Singapore Cohort Research Articles

Sacroiliitis at diagnosis as a protective predictor against disease flare after stopping medication: outcomes of a Southeast Asian enthesitis-related arthritis (ERA) longitudinal cohort.

To assess short- and long-term outcomes of ERA in a large monocentric cohort in Singapore. Children diagnosed with ERA according to ILAR criteria from 2002 to 2021 were recruited. Nonparametric statistics were used to describe the data. Outcomes were defined according to modified Wallace criteria, and probabilities and predictors were determined using Kaplan-Meier survival and logistic regression analyses. One hundred fifty-one ERA patients (male 86%; Chinese 81%) were included. The median age at onset was 11.9years (IQR: 9.4-13.9), and disease duration was 5.3years (IQR: 2.9-8.4). At diagnosis, 39% of the patients had sacroiliitis. HLA-B27 was positive in 83%, and biologics were used in 72% of the patients. Clinical inactive disease (CID) was achieved in 92% of the patients, of which 27% achieved within 6months. Sacroiliitis at diagnosis is an unfavorable predictor of early CID at 6months. Medication was discontinued in one-third of the patients. Favorable predictor of medication withdrawal includes male gender, while unfavorable predictors include positive HLA-B27 and ANA. Two-thirds of the patients with CID had at least one disease flare. Sacroiliitis at diagnosis is a protective predictor of flare after stopping medication. Despite a high proportion of ERA patients achieving CID, only one-third could stop medication with high rates of disease flare. Unfavorable predictors include older age at onset, HLA-B27, and ANA positivity. While sacroiliitis at diagnosis is a negative predictor of CID at 6months, it is associated with less disease flare after discontinuing medication.

Cluster phenotypes in a non-idiopathic pulmonary fibrosis fibrotic interstitial lung diseases cohort in Singapore.

BackgroundNon-idiopathic pulmonary fibrosis fibrosing interstitial lung diseases (F-ILDs) may demonstrate a progressive disease trajectory similar to idiopathic pulmonary fibrosis (IPF). We aimed to identify novel F-ILD phenotypes in a multi-ethnic South-East Asian population.MethodsF-ILD subjects (n=201) were analysed using unsupervised hierarchical cluster analysis and their outcomes compared against IPF (n=86).ResultsFour clusters were identified. Cluster 1 (n=53, 26.4%) comprised older Chinese males with high body mass index (BMI) and comorbidity burden, higher baseline forced vital capacity (FVC) percentage predicted and lower diffusing capacity of the lung for carbon monoxide (DLCO) percentage predicted. They had similar mortality to IPF. Cluster 2 (n=67, 33.3%) had younger female non-smokers with low comorbidity burden, groundglass changes on high-resolution chest computed tomography (HRCT) and a positive anti-nuclear antibody (ANA) titre ≥1:160. They had lower baseline FVC and higher DLCO, low mortality and slower lung function decline. Cluster 3 (n=42, 20.9%) consisted male smokers with low comorbidity burden, emphysema on HRCT and high baseline lung function. They had low mortality and slow lung function decline. Cluster 4 (n=39, 19.4%) was the highest risk and comprised of mainly Indians with high BMI. They had the highest proportion of ischemic heart disease (IHD) and previous pulmonary tuberculosis. Subjects had the lowest baseline lung function, highest mortality, and fastest lung function decline. Survival differences across clusters remained significant following adjustment for treatment.ConclusionsWe identified four distinct F-ILD clinical phenotypes with varying disease trajectories. This demonstrates heterogeneity in F-ILD and the need for complementary approaches for classification and prognostication beyond ATS/ERS guideline diagnosis.

Validation of the CaRdiac Arrest Survival Score (CRASS) for predicting good neurological outcome after out-of-hospital cardiac arrest in an Asian emergency medical service system

BackgroundSurvival with favorable neurological outcomes is an important indicator of successful resuscitation in out-of-hospital cardiac arrest (OHCA). We sought to validate the CaRdiac Arrest Survival Score (CRASS), derived using data from the German Resuscitation Registry, in predicting the likelihood of good neurological outcomes after OHCA in Singapore. MethodsWe conducted a retrospective population-based validation study among EMS-attended OHCA patients (≥18 years) in Singapore, using data from the prospective Pan-Asian Resuscitation Outcomes Study registry. Good neurological outcome was defined as a cerebral performance category of 1 or 2. To evaluate the CRASS score in light of the difference in patient characteristics, we used the default constant coefficient (0.8) and the adjusted coefficient (0.2) to calculate the probability of good neurological outcomes. ResultsOut of 11,404 analyzed patients recruited between April 2010 and December 2018, 260 had good and 11,144 had poor neurological function. The CRASS score demonstrated good discrimination, with an area under the curve of 0.963 (95% confidence interval: 0.952–0.974). Using the default constant coefficient of 0.8, the CRASS score consistently overestimated the predicted probability of a good outcome. Following adjustment of the coefficient to 0.2, the CRASS score showed improved calibration. ConclusionCRASS demonstrated good discrimination and moderate calibration in predicting favorable neurological outcomes in the validation Singapore cohort. Our study established a good foundation for future large-scale, cross-country validations of the CRASS score in diverse sociocultural, geographical, and clinical settings.

