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Thyroid hormones (TH), adiponectin and brown adipose tissue (BAT) are regulators of energy homoeostasis. Influence of BAT activity on the relationship between TH and adiponectin remains unexplored. The aim of the study was to identify the relationship between TH and adiponectin and to clarify the impact of active BAT on the metabolic effects of adiponectin before and after the correction of thyrotoxicosis. Twenty-one patients with newly diagnosed hyperthyroidism from Graves' disease were recruited. A titration dosing regimen of thionamide anti-thyroid drug (ATD) was used to establish euthyroidism over 12-24 weeks. Anthropometric, biochemical and adipocytokine parameters were measured before and after control of hyperthyroidism. BAT activity was quantified by fusion 18 F-fluorodeoxyglucose (18 F-FDG) PET/MR imaging, and patients were grouped based on BAT status. Plasma adiponectin level was significantly increased following correction of hyperthyroidism in the overall sample. Free thyroxine (FT4) was also identified as a predictor of adiponectin level in thyroid dysfunction. However, significant changes in adiponectin level and correlations involving adiponectin were absent in BAT-positive patients but maintained in BAT-negative patients. BAT activity diminishes the correlative relationship with body composition and abolishes TH and adiponectin relationships when transitioning from a hyperthyroid to euthyroid state. Agency for Science, Technology and Research (A*STAR) Published version The study was supported by the Singapore Ministry of Health’s National Medical Research Council (NMRC) Clinician Scientist Award. (grant ID NMRC/CSA-INV /0003/2015) and the Agency for Science, Technology and Research (A *STAR) awarded to A/Prof. Melvin Leow.

Currently, there is no effective method to prevent the formation of hypertrophic scars and keloids, which can cause severe physical and psychological burdens to patients. Secreted protein acidic and cysteine-rich (SPARC) is involved in wound fibrosis by modulating fibroblast functions, causing excessive collagen deposition during wound healing. Thus, the reduction in SPARC gene expression after wounding can contribute to the downstream reduction in collagen production at the wound site and prevent scar formation. In this study, a dissolvable and biocompatible hyaluronic acid (HA) microneedle patch loaded with nanoplexes containing tyramine-modified gelatin and siRNA for SPARC (siSPARC/Gtn-Tyr) was investigated for topical scar prevention. Tyramine-modified gelatin (Gtn-Tyr) provides electrostatic protection and enhances cell internalization for siSPARC. In vitro studies using human dermal fibroblasts showed that both siSPARC/Gtn-Tyr nanoplexes and siSPARC/Gtn-Tyr-loaded microneedle patches can significantly reduce SPARC gene expression (P < 0.05) and do not cause discernable cytotoxic effects. Further studies using a mouse wound model demonstrate that the siSPARC/Gtn-Tyr-loaded microneedle patch can reduce collagen production during wound healing without triggering an immune response. When Gtn-Tyr-siSPARC is administered transdermally at the wound site, effective collagen reduction is achieved through silencing of the matricellular SPARC protein, thus promising the reduction of scar formation. Overall, the siSPARC/Gtn-Tyr loaded microneedle patch can potentially provide an effective transdermal anti-fibrotic treatment. Ministry of Education (MOE) Ministry of Health (MOH) National Medical Research Council (NMRC) The authors gratefully acknowledge the support by Singapore Ministry of Education under its NTUitive Gap Fund grant scheme (NGF-2019-07-004) and Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist Award (CSAINV20nov-0003).

The rise of primary topical monotherapy with chemotherapeutic drugs and immunomodulatory agents represents an increasing recognition of the medical management of ocular surface squamous neoplasia (OSSN), which may replace surgery as the standard of care in the future. Currently, there is no consensus regarding the best way to manage OSSN with no existing guidelines to date. This paper seeks to evaluate evidence surrounding available treatment modalities and proposes an approach to management. The approach will guide ophthalmologists in selecting the most appropriate treatment regime based on patient and disease factors to minimize treatment related morbidity and improve OSSN control. Further work can be done to validate this algorithm and to develop formal guidelines to direct the management of OSSN. Published version Publication fees associated with this article have been funded through the ExxonmobileNUS grant awarded to Chris Lim.

The aims of this study were to compare inpatient rehabilitation outcomes between acute stroke subtypes of Cerebral Infarction (CI) and Intracerebral Hemorrhage (ICH), and to determine the predictors of discharge outcomes. A retrospective study of stroke inpatients was carried out using the discharge Functional Independence Measure (FIM) as the primary outcome measure. Relationships between stroke subtype, rehabilitation impairments, and medical complications on FIM -gain were analyzed. Altogether, 280 datasets including 211 (75.4%) CI and 69 (24.6%) ICH were analyzed. ICH patients were significantly younger than CI patients (55 years ICH vs. 64.0 years CI years, p < 0.001), had a 10-fold higher proportion needing ICU admission (ICH 82.6% vs. CI 7.6%, p < 0.001), and had significantly lower total admission FIM scores (67 points ICH vs. 74 CI points, p = 0.006), with lower motor-FIM scores in particular (38 points ICH vs. 48 points CI, p = 0.003). Significant functional improvements after inpatient rehabilitation, i.e., FIM gain, occurred regardless of stroke subtype (FIM-ICH Δ 27 vs. FIM-CI Δ 21, p = 0.05). Despite significantly worse initial stroke severity, ICH patients achieved similar functional gains, independence levels, and return-home rates compared with their CI counterparts after inpatient rehabilitation.

