ABSTRACT
Background/Aims@#Some management strategies for acute colonic diverticulitis remain controversial in Korean real-world practice because their clinical features differ from those in the West. This study aimed to investigate the opinions of Korean physicians regarding the diagnosis and treatment of acute diverticulitis. @*Methods@#A web-based survey was conducted among gastroenterologists specializing on treating lower gastrointestinal disorders. The questionnaires concerned overall management strategies for colonic diverticulitis, including diagnosis, treatment, and follow-up. @*Results@#In total, 209 gastroenterologists responded to the survey. Less than one-fourth of the respondents (23.6%) answered that left-sided colonic diverticulitis is more likely to be complicated than right-sided colonic diverticulitis. Most respondents agreed that immunocompromised patients with diverticulitis have worse clinical outcomes than immunocompetent patients (71.3%). Computed tomography was the most preferred tool for diagnosing diverticulitis (93.9%). Approximately 89% of the respondents answered that they believed antibiotic treatment is necessary to treat acute uncomplicated diverticulitis. Most respondents (92.6%) agreed that emergency surgery is not required for diverticulitis with an abscess or microperforation without panperitonitis. Further, 94.7% of the respondents agreed that colon cancer screening is necessary in patients aged ≥ 50 years with diverticulitis after they have recovered from acute illness. Many respondents (71.4%) agreed that surgery for recurrent diverticulitis should be individualized. @*Conclusions@#Opinions regarding management strategies for colonic diverticulitis among Korean gastroenterologists were well agreed upon in some areas but did not agree well in other areas. Evidence-based guidelines that meet the practical needs of the Korean population should be developed.
ABSTRACT
Background/Aims@#Immunocompromised patients with acute colonic diverticulitis are at high risk for complications and failure of non-surgical treatment. However, evidence on the comparative outcomes of immunocompromised and immunocompetent patients with diverticulitis is lacking. This systematic review and meta-analysis investigated the outcomes of medical treatment in immunocompromised and immunocompetent patients with diverticulitis. @*Methods@#A comprehensive literature search was conducted in PubMed, Embase, and the Cochrane Library. Studies comparing the clinical outcomes of immunocompromised and immunocompetent patients with diverticulitis were included. @*Results@#A total of 10 studies with 1,946,461 subjects were included in the quantitative synthesis. The risk of emergency surgery and postoperative mortality after emergency surgery was significantly higher in immunocompromised patients than in immunocompetent patients with diverticulitis (risk ratio [RR], 1.76; 95% confidence interval [CI], 1.31–2.38 and RR, 3.05; 95% CI, 1.70–5.45, respectively). Overall risk of complications associated with diverticulitis was non-significantly higher in immunocompromised than in immunocompetent patients (RR, 1.24; 95% CI, 0.95–1.63). Overall mortality irrespective of surgery was significantly higher in immunocompromised than in immunocompetent patients with diverticulitis (RR, 3.65; 95% CI, 1.73–7.69). By contrast, postoperative mortality after elective surgery was not significantly different between immunocompromised and immunocompetent patients with diverticulitis. In subgroup analysis, the risk of emergency surgery and recurrence was significantly higher in immunocompromised patients with complicated diverticulitis, whereas no significant difference was shown in mild disease. @*Conclusions@#Immunocompromised patients with diverticulitis should be given the best medical treatment with multidisciplinary approach because they had increased risks of surgery, postoperative morbidity, and mortality than immunocompetent patients.
ABSTRACT
Background/Aims@#Various endoscopic submucosal dissection (ESD) methods for gastric tumors have been tried. However, no studies have yet compared results according to the ESD method for gastric body tumors using a dual knife. The objective of this study was to compare outcomes of two ESD methods for gastric body tumors: the pocket-creation method and conventional method. @*Methods@#Patients who underwent ESD for a gastric body tumor were retrospectively reviewed.Patients were divided into two groups according to the ESD method: the conventional method (group I) and pocket-creation method (group II). Characteristics of patients and tumors, hospitalization period, incidence of complications, resection margin status, incidence of surgical operation, procedure time, and laboratory findings were investigated. @*Results@#Of the total of 100 patients, 52 belonged to group I and 48 to group II. All tumors were successfully resected en bloc. Resection margin involvement was found in six (11.5%) of group I and six (12.5%) of group II. Complications were observed in seven (13.5%; major complication five, minor two) of group I and eight (16.7%; major two, minor six) of group II. There were no significant differences in ESD outcomes such as hospitalization period, incidence of complications, resection margin status, incidence of surgical operation, procedure time, or inflammatory response after ESD between the two groups. @*Conclusions@#Both methods are suitable for treating gastric body tumors with adequate treatment success rates and comparable complication rates.
