Gray Matter Microstructural Abnormalities and Working Memory Deficits in Individuals with Schizophrenia

OBJECTIVE: Working memory impairments serve as prognostic factors for patients with schizophrenia. Working memory deficits are mainly associated with gray matter (GM) thickness and volume. We investigated the association between GM diffusivity and working memory in controls and individuals with schizophrenia. METHODS: T1 and diffusion tensor images of the brain, working memory task (letter number sequencing) scores, and the demographic data of 90 individuals with schizophrenia and 97 controls were collected from the SchizConnect database. T1 images were parcellated into the 68 GM Regions of Interest (ROI). Axial Diffusivity (AD), Fractional Anisotropy (FA), Radial Diffusivity (RD), and Trace (TR) were calculated for each of the ROIs. RESULTS: Compared to the controls, schizophrenia group showed significantly increased AD, RD, and TR in specific regions on the frontal, temporal, and anterior cingulate area. Moreover, working memory was negatively correlated with AD, RD, and TR in the lateral orbitofrontal, superior temporal, inferior temporal, and rostral anterior cingulate area on left hemisphere in the individuals with schizophrenia. CONCLUSION: These results demonstrated GM microstructural abnormalities in the frontal, temporal, and anterior cingulate regions of individuals with schizophrenia. Furthermore, these regional GM microstructural abnormalities suggest a neuropathological basis for the working memory deficits observed clinically in individuals with schizophrenia.

Methanol-Induced Encephalopathy: a Case Report

A characteristic imaging finding in cases of methanol intoxication is putaminal necrosis, but its presence is usually not suspected due to its rarity. Methanol intoxication generally produces serious neurological symptoms that include visual disturbances and diminished consciousness, characteristically with metabolic acidosis. We reported the case of a 59-year-old man who was admitted to the hospital with diminished consciousness. Acute methanol intoxication was determined as the cause. Laboratory tests revealed high anion gap metabolic acidosis. Diffusion-weighted MRI indicated diffuse symmetric diffusion restriction lesions in the subcortical white matter of both cerebral hemispheres.

High serum C-reactive protein level predicts mortality in patients with stage 3 chronic kidney disease or higher and diabetic foot infections

BACKGROUND: Diabetic patients are predisposed to foot infections because of vascular insufficiency and peripheral neuropathy. Diabetic foot infection is a common cause of mortality and lower extremity amputations (LEAs) in patients with chronic kidney disease (CKD). We evaluated the risk factors for mortality and LEAs in patients with stage 3 CKD or higher with diabetic foot infections. METHODS: We retrospectively evaluated a cohort of 105 CKD patients with diabetic foot infections between July 1998 and December 2011. We reviewed their demographic characteristics and laboratory parameters to evaluate the risk factors for mortality and amputations at 24 weeks after diagnosis of a diabetic foot infection. RESULTS: The mortality of the 105 enrolled CKD patients was 21% at 24 weeks after the diagnosis of a diabetic foot infection. Cox proportional regression analyses revealed that age 60 years or older [odds ratio (OR) 3.03, 95% confidence interval (CI) = 1.02-9.02, P = 0.047] and initial serum C-reactive protein (CRP) level > or = 3 mg/dL (OR 3.97, 95%CI = 1.17-13.43, P = 0.027) were independent risk factors for mortality at 24 weeks.Twenty-four patients (23%) underwent LEAs. On Cox proportional regression analyses, peripheral vascular disease (OR=4.49,95% CI=1.98-10.17, P=0.01) and cerebrovascular accident (OR 2.42, 95%CI=1.09-5.39, P=0.03) were independently associated with LEAs. CONCLUSION: This study showed that age and serum CRP level, were independent risk factors for mortality at 24 weeks in patients with stage 3-5 CKD with diabetic foot infections. Peripheral vascular disease and cerebrovascular accident were significantly associated with LEAs.