Surgical patients with obstructive sleep apnea (OSA) have increased risk of perioperative complications. The primary objective is to determine the characteristics of surgical patients with unrecognized OSA requiring oxygen therapy for postoperative hypoxemia. The secondary objective is to investigate the characteristics of patients who were responsive to oxygen therapy. This was a post-hoc multicenter study involving patients with cardiovascular risk factors undergoing major non-cardiac surgery. Patients ≥45 years old underwent Type 3 sleep apnea testing and nocturnal oximetry preoperatively. Responders to oxygen therapy were defined as individuals with ≥50% reduction in oxygen desaturation index (ODI) on postoperative night 1 versus preoperative ODI. In total, 624 out of 823 patients with unrecognized OSA required oxygen therapy. These were mostly males, had larger neck circumferences, higher Revised Cardiac Risk Indices, higher STOP-Bang scores, and higher ASA physical status, undergoing intraperitoneal or vascular surgery. Multivariable regression analysis showed that the preoperative longer cumulative time SpO2 < 90% or CT90% (adjusted p = 0.03), and lower average overnight SpO2 (adjusted p < 0.001), were independently associated with patients requiring oxygen therapy. Seventy percent of patients were responders to oxygen therapy with ≥50% ODI reduction. Preoperative ODI (19.0 ± 12.9 vs. 14.1 ± 11.4 events/h, p < 0.001), CT90% (42.3 ± 66.2 vs. 31.1 ± 57.0 min, p = 0.038), and CT80% (7.1 ± 22.6 vs. 3.6 ± 8.7 min, p = 0.007) were significantly higher in the responder than the non-responder. Patients with unrecognized OSA requiring postoperative oxygen therapy were males with larger neck circumferences and higher STOP-Bang scores. Those responding to oxygen therapy were likely to have severe OSA and worse preoperative nocturnal hypoxemia. Preoperative overnight oximetry parameters may help in stratifying patients. Published version This research was funded by University Health Network Foundation; ResMed Foundation; Health and Medical Research Fund (09100351), Hong Kong; National Healthcare Group Small Innovative Grant (12019, 15201); University of Malaya, High Impact Research Grant (UM.C/625/1/HIR/067).

Although primary brain tumors are relatively rare, they cause significant morbidity and mortality due to the high rates of neurological impairment. The purpose of this study was to examine the physical and functional outcomes of patients with primary brain tumors who had undergone inpatient rehabilitation. This was a retrospective study which recruited 163 patients who had been admitted for inpatient rehabilitation. Rehabilitation outcomes, including the Functional Independence Measure (FIM) and Glasgow Outcome Scale (GOS), were recorded up to 1 year post-discharge. The majority of patients (79.1%) had low-grade (WHO Class I-II) tumors, 35 (21.5%) were diagnosed with GBM and 52 (31.9%) had recurrent brain tumors. Rehabilitation outcomes were sustained, with 125 (76.7%) and 113 (69.3%) patients having a GOS of ≥4 at 6 months and 1 year after discharge, respectively. A GOS of ≥4 at 1 year was negatively associated with high-grade tumors (p < 0.001) and radiotherapy (p = 0.028), and positively associated with a higher discharge FIM motor score (p < 0.001) and the presence of a caregiver after discharge (p = 0.034). Our study demonstrates significant positive functional benefits from 4 weeks of inpatient neuro-oncological rehabilitation for patients with primary brain tumors, as well as the importance of supportive care from caregivers.

Aggression risk assessments are vital to prevent injuries and morbidities amongst patients and staff in psychiatric settings. More recent studies have harnessed artificial intelligence (AI) methods such as machine learning algorithms to determine factors associated with aggression in psychiatric treatment settings. In this review, using Cooper's five-stage review framework, we aimed to evaluate the: (1) predictive accuracy, and (2) clinical variables associated with AI-based aggression risk prediction amongst psychiatric inpatients. Databases including PubMed, Cochrane, Scopus, PsycINFO, CINAHL were searched for relevant articles until April 2022. The eight included studies were independently evaluated using critical appraisal tools for systematic review developed by Joanna Briggs Institute. Most of the studies (87.5%) examined health records in predicting aggression and reported acceptable to excellent accuracy with specific machine learning algorithms employed (area under curve range 0.75-0.87). No particular machine learning algorithm outperformed the others consistently across studies (area under curve range 0.61-0.87). Relevant factors identified with aggression related to demographic and social profile, past aggression, forensic history, other psychiatric history, psychopathology, challenging behaviors and management domains. The limited extant studies have highlighted a potential role for the use of AI methods to clarify factors associated with aggression in psychiatric inpatient treatment settings. Published version The study was funded by West Region, Institute of Mental Health.

Brown adipose tissue (BAT) is a promising weapon to combat obesity and metabolic disease. BAT is thermogenic and consumes substantial amounts of glucose and fatty acids as fuel for thermogenesis and energy expenditure. To study BAT function in large human longitudinal cohorts, safe and precise detection methodologies are needed. Although regarded a gold standard, the foray of PET-CT into BAT research and clinical applications is limited by its high ionizing radiation doses. Here, we show that brown adipocytes release exosomes in blood plasma that can be utilized to assess BAT activity. In the present study, we investigated circulating protein biomarkers that can accurately and reliably reflect BAT activation triggered by cold exposure, capsinoids ingestion and thyroid hormone excess in humans. We discovered an exosomal protein, methylene tetrahydrofolate dehydrogenase (NADP+ dependent) 1-like (MTHFD1L), to be overexpressed and detectable in plasma for all three modes of BAT activation in human subjects. This mitochondrial protein is packaged as a cargo within multivesicular bodies of the endosomal compartment and secreted as exosomes via exocytosis from activated brown adipocytes into the circulation. To support MTHFD1L as a conserved BAT activation response in other vertebrates, we examined a rodent model and also proved its presence in blood of rats following BAT activation by cold exposure. Plasma concentration of exosomal MTHFD1L correlated with human BAT activity as confirmed by PET-MR in humans and supported by data from rats. Thus, we deduce that MTHFD1L appears to be overexpressed in activated BAT compared to BAT in the basal nonstimulated state. Agency for Science, Technology and Research (A*STAR) Ministry of Health (MOH) National Medical Research Council (NMRC) Published version The study was funded by the Singapore Ministry of Health’s National Medical Research Council (NMRC) Clinician Scientist Award [grant number NMRC/CSA-INV/0003/2015] awarded to A/Prof. MKSL and also partly supported by the Agency for Science, Technology and Research (A*STAR).

