Rates and determinants of antibiotics and probiotics prescription to children in Asia-Pacific countries.

Antibiotic therapy may have important side effects. Guidelines recommend the administration of specific probiotics to reduce the risk of antibiotic-associated diarrhoea (AAD). The rates and determinants of antibiotics and co-prescription of probiotics in children remain poorly known in Asia-Pacific countries, which are very heterogenous in terms of economic development, health care organization and health policies. A survey among general practitioners (GPs) and paediatricians was performed in seven countries of the Asia-Pacific area (Australia, Japan, Indonesia, India, China, Singapore, and South Korea). Physicians completed an online questionnaire that explored their current habits and the determinants for prescribing antibiotics and probiotics. For the 731 physicians who completed the questionnaire (390 paediatricians and 341 GPs), 37% of all consultations for a child led to the prescription of antibiotics (ranging from 17% in Australia to 47% in India). A large majority of physicians (84%) agreed that antibiotics disrupted gut microbiota and considered probiotics an effective intervention to prevent AAD (68%). However, only 33% co-prescribed probiotics with antibiotics (ranging from 13% in Japan to 60% in South Korea). The main reasons for prescribing probiotics were previous episodes of AAD (61%), presence of diarrhoea (55%), prolonged antibiotic treatment (54%) or amoxicillin-clavulanic acid therapy (54%). Although current local guidelines recommend the use of selected probiotics in children receiving antibiotics in Asia-Pacific area, the rates of antibiotics and probiotics prescription significantly vary among countries and are deeply affected by country-related cultural and organisational issues.

Bocavirus infection following paediatric liver transplantation.

HBoV is an emergent virus, which is frequently detected as a co-infective agent. However, it can cause disease on its own. It is associated with respiratory and diarrhoeal illness in children and adults, whether immunocompetent or immunocompromised. We report HBoV infection in a child post-liver transplantation, who presented with persistent fever and mild tachypnea, 3 weeks after a successful transplant. She recovered spontaneously with no graft dysfunction.

Two consecutive partial liver transplants in a patient with Classic Maple Syrup Urine Disease.

Maple syrup urine disease is caused by a deficiency in the branched chain ketoacid dehydrogenase (BCKAD) complex. This results in the accumulation of branched chain amino acids (BCAA) and branched chain ketoacids in the body. Even when aggressively treated with dietary restriction of BCAA, patients experience long term cognitive, neurological and psychosocial problems. Liver transplantation from deceased donors has been shown to be an effective modality in introducing adequate BCKAD activity, attaining a metabolic cure for patients. Here, we report the clinical course of the first known patient with classic MSUD who received two consecutive partial liver grafts from two different living non-carrier donors and his five year outcome posttransplant. We also show that despite the failure of the first liver graft, and initial acute cellular rejection of the second liver graft in our patient, his metabolic control remained good without metabolic decompensation.

Vascular complications in pediatric liver transplantation; single-center experience from Singapore.

AIM: Vascular complications (VC) are a major cause of significant morbidity and mortality in pediatric liver transplantation (LT). We reviewed our series to study the evolution of vascular reconstructions and its effect on the incidence of VC after LT, particularly with regard to the portal vein (PV). METHODS: The medical records of 81 pediatric LT performed in 76 children (38 boys) from 1991 to 2010 in the National University Hospital, Singapore, were reviewed to identify VC pertaining to PV, hepatic artery (HA), and hepatic veins (HV) and to analyse the data for the entire series and in 2 consecutive cohorts: initial 40 LT (group 1) and subsequent 41 LT (group 2). Specific interventions in group 2 were characterized by surgical innovations for reconstruction of the difficult PV and routine use of Doppler ultrasound intraoperatively and postoperatively. RESULTS: The overall incidence of VC was 19.7% (n = 16) and individually HA thrombosis 4.9% (n = 4), HA stenosis 1.2% (n = 1), PV thrombosis 12.3% (n = 9), PV stenosis 1.2% (n = 1), and HV thrombosis 1.2% (n = 1). The overall 1- and 5-year survival rates in our series were 89% and 85%, respectively. The 1- and 5-year survival rates in patients with and without VC were 81.25% and 68.75% and 90.8% and 89.2%, respectively. The incidence of VC decreased from 27.5% in group 1 to 12.1% in group 2 (p = .08). The major contribution to this appears to be a decrease in PV complications from 17.5% in group 1 to 7.3% in group 2 (P = .1). The incidence of HA (3 vs 2) and HV (1 vs 0) complications was similar between the 2 groups. CONCLUSIONS: Vascular reconstructions in small recipients are technically challenging and associated with a learning curve. Application of meticulous techniques in general, surgical innovations to the difficult PV in particular and attention to postoperative monitoring contribute toward a major reduction in VC.

