Development and Validation of a Novel Warfarin Dosing Algorithm for Korean Patients With VKORC1 1173C

BACKGROUND: Differences in the performance of suggested warfarin dosing algorithms among different ethnicities and genotypes have been reported; this necessitates the development of an algorithm with enhanced performance for specific population groups. Previous warfarin dosing algorithms underestimated warfarin doses in VKORC1 1173C carriers. We aimed to develop and validate a new warfarin dosing algorithm for Korean patients with VKORC1 1173C.METHODS: A total of 109 patients carrying VKORC1 1173CT (N=105) or 1173CC (N=4) were included in this study. Multiple regression analysis was performed to deduce a new dosing algorithm. Following literature searches for genotype-guided warfarin dosing algorithms, 21 algorithms were selected and evaluated using the correlation coefficient (ρ) of actual dose and estimated dose, mean error, and root mean square error.RESULTS: The developed algorithm is as follows: maintenance dose (mg/week)=exp [3.223−0.009×(age)+0.577×(body surface area [BSA])+0.178×(sex)−0.481×(CYP2C9 genotype)+0.227×(VKORC1 genotype)]. Integrated variables explained 44% of the variance in the maintenance dose. The predicted and actual doses showed moderate correlation (ρ=0.641) with the best performance with a mean error of −1.30 mg/week. The proportion of underestimated groups was 17%, which was lower than with the other algorithms.CONCLUSIONS: This is the first study to develop and validate a warfarin dosing algorithm based on data from VKORC1 1173C carriers; it showed superior predictive performance compared with previously published algorithms.

Prevalence of Multidrug-Resistant Organisms and Risk Factors for Carriage among Patients Transferred from Long-Term Care Facilities

Background@#Patient transport between acute care hospitals and long-term care facilities (LTCFs) plays a significant role in microbial migration. The study aimed to estimate the prevalence and risk factors associated with the colonization of multidrug-resistant organisms (MDROs) among patients transferred from LTCFs. @*Materials and Methods@#We retrospectively reviewed medical records to examine the colonization of MDROs. All patients who were transferred from LTCFs and admitted to an acute care hospital with 800 beds in Daejeon between March 2018 and February 2019 were included in the study. We surveyed rectal cultures and nasal swabs obtained for screening vancomycinresistant Enterococcus (VRE), carbapenem-resistant Enterobacteriaceae (CRE), and methicillinresistant Staphylococcus aureus (MRSA) at the time of hospitalization. We conducted a multivariable logistic regression to assess the association between clinical variables and the carriage of MDROs. @*Results@#Four hundred and fifteen patients from 86 LTCFs were enrolled. A total of 31.1% (130/415) of participants carried MDROs; VRE colonization was detected in 17.1% (71/415) of participants, and MRSA colonization was shown in 19.5% (81/415) of participants. No CRE was isolated. Previous use of antibiotics within three months [odds ratio (OR) 2.28; (95% confidence interval (CI) 1.30 - 4.00), P = 0.004], use of antibiotics for longer than two weeks [OR 2.16; (95% CI 1.03 - 4.53), P = 0.040], and previous colonization of MDROs within one year [OR 2.01; (95% CI 1.15 - 3.54), P = 0.015] were independently associated with increased risk for carriage of MDROs. @*Conclusion@#Our study showed that a third of patients transferred from LTCFs carried VRE or MRSA, and prior antibiotic therapy was highly associated with the carriage of MDROs, which suggested more efficient management approaches for high-risk patients.

Clinical Pharmacogenetic Testing and Application: Laboratory Medicine Clinical Practice Guidelines

Pharmacogenetic testing for clinical applications is steadily increasing. Correct and adequate use of pharmacogenetic tests is important to reduce unnecessary medical costs and adverse patient outcomes. This document contains recommended pharmacogenetic testing guidelines for clinical application, interpretation, and result reporting through a literature review and evidence-based expert opinions for the clinical pharmacogenetic testing covered by public medical insurance in Korea. This document aims to improve the utility of pharmacogenetic testing in routine clinical settings.