Circulating Ly6Chi monocytes often undergo cellular death upon exhaustion of their antibacterial effector functions, which limits their capacity for subsequent macrophage differentiation. This shrouds the understanding on how the host replaces the tissue-resident macrophage niche effectively during bacterial invasion to avert infection morbidity. Here, we show that proliferating transitional premonocytes (TpMos), an immediate precursor of mature Ly6Chi monocytes (MatMos), were mobilized into the periphery in response to acute bacterial infection and sepsis. TpMos were less susceptible to apoptosis and served as the main source of macrophage replenishment when MatMos were vulnerable toward bacteria-induced cellular death. Furthermore, TpMo and its derived macrophages contributed to host defense by balancing the proinflammatory cytokine response of MatMos. Consequently, adoptive transfer of TpMos improved the survival outcome of lethal sepsis. Our findings hence highlight a protective role for TpMos during bacterial infections and their contribution toward monocyte-derived macrophage heterogeneity in distinct disease outcomes. Agency for Science, Technology and Research (A*STAR) National Research Foundation (NRF) Published version This research was funded by Singapore Immunology Network (SIgN) core funding and A*STAR, Singapore. F.G. is an EMBO YIP awardee and is supported by SIgN core funding and Singapore National Research Foundation Investigatorship (NRF2016NRF-NRF1001-02). L.G.N. is supported by SIgN core funding. S.Z.C. is supported by the Ministry of Health, Singapore’s National Medical Research Council under its Open Fund-Young Individual Research Grant (OFYIRG17may036), and A*STAR Career Development Award (192D8043). Y.C.T. is a graduate scholar supported by the Ministry of Education, Singapore. M.Y.C. is a graduate scholar supported by the SIgN-NTU-NUS scholarship, Singapore. SIgN Flow Cytometry facility is supported by National Research Foundation (NRF) Singapore under Shared Infrastructure Support (SIS) (NRF2017_SISFP09).

p53 is primarily known as a downstream transcriptional effector in the DNA damage-response cascade. We report that endogenous p53 rapidly accumulates at DNA damage sites within 2 s of UVA microirradiation. The kinetics of p53 recruitment mimics those of known DNA damage-response proteins, such as Ku70 and poly(- ADP-ribose) polymerase (PARP), and precedes recruitment of Nbs1, 53BP1, and DDB1. Mutations in the DNA-binding and C-terminal domains significantly suppress this rapid recruitment. The C-terminal domain of p53 contains key residues for PARP interaction that are required for rapid recruitment of p53 to DNA damage sites, as is PARP-dependent modification. The presence of p53 at damage sites influences the recruitment kinetics of 53BP1 and DDB1 and directs the choice of nonhomologous end joining repair (NHEJ) and nucleotide excision repair. Mutations that suppressed rapid recruitment of p53 promoted error-prone alternative end-joining (alt-NHEJ) and inhibited nucleotide excision repair. Our finding that p53 is a critical early responder to DNA damage stands in contrast with its extensively studied role as a downstream transcriptional regulator in DNA damage repair. We highlight an unrecognized role of p53 in directing DNA repair dynamics and integrity and suggest a parallel mode of p53 tumor suppression apart from its function as a transcription factor. Ministry of Education (MOE) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version D.P.L. and T.L.F.H. were supported by A*STAR core funding. M.P.S. and Y.-H.W. were supported by the Mechanobiology Institute at the National University of Singapore, and, more recently, by a Cancer Prevention and Research Institute of Texas grant at the University of Texas Medical Branch. W.L.T. and M.Y.L. were supported by funding from the National Medical Research Council, Singapore (OFIRG17may-061, OFIRG19nov-0106, CTGIIT18may-0012, NMRC/OFLCG/002-2018), the National Research Foundation, Singapore (NRF-NRFF2015-04, NRF-CRP22- 2019-0003, NRF-CRP23-2019-0004), and the Singapore Ministry of Education under its Research Centers of Excellence initiative.

Background Key knowledge gaps remain in the understanding of viral dynamics and immune response of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Methods We evaluated these characteristics and established their association with clinical severity in a prospective observational cohort study of 100 patients with PCR-confirmed SARS-CoV-2 infection (mean age, 46 years; 56% male; 38% with comorbidities). Respiratory samples (n = 74) were collected for viral culture, serum samples for measurement of IgM/IgG levels (n = 30), and plasma samples for levels of inflammatory cytokines and chemokines (n = 81). Disease severity was correlated with results from viral culture, serologic testing, and immune markers. Results Fifty-seven (57%) patients developed viral pneumonia, of whom 20 (20%) required supplemental oxygen, including 12 (12%) with invasive mechanical ventilation. Viral culture from respiratory samples was positive for 19 of 74 patients (26%). No virus was isolated when the PCR cycle threshold (Ct) value was >30 or >14 days after symptom onset. Seroconversion occurred at a median (IQR) of 12.5 (9–18) days for IgM and 15.0 (12–20) days for IgG; 54/62 patients (87.1%) sampled at day 14 or later seroconverted. Severe infections were associated with earlier seroconversion and higher peak IgM and IgG levels. Levels of IP-10, HGF, IL-6, MCP-1, MIP-1α, IL-12p70, IL-18, VEGF-A, PDGF-BB, and IL-1RA significantly correlated with disease severity. Conclusions We found virus viability was associated with lower PCR Ct value in early illness. A stronger antibody response was associated with disease severity. The overactive proinflammatory immune signatures offer targets for host-directed immunotherapy, which should be evaluated in randomized controlled trials.

The time period before, during and after pregnancy represents a unique opportunity for interventions to cultivate sustained healthy lifestyle behaviors to improve the metabolic health of mothers and their offspring. However, the success of a lifestyle intervention is dependent on uptake and continued compliance. To identify enablers and barriers towards engagement with a lifestyle intervention, thematic analysis of 15 in-depth interviews with overweight or obese women in the preconception, pregnancy or postpartum periods was undertaken, using the integrated-Promoting Action on Research Implementation in Health Services framework as a guide to systematically chart factors influencing adoption of a novel lifestyle intervention. Barrier factors include time constraints, poor baseline knowledge, family culture, food accessibility, and lack of relevant data sources. Enabling factors were motivation to be healthy for themselves and their offspring, family and social support, a holistic delivery platform providing desired information delivered at appropriate times, regular feedback, goal setting, and nudges. From the findings of this study, we propose components of an idealized lifestyle intervention including (i) taking a holistic life-course approach to education, (ii) using mobile health platforms to reduce barriers, provide personalized feedback and promote goal-setting, and (iii) health nudges to cultivate sustained lifestyle habits. National Medical Research Council (NMRC) Published version This research was supported by the National Medical Research Council Singapore (Grant Number NMRC/CG/ M003/2017). The funding body did not influence either the data collection and analysis or the writing and the decision to submit the manuscript. KCW and JCKY received salary support from Singapore’s Ministry of Health’s National Medical Research Council (NMRC/MOH-000596-00 and NMRC/CSA-SI-008–2016 respectively).