Risk factors for mortality in patients with acute kidney injury and hypotension treated with continuous veno-venous hemodiafiltration

BACKGROUND: Continuous veno-venous hemodiafiltration (CVVHDF) is a preferred treatment modality in hemodynamically unstable acute kidney injury (AKI) patients, because it has advantages over intermittent dialysis in terms of hemodynamic stability. However, this patient group still shows a significantly high mortality rate. To aid in the management of these high-risk patients, we evaluated the risk factors for mortality in CVVHDF-treated hypotensive AKI patients. METHODS: We studied 67 patients with AKI and hypotension who were treated with CVVHDF from February 2008 to August 2010. We reviewed patient characteristics and laboratory parameters to evaluate the risk factors for 90-day mortality. RESULTS: Of the 67 enrolled patients (male:female=42:25; mean age=69+/-14 years), 18 (27%) survived until 90 days after the initiation of CVVHDF. There was no significant difference in survival rates according to the etiology of AKI [hypovolemic shock 2/10 (20%), cardiogenic shock 4/20 (20%), septic shock 12/37 (32%)]. Univariate analysis did show significant differences between survivors and non-survivors in the frequency of ventilator use (44% vs. 76%, respectively; P=0.02), APACHE II score (29+/-7 vs. 34+/-7, respectively; P=0.01), SOFA score (11+/-4 vs. 13+/-4, respectively; P=0.03), blood pH (7.3+/-0.1 vs. 7.2+/-0.1, respectively; P=0.03), and rate of urine output <500mL for 12hours (50% vs. 80%, respectively; P=0.03). A multivariate Cox proportional hazards model showed that a urine output <500mL for 12hours was the only significant risk factor for 90-day mortality following CVVHDF treatment (odds ratio=2.1, confidence interval=1.01-4.4, P=0.048). CONCLUSION: A urine output <500mL for 12hours before the initiation of CVVHDF is an independent risk factor for 90-day mortality in hypotensive AKI patients treated with CVVHDF.

Daily Functioning in Chronic Pain: Study of Structural Relations with Posttraumatic Stress Disorder Symptoms, Pain Intensity, and Pain Avoidance / 대한통증학회지

BACKGROUND: This study aimed to evaluate processes from the mutual maintenance model in relation to daily functioning in patients with both chronic pain and a history of a traumatic experience. The mechanism illustrated the structural relations for daily functioning among pain intensity, hyperarousal, re-experiencing, trauma avoidance, and pain avoidance. METHODS: Archival data (N = 214) was used for this study and data were analyzed for 142 chronic pain patients reporting a traumatic experience and seeking treatment at a tertiary pain clinic in Korea. RESULTS: The results indicated that pain intensity, hyperarousal, and pain avoidance had significant direct effects on daily functioning. Also, pain intensity showed significant indirect effects on daily functioning through hyperarousal and pain avoidance; and hyperarousal through pain avoidance. CONCLUSIONS: Results suggest a direct contribution of high levels of pain, hyperarousal symptoms of PTSD, and pain avoidance behaviors to reduced daily functioning. Also, elevated pain as reminders of the trauma may trigger high levels of hyperarousal symptoms of PTSD. Subsequently, avoidant coping strategies may be used to minimize pain so that the trauma would not be re-experienced, thus inhibiting the activation of hyperarousal symptoms of PTSD. However, prolonged use of such strategies may contribute to decline in daily functioning.

Daily Functioning in Chronic Pain: Study of Structural Relations with Posttraumatic Stress Disorder Symptoms, Pain Intensity, and Pain Avoidance

BACKGROUND: This study aimed to evaluate processes from the mutual maintenance model in relation to daily functioning in patients with both chronic pain and a history of a traumatic experience. The mechanism illustrated the structural relations for daily functioning among pain intensity, hyperarousal, re-experiencing, trauma avoidance, and pain avoidance. METHODS: Archival data (N = 214) was used for this study and data were analyzed for 142 chronic pain patients reporting a traumatic experience and seeking treatment at a tertiary pain clinic in Korea. RESULTS: The results indicated that pain intensity, hyperarousal, and pain avoidance had significant direct effects on daily functioning. Also, pain intensity showed significant indirect effects on daily functioning through hyperarousal and pain avoidance; and hyperarousal through pain avoidance. CONCLUSIONS: Results suggest a direct contribution of high levels of pain, hyperarousal symptoms of PTSD, and pain avoidance behaviors to reduced daily functioning. Also, elevated pain as reminders of the trauma may trigger high levels of hyperarousal symptoms of PTSD. Subsequently, avoidant coping strategies may be used to minimize pain so that the trauma would not be re-experienced, thus inhibiting the activation of hyperarousal symptoms of PTSD. However, prolonged use of such strategies may contribute to decline in daily functioning.

