Publications by authors named "Yiong Huak Chan"

372 Publications

Integrative epigenomic and high-throughput functional enhancer profiling reveals determinants of enhancer heterogeneity in gastric cancer.

Genome Med 2021 Oct 11;13(1):158. Epub 2021 Oct 11.

Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, 169857, Singapore.

Background: Enhancers are distal cis-regulatory elements required for cell-specific gene expression and cell fate determination. In cancer, enhancer variation has been proposed as a major cause of inter-patient heterogeneity-however, most predicted enhancer regions remain to be functionally tested.

Methods: We analyzed 132 epigenomic histone modification profiles of 18 primary gastric cancer (GC) samples, 18 normal gastric tissues, and 28 GC cell lines using Nano-ChIP-seq technology. We applied Capture-based Self-Transcribing Active Regulatory Region sequencing (CapSTARR-seq) to assess functional enhancer activity. An Activity-by-contact (ABC) model was employed to explore the effects of histone acetylation and CapSTARR-seq levels on enhancer-promoter interactions.

Results: We report a comprehensive catalog of 75,730 recurrent predicted enhancers, the majority of which are GC-associated in vivo (> 50,000) and associated with lower somatic mutation rates inferred by whole-genome sequencing. Applying CapSTARR-seq to the enhancer catalog, we observed significant correlations between CapSTARR-seq functional activity and H3K27ac/H3K4me1 levels. Super-enhancer regions exhibited increased CapSTARR-seq signals compared to regular enhancers, even when decoupled from native chromatin contexture. We show that combining histone modification and CapSTARR-seq functional enhancer data improves the prediction of enhancer-promoter interactions and pinpointing of germline single nucleotide polymorphisms (SNPs), somatic copy number alterations (SCNAs), and trans-acting TFs involved in GC expression. We identified cancer-relevant genes (ING1, ARL4C) whose expression between patients is influenced by enhancer differences in genomic copy number and germline SNPs, and HNF4α as a master trans-acting factor associated with GC enhancer heterogeneity.

Conclusions: Our results indicate that combining histone modification and functional assay data may provide a more accurate metric to assess enhancer activity than either platform individually, providing insights into the relative contribution of genetic (cis) and regulatory (trans) mechanisms to GC enhancer functional heterogeneity.
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http://dx.doi.org/10.1186/s13073-021-00970-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504099PMC
October 2021

Lifestyle and Symptom Management Needs: A Network Analysis of Family Caregiver Needs of Cancer Patients.

Front Psychiatry 2021 20;12:739776. Epub 2021 Sep 20.

Department of Psychological Medicine, National University Hospital, Singapore, Singapore.

Previous research on the needs of family cancer caregivers (FCCs) have not elucidated associations between specific caregiving needs. Network analysis, a statistical approach that allows the estimation of complex relationship patterns, helps facilitate the understanding of associations between needs and provides the opportunity to identify and direct interventions at relevant and specific targets. No studies to date, have applied network analysis to FCC populations. The aim of the study is to explore the network structure of FCC needs in a cohort of caregivers in Singapore. FCCs ( = 363) were recruited and completed a self-report questionnaire on socio-demographic data, medical data on their loved ones, and the Needs Assessment of Family Caregivers-Cancer scale. The network was estimated using state-of-the-art regularized partial correlation model. The most central needs were having to deal with lifestyle changes and managing care-recipients cancer-related symptoms. The strongest associations were between (1) having enough insurance coverage and understanding/navigating insurance coverage, (2) managing cancer-related pain and managing cancer-related symptoms, (3) being satisfied with relationships and having intimate relationships, and (4) taking care of bills and paying off medical expenses. Lifestyle changes, living with cancer, and symptom management are central to FCCs in Singapore. These areas deserve special attention in the development of caregiver support systems. Our findings highlight the need to improve access to social and medical support to help FCCs in their transition into the caregiving role and handle cancer-related problems.
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http://dx.doi.org/10.3389/fpsyt.2021.739776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488172PMC
September 2021

Mental Resilience of Medical Practitioners in Singapore during COVID-19: Survey Results from a Webinar Course on Resilience.

Int J Environ Res Public Health 2021 09 17;18(18). Epub 2021 Sep 17.

Yong Loo Lin School of Medicine, National University of Singapore, 1E, Kent Ridge Rd, NUHS Tower Block, Level 11, Singapore 119228, Singapore.

Front-line doctors are at high risk of exposure to COVID-19. The mental resilience of general practitioners and their areas of concerns and support required are important during this COVID-19 period. A total of 403 general practitioners attending a webinar on resiliency, hosted by the College of Family Physicians, Singapore, participated in the survey anonymously. Participants provided responses to questions relating to COVID-19 in the domains of , , , and . Responses are categorized into LEARNING, FEAR, and GROWTH zones. The majority of the doctors reported to be in the GROWTH zone in relation to (39%) and (38%) as compared to and , OR = 4.5 (95% CI 3.4 to 5.9), < 0.001. 34% of the participants reported being in the FEAR zone in relation to , OR = 8.0 (95% CI = 5.6 to 11.2), < 0.001; at least 81% reported being in the LEARNING zone in relation to and , OR = 7.5 (95% CI = 5.8 to 9.6), < 0.001, compared to other domains. Supporting and protecting the doctors is important in strategic planning and management of the current pandemic and building preparedness and an effective response towards future crises.
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http://dx.doi.org/10.3390/ijerph18189801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471345PMC
September 2021

Is it time to revisit the PaO/FiO ratio to define the severity of oxygenation in ARDS?

Ann Intensive Care 2021 Sep 22;11(1):138. Epub 2021 Sep 22.

FAST and Chronic Programmes, Alexandra Hospital, National University Health System, Singapore, Singapore.

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http://dx.doi.org/10.1186/s13613-021-00927-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456403PMC
September 2021

Feeding difficulties in Asian children with autism spectrum disorder.

Pediatr Neonatol 2021 Aug 28. Epub 2021 Aug 28.

Child Development Unit, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

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.
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http://dx.doi.org/10.1016/j.pedneo.2021.06.015DOI Listing
August 2021

Antipruritic Effect of Topical Acetaminophen Gel in Histaminergic and Non-histaminergic Itch Provocation: A Double-blind, Vehicle-controlled Pilot Study.

Acta Derm Venereol 2021 Aug 26. Epub 2021 Aug 26.

Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 33136 Miami, FL, USA. E-mail:

There is a need for new topical antipruritics that are effective on many types of itch. This study examined the antipruritic efficacy of a new formulation of topical acetaminophen. In vitro skin permeability studies showed that 2.5% and 5% formulations are able to rapidly deliver an adequate amount of the drug into the skin. In a double-blind, vehicle-controlled, randomized study in 17 healthy volunteers, 1%, 2.5% and 5% acetaminophen gels and a vehicle gel were applied to the skin prior to histaminergic and non-histaminergic itch induction and assessment of thermal pain thresholds. The 2.5% and 5% gel formulations significantly reduced the itch intensity time course and the area under the curve for both histamine and cowhage itch. No effect was noted on heat pain thresholds and no adverse effects were observed. These results suggest that topical acetaminophen would be a safe and effective over-the-counter medication for itch.
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http://dx.doi.org/10.2340/00015555-3910DOI Listing
August 2021

Cancer caregivers unmet needs and emotional states across cancer treatment phases.

PLoS One 2021 11;16(8):e0255901. Epub 2021 Aug 11.

