Comparing the Performance of Multiple Small-Data Personalized Tacrolimus Dosing Models for Pediatric Liver Transplant: A Retrospective Study.

Tacrolimus is a potent immunosuppressant used after pediatric liver transplant. However, tacrolimus's narrow therapeutic window, reliance on physicians' experience for the dose titration, and intra- and inter-patient variability result in liver transplant patients falling out of the target tacrolimus trough levels frequently. Existing personalized dosing models based on the area-under-the-concentration over time curves require a higher frequency of blood draws than the current standard of care and may not be practically feasible. We present a small-data artificial intelligence-derived platform, CURATE.AI, that uses data from individual patients obtained once daily to model the dose and response relationship and identify suitable doses dynamically. Retrospective optimization using 6 models of CURATE.AI and data from 16 patients demonstrated good predictive performance and identified a suitable model for further investigations.Clinical Relevance- This study established and compared the predictive performance of 6 personalized tacrolimus dosing models for pediatric liver transplant patients and identified a suitable model with consistently good predictive performance based on data from pediatric liver transplant patients.

Early-Life Gut Health Indicators and Reported Prevalence of Infant Functional Constipation by Healthcare Professionals.

A healthy gut during early childhood is important. However, it seems that there are no standard indicators used to assess it. Healthcare professionals (HCPs) were asked via an electronic survey question about gut health indicators (GHIs) for infants and toddlers, in addition to an estimated prevalence of infant's functional constipation (FC) and its management. HCPs from eight countries participated in the survey (Russia (66.0%, 1449), Indonesia (11.0%, 242), Malaysia (6.0%, 132), Mexico (5.7%, 125), KSA (5.1%, 113), Turkey (3.0%, 66), Hong Kong (2.2%, 49), and Singapore (1.0%, 23)). The 2199 participating respondents were further classified into three continents (Asia (20.2%), Europe (68.8%), and others (11.0%)). Most of them were pediatricians (80.3%), followed by pediatric gastroenterologists (7.0%), general practitioners (6.4%), and others (6.3%). The top three preferred GHIs were similar for infants and toddlers: an absence of gastrointestinal (GI) symptoms, effective digestion/absorption as assessed by normal growth, and a general feeling of well-being. The absence of GI-related infection was the least preferred indicator. Most of the respondents reported the prevalence of FC among infants was less than 5%, with the peak incidence between the ages of 3 and 6 months. The reported choices of intervention to manage FC in infants were a change to a specific nutritional solution from a standard formula (40.2%), parental reassurance (31.7%), and lactulose (17.0%). Conclusion: The HCPs in the eight countries preferred the absence of GI symptoms, normal growth for effective digestion and absorption, and general well-being as the gut health indicators in infants and toddlers. The reported prevalence of FC in infants was less than 5%.

Management and monitoring of pediatric inflammatory bowel disease in the Asia-Pacific region: A position paper by the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition (APPSPGHAN) PIBD Working Group: Surgical management, disease monitoring, and special considerations.

Disease phenotype of pediatric inflammatory bowel disease (PIBD) in children from the Asia-Pacific region differs from that of children from the West. Many parts of Asia are endemic for tuberculosis, making diagnosis and management of pediatric Crohn's disease a challenge. Current available guidelines, mainly from Europe and North America, may not be completely applicable to clinicians caring for children with PIBD in Asia due to differences in disease characteristics and regional resource constraints. This position paper is an initiative from the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology and Nutrition (APPSPGHAN) that aims to provide an up-to-date, evidence-based approach to PIBD in the Asia-Pacific region. A group of pediatric gastroenterologists with a special interest in PIBD performed an extensive literature search covering epidemiology, disease characteristics and natural history, management, and monitoring. Attention was paid to publications from the region with special consideration to a resource-limited setting. This current position paper deals with surgical management, disease monitoring, immunization, bone health, and nutritional issues of PIBD in Asia. A special section on differentiating pediatric Crohn's disease from tuberculosis in children is included. This position paper provides a useful guide to clinicians in the surgical management, disease monitoring, and various health issues in children with IBD in Asia-Pacific region.