ABSTRACT
Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus, is threatening global health worldwide with unprecedented contagiousness and severity. The best strategy to overcome COVID-19 is a vaccine. Various vaccines are currently being developed, and mass vaccination is in progress. Despite the very encouraging clinical trial results of these vaccines, there is insufficient information on the safety and efficacy of vaccines for inflammatory bowel disease (IBD) patients facing various issues. After reviewing current evidence and international guidelines, the Korean Association for the Study of Intestinal Diseases developed an expert consensus statement on COVID-19 vaccination issues for Korean IBD patients. This expert consensus statement emphasizes that severe acute respiratory syndrome coronavirus 2 vaccination be strongly recommended for IBD patients, and it is safe for IBD patients receiving immunomodulatory therapy.
ABSTRACT
The coronavirus disease 2019 (COVID-19) pandemic has reduced the ability to prevent or control chronic disease due to the concerns about safety in accessing health care. Inflammatory bowel disease (IBD) is a chronic condition requiring long- term sustained treatment, which is difficult in the current panedemic situation. The Korean Association for the Study of Intestinal Diseases (KASID) has developed an expert consensus statement on the clinical practice management of adult inflammatory bowel disease during the COVID-19 pandemic. This expert consensus statement is based on guidelines and clinical reports from several countries around the world. It provides recommendations to deal with the risk of COVID-19 and medication use in IBD patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and emphasizes the importance of right treatment approach to avoid worsening of the disease condition in IBD patients.
ABSTRACT
Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus, is threatening global health worldwide with unprecedented contagiousness and severity. The best strategy to overcome COVID-19 is a vaccine. Various vaccines are currently being developed, and mass vaccination is in progress. Despite the very encouraging clinical trial results of these vaccines, there is insufficient information on the safety and efficacy of vaccines for inflammatory bowel disease (IBD) patients facing various issues. After reviewing current evidence and international guidelines, the Korean Association for the Study of Intestinal Diseases (KASID) developed an expert consensus statement on COVID-19 vaccination issues for Korean IBD patients. This expert consensus statement emphasizes that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination be strongly recommended for IBD patients, and it is safe for IBD patients receiving immunomodulatory therapy.
ABSTRACT
Background/Aims@#High-quality colonoscopy is essential to reduce colorectal cancer-related deaths. Little is known about colonoscopy quality in non-academic practice settings. We aimed to evaluate the quality of colonoscopies performed in community hospitals and nonhospital facilities. @*Methods@#Colonoscopy data were collected from patients referred to six tertiary care centers after receiving colonoscopies at community hospitals and nonhospital facilities. Based on their photographs, we measured quality indicators including cecal intubation rate, withdrawal time, adequacy of bowel preparation, and number of polyps. @*Results@#Data from a total of 1,064 colonoscopies were analyzed. The overall cecal intubation rate was 93.1%. The median withdrawal time was 8.3 minutes, but 31.3% of colonoscopies were withdrawn within 6 minutes. Community hospitals had longer withdrawal time and more polyps than nonhospital facilities (median withdrawal time: 9.9 minutes vs. 7.5 minutes, p < 0.001; mean number of polyps: 3.1 vs. 2.3, p = 0.001). Board-certified endoscopists had a higher rate of cecal intubation than non-board-certified endoscopists (93.2% vs. 85.2%, p = 0.006). A total of 819 follow-up colonoscopies were performed at referral centers with a median interval of 28 days. In total, 2,546 polyps were detected at baseline, and 1,088 were newly identified (polyp miss rate, 29.9%). Multivariable analysis revealed that older age (odds ratio [OR], 1.032; 95% confidence interval [CI], 1.020 to 1.044) and male sex (OR, 1.719; 95% CI, 1.281 to 2.308) were associated with increased risk of missed polyps. @*Conclusions@#The quality of colonoscopies performed in community hospitals and nonhospital facilities was suboptimal. Systematic reporting, auditing, and feedback are needed for quality improvement.