Clinical Pharmacogenetic Testing and Application: Laboratory Medicine Clinical Practice Guidelines Part 1

Pharmacogenetics is a rapidly evolving field, and the number of pharmacogenetic tests for clinical use is steadily increasing. However, incorrect or inadequate implementation and use of pharmacogenetic testing in clinical practice may result in an increase in medical costs and adverse patient outcomes. This document contains suggested pharmacogenetic testing guidelines for clinical application, interpretation, and reporting of the results through a literature review and evidence-based expert opinions. The clinical laboratory practice guideline includes clinical pharmacogenetic testing covered by public medical insurance in Korea. Technical, ethical, and regulatory issues related to clinical pharmacogenetic testing are also addressed. This document aims to improve the utility of pharmacogenetic testing in routine clinical settings.

Clinical Pharmacogenetic Testing and Application: Laboratory Medicine Clinical Practice Guidelines Part 2

Pharmacogenetics is a rapidly evolving field and the number of pharmacogenetic tests for clinical use is steadily increasing. However, incorrect or inadequate implementation of pharmacogenetic tests in clinical practice may result in a rise in medical costs and adverse outcomes in patients. This document suggests guidelines for the clinical application, interpretation, and reporting of pharmacogenetic test results based on a literature review and the collection of evidence-based expert opinions. The clinical laboratory practice guidelines encompass the clinical pharmacogenetic tests covered by public medical insurance in Korea. Technical, ethical, and regulatory issues related to clinical pharmacogenetic tests have also been addressed. In particular, this document comprises the following pharmacogenetic tests: CYP2C9 and VKORC1 for warfarin, CYP2C19 for clopidogrel, CYP2D6 for tricyclic antidepressants, codeine, tamoxifen, and atomoxetine, NAT2 for isoniazid, UGT1A1 for irinotecan, TPMT for thiopurines, EGFR for tyrosine kinase inhibitors, ERBB2 (HER2) for erb-b2 receptor tyrosine kinase 2-targeted therapy, and KRAS for anti-epidermal growth factor receptor drugs. These guidelines would help improve the usefulness of pharmacogenetic tests in routine clinical settings.

A Case of Ischemic Gastric Necrosis after Epinephrine Injection in a Patient with Anemia / 대한내과학회지

Endoscopic epinephrine injection is a safe and easy treatment for non-variceal gastrointestinal bleeding. It has low complication rates and is used widely. Ischemic gastric necrosis occurs rarely because of the rich vascular supply of the stomach and the vascular reserve of the intramural anastomosis. Endoscopic injection therapy, smoking, hypertension, and atherosclerosis are risk factors for gastric ischemia. There have been a few case reports of gastric ischemia after endoscopic injection therapy. We report a case of gastric ischemia after submucosal epinephrine injection in a 29-year-old woman with anemia.

A Case of Acute Cholecystitis Caused by Plasmodium vivax Infection / 대한췌담도학회지

Acute cholecystitis as a complication of malarial disease is a rare condition, especially with Plasmodium vivax infection. A 62 year-old-female was admitted via emergency room (ER) due to high fever (40.3degrees C) and epigastric pain. Initial abdominal ultrasound and computed tomography (CT) scan showed edematous gallbladder with stone, which suggested acute calculous cholecystitis. Emergency percutaneous transhepatic gallbladder drainage (PTGBD) was done with systemic antibiotic therapy. The clinical course, however, unusually worsened with hypotension and intensive care unit (ICU) management was done. Four days after admission multi-focal splenic infarction was developed and Plasmodium vivax infection was diagnosed afterward. The clinical symptoms and laboratory results, including fever and epigastric pain, improved dramatically after anti-malarial treatment and cholecystectomy was done. The resected gallbladder (GB) specimen shows vasculitis pattern with capillary red blood cell (RBC) engorgement, which suggests the cause of cholecystitis was due to Plasmodium vivax rather than GB stone.