Medical Management of Pediatric Inflammatory Bowel Disease (PIBD) in the Asia Pacific Region: A Position Paper by the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition (APPSPGHAN) PIBD Working Group.

Pediatric inflammatory bowel disease (PIBD) is rising rapidly in many industrialised and affluent areas in the Asia Pacific region. Current available guidelines, mainly from Europe and North America, may not be completely applicable to clinicians caring for children with PIBD in this region due to differences in disease characteristics and regional resources constraints. This position paper is an initiative from the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology and Nutrition (APPSPGHAN) with the aim of providing an up-to-date, evidence-based approach to PIBD in the Asia Pacific region, taking into consideration the unique disease characteristics and financial resources available in this region. A group of pediatric gastroenterologists with special interest in PIBD performed an extensive literature search covering epidemiology, disease characteristics and natural history, management and monitoring. Gastrointestinal infections, including tuberculosis, need to be excluded before diagnosing IBD. In some populations in Asia, the Nudix Hydrolase 15 (NUD15) gene is a better predictor of leukopenia induced by azathioprine than thiopurine-S-methyltransferase (TPMT). The main considerations in the use of biologics in the Asia Pacific region are high cost, ease of access, and potential infectious risk, especially tuberculosis. Conclusion: This position paper provides a useful guide to clinicians in the medical management of children with PIBD in the Asia Pacific region.

Reported Prevalence and Nutritional Management of Functional Constipation among Young Children from Healthcare Professionals in Eight Countries across Asia, Europe and Latin America.

Background: The prevalence of functional constipation (FC) among children varies widely. A survey among healthcare professionals (HCPs) was conducted to better understand the HCP-reported prevalence and (nutritional) management of FC in children 12−36 months old. Methods: An anonymous e-survey using SurveyMonkey was disseminated via emails or WhatsApp among HCPs in eight countries/regions. Results: Data from 2199 respondents were analyzed. The majority of the respondents (65.9%) were from Russia, followed by other countries (Indonesia (11.0%), Malaysia (6.0%)), Mexico, KSA (5.1% (5.7%), Turkey (3.0%), Hong Kong (2.2%), Singapore (1.1%)). In total, 80% of the respondents (n = 1759) were pediatricians. The prevalence of FC in toddlers was reported at less than 5% by 43% of the respondents. Overall, 40% of the respondents reported using ROME IV criteria in > 70% of the cases to diagnose FC, while 11% never uses Rome IV. History of painful defecation and defecations < 2 x/week are the two most important criteria for diagnosing FC. In total, 33% of the respondents reported changing the standard formula to a specific nutritional solution, accompanied by parental reassurance. Conclusion: The most reported prevalence of FC in toddlers in this survey was less than five percent. ROME IV criteria are frequently used for establishing the diagnosis. Nutritional management is preferred over pharmacological treatment in managing FC.

Prevalence, risk factors and parental perceptions of gastroesophageal reflux disease in Asian infants in Singapore.

INTRODUCTION: Infant gastroesophageal reflux disease (GERD) is a significant cause of concern to parents. This study seeks to describe GERD prevalence in infants, evaluate possible risk factors and assess common beliefs influencing management of GERD among Asian parents. METHODS: Mother-infant dyads in the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO) cohort were prospectively followed from preconception to 12 months post-delivery. GERD diagnosis was ascertained through the revised Infant Gastroesophageal Reflux Questionnaire (I-GERQ-R) administered at 4 time points during infancy. Data on parental perceptions and lifestyle modifications were also collected. RESULTS: The prevalence of infant GERD peaked at 26.5% at age 6 weeks, decreasing to 1.1% by 12 months. Infants exclusively breastfed at 3 weeks of life had reduced odds of GERD by 1 year (adjusted odds ratio 0.43, 95% confidence interval 0.19-0.97, P=0.04). Elimination of "cold or heaty food" and "gas producing" vegetables, massaging the infant's abdomen and application of medicated oil to the infant's abdomen were quoted as major lifestyle modifications in response to GERD symptoms. CONCLUSION: Prevalence of GERD in infants is highest in the first 3 months of life, and the majority outgrow it by 1 year of age. Infants exclusively breastfed at 3 weeks had reduced odds of GERD. Cultural-based changes such as elimination of "heaty or cold" food influence parental perceptions in GERD, which are unique to the Asian population. Understanding the cultural basis for parental perceptions and health-seeking behaviours is crucial in tailoring patient education appropriately for optimal management of infant GERD.

