Yunchan Chi

Long‐term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B

One year of treatment with entecavir (0.5 mg daily) in nucleoside‐naive patients with hepatitis B e antigen (HBeAg)‐positive or HBeAg‐negative chronic hepatitis B (CHB) resulted in significantly improved liver histology and virological and biochemical endpoints in comparison with lamivudine. Patients who received at least 3 years of cumulative entecavir therapy in phase 3 studies and a long‐term rollover study and underwent long‐term liver biopsy were evaluated for improvements in histological appearance. Sixty‐nine patients [50 HBeAg‐positive and 19 HBeAg‐negative] receiving entecavir therapy underwent long‐term liver biopsy (median time of biopsy = 6 years, range = 3‐7 years). Histological improvement was analyzed for 57 patients who had adequate baseline biopsy samples, baseline Knodell necroinflammatory scores ≥2, and adequate long‐term biopsy samples. At the time of long‐term biopsy, all patients in the cohort had a hepatitis B virus DNA level <300 copies/mL, and 86% had a normalized alanine aminotransferase level. Histological improvement (≥2‐point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score) was observed in 96% of patients, and a ≥1‐point improvement in the Ishak fibrosis score was found in 88% of patients, including all 10 patients with advanced fibrosis or cirrhosis at the phase 3 baseline. Conclusion: The majority of nucleoside‐naive patients with CHB who were treated with entecavir in this long‐term cohort achieved substantial histological improvement and regression of fibrosis or cirrhosis. (HEPATOLOGY 2010)

Risk factors for a first febrile convulsion in children: A population study in southern Taiwan

Summary: Purpose: To identify risk factors for a first febrile convulsion among 3‐year‐old children by a matched case‐control population study.

The Association between Enterovirus 71 Infections and Meteorological Parameters in Taiwan

Background Enterovirus 71 (EV71) infections are a significant cause of neurological disorder and death in children worldwide. Seasonal variations in EV71 infections have been recognized, but the mechanisms responsible for this phenomenon remain unknown. The purpose of this study was to examine the relationship between meteorological parameters and EV71 infection. Methods and Findings We analyzed the number of EV71 infections and daily climate data collected in Taiwan between 1998 and 2008 and used Poisson regression analysis and case-crossover methodology to evaluate the association between weather variability and the incidence of EV71 infection. A total of 1,914 EV71-infected patients were reported between 1998 and 2008. The incidence of EV71 infections reflected significant summertime seasonality (for oscillation, p<0.001). The incidence of EV71 infections began to rise at temperatures above 13°C (r2 = 0.76, p<0.001); at temperatures higher than approximately 26°C (r2 = 0.94, p<0.05), the incidence began to decline, producing an inverted V-shaped relationship. The increase in the incidence with increasing relative humidity was positive and linear (r2 = 0.68, p<0.05). EV71 infection was most highly correlated with temperature and relative humidity in the period that likely preceded the infection. Conclusion Our study provides quantitative evidence that the rate of EV71 infection increased significantly with increasing mean temperature and relative humidity in Taiwan.

Simultaneous Quantification and Genotyping of Hepatitis B Virus for Genotypes A to G by Real-Time PCR and Two-Step Melting Curve Analysis

ABSTRACT Both the viral titer and the genotype significantly determine clinical outcomes and responses to antiviral treatment in chronic hepatitis B virus (HBV) infection. A method was developed for large-scale A-to-G genotyping with simultaneous viral quantification. The assay was run on a LightCycler instrument using hybridization probes. The genotype was determined from the melting points of the probes in a two-step manner. Set 1 amplicons differentiated genotypes B, E, and F from A, C, D, and G and simultaneously quantified viremia by real-time PCR. Melting curve analysis using the set 2-1 amplicon or the set 2-2 amplicon reaction mixture was then used to differentiate these genotype groups into single genotypes. HBV DNA quantification was consistent with that of the Amplicor assay and linear in a range from 102 to 1013 copies/ml. By comparison with the restriction fragment length polymorphism method, 92.3% of 441 samples were accurately genotyped by the current assay. The method should be useful for genotyping and quantification of HBV DNA in areas where all genotypes exist.

Parental concerns for the child with febrile convulsion: Long-term effects of educational interventions

Objective– To evaluate long‐term effects of educational interventions on parental concerns for children with febrile convulsions (FC). Subjects and methods– 209 FC parents were recruited from southern Taiwan, and assigned into program or pamphlet groups by their choices. A questionnaire was used to examine the parental concerns at 4 time points: prior to the interventions, 3 months, 1 year, and 2 years after the interventions. Results– The concern scores were high before the interventions. Parents concerned that their child is apt to get a fever, has further seizures in the night, that FC results in potential brain damage and is life threatening. After interventions the concern scores were significantly lower for the program group than for the pamphlet group. The educational program was the most significant factor that influenced the change in parental concerns. The recurrence of FC did not significantly influence the change in the concern trajectory in the program group but showed a significant difference in the pamphlet group. Conclusion– FC parental concerns decreased as time passed particularly in the program group. The educational program was the significant factor that influenced the change of concern trajectories, and the recurrent/non‐recurrent factor influenced the change of concern only in pamphlet group. FC parental concerns should be assessed, and information given combined with emotional support.

