Background/Aims: Despite the high efficacy of direct-acting antivirals (DAAs), approximately 1–3% of hepatitis C virus (HCV) patients fail to achieve a sustained virological response. We conducted a nationwide study to investigate risk factors associated with DAA treatment failure. Machine-learning algorithms have been applied to discriminate subjects who may fail to respond to DAA therapy. Methods: We analyzed the Taiwan HCV Registry Program database to explore predictors of DAA failure in HCV patients. Fifty-five host and virological features were assessed using multivariate logistic regression, decision tree, random forest, eXtreme Gradient Boosting (XGBoost), and artificial neural network. The primary outcome was undetectable HCV RNA at 12 weeks after the end of treatment. Results: The training (n=23,955) and validation (n=10,346) datasets had similar baseline demographics, with an overall DAA failure rate of 1.6% (n=538). Multivariate logistic regression analysis revealed that liver cirrhosis, hepatocellular carcinoma, poor DAA adherence, and higher hemoglobin A1c were significantly associated with virological failure. XGBoost outperformed the other algorithms and logistic regression models, with an area under the receiver operating characteristic curve of 1.000 in the training dataset and 0.803 in the validation dataset. The top five predictors of treatment failure were HCV RNA, body mass index, α-fetoprotein, platelets, and FIB-4 index. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the XGBoost model (cutoff value=0.5) were 99.5%, 69.7%, 99.9%, 97.4%, and 99.5%, respectively, for the entire dataset. Conclusions Machine learning algorithms effectively provide risk stratification for DAA failure and additional information on the factors associated with DAA failure.

Background/Aims: Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients. Methods: We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan’s cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray’s cumulative incidence and Cox subdistribution hazards models to analyze HCC development. Results: Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P<0.001). Notably, the increased HCC risk associated with non-use of metformin was primarily seen in non-cirrhotic patients, whereas statins decreased HCC risk in both cirrhotic and non-cirrhotic patients. Conclusions Metformin and statins may have a chemopreventive effect against HCC in CHC patients who failed antiviral therapy. These results support the need for personalized preventive strategies in managing HCC risk.

BACKGROUND: Cervical cytology for uterine cervical cancer screening has transitioned from conventional smear (CS) to liquid-based cytology (LBC), which has many advantages. The aim of this study was to compare the proportion of unsatisfactory specimens from CS versus LBC at multiple institutions including general hospitals and commercial laboratories. METHODS: Each participating institution provided a minimum of 500 Papanicolaou (Pap) test results for analysis. Pap tests were classified according to the participating institution (commercial laboratory or general hospital) and the processing method (CS, ThinPrep, SurePath, or CellPrep). The causes of unsatisfactory results were classified as technical problems, scant cellularity, or complete obscuring factors. RESULTS: A total of 38,956 Pap test results from eight general hospitals and three commercial laboratories were analyzed. The mean unsatisfactory rate of LBC was significantly lower than that of CS (1.26% and 3.31%, p = .018). In the LBC method, samples from general hospitals had lower unsatisfactory rates than those from commercial laboratories (0.65% vs 2.89%, p = .006). The reasons for unsatisfactory results were heterogeneous in CS. On the other hand, 66.2% of unsatisfactory results in LBC were due to the scant cellularity. CONCLUSIONS: Unsatisfactory rate of cervical cancer screening test results varies according to the institution and the processing method. LBC has a significantly lower unsatisfactory rate than CS.
Hand ; Hospitals, General ; Mass Screening* ; Methods ; Papanicolaou Test ; Uterine Cervical Neoplasms*

