E2 increased Snail expression and cell motility, and decreased E-cadherin expression. Membranous E-cadherin expression was lower in adenomas and cancers than in the adjacent, non-neoplastic epithelium. In contrast, the expressions of Snail and COX-2 were higher in cancers than in normal tissues and adenomas. The expressions of COX-2 and Snail increased in areas with abnormal E-cadherin expression. Moreover, COX-2 expression was related to higher tumor stages and was significantly higher in nodal metastatic lesions than primary cancers. CONCLUSION: This study suggests that COX-2 may have a role in tumor metastasis via EMT.

The Relationship between Senior Year Examinations at a Medical School and the Korean Medical Licensing Examination / 한국의학교육

PURPOSE: Most medical schools prepare for the Korean medical licensing examination (KMLE) with various tests. By assessing the degree to which these exams and the KMLE are related, students, professors, and institutions can be well prepared and some schools use these exams as predictive tools for KMLE scores. Therefore, we determined the relevance of KMLE results to midterm exams and the objective structured clinical examination (OSCE), administered to senior students at a medical school. METHODS: From 2002 to 2004, KMLE results were compared with midterm examinations, the KMLE, and the OSCE. The total score, or T-score, of the KMLE was used, as was a pass or nonpass score. Windows SPSS 14.0 and MedCalc 9.0 were used for statistical analysis. RESULTS: The yearly correlation coefficient of the KMLE and school exams was highest for the midterm exams in 2002 and the KMLE in 2003 and 2004. The correlation coefficient of midterm exams and the KMLE were related to a high degree, yet the values were as low as that of the OSCE. Compared with the KMLE results, the sensitivity and specificity of the average midterm exam were 100.0% and 93.8%, and the sensitivity and specificity of the average trial exams were 100.0% and 95.8%, respectively. CONCLUSION: In conclusion, the KMLE results have a strong relationship with midterm exams, trial exams, and the combination of midterm and trial exams, but not with the OSCE. Thus, we believe that using both midterm exams and trial exams to predict KMLE results is superior to the use of only one type of school exam.

Decreased Expression of 15-hydroxyprostaglandin Dehydrogenase in Gastric Carcinomas

PURPOSE: Gastric carcinoma tissues release high level of prostaglandin E2 (PGE2) when compared to non-neoplastic mucosa, and cyclooxygenase-2 (COX-2), which is the rate-limiting enzyme in prostaglandin (PG) biosynthesis, is often overexpressed in gastric carcinomas and during gastric carcinogenesis. However, little is known about the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for the biological inactivation of PG, in gastric carcinomas. MATERIALS AND METHODS: We investigated the expression of 15-PGDH in 28 cases of advanced gastric carcinomas by Western blot analysis and also the relation between its expression and the gene promoter methylation. RESULTS: 15-PGDH expression was significantly decreased in gastric carcinomas compared to corresponding non-neoplastic tissues and inversely correlated with the expression of proliferating cell nuclear antigen in gastric carcinomas. However, there was no correlation between 15-PGDH expression and pathological findings such as nodal metastasis and vascular invasion. Promoter hypermethylation of 15-PGDH gene was not detected in carcinomas, with only a negligible expression of the enzyme. CONCLUSION: Our results suggested that 15-PGDH has tumor suppressor activity in gastric carcinomas.

Sulindac Prevents Esophageal Adenocarcinomas Induced by Gastroduodenal Reflux in Rats

PURPOSE: It is known that cyclooxygenase (COX)-2 expression is increased in Barrett's esophagus and esophageal adenocarcinomas. We studied COX-2 expression and the effect sulindac has on the genesis of Barrett's esophagus and adenocarcinoma in rats undergoing esophagogastroduodenal anastomosis (EGDA). MATERIALS AND METHODS: Fifty-one rats were divided into a control group (n=27), a 500ppm sulindac-treated group (n=15) and 1000 ppm sulindac-treated group (n=9). Randomly selected rats were killed by diethyl ether inhalation at 20 and 40 weeks after surgery. RESULTS: At 40 weeks, rats treated with 1000 ppm sulindac showed narrower esophageal diameter and milder inflammation than the control rats. At 40 weeks, the incidence of Barrett's esophagus was similar between control and sulindac-treated groups, but the incidence of adenocarcinoma was significantly lower in the 1000ppm sulindac-treated group than either the control or 500 ppm sulindac-treated groups. COX-2 was significantly increased in the lower esophagus of control rats killed at 40 weeks. Cyclin D1 expression was negligible in the sulindac- treated group compared with the control group. CONCLUSION: We suggest that the chemopreventive effect of sulindac is related to decreased COX-2 and cyclin D1 expression, which may be influenced by reduced inflammation.