Complements and neutrophils are two key players of the innate immune system that are widely implicated as drivers of severe COVID-19 pathogenesis, as evident by the direct correlation of respiratory failure and mortality with elevated levels of terminal complement complex C5b-9 and neutrophils. In this study, we identified a feed-forward loop between complements and neutrophils that could amplify and perpetuate the cytokine storm seen in severe SARS-CoV-2-infected patients. We observed for the first time that the terminal complement activation complex C5b-9 directly triggered neutrophil extracellular trap (NET) release and interleukin (IL)-17 production by neutrophils. This is also the first report that the production of NETs and IL-17 induced by C5b-9 assembly on neutrophils could be abrogated by mesenchymal stem cell (MSC) exosomes. Neutralizing anti-CD59 antibodies abolished this abrogation. Based on our findings, we hypothesize that MSC exosomes could alleviate the immune dysregulation in acute respiratory failure, such as that observed in severe COVID-19 patients, by inhibiting complement activation through exosomal CD59, thereby disrupting the feed-forward loop between complements and neutrophils to inhibit the amplification and perpetuation of inflammation during SARS-CoV-2 infection. Agency for Science, Technology and Research (A*STAR) Published version This work was funded by institutional core funds from A*STAR and IAF-PP (H19H6a0026, TEx2Pharm) to SKL and KPL.

Importance: There is a lack of studies comparing the intended and unintended consequences of prospective review and feedback (PRF) with computerized decision support systems (CDSS), especially in the longer term in antimicrobial stewardship. Objective: To examine the outcomes associated with the sequential implementation of PRF and CDSS and changes to these interventions with long-term use of antibiotics for and incidence of multidrug resistant organisms (MDROs) and other unintended outcomes. Design, Setting, and Participants: This cohort study used an interrupted time series with segmented regression analysis of data from January 2007 to December 2018. Data were extracted from the electronic medical records of patients admitted at a large university teaching hospital with high rates of antibiotic resistance in Singapore. Data were analyzed from June 2019 to June 2020. Exposures: PRF of piperacillin-tazobactam and carbapenems (intervention 1, April 2009), with the addition of hospital-wide CDSS (intervention 2, April 2011), and lifting of CDSS for half of the hospital wards for 6 months (intervention 3, March 2017). Main Outcomes and Measures: Monthly antimicrobial use was measured in defined daily doses (DDDs) per 1000 patient-days. The monthly incidence of MDROs was calculated as number of clinical isolates detected per 1000 inpatient-days over a 6-month period. Unintended outcomes examined included in-hospital mortality and age-adjusted length of stay (LOS). Results: The number of inpatients increased from 56263 in 2007 to 63572 in 2018. During the same period, the mean monthly patient days increased from 33929 in 2007 to 45603 in 2018, and the proportion of patients older than 65 years increased from 45.5% in 2007 to 56.6% in 2018. After intervention 1, there were 0.33 (95% CI, 0.18 to 0.48) more DDDs per 1000 patient-days per month of piperacillin-tazobactam and carbapenems and-11.05 (95% CI,-15.55 to-6.55) fewer DDDs per 1000 patient-days per month for other broad-spectrum antibiotics. After intervention 2, there were-0.22 (95% CI,-0.33 to-0.10) fewer DDDs per 1000 patient-days per month of piperacillin-tazobactam and carbapenems and-2.10 (95% CI,-3.13 to-1.07) fewer DDDs per 1000 patient-days per month for other broad-spectrum antibiotics. After intervention 3, use of piperacillin-tazobactam and carbapenem increased by 0.28 (95% CI, 0.02 to 0.55) DDDs per 1000 patient-days per month. After intervention 2, incidence of Clostridioides difficile decreased (estimate,-0.02 [95% CI,-0.03 to-0.01] cases per 1000 patient-days per month). Conclusions and Relevance: In this cohort study, concurrent PRF and CDSS were associated with limiting the use of piperacillin-tazobactam and carbapenems while reducing use of other antibiotics. Published version

The advent of the Omicron variant globally has hastened the requirement for a booster vaccination dose to confer continuous protection against symptomatic SARS-CoV2 infection. However, different vaccines are available in different countries, and individuals who had adverse reactions to certain vaccine types require heterologous vaccine boosters. To understand the efficacy of different vaccination regimens in inducing humoral responses to SARS-CoV2, we examined plasma antibodies and frequencies of Omicron RBD-specific B cells in individuals who had different priming-booster vaccination regimens. We found that individuals with three homologous doses of mRNA vaccines had higher levels of IgG of all subclasses against RBD of Omicron than individuals with three homologous doses of inactivated virus vaccine. A booster with mRNA vaccine resulted in significant increases in median levels of RBD-reactive IgG1 (17–19 fold) and IgG3 (2.3–3.3 fold) as compared to individuals receiving inactivated virus booster shots regardless of priming vaccine types. More importantly, individuals who received a booster dose of mRNA vaccine, irrespective of the priming vaccine, had antibodies with higher neutralizing capability against the Omicron variant than those who received a booster dose of inactivated virus vaccine. Corroborating the antibody results, boosting with the mRNA vaccine increased the frequencies of Omicron RBD-binding B cells by (1.5–3.3 fold) regardless of priming vaccine types. Together, our data demonstrate that an mRNA vaccine (BNT162b2 or mRNA-1273) booster enhances humoral responses against the Omicron variant in individuals vaccinated with either two prior doses of mRNA or inactivated virus vaccine (CoronaVac or BBIBP-CorV), potentially providing more effective protection against SARS-CoV-2 infection, particularly by the Omicron variant.