Comparison of Drug-Eluting Stent and Bare Metal Stent in Reducing Adverse Cardiac Event after Coronary Stenting in Hemodialysis Patients / 대한신장학회지

PURPOSE: The patients treated with hemodialysis have been known to have a high 1-year mortality rate after percutaneous coronary intervention (PCI). We evaluated the clinical benefits of drug-eluting stent (DES), compared to bare-metal stent (BMS) in Korean hemodialysis patients. METHODS: We studied 72 hemodialysis patients (M:F=49:23, age 60+/-11 years) treated with percutaneous coronary intervention (PCI) from January, 1999 to February, 2006. Forty four patients (M:F=28: 16, age 60+/-11 years) treated with DES and 28 patients (M:F=21:7, age 60+/-12 years) with BMS were enrolled. A composite of major adverse cardiac and cerebral endpoints (MACCE) was defined as all-cause death, myocardial infarction, stroke, and target-vessel revascularization (TVR). We compared the incidence of MACCE between DES and BMS group. RESULTS: A composite of MACCE occurred in none in DES group (n=44) and 4 in BMS group (n=28) within 3 months after coronary stenting (Kaplan-Meier survival analysis: 0% vs 14%, respectively, p= 0.02). After 3 months, there was no difference in the incidence of primary end points between two groups. Multi-vessel disease (OR 2.47, 95% CI 1.02-6.11, p<0.05) was associated with a significant increase in the incidence of MACCE within 18 months after coronary artery stenting CONCLUSION: DES may be superior to BMS in reducing adverse cardiac outcome at early period after coronary stenting in HD patients. However, this study showed no significant difference with the lapse of time.

The Effects of Methylphenidate on Neural Substrates Associated with Interference Suppression in Children with ADHD: A Preliminary Study Using Event Related fMRI

OBJECTIVE: The core deficit of attention deficit hyperactivity disorder (ADHD) is associated with frontal cortex and related circuitry. Children with ADHD and a medication history have shown atypical brain activation in prefrontal and striatal brain regions during cognitive challenge. We investigated two cognitive control operations such as interference suppression (IS) and response inhibition (RI) in children with ADHD. We also assessed the brain functions affected by the methylphenidate (MPH) effect by comparing the blood-oxygen level dependent (BOLD) signals in ADHD children on and off medication. METHODS: Eight children (9-11 years of age) with combined-type ADHD underwent rapid event-related functional magnetic resonance imaging (fMRI) during performance of a modified flanker task. Two fMRI (3.0 T) scans were conducted with a one week interval-one with MPH treatment and the other without. Functional maps were generated through group averaging and performance-based correlational analyses. RESULTS: Performances of the two cognitive control operations did not differ significantly between on-MPH and off-MPH status other than the reaction time to incongruent stimuli in ADHD children. In those affected by MPH treatment, an increased activation in the right prefrontal cortex during incongruent task was observed relative to a neutral trial in children with ADHD. CONCLUSION: On the treatment of MPH, the ADHD children exhibited increased activation of the right frontal cortex during interference suppression. This finding suggested that MPH affected the right frontal cortex in ADHD compensating for a reduced level of interference suppression. Future studies will be required to ascertain the MPH effect of cognitive brain regions among large number of children with ADHD.

Direct Inoculation in BACTEC Culture Media is Superior to Thioglycollate Broth and Solid Culture Medium Method after Centrifugation in Identifying Gram Positive Microorganism in Peritoneal Dialysis Peritonitis Patients / 대한신장학회지

PURPOSE: Peritonitis remains one of most important complications of long-term peritoneal dialysis. This study was prospectively performed to compare the ability of identifying the causative organism for continuous ambulatory peritoneal dialysis (CAPD) peritonitis between bedside inoculation into BACTEC culture bottles and method involving centrifugation of effluent followed by plating into solid and liquid media. METHODS: We studied 38 patients with CAPD peritonitis (M:F=21:17, age 53+/-13 years) between July, 2005 and May, 2006. They had 50 episodes of CAPD peritonitis during the study period. From each peritonitis patient, two aliquots of peritoneal effluent were obtained at the same time. One aliquot was inoculated into two BACTEC culture bottles (aerobic and anaerobic, each 10 mL). The other aliquot was inoculated into thioglycollate broth (TGB, 10mL) and also spread on solid culture media (SCM) after centrifuge 50 mL of effluents. We compared positive-culture results, time from inoculation to identification of growth, and causative organism between these two culture methods. RESULTS: The BACTEC culture method was superior to the TGB & SCM culture method in identifying microorganisms (80% vs. 56%, respectively, p=0.01). Especially, there was significant difference in identifying the gram-positive bacteria between the BACTEC culture method and the TGB & SCM culture method [52% (26/50) vs 36% (18/50), p=0.001]. CONCLUSION: This study indicated that direct inoculation in BACTEC culture media is superior, especially for the gram-positive bacteria, to TGB & SCM in identifying the causative organisms in CAPD peritonitis patients.