The Associations Between Preoperative Anthropometry and Postoperative Outcomes in Infants Undergoing Congenital Heart Surgery.

Aim: We explored the association between preoperative anthropometry and biochemistry, and postoperative outcomes in infants with CHD after cardiac surgery, as infants with congenital heart disease (CHD) often have feeding difficulties and malnutrition. Methodology: This was a retrospective review of infants (≤ 1-year-old) who underwent congenital heart surgery. Preoperative anthropometryin terms of preoperative weight-for-age z-score (WAZ), length-for-age z-score (LAZ), as well as preoperative serum albumin and hemoglobin concentrations, were evaluated against 6-month mortality, and morbidity outcomes including postoperative complications, vasoactive inotrope score, duration of mechanical ventilation, length of stay in the pediatric intensive care unit and in hospital, using the logistic regression or median regression models accounting for infant-level clustering. Results: One hundred and ninety-nine operations were performed in 167 infants. Mean gestational age at birth was 38.0 (SD 2.2) weeks (range 26 to 41 weeks). Thirty (18.0%) infants were born preterm (<37 weeks). The commonest acyanotic and cyanotic lesions were ventricular septal defect (26.3%, 44/167), and tetralogy of Fallot (13.8%, 23/167), respectively. Mean age at cardiac surgery was 94 (SD 95) days. Feeding difficulties, including increased work of breathing during feeding, diaphoresis, choking or coughing during feeding, and inability to complete feeds, was present in 54.3% (108/199) of infants prior to surgery, of which 21.6% (43/199) required tube feeding. The mean preoperative WAZ was-1.31 (SD 1.79). Logistic regression models showed that low preoperative WAZ was associated with increased risk of postoperative complications (odds ratio 1.82; p = 0.02), and 6-month mortality (odds ratio 2.38; p = 0.008) following CHD surgery. There was no meaningful association between the other preoperative variables and other outcomes. Conclusion: More than 50% of infants with CHD undergoing cardiac surgery within the first year of life have feeding difficulties, of which 22% require to be tube-fed. Low preoperative WAZ is associated with increased postoperative complications and 6-month mortality.

Feeding difficulties in Asian children with autism spectrum disorder.

BACKGROUND: To characterize the nature and severity of feeding difficulties in Asian young children with Autism Spectrum Disorders (ASD) and identify potential predictors of poorer feeding outcomes. METHODS: Cross sectional study of children aged 1-7 years with ASD. Parents completed the following: demographic information, brief autism mealtime behavior inventory, aberrant behavior checklist (ABC), behavioral pediatrics feeding assessment scale (BPFAS) and caregiver feeding style questionnaire. Additional information (medical data, cognitive and developmental assessment results, e.g., Autism Diagnostic Observation Schedule Second Edition, Autism Diagnostic Interview, Revised, Vineland Adaptive Behaviour Scales, etc.) were subsequently obtained from electronic medical records retrospectively by one of the study team members. RESULTS: Of the 67 children, 28.4% had feeding difficulties (high BPFAS total frequency score). Caregiver feeding styles were authoritarian (34.8%) or indulgent (39.4%). Child characteristics did not significantly predict for the severity of feeding difficulties. Univariate analysis revealed that authoritarian feeding style (p = 0.001) and ABC hyperactivity score (p = 0.006) were significantly associated with BPFAS severity score. Multivariate analysis revealed that ABC hyperactivity score remained significantly associated with BPFAS severity score after controlling for all other ABC subscale scores. A final regression model including all child characteristics and ABC scores did not reveal any significant predictors of BPFAS total frequency score (R2 = 0.557). CONCLUSION: Our findings suggest an association between hyperactivity, authoritarian feeding style and feeding difficulties. Children with ASD who have significant hyperactivity behaviors in the context of parents with an authoritarian feeding style should be actively screened for problematic feeding behaviors.

Effect of Oral Nutritional Supplementation on Growth in Children with Undernutrition: A Systematic Review and Meta-Analysis.