Both hyperthyroidism and elevated plasma branched chain amino acids (BCAA) are associated with insulin resistance. BCAA utilization and clearance relative to thyroid status changes remains unclear. We investigate amino acids changes, specifically BCAA, during the transition from hyperthyroidism to euthyroidism, and the impact of active brown adipose tissue (BAT) on the metabolic effects of BCAA. Newly diagnosed Graves' disease participants were recruited. Hyperthyroidism was treated via a titration dosing regimen of thionamide anti-thyroid drug to establish euthyroidism over 12-24 weeks. All underwent energy expenditure (EE) measurement within a chamber calorimeter, 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging and plasma amino acids measurement during hyperthyroidism and euthyroidism. PET BAT maximum standardized uptake value (SUVmax), SUVmean and MR supraclavicular fat fraction (FF) quantified BAT activity. Twenty-two patients completed the study. Plasma BCAA level was significantly reduced in BAT-positive but not in BAT-negative patients during the transition from hyperthyroidism to euthyroidism. Plasma valine but not leucine and isoleucine correlated positively with insulin and HOMA-IR in hyperthyroidism. Plasma valine, leucine and isoleucine correlated with insulin and HOMA-IR in euthyroidism. Plasma valine correlated with insulin and HOMA-IR in BAT-negative but not in BAT-positive participants in both hyperthyroid and euthyroid state. However, the change (i.e. decrease) in plasma valine concentration from hyperthyroid to euthyroid state was affected by BAT-status. BAT utilizes and promotes BCAA plasma clearance from hyperthyroid to euthyroid state. Active BAT can potentially reduce circulating BCAA and may help to ameliorate insulin resistance and improve metabolic health.Clinical trial registration: The trial was registered at clinicaltrials.gov as NCT03064542. National Medical Research Council (NMRC) Published version The study was supported by the National Medical Research Council Award grant. Grant number: NMRC/ CSA-INV/0003/2015.

Background: COVID-19 imposes challenges in antibiotic decision-making due to similarities between bacterial pneumonia and moderate to severe COVID-19. We evaluated the effects of antibiotic therapy on the clinical outcomes of COVID-19 pneumonia patients and diagnostic accuracy of key inflammatory markers to inform antibiotic decision-making. Methods: An observational cohort study was conducted in patients hospitalised with COVID-19 at the National Centre for Infectious Diseases and Tan Tock Seng Hospital, Singapore, from January to April 2020. Patients were defined as receiving empiric antibiotic treatment for COVID-19 if started within 3 days of diagnosis. Results: Of 717 patients included, 86 (12.0%) were treated with antibiotics and 26 (3.6%) had documented bacterial infections. Among 278 patients with COVID-19 pneumonia, those treated with antibiotics had more diarrhoea (26, 34.7% vs. 24, 11.8%, p < 0.01), while subsequent admissions to the intensive care unit were not lower (6, 8.0% vs. 10, 4.9% p = 0.384). Antibiotic treatment was not independently associated with lower 30-day (adjusted odds ratio, aOR 19.528, 95% confidence interval, CI 1.039–367.021) or in-hospital mortality (aOR 3.870, 95% CI 0.433–34.625) rates after adjusting for age, co-morbidities and severity of COVID-19 illness. Compared to white cell count and procalcitonin level, the C-reactive protein level had the best diagnostic accuracy for documented bacterial infections (area under the curve, AUC of 0.822). However, the sensitivity and specificity were less than 90%. Conclusion: Empiric antibiotic use in those presenting with COVID-19 pneumonia did not prevent deterioration or mortality. More studies are needed to evaluate strategies to diagnose bacterial co-infections in these patients.

Pyogenic liver abscess (PLA) is a common cause of hepatobiliary sepsis. Klebsiella pneumoniae (KP) is the most common organism causing PLA. Evidence is scarce on the demographics, radiological findings, and outcomes of KPPLA versus non-KPPLA (N-KPPLA). PubMed, Embase, The Cochrane Library, and Scopus were systematically searched until 14 May 2022 for studies comparing KPPLA and N-KPPLA. Exclusion criteria were single-arm studies. Primary outcomes were mortality (30-day/in-hospital) and metastatic complications. There were 16 studies, including 5127 patients (KPPLA n = 3305, N-KPPLA n = 1822). Patients with KPPLA were younger (mean difference: −2.04 years, p = 0.02). History of hepatobiliary disease (Odds ratio (OR) 0.30, 95% CI: 0.20, 0.46) and malignancy (OR 0.26, 95% CI: 0.16, 0.42) were less common in KPPLA. KPPLA was associated with lower incidence of multiple abscesses (OR 0.52, 95% CI: 0.35, 0.76, p < 0.001) and bilobar abscesses (OR 0.60, 95% CI: 0.49, 0.74, p < 0.001). KPPLA has higher overall metastatic complications (KPPLA 9.7% vs. N-KPPLA 4.8%, OR 3.16, 95% CI: 2.00, 4.99, p < 0.001), but lower mortality (KPPLA 3.9% vs. N-KPPLA 7.6%, OR 0.51, 95% CI: 0.34, 0.78, p < 0.001). Trial sequential analysis showed conclusive evidence that KPPLA has lower mortality than N-KPPLA. In conclusion, KPPLA has lower mortality than N-KPPLA.

Data on use of monoclonal antibodies (mAbs) in hospitalized patients are limited. In this cross-sectional study, we evaluated the use of mAbs for early treatment of unvaccinated hospitalized patients with mild-to-moderate COVID-19. All inpatients at our center were screened on 27 October 2021. Primary outcome was in-hospital deterioration as defined by a composite of oxygen requirement, intensive care unit (ICU) admission, or mortality within 28 days of admission. Ninety-four out of 410 COVID-19 inpatients were included in the final analysis, of whom 19 (20.2%) received early treatment with sotrovimab. The median age was 73 years (IQR 61–83), and 35 (37.2%) were female. Although the treatment group was significantly older and had more comorbidities, there was a lower proportion of progression to oxygen requirement (31.6% vs. 54.7%), ICU admission (10.5% vs. 24.0%), or mortality (5.3% vs. 13.3%). Kaplan–Meier curves showed a significant difference in time to in-hospital deterioration (log-rank test, p = 0.043). Cox proportional hazards model for in-hospital deterioration showed that sotrovimab treatment was protective (hazard ratio, 0.41; 95% CI, 0.17–0.99; p = 0.047) after adjustment for baseline ISARIC deterioration score. Our findings support the use of sotrovimab for early treatment in hospitalized patients with mild-to-moderate COVID-19 at a high risk of disease progression.