Effects of Educational Intervention on Changing Parental Practices for Recurrent Febrile Convulsions in Taiwan

Summary:  Purpose: To evaluate the effects of educational interventions on parental practices for recurrent febrile convulsions (FC).

Curtailed two-stage designs in Phase II clinical trials.

When the accrual rate is low and the treatment period is long, a long observational period is required before information concerning the primary end point, such as binary response, becomes available in the study. Simons two-stage designs are often employed in Phase II clinical trials to avoid giving patient an ineffective drug. Thus, if the new drug is ineffective then this design would certainly accelerate the process of drug discovery and development. However, for a promising new drug this design may still require a long observational period. Therefore, when drug safety is not a primary concern, this paper proposes curtailed two-stage designs to shorten the drug development process as soon as the treatment either shows lack of efficacy or is very effective. The proposed design is superior to Simons two-stage designs in terms of savings in expected sample size and is much easier to implement in practice than stochastically curtailed Simons designs.

SOME VERSATILE TESTS BASED ON THE SIMULTANEOUS USE OF WEIGHTED LOGRANK AND WEIGHTED KAPLAN-MEIER STATISTICS

It is well known that the logrank test is locally most powerful under proportional hazards model for right censored data when two groups have same censoring distributions. For a given data set, however, one seldom knows what the exact alternative is. Therefore, Lee [1] constructed versatile tests by combining four weighted logrank (WLR) tests with various weight functions detecting proportional, early, late and middle hazards differences, respectively. However, Pepe and Fleming [2] had pointed out that WLR tests are based on ranks, and these tests might not be sensitive to the magnitude of the difference in survival times against a specific alternative. Hence, they constructed weighted Kaplan-Meier (WKM) tests that are more sensitive than the logrank test under various alternatives. Therefore, another type of versatile tests based on the simultaneous use of WLR and WKM tests is developed in this paper and the performances of the proposed tests and Lees tests are compared by simulation. None of the tests investigated in this paper is uniformly better than the others. Lees maximum test is more robust for detecting various alternatives; however, for computation simplicity, the linear combination of WLR and WKM tests is recommended to apply in practice and its overall performance is better than Lees linear combination test.

Analyzing survival curves at a fixed point in time for paired and clustered right-censored data

In clinical trials, information about certain time points may be of interest in making decisions about treatment effectiveness. Rather than comparing entire survival curves, researchers can focus on the comparison at fixed time points that may have a clinical utility for patients. For two independent samples of right-censored data, Klein et al. (2007) compared survival probabilities at a fixed time point by studying a number of tests based on some transformations of the Kaplan-Meier estimators of the survival function. However, to compare the survival probabilities at a fixed time point for paired right-censored data or clustered right-censored data, their approach would need to be modified. In this paper, we extend the statistics to accommodate the possible within-paired correlation and within-clustered correlation, respectively. We use simulation studies to present comparative results. Finally, we illustrate the implementation of these methods using two real data sets.

Potential value of urinary intercellular adhesion molecule-1 determination in patients with bladder cancer

OBJECTIVE Intercellular adhesion molecule-1 (ICAM-1) is known to play a role in immunity against bladder cancer and can be detected in the supernatants of cultured bladder cancer cells that constitutively express ICAM-1. This study was performed to examine the relevance of the ICAM-1 urine test in patients with bladder cancer. METHODS A total of 53 patients with bladder carcinoma, 35 with history of bladder cancer, and 30 normal control subjects were included in this analysis. Urinary ICAM-1 (ulCAM-1) levels were measured by immunoassay and corrected for hydration status. RESULTS Levels of ulCAM-1 were significantly elevated in patients with bladder cancer or those at tumor-free status compared with normal control subjects (P=0.001). However, there was no apparent difference between the two groups of urothelial disorders (P >0.1). ulCAM-1 did not correlate with clinicopathologic variables of bladder cancer or patient outcome (P >0.1). Six patients at tumor-free status had multiple ulCAM-1 determinations during the study period. Three of these 6 patients had elevated ulCAM-1 levels and proved to have recurrent tumors; 3 of the 6 had stable ulCAM-1 levels and were still free of disease. CONCLUSIONS Our results suggest that urinary excretion of ICAM-1 is elevated in the early stage of bladder carcinogenesis, but is independent of biologic properties of bladder cancer. Serial monitoring of ulCAM-1 may be helpful in selecting patients who are at risk of tumor recurrence.