Unusual shunt for symptomatic portal vein thrombosis after liver transplantation - Clatworthy revisited.

PV thrombosis is not an uncommon occurrence following pediatric LT. Symptomatic PHT following PV thrombosis is treated medically, surgical portosystemic shunting (mesorex, splenorenal, and mesocaval) being reserved for refractory cases. A 10-yr-old boy suffered recurrent malena and hemorrhagic shock because of chronic PV thrombosis following LT nine yr ago (1999). Extensive work-up failed to localize the bleeding source. The liver function remained normal. Initial attempts at surgical shunts failed owing to thrombosis (mesocaval 2001, splenorenal, inferior mesenteric-left renal vein, splenic-left external iliac vein 2008). In this situation, we performed a Clatworthy shunt by anastomosing the divided lower end of the LCIV to the side of SMV. There was a single, large caliber anastomosis. Post-operatively, the malena stopped completely, and clinically, there was no lower limb edema or encephalopathy. Doppler USG revealed persistence of hepatopetal flow within the portal collaterals. Follow-up at two yr reveals stable hepatic function with a patent shunt. To the best of our knowledge, we are not aware of a Clatworthy shunt being performed in a transplant setting. We reviewed the literature pertaining to this shunt in non-transplant patients with PHT.

Novel multiplex oligonucleotide-conjugated bead suspension array for rapid identification of enterovirus 71 subgenogroups.

A high-throughput multiplex bead suspension array was developed for the rapid subgenogrouping of EV71 strains, based on single nucleotide polymorphisms observed within the VP1 region with a high sensitivity as low as 1 PFU. Of 33 viral isolates and 55 clinical samples, all EV71 strains were successfully detected and correctly subgenogrouped.

The largest outbreak of hand; foot and mouth disease in Singapore in 2008: the role of enterovirus 71 and coxsackievirus A strains.

BACKGROUND: During 2008, Singapore experienced its largest ever outbreak of hand, foot and mouth disease (HFMD), resulting in 29686 cases, including four cases of encephalitis and one fatality. METHODS: A total of 51 clinical specimens from 43 patients with suspected HFMD at the National University Hospital, Singapore were collected for virus isolation and identification by reverse transcription polymerase chain reaction (RT-PCR) and sequencing. RESULTS: Enteroviruses were identified in 34 samples (66.7%), with 11 samples (21.6%) being positive for enterovirus 71 (EV71). Other non-EV71 enteroviruses (including coxsackievirus A4, A6, A10, and A16) were identified in 23 samples (45.1%). The most prevalent virus serotypes were CA6, CA10, and EV71. CA6 and CA10 accounted for 35.3% of all HFMD cases, which may explain the high transmissibility and low fatality that characterized this unprecedented epidemic associated with relatively mild disease. Phylogenetic analyses of 10 circulating EV71 strains indicated that they belonged to two subgenogroups, i.e., B5 (80%) and C2 (20%). The VP1 sequences of the 2008 EV71 strains also exhibited continuous mutations during the outbreak, reflecting the relatively high mutation rate of the EV71 capsid protein, which may have implications for future vaccine development. CONCLUSIONS: A safe and effective vaccine against EV71 is certainly warranted in view of its potential neurovirulence and its role in HFMD epidemics of recurring frequency with resultant fatalities in Asia, as well as other parts of the world.

Safety and efficacy of human rotavirus vaccine during the first 2 years of life in Asian infants: randomised, double-blind, controlled study.