ABSTRACT
Background/Aims@#Infliximab (IFX) has proven effective as rescue therapy in steroid-refractory acute severe ulcerative colitis (ASUC), however, the long-term real-world data are scarce. Our study aimed to assess the long-term treatment outcomes of IFX in a real-life cohort. @*Methods@#We established a multicenter retrospective cohort of hospitalized patients with ASUC, who met Truelove and Witt’s criteria and received intravenous corticosteroid (IVCS) or IFX during index hospitalization between 2006 and 2016 in 5 university hospitals in Korea. The cohort was systematically followed up until colectomy, death or last follow-up visit. @*Results@#A total of 296 patients were followed up for a mean of 68.9 ± 44.0 months. During index hospitalization, 49 patients were treated with IFX; as rescue therapy for IVCS failure in 37 and as first-line medical therapy for ASUC in 12. All patients treated with IFX avoided colectomy during index hospitalization. The cumulative rates of rehospitalization and colectomy were 20.4% and 6.1% at 3 months and 39.6% and 18.8% at the end of follow-up, respectively. Patients treated with IFX presented with significantly shorter colectomy-free survival than IVCS responders (P= 0.04, log-rank test). Both cytomegalovirus colitis and Clostridioides difficile infection (CDI) were the significant predictors of colectomy in the overall study cohort (hazard ratios of 6.57 and 4.61, respectively). There were no fatalities. @*Conclusions@#Our real-world cohort study demonstrated that IFX is an effective therapeutic option in Korean patients with ASUC, irrespective of IFX indication. Aggressive vigilance for cytomegalovirus colitis and CDI is warranted for hospitalized patients with ASUC.
ABSTRACT
The coronavirus disease 2019 (COVID-19) pandemic has reduced the ability to prevent or control chronic disease due to the concerns about safety in accessing health care. Inflammatory bowel disease (IBD) is a chronic condition requiring long- term sustained treatment, which is difficult in the current panedemic situation. The Korean Association for the Study of Intestinal Diseases (KASID) has developed an expert consensus statement on the clinical practice management of adult inflammatory bowel disease during the COVID-19 pandemic. This expert consensus statement is based on guidelines and clinical reports from several countries around the world. It provides recommendations to deal with the risk of COVID-19 and medication use in IBD patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and emphasizes the importance of right treatment approach to avoid worsening of the disease condition in IBD patients.
ABSTRACT
Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus, is threatening global health worldwide with unprecedented contagiousness and severity. The best strategy to overcome COVID-19 is a vaccine. Various vaccines are currently being developed, and mass vaccination is in progress. Despite the very encouraging clinical trial results of these vaccines, there is insufficient information on the safety and efficacy of vaccines for inflammatory bowel disease (IBD) patients facing various issues. After reviewing current evidence and international guidelines, the Korean Association for the Study of Intestinal Diseases (KASID) developed an expert consensus statement on COVID-19 vaccination issues for Korean IBD patients. This expert consensus statement emphasizes that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination be strongly recommended for IBD patients, and it is safe for IBD patients receiving immunomodulatory therapy.
ABSTRACT
Background/Aims@#Infliximab (IFX) has proven effective as rescue therapy in steroid-refractory acute severe ulcerative colitis (ASUC), however, the long-term real-world data are scarce. Our study aimed to assess the long-term treatment outcomes of IFX in a real-life cohort. @*Methods@#We established a multicenter retrospective cohort of hospitalized patients with ASUC, who met Truelove and Witt’s criteria and received intravenous corticosteroid (IVCS) or IFX during index hospitalization between 2006 and 2016 in 5 university hospitals in Korea. The cohort was systematically followed up until colectomy, death or last follow-up visit. @*Results@#A total of 296 patients were followed up for a mean of 68.9 ± 44.0 months. During index hospitalization, 49 patients were treated with IFX; as rescue therapy for IVCS failure in 37 and as first-line medical therapy for ASUC in 12. All patients treated with IFX avoided colectomy during index hospitalization. The cumulative rates of rehospitalization and colectomy were 20.4% and 6.1% at 3 months and 39.6% and 18.8% at the end of follow-up, respectively. Patients treated with IFX presented with significantly shorter colectomy-free survival than IVCS responders (P= 0.04, log-rank test). Both cytomegalovirus colitis and Clostridioides difficile infection (CDI) were the significant predictors of colectomy in the overall study cohort (hazard ratios of 6.57 and 4.61, respectively). There were no fatalities. @*Conclusions@#Our real-world cohort study demonstrated that IFX is an effective therapeutic option in Korean patients with ASUC, irrespective of IFX indication. Aggressive vigilance for cytomegalovirus colitis and CDI is warranted for hospitalized patients with ASUC.