National University of Singapore, Singapore, Singapore.

Study Objective: To investigate the association between family cancer caregivers' unmet daily needs and emotional states of depression, anxiety and stress across their care recipient's treatment phases.

Method: A cross-sectional study design and self-report questionnaires were used. Family caregivers (N = 237) of cancer patients in ambulatory cancer clinics were recruited from May to December 2017, and completed a sociodemographic and medical questionnaire, the Depression Anxiety Stress Scale and Needs Assessment of Family Caregivers-Cancer Scale. Hierarchical linear regression was conducted to examine the influence of each predictor (sociodemographic variables, unmet personal care and role management needs, cancer treatment phase) on the Depression Anxiety Stress Scale total score, depression subscale, anxiety subscale, and the stress subscale.

Results: Family caregivers' unmet daily activity needs, in particular higher unmet personal care needs, during the intermediate phase (6-9 months), were significantly associated (ps<0.05) with overall distress (b = 4.93) and stress (b = 2.26). In the chronic treatment phase (>9 months), the significant association of unmet personal care needs was with overall distress (b = 5.91), anxiety (b = 1.97) and stress (b = 2.53). After completing treatment, unmet role management needs were only significantly associated with stress (b = -1.59). Caregivers' higher depression was also associated with greater unmet role management needs, regardless of treatment phases.

Conclusions: Intermediate and chronic cancer treatment phases were identified as having greatest effect on caregivers' unmet daily activity needs and emotions. Unmet personal care needs played the major effect on overall negative emotional states in the intermediate treatment phase and stress in the chronic treatment phase. Close attention to caregivers needs in intermediate and chronic treatment phases, would be highly beneficial in alleviating negative emotional disturbances.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255901PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357113PMC
August 2021

P/FP ratio: incorporation of PEEP into the PaO/FiO ratio for prognostication and classification of acute respiratory distress syndrome.

Ann Intensive Care 2021 Aug 9;11(1):124. Epub 2021 Aug 9.

FAST and Chronic Programmes, Alexandra Hospital, National University Health System, Singapore, Singapore.

Background: The current Berlin definition of acute respiratory distress syndrome (ARDS) uses the PaO/FiO (P/F) ratio to classify severity. However, for the same P/F ratio, a patient on a higher positive end-expiratory pressure (PEEP) may have more severe lung injury than one on a lower PEEP.

Objectives: We designed a new formula, the P/FP ratio, incorporating PEEP into the P/F ratio and multiplying with a correction factor of 10 [(PaO*10)/(FiO*PEEP)], to evaluate if it better predicts hospital mortality compared to the P/F ratio post-intubation and to assess the resultant changes in severity classification of ARDS.

Methods: We categorized patients from a dataset of seven ARDS network trials using the thresholds of ≤ 100 (severe), 101-200 (moderate), and 201-300 (mild) for both P/F (mmHg) and P/FP (mmHg/cmHO) ratios and evaluated hospital mortality using areas under the receiver operating characteristic curves (AUC).

Results: Out of 3,442 patients, 1,057 (30.7%) died. The AUC for mortality was higher for the P/FP ratio than the P/F ratio for PEEP levels > 5 cmHO: 0.710 (95% CI 0.691-0.730) versus 0.659 (95% CI 0.637-0.681), P < 0.001. Improved AUC was seen with increasing PEEP levels; for PEEP ≥ 18 cmHO: 0.963 (95% CI 0.947-0.978) versus 0.828 (95% CI 0.765-0.891), P < 0.001. When the P/FP ratio was used instead of the P/F ratio, 12.5% and 15% of patients with moderate and mild ARDS, respectively, were moved to more severe categories, while 13.9% and 33.6% of patients with severe and moderate ARDS, respectively, were moved to milder categories. The median PEEP and FiO were 14 cmHO and 0.70 for patients reclassified to severe ARDS, and 5 cmHO and 0.40 for patients reclassified to mild ARDS.

Conclusions: The multifactorial P/FP ratio has a greater predictive validity for hospital mortality in ARDS than the P/F ratio. Changes in severity classification with the P/FP ratio reflect both true illness severity and the applied PEEP strategy.

Trial Registration: ClinialTrials.gov-NCT03946150.
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http://dx.doi.org/10.1186/s13613-021-00908-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350287PMC
August 2021

Psychometric properties of the thyroid-specific quality of life questionnaire ThyPRO in Singaporean patients with Graves' disease.

J Patient Rep Outcomes 2021 Jul 8;5(1):54. Epub 2021 Jul 8.

Department of Diabetes and Endocrinology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore.

Background: Graves' disease is the most common cause of hyperthyroidism. It results in accelerated tissue metabolism with multi-organ involvement ranging from cardiovascular to neuropsychological function. This results in a negative impact on the quality of life (QOL) of the individual patient. We aim to evaluate the psychometric properties of ThyPRO, a Thyroid-related Patient Reported Outcome questionnaire, and validate its use in our multi-ethnic Asian patients with Graves' hyperthyroidism.

Methods: Forty-seven consecutive Graves' hyperthyroidism patients answered the ThyPRO questionnaire at baseline and at 4 months after treatment initiation. Data were recorded for thyroid related symptoms and signs, thyroid function tests and thyroid volume. We analyzed the internal consistency using Cronbach's alpha, construct validity by evaluating relationship between clinical variables and ThyPRO scales, ceiling and floor effects, and responsiveness of ThyPRO to treatment based on Cohen's effect size.

Results: Correlations between individual scale scores and free thyroxine concentrations were moderate and statistically significant: 0.21-0.64 (p <  0.05). There was high internal consistency between the items in this instrument, Cronbach's alpha > 0.7 for all scales. ThyPRO was responsive to the changes in QOL after treatment (Effect Size: 0.20-0.77) in 9 of the 14 scales including the hyperthyroid symptoms and psychosocial scales (Tiredness, Cognitive complaints, Anxiety, Emotional susceptibility, Impact on Social, Daily and Sex life).

Conclusion: This study provides evidence that ThyPRO has satisfactory measurement properties in hyperthyroid Graves' disease patients in Singapore population with the potential to complement clinical care.
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http://dx.doi.org/10.1186/s41687-021-00309-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266927PMC
July 2021

What is the potential for over-compression using current paediatric chest compression guidelines? - A chest computed tomography study.

Resusc Plus 2021 Jun 27;6:100112. Epub 2021 Mar 27.

Center for Simulation, Advanced Education and Innovation, Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, USA.

Aim: We explored the potential for over-compression from current paediatric chest compression depth guidelines using chest computed tomography(CT) images of a large, heterogenous, Asian population.

Methods: A retrospective review of consecutive children, less than 18-years old, with chest CT images performed between from 2005 to 2017 was done. Demographic data were extracted from the electronic medical records. Measurements for internal and external anterior-posterior diameters (APD) were taken at lower half of the sternum. Simulated chest compressions were performed to evaluate the proportion of the population with residual internal cavity dimensions less than 0 mm (RICD < 0 mm, representing definite over-compression; with chest compression depth exceeding internal APD), and RICD less than 10 mm (RICD < 10 mm, representing potential over-compression).