There are more than 7,000 paediatric genetic diseases (PGDs) but less than 5% have treatment options. Treatment strategies targeting different levels of the biological process of the disease have led to optimal health outcomes in a subset of patients with PGDs, where treatment is available. In the past 3 decades, there has been rapid advancement in the development of novel therapies, including gene therapy, for many PGDs. The therapeutic success of treatment relies heavily on knowledge of the genetic basis and the disease mechanism. Specifically, gene therapy has been shown to be effective in various clinical trials, and indeed, these trials have led to regulatory approvals, paving the way for gene therapies for other types of PGDs. In this review, we provide an overview of the treatment strategies and focus on some of the recent advancements in therapeutics for PGDs. Published version

IDentif.AI-x, a clinically actionable artificial intelligence platform, was used to rapidly pinpoint and prioritize optimal combination therapies against COVID-19 by pairing a prospective, experimental validation of multi-drug efficacy on a SARS-CoV-2 live virus and Vero E6 assay with a quadratic optimization workflow. A starting pool of 12 candidate drugs developed in collaboration with a community of infectious disease clinicians was first narrowed down to a six-drug pool and then interrogated in 50 combination regimens at three dosing levels per drug, representing 729 possible combinations. IDentif.AI-x revealed EIDD-1931 to be a strong candidate upon which multiple drug combinations can be derived, and pinpointed a number of clinically actionable drug interactions, which were further reconfirmed in SARS-CoV-2 variants B.1.351 (Beta) and B.1.617.2 (Delta). IDentif.AI-x prioritized promising drug combinations for clinical translation and can be immediately adjusted and re-executed with a new pool of promising therapies in an actionable path towards rapidly optimizing combination therapy following pandemic emergence. Published version D.H. gratefully acknowledges funding from the Institute for Digital Medicine (WisDM) Translational Research Program [grant number R-719-000-037-733] at the Yong Loo Lin School of Medicine, National University of Singapore, Ministry of Education Tier 1 FRC Grant [grant number R-397-000-333-114], Micron Foundation, and Sun Life Singapore. D.H. and E.K.-H.C. gratefully acknowledge the National Research Foundation Singapore under its AI Singapore Program [Award Number: AISG-GC-2019-002], and Singapore Ministry of Health’s National Medical Research Council under its Open Fund- Large Collaborative Grant (“OF-LCG”) [grant number MOH-OFLCG18May-0028]. E.K.-H.C. is supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centers of Excellence Initiative (Cancer Science Institute of Singapore RCE Main Grant), Ministry of Education Academic Research Fund (MOE AcRF Tier 2 [grant number MOE2019-T2-1-115]), Singapore Ministry of Health’s National Medical Research Council under its Open Fund- Large Collaborative Grant (“OF-LCG”) [grant numbers MOH-OFLCG18May-0023 and MOHOFLCG18May-0028] and National Research Foundation Competitive Proton Research Program [grant number NRF-CRP-2017-05]. S.G.K.S., D.H.C., A.P.C.L., G.-Y.G.T. and C.E.Z. C. gratefully acknowledge funding support from Future Systems and Technology Directorate, Singapore Ministry of Defense.

Background: Rapid spread of the COVID-19 pandemic raised an urgent need for preparedness in the healthcare sector, including training of healthcare workers to cope with the burden of infected cases while ensuring proper protection of themselves. Improper infection prevention and control measures were key reasons for infection in healthcare workers during the early phase of the outbreak.Objectives/Methods: This paper describes the combined approach of 3 restructured hospitals in Singapore in preparing and training neonatal healthcare workers' during the COVID-19 pandemic crisis, as well as lessons learnt during this process.Results: Information sharing was conducted in the form of e-learning, emphasizing on topics like disease knowledge and infection prevention and control procedures. Skills and competency training were carried out in the form of simulation, with sessions scaled into 4 levels progressing from individual task training to larger group simulations involving multiple disciplines and departments. Challenges encountered included information fatigue by large amount of constantly changing information and multiple amendments to workflows as more information arose. Difficulties conducting training and simulation sessions included restriction of group size to mitigate infection risk amongst participants and the limited supply of personal protective equipment prioritized for direct patient care.Conclusion: Healthcare institutions should ensure adequate dissemination of conceptual knowledge as well as skills competency training of staff in infection control measures for the protection of healthcare workers and patient safety. Ongoing training for sustainability of knowledge and skills, while adapting to the rapidly evolving situation is important in the preparation for future outbreaks.

Objectives: Understanding factors influencing inappropriate antibiotic use can guide the design of interventions to improve antibiotic practices and reduce antimicrobial resistance (AMR). Methods: A nationally representative cross-sectional survey (N = 2004) was conducted between November 2020 and January 2021. Knowledge of antibiotic use and AMR using the World Health Organization’s Multi-Country AMR Survey questionnaire, and antibiotic practices were examined. Multivariable logistic regression was performed to identify factors associated with inappropriate antibiotic use and examine effect measure modifications. Results: After adjusting for potential con-founding, poor knowledge of antibiotic use was associated with a 3x increased odds of inappropriate antibiotic use in adults aged ≥50 years (aOR 3.11, 95% CI [2.24–4.32]), 5× increased odds in those aged 35–49 years (aOR 4.88, 95% CI [3.32–7.16]), and 7× increased odds in those aged 21–34 years (aOR 6.58, 95% CI [4.19–10.33]). While there was no statistically significant association in adults aged ≥50 years, poor knowledge of AMR increased the odds of inappropriate antibiotic use by 4 times in adults aged 35–49 years (aOR 3.73, 95% CI [1.53–9.11]) and 5 times in those aged 21–34 years (aOR 4.90, 95% CI [1.84–13.02]). Conclusions: Targeted educational interventions for specific age groups are needed in conjunction with empowering the public with knowledge of antibiotic use and AMR. National Medical Research Council (NMRC) Published version This research was funded by the National Medical Research Council Singapore, Health Services Research Grant (NMRC/HSRG/0083/2017).