The Effect of Building-Level Socioeconomic Status on Bystander Cardiopulmonary Resuscitation: A Retrospective Cohort Study

Objective Understanding the social determinants of bystander cardiopulmonary resuscitation (CPR) receipt can inform the design of public health interventions to increase bystander CPR. The association of socioeconomic status with bystander CPR is generally poorly understood. We evaluated the relationship between socioeconomic status and bystander CPR in cases of out-of-hospital cardiac arrest (OHCA). Methods This was a retrospective cohort study based on the Singapore cohort of the Pan-Asian Resuscitation Outcomes Study registry between 2010 and 2018. We categorized patients into low, medium, and high Singapore Housing Index (SHI) levels—a building-level index of socioeconomic status. The primary outcome was receipt of bystander CPR. The secondary outcomes were prehospital return of spontaneous circulation and survival to discharge. Results A total of 12,730 OHCA cases were included, the median age was 71 years, and 58.9% were male. The bystander CPR rate was 56.7%. Compared to patients in the low SHI category, those in the medium and high SHI categories were more likely to receive bystander CPR (medium SHI: adjusted odds ratio [aOR] 1.48, 95% CI 1.30–1.69; high SHI: aOR 1.93, 95% CI 1.67–2.24). High SHI patients had higher survival compared to low SHI patients on unadjusted analysis (OR 1.79, 95% CI 1.08–2.96), but not adjusted analysis (adjusted for age, sex, race, witness status, arrest time, past medical history of cancer, and first arrest rhythm). When comparing high with low SHI, females had larger increases in bystander CPR rates than males. Conclusions Lower building-level socioeconomic status was independently associated with lower rate of bystander CPR, and females were more susceptible to the effect of low socioeconomic status on lower rate of bystander CPR.

Variant landscape of the RYR1 gene based on whole genome sequencing of the Singaporean population

The RYR1 gene codes for a ryanodine receptor which is a calcium release channel in the skeletal muscle sarcoplasmic reticulum. It is associated with Malignant Hyperthermia (MH) and congenital myopathies including Central Core Disease (CCD), Multiminicore Disease (MMD) and Congenital Fibre-Type Disproportion (CFTD). There is currently little information on the epidemiology of RYR1 variants in Asians. Our study aims to describe the RYR1 variant landscape in a Singapore cohort unselected for RYR1-associated conditions. Data was retrieved from the SG10K pilot project, where whole genome sequencing was performed on volunteers unselected and undetermined for RYR1-associated conditions. Variants were classified based on pathogenicity using databases ClinVar and InterVar. Allele frequencies of pathogenic variants were compared between Chinese, Indians and Malays. Using databases ExAC, GnomAD and GenomeAsia 100k study, we further compared local allele frequencies to those in Europe, America and Asia. Data was analysed using R Commander. Significant P value was set at p < 0.05. Majority of the RYR1 variants were missense mutations. We identified four pathogenic and four likely pathogenic RYR1 variants. All were related to the aforementioned RYR1-associated conditions. There were 6 carriers of RYR1 pathogenic variants amongst 4810 individuals, corresponding to an allele frequency of 0.06%. The prevalence of pathogenic variants was the highest amongst Indians (4 in 1127 individuals) (p = 0.030). Majority of pathogenic and likely pathogenic mutations were missense and located in mutational hotspots. These variants also occurred at higher frequencies in Asians than globally. This study describes the variant landscape of the RYR1 gene in Singapore. This knowledge will facilitate genetic screening for RYR1-related conditions.

Clinicopathological correlates of out-of-hospital cardiac arrests.