Results: 592 paediatric chest CT studies were included for the study. Simulated chest compressions of one-third external APD had the least potential for over-compression; no infants and 0.3% children had potential over-compression (RICD < 10 mm). 4 cm simulated chest compressions led to 18% (95% CI 13%-24%) of infants with potential over-compression, and this increased to 34% (95% CI 27%-41%) at 4.4 cm (upper limit of "approximately" 4 cm; 4 cm + 10%). 5 cm simulated compressions resulted in 8% (95% CI 4%-12%) of children 1 to 8-years-old with potential over-compression, and this increased to 22% (95% CI 16%-28%) at 5.5 cm (upper limit of "approximately" 5 cm, 5 cm + 10%).

Conclusion: In settings whereby chest compression depths can be accurately measured, compressions at the current recommended chest compression of approximately 4 cm (in infants) and 5 cm (in young children) could result in potential for over-compression.
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http://dx.doi.org/10.1016/j.resplu.2021.100112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244421PMC
June 2021

Effect of a Smartphone App on Weight Change and Metabolic Outcomes in Asian Adults With Type 2 Diabetes: A Randomized Clinical Trial.

JAMA Netw Open 2021 Jun 1;4(6):e2112417. Epub 2021 Jun 1.

Division of Endocrinology, National University Hospital, Singapore.

Importance: Lifestyle interventions are effective in diabetes management, with smartphone apps that manage health data and dietary and exercise schedules gaining popularity. However, limited evidence from randomized clinical trials exists regarding the effectiveness of smartphone-based interventions among Asian adults with type 2 diabetes.

Objective: To compare the effects of a culturally contextualized smartphone-based intervention with usual care on weight and metabolic outcomes.

Design, Setting, And Participants: This randomized clinical trial conducted at multiple primary care centers in Singapore included 305 adults with type 2 diabetes and body mass index (BMI) of 23 or greater who had literacy in English and smartphone access. Participants were recruited between October 3, 2017, and September 9, 2019, and were randomly assigned (1:1; stratified by gender, age, and BMI) to intervention (99 participants) or control (105 participants) groups. Participants' data were analyzed using intention-to-treat analysis.

Interventions: Both control and intervention participants received diet and physical activity advice from a dietitian at a baseline face-to-face visit. Intervention participants additionally used a smartphone app to track weight, diet, physical activity, and blood glucose and then communicated with dietitians for 6 months.

Main Outcomes And Measures: Primary outcome was change in body weight, while secondary outcomes were changes in hemoglobin A1c (HbA1c), fasting blood glucose, blood pressure, lipids, and diet. Post hoc analyses included glycemic changes in the subgroup with HbA1c levels of 8% or greater and diabetes medication changes.

Results: Among the 204 randomized participants (mean [SD] age, 51.2 [9.7] years; 132 [64.7%] men), baseline mean (SD) BMI was 30.6 (4.3). Compared with the control group, intervention participants achieved significantly greater reductions in weight (mean [SD] change, -3.6 [4.7] kg vs -1.2 [3.6] kg) and HbA1c levels (mean [SD] change, -0.7% [1.2] vs -0.3% [1.0]), with a greater proportion having a reduction in diabetes medications (17 participants [23.3%] vs 4 participants [5.4%]) at 6 months. The intervention led to a greater HbA1c reduction among participants with HbA1c levels of 8% or higher (mean [SD] change, -1.8% [1.4] vs -1.0% [1.4]; P = .001). Intergroup differences favoring the intervention were also noted for fasting blood glucose, diastolic blood pressure, and dietary changes.

Conclusions And Relevance: In this study, a smartphone-based lifestyle intervention was more effective in achieving weight and glycemic reductions among Asian adults with type 2 diabetes compared with usual care, supporting the use of apps in lifestyle intervention delivery.

Trial Registration: anzctr.org.au Identifier: ACTRN12617001112358.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.12417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176331PMC
June 2021

Defining negative symptoms remission in schizophrenia using the Brief Negative Symptom Scale.

Rev Psiquiatr Salud Ment (Engl Ed) 2021 May 29. Epub 2021 May 29.

Research Division, Institute of Mental Health, Singapore, Singapore; North Region & Department of Psychosis, Institute of Mental Health, Singapore, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.

Introduction: This study aimed to propose criteria for negative symptoms remission (NSR) in schizophrenia using the Brief Negative Symptom Scale (BNSS).

Material And Methods: 274 participants were assessed on the Positive and Negative Syndrome Scale (PANSS), BNSS and Social and Occupational Functioning Assessment Scale (SOFAS). Two criteria for NSR on the BNSS were proposed - NSR based on the BNSS domains scores (NSR) and NSR based on 5 key items of the BNSS (NSR) A SOFAS score of 61 and above was considered as functional remission (FR). Logistic regressions were run to examine the association between FR and NSR. Receiver operating characteristic (ROC) curve analysis was performed for the NSR criteria on FR. Kappa agreement statistic was used to evaluate the agreement between the two NSR criteria.

Results: Eighty-nine (32.5%) participants fulfilled NSR criterion whereas 70 (25.6%) participants fulfilled NSR criterion. The two NSR criteria had substantial agreement (Kappa statistic=0.797) with each other. Sixty-one (25.3%) participants were in FR. FR was significantly associated with NSR, irrespective of the criterion used. To predict FR, the Area Under the Curve for NSR and NSR were 0.761 (CI: 0.696-0.826, p<0.001) and 0.723 (CI: 0.656-0.790, p<0.001), respectively. Hence, both NSR criteria demonstrated a fair ability to discriminate between functional remitters and non-remitters.

Conclusions: Depending on the setting and needs, clinicians and researchers might employ either the full BNSS or an abbreviated 5-item BNSS scale to identify NSR in schizophrenia. More research is needed to further examine the validity of these criteria in schizophrenia.
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http://dx.doi.org/10.1016/j.rpsm.2021.05.003DOI Listing
May 2021

Role of maternal tryptophan metabolism in allergic diseases in the offspring.

Clin Exp Allergy 2021 Oct 24;51(10):1346-1360. Epub 2021 Jun 24.

Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore City, Singapore.

Background: Nicotinamide (vitamin B3) is a metabolite of tryptophan and dietary precursor of enzymes involved in many regulatory processes, which may influence fetal immune development.

Objective: We examined whether maternal plasma concentrations of nicotinamide, tryptophan or nine related tryptophan metabolites during pregnancy were associated with the risk of development of infant eczema, wheeze, rhinitis or allergic sensitization.

Methods: In the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) study, we analysed the associations between maternal plasma levels of nicotinamide, tryptophan and tryptophan metabolites at 26-28 weeks of gestation and allergic outcomes collected through interviewer-administered questionnaires at multiple time-points and skin prick testing to egg, milk, peanut and mites at age 18 months. Multivariate analysis was undertaken adjusting for all metabolites measured and separately adjusting for relevant demographic and environmental exposures. Analyses were also adjusted for multiple comparisons using the false discovery method.

Results: Tryptophan metabolites were evaluated in 976/1247 (78%) women enrolled in GUSTO. In multivariate analysis including all metabolites, maternal plasma 3-hydrokynurenine was associated with increased allergic sensitization at 18 months (AdjRR 2.6, 95% CI 1.3-5.2 for highest quartile) but the association with nicotinamide was not significant (AdjRR 1.8, 95% CI 0.9-3.6). In analysis adjusting for other exposures, both 3-hydrokynurenine and nicotinamide were associated with increased allergic sensitization (AdjRR 2.0, 95% CI 1.1-3.6 for both metabolites). High maternal plasma nicotinamide was associated with increased infant eczema diagnosis by 6 and 12 months, which was not significant when adjusting for all metabolites measured, but was significant when adjusting for relevant environmental and demographic exposures. Other metabolites measured were not associated with allergic sensitization or eczema, and maternal tryptophan metabolites were not associated with offspring rhinitis and wheeze.