Aims: High cost of cellulases remains the most significant barrier to the economical production of bio-ethanol from lignocellulosic biomass (LB). The present study aims at developing a local cellulolytic fungal strain through random mutagenesis coupled with the feasibility of solid-state fermentation (SSF) by utilizing agricultural wastes such as oil palm frond (OPF) as the substrate. Methodology and results: Out of 95 wild isolates tested, native fungal strain Aspergillus niger, designated DWA8 was isolated as the top enzymatic secretor. For quantitative enzyme analysis, SSF was conducted using 1x106 spore/mL inoculated onto 5 g of ground OPF, incubated at room temperature for 7 days, with 70% moisture content and an initial medium pH of 7. Random mutagenesis has always been tempting in the enhancement of enzyme production. In this work, the compounded treatment of microwave, ultraviolet (UVC) and Ethyl Methanesulfonate (EMS) have generated an Aspergillus niger MUE3.06 mutant with an overall increase of 114% in CMCase activity, approximately 70% in FPase and Xylanase activity respectively compared with the parental DWA8 strain. Thus this finding is capable to be fully developed as an established mutational scheme to create highly productive filamentous fungus in a cheap, simple and sustainable way. Conclusion, significance and impact of study: It was the first attempt to explore the combine effect of the three popular mutagens upon cellulases and xylanases. It is believed that more diversified of mutagen types induce more diversified mutation pattern (with instructive planning), which is very desirable in creating new enzymes with novel abilities.
Cellulases

BACKGROUND/AIMS: The modified early warning score (MEWS) is used to predict patient intensive care unit (ICU) admission and mortality. Lactate (LA) in the blood lactate (BLA) is measured to evaluate disease severity and treatment efficacy in patients with severe sepsis/septic shock. The usefulness of a combination of MEWS and BLA to predict ICU transfer in severe sepsis/septic shock patients is unclear. We evaluated whether use of a combination of MEWS and BLA enhances prediction of ICU transfer and mortality in hospitalized patients with severe sepsis/septic shock. METHODS: Patients with severe sepsis/septic shock who were screened or contacted by a medical emergency team between January 2012 and August 2012 were enrolled at a university-affiliated hospital with ~2,700 beds, including 28 medical ICU beds. RESULTS: One hundred patients were enrolled and the rate of ICU admittance was 38%. MEWS (7.37 vs. 4.85) and BLA concentration (5 mmol/L vs. 2.19 mmol/L) were significantly higher in patients transferred to ICU than those in patients treated in general wards. The combination of MEWS and BLA was more accurate than MEWS alone in terms of ICU transfer (C-statistics: 0.898 vs. 0.816, p = 0.019). The 28-day mortality rate was 19%. MEWS was the only factor significantly associated with 28-day mortality rate (odds ratio, 1.462; 95% confidence interval, 1.122 to 1.905; p = 0.005). CONCLUSIONS: The combination of MEWS and BLA may enhance prediction of ICU transfer in patients with severe sepsis/septic shock.
Adult ; Aged ; Biomarkers/blood ; *Decision Support Techniques ; Female ; Health Status ; *Health Status Indicators ; Hospital Bed Capacity ; Hospital Mortality ; Hospitals, University ; Humans ; *Intensive Care Units ; Lactic Acid/*blood ; Male ; Middle Aged ; *Patient Transfer ; Predictive Value of Tests ; Prognosis ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Sepsis/blood/*diagnosis/mortality/therapy ; Shock, Septic/blood/*diagnosis/mortality/therapy ; Time Factors