ABSTRACT
Background/Aims@#It is unclear whether continuous infusion or intermittent bolus injection of propofol is better for achieving adequate sedation in endoscopic retrograde cholangiopancreatography (ERCP). We aimed to compare the efficacy and safety of continuous infusion and intermittent bolus injection of propofol during therapeutic ERCP. @*Methods@#In this prospective study, we randomly assigned 232 patients undergoing therapeutic ERCP to either continuous infusion (CI group, n = 113) or intermittent bolus injection (BI group, n = 119) of propofol. The primary outcome was the quality of sedation as assessed by the endoscopist. Other sedation-related parameters included sedation induction time, total dose of propofol, recovery time, involuntary patient movement, and adverse events. @*Results@#Overall satisfaction with sedation by the endoscopist and monitoring nurse were significantly higher in the CI group than the BI group (mean satisfaction score, 9.66 vs. 8.0 and 9.47 vs. 7.96, respectively, p < 0.01 for both). However, patients in the CI group had a significantly longer sedation induction time (5.28 minutes vs. 4.34 minutes, p < 0.01) and received a higher dose of propofol than patients in the BI group (4.22 mg/kg vs. 2.08 mg/kg, p < 0.01). There was no significant difference in adverse events between the two groups. @*Conclusions@#Continuous infusion of propofol during therapeutic ERCP had the advantage over intermittent bolus injection of maintaining a constant level of sedation without increasing adverse events. However, it was associated with an increased total dose of propofol and prolonged sedation induction time.
ABSTRACT
Background/Aims@#Both hepatic venous pressure gradient (HVPG) and liver stiffness (LS) are useful tools for predicting mortality in patients with cirrhosis. We investigated the combined effect of HVPG and LS on long-term mortality in patients with cirrhosis. @*Methods@#We retrospectively collected data from 103 patients with cirrhosis, whose HVPG and LS were measured between November 2009 and September 2013. The patients were divided into four groups according to the results of the HVPG and LS measurements. Long-term mortality and the risk factors for mortality were analyzed. @*Results@#Of the 103 patients, 35 were in group 1 (low HVPG and low LS), 16 in group 2 (high HVPG and low LS), 24 in group 3 (low HVPG and high LS), and 28 in group 4 (high HVPG and high LS). Over a median follow-up of 47.3 months, 18 patients died. The mortality rate of patients in group 4 was significantly higher than in the other three groups (vs. group 1, p = 0.005; vs. group 2, p = 0.049; vs. group 3, p = 0.004), but there were no significant differences in survival between groups 1, 2, and 3. In multivariable analyses, both HVPG and LS were identified as independent risk factors for mortality (hazard ratio [HR], 1.127, p = 0.018; and HR, 1.062, p = 0.009, respectively). @*Conclusions@#In patients with cirrhosis, those with concurrent elevation of HVPG and LS had the highest long-term mortality rates. However, when either HVPG or LS alone was elevated, mortality did not increase significantly.