BackgroundSudden cardiac arrest with or without sudden cardiac death (SCD) represents a heterogeneous spectrum of underlying etiology but is often a catastrophic event. Despite improvements in pre‐hospital response and post‐resuscitation care, outcomes remain grim. Thus, we aim to evaluate the predictors of survival in out‐of‐hospital cardiac arrests (OHCAs) and describe autopsy findings of those with the uncertain cause of death (COD).MethodsThis is a subgroup analysis of the Singapore cohort from the Pan Asian Resuscitation Outcome Study which studied 933 OHCAs admitted to two Singapore tertiary hospitals from April 2010 to May 2012.ResultsOf the patients analysed, 30.2% (n = 282) had an initial return of spontaneous circulation (ROSC) at the emergency department, 18.0% (n = 168) had sustained ROSC with subsequent admission and 3.4% (n = 32) had survival to discharge. On multivariate analysis, an initial shockable rhythm, a witnessed event, prehospital defibrillation, and shorter time to hospital predicted ROSC as well as survival to discharge. A total of 163 (17.5%) autopsies were performed of which a cardiac etiology of SCD was noted in 92.1% (n = 151). Ischemic heart disease accounted for 54.3% (n = 89) of the autopsy cohort, with acute myocardial infarction (26.9%, n = 44) and myocarditis (3.7%, n = 6) rounding out the top three causes of demise.ConclusionOHCA remains a clinical presentation that portends a poor prognosis. Of those with uncertain COD, cardiac etiology appears to predominate from autopsy study. Identification of prognostic factors will play an important role in improving individual‐level and systemic‐level variables to further optimize outcomes.

Finding a reliable assay for soluble neprilysin

BackgroundLack of validation and standardization of research-use-only (RUO) immunoassays brings with it inherent threats to authenticity and functional quality. Poor correlation between different commercial neprilysin RUO immunoassays is concerning and discordant findings need to be resolved. We seek to identify and validate reliable neprilysin immunoassays to strengthen the scientific rigor and reproducibility of neprilysin-related investigation and of biomarker research in general. MethodsSoluble neprilysin (sNEP) concentrations were determined in cohorts (n = 532) from Spain (Cohort 1), New Zealand (NZ, Cohort 2) and Singapore (Cohort 3), using commercial kits from six vendors. Apparent sNEP concentrations were correlated between different assays and with plasma neprilysin activity. Assay reliability was further validated by performance verification, MS analysis and cross-reactivity tests. ResultssNEP in Cohorts 1 and 2 measured concurrently in Spain and NZ showed significant inter-laboratory correlation only for the Aviscera Bioscience sNEP ELISA SK00724-01. Neprilysin concentrations obtained with the R&D systems and SK00724-01 ELISAs correlated with each other but not with neprilysin activity. In Cohort 3, sNEP concentrations from the Perkin Elmer AlphaLISA and Biotechne ELLA assays agreed (r = 0.89) and both correlated with neprilysin activity (r = 0.87, 0.77 respectively). MS analysis detected authentic neprilysin in the AlphaLISA kit calibrator and in antibody pull-down material from human plasma. The AlphaLISA assay performed within acceptable limits (spike and recovery, dilutional linearity, inter- and intra-assay CV) and showed no cross-reactivity against neprilysin substrates and closely-related analogues. ConclusionAlphaLISA and ELLA assays provide reliable measures of sNEP concentrations. Reliability of other commercial neprilysin assays remains in question.

Abstract WP205: Trans-ethnic Genome-wide Association Studies Meta-analysis Of Large Brain Arterial Diameters Identifies Two Novel Genetic Loci

Introduction: Larger brain arterial diameters, which may be a consequence of connective tissue disorders or hypertension, are associated with mortality, cognitive decline and risk of dementia. Whether there may be genetic determinants of large brain arterial diameters is unknown, but identifying such traits may shed light into possible mechanistic links between large brain arterial diameters and the observed outcomes. Methods: We studied 3654 participants from four ethnically diverse population-based cohorts: The Atherosclerosis Risk in Communities study (n=1565: 74.3% white, 25.7% black), The Northern Manhattan Study (n=1092: 13.8% white, 16.6% black, 69.6% Hispanic), Epidemiology of Dementia in Singapore (n=647: 31.7% Chinese, 35.7% Malay, 32.6% Indian), and Memory Clinic Cohort in Singapore (n=350: 84.9% Chinese, 7.8% Malay, 7.3% Indian). We measured brain arterial diameters for 13 segments and normalized the averaged diameter per participant to obtain global brain arterial diameter as dependent variable. Genome-wide association studies (GWAS) was performed in each study using linear regression, adjusted for sex, age, head size, number of missing arteries and population substructure. Meta-analysis of association statistics was performed using the METAL to generate combined trait-specific effect estimates. We also performed trans-ethnic meta-regression by MR-MEGA to account for the heterogeneity in allelic effect that is correlated with ancestry. Results: Genome-wide significant (P&lt;5x10 -8 ) associations were observed for global brain arterial diameter with three SNPs: rs7921574(P=1.2x10 -8 ) mapping to an intron of CNNM2; rs2075858(P=2.47x10 -8 ) and rs2075857 (P=2.37x10 -8 ) mapping to introns of MUC5B. MR-MEGA analysis showed suggestive evidence of association (P=5.05x10 -8 ) for rs7921574. These loci comprise genes involved in response to magnesium transport, neuronal transmission, hypertension, mucociliary clearance and host defense. Conclusion: Our study reveals two novel risk loci for large brain arterial diameters. We have begun to replicate these associations and to identify functional causal variants in independent studies. Identifying these loci may help us to elucidate underlying disease mechanisms.