BACKGROUND: The Korean Obstructive Lung Disease (KOLD) Cohort Study is a prospective longitudinal study of patients with chronic obstructive pulmonary disease (COPD), asthma, or other unclassified obstructive lung diseases. It was designed to develop new classification models and biomarkers that predict clinically relevant outcomes for patients with obstructive lung diseases. METHODS: Patients over 18 years old who have chronic respiratory symptoms and airflow limitations or bronchial hyper-responsiveness were enrolled at 17 centers in South Korea. After a baseline visit, the subjects were followed up every 3 months for various assessments. RESULTS: From June 2005 to October 2013, a total of 477 subjects (433 [91%] males; 381 [80%] diagnosed with COPD) were enrolled. Analyses of the KOLD Cohort Study identified distinct phenotypes in patients with COPD, and predictors of therapeutic responses and exacerbations as well as the factors related to pulmonary hypertension in COPD. In addition, several genotypes were associated with radiological phenotypes and therapeutic responses among Korean COPD patients. CONCLUSION: The KOLD Cohort Study is one of the leading long-term prospective longitudinal studies investigating heterogeneity of the COPD and is expected to provide new insights for pathogenesis and the long-term progression of COPD.
Asthma ; Biomarkers ; Classification ; Cohort Studies* ; Genotype ; Humans ; Hypertension, Pulmonary ; Korea ; Longitudinal Studies ; Lung Diseases, Obstructive* ; Male ; Phenotype ; Population Characteristics ; Prospective Studies ; Pulmonary Disease, Chronic Obstructive

BACKGROUND: The aim of our study was to evaluate the "diagnosis changed" rate in patients notified as tuberculosis (TB) on the Korean TB surveillance system (KTBS). METHODS: A total of 1,273 patients notified as TB cases on the KTBS in one private tertiary hospital in 2011 were enrolled in the present study. Patients were classified into three groups: "diagnosis maintained", "diagnosis changed" (initially notified as TB, but ultimately diagnosed as non-TB), and "administrative error" (notified as TB due to administrative errors). RESULTS: Excluding 17 patients in the "administrative error" group, the "diagnosis maintained" and "diagnosis changed" groups included 1,097 (87.3%) and 159 patients (12.7%), respectively. Common causes of "diagnosis changed" were nontuberculous mycobacterial (NTM) disease (51.7%, 61/118), and pneumonia (17.8%) in cases notified as pulmonary TB, and meningitis (19.5%, 8/41) and Crohn's disease (12.2%) in cases notified as extrapulmonary TB. Being older than 35 years of age (odds ratio [OR], 2.18) and a positive acid-fast bacilli stain (OR, 1.58) were positive predictors and a TB-related radiological finding (OR, 0.42) was a negative predictor for a "diagnosis changed" result via multivariate logistic regression analysis in pulmonary TB cases. CONCLUSION: Because of a high "diagnosis changed" rate in TB notifications to the KTBS, the TB incidence rate measured by the KTBS may be overestimated. Considering the worldwide trend toward increased NTM disease, the "diagnosis changed" rate may increase over time. Thus, when reporting the annual TB notification rate in Korea, the exclusion of "diagnosis changed" cases is desirable.
Crohn Disease ; Diagnostic Errors ; Humans ; Incidence ; Korea ; Logistic Models ; Meningitis ; Nontuberculous Mycobacteria ; Pneumonia ; Tertiary Care Centers* ; Tuberculosis*

Writing Committee of Korean clinical practice guidelines for secondary prevention of stroke has reviewed recent randomized controlled trials of cilostazol published after the first edition of Korean clinical practice guidelines that considered evidences published before June 2007. Two clinical trials and 1 meta-analysis which compared cilostazol directly with aspirin in the prevention of stroke in patients with cerebral infarction or transient ischemic attack (TIA) were identified and included for the current guideline update. Review of findings indicates that cilostazol as compared to aspirin achieved a greater reduction of stroke as well as composite vascular events of stroke, myocardial infarction, and vascular death. For safety, cilostazol was associated with fewer major bleeding events than aspirin. Accordingly, new recommendations for cilostazol are made for prevention of stroke in the setting of noncardioembolic stroke or TIA. Changes in the guidelines necessitated by new evidences will be continuously reflected in future guidelines.
Aspirin ; Cerebral Infarction ; Hemorrhage ; Humans ; Ischemic Attack, Transient ; Myocardial Infarction ; Secondary Prevention ; Stroke ; Tetrazoles ; Writing

BACKGROUNDData of classical inborn errors of metabolism (IEM) of amino acids, organic acids and fatty acid oxidation are largely lacking in Hong Kong, where mass spectrometry-based expanded newborn screening for IEM has not been initiated. The current study aimed to evaluate the approximate incidence, spectrum and other characteristics of classical IEM in Hong Kong, which would be important in developing an expanded newborn screening program for the local area.