Necrotizing Fasciitis Secondary to Infected Bedsore

Necrotizing fasciitis is a progressive soft tissue infection involving the superficial fascia which can be a lethal disease without proper treatment. The predisposing factors of necrotizing fasciitis are diabetes mellitus, alcohol abuse, drug abuse, obesity, malnutrition and immunocompromised state. Most of the recently reported cases of necrotizing fasciitis were caused by perianal disease. We treated a young woman with necrotizing fasciitis secondary to infected bedsore who had been held in hospital for 15 years due to schizophrenia and epilepsy. Here, we emphasize the specific concern when treating patients with bedsore.

Significance of Serum Ferritin in Multiple Trauma Patients with Acute Respiratory Distress Syndrome

PURPOSE: Clinically, acute respiratory distress syndrome (ARDS) occurs within 72 hours after acute exposure of risk factors. Because of its high fatality rate once ARDS progresses, early detection and management are essential to reduce the mortality rate. Accordingly, studies on early changes of ARDS were started, and serum ferritin, as well the as injury severity score (ISS), which has been addressed in previous studies, thought to be an early predictive indicator for ARDS METHODS: From March 2003 to March 2005, we investigated 50 trauma patients who were admitted to the intensive care unit in Dongguk University Medical Center, Gyeongju. The patients were characterized according to age, sex, ISS, onset of ARDS, time onset of ARDS, serum ferritin level (posttraumatic 1st & 2nd day), amount of transfused blood, and death. Abdominal computed topography was performed as an early diagnostic tool to evaluate the onset of ARDS according to its diagnostic criteria. The serum ferritin was measured by using a VIDAS(R) Ferritin (bioMeriux, Marcy-1' Etoile, France) kit with an enzyme-linked fluorescent assay method. For statistical analysis, Windows SPSS 13.0 and MedCalc were used to confirm the probability of obtaining a predictive measure from the receiver operating characteristics (ROC) curve. RESULTS: The ISS varied from 14 to 66 (mean: 33.8) whereas the onset of ARDS could be predicted with the score above 30 (sensitivity: 90.0%, specificity: 60.0%, p<0.05). On the posttraumatic 1st day, the serum ferritin levels were measured to be from 31 mg/dL to 1,200 mg/dL (mean: 456 mg/dL), and the onset of ARDS could be predicted when the value was over 340 mg/dL (sensitivity: 80.0%, specificity: 65.0%, p<0.05). On the posttraumatic 2nd day , the serum ferritin levels were measured to be from 73 mg/dL to 1,200 mg/dL (mean: 404 mg/dL), and the onset of ARDS could be predicted when the value was over 627 mg/dL (sensitivity: 60.0%, specificity: 92.5%, p<0.05). The serum ferritin levels and the ISS were significantly higher on the posttraumatic 1st and 2nd day in the ARDS group, suggesting that they are suitable indices predicting the onset of ARDS, however relationship between the serum ferritin levels and the ISS was not statistically significant. CONCLUSION: In this study, we discovered increasing serum ferritin levels in multiple- trauma patients on the posttraumatic 1st & 2nd day and concluded that both the serum ferritin level and the ISS were good predictors of ARDS. Although they do not show statistically significant relationship to each other, they can be used as independent predictive measures for ARDS. Since ARDS causes high mortality, further studies, including the types of surgery and the methods of anesthesia on a large number of patients are essential to predict the chance of ARDS earlier and to reduce the incidence of death.

Clinical Manifestations and Microbiological Features Correlating with Central Venous Catheter Related Infection