Histone acetylome-wide associations in immune cells from individuals with active Mycobacterium tuberculosis infection

Host cell chromatin changes are thought to play an important role in the pathogenesis of infectious diseases. Here we describe a histone acetylome-wide association study (HAWAS) of an infectious disease, on the basis of genome-wide H3K27 acetylation profiling of peripheral blood granulocytes and monocytes from persons with active Mycobacterium tuberculosis (Mtb) infection and healthy controls. We detected >2,000 differentially acetylated loci in either cell type in a Singapore Chinese discovery cohort (n = 46), which were validated in a subsequent multi-ethnic Singapore cohort (n = 29), as well as a longitudinal cohort from South Africa (n = 26), thus demonstrating that HAWAS can be independently corroborated. Acetylation changes were correlated with differential gene expression. Differential acetylation was enriched near potassium channel genes, including KCNJ15, which modulates apoptosis and promotes Mtb clearance in vitro. We performed histone acetylation quantitative trait locus (haQTL) analysis on the dataset and identified 69 candidate causal variants for immune phenotypes among granulocyte haQTLs and 83 among monocyte haQTLs. Our study provides proof-of-principle for HAWAS to infer mechanisms of host response to pathogens.

Multimodal Imaging-Based Phenotyping of a Singaporean Hospital-Based Cohort of High Myopia Patients

Purpose: To assess the effect of axial length (AL) on the prevalence of pathologic myopia (PM) and associated myopic features in a Singaporean hospital-based cohort of patient with high myopia (HM).Methods: In total, 923 HM eyes from 495 individuals were recruited from the Myopic and Pathologic Eyes in Singapore (MyoPES) cohort and underwent ocular biometry, fundus photography, fundus autofluorescence, and swept-source optical coherence tomography (SS-OCT). Images were analyzed for the presence of myopic macular degeneration (MMD), myopic choroidal neovascularization (mCNV), myopic traction maculopathy (MTM), peripapillary atrophy (PPA), myopic tilted disc, posterior staphyloma (PS), dome-shaped macula (DSM), vitremacular adhesions (VMA), and the epiretinal membrane (ERM). Eyes were stratified into quartiles based on ALs to determine cut-off values to perform comparisons between shorter-length and longer-length groups. A χ2-test was done to determine the difference in the prevalence of pathologies between groups.Results: Overall, mean AL was 29.2 ± 2.2 mm (range 25.0–36.7 mm). Myopic macular degeneration, PPA, myopic tilted disc, and ERM have AL threshold of ≥27.5 mm, whereas MTM has an AL threshold of ≥29.0 mm. We found that there was a significantly higher prevalence of MMD (88.2 vs. 49.4%; p < 0.001), PPA (98.1 vs. 80.1%; p < 0.001), myopic tilted disc (72.7 vs. 50.2%; p < 0.001), and ERM (81.4 vs. 17.3%; p = 0.003) in eyes with AL ≥ 27.5 mm vs. eyes without AL <27.5 mm. Prevalence of MTM (34.7 vs. 32.1%; p < 0.001), mCNV (17.4 vs. 12.1%; p = 0.03), PS (43.4 vs. 34.7%; p = 0.012), DSM (21.3 vs. 13.2%; p = 0.002), and VMA (5.9 vs. 2.6%; p = 0.014) in eyes with AL ≥ 29.0 mm compared with AL < 29.0 mm.Conclusion: Our study describes the overall prevalence of PM and related pathologies among patients with HM in our hospital-based cohort. Longer eyes even among HM eyes had a significantly higher prevalence of PM-associated pathologies studied. This supports the premise that eyes with longer AL, even among HM eyes may be at greater risk of vision-threatening changes and therefore merit regular follow-up.

Obtaining spatially resolved tumor purity maps using deep multiple instance learning in a pan-cancer study

SummaryTumor purity is the percentage of cancer cells within a tissue section. Pathologists estimate tumor purity to select samples for genomic analysis by manually reading hematoxylin-eosin (H&E)-stained slides, which is tedious, time consuming, and prone to inter-observer variability. Besides, pathologists' estimates do not correlate well with genomic tumor purity values, which are inferred from genomic data and accepted as accurate for downstream analysis. We developed a deep multiple instance learning model predicting tumor purity from H&E-stained digital histopathology slides. Our model successfully predicted tumor purity in eight The Cancer Genome Atlas (TCGA) cohorts and a local Singapore cohort. The predictions were highly consistent with genomic tumor purity values. Thus, our model can be utilized to select samples for genomic analysis, which will help reduce pathologists' workload and decrease inter-observer variability. Furthermore, our model provided tumor purity maps showing the spatial variation within sections. They can help better understand the tumor microenvironment.

