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Yeh C.-T.,Liver Research Center | Yeh C.-T.,Chang Gung University | So M.,New York University | Ng J.,New York University | And 7 more authors.
Hepatology | Year: 2010

Hepatitis B virus (HBV) is a major etiological factor of hepatocellular carcinoma (HCC). However, the postoperative prognostic value of the virological factors assayed directly from liver tissue has never been investigated. To address this issue, 185 liver samples obtained from the noncancerous part of surgically removed HBV-associated HCC tissues were subjected to virological analysis. Assayed factors included the amount of HBV-DNA in the liver tissues; genotype; and the presence of the HBV precore stop codon G1896A mutation, basal core promoter A1762T/G1764A mutation, and pre-S deletions/stop codon mutation. All virological factors and clinicopathological factors were subjected to Cox proportional hazard model analysis to estimate postoperative survival. It was found that an HBV-DNA level >3.0 × 107 copies/g of liver tissue and the presence of the basal core promoter mutation independently predicted disease-free (adjusted hazard ratio 1.641 [95% confidence interval (CI) 1.010-2.667] and 2.075 [95% CI 1.203-3.579], respectively) and overall (adjusted hazard ratio 2.807 [95% CI 1.000-7.880] and 5.697 [95% CI 1.678-19.342], respectively) survival. Kaplan-Meier survival analysis indicated that in-frame, short stretch (<100 bp) pre-S deletions, but not large fragment (>100 bp) pre-S deletions, were significantly associated with poorer disease-free (P = 0.005) and overall (P = 0.020) survival. A hot deletion region located between codons 107 and 141 of the pre-S sequence was identified for the short stretch pre-S deletion mutants. Conclusion: The amount of HBV-DNA in liver tissue and the presence of the basal core promoter mutation were two independent predictors for postoperative survival in HCC. A short stretch pre-S deletion located between codons 107 and 141 was strongly associated with a poorer postoperative prognosis. Copyright © 2010 American Association for the Study of Liver Diseases.


Chen C.-J.,Chang Gung Childrens Hospital | Chen C.-J.,Chang Gung University | Lin M.-H.,Chang Gung University | Shu J.-C.,Chang Gung University | And 2 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2014

Objectives: Vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA) phenotypes are increasingly reported in methicillin-resistant S. aureus (MRSA) strains of distinct genetic backgrounds. This study tracked genetic evolution during the development of vancomycin non-susceptibility in a prevalent Asian community-associated MRSA clone of sequence type (ST) 59. Methods: ST59 strains were consecutively isolated from a patient who failed chemotherapy for a septic knee over 15 months. The genetic mutations associated with the VISA phenotype were identified by whole-genome sequencing of two strains, which had the vancomycin-susceptible S. aureus (VSSA) and VISA phenotypes. The mutations were subsequently screened in other strains. By correlating the accumulated mutations with vancomycin susceptibility, genetic evolution was tracked at the whole-genome scale. Results: Nine non-synonymous mutations and two steps of genetic evolution were identified during the development of the VISA phenotype. The first step involved a nonsense mutation in agrC and point mutations at five other loci, which were associated with the VSSA-to-hVISA conversion. Mutations of rpoB and fusA following the use of rifampicin and fusidic acid were identified in the second step of evolution, which corresponded to the development of dual resistance to rifampicin and fusidic acid and the conversion of hVISA to VISA. Conclusions: In vivo genetic evolution of S. aureus occurred in stepwise order during the development of incremental vancomycin non-susceptibility and was related to the use of antimicrobial agents. © The Author 2013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.


Lee M.-S.,National Health Research Institute | Chiang P.-S.,National Health Research Institute | Luo S.-T.,National Health Research Institute | Huang M.-L.,National Health Research Institute | And 4 more authors.
PLoS Neglected Tropical Diseases | Year: 2012

Objective: Enterovirus 71 (EV71) is causing life-threatening outbreaks in tropical Asia. In Taiwan and other tropical Asian countries, although nationwide EV71 epidemics occur cyclically, age-specific incidence rates of EV71 infections that are critical to estimate disease burden and design vaccine trials are not clear. A nationwide EV71 epidemic occurred in 2008-09 in Taiwan, which provided a unique opportunity to estimate age-specific incidence rates of EV71 infections. Study Design: We prospectively recruited 749 healthy neonates and conducted follow-ups from June 2006 to December 2009. Sera were obtained from participants at 0, 6, 12, 24, and 36 months of age for measuring EV71 neutralizing antibody titers. If the participants developed suspected enterovirus illnesses, throat swabs were collected for virus isolation. Results: We detected 28 EV71 infections including 20 symptomatic and 8 asymptomatic infections. Age-specific incidence rates of EV71 infection increased from 1.71 per 100 person-years at 0-6 months of age to 4.09, 5.74, and 4.97 per 100 person-years at 7-12, 13-24, and 25-36 months of age, respectively. Cumulative incidence rate was 15.15 per 100 persons by 36 months of age, respectively. Conclusions: Risk of EV71 infections in Taiwan increased after 6 months of age during EV71 epidemics. The cumulative incidence rate was 15% by 36 months of age, and 29% of EV71 infections were asymptomatic in young children. © 2012 Lee et al.