Conclusions And Clinical Relevance: Maternal tryptophan metabolism during pregnancy may influence the development of allergic sensitization and eczema in infants.
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http://dx.doi.org/10.1111/cea.13953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611755PMC
October 2021

Admission discipline and timing of admission may influence outcomes for gastrointestinal bleeding patients.

ANZ J Surg 2021 09 13;91(9):1832-1840. Epub 2021 May 13.

Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Background: Bleeding of the gastrointestinal tract (BGIT) is a common gastrointestinal emergency. There is no consensus whether this condition should be admitted to medical or surgical discipline. Timing of presentation may also impact patient outcomes due to differences in healthcare resource availability. This study thus aims to investigate the impact of admitting discipline and timing of admission on patient outcomes in BGIT.

Methods: A 2-year tertiary institution database was retrospectively reviewed. Outcome measures included 30-day mortality, 30-day readmissions and rebleeding requiring repeat endoscopic, angiographic or surgical interventions. Secondary outcome measures included time to endoscopy, percutaneous angiographic interventions and surgery. The effect of admission discipline (medical versus surgical) and time of admission (office-hours versus after office-hours) were analysed using a propensity-score-adjusted estimate.

Results: A total of 1384 patients were included for analysis, medical (n = 853), surgical (n = 530); during office-hours (n = 785) and after office-hours (n = 595). After propensity-score-adjusted analysis, no significant differences in mortality or readmissions were noted between medical or surgical admissions. Patients admitted under surgery were less likely to sustain rebleeding (P = 0.004) for lower BGIT and had an earlier time to endoscopy for upper BGIT (P = 0.04). Patients admitted after office-hours had similar outcomes with those admitted during office hours apart from a delay in time to endoscopy (P = 0.02).

Conclusion: For BGIT patients, admission to a surgical discipline compared to a medical discipline appeared to have at least equivalent patient outcomes. Patients presenting with BGIT after office-hours were more likely to experience a delay to endoscopy, although it did not affect patient mortality.
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http://dx.doi.org/10.1111/ans.16873DOI Listing
September 2021

Machine-learning model derived gene signature predictive of paclitaxel survival benefit in gastric cancer: results from the randomised phase III SAMIT trial.

Gut 2021 May 12. Epub 2021 May 12.

Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore

Objective: To date, there are no predictive biomarkers to guide selection of patients with gastric cancer (GC) who benefit from paclitaxel. Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) was a 2×2 factorial randomised phase III study in which patients with GC were randomised to Pac-S-1 (paclitaxel +S-1), Pac-UFT (paclitaxel +UFT), S-1 alone or UFT alone after curative surgery.

Design: The primary objective of this study was to identify a gene signature that predicts survival benefit from paclitaxel chemotherapy in GC patients. SAMIT GC samples were profiled using a customised 476 gene NanoString panel. A random forest machine-learning model was applied on the NanoString profiles to develop a gene signature. An independent cohort of metastatic patients with GC treated with paclitaxel and ramucirumab (Pac-Ram) served as an external validation cohort.

Results: From the SAMIT trial 499 samples were analysed in this study. From the Pac-S-1 training cohort, the random forest model generated a 19-gene signature assigning patients to two groups: Pac-Sensitive and Pac-Resistant. In the Pac-UFT validation cohort, Pac-Sensitive patients exhibited a significant improvement in disease free survival (DFS): 3-year DFS 66% vs 40% (HR 0.44, p=0.0029). There was no survival difference between Pac-Sensitive and Pac-Resistant in the UFT or S-1 alone arms, test of interaction p<0.001. In the external Pac-Ram validation cohort, the signature predicted benefit for Pac-Sensitive (median PFS 147 days vs 112 days, HR 0.48, p=0.022).

Conclusion: Using machine-learning techniques on one of the largest GC trials (SAMIT), we identify a gene signature representing the first predictive biomarker for paclitaxel benefit.

Trial Registration Number: UMIN Clinical Trials Registry: C000000082 (SAMIT); ClinicalTrials.gov identifier, 02628951 (South Korean trial).
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http://dx.doi.org/10.1136/gutjnl-2021-324060DOI Listing
May 2021

Deep Learning Model for Automated Detection and Classification of Central Canal, Lateral Recess, and Neural Foraminal Stenosis at Lumbar Spine MRI.

Radiology 2021 07 11;300(1):130-138. Epub 2021 May 11.

From the Department of Diagnostic Imaging, National University Hospital, 5 Lower Kent Ridge Rd, Singapore 119074 (J.T.P.D.H., A.M., Y.L.T., S.L., Y.S.C., S.E.E., S.T.Q.); Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (J.T.P.D.H., A.M., Y.L.T., S.L., Y.S.C., S.E.E., S.T.Q.); NUS Graduate School, Integrative Sciences and Engineering Programme, National University of Singapore, Singapore (L.Z.); Department of Computer Science, School of Computing, National University of Singapore, Singapore (K.Y., B.C.O.); Department of Radiology, Dammam Medical Complex, Dammam, Saudi Arabia (D.A.R.A.); Biostatistics Unit, Yong Loo Lin School of Medicine, Singapore (Q.V.Y., Y.H.C.); University Spine Centre, Department of Orthopaedic Surgery, National University Health System, Singapore (J.H.T., N.K.); and Department of Radiological Sciences, University of California, Irvine, Orange, Calif (H.Y.).

Background Assessment of lumbar spinal stenosis at MRI is repetitive and time consuming. Deep learning (DL) could improve -productivity and the consistency of reporting. Purpose To develop a DL model for automated detection and classification of lumbar central canal, lateral recess, and neural -foraminal stenosis. Materials and Methods In this retrospective study, lumbar spine MRI scans obtained from September 2015 to September 2018 were included. Studies of patients with spinal instrumentation or studies with suboptimal image quality, as well as postgadolinium studies and studies of patients with scoliosis, were excluded. Axial T2-weighted and sagittal T1-weighted images were used. Studies were split into an internal training set (80%), validation set (9%), and test set (11%). Training data were labeled by four radiologists using predefined gradings (normal, mild, moderate, and severe). A two-component DL model was developed. First, a convolutional neural network (CNN) was trained to detect the region of interest (ROI), with a second CNN for classification. An internal test set was labeled by a musculoskeletal radiologist with 31 years of experience (reference standard) and two subspecialist radiologists (radiologist 1: A.M., 5 years of experience; radiologist 2: J.T.P.D.H., 9 years of experience). DL model performance on an external test set was evaluated. Detection recall (in percentage), interrater agreement (Gwet κ), sensitivity, and specificity were calculated. Results Overall, 446 MRI lumbar spine studies were analyzed (446 patients; mean age ± standard deviation, 52 years ± 19; 240 women), with 396 patients in the training (80%) and validation (9%) sets and 50 (11%) in the internal test set. For internal testing, DL model and radiologist central canal recall were greater than 99%, with reduced neural foramina recall for the DL model (84.5%) and radiologist 1 (83.9%) compared with radiologist 2 (97.1%) ( < .001). For internal testing, dichotomous classification (normal or mild vs moderate or severe) showed almost-perfect agreement for both radiologists and the DL model, with respective κ values of 0.98, 0.98, and 0.96 for the central canal; 0.92, 0.95, and 0.92 for lateral recesses; and 0.94, 0.95, and 0.89 for neural foramina ( < .001). External testing with 100 MRI scans of lumbar spines showed almost perfect agreement for the DL model for dichotomous classification of all ROIs (κ, 0.95-0.96; < .001). Conclusion A deep learning model showed comparable agreement with subspecialist radiologists for detection and classification of central canal and lateral recess stenosis, with slightly lower agreement for neural foraminal stenosis at lumbar spine MRI. © RSNA, 2021 See also the editorial by Hayashi in this issue.
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http://dx.doi.org/10.1148/radiol.2021204289DOI Listing
July 2021

The association of maternal gestational hyperglycemia with breastfeeding duration and markers of milk production.