This study evaluates the safety and efficacy against severe rotavirus gastroenteritis of the oral live attenuated human rotavirus vaccine RIX4414 (Rotarix) during the first 2 years of life in Asian infants from high-income countries. Healthy infants were enrolled to receive 2 doses of RIX4414 (N=5,359) or placebo (N=5,349). From 2 weeks post-dose 2 to 2 years of age, vaccine efficacy was 96.1% (95%CI:85.1%; 99.5%) against severe rotavirus gastroenteritis, 100% (95%CI:80.8%; 100%) against wild-type G1P[8] and 93.6% (95%CI:74.7%; 99.3%) against circulating non-G1 rotavirus types. No intussusception cases were reported within 31 days post-vaccination. RIX4414 shows a good safety profile and offers high protection during the first 2 years of life with potentially significant public health impact in this population.

Identification of immunodominant VP1 linear epitope of enterovirus 71 (EV71) using synthetic peptides for detecting human anti-EV71 IgG antibodies in Western blots.

A major IgG-specific immunodominant VP1 linear epitope of enterovirus 71 (EV71) strain 41 (5865/SIN/00009), defined by the core sequence LEGTTNPNG, was identified by Pepscan analysis. Oligonucleotides corresponding to the amino-acid sequence of synthetic peptide SP32 were cloned and over-expressed in Escherichia coli as a recombinant glutathione-S-transferase (GST)-SP32 fusion protein. In ELISAs, this protein did not react with human anti-EV71 IgG antibodies, but there was significant immunoreactivity according to western blot analysis. The amino-acid sequence of SP32 was highly specific for detecting EV71 strains in western blot analysis, and showed no immunoreactivity with monoclonal antibodies raised against other enteroviruses, e.g., CA9 and Echo 6.

Liver transplantation in Singapore 1990-2004.

INTRODUCTION: Liver transplantation is the accepted standard of care for patients with hepatocellular carcinoma, decompensated liver cirrhosis, and acute liver failure. Since the first liver transplant done in Singapore in 1990, results have been improving. We review the overall results of liver transplantation over the last 15 years. METHODS: All transplant cases from 1990 to 2004 were reviewed retrospectively. RESULTS: 100 liver transplants were performed over the last 15 years; four in the first five years and 96 in the subsequent ten years. Overall one- and five-year survival rates were 80 percent and 78 percent, respectively. 44 were paediatric transplants, of which biliary atresia was the commonest indication for paediatric transplant. 56 were adult transplants of which hepatocellular carcinoma and decompensated hepatitis B cirrhosis were the commonest indications for adult transplant. Infection remained the commonest cause of mortality. CONCLUSION: The number of transplants carried out per year was small due to the low cadaveric donation rate, but the survival of liver transplant patients was comparable to well-established liver transplant centres.

Outcome of liver transplantation for children with liver disease.

INTRODUCTION: The advent of liver transplantation has revolutionised the outcome of children with both acute liver failure and chronic end-stage liver disease. The aim of this study was to review the outcome of all paediatric liver transplants performed since the National Liver Transplant Programme began in 1990. METHODS: A retrospective review of all paediatric liver transplants from 1990 to December 2004 was performed. RESULTS: 46 liver transplants were performed in 43 children, of whom 23 (53.3 percent) were female. Median age at transplant was 21 months (range 11 months to 14 years). The most common indication for liver transplant was biliary atresia (71.7 percent). Living-related transplants accounted for 63 percent (29). Re-transplant rate was 6.5 percent with allograft loss as a result of hepatic artery thrombosis (two) and hepatic vein thrombosis (one). Tacrolimus was the primary immunosuppressive agent used in 89 percent of patients, with a 19.6 percent incidence of acute allograft rejection within the first six months. There were nine deaths. They were related to portal vein thrombosis (three), chronic rejection (one), sepsis (two), post-transplant lymphoproliferative disease (two) and primary graft non-function (one). Overall actuarial one- and five-year survival rate was 85.7 percent and 81.8 percent, respectively. CONCLUSION: Liver transplantation is an established form of intervention for end-stage liver disease and a variety of liver-related metabolic disease. Our results are comparable to those of well-established liver transplant centres.

Referral patterns and waiting times for liver transplantation in Singapore.