Wang C.-H.,Chang Gung University | Chung F.-T.,Chang Gung University | Lin S.-M.,Chang Gung University | Huang S.-Y.,Chang Gung Memorial Hospital | And 4 more authors.
Critical Care Medicine | Year: 2014

OBJECTIVES:: Severe H1N1 pneumonia with acute respiratory failure results in infiltration of lungs due to the presence of hyperactive immune cells. Rapamycin and corticosteroids inhibit this immune response by blocking the activation of T and B cells. DESIGN:: Open-label prospective randomized controlled trial. SETTING:: A tertiary medical center, Chang Gung Memorial Hospital, located in Taiwan. PATIENTS:: Between 2009 and 2011, of 4,012 H1N1-infected patients, 38 patients with severe H1N1 pneumonia and acute respiratory failure were enrolled. MEASUREMENTS AND MAIN RESULTS:: Thirty-eight patients with confirmed H1N1 pneumonia and on mechanical ventilatory support were randomized to receive adjuvant treatment of corticosteroids with an mTOR inhibitor, either with sirolimus (Rapamune 2 mg/d) (sirolimus group, n = 19) for 14 days or without sirolimus (nonsirolimus group, n = 19). The clinical values measured included PaO2/FIO2, Sequential Organ Failure Assessment score, duration of ventilatory support, and mortality. The baseline demography was similar between the two groups. After treatment, the PaO 2/FIO2 values on day 3 (167.5 [95% CI, 86.7-209.2 mm Hg], n = 19 vs 106.8 [95% CI, 73.0-140.7 mm Hg], n = 19; p = 0.025] and day 7 (241.6 [95% CI, 185.2-297.9 mm Hg], n = 19 vs 147.0 [95% CI, 100.7-193.7 mm Hg], n = 17; p = 0.008) in the sirolimus group were significantly better over the nonsirolimus group. Similarly, the Sequential Organ Failure Assessment score on day 3 (4.3 [95% CI, 3.1-5.5]; p = 0.029) and day 7 (5.9 [95% CI, 4.8-6.9], n = 19 and 6.2 [95% CI, 4.7-7.8], n = 17, respectively) significantly improved in the sirolimus group. The liberation from a mechanical ventilator at 3 months was also better in the sirolimus combined with corticosteroids treatment. Similarly, the duration of ventilator use was significantly shorter in the sirolimus group (median, 7 vs 15 d; p = 0.03 by log-rank test). In the sirolimus combined with corticosteroids treatment group, a rapid clearance of virus also occurred after 7 days of treatment. CONCLUSIONS:: In patients with severe H1N1 pneumonia, early adjuvant treatment with corticosteroids and an mTOR inhibitor was associated with improvement in outcomes, such as hypoxia, multiple organ dysfunction, virus clearance, and shortened liberation of ventilator and ventilator days. © 2013 by the Society of Critical Care Medicine and Lippincott.


Jaing T.-H.,Chang Gung Childrens Hospital | Chen S.-H.,Chang Gung Childrens Hospital | Tsai M.H.,Chang Gung Childrens Hospital | Yang C.-P.,Chang Gung Childrens Hospital | Hung I.-J.,Chang Gung Childrens Hospital
Biology of Blood and Marrow Transplantation | Year: 2010