Am J Clin Nutr 2021 09;114(3):1219-1228

Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore.

Background: Previous studies focusing on the association between gestational diabetes and breastfeeding duration have been inconclusive.

Objectives: We aimed to determine whether maternal gestational hyperglycemia is associated with the duration of breastfeeding and the concentrations of markers linked to breastmilk production.

Methods: Data from the prospective, multiethnic Growing Up in Singapore Towards Healthy Outcomes study were used to assess the association of fasting plasma glucose (FPG) and 2-h postglucose challenge (2hPG) measured at 26-28 wk of gestation with duration of breastfeeding and concentrations of protein, lactose, citrate, sodium, potassium, and zinc in breastmilk 3 wk postpartum.

Results: Of the 1035 participants, 5.2% and 9.5% had elevated FPG and 2hPG, respectively, consistent with a diagnosis of gestational diabetes mellitus based on International Association of Diabetes and Pregnancy Study Groups criteria. FPG ≥5.1 mmol/L was associated with a crude reduction in median breastfeeding duration of 2.3 mo. In a model adjusted for maternal prepregnancy BMI and intention to breastfeed, FPG ≥5.1 mmol/L predicted earlier termination of any breastfeeding (adjusted HR: 1.47; 95% CI: 1.04, 2.08) but not full breastfeeding (adjusted HR: 1.08; 0.76, 1.55). 2hPG ≥8.5 mmol/L was not significantly associated with the durations of any (adjusted HR: 0.86; 95% CI: 0.62, 1.19) or full (adjusted HR: 0.85; 95% CI: 0.62, 1.18) breastfeeding. Maternal FPG was significantly and positively associated with breastmilk sodium (adjusted coefficient: 1.28; 95% CI: 1.08, 1.51) and sodium-to-potassium ratio (adjusted coefficient: 1.29; 95% CI: 1.08, 1.54) but not with other measured breastmilk components.

Conclusions: Women with FPG ≥5.1 mmol/L during pregnancy breastfeed for a shorter duration. Future work involving measurement of milk production is needed to determine whether low milk production predicts breastfeeding duration among women with elevated FPG. This trial was registered at www.clinicaltrials.gov as NCT01174875.
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http://dx.doi.org/10.1093/ajcn/nqab142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611668PMC
September 2021

Possible Sarcopenia and Impact of Dual-Task Exercise on Gait Speed, Handgrip Strength, Falls, and Perceived Health.

Front Med (Lausanne) 2021 16;8:660463. Epub 2021 Apr 16.

Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, MO, United States.

Sarcopenia is defined as a progressive age-related loss in muscle mass and strength affecting physical performance. It is associated with many negative outcomes including falls, disability, cognitive decline, and mortality. Protein enriched diet and resistance training have shown to improve muscle strength and function but there is limited evidence on impact of dual-task exercise in possible sarcopenia. To evaluate impact of community-based dual-task exercise on muscle strength and physical function in possible sarcopenia defined by either slow gait (SG) or poor handgrip strength (HGS). The secondary aims include effect on cognition, frailty, falls, social isolation, and perceived health. Community-dwelling older adults ≥60 years old were recruited from screening program intended to identify seniors at risk, and invited to participate in dual-task exercise program called HAPPY (Healthy Aging Promotion Program for You). One hundred and eleven participants with possible sarcopenia completed 3 months follow-up. Questionnaire was administered on demographics, frailty, sarcopenia, falls, perceived health, social network, functional, and cognitive status. Physical performance included assessment of HGS, gait speed, and Short Physical Performance Battery test (SPPB). The mean age of the Exercise group was 75.9 years old and 73.0% were women. The Exercise group had more female (73.0 vs. 47.5%), were older (75.9 vs. 72.5 years old), had higher prevalence of falls (32.4 vs. 15.0%), lower BMI (23.7 vs. 25.8), and education (4.0 vs. 7.2 years). The gait speed of the Exercise group increased significantly with significant reduction in the prevalence of SG and poor HGS. All components of SPPB as well as the total score increased significantly while the prevalence of pre-frailty and falls dropped by half. The risk of social isolation reduced by 25% with significant improvement in perceived health and cognition in the Exercise group. Significant impact on improvement gait speed and SPPB persisted after adjustment for baseline factors. Dual-task exercise program is effective in improving gait speed, SPPB score, and reducing the prevalence of poor HGS with significant improvement in perceived health, cognition, and reduction in falls and frailty. Future prospective randomized control trials are needed to evaluate the effectiveness of dual-task interventions in reversing sarcopenia.
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http://dx.doi.org/10.3389/fmed.2021.660463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086796PMC
April 2021

Multinational survey on the preferred approach to management of Barrett's esophagus in the Asia-Pacific region.

World J Gastrointest Oncol 2021 Apr;13(4):279-294

Department of Medicine, National University Hospital, Singapore 119074, Singapore.

Background: Major societies provide differing guidance on management of Barrett's esophagus (BE), making standardization challenging.

Aim: To evaluate the preferred diagnosis and management practices of BE among Asian endoscopists.

Methods: Endoscopists from across Asia were invited to participate in an online questionnaire comprising eleven questions regarding diagnosis, surveillance and management of BE.

Results: Five hundred sixty-nine of 1016 (56.0%) respondents completed the survey, with most respondents from Japan ( = 310, 54.5%) and China ( = 129, 22.7%). Overall, the preferred endoscopic landmark of the esophagogastric junction was squamo-columnar junction (42.0%). Distal palisade vessels was preferred in Japan (59.0% 10.0%, < 0.001) while outside Japan, squamo-columnar junction was preferred (59.5% 27.4%, < 0.001). Only 16.3% of respondents used Prague C and M criteria all the time. It was never used by 46.1% of Japanese, whereas 84.2% outside Japan, endoscopists used it to varying extents ( < 0.001). Most Asian endoscopists (70.8%) would survey long-segment BE without dysplasia every two years. Adherence to Seattle protocol was poor with only 6.3% always performing it. 73.2% of Japanese never did it, compared to 19.3% outside Japan ( < 0.001). The most preferred (74.0%) treatment of non-dysplastic BE was proton pump inhibitor only when the patient was symptomatic or had esophagitis. For BE with low-grade dysplasia, 6-monthly surveillance was preferred in 61.9% within Japan 47.9% outside Japan ( < 0.001).