Mild behavioral impairment: Prevalence, clinical profile, and prognosis in a memory clinic cohort in Singapore

AbstractBackgroundMild behavioral impairment (MBI) is characterized as later‐life emergent and persistent neuropsychiatric symptoms (NPS) that are suggestive of early manifestations of Alzheimer’s Disease (AD) and dementia. This study aims to investigate the prevalence, clinical correlates, cognitive trajectories, and dementia risk of MBI in a clinical cohort.MethodIn a Singaporean longitudinal cohort, 309 dementia‐free participants (mean age=71.6 [SD=7.8], 52% females) underwent annual neuropsychological, neuropsychiatric, and clinical assessments for up to four years. The diagnosis of MBI was ascertained using neuropsychiatric inventory assessments at two time‐points. Global and domain‐specific cognitive Z‐scores were calculated from a comprehensive neuropsychological battery, and Clinical Dementia Rating sum‐of‐boxes (CDR‐SoB) scores were used to assess disease progression.ResultA total of 72 (23.3%) participants had MBI. Cross‐sectionally, MBI patients performed poorer in global cognition (β=‐0.27 [‐0.51–0.03], p=0.026), particularly in memory (β=‐0.56 [‐0.79–0.33], p&lt;0.001), executive function (β=‐0.33 [‐0.62–0.03], p=0.030), and visuomotor speed (β=‐0.20 [‐0.39–0.02], p=0.031) domains. On follow‐up, MBI patients showed faster decline in global cognition (β=‐0.19 [‐0.27–0.11], p&lt;0.001) (Fig. 1) and faster increment in CDR‐SoB (β=0.96 [0.74‐1.19], p&lt;0.001) (Fig. 2) as compared to non‐MBI elderly, regardless of cognitive status. On follow‐up, 40.3% (n=29) of MBI patients progressed to dementia, compared with 8% (n=19) of non‐MBI elderly. MBI diagnosis was associated with a significantly higher risk of dementia (Hazard Ratio=6.28 [3.51‐11.23], p&lt;0.001) (Fig. 3).ConclusionMBI may be an early neurobehavioral marker of cognitive decline leading to dementia. Incorporating MBI evaluations into clinical assessments may identify high risk patients for dementia who may benefit from intervention.

Domain‐specific cognitive trajectory among patients with minor stroke or transient ischemic attack in a 6‐year Asian cohort: Temporal patterns and indicators

AbstractBackgroundThis study aimed to assess the 6‐year domain‐specific patterns of cognitive trajectory among survivors of minor stroke or transient ischemic attack (TIA) in a multi‐ethnic clinical cohort in Singapore, and to identify possible demographic, clinical and vascular indicators of different trajectory patterns.MethodElderly participants completed cognitive and clinical assessments at 2 weeks, 3‐6 months, 1 year, 3/4 years, 5 years and 6 years post‐stroke. Global and domain‐specific cognition was transformed to standardized z‐scores. Generalized estimating equation and mixed linear model were used to examine baseline predictors of long‐term cognitive impairment and domain‐specific cognitive trajectory. Survival analysis was performed for incident cognitive impairment during the 6‐year study duration.ResultA total of 244 participants were included in the analysis. A fluctuating yet stable pattern was observed in all cognitive domains, except for visual memory, which showed a significant improvement across the six‐year follow‐up. Regardless of baseline characteristics, baseline MoCA was associated with lower odds of long‐term cognitive impairment (0.67, 95%CI= (0.60, 0.75)), whilst both MoCA improvement from baseline to 3‐6 months, and from baseline to 1 year were associated with lower risk of cognitive impairment (OR 0.80, 95%CI= (0.71, 0.90) and 0.86, 95%CI= (0.77, 0.97) respectively) after controlling for covariates.ConclusionPost‐stroke cognitive trajectory showed varying patterns across different cognitive domains. Our findings provide evidence on practice effects of the MoCA which can be used for identifying patients with higher risk of long‐term cognitive impairment.

Evaluating Rates and Determinants of COVID-19 Vaccine Hesitancy for Adults and Children in the Singapore Population: Strengthening Our Community's Resilience against Threats from Emerging Infections (SOCRATEs) Cohort.