ABSTRACT
BACKGROUND: Sarcopenia is associated with a poor prognosis in patients with liver cirrhosis. However, it is not known whether the rate of skeletal muscle depletion is also associated with a poor prognosis. We investigated the prognostic impact of the rate of skeletal muscle depletion in patients with liver cirrhosis. METHODS: We included retrospectively all patients with liver cirrhosis who underwent both multiple computed tomography scans and hepatic venous pressure gradient (HVPG) measurements. RESULTS: A total of 131 patients with liver cirrhosis were enrolled. The mean age of the patients was 53.7 years and alcoholic liver disease was the most common cause (61.8%). Sixty-four patients (48.9%) were diagnosed with sarcopenia. The median changes in skeletal muscle area per year (ΔSMA/y) were −0.89%. During a median follow-up period of 46.2 months (range, 3.4–87.6), 45 patients (34.4%) died. In multivariate analyses, age, Child-Pugh score, HVPG, presence of sarcopenia and ΔSMA/y were independently associated with mortality. Cumulative mortality was significantly higher in patients with ΔSMA/y <−2.4% than those with ΔSMA/y ≥−2.4% (log-rank test, P < 0.001). CONCLUSION: Both the presence and rate of change of sarcopenia are independently associated with long-term mortality in patients with liver cirrhosis.
Subject(s)
Humans , Follow-Up Studies , Liver Cirrhosis , Liver Diseases, Alcoholic , Liver , Mortality , Multivariate Analysis , Muscle, Skeletal , Prognosis , Retrospective Studies , Sarcopenia , Venous PressureABSTRACT
Liver infarction is rare because of dual blood supply of the liver with hepatic artery and portal vein. And its occurrence as a complication of chronic pancreatitis is rarer. We present a case of chronic pancreatitis complicated by liver infarction and inferior pancreaticoduodenal artery pseudoaneurysm. A 31-year-old female with alcoholism presented with severe acute epigastric pain. Serum amylase and lipase were 203 IU/L and 78 IU/L, respectively. Initial computed tomography (CT) scan showed peripancreatic infiltration, fluid collection, right portal vein thrombosis, and a large wedge-shaped low attenuation in the right hepatic lobe. The patient has been treated with heparin. Follow-up CT scan done after 4 days of heparin treatment demonstrated a pseudocyst with internal hemorrhage and a pseudoaneurysm. Angiography revealed a pseudoaneurysm in inferior pancreaticoduodenal artery. Coil embolization of the artery was done. The patient has been discharged without complication. Follow-up CT scan showed resolution of liver infarction, portal vein thrombosis and pseudoaneurysm.
Subject(s)
Adult , Female , Humans , Alcoholism , Amylases , Aneurysm, False , Angiography , Arteries , Embolization, Therapeutic , Follow-Up Studies , Hemorrhage , Heparin , Hepatic Artery , Infarction , Lipase , Liver , Pancreatitis , Pancreatitis, Chronic , Portal Vein , Thrombosis , Tomography, X-Ray Computed , Venous ThrombosisABSTRACT
Liver infarction is rare because of dual blood supply of the liver with hepatic artery and portal vein. And its occurrence as a complication of chronic pancreatitis is rarer. We present a case of chronic pancreatitis complicated by liver infarction and inferior pancreaticoduodenal artery pseudoaneurysm. A 31-year-old female with alcoholism presented with severe acute epigastric pain. Serum amylase and lipase were 203 IU/L and 78 IU/L, respectively. Initial computed tomography (CT) scan showed peripancreatic infiltration, fluid collection, right portal vein thrombosis, and a large wedge-shaped low attenuation in the right hepatic lobe. The patient has been treated with heparin. Follow-up CT scan done after 4 days of heparin treatment demonstrated a pseudocyst with internal hemorrhage and a pseudoaneurysm. Angiography revealed a pseudoaneurysm in inferior pancreaticoduodenal artery. Coil embolization of the artery was done. The patient has been discharged without complication. Follow-up CT scan showed resolution of liver infarction, portal vein thrombosis and pseudoaneurysm.