The potential benefits of unrelated donor bone marrow transplantation are offset by the immunologic complications of graft-versus-host disease (GVHD) and infection. We used cryopreserved umbilical cord blood (UCB) as a strategy to reduce the risks of GVHD and treatment-related mortality (TRM) and improved survival. Data on 45 patients with median age of 4.5 years who received transplants between October 2003 and February 2009 for the treatment of nonmalignant diseases were evaluated. As of May 15, 2009, the median follow-up was 25 months (range: 3-66). The majority (82%) of patients received an HLA-mismatched graft. The median infused total nucleated cell dose was 7.6 × 107/kg and CD34+ count 4.0 × 105/kg. Primary graft failure was encountered after 4 transplantations (8%). Log-rank tests and Cox regression analyses were used to determine the effects of various demographic, graft-related, and treatment factors on engraftment, GVHD, TRM, graft failure, and survival. Incidences of neutrophil and platelet engraftment were 88% and 82%, respectively. The incidence of severe grade III-IV acute GVHD (aGVHD) was 42%. Five-year overall survival (OS) and disease-free survival (DFS) were 88.1% and 77.1%, respectively. The cumulative incidence of TRM at 2 years was 12.0%. When cell dose and other factors are optimal, unrelated CBT is a promising approach for curative therapy of nonmalignant diseases. © 2010 American Society for Blood and Marrow Transplantation.


Liang D.-C.,Mackay Memorial Hospital | Liu H.-C.,Mackay Memorial Hospital | Yang C.-P.,Chang Gung Childrens Hospital | Jaing T.-H.,Chang Gung Childrens Hospital | And 10 more authors.
Blood | Year: 2013

Gene mutations involving epigenetic regulators recently have been described in adult acute myeloid leukemia (AML). Similar studies are limited in children. We analyzed gene mutations and cooperation in pediatric AML with special reference on mutated epigenetic regulators. Nineteen gene mutations, including 8 class I genes, 4 class II genes, WT1 and TP53 (class III), and 5 epigenetic regulator genes (class IV), were analyzed in 206 children with de novo AML. Mutational analysis was performed with polymerase chain reaction-based assay followed by direct sequencing. One hundred seventeen of 206 patients (56.8%) had at least onemutation: 51%class I, 13%class II, 6.8% class III, and 5.6% class IV. FLT3-internal tandem duplication was most frequent, and 29% of patients had more than one gene mutation. Two patients carried ASXL1 mutations, both with t(8;21), 2 had DNMT3A mutations, 2 had IDH1 mutations, 1 had IDH2 mutation, and 3 had TET2 mutations. Both patients with IDH1 mutations had AML-M0 subtype and MLL-partial tandem duplication. Cooperating mutations with mutated epigenetic regulators were observed in 8 of 10 patients. We conclude that mutated epigenetic regulators were much less than those in adult AML butwith frequent cooperating mutations. ASXL1, TET2, andI DH1 mutations were associated with specific genetic subtypes. © 2013 by The American Society of Hematology.


Chen C.-B.,Chang Gung University | Chang H.-C.,Chang Gung University | Huang Y.-C.,Chang Gung University | Huang Y.-C.,Chang Gung Childrens Hospital
Journal of Hospital Infection | Year: 2010

From 25 June to 11 July 2008, a total of 177 adult patients hospitalised in an intensive care unit (ICU) (94 in medical ICUs and 83 in surgical ICUs) at a tertiary care hospital were screened for nasal carriage of meticillin-resistant Staphylococcus aureus (MRSA) by polymerase chain reaction. The overall prevalence of S. aureus and MRSA nasal carriage among the patients was 42% and 32%, respectively. MRSA carriage rate of the patients hospitalised in medical ICUs was significantly higher than that of those hospitalised in surgical ICUs (47% vs 16%, P < 0.001). Multivariate logistic regression analysis revealed that pneumonia, chronic obstructive pulmonary disease, current MRSA infection, and medical ICU admission were independent predictors for nasal carriage of MRSA. Of the 38 MRSA isolates available for molecular analysis, a total of six pulsed-field gel electrophoresis (PFGE) patterns with two major patterns (F, 42%; A, 37%) were identified. Most MRSA isolates belonged to one of two major clones characterised as sequence type 5/PFGE F/staphylococcal cassette chromosome mec (SCCmec) II/Panton-Valentine leucocidin (PVL) genes negative (34%) and ST239/PFGE A/SCCmec III/PVL negative (26%), both clones being associated with healthcare-associated (HA) clones in Taiwan. Six isolates (16%) were characterised as ST59/SCCmec IV or VT and were associated with community strains in Taiwan. In conclusion, 32% of ICU hospitalised adult patients in a Taiwanese tertiary care teaching hospital between June and July 2008 were colonised with MRSA in their nares. Though most isolates were HA-MRSA, community strains accounted for a proportion of the isolates. © 2009 The Hospital Infection Society.