Diagnostic Utility of Serum Cytokeratin Fragment 21-1 in Patients with Lung Cancer

BACKGROUND: Lung cancer is the most lethal malignant neoplasm in the world. Serum cytokeratin fragment 21-1 (Cyfra 21-1) is a valuable tumor marker for detection of lung cancer, and it has good sensitivity and specificity. The aim of this study was to investigate the diagnostic value of Cyfra 21-1 levels in patients with lung cancer. METHODS: We retrospectively reviewed 814 samples from 169 patients with lung cancer, 124 patients with benign pulmonary diseases, and 521 normal controls from health check-up clinic. Serum Cyfra 21-1 levels were determined with Architect CYFRA 21-1 kit (Abbott, USA) using Architect i2000 analyzer. RESULTS: Median levels and interquartile ranges for Cyfra 21-1 in patients with lung cancer (non-small cell lung cancer: 3.16 [1.98, 9.00] ng/mL, small cell lung cancer: 3.32 [2.07, 5.20] ng/mL) were higher than those in patients with benign pulmonary diseases (1.50 [1.17, 2.17] ng/mL; P<0.01) and in normal controls (1.26 [0.93, 1.75] ng/mL; P<0.01). Sensitivity, specificity, positive predictive value, and negative predictive value for Cyfra 21-1 were 70.4%, 81.2%, 49.6%, and 91.3%, respectively. The area under the curve for Cyfra 21-1 was 0.839 (95% confidence interval, 0.802-0.877). CONCLUSIONS: We concluded that Cyfra 21-1 may be useful in the diagnosis of lung cancer.

Performance Evaluation of the ARKRAY ADAMS A1c HA-8180

The hemoglobin A1c (Hb A1c) test is widely used to diagnose diabetes mellitus and monitor glycemic control in patients with diabetes. We evaluated the performance of the ARKRAY ADAMS A1c HA-8180 (ARKRAY KDK, Japan), an automated, HPLC-based Hb A1c analyzer. The ARKRAY ADAMS A1c HA-8180 was evaluated for its linearity and precision and compared to the HLC-723 G7 (Tosoh Corporation, Japan), according to the Clinical and Laboratory Standards Institute's guidelines. The coefficients of variation (CVs) for within-run precision at low and high levels were 0.6% and 0.3%, respectively, and the total CVs at low and high levels were 0.8% and 0.6%, respectively. The coefficient of determination (R2) was 0.9975, with linearity in the range of 3.0-18.5%. A comparison between the ARKRAY ADAMS A1c HA-8180 and HLC-723 G7 revealed a good correlation (r=0.9955) in the range of 4.8-14.6%. The runtime was 57 s per sample. The ARKRAY ADAMS A1c HA-8180 showed good analytical performance and high throughput. Therefore, it is suitable for routine use for clinical measurements of Hb A1c.

A 6-year-old girl with vaginal spotting who was diagnosed with perivascular epithelioid cell neoplasm after vaginoscopic resection

Perivascular epithelioid cell neoplasm (PEComa) is a rare tumor with unknown malignant potential. We report a case of a 6-year-old child with history of brain tumor (pineoblastoma), who presented with intermittent vaginal spotting for 6 months. A vaginoscopy revealed a 1.5x1.0-cm mass on the vaginal wall. Pathological examination demonstrated that the tumor was composed of clear cells with organoid patterns, which were immunohistochemically positive for HMB-45 and TFE3, and negative for CK, HNF1-B, SOX10, Melan A, and S-100 protein. These findings were consistent with PEComa arising from the vagina. Regular follow-up with magnetic resonance imaging has shown no signs of recurrence. This case shows that early detection of PEComa and subsequent regular follow-ups are important because of the neoplasm's unknown malignant potential.

Primary Sjogren's Syndrome Presenting with Rapidly Progressive Cognitive Impairment

Primary Sjogren's syndrome (pSS) is characterized by chronic inflammation and dysfunction in exocrine organs; however, it also has protean clinical features, including neuropsychiatric symptoms. A major neurological manifestation is peripheral neuropathy and involvement of the central nervous system is uncommonly described in pSS. A 52-year-old female was admitted because of depression, dysarthria, gait abnormality, and memory disturbance, which had developed over two months, and was diagnosed as pSS. She was treated successfully with high-dose glucocorticoid and cyclophosphamide pulse therapy without recurrence during the follow-up period of two years. Herein, we describe the first Korean case of pSS presenting with rapidly progressive cognitive impairment along with a review of the literature.