METHODSThe laboratory records of plasma amino acids, plasma acylcarnitines and urine organic acids analyses from year 2005 to 2009 inclusive in three regional chemical pathology laboratories providing biochemical and genetic diagnostic services for IEM were retrospectively reviewed.

RESULTSAmong the cohort, 43 patients were diagnosed of IEM, including 30 cases (69%) of amino acidemias (predominantly citrin deficiency, hyperphenylalaninemia due to 6-pyruvoyl-tetrahydropterin synthase deficiency and tyrosinemia type I), 5 cases (12%) of organic acidemias (predominantly holocarboxylase synthetase deficiency) and 8 cases (19%) of fatty acid oxidation defects (predominantly carnitine-acylcarnitine translocase deficiency). The incidence of classical IEM in Hong Kong was roughly estimated to be at least 1 case per 4122 lives births, or 0.243 cases per 1000 live births. This incidence is similar to those reported worldwide, including the mainland of China. The estimated incidence of hyperphenylalaninemia was 1 in 29 542 live births.

CONCLUSIONSOur data indicate that it is indisputable for the introduction of expanded newborn screening program in Hong Kong. Since Hong Kong is a metropolitan city, a comprehensive expanded newborn screening program and referral system should be available to serve the neonates born in the area.

Acids ; urine ; Amino Acids ; blood ; Carnitine ; analogs & derivatives ; blood ; Hong Kong ; epidemiology ; Humans ; Infant, Newborn ; Metabolism, Inborn Errors ; blood ; diagnosis ; epidemiology ; urine ; Neonatal Screening ; methods ; Tandem Mass Spectrometry

OBJECTIVE: To evaluate the clinicopathologic characteristics and prognostic factors of ovarian granulosa cell tumors. METHODS: Medical records of 113 patients presenting between January 1995 and December 2007 were retrospectively reviewed. RESULTS: One-hundred two patients had adult type disease, with a mean age of 46.2 years (range, 18 to 83 years) and a mean follow-up period of 54.7 months (range, 1 to 155 months). The distribution of FIGO stages was 86 patients at stage I, 11 at stage II, and 5 at stage III. During follow-up, ten patients recurred at a mean time of 48 months (range, 4 to 109 months). Among them, three patients died after a mean of 57 months (range, 25 to 103 months). In recurrence analysis, advanced stage (p=0.032) and presence of residual disease (p=0.012) were statistically significant, and age<40 years, premenopause and positive washing cytology were marginally significant (p<0.1). In multivariate analysis, stage was the only factor associated with recurrence; adjuvant chemotherapy and fertility-sparing surgery were not statistically significant. Among 36 patients with fertility-sparing operations, eight patients had nine pregnancies and delivered seven babies. Eleven patients had juvenile type tumors; the mean age was 20.0 years (range, 8 to 45 years) and the mean follow-up period was 69.8 months (range, 20 to 156 months). The distribution of FIGO stage was nine patients at stage I and two at stage III. There were no recurrences or deaths reported. Four patients had seven pregnancies and delivered six babies. CONCLUSION: Stage is the only factor associated with disease-free survival, and fertility-sparing surgery may be a treatment option for women with early-stage disease who want to retain fertility.
Adult ; Chemotherapy, Adjuvant ; Disease-Free Survival ; Female ; Fertility ; Follow-Up Studies ; Granulosa Cell Tumor ; Granulosa Cells ; Humans ; Medical Records ; Multivariate Analysis ; Ovary ; Pregnancy ; Premenopause ; Recurrence ; Retrospective Studies