Assessment of Post-Stroke Cognitive Dysfunction Using 3-Dimensional Virtual Reality Program

OBJECTIVE: To test the feasibility of newly developed 3- dimensional virtual reality (VR) program for assessing the post-stroke cognitive dysfunction. METHOD: Thirty five post-stroke patients and twenty normal healthy subjects were recruited in this study, and post-stroke patients were classified into three groups according to the severity of cognitive dysfunction. We developed three dimensional virtual reality program to assess the cognitive function with virtual subway environment from taking a subway to arriving at one's destination. The total score, number of success and cue were obtained during completing virtual tasks. We investigated the test-retest reliability, and the parameters of the 3-dimensional VR program were compared with Korean Mini-mental status examination. RESULTS: All parameters of the VR program were significantly correlated with MMSE score (p<0.01), and showed the significant difference between patient subgroups and control group (p<0.05). The test-retest reliability of the VR program was significantly high (p<0.01). CONCLUSION: Three dimensional virtual reality program may be helpful to assess the cognitive function in patients with stroke.

Cognitive Perceptual Assessment Tool for Evaluation of Driving Ability of Persons with Brain Injury

OBJECTIVE: To develop an evaluation tool of cognitive perceptual function for safe driving of the brain injured patients and to check the suitability of the tool. METHOD: Cognitive Perceptual Assessment for Driving (CPAD) was constructed with 8 tasks of depth perception, sustained attention, divided attention, Stroop test, digit span test, field dependence, trail making test A, and trail making test B. The predriving assessment with CPAD and road test were applied to 101 brain injured patients. The reliability and the validity of CPAD, and the cut-off score to resume driving were determined. RESULTS: The CPAD scores of pass group (n=46) and fail group (n=55) for on-road test were 51.67+/-5.53 and 44.30+/-8.44 respectively (p=0.0001). The internal consistency of the CPAD measured by Cronbach's alpha was 0.85. The cut-off score based on 95% confidence interval was 53 or above for pass group, 42 or below for fail group, 43~52 for borderline group. The positive and negative predictive value was 90.7% and 50.3%, respectively. CONCLUSION: The CPAD could be useful for the evaluation of driving ability of persons with brain injury.

Efficacy of Percutaneous Cholangioscopic Ethanol Injection in Hepatocellular Carcinoma Invading the Bile Duct / 대한소화기내시경학회지

BACKGROUND/AIMS: To evaluate the clinical outcomes of the percutaneous cholangioscopic ethanol injection in the hepatocellular carcinoma (HCC) invading the bile duct, we conducted a retrospective study. METHODS: Ten patients who received the percutaneous cholangioscopic ethanol injection were selected patients were diagnosed as HCC invading the bile duct between January 1998 and February 2004. Treatment response, complications, survival or death and survival time were analyzed. RESULTS: Ten patients received mean of 5.3 sessions (range 2~19) of cholangioscopic ethanol injection. Eight patients had decreased tumor mass, and the rest 2 patients had no response. Complications were pain (n=10), hemobilia (n=6: bleeding was minimal), cholangitis (n=2), bile duct rupture (n=1), and bile duct stricture (n=1). Nine patients died from severe hepatic failure and sepsis, one patient has survived for 19 months as of now. Median survival time was 5 months (range 2~19 months). Percutaneous transhepatic biliary drainage (PTBD) could be removed in two patients. CONCLUSIONS: Percutaneous cholangioscopic ethanol injection in HCC invading the bile duct showed size reduction of mass. PTBD could be no longer needed in some patients. However, supportive cares such as PTBD may be appropriate considering their short survival period and risk of procedure.