Subject(s)
Adult , Female , Humans , Alcoholism , Amylases , Aneurysm, False , Angiography , Arteries , Embolization, Therapeutic , Follow-Up Studies , Hemorrhage , Heparin , Hepatic Artery , Infarction , Lipase , Liver , Pancreatitis , Pancreatitis, Chronic , Portal Vein , Thrombosis , Tomography, X-Ray Computed , Venous ThrombosisABSTRACT
PURPOSE: The present study aimed to investigate the role of hepatic venous pressure gradient (HVPG) for prediction of long-term mortality in patients with decompensated cirrhosis. MATERIALS AND METHODS: Clinical data from 97 non-critically-ill cirrhotic patients with HVPG measurements were retrospectively and consecutively collected between 2009 and 2012. Patients were classified according to clinical stages and presence of ascites. The prognostic accuracy of HVPG for death, survival curves, and hazard ratios were analyzed. RESULTS: During a median follow-up of 24 (interquartile range, 13-36) months, 22 patients (22.7%) died. The area under the receiver operating characteristics curves of HVPG for predicting 1-year, 2-year, and overall mortality were 0.801, 0.737, and 0.687, respectively (all p17 mm Hg, respectively (p=0.015). In the ascites group, the mortality rates at 1 and 2 years were 3.9% and 17.6% with HVPG 17 mm Hg, respectively (p=0.044). Regarding the risk factors for mortality, both HVPG and model for end-stage liver disease were positively related with long-term mortality in all patients. Particularly, for the patients with ascites, both prothrombin time and HVPG were independent risk factors for predicting poor outcomes. CONCLUSION: HVPG is useful for predicting the long-term mortality in patients with decompensated cirrhosis, especially in the presence of ascites.
Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Ascites/mortality , Hepatic Veins/physiopathology , Kaplan-Meier Estimate , Liver Cirrhosis/blood , Liver Failure/diagnosis , Predictive Value of Tests , Prognosis , Proportional Hazards Models , ROC Curve , Retrospective Studies , Risk Factors , Severity of Illness Index , Venous PressureABSTRACT
Femoral artery pseudoaneurysm (FAP) is one of the most troublesome groin complications related to femoral arterial access during invasive cardiovascular procedures. Ultrasound-guided compression is the initial treatment for FAP. Here, we describe the case of a 65 year-old female who developed significant deep vein thrombosis (DVT) following ultrasound-guided compression of FAP after percutaneous coronary intervention. She was successfully treated with anti-coagulation medications. This case, along with a brief review of the literature, should remind physicians of the possible occurrence of delayed vascular complications, such as DVT, after ultrasound-guided compression of FAP.
Subject(s)
Aged , Female , Humans , Aneurysm, False , Femoral Artery , Groin , Percutaneous Coronary Intervention , Venous ThrombosisABSTRACT
Here we report a 65-year-old male patient initially presented with dyspnea and chest discomfort. This patient was finally diagnosed with severe hypothyroidism accompanied by heart failure, pericardial effusion and acute renal failure. We suspected that heart failure, pericardial effusion and acute kidney injury were induced by severe hypothyroidism. Thus, we began thyroid hormone replacement therapy. After the therapy, the patient's dyspnea and chest discomfort were improved. Hypothyroidism has many complications, such as myxedema, dyslipidemia, and depression. In contrast, heart failure, pericardial effusion, and acute kidney injury are very rare complications of hypothyroidism. Only a few cases of heart failure or renal failure combined with hypothyroidism have been reported. Our case suggests that severe hypothyroidism can lead to multiorgan failure, such as heart failure as well as renal failure. Moreover, congestive heart failure induced by severe hypothyroidism can be reversed by thyroid hormone replacement therapy.
Subject(s)
Aged , Humans , Male , Acute Kidney Injury , Depression , Dyslipidemias , Dyspnea , Heart Failure , Heart , Hormone Replacement Therapy , Hypothyroidism , Myxedema , Pericardial Effusion , Renal Insufficiency , Thorax , Thyroid GlandABSTRACT
Acute pancreatitis caused by primary hyperparathyroidism-induced hypercalcemia is a rare condition, as acute pancreatitis is typically associated with a decrease in serum calcium levels. If hypercalcemia is present in a patient with acute pancreatitis, the possibility of hyperparathyroidism should be considered, and parathyroid hormone levels should be evaluated and the parathyroid gland imaged. We present a case of a 48-year-old male with acute recurrent pancreatitis caused by hyperparathyroidism. Initially, the acute pancreatitis improved after conservative therapy. However, the patient relapsed 1 month later. The patient had hypercalcemia and was diagnosed with parathyroid adenoma. He underwent surgical resection of the parathyroid adenoma and recovered. After 24 months of the treatment, there was no recurrence of the hypercalcemia or pancreatitis.