COVID-19 vaccines are crucial for achieving sufficient immunisation coverage to manage the pandemic, but vaccine hesitancy persists. This study aimed to investigate the prevalence and determinants of vaccine hesitancy in adults and in parents for vaccinating their children using an integrated social cognition model. A community-based cohort in Singapore [N = 1623] completed a survey (wave 25) between June and July 2021 which measured their risk perceptions, distress, trust, vaccination beliefs, and vaccine intentions/behaviours. Results indicated low rates of hesitancy (9.9%) for own vaccination, with most concerns citing side effects, safety, and hasty development. Remaining respondents were vaccinated (69%) or intended to vaccinate (21%). The multivariable model (non-vaccinated respondents) indicated that, living with people in poor health, subjective norm, moral norm, benefits, and necessity of vaccination were associated with lower vaccine hesitancy (R2 Cox & Snell: 51.4%; p < 0.001). Hesitancy rates were higher for children’s vaccination (15.9%), with male gender, lower perceived vaccine benefits, high COVID-19 risk perceptions, vaccination concerns, and necessity beliefs associated with higher odds of parental vaccine hesitancy (R2 Cox & Snell = 36.4%; p < 0.001). While levels of vaccine acceptance are high, more targeted messages are needed. For adults’ vaccination, more emphasis should be on benefits and social gains, while for parental hesitancy, messages related to safety should be prioritised.

Clinical Outcomes of Adults and Young Adults (AYA) with Acute Lymphoblastic Leukemia (ALL): A Multicenter Analysis of Pediatric-Inspired Protocol (MASPORE) Vs Hyper-CVAD in Singapore

Introduction:In acute lymphoblastic leukemia (ALL) adolescents and young adults (AYA), there are benefits when using pediatric over adult treatment regimes. There is improved overall survival (OS), progression free survival (PFS) and reduced need for hematopoietic stem cell transplantation; all while having an acceptable toxicity profile. Yet, studies supporting this were largely performed in a western population (e.g., United Kingdom and United States) and thus may have had limited representation of the Asian population. Whether these results are generalizable and applicable to an Asian population is in question. MASPORE, a locally designed pediatric regiment based on BFM regimen, which has been used successfully in Singapore and Malaysia's AYA cohort since 2007. MASPORE protocol utilized PCR-based minimal residual disease (MRD) marker to risk stratify patients according to disease severity and used a 3- or 4-drug induction regimen depending on intermediate or high-risk stratification (L-asparaginase, Vincristine, Dexamethasone +/- daunorubicin). In contrast HyperCVAD does not use MRD to stratify or guide management. In this retrospective study performed in Singapore, we aim to demonstrate that MASPORE is an effective treatment option for AYA ALL in Asian population.Methods:Patient registries (IRB approved) spanning from January 2005 to June 2021 from three tertiary hospitals in Singapore were reviewed. ALL patients who were AYA, defined as less than 40 years of age, treated during this time were included and analyzed. Patients were treated with either the pediatric protocol MASPORE or with the adult protocol HyperCVAD. Patients who are Philadelphia positive were excluded from the MASPORE arm up to 2020. Patients' demographics, functional status, risk profile, adverse events, as well as the hematological response and transplant status were collected and analyzed with Pearson chi-square test. Kaplan Meier curve analysis were performed for OS and PFS with SPSS software.Results:In this retrospective study, 116 patients were analyzed. Among these patients 29 (25%) received MASPORE and 87 (75%) received HyperCVAD. The median age was 23 (range 18-40) for MASPORE arm vs 28 years (range 15-40) for the HCVAD arm. median follow-up time was 4.5 vs 10.8 years. Both groups were similar in gender, race, ECOG status, and ALL risk status at diagnosis. Likewise, both arms did not have differences in starting hematological parameters: hemoglobin, total white blood cell count, platelet count, absolute neutrophil count, and bone marrow blast percentages. Median time from diagnosis to treatment was 3 and 4 days for MASPORE and HyperCVAD arms respectively. There were increased adverse rates for patients in the MASPORE arm. They had more (13.8 vs 0.0%, p < 0.001) of which 75% of the pancreatitis were CTCAE grade 3/4, avascular necrosis (13.8 vs 2.2%, p = 0.016), cerebral venous thrombosis (13.8 vs 1.1%, p = 0.004) and other thrombosis (27.6 vs 5.7%, p = 0.004). For the MASPORE and HyperCVAD arms there was one induction death, one from sepsis and the other from pneumonia . Both arms managed to achieve complete response (CR) with equivalent rates (82.5 vs 80.5%, p = 0.752). However, there was less relapsed or refractory disease in those treated with MASPORE (10.3 vs 44.8%, p < 0.001). The 5- OS was better in the MASPORE versus the HyperCVAD arm (4.4 vs 3.7 years; p = 0.049). Likewise, the 5-year PFS was superior in the MASPORE arm (4.2 vs 3.2 years, p = 0.034). Furthermore, a smaller proportion of patients required consolidative stem cell transplant (13.8 vs 49.4%, p < 0.001).Conclusion:The pediatric-inspired protocol MASPORE achieved similar CR rates with OS and PFS benefit, reduced relapse rates, and less need for consolidative stem cell transplant. MASPORE serves as a viable treatment option when treating AYA patients with ALL. Larger prospective studies are needed to further explore its use. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Generalisability and performance of an OCT-based deep learning classifier for community-based and hospital-based detection of gonioscopic angle closure