The practice of emergency medicine has reached its cross roads. Emergency physicians (EPs) are managing many more time-dependent conditions, initiating complex treatments in the emergency department (ED), handling ethical and end of life care discussions upfront, and even performing procedures which used to be done only in critical care settings, in the resuscitation room. EPs manage a wide spectrum of patients, 24 h a day, which reflects the community and society they practice in. Besides the medical and "technical" issues to handle, they have to learn how to resolve confounding elements which their patients can present with. These may include social, financial, cultural, ethical, relationship, and even employment matters. EPs cannot overlook these, in order to provide holistic care. More and more emphasis is also now given to the social determinants of health. We, from the emergency medicine fraternity, are proposing a unique "BRAVE model," as a mnemonic to assist in the provision of point of care, adaptive leadership at the bedside in the ED. This represents another useful tool for use in the current climate of the ED, where patients have higher expectations, need more patient-centric resolution and handling of their issues, looming against the background of a more complex society and world. Published version

Background The COVID-19 pandemic has disrupted medical education, shifting learning online. Social media platforms, including messaging apps, are well integrated into medical education. However, Telegram’s role in medical education remains relatively unexplored. Objective This study aims to explore the perceptions of medical students regarding the role of messaging apps in medical education and their experience of using Telegram for surgical education. Methods A Telegram channel “Telegram Education for Surgery Learning and Application (TESLA)” was created to supplement medical students’ learning. We invited 13 medical students who joined the TESLA channel for at least a month to participate in individual semistructured interviews. Interviews were conducted via videoconferencing using an interview guide and were then transcribed and analyzed by 2 researchers using inductive thematic content analysis. Results Two themes were identified: (1) learning as a medical student and (2) the role of mobile learning (mLearning) in medical education. Students shared that pandemic-related safety measures, such as reduced clinic allocations and the inability to cross between wards, led to a decrease in clinical exposure. Mobile apps, which included proprietary study apps and messaging apps, were increasingly used by students to aid their learning. Students favored Telegram over other messaging apps and reported the development of TESLA as beneficial, particularly for revision and increasing knowledge. Conclusions The use of apps for medical education increased during the COVID-19 pandemic. Medical students commonly used apps to consolidate their learning and revise examination topics. They found TESLA useful, relevant, and trustworthy.

Objectives: Highly effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) have been developed but variants of concerns are worrisome, especially B.1.617.2 (Delta) which has rapidly spread across the world. We aim to study if vaccination alters virological and serological kinetics in breakthrough infections. Methods: We conducted a multicentre retrospective cohort study of patients in Singapore who had received a licensed mRNA vaccine and been admitted to hospital with B.1.617.2 SARS-CoV-2 infection. We compared clinical features, virological and serological kinetics (anti-nucleocapsid, anti-spike and surrogate virus neutralization titres) between fully vaccinated and unvaccinated individuals. Results: Out of 218 individuals with B.1.617.2 infection, 84 received an mRNA vaccine of which 71 were fully vaccinated, 130 were unvaccinated and four received a non-mRNA vaccine. Despite significantly older age in the vaccine breakthrough group, only 2.8% (2/71) developed severe COVID-19 requiring oxygen supplementation compared with 53.1% (69/130) in the unvaccinated group (p < 0.001). Odds of severe COVID-19 following vaccination were significantly lower (adjusted odds ratio 0.07 95% CI 0.015 e0.335, p 0.001). PCR cycle threshold values were similar between vaccinated and unvaccinated groups at diagnosis, but viral loads decreased faster in vaccinated individuals. Early, robust boosting of anti-spike protein antibodies was observed in vaccinated patients; however, these titres were significantly lower against B.1.617.2 than the wildtype vaccine strain. Discussion: The mRNA vaccines are highly effective at preventing symptomatic and severe COVID-19 associated with B.1.617.2 infection. Vaccination is associated with faster decline in viral RNA load and a robust serological response. Vaccination remains a key strategy for control of the COVID-19 pandemic. National Medical Research Council (NMRC) Published version B.E.Y. reports personal fees from Roche, Sanofi and Gilead, outside the submitted work. All other authors declare no competing interests. This study was funded by grants from the Singapore National Medical Research Council (COVID19RF-001, COVID19RF-008). The funders had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.

Intra-tumor heterogeneity (ITH) is a key challenge in cancer treatment, but previous studies have focused mainly on the genomic alterations without exploring phenotypic (transcriptomic and immune) heterogeneity. Using one of the largest prospective surgical cohorts for hepatocellular carcinoma (HCC) with multi-region sampling, we sequenced whole genomes and paired transcriptomes from 67 HCC patients (331 samples). We found that while genomic ITH was rather constant across stages, phenotypic ITH had a very different trajectory and quickly diversified in stage II patients. Most strikingly, 30% of patients were found to contain more than one transcriptomic subtype within a single tumor. Such phenotypic ITH was found to be much more informative in predicting patient survival than genomic ITH and explains the poor efficacy of single-target systemic therapies in HCC. Taken together, we not only revealed an unprecedentedly dynamic landscape of phenotypic heterogeneity in HCC, but also highlighted the importance of studying phenotypic evolution across cancer types. National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This work is supported in part by the Singapore National Medical Research Council grants (TCR/015-NCC/2016, CIRG18may-0057l, NMRC/CSA-SI/0018/2017, and NMRC/ OFIRG/0064/2017) and the National Research Foundation, Singapore (NRF-NRFF2015-04). W.Z. is supported in part by the National Key R&D Program of China (2018YFC1406902 and 2018YFC0910400), the National Natural Science Foundation of China (31970566), and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDPB17). H.Y. is supported by the National Natural Science Foundation of China (32000407).