A Case of Rheumatoid Arthritis Associated with Klinefelter's Syndrome / 대한내과학회지

Klinefelter's syndrome is a disorder of sexual differentiation in males, characterized by the presence of two or more X-chromosomes, hypogonadism, and lack of secondary sexual characteristics. The association between Klinefelter's syndrome and systemic lupus erythematous has been described, while cases of rheumatoid arthritis associated with Klinefelter's syndrome are rare. We report the first Korean case: a 29-year-old man with Klinefelter's syndrome who developed rheumatoid arthritis. The sex hormone imbalance might have influenced the onset and course of his disease.

Application of Single-nucleotide Polymorphism and Mycobacterial Interspersed Repetitive Units-Variable Number of Tandem Repeats Analyses to Clinical Mycobacterium tuberculosis Isolates from Korea / 대한진단검사의학회지

BACKGROUND: Single-nucleotide polymorphism (SNP) analysis is a powerful strategy for large-scale molecular population studies examining phylogenetic relationships among bacterial strains. Mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR) can be easily digitized to share data among laboratories. This study applied SNP and MIRU-VNTR analyses for molecular strain typing of Mycobacterium tuberculosis isolates collected throughout Korea. METHODS: We studied 102 clinical M. tuberculosis isolates, including 6 paired strains, collected from 11 university hospitals in Korea in 2008 and 2009. SNPs were detected using hairpin primer assays, and then, MIRU-VNTR analysis was performed. RESULTS: Thirty-five SNPs contained polymorphisms that helped differentiate the 96 tested isolates. The isolates were classified into 15 clusters. The Beijing family strains were distributed within closely related clusters in the SNP dendrogram. For MIRU-VNTR analysis, the 96 isolates were divided into 12 groups. The discriminatory index in 8 of these groups (MIRU-10, -23, -26, and -31; ETR-A, -B, -C, and -F) was high (Hunter-Gaston diversity index > 0.6). Unlike the SNP method, MIRU-VNTR analysis did not identify any notable localizations of Beijing or non-Beijing family isolates in specific clusters. CONCLUSIONS: SNP and MIRU-VNTR analyses are surrogate molecular strain-typing methods for M. tuberculosis in Korea where Beijing family isolates are predominant.

MicroRNA-23a: A Novel Serum Based Diagnostic Biomarker for Lung Adenocarcinoma / 결핵및호흡기질환

BACKGROUND: MicroRNAs (miRNAs) have demonstrated their potential as biomarkers for lung cancer diagnosis. In recent years, miRNAs have been found in body fluids such as serum, plasma, urine and saliva. Circulating miRNAs are highly stable and resistant to RNase activity along with, extreme pH and temperatures in serum and plasma. In this study, we investigated serum miRNA profiles that can be used as a diagnostic biomarker of non-small cell lung cancer (NSCLC). METHODS: We compared the expression profile of miRNAs in the plasma of patients diagnosed with lung cancer using an miRNA microarray. The data from this assay were validated by quantitative real-time PCR (qRT-PCR). RESULTS: Six miRNAs were overexpressed and three miRNAs were underexpressed in both tissue and serum from squamous cell carcinoma (SCC) patients. Sixteen miRNAs were overexpressed and twenty two miRNAs were underexpressed in both tissue and serum from adenocarcinoma (AC) patients. Of the four miRNAs chosen for qRT-PCR analysis, the expression of miR-23a was consistent with microarray results from AC patients. Receiver operating characteristic (ROC) curve analyses were done and revealed that the level of serum miR-23a was a potential marker for discriminating AC patients from chronic obstructive pulmonary disease (COPD) patients. CONCLUSION: Although a small number of patients were examined, the results from our study suggest that serum miR-23a can be used in the diagnosis of AC.