INTRODUCTION: Referral patterns, waiting times, waiting list, and mortality provide information on how effectively a transplant programme deals with referred patients. This paper aims to review these parameters in the Singapore National Liver Transplant Programme. METHODS: Data of all patients referred to the Singapore National Liver Transplant Programme since its inception were captured and outcomes were retrieved and described. RESULTS: 562 patients were referred for liver transplant evaluation from 1990-2004, consisting of 457 adults and 105 children. The main indications for referral were hepatitis B liver disease and hepatocellular carcinoma in adults, and biliary atresia in children. Most patients were of United Network of Organ Sharing (UNOS) status 3 or 4 at the time of referral. 114 (20.28 percent) patients had transplants, consisting of 66 adults (14.44 percent) and 48 (45.71 percent) children. 138 adults and ten children were rejected for transplant, mainly for the reason of being "too early". The median waiting time for adults who had transplants was 3.3 months while adults still on the waiting list had been waiting for 16.2 months. The overall waiting list mortality was 44.3 percent, being 52.5 percent in adults and 23.2 percent in children. CONCLUSION: The overall transplantation rate is low and the waiting list mortality is high as a result of low availability of organs, particularly in adults. Paediatric liver transplant appears to have been better at dealing with referred patients but this is probably due to availability of living-related liver transplant. Improvement in these may result from the Human Organ Transplant Act.

A short report on highlights of worldwide development of RIX4414: a Singaporean experience.

In Singapore, we conducted a phase II randomized, double-blind, placebo-controlled dose ranging study using an attenuated human rotavirus vaccine, RIX4414. Altogether, 2464 healthy infants were recruited. Two oral doses of vaccine at 104.7, 105.2 or 106.1 ffu or placebo were administered with routine immunizations at 3 and 4 months of age. Seroconversion and 'vaccine take' in the vaccine groups 1-month post dose 2 varied from 76 to 91% and 98 to 100% respectively. Vaccine was well tolerated and did not interfere with response of concomitantly administered vaccines.

A rotavirus vaccine for infants: the Asian experience.

INTRODUCTION: Severe rotavirus gastroenteritis in children causes significant morbidity worldwide and substantial deaths in developing countries. Hence, a live attenuated vaccine Rotarix was developed with human strain RIX4414 of G1P1A P[8] specificity. RIX4414 trials in infants have begun in developed and developing countries worldwide. An overview of RIX4414 in developed and developing countries and prospects with this vaccine in Asia are presented. METHODS: Completed RIX4414 trials have been reviewed. RESULTS: Two oral doses of RIX4414 were well tolerated with a reactogenicity profile similar to placebo. RIX4414 was also highly immunogenic, e.g., in a dose-ranging study conducted in Singapore, 98.8% to 100% of infants had a vaccine take after 2 doses. RIX4414 did not affect the immune response of simultaneously administered routine infant vaccines. RIX4414 significantly reduced severe rotavirus gastroenteritis in settings where multiple serotypes including the emerging G9 type co-circulated. CONCLUSION: These encouraging results warrant further evaluation of the vaccine worldwide and especially in developing countries with the highest need. Therefore, evaluation of the Rotarix vaccine is continuing in large phase III trials in Asia and worldwide.

Surgical complications and outcome of paediatric liver transplantation: the Singapore experience.

The purpose of this study was to analyse the early and late results of paediatric liver transplantation (LT), with particular reference to complications that required surgical intervention. The charts of all children who underwent LT between 1990 and 2002 were reviewed retrospectively. Results were analysed with a minimum follow up of 9 months. Thirty-five children have undergone 38 LTs; 22 received grafts from their parents, 16 received cadaveric organs and three children had retransplantation. The ages of the children ranged from 12 to 168 months. Biliary atresia was the most frequent indication for transplant (n=27). Twenty-seven children had complications that required surgical or radiological interventional procedures. Vascular complications included hepatic artery thrombosis (n=2), hepatic vein (HV) thrombosis (n=1), and the majority being portal vein thrombosis (n=6). Bile leaks were observed in eight children. Other complications included intestinal perforation (n=2), intra-abdominal abscesses (n=1), wound dehiscence (n=2), post-operative bleed (n=2), intestinal obstruction (n=2), ventral hernia (n=1), and multiple abdominal wound sinuses (n=1). Three children underwent retransplantation, two for hepatic artery thrombosis with multiple episodes of cholangitis and intrahepatic biliomas and the third was done for hepatic vein thrombosis. Patient and graft survival at 1 year is 81.5 and 74.2%, respectively. Paediatric LT is associated with significant morbidity, the main complications being vascular and biliary.