PURPOSE: Central venous catheterization is widely used to supply substantial amounts of fluids, total parenteral nutrition and hemodialysis in renal failure patients, as well as for measuring the central venous pressure. The most common complications encountered during central venous catheterization include catheter-related infections and subsequent sepsis. Therefore, when fever exists in patients with a central venous catheter, an immediate blood culture should be performed, and if the fever persists, an infection must be suspected and the catheter immediately removed; a culture of the catheter tip should also be performed. To date, no definite clinical details relating to this matter have been reported. METHODS: Between December 2002 and March 2005, a retrospective study was undertaken using the medical records of 85 patients. In those patients where a fever lasted for more than 8 hours, or when catheterization was no longer needed, the catheter tip cultures were sent to the microbiology laboratory. Blood cultures were also performed on 49 patients with a fever. The Chi-square method using the PC SPSS program, with P value less than 0.05 as statically significant. RESULTS: Of the 85 patients where the catheters were removed, significant microorganisms were detected 20 of the 49 with a fever. Only 5 of the remaining 36 patients had their catheters spontaneously removed. Moreover, 14 of the 20 patients with significant microorganisms were found to have kept their catheter in place for more than 14 days. Of the 49 patients with a fever, in who blood cultures were undertaken, 13 showed specific microorganisms, with 6 of these showing the same results for both their blood and catheter tip cultures, which enabled the definite diagnosis of the catheter-related infection and underlying sepsis. Various microorganisms were detected from the catheter tip cultures, including Staphylococcus species the CNS, with S. aureus being the most common, at 61.6%. CONCLUSION: A central venous catheter should be removed immediately when an infection is suspected, but early broad-spectrum antibiotics therapy should be commenced due to the time required to obtain the culture results. Moreover, even if a fever does not exist in patients with a catheter inserted for more than 14 days, infection and sepsis from the catheter should be of concern, with a more cautious approach being mandatory.

Mondor's Disease in Antecubital Area

Mondor's disease is also called thrombophlebitis and it is not a common condition. The characteristics finding of Mondor's disease is a subcutaneous cord that is tender and tense. This disease commonly occurs in the breast and abdomen. The etiology of Mondor's disease is unknown, but the generally agreed on causes are trauma, excessive exercise and breast surgery. On rare occasions, this disease is related to malignancy, pregnancy, filariasis and so on. This disease is self limiting and it is usually treated conservatively and symptomatically. We treated one woman who had Mondor's disease on the anterior side of the left elbow. This is a very rare location for Mondor's disease and so clinicians need to be aware about the possibility of this unusual presentation for this disease.

Comparison of Professional Standardized and Amateur Standardized Patients in OSCE / 한국의학교육

PURPOSE: The standardized patient (SP) is a person carefully trained to represent a real patient case for consistent and accurate use in student performance evaluation and/or training, has added a very important dimension in OSCE. The purpose of this study is compared a well-trained professional SP (PSP) and a amateur SP (ASP) in OSCE. METHODS: We surveyed 378 students apprentices and staffs involving OSCE of Daegu-Kyungbuk Consortium and analysed the validity between the PSP and ASP after OSCE. RESULTS: Of 92 total stations in which students were evaluated by staff evaluator, SP were used in 47 stations (48%). Of the 47 stations, professional SP 7 stations (16%). The questionnaires were made to know the effectiveness and realistics of SP. The results were different between station used PSP and ASP. Moreover, it was significantly different between the staffs and the students. The SP can offer advantages such as availability, adaptability and effectivity. If trained well, they also can provide positive effects to the students and the staffs. The PSP provides efficient and reliable opportunity to assess clinical skills in a safe situation without any harm to the real patients. CONCLUSION: It is suggested that the use of SP is stimulating and challenging way of evaluating the OSCE. Also, It appeared to be financially and availably feasible if it commonly owned in the boundary of the land such Daegu-Kyungbuk Consortium.

Expression of Inducible Nitric Oxide Synthase Is Increased in Rat Barrett's Esophagus Induced by Duodenal Contents Reflux

Barrett's esophagus is a premalignant condition of esophageal adenocarcinoma. Inducible nitric oxide synthase (iNOS) is induced by cytokines and can generate locally high concentrations of nitric oxide (NO), whose metabolites can mediate genotoxicity and influence multistage carcinogenesis by causing DNA damage. Therefore, we evaluated the immunolocalization and expression of iNOS in surgically induced rat Barrett's esophagus. Esophagoduodenal anastomosis was performed in rats for inducing reflux of duodenal contents. Rats were killed at postoperative 10, 20, 30 and 40 weeks. We examined histologic changes and iNOS expression in esophagus by immunohistochemistry and reverse transcription-poly-merase chain reaction. Eighty six percent of experimental rats showed Barrett's esophagus above esophagoduodenal junction. iNOS immunoreactivity was clearly observed in the epithelial cells of Barrett's esophagus, predominantly at the apical surface of epithelial cells. Cytoplasmic staining was also seen only in atypical Barrett's esophagus. iNOS mRNA was detected only in the lower esophagus of experimental group. In conclusion, this study suggests that iNOS has some roles on Barrett's esophagus formation.