Wilkinson T.M.,University of Southampton | Li C.K.F.,Weatherall Institute of Molecular Medicine | Chui C.S.C.,Weatherall Institute of Molecular Medicine | Huang A.K.Y.,Weatherall Institute of Molecular Medicine | And 12 more authors.
Nature Medicine | Year: 2012

Protective immunity against influenza virus infection is mediated by neutralizing antibodies, but the precise role of T cells in human influenza immunity is uncertain. We conducted influenza infection studies in healthy volunteers with no detectable antibodies to the challenge viruses H3N2 or H1N1. We mapped T cell responses to influenza before and during infection. We found a large increase in influenza-specific T cell responses by day 7, when virus was completely cleared from nasal samples and serum antibodies were still undetectable. Preexisting CD4 +, but not CD8 +, T cells responding to influenza internal proteins were associated with lower virus shedding and less severe illness. These CD4 + cells also responded to pandemic H1N1 (A/CA/07/2009) peptides and showed evidence of cytotoxic activity. These cells are an important statistical correlate of homotypic and heterotypic response and may limit severity of influenza infection by new strains in the absence of specific antibody responses. Our results provide information that may aid the design of future vaccines against emerging influenza strains. © 2012 Nature America, Inc. All rights reserved. © 2012 Nature America, Inc. All rights reserved.


Lin T.-Y.,Chang Gung Childrens Hospital | Shah N.K.,Hinduja National Hospital and Research Center | Brooks D.,Pfizer | Garcia C.S.,Pfizer
Vaccine | Year: 2010

Invasive pneumococcal disease (IPD) burden is significant in the Asia-Pacific region. This review describes the epidemiology and Streptococcus pneumoniae (SP) serotype distribution of IPD in children in the Asia-Pacific region from studies published from 1999 to 2010. IPD incidence varies widely in Asia-Pacific countries depending on the method of surveillance, the population studied, and the time period. Incidences are highest for younger children, with rates near 100-200 cases per 100,000 children aged <1 or 2 years. Incidences of preventable disease are estimated to be 6-200 cases per 100,000. Heptavalent pneumococcal conjugate vaccine (PCV7) serotype coverage shows a very wide range over the Asia-Pacific region. Ten countries have high vaccine serotype coverage (>70%), and six countries have low vaccine serotype coverage (<50%). The majority of SP serotypes in children with IPD in most countries in the Asia-Pacific region are susceptible to penicillin (intermediate and resistant <50%); a few countries have SP serotypes with high level resistance to penicillin (intermediate and resistant >50%). Japan, Taiwan, and Thailand have high PCV7 serotype coverage. Countries with low pneumococcal resistance to antimicrobials have shown increasingly higher nonsusceptibility with time. National vaccination programmes that include PCV7, 10-valent pneumococcal conjugate vaccine (PCV), or 13-valent PCV would significantly affect IPD burden in children aged <5 years in the Asia-Pacific region, as well as the burden of penicillin-nonsusceptible IPD. © 2010.


Huang Y.-C.,Chang Gung Childrens Hospital | Huang Y.-C.,Chang Gung University | Chen C.-J.,Chang Gung Childrens Hospital | Chen C.-J.,Chang Gung University
International Journal of Antimicrobial Agents | Year: 2011

Meticillin-resistant Staphylococcus aureus (MRSA) has been increasingly identified as the major cause of community-associated (CA) infections in previously healthy hosts since the late 1990s. CA-MRSA strains were recognised as a novel pathogen that is genetically different from healthcare-associated MRSA, and five major epidemic clones have been identified worldwide. In Taiwan, a significantly increasing rate of MRSA carriage and infection amongst healthy subjects was observed in the past decade. Up to 9.5% of healthy Taiwanese children carried MRSA in the nares and >50% of paediatric CA S. aureus infections were MRSA. The adult population was also affected, but this was relatively limited. The majority of CA-MRSA isolates in Taiwan belonged to the sequence type (ST) 59 lineage, defined by multilocus sequence typing, and were multiresistant to non-β-lactams. The clone of ST59 lineage can be further classified into at least two major clones by pulsed-field gel electrophoresis (PFGE) typing, staphylococcal chromosomal cassette mec (SCCmec) elements and Panton-Valentine leukocidin (PVL) genes. The clone characterised as ST59/PFGE type C/SCCmec IV/PVL-negative was prevalent amongst the colonising isolates, whereas ST59/PFGE type D/SCCmec VT/PVL-positive was prevalent amongst the clinical isolates. Evidence suggested that the ST59 CA-MRSA clone was not only circulating in Taiwan but also in other areas of the world. In this article, the current status of CA-MRSA in Taiwan was extensively reviewed. The information provided here is not only important for local public health but can also enhance a general understanding of the successful epidemic clones of CA-MRSA worldwide. © 2011 Elsevier B.V. and the International Society of Chemotherapy.

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