Paediatrics in Singapore: the early days.

Paediatric services in Singapore started at the end of the 19th century. Because of inadequate housing, poor sanitation and inadequate health services, malnutrition and infections were the main problems. Infant mortality was in excess of 300/1000. There were many prominent doctors who worked in extremely demanding environments in order to better the health of children at that time. Over the years, there has been a steady improvement of healthcare in Singapore and this has been mainly due to the foresight and hard work of the pioneers. With excellent primary healthcare and specialised paediatric centres, paediatric services in Singapore are among the best in the world.

Successful listing of patients for liver transplant was related to participation of referring doctor in the transplant program.

INTRODUCTION: Experience with liver transplantation is limited in many parts of Asia. Therefore, patients from nontransplant centers may not be referred in a timely fashion for transplants. Our aim was to evaluate the pattern of referral for liver transplantation and their outcomes in Singapore. METHODS: Consecutive patients referred from 1990 to 2001 were reviewed. Patients from any hospital in Singapore (or the region) could be referred to the program. They were discussed at the weekly meetings. Appropriate patients were placed on the waiting list. "Pending" indicated that the disease was early or there were unsettled medical or social issues. Unsuitable patients were "rejected" for transplant. RESULTS: There were 385 patients referred over a 12-year period. Hepatitis B cirrhosis and hepatocellular carcinoma (HCC) were the most common indications among adults, whereas biliary atresia was the most common for children. Pediatric patients were more likely than adult patients to be listed for transplant (53/76 vs 106/309, P < .001). Patients referred by regular attendees of the program were more likely to be accepted than nonattendees (38% vs 25%, P = .04). "Disease too early", "advanced HCC", and "refusal by family members" were the most common reasons for rejection. CONCLUSION: Members of the Liver Transplant Program were more likely to refer suitable patients for transplant at the appropriate time. Better interaction between gastroenterologists inside and outside the transplant program would help to improve the timing of referrals for liver transplantation, and hence, patient survival.

Renal impairment and diabetes mellitus after liver transplant.

INTRODUCTION: One of the major concerns in liver transplant patients who survive past 1 year posttransplant is the development of chronic diseases. AIM: We studied two important clinical conditions that can have a chronic course-renal impairment and diabetes mellitus-among long-term liver transplant survivors. METHODS: All adult patients transplanted and followed for at least 1 year were evaluated for clinical status, blood tests, and imaging studies. The occurrence and development of renal impairment, defined as a serum creatinine above 125 micromol/L or creatinine clearance less than 75 mL/min, or diabetes mellitus were evaluated for contributing factors. RESULTS: The 35 evaluated patients of mean age at transplant of 50 years had a mean follow-up duration of 45 months. The incidence of posttransplant renal impairment was 22.8% at 1 year and 47.6% at 3 years. This disorder was associated with pretransplant renal impairment and with a diagnosis of diabetes. Posttransplant diabetes mellitus was observed in 48.6% with 41.1% resolving over time. CONCLUSION: Posttransplant renal impairment appears to be a potential long-term problem. Although this relates to pretransplant conditions, longer follow-up is required to examine whether posttransplant factors contribute to its progression.

Persistent thrombocytopenia in liver transplant patients.

INTRODUCTION: The occurrence of thrombocytopenia in the perioperative period after a liver transplant is not uncommon. However, there are few studies on persistent thrombocytopenia during the longer follow up period of patients after liver transplantation. We examined the prevalence of and contributing factors to persistent thrombocytopenia beyond 1 year post-liver transplantation. METHODS: We analyzed adult patients followed for at least 1 year posttransplant with full blood counts and abdominal scans, as well as clinical notes. RESULTS: The 35 patients of mean age at transplant of 50 years and showed a mean follow-up of about 4 years showed a prevalence of persistent thrombocytopenia at 12 months of 54% and at 3 years of 25%. Factors that were associated with persistent thrombocytopenia were pretransplant variceal bleeding, splenomegaly, and thrombocytopenia at 3 and 6 months posttransplant. After multivariate analysis only the latter represented independent factors for persistent thrombocytopenia at 1 and 3 years posttransplant, respectively. CONCLUSION: Persistent thrombocytopenia improved over time posttransplant; no bleeding problem was observed among the affected cases.