Acute Appendicitis in Children under Age of 5 Years

PURPOSE: Acute appendicitis is one of the most common causes of abdominal emergency. Children, under age of 5 years, are unable to give an accurate history, but other nonspecific abdominal pain is more common at this age. Because diagnosis is often delayed and progression of appendicitis is faster, incidence and perforation rate is higher than those of adults. Abdominal US and CT are helpful in diagnosis of acute appendicitis. METHODS: Between July, 1997 and April, 2004, 39 patients below 5-year-old were participated, but 2 (Negative) patients were excluded. This study was done retrospectively based on medical charts. For statistical analysis, Chi-squre test was used. RESULTS: All patients undergone emergency operations, in which male to female ratio was 1.79: 1, with its mean age of 4.05. 19 patients (49%) were perforated and fever developed more frequently in perforating group, but leukocytosis was not significant. Delayed preoperative duration was associated with perforation rate significantly. All complications were occurred in perforating group. CONCLUSION: To decrease perforation rate and complications, early diagnosis and management are necessary to avoid delaying preoperative time.

Idiopathic Perforated Cecitis Mistaken as Perforated Appendicitis

The cecal perforation is very rare in pediatrics. Our center has experienced a 7-year-old girl with idiopathic perforated cecitis. The surgeon couldn't differentiate perforated cecitis from perforated appendicitis because of anatomical location, incidence and ambiguous radiologic result when this patient was admitted to our clinic due to RLQ pain.

Trauma-related Acute Spigelian Hernia in Right Upper Abdomen

Trauma-related spigelian hernia is a rare event that has been reported only sporadically. Because of its rare nature and nonspecific physical findings, its diagnosis is difficult. This hernia most commonly presents at the level of the semicircular line known as the arcuate line. A 70-year-old man was admitted after overturn of his cultivator. A scratch wound surrounding a cutaneous sign of the cultivator handlebar impact was evident on his right upper abdominal wall. Trauma-related spigelian hernia occurred in the site of the handlebar impact. We report this cases of trauma-related spigelian hernia that was treated by primary repair with a brief review of the literature.

Traumatic Diaphragmatic Ruputure: 4-Year Clinical Experience

PURPOSE: A traumatic diaphragmatic rupture (TDR) is a diagnostic challenge and the associated injuries determine the outcome in those diagnosed early. A TDR has long been considered to be a marker of the severity of injury with an average reported Injury Severity Score (ISS) between 31 and 50. This report reviewed the TDR cases in order to emphasize the method and timing of the diagnosis, associated injuries and the outcome. METHODS: A retrospective analysis was performed on 30 patient treated for TDR between August 1998 and september 2002. RESULTS: The mean age of the patients was 33.4 years and the injury predomiantly affected males (male: female=2: 1). Blunt trauma by TA was the most common cause of the TDR (25 patients). The ruptured sites were on the left in 22 cases and on the right in 8 cases. The most common symptom was chest pain (23 cases) followed dyspnea (21 cases). Liver injuries and a pneumo-hemothorax were the most common associated injuries. The mean CRAMS scale was 6.47 and Injury Severity Score (ISS) was 18.93. Eighteen TDR cases were suspected based on the abnormal chest X-ray findings. Nineteen cases underwent surgery within 6 hours after the trauma (early diagnosis). Although many complications occurred in 11 cases, there were no lethal complications. The mean size of the diaphragmatic rupture was 9.77 cm and an intraabdominal organ herniation had not occurred in ruptures smaller than 6 cm. Surgical repair of the diaphragm was performed via a laparotomy in 20 cases and thoracotomy in 7 cases. A left side TDR was preferred to a laparotomy whereas a right sided TDR was preferred to a thoracotomy. Pulmonary complications (atelectasis, pneumonia, pleural effusion) occurred in 14 cases postoperatively. CONCLUSION: The patient's complaints and physical findings were not a reliable indicator of the diagnosis, but usually a manifestation of the associated injuries. A suspicion and routine chest X-ray was the most reliable diagnostic tool, even though the chest X-ray was normal in 12 cases. A high rate of early diagnosis can be achieved using an aggresive investigation protocol, suspicion and a combined radiologic evaluation in multiple trauma patients. Although pulmonary complications occurred in the early diagnosed cases, lethal complications and long term sequela were directly related to the time of diagnosis. The higher ISS had many complications (11 cases) but there were no lethal complications, long term sequela.