Oral nutritional supplements (ONS) are used to promote catch-up growth in children with undernutrition. We conducted a systematic review and meta-analysis to summarize the evidence of ONS intervention effects on growth for 9-month- to 12-year-old children who were undernourished or at nutritional risk. Eleven randomized controlled trials met the inclusion criteria; trials compared changes in anthropometric measures in children using ONS or ONS + DC (dietary counselling) to measures for those following usual diet or placebo or DC alone. The RCTs included 2287 children without chronic diseases (mean age 5.87 years [SD, 1.35]; 56% boys). At follow-up time points up to 6 months, results showed that children in the ONS intervention group had greater gains in weight (0.423 kg, [95% confidence interval 0.234, 0.613], p < 0.001) and height (0.417 cm [0.059, 0.776], p = 0.022) versus control; greater gains in weight (0.089 kg [0.049, 0.130], p < 0.001) were evident as early as 7-10 days. Longitudinal analyses with repeated measures at 30, 60, and 90 days showed greater gains in weight parameters from 30 days onwards (p < 0.001), a trend towards greater height gains at 90 days (p = 0.056), and significantly greater gains in height-for-age percentiles and Z-scores at 30 and 90 days, respectively (p < 0.05). Similar results were found in subgroup analyses of studies comparing ONS + DC to DC alone. For children with undernutrition, particularly those who were mildly and moderately undernourished, usage of ONS in a nutritional intervention resulted in significantly better growth outcomes when compared to control treatments (usual diet, placebo or DC alone).

A Narrative Review on the Update in the Prevalence of Infantile Colic, Regurgitation, and Constipation in Young Children: Implications of the ROME IV Criteria.

Regurgitation, colic, and constipation are frequently reported Functional Gastrointestinal Disorders (FGIDs) in the first few years of life. In 2016, the diagnostic criteria for FGIDs were changed from ROME III to ROME IV. This review assesses the prevalence of the most frequent FGIDs (colic, regurgitation and constipation) among children aged 0-5 years after the introduction of the later criteria. Articles published from January 1, 2016 to May 1, 2021 were retrieved from PubMed and Google Scholar using relevant keywords. A total of 12 articles were further analyzed based on the inclusion and exclusion criteria. This review consists of two studies (17%) from the Middle East, three (25%) from Asia, two (17%) from the USA, three (25%) from Europe, and one (8%) from Africa. Three studies (25%) were based on data obtained from healthcare professionals, while the rest were parent or caregiver reports. About half of the retrieved studies used the ROME IV criteria. Among infants aged 0-6 months, the reported prevalence of colic ranged between 10-15%, whilst that of regurgitation was 33.9%, and constipation was 1.5%. Among infants aged 0-12 months, the reported prevalence of regurgitation and constipation were 3.4-25.9% and 1.3-17.7%, respectively. The reported prevalence of constipation was 1.3-26% among children aged 13-48 months and 13% among children aged 4-18 years. Despite the large variations due to differences in diagnostic criteria, study respondents and age group, the prevalence of infantile colic was higher, while that for infantile regurgitation and constipation were similar using the ROME IV or III criteria.

Long-term outcome after liver transplantation in children with type 1 glycogen storage disease.

Patients with GSD type 1 (von Gierke disease) are initially managed medically to maintain normoglycemia. However, if they do not achieve good metabolic control, LT is then considered. We describe the long-term outcome of 6 children with GSD type 1 who underwent LT. Retrospective chart review of the data of 6 children with GSD type 1 who underwent LT at National University Hospital, Singapore, from May 1998 to October 2018, was performed. The median (IQR) age at diagnosis of the GSD was 1 year (0.92-5.50) and at transplant was 13.88 years (11.46-16.38). All of the patients had elevated liver enzymes, hypercholesterolemia, hypertriglyceridemia, and hyperlactatemia prior to transplant. All of the patients are alive at the time of analysis and follow-up. None of them required a re-transplant. For the three patients who had hypoglycemia pretransplant, there was no recurrence post-transplant. All of the patients had normalization of liver enzymes by 1 year post-transplant. Long-term outcome of patients with GSD who underwent LT has been positive with improvement in metabolic control for most patients. We report the unusual finding of two siblings with persistent hyperuricemia post-transplant requiring allopurinol.