PurposeTo assess the generalisability and performance of a deep learning classifier for automated detection of gonioscopic angle closure in anterior segment optical coherence tomography (AS-OCT) images.MethodsA convolutional neural network (CNN)...

Metabolic syndrome and its effect on the outcomes of rheumatoid arthritis in a multi-ethnic cohort in Singapore.

Over-expression of common inflammatory mediators in the metabolic syndrome (MetS) and in rheumatoid arthritis (RA) may lead to mutually adverse outcomes. We investigate the prevalence of MetS in a multi-ethnic population of RA patients and its effect on clinical and patient-reported outcomes. Six hundred sixty RA (561 women) patients from a public-sector specialist clinic in a hospital in Singapore were assessed for MetS according to the 2009 Joint Consensus (JC) and the 2004 National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) definitions. Univariable and multivariable regression modelling were used to investigate the associations between patients' demographics with MetS and MetS with RA outcomes. The prevalence of MetS in our RA cohort was 49.4% and 44.9% according to the JC and NCEP ATP III definitions, respectively. The diagnosis of MetS was largely due to hypertriglyceridemia, hypertension, and obesity. MetS was associated with older age (OR1.06 [95% CI 1.04-1.08]), Malay ethnicity (OR 1.78 [95% CI 1.02-3.09]), or Indian ethnicity (OR3.07 [95% CI 1.68-5.59]). No significant associations between MetS and RA outcomes were observed. RA patients with MetS are more likely to suffer from stroke and ischemic heart disease. The prevalence of MetS in RA patients in Singapore was almost double that in the general population. MetS does not adversely affect RA outcomes but raises the risks of stroke and heart disease. RA patients, especially those older and of Indian and Malay ethnicities, should be routinely screened for MetS. Any MetS-defining condition should be actively controlled. Key Points • Approximately half of the RA sample from the Singapore RA population can be diagnosed with MetS. • Older patients, and patients of Malay and Indian ethnicities have higher odds of MetS. • MetS does not adversely affect RA outcomes but raises the risks of stroke and heart disease.

Associations Between Prognostic Awareness, Acceptance of Illness, and Psychological and Spiritual Well-being Among Patients With Heart Failure

This study aimed to (1) investigate the association of prognostic awareness with psychological (distress level and emotional well-being) and spiritual well-being among patients with heart failure, and (2) assess the main and moderating effects of illness acceptance on the relationship between prognostic awareness and psychological and spiritual well-being. This study used baseline data of a Singapore cohort of patients with heart failure (N = 245) who had New York Heart Association class 3 or 4 symptoms. Patients reported their awareness of prognosis and extent of illness acceptance. Multivariable linear regressions were used to investigate the associations. Prognostic awareness was not significantly associated with psychological and spiritual well-being. Illness acceptance was associated with lower levels of distress (β [SE] = -0.9 [0.2], P < .001), higher emotional well-being (β [SE] = 2.2 [0.4], P < .001), and higher spiritual well-being (β [SE] = 5.4 [0.7], P < .001). Illness acceptance did not moderate the associations of prognostic awareness with psychological and spiritual well-being. This study suggests that illness acceptance could be a key factor in improving patient well-being. Illness acceptance should be regularly assessed and interventions to enhance illness acceptance should be considered for those with poor acceptance.