A Case of Providencia rettgeri Sepsis in a Patient with Cervical Cord Injury

Providencia rettgeri is a member of Enterobacteriacea that is known to cause urinary tract infection (UTI), septicemia, and wound infections, especially in immunocompromised patients and in those with indwelling urinary catheters. We experienced a case of UTI sepsis by Providencia rettgeri in a patient with spinal cord injury. The patient had only high fever without urinary symptoms or signs after high dose intravenous methylprednisolone. The laboratory results showed leukocytosis (21,900/microL, segmented neutrophils 91.1%) and pyuria. Cefepime was given empirically and it was switched to oral trimethoprim-sulfamethoxazole because P. rettgeri was identified from blood and urine culture which was susceptible to TMP-SMX. The patient was improved clinically but P. rettgeri was not eradicated microbiologically. To the best of our knowledge, this is the first case report on sepsis caused by Providencia rettgeri in Korea.

Prevalence of IgG anti-HAV in patients with chronic hepatitis B and in the general healthy population in Korea / 대한간학회지

BACKGROUND/AIMS: Few studies have investigated hepatitis A virus (HAV) seroepidemiology in Koreans with chronic liver disease (CLD). This study compared the prevalence of IgG anti-HAV between the general healthy population and patients with hepatitis B virus-related CLD (HBV-CLD), with the aim of identifying predictors of HAV prior exposure. METHODS: In total, 1,319 patients were recruited between June 2008 and April 2010. All patients were tested for IgG anti-HAV, hepatitis B surface antigen (HBsAg), and antibodies to hepatitis C virus. The patients were divided into the general healthy population group and the HBV-CLD group based on the presence of HBsAg. The seroprevalence of IgG anti-HAV was compared between these two groups. RESULTS: The age-standardized seroprevalence rates of IgG anti-HAV in the general healthy population and patients with HBV-CLD were 52.5% and 49.1%, respectively. The age-stratified IgG anti-HAV seroprevalence rates for ages or =60 years were 14.3%, 11.2%, 45.5%, 90.5%, 97.6% and 98.3%, respectively, in the general healthy population, and 0%, 9.8%, 46.3%, 91.1%, 97.7%, and 100% in the HBV-CLD group. In multivariate analysis, age ( or =60 years: OR=1060.5, 95% CI=142.233-7907.964, P<0.001) and advanced status of HBV-CLD (OR=19.180, 95% CI=4.550-80.856, P<0.001) were independent predictors of HAV prior exposure. CONCLUSIONS: The seroprevalence of IgG anti-HAV did not differ significantly between the general-healthy-population and HBV-CLD groups. An HAV vaccination strategy might be warranted in people younger than 35 years, especially in patients with HBV-CLD.

Improved Detection of Germline Mutations in Korean VHL Patients by Multiple Ligation-dependent Probe Amplification Analysis

von Hippel-Lindau (VHL) disease is an autosomal dominant inherited tumor syndrome characterized by the development of tumors in the eye, brain, spinal cord, inner ear, adrenal gland, pancreas, kidney, and epididymis, associated with germline mutations in the VHL gene. We used sequentially sequencing method and multiple ligation-dependent probe amplification (MLPA) analysis and detected germline mutations in the VHL in 15/15 (100%) of VHL patients fulfilling the clinical criteria. Of the 15 distinct mutations detected, large deletions were detected in 5/15 (33.3%) patients, including 4/15 (26.7%) partial deletions and 1/15 (6.6%) deletion of the entire VHL gene by MLPA and the remainder were point mutations detected by sequencing method, of which five mutations were novel. Using MLPA analysis, we detected large deletions including both partial deletions and complete gene deletion, which has not been reported in Korean VHL patients. In conclusion, sequential application of sequencing method and MLPA analysis might make possible to identify germline mutations in most patients with VHL.