Pediatric Inflammatory Bowel Disease in Asia: Epidemiology and natural history.

Pediatric inflammatory bowel disease (PIBD) in Asia, once considered a rare entity, has seen a sharp increase in incidence over the preceding decade. However, there is a paucity of epidemiological data on PIBD in Asia, and the true disease burden is difficult to estimate due to the lack of national disease registries, prospective databases and the fact that much of existing published data are limited to single-center experiences. This sets the stage for examining recent published data on epidemiological trends and its natural history. Hence, we reviewed the relevant published literature on PIBD in order to summarize the epidemiological data in the Asian populations and compare it with the data available from the other population including Western population. Our review demonstrates that the rapid surge in PIBD incidence across Asian centers lies in contrast to the plateauing albeit high incidence rates in larger established Western cohorts. Important epidemiological trends observed across emerging Asian literature are the higher rates of perianal involvement at disease onset amongst pediatric Crohn's disease (CD) patients, a higher proportion of early-onset disease and the over-representation of the Indian ethnicity in multi-ethnic cohorts. A number of issues currently limit a robust comparison and hence the way forward would be to advocate the recognition of PIBD as an increasingly important public health problem with the need to establish robust disease registries.

Response and Lessons Learnt Managing the COVID-19 Crisis by School of Medicine, National University of Singapore.

This article was migrated. The article was marked as recommended. Background: Healthcare professionals are playing an important role in the recent COVID-19 outbreak. It is crucial that the health systems maintain their ability to train students and residents during this time. However, there is a paucity of literature on the measures taken by higher education institutions to ensure academic continuity. The aim of this article is to share the systematic measures that were taken during the COVID-19 pandemic by Yong Loo Lin School of Medicine, National University of Singapore. Methods: We discussed our multi-faceted approach to protect students, staff and patients/ standardized patients during the COVID-19 outbreak that occurred during a pivotal time in the school's academic calendar. Results: Our approach to ensuring academic continuity and quality were based on best practices in the following areas: 1) A coordinated leadership and management process 2) Prioritising safety for all stakeholders 3) Dissemination of information amongst the stakeholders in a transparent and efficient way, and 4) Maintaining the rigour and quality of training. Conclusion: The initiatives were implemented as we leveraged on the available infrastructure and the collective team efforts of all involved. Further research will be done to evaluate the usefulness of these measures. We hope that this article would be a useful reference for other schools as they evaluate their pandemic preparedness in the event that the COVID-19 outbreak affects their country or similar crisis event in the future.

Cost-effectiveness analysis of antiviral treatment for pregnant women with high viral load to prevent hepatitis B virus vertical transmission.

INTRODUCTION: Vertical transmission of the hepatitis B virus (HBV) is higher in infants born to pregnant women with a higher HBV DNA viral load even if the infants complete both active and passive vaccination. Although antiviral treatment is recommended for pregnant women during the antenatal period to reduce the rate of vertical transmission, most of them decline treatment. METHODS: A decision tree was made to evaluate the costs and benefits involved when pregnant women either agreed or declined to take antiviral treatment during the antenatal period. The cost-effectiveness price was arrived at by multiplying the reduced vertical transmission rate with expenses of future medical care associated with vertical transmission. RESULTS: From an individual mother's perspective, it was not cost-effective to receive antenatal antiviral treatment given the observed medication price and transmission rate in Singapore. However, the health system asserts that the current price of antiviral treatment is already far below the cost-effectiveness level, even without the Ministry of Health subsidies. Additionally, the awareness and perception of pregnant women also impacted treatment decisions. CONCLUSION: By analysing the decision-making process, our result explained the current low uptake rates of antenatal antiviral treatment for HBV among pregnant women. We also concluded that from the health system's perspective, it was worth providing subsidies for perinatal antiviral treatment to prevent huge expenses generated in the future by chronic HBV complications.

Health-related quality of life, clinical outcomes, and subjective experiences of parent donors of pediatric liver transplant recipients.