Retinal microvasculature and time to pregnancy in a multi-ethnic pre-conception cohort in Singapore

Abstract STUDY QUESTION Can abnormalities in retinal microvasculature representing adverse microcirculatory perfusion and inflammation shed light on the pathophysiology of female fecundability? SUMMARY ANSWER In our prospective study, abnormalities in retinal vascular geometric morphology (i.e. sparser arteriolar fractal and larger venular bifurcation) during pre-conception phase are temporarily associated with a prolonged time-to-pregnancy (TTP). WHAT IS KNOWN ALREADY Suboptimal retinal microcirculatory morphology has been associated with obesity, psychological stress and hypertension, all of which are known risk factors for reduced female fecundability. STUDY DESIGN, SIZE, DURATION A total of 652 women of Chinese, Malay or Indian ethnicity 18–45 years of age and planning to conceive spontaneously within the next 12 months were recruited during the pre-conception period into the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO), from February 2015 to October 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS During recruitment, we collected information on socio-demographic factors, menstrual characteristics and lifestyle behaviors and made anthropometric measurements. We assessed the following retinal microvascular features: caliber, branching angle and fractal dimension. We conducted follow-up telephone surveys to track each participant’s pregnancy status at 6, 9 and 12 months after enrolment. We ascertained clinical pregnancies via ultrasonography, with TTP measured by the number of menstrual cycles required to achieve a clinical pregnancy over a 1-year follow-up. Then, we performed discrete-time proportional hazards models to estimate the fecundability odds ratio (FOR) and 95% CI for each retinal microvascular feature in association with TTP, after adjusting for major confounders, including body mass index and fasting glycemic level at study entry. MAIN RESULTS AND THE ROLE OF THE CHANCE Among 652 recruited women, 276 (42.3%) successfully conceived within 1 year of follow-up. The mean (and SD) was 1.24 (0.05) Df for retinal arteriolar dimension fraction and 78.45 (9.79) degrees for retinal venular branching angle, respectively. Non-linear relationship testing was performed before multiple adjustment in all associations and a non-monotonic association was detected between retinal venular branching angle and TTP. Compared with women in the highest tertile of retinal arteriolar fractal dimension, women in the second tertile had a prolonged TTP (FOR: 0.68; 95% CI: 0.51–0.92), as did women in the lowest tertile (FOR: 0.73; 95% CI: 0.55–0.98). Compared with women in the middle tertile of retinal venular branching angle, women in the highest tertile had a borderline prolonged TTP (FOR: 0.75; 95% CI: 0.56–1.02). No other retinal vascular features were significantly associated with TTP. LIMITATIONS, REASONS FOR CAUTION We were unable to adjust for other potential confounding factors such as female sexual function (e.g. frequency of sexual intercourse), which might introduce a residual bias. Moreover, even though this is a prospective cohort design, our findings can identify the temporal relationship but not necessarily infer a causal relationship between maternal microvasculature and TTP. Lastly, our study involving mainly Chinese, Malay and Indian ethnicities might not be generalizable to other races or ethnicities. WIDER IMPLICATIONS OF THE FINDINGS Suboptimal microcirculation may lead to reduced female fecundability. In the future, in addition to conventional ultrasonographic evaluation of ovarian and uterine physiological function, assessing the retinal microvasculature might be useful for assessment of ovarian age, fertility prediction and endometrial evaluation before assisted reproductive techniques for fertility treatments. STUDY FUNDING/COMPETING INTEREST(S) This research is supported by the Singapore National Research Foundation (NRF) under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC) (Singapore-NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014) and Singapore National Medical Research Council Transition Award (NMRC TA/0027/2014). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER ClinicalTrials.gov, NCT03531658.

1232Relationship between leucine metabolism and executive function development: the GUSTO cohort

Abstract Background Molecular biomarkers for cognitive function have also been widely investigated. However, few investigated early development of executive function (EF) comprehensively, which is a higher-level of cognitive function responsible for coordinating other cognitive ability. Methods We investigated the metabolomic biomarkers for EF in a multi-ethnicity birth cohort in Singapore. Circulating level of 165 metabolites were quantified using a nuclear magnetic resonance (NMR)-based metabolomics platform in 457 and 524 children at age 6 and 8 years. EF was assessed in 495 children (∼7 years) using parent-reported Behavior Rating Inventory of Executive Function, Second Edition. We incorporated genetic data and performed mediation analysis to investigate the role of rs1260326 (GCKR) in the relationship between leucine metabolism and EF. Results Higher circulating level of leucine was consistently associated with poorer EFs (Initiate, Working Memory, Plan/Organize, Task-Monitor, and Organization of Materials) after adjusting for age, sex, maternal ethnicity, maternal educational level, household income at recruitment, and child body-mass index (BMI). Comparing to CT genotype, CC genotype in rs1260326 is potentially associated with poorer EFs. But these associations were not mediated via circulating leucine level or BMI. Higher circulating leucine exerts effect on EFs and part of the effect may be via impact on BMI. Leucine-BMI interaction may exist in CT subgroup. Conclusions Our analysis suggested that leucine exerts harmful effect on EF, but at a lower level, leucine-BMI interaction may counteract with the effect of leucine. Key messages Higher level of circulating leucine was associated with poorer EF. Leucine-BMI interaction influences the leucine-EF association.