Conclusion: Diagnosis and management of BE varied within Asia, with stark contrast between Japan and outside Japan. Most Asian endoscopists chose squamo-columnar junction to be the landmark for esophagogastric junction, which is incorrect. Most also did not consistently use Prague criteria, and Seattle protocol. Lack of standardization, education and research are possible reasons.
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http://dx.doi.org/10.4251/wjgo.v13.i4.279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040063PMC
April 2021

Motoric cognitive risk syndrome, physio-cognitive decline syndrome, cognitive frailty and reversibility with dual-task exercise.

Exp Gerontol 2021 07 19;150:111362. Epub 2021 Apr 19.

Division of Geriatric Medicine, Saint Louis University School of Medicine, St Louis, MO, USA.

Introduction: Cognitive frailty (CF) is associated with dementia and disability. It was initially proposed in 2013 by the International Institute of Nutrition and Aging and the International Geriatrics Association. Over the years, there have been many emerging definitions e.g., Motoric Cognitive Risk Syndrome (MCR), Physio-cognitive Decline Syndrome (PCDS), reversible CF and potentially reversible CF.

Objective: Our objective was to determine the demographics including physical, functional, and psychosocial factors for the four CF definitions amongst community-dwelling older adults. In addition, the effect of dual-task exercise on the reversibility of different definitions of CF was also studied.

Methods: Participants were community-dwelling older adults aged ≥60 years recruited between August 2017 and December 2019. Older adults screened to be frail, prefrail or have cognitive impairment were invited to participate in dual-task exercise program called HAPPY (Healthy Ageing Promotion Program for You). Improvement in cognition, frailty, and physical performance after a 3-month dual-task exercise intervention program was compared with controls.

Results: The prevalence of CF depending on definition ranged from 8.8% to 28.7% with minimal overlap. The cognitive scores were significantly lower in all the groups predominantly affecting non-memory domains except for reversible CF. Frailty was three to seven times more prevalent in CF. MCR group had higher prevalence of functional limitation, pain and depression. All four groups had significant increase in global cognition scores especially in the attention domain where the control group declined, and reduction in the prevalence of frailty post intervention. MCR and reversible CF were significantly associated with increased odds of cognitive improvement after 3 months of intervention compared with control.

Conclusion: CF is a novel concept and regardless of the definitions, is a target for reversing frailty, functional limitation and cognitive impairment through dual-task exercise. Long-term prospective studies are needed to evaluate the effectiveness of dual-task interventions in delaying the conversion to dementia and reduction of disability.
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http://dx.doi.org/10.1016/j.exger.2021.111362DOI Listing
July 2021

Determinants of burnout and other aspects of psychological well-being in healthcare workers during the Covid-19 pandemic: A multinational cross-sectional study.

PLoS One 2021 16;16(4):e0238666. Epub 2021 Apr 16.

Department of Surgery and Cancer, Imperial College London, London, United Kingdom.

The Covid-19 pandemic has placed unprecedented pressure on healthcare systems and workers around the world. Such pressures may impact on working conditions, psychological wellbeing and perception of safety. In spite of this, no study has assessed the relationship between safety attitudes and psychological outcomes. Moreover, only limited studies have examined the relationship between personal characteristics and psychological outcomes during Covid-19. From 22nd March 2020 to 18th June 2020, healthcare workers from the United Kingdom, Poland, and Singapore were invited to participate using a self-administered questionnaire comprising the Safety Attitudes Questionnaire (SAQ), Oldenburg Burnout Inventory (OLBI) and Hospital Anxiety and Depression Scale (HADS) to evaluate safety culture, burnout and anxiety/depression. Multivariate logistic regression was used to determine predictors of burnout, anxiety and depression. Of 3,537 healthcare workers who participated in the study, 2,364 (67%) screened positive for burnout, 701 (20%) for anxiety, and 389 (11%) for depression. Significant predictors of burnout included patient-facing roles: doctor (OR 2.10; 95% CI 1.49-2.95), nurse (OR 1.38; 95% CI 1.04-1.84), and 'other clinical' (OR 2.02; 95% CI 1.45-2.82); being redeployed (OR 1.27; 95% CI 1.02-1.58), bottom quartile SAQ score (OR 2.43; 95% CI 1.98-2.99), anxiety (OR 4.87; 95% CI 3.92-6.06) and depression (OR 4.06; 95% CI 3.04-5.42). Significant factors inversely correlated with burnout included being tested for SARS-CoV-2 (OR 0.64; 95% CI 0.51-0.82) and top quartile SAQ score (OR 0.30; 95% CI 0.22-0.40). Significant factors associated with anxiety and depression, included burnout, gender, safety attitudes and job role. Our findings demonstrate a significant burden of burnout, anxiety, and depression amongst healthcare workers. A strong association was seen between SARS-CoV-2 testing, safety attitudes, gender, job role, redeployment and psychological state. These findings highlight the importance of targeted support services for at risk groups and proactive SARS-CoV-2 testing of healthcare workers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238666PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051812PMC
May 2021

Comparing conventional and high sensitivity troponin T measurements in identifying adverse cardiac events in patients admitted to an Asian emergency department chest pain observation unit.

Int J Cardiol Heart Vasc 2021 Jun 25;34:100758. Epub 2021 Mar 25.

Department of Cardiology, National Heart Centre, Singapore.

Background: High sensitive cardiac troponin assays can be used for prediction of major adverse cardiac events (MACE) in patients with chest pain.

Methods: We included patients with symptoms suggestive of acute coronary syndrome in the emergency department observation unit. We compared the accuracy of conventional troponin T (cTnT) with high sensitive troponin T (hsTnT) at various ranges, as well as the utility of hsTnT and cTnT in prediction of 30-day and 1-year MACE.

Results: 1023 patients were included (68.1% male, median age 56 years). There were 2712 hsTnT and cTnT values compared. hsTnT had a higher AUC than cTnT for 30-day and 1-year MACE. The optimal cut-off of 0-hour hsTnT for 30-day (PPV 34%, NPV 96.6%) and 1-year MACE (PPV 40.2%, NPV 94.2%) was 16 ng/L.For 844 patients who had values for both 0 and 2 h hsTnT, we proposed a rule-out cut-off of 0 and 2 h hsTnT < 16 ng/L (NPV 97.0%, 95%CI 95.5-98.1%) and a rule-in cut-off of 0 and 2 h hsTnT ≥ 26 ng/L (PPV 58.8%, 95%CI 40.7%-75.4%) for 30-day MACE. Negative 0-2 h delta-hsTnT had poor predictive discriminant capabilities on 30-day (PPV 8.2%) and 1-year MACE (PPV 12.3%).

Conclusion: The cut off values of hsTnT used in the 0 and 2-hour algorithm to rule-out (16 ng/L) and rule-in MACE (26 ng/L) are in the range that previous cTnT assays are unable to measure accurately. Risk scores can be used to further improve NPV of the rule-out group. A fall in hsTnT level acutely is not predictive of MACE.
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http://dx.doi.org/10.1016/j.ijcha.2021.100758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027767PMC
June 2021

Low regulatory T-cells: A distinct immunological subgroup in minimal change nephrotic syndrome with early relapse following rituximab therapy.

Transl Res 2021 09 1;235:48-61. Epub 2021 Apr 1.

Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore. Electronic address:

Rituximab is an important second line therapy in difficult nephrotic syndrome (NS), especially given toxicity of long-term glucocorticoid or calcineurin inhibitor (CNI) use. However, clinical response to rituximab is heterogenous. We hypothesized that this was underpinned by immunological differences amongst patients with NS. We recruited a cohort of 18 subjects with glucocorticoid-dependent or glucocorticoid-resistant childhood-onset minimal change NS who received rituximab either due to CNI nephrotoxicity, or due to persistent glucocorticoid toxicity with inadequate response to cyclophosphamide or CNIs. Immunological subsets, T-cell activation assays and plasma cytokines were measured at baseline and 6-months post-rituximab. Time to relapse was bifurcated: 56% relapsed within one year ("early relapse"), while the other 44% entered remission mainly lasting ≥3 years ("sustained remission"). At baseline, early relapse compared to sustained remission group had lower regulatory T-cells (Tregs) [2.94 (2.25, 3.33)% vs 6.48 (5.08, 7.24)%, P<0.001], PMA-stimulated IL-2 [0.03 (0, 1.85)% vs 4.78 (0.90, 9.18)%, P=0.014] and IFNγ [2.22 (0.18, 6.89)% vs 9.47 (2.72, 17.0)%, P=0.035] levels. Lower baseline Treg strongly predicted early relapse (ROC-AUC 0.99, 95% CI 0.97-1.00, P<0.001). There were no differences in baseline plasma cytokine levels. Following rituximab, there was significant downregulation of Th2 cytokines in sustained remission group (P=0.038). In particular, IL-13 showed a significant decrease in sustained remission group [-0.56 (-0.64, -0.35)pg/ml, P=0.007)], but not in the early relapse group. In conclusion, early relapse following rituximab is associated with baseline reductions in Treg and T-cell hyporesponsiveness, which suggest chronic T-cell activation and may be useful predictive biomarkers. Sustained remission, on the other hand, is associated with downregulation of Th2 cytokines following rituximab.
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http://dx.doi.org/10.1016/j.trsl.2021.03.019DOI Listing
September 2021

Neutrophil-to-Lymphocyte Ratio Predicts Development of Immune-Related Adverse Events and Outcomes from Immune Checkpoint Blockade: A Case-Control Study.

Cancers (Basel) 2021 Mar 15;13(6). Epub 2021 Mar 15.

Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.

The utility of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) utility in predicting immune-related adverse events (irAEs) and survival have not been well studied in the context of treatment with immune checkpoint inhibitors (ICIs). We performed a case-control study of cancer patients who received at least one dose of ICI in a tertiary hospital. We examined NLR and PLR in irAE cases and controls. Logistic and Cox regression models were used to identify independent risk factors for irAEs, progression-free survival (PFS), and overall survival (OS). The study included 91 patients with irAEs and 56 controls. Multiple logistic regression showed that NLR < 3 at baseline was associated with higher occurrence of irAEs. Multivariate Cox regression showed that development of irAEs and reduction in NLR from baseline to week 6 were associated with longer PFS. Higher NLR values at baseline and/or week 6 were independently associated with shorter OS. A reduction in NLR from baseline to week 6 was associated with longer OS. In this study of cancer patients treated with ICIs, NLR has a bidirectional relationship with adverse outcomes. Lower NLR was associated with increased occurrence of irAEs while higher NLR values were associated with worse clinical outcomes.
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http://dx.doi.org/10.3390/cancers13061308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001500PMC
March 2021

Structured re-training to reduce peritonitis in a pediatric peritoneal dialysis program: a quality improvement intervention.

Pediatr Nephrol 2021 Oct 2;36(10):3191-3200. Epub 2021 Apr 2.

Shaw-NKF-NUH Children's Kidney Centre, Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, NUHS Tower Block Level 12, 1E Kent Ridge Road, Singapore, 119228, Singapore.

Background: Decline in skills and knowledge among patients and/or caregivers contributes to peritoneal-dialysis (PD)-related peritonitis. Re-training is important, but no guidelines exist. We describe the implementation of a structured re-training program to decrease peritonitis rates.

Methods: This is a prospective quality improvement study involving pediatric patients on long-term home automated PD at National University Hospital, Singapore, between 2012 and 2018. With increasing peritonitis rates, systematic root cause analysis was performed, and based on the contributory factors identified, a structured re-training program was implemented from 2015. This was conducted in 5 cycles, each consisting of 4 modules (hand hygiene, exit site care, peritonitis, and PD troubleshooting).

Results: Peritonitis rates were analyzed in 2 phases: Phase 1 (2012-2014) when no re-training was performed and Phase 2 (2016-2018) after re-training was instituted. Fifty-nine patients were included. Of these, 45 patients were in Phase 1, 32 in Phase 2, and 18 in both phases. Peritonitis rates decreased from 0.37 ± 0.67 episodes per patient-year in Phase 1 to 0.13 ± 0.32 episodes per patient-year in Phase 2. After adjusting for age at kidney failure onset, PD vintage, years of nursing experience, and the average patient-to-nurse ratio over the study period for each patient, the adjusted peritonitis rates decreased by 0.38 episodes per patient-year (95% CI, 0.09 to 0.67, p = 0.011) from Phase 1 to Phase 2.

Conclusion: Despite an improvement in staffing ratio, peritonitis rates only improved significantly after intensive structured re-training was instituted.
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http://dx.doi.org/10.1007/s00467-021-05039-2DOI Listing
October 2021

Effect of body mass index (BMI) on phenotypic features of polycystic ovary syndrome (PCOS) in Singapore women: a prospective cross-sectional study.

BMC Womens Health 2021 04 1;21(1):135. Epub 2021 Apr 1.

Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, 1E Kent Ridge Road, Level 12, Singapore, Republic of Singapore, 119228.

Background: A diagnosis of Polycystic Ovary Syndrome (PCOS) and its related phenotypic features including increased hair growth can affect a woman's social and emotional well-being. We aim to determine firstly, if excess body weight affects menstrual cycle length, excessive hair growth and other phenotypic features in healthy women without PCOS and secondly, whether having PCOS exacerbates the effects of high body mass index (BMI).

Methods: A prospective cross-sectional study involving healthy women (21-45 years) recruited at an annual health screen for hospital staff and volunteers from the university community, and PCOS cases referred to tertiary gynecological clinics in Singapore. To dissect the independent and/or combinatorial effects of PCOS and BMI on the phenotypic features, subjects were divided into four categories: non-PCOS (normal BMI), non-PCOS (high BMI), PCOS (normal BMI), and PCOS (high BMI). General linear modelling was performed to compare clinical, ovarian, hormonal and metabolic parameters across these four categories.

Results: Of 389 participants, 134 (34.4%) were classified as PCOS and the remaining 255 (65.6%), as the non-PCOS population. Overall 45.2% of women had high BMI (≥ 23). Compared to non-PCOS subjects, women with PCOS had a higher BMI (mean (SD): 25.14 ± 6.46 vs 23.08 ± 4.36, p < 0.001). Women with PCOS and high BMI had increased hair growth with modified Ferriman-Gallwey (mFG) scores that were 2.96-fold higher versus healthy-normal BMI women (mean difference; 1.85, 95% CI 0.80-2.90). Compared to healthy-high BMI women, PCOS women with high BMI had significantly higher mean differences in mFG scores (1.79, 95% CI 0.64-2.93). In PCOS women, having high BMI also significantly increased mFG scores by 1.85-fold (mean difference; 1.82. 95% CI 0.52-3.12). This effect was mirrored by the additive effect of BMI and PCOS on free androgen index. No independent effect of high BMI on rates of oligomenorrhoea, antral follicle count, ovarian volume or serum androgens were observed.