PURPOSE: The understanding of the HRQOL issues for parent donors of children who underwent LDLT is lacking. We evaluated the HRQOL of donor and non-donor parents, described their subjective experiences and identified factors associated with lower HRQOL post-donation. METHODS: This is a cross-sectional study of parent donors whose children underwent LDLT, using SF-36v2 Health Survey to measure HRQOL, and a self-developed questionnaire to evaluate their subjective experiences. RESULTS: Of 32 pairs of donor and non-donor parents, 27 donor and 19 non-donor parents responded. The data of respondents were analyzed. Both donor and non-donor parents' SF-36v2 norm-based scores were average or above average as compared to the Singapore population. Donors who made lifestyle changes post-donation (adopting a healthy balanced diet, regular physical activity, quitting smoking, and moderate alcohol intake) were associated with lower GH (P = 0.009) and PF (P = 0.002) scores. Donors who took more than 3 months for full recovery had lower RP (P = 0.022) and BP scores (P = 0.038). On multivariate analysis, recipient complication of Clavien grade 3 or 4 was associated with increased RP score by 8.71 points (95% CI: 1.74-15.68), after adjusting for time taken for full recovery. Majority (88.8%) had self-reported recovery time under 6 months and returned to work within 3 months (74.0%). CONCLUSIONS: Donors with factors potentially associated with lower HRQOL may need more support to ensure better HRQOL outcomes post-donation.

De novo aortopathy and cardiovascular outcomes in paediatric liver transplant recipients.

With the increase in long-term survival of post-transplant children, there is a paradigm shift in the emphasis of post-transplant care. We describe de novo cardiovascular abnormalities, which occurred in otherwise asymptomatic paediatric liver transplant recipients, who received liver allografts between 1991 and 2014 at the National University Hospital, Singapore, detected during routine post-transplant monitoring. A total of 96 paediatric liver transplants were performed in 90 children. After transplant, 7/90 (7.8%) recipients were identified with new-onset aortopathy. Glycogen storage disease type I (42.9% versus 2.4%; p<0.001) and recipient Epstein-Barr virus seropositivity (85.7 versus 31.0%, p=0.004) were significant risk factors for aortopathy on univariate analysis. On multivariate analysis, only glycogen storage disease type I remained as the significant risk factor (odds ratio 51.3 [95% confidence intervals: 1.1-2498.1, p=0.047]). Liver transplant is a double-edged sword that reverses certain cardiopulmonary complications of end-stage liver disease but may induce de novo structural cardiac injury in the form of aortic dilation.

Rapid rise in the incidence and clinical characteristics of pediatric inflammatory bowel disease in a South-East Asian cohort in Singapore, 1994-2015.

OBJECTIVES: Epidemiological studies on pediatric-onset inflammatory bowel disease (PIBD) are scarce in South-East Asia (SEA). This study aimed to evaluate the incidence trend and clinical characteristics of PIBD in a SEA cohort in Singapore over 22 years (1994-2015). METHODS: Case records of PIBD ≤18 years from the only two tertiary pediatric hospitals in Singapore were reviewed. The mean annual incidence (MAI) of PIBD was calculated based on Singapore's age-specific population data. RESULTS: Overall MAI of PIBD was 1.26 per 100 000 (95% confidence interval [CI] 0.56-1.96). During the first decade (1994-2004) MAI was 0.23 per 100 000 (95% CI 0.08-0.39); this rose almost 10-fold to 2.28 per 100 000 (95% CI 1.15-3.41) during the second decade (2005-2015). Linear regression analysis showed significant increase in MAI over the 22-year period (r = 0.826, P < 0001). Of the 228 patients, 61.0% had Crohn's disease (CD), 30.3% ulcerative colitis and 8.7% IBD-unclassified, with a mdian age at diagnosis of 10.47 years and a male predominance (58.3%); 37.7% of them aged <10 years at diagnosis and 17.5% were very early-onset IBD. In CD, 27.3% had stricturing and/or penetrating disease and 21.6% were with perianal disease. Indians had a disproportionately high representation while positive family history was rare (1.3%). CONCLUSIONS: Although PIBD is uncommon in Singapore, its incidence has risen dramatically over recent decades. A younger age of disease onset and higher proportions of perianal and stricturing/penetrating diseases suggest more aggressive disease than in Western data.