The Cutcome of Living-related Renal Transplantation with Previously Positive but Currently Negative HLA Crossmatching / 대한신장학회잡지

PURPOSE: Previously positive but currently negative HLA crossmatching is considered to be a risk factor not in the first renal transplantation but in the second renal transplantation. The aim of this study is to analyse the outcome of living-related renal transplantation with previously positive but currently negative HLA crossmatching. METHODS: The results of first HLA crossmatching, demographic characteristics, the outcome of renal trasplantation were examined in four patients undergoing renal transplantation with previously positive but currently negative HLA crossmatching. RESULTS: The acute rejection was occurred in 3 patients. Azotemia was improved with the immunosuppressive therapy containing tacrolimus. There were no graft failures in four patients for 1 year. In the first HLA crossmatching, anti-human globulin T cell HLA crossmatching was positive in all patients with acute rejection. The period that positive HLA crossmatchings were converted to negative was longer in patients with acute rejections than without acute rejections (177 days vs 22 days). CONCLUSION: There were 3 acute rejections in 6 patients undergoing living related renal transplantations with previously positive and current negative HLA crossmatching. There were no graft failure for 1 year.

Assessment of Post-stroke Unilateral Neglect Using 3-Dimensional Virtual Reality Program

OBJECTIVE: To investigate the clinical usefulness of newly developed 3-dimensional virtual reality (VR) program to assess the unilateral neglect. METHOD: Sixteen unilateral neglect patients and forty healthy subjects were included in this study. Forty healthy subjects were classified into two groups (control group I, II) based on the previous computer experience. This VR program was composed of two sessions, the first session was to search the midpoint of the monitor and the second session was to scan the randomized target movement. Head-mounted display and 3-dimensional position sensor were used during VR program. The unilateral neglect patients performed the line bisection test and the letter cancellation test. The correlations of the clinical measurements and the parameters of the 3-dimensional VR program were analyzed. RESULTS: All parameters of the VR program in patient group were significantly different with those in control group I, II (p <0.05). Left directional parameters were significantly different with right directional parameters of the VR program in patient group (p <0.05), but not in control group I, II. The parameters of the VR program were significantly correlated with clinical measurements (p <0.05). CONCLUSION: The assessment of unilateral neglect using 3- dimensional virtual reality program may be clinically useful.

A case of pyelonephritis caused by Candida kefyr / 대한내과학회지

We report a case of pyelonephritis caused by Candida kefyr, which has been previously described as C. pseudotropicalis. The patient who had been having multiple intrarenal stones and ureteral stones for ten years was admitted for fever, left flank pain, and dysuria. In the blood culture, C. kefyr was isolated. These symptoms and signs were successfully resolved with a new antifungal agent, voriconazole. After the resolution of symptoms and signs, the patient took extracorporeal shock wave lithotripsy for intrarenal stones and ureteral stones.

28 cases of primary sclerosing cholangitis / 대한내과학회지

Backgroud : Primary sclerosing cholangitis (PSC) is a chronic progressive cholestatic hepatobiliary disease of unknown etiology, a characterized by inflammation, scarring and obliteration of bile ducts, eventually leading to biliary cirrhosis and liver failure. In Korea, reports on PSC have only been done anecdotally and there are hardly any large scale studies. METHODS: We retrospectively analyzed the clinical, laboratory, radiologic and histologic feature of 28 patients, who were diagnosed in Asan Medical Center during the last decade. A diagnosis of PSC was made by typical direct cholangiographic findings. RESULTS: The median age of the enrolled patients at diagnosis was 39.3 years, and there was a preponderance of men (M:F = 2.1:1). The major clinical features were abdominal pain and abnormal liver function tests of cholestatic pattern. The rate of positivity for autoantibody was 30.8% (8/26). On cholangiogram, 82.1% had evidence of both extra- and intrahepatic bile duct involvement, 10.7% of intrahepatic involvement only, and 7.1% of hilar involvement only. The pancreatic duct involvement was seen in 10.5% (2/19). The incidence of associated inflammatory bowel disease was 50% (6/12), UC in 5 cases and Crohn's disease in 1 case, respectively. Endoscopic or radiologic intervention for the dilatation of narrowed bile ducts were performed in 14.3% and 71.4%, respectively. Two cases (7.1%) underwent liver transplantation. CONCLUSION: Although PSC is a rare disease in Korea, we prospect that more cases will be reported as concern and knowledge of this entity increase.