Conclusions: We observed an additive effect of body weight to increase hair growth in women with PCOS. Maximum mFG scores were present in PCOS women with high BMI. Such increases in mFG score may affect the self-esteem of women with PCOS.
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http://dx.doi.org/10.1186/s12905-021-01277-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017849PMC
April 2021

Comparing outcomes of tunnelled dialysis catheter insertions and exchanges with or without fluoroscopy.

J Vasc Access 2021 Mar 12:11297298211000872. Epub 2021 Mar 12.

Division of Nephrology, Department of Medicine, National University Health System, Singapore, Singapore.

Background/objective: To study the safety and outcome profiles of tunnelled dialysis catheter (TDC) insertions and exchanges with fluoroscopy versus without fluoroscopy.

Methods: This was a retrospective cohort study of all TDC insertions or exchanges performed at our centre, between January 2017 and December 2017. Patient demographics, laboratory results and catheter placement information were obtained from electronic records. Immediate technical success, early and late catheter associated complications were collected. Outcomes for TDC inserted with or without fluoroscopy were statistically analysed.

Results: A total of 351 TDC insertions and 253 TDC exchanges were performed. Out of 351 TDC insertions, 261 were done with fluoroscopy while 90 were done without. Out of 253 TDC exchanges, 219 were done with fluoroscopy while 34 were done without. For both TDC insertions and exchanges, there were no significant differences in complication rates when done with or without fluoroscopy. Mean duration of catheter patency was longer for TDC inserted without fluoroscopy, after adjusting for site of insertion and presence of previous TDC.

Conclusions: The technique of inserting TDC in the right internal jugular vein (IJV) without fluoroscopy is a safe and effective method in selected patients. This supports the practice of performing the procedure without fluoroscopy, especially in institutions where fluoroscopy facilities are not readily available. This potentially translates into reduced healthcare resources and hospitalisation days, which is particularly valuable in times of limited resources such as the current Coronavirus Disease 2019 (COVID-19) pandemic.
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http://dx.doi.org/10.1177/11297298211000872DOI Listing
March 2021

Preventing early-onset group B streptococcal sepsis: clinical risk factor-based screening or culture-based screening?

Singapore Med J 2021 Jan 2;62(1):34-38. Epub 2019 Dec 2.

Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Introduction: Two strategies are available for prevention of early-onset group B streptococcal (GBS) sepsis - clinical risk factor-based screening and routine culture-based screening of pregnant women for GBS colonisation. In our hospital, we switched from the former to the latter approach in 2014.

Methods: We compared the incidence of early-onset GBS sepsis during 2001-2015 between infants born to pregnant women who were screened for GBS colonisation and those born to women who were not screened.

Results: Among 41,143 live births, there were nine cases of early-onset GBS sepsis. All infants with GBS sepsis were born to pregnant women who were not screened for GBS colonisation. The incidence of early-onset GBS sepsis among infants of women who were not screened was 0.41 per 1,000 live births (95% confidence interval [CI] 0.19-0.77) when compared to infants of women who were screened, for whom the sepsis incidence was zero per 1,000 live births (95% CI 0-0.19; p = 0.005).

Conclusion: Our data suggests that routine culture-based screening of pregnant women for GBS colonisation is a better preventive strategy for early-onset GBS sepsis in neonates when compared to clinical risk factor-based screening.
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http://dx.doi.org/10.11622/smedj.2019155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027162PMC
January 2021

Psychological Health of Surgeons in a Time of COVID-19: A Global Survey.

Ann Surg 2021 Jan 22. Epub 2021 Jan 22.

Department of Urology, National University Hospital, National University Health System, Singapore Biostatistics Unit, Yong Loo Lin School of Medicine, National University of Singapore Department of Psychological Medicine, National University of Singapore Department of Urology, CiptoMangunkusumo Hospital, Jakarta, Indonesia General Surgery and Digestive System Service, Alfredo Espinosa Hospital, Urduliz, Vizcaya, Spain Colorectal Unit, Vall d'Hebron University Hospital, Barcelona, Spain; Department of Advanced Medical and Surgical Sciences, Luigi Vanvitelli University of Campania, Italy Department of Urology, Ng Teng Fong General Hospital, National University Health System, Singapore Wellcome EPSRC Centre for Interventional and Surgical Sciences (WEISS), University College London, London, United Kingdom Hospital Israelita Albert Einstein, Sao Paulo, Brazil; BP-a Beneficencia Portuguesa de Sao Paulo, Sao Paulo, Brazil Department of Urology, Kasturba Medical College Manipal, Manipal Academy of Higher Education, India Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR Eastern Health and Monash University Eastern Health Clinical School, Box Hill, VIC, Australia Department of Medical and Surgical Sciences, University of Catanzaro, Catanzaro, Italy SH Ho Urology Center, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China Department of Urology, Marmara University Research and Training Hospital, Turkey Conselleria de Sanidad Universal y salud Publica, Spain Hospital Universitario Parc Taulí Sabadell, Spain Escola Paulista de Medicina - Universidade Federal de São Paulo, Brazil Department of Surgery, Faculty of Medicine, Universiti Teknologi MARA, Malaysia Unit of Urological Robotic Surgery and Renal Transplantation, Careggi University Hospital, Florence, Italy Department of Urology, Campus Biomedico University of Rome, Italy Servicio de Urología, Hospital Universitario La Paz, Madrid, Spain Division of Urology, University Health Network, Department of Surgery, University of Toronto, Canada Macquarie University Hospital and Royal North Shore Hospital, Department of Urology, Sydney, New South Wales, Australia Department of Urology- Luzerner Kantonsspital- Luzern, CH, Switzerland Instituto de Investigación Sanitaria San Carlos, Hospital Clinico San Carlos, Madrid, Spain Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore (NUS).

Objective: To assess the degree of psychological impact among surgical providers during the COVID-19 pandemic.

Summary Background Data: The COVID-19 pandemic has extensively impacted global healthcare systems. We hypothesized that the degree of psychological impact would be higher for surgical providers deployed for COVID-19 work, certain surgical specialties, and for those who knew of someone diagnosed with, or who died, of COVID-19.

Methods: We conducted a global web-based survey to investigate the psychological impact of COVID-19. The primary outcomes were the Depression Anxiety Stress Scale-21 (DASS-21) and Impact of Event Scale-Revised (IES-R) scores.

Results: 4283 participants from 101 countries responded. 32.8%, 30.8%, 25.9% and 24.0% screened positive for depression, anxiety, stress and Post-Traumatic Stress Disorder (PTSD) respectively. Respondents who knew someone who died of COVID-19 were more likely to screen positive for depression, anxiety, stress and PTSD (OR 1.3, 1,6, 1.4, 1.7 respectively, all p < 0.05). Respondents who knew of someone diagnosed with COVID-19 were more likely to screen positive for depression, stress and PTSD (OR 1.2, 1.2 and 1.3 respectively, all p < 0.05). Surgical specialities that operated in the Head and Neck region had higher psychological distress among its surgeons. Deployment for COVID-19-related work was not associated with increased psychological distress.

Conclusions: The COVID-19 pandemic may have a mental health legacy outlasting its course. The long-term impact of this ongoing traumatic event underscores the importance of longitudinal mental health care for healthcare personnel, with particular attention to those who know of someone diagnosed with, or who died of COVID-19.
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http://dx.doi.org/10.1097/SLA.0000000000004775DOI Listing
January 2021
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