Determination of Plasma Warfarin Concentrations in Korean Patients and Its Potential for Clinical Application / 대한진단검사의학회지

BACKGROUND: Warfarin is a widely used oral anticoagulant with broad within- and between-individual dose requirements. Warfarin concentrations can be monitored by assessing its pharmacologic effects on International Normalized Ratio (INR). However, this approach has not been applied in the routine clinical management of patients receiving warfarin therapy. We performed a plasma warfarin assay using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) to determine if such an assay can be utilized in routine clinical practice. METHODS: We included a total of 105 patients with atrial fibrillation, and who were receiving warfarin for more than 1 yr. The plasma concentrations of total warfarin and 7-hydroxywarfarin were determined by HPLC-MS/MS (Waters, UK). We assessed the association between warfarin dose, concentration, and INR as well as the effects of these factors on warfarin concentrations. RESULTS: The mean maintenance dose of warfarin in 105 patients was 4.1+/-1.3 mg/day (range, 1.7-8.0 mg/day) and their mean plasma warfarin concentration was 1.3+/-0.5 mg/L. We defined a concentration range of 0.6-2.6 mg/L (corresponding to the 2.5th to 97.5th percentile range of the Plasma warfarin levels in the 74 patients showing INR within target range) as the therapeutic range for warfarin. The correlation of warfarin dose with warfarin concentration (r2=0.259, P<0.001) was higher than that with INR (r2=0.029, P=0.072). CONCLUSIONS: There was a significant correlation between warfarin dose and plasma warfarin concentrations in Korean patients with atrial fibrillation. Hence, plasma warfarin monitoring can help determine dose adjustments and improve our understanding of individual patient response to warfarin treatment.

The First Metatarsophalangeal Arthrodesis with Screws Fixation / 대한족부족관절학회지

PURPOSE: The aim of this study was to retrospectively evaluate the clinical and radiological results of the first metatarsophalangeal joint arthrodesis with two crossed screws fixation. MATERIALS AND METHODS: We treated 23 patients (24 cases) with arthrodesis of the first metatarsophalangeal joint using two crossed screws fixation between December 2000 and May 2005. There were 3 male patients and 20 female patients. Ages ranged from 28 to 74 years (mean, 50 years). Follow-up ranged from 4.1 to 8.2 years (mean, 6.5 years). The American Orthopaedic Foot and Ankle Society (AOFAS) score and their satisfaction was evaluated clinically, foot anteroposterior and lateral radiograph, radiologically. RESULTS: Of the 24 cases, 6 had surgery for dorsal plate and screws fixation because of failure to acquire firm fixation with two crossed screws fixation. All 6 cases acquired bony union. Fusion of the hallux first metatarsophalangeal joint occurred in 16/18 cases (89%). Nonunion occurred in 2 cases (11%) and was asymptomatic. At last follow-up, hallux valgus angle ranged from 11 to 25 degrees(mean, 17.7 degrees), dorsiflexion ranged from 15 to 25 degrees (mean, 22 degrees).The mean preoperative AOFAS score of 37 points(range, 28 to 45 points) improved to a mean of 77 points (range, 65~90 points) postoperatively. The result of the procedure as rated subjectively by the patient was excellent for 5 cases, good for 11 cases and fair for 2. CONCLUSION: Comparatively, the arthrodesis of the first metatarsophalangeal joint with crossed screws fixation showed a satisfactory clinical results, we thought that require technical attention for firm fixation in operation.

Identification of Proteolipid Protein 1 Gene Duplication by Multiplex Ligation-Dependent Probe Amplification: First Report of Genetically Confirmed Family of Pelizaeus-Merzbacher Disease in Korea

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive disorder with a prototype of a dysmyelinating leukodystrophy that is caused by a mutation in the proteolipid protein 1 (PLP1) gene on the long arm of the X chromosome in band Xq22. This mutation results in abnormal expression or production of PLP. We here present a Korean boy with spastic quadriplegia, horizontal nystagmus, saccadic gaze, intentional tremor, head titubation, ataxia, and developmental delay. The brain magnetic resonance imaging (MRI) showed abnormally high signal intensities in the white matter tract, including a subcortical U fiber on the T2-weighted and fluid attenuated inversion recovery (FLAIR) image. The chromosomal analysis was normal; however, duplication of the PLP1 gene in chromosome Xq22 was detected when the multiplex ligation-dependent probe amplification (MLPA) method was used. We also investigated the pedigree for a genetic study related to PMD. This case suggests that the duplication mutation of the PLP1 gene in patients with PMD results in a mild clinical form of the disorder that mimics the spastic quadriplegia of cerebral palsy.