A role of neuropsychological test in the patients with chronic liver disease / 대한내과학회지

BACKGROUND: Minimal (subclinical) hepatic encephalopathy (mHE) currently diagnosed by psychometric tests or neurophysiological test adversely affects daily functioning. In view of its sociomedical relevance, simple and reproducible tests for routine diagnosis are required. The aims of this study are to evaluate cognitive function of patients with chronic liver disease by computerized neuropsychological test (STIM), and the difference of cognitive function according to Child classification. METHODS: Between June, 2002 and February, 2003 We enrolled 61 randomized consecutive patients diagnosed with chronic liver disease by biochemical tests, ultrasonographic finding or histology. This study used finger tapping, visual CPT, spatial memory test, Wisconsin card sorting test chosen from Neuscan and STIM system (Neurosoft company, U.S.A) and global-local processing test. RESULTS: In the present study, significant correlation was found between neurologic abnormalities and the degree of liver disease. The result of neuropsychological test showed that cognitive function was decreased according to the severity of chronic liver disease, especially liver cirrhosis. Cirrhotic patients, especially Child C group, exhibited selective deficits in complex attentional and fine motor skills, visuospatial perception, with preservation of memory. CONCLUSION: The STIM in this study is simple, objective and reproducible method because it can subdivide evaluation of cognitive function and computerize the measurement of response. We assume that STIM may be used early detection method of mHE if the study will be in a large scale. Because psychomotor deficits found in mHE could have a disadvanting influence on daily functioning of patients, e.g., driving abilty of a car or performance at work, we concluded early detection of mHE and aggressive treatment of mHE in clinically asymptomatic cirrhotic patients is necessary for improvement of their quality of life.

A Case of Septicemia and Septic Pneumonia due to Burkholderia pseudomallei

Melioidosis is an infectious disease caused by a gram-negative saprophyte bacterium, Burkholderia pseudomallei. It is endemic to Southeast Asia and Northern Australia. It mostly infects adults with predisposing conditions, mainly diabetes mellitus. The lung is the most commonly affected organ. The spectrum of melioidois in human varies from subclinical to overwhelming protean manifestations resembling other acute and chronic bacterial infections. We report herein a case of septicemia and septic pneumonia due to Burkholderia pseudomallei in 47-year-old man with diabetes mellitus who has history of traveling to Malaysia. This is the first report of melioidosis in Korea.

Development and Application of Cognitive Perceptual Assessment for Driving of People with Brain Injury - Comparison with Cognitive Behavioral Driver's Inventory

OBJECTIVE: We developed the Cognitive Perceptual Assessment for Driving (CPAD) to assess the driving ability of people with acquired brain injury. To find out the usefulness of this tool as a screening test for safe driving, we compared it with the Cognitive Behavioral Driver's Inventory (CBDI). METHOD: Subjects were 101 people with acquired brain injury who had driven a car before the injury. Each subject was evaluated with CPAD and CBDI. CPAD consisted of 8 tasks and 10 variables. We calculated CPAD score using 10 variables and compared CPAD with CBDI result and score. RESULTS: The average CPAD score was 49.65 7.97. According to CBDI test, the number of CBDI passing group was 36, borderline group was 27, and failing group was 38. CPAD variables and score showed significant correlation with CBDI score (p<0.05). There was significant difference in CPAD variables and score among the 3 groups (p<0.05). CONCLUSION: CPAD can be a useful tool for assessing the driving ability of the people with acquired brain injury.

A Case of Septicemia and Septic Pneumonia due to Burkholderia pseudomallei

Melioidosis is an infectious disease caused by a gram-negative saprophyte bacterium, Burkholderia pseudomallei. It is endemic to Southeast Asia and Northern Australia. It mostly infects adults with predisposing conditions, mainly diabetes mellitus. The lung is the most commonly affected organ. The spectrum of melioidois in human varies from subclinical to overwhelming protean manifestations resembling other acute and chronic bacterial infections. We report herein a case of septicemia and septic pneumonia due to Burkholderia pseudomallei in 47-year-old man with diabetes mellitus who has history of traveling to Malaysia. This is the first report of melioidosis in Korea.