ImportanceAssessing booster effectiveness of COVID-19 mRNA vaccine and inactivated SARS-CoV-2 vaccine over longer time intervals and in response to any further SARS-CoV-2 variants is crucial in determining optimal COVID-19 vaccination strategies.ObjectiveTo determine levels of protection against severe COVID-19 and confirmed SARS-CoV-2 infection by types and combinations of vaccine boosters in Singapore during the Omicron wave.Design, Setting, and ParticipantsThis cohort study included Singapore residents aged 30 years or more vaccinated with either at least 2 doses of mRNA COVID-19 vaccines (ie, Pfizer-BioNTech BNT162b2 or Moderna mRNA-1273) or inactivated SARS-CoV-2 vaccines (Sinovac CoronaVac or Sinopharm BBIBP-CorV) as of March 10, 2022. Individuals with a known SARS-CoV-2 infection prior to December 27, 2021, an infection on or before the date of their second vaccine dose, or with reinfection cases were excluded.ExposuresTwo or 3 doses of Pfizer-BioNTech BNT162b2, Moderna mRNA-1273, Sinovac CoronaVac, or Sinopharm BBIBP-CorV.Main Outcomes and MeasuresNotified infections from December 27, 2021, to March 10, 2022, adjusted for age, sex, race, housing status, and calendar days. Estimated booster effectiveness, defined as the relative incidence-rate reduction of severe disease (supplemental oxygen, intensive care, or death) or confirmed infection following 3-dose vaccination compared with 5 months after second mRNA dose, was determined using binomial regression.ResultsAmong 2 441 581 eligible individuals (1 279 047 [52.4%] women, 846 110 (34.7%) aged 60 years and older), there were 319 943 (13.1%) confirmed SARS-CoV-2 infections, of which 1513 (0.4%) were severe COVID-19 cases. mRNA booster effectiveness against confirmed infection 15 to 60 days after boosting was estimated to range from 31.7% to 41.3% for the 4 boosting combinations (homologous BNT162b2, homologous mRNA-1273, 2-dose BNT162b2/mRNA-1273 booster, and 2-dose mRNA-1273/BNT162b2 booster). Five months and more after boosting, estimated booster effectiveness against confirmed infection waned, ranging from –2.8% to 14.6%. Against severe COVID-19, estimated mRNA booster effectiveness was 87.4% (95% CI, 83.3%-90.5%) 15 to 60 days after boosting and 87.2% (95% CI, 84.2%-89.7%) 5 to 6 months after boosting, with no significant difference comparing vaccine combinations. Booster effectiveness against severe COVID-19 15 days to 330 days after 3-dose inactivated COVID-19 vaccination, regardless of combination, was estimated to be 69.6% (95% CI, 48.7%-81.9%).Conclusions and RelevanceBooster mRNA vaccine protection against severe COVID-19 was estimated to be durable over 6 months. Three-dose inactivated SARS-CoV-2 vaccination provided greater protection than 2-dose but weaker protection compared with 3-dose mRNA.

Objectives: Predictive scores are important tools for the triage of patients with coronavirus disease 2019. The PRIORITY score is advantageous because it does not require laboratory and radiologic information. However, the original development and validation cohorts studied only unvaccinated patients in early 2020. We aimed to externally validate the PRIORITY score in a cohort of patients with the novel delta and omicron variants of coronavirus disease 2019 and mixed vaccination status. Methods: A total of 410 patients were included in a cross-sectional sampling of all patients admitted to the National Centre of Infectious Diseases on October 27, 2021. A further 102 and 136 patients with vaccine-breakthrough Delta and Omicron variant infection from April to August and December 2021, respectively, were also included. Variables at the time of admission were collected retrospectively from medical records and used to calculate the probability of deterioration using the PRIORITY model. Results: Of the total 648 included patients, 447 (69.0%) were vaccinated. The mean age was 61.6 years (standard deviation ± 19.0 years), and 268 patients (41.4%) were female. A total of 112 patients (17.3%) met the primary outcome of developing critical illness or mortality. The performance of the score in this cohort was comparable with the original cohorts, with an area under the receiver operating characteristic curve for all patients of 0.794 (95% CI, 0.752e0.835; p < 0.001), regression coefficient of 1.069, and intercept of 0.04. Subgroup analysis of unvaccinated and vaccinated patients showed that performance was superior in vaccinated individuals, with an area under the receiver operating characteristic curve of 0.684 (95% CI, 0.608e0.760; p < 0.0001) and 0.831 (95% CI, 0.772e0.891; p < 0.0001), respectively. Discussion: Our data support the continued use of the PRIORITY score in this era of novel variants and increased vaccination uptake. BEY reports personal fees from Roche and Sanofi outside of the submitted work. All other authors declare no competing interests. No additional funding was required for this study.

INTRODUCTION Perinatal transmission remains one of the important causes of transmission of the human immunodeficiency virus (HIV). Over the years, with better knowledge and awareness of HIV infection, the perinatal transmission rate has been significantly reduced. We previously reported on the pregnancy outcomes of HIV-positive mothers from 1997 to 2007 in our institution. This article aimed to review the standards of care of HIV-positive pregnant women since then. METHODS A retrospective study reviewed 84 HIV-positive women who delivered in a tertiary centre from January 2008 to December 2015. Patient demographics and antenatal, intrapartum, postnatal and immediate neonatal data were analysed. RESULTS A total of 97 deliveries with 98 neonates were recorded; 12 women delivered more than once, and there was one set of twins. The mean maternal age at diagnosis of HIV infection was 27.8 years. Of the study population, 63.1% of women were non-Singaporeans. 56 women were known to have HIV infection on presentation and 90.7% were on antiretroviral therapy during pregnancy. 88.7% of the women received intrapartum intravenous zidovudine, and 93.1% of women with detectable and 58.7% with undetectable viral load underwent Caesarean sections. All neonates were HIV-negative. CONCLUSION The high standards of care for HIV-positive women have successfully reduced our perinatal transmission rate to zero.

The components of each stage have similarities as well as differences, which make each unique in its own right. As the film-making and the movie industry may have much we can learn from, some of these will be covered under the different sections of the paper, for example, "Writing Powerful Narratives," depiction of emotional elements, specific industry-driven developments as well as the "cultural considerations" in both. For medical simulation and simulation-based education, the corresponding stages are as follows: Development, Preproduction, Production, Postproduction and Distribution. The art of sim-making has many similarities to that of film-making. In fact, there is potentially much to be learnt from the film-making process in cinematography and storytelling. Both film-making and sim-making can be seen from the artistic perspective as starting with a large piece of blank, white sheet of paper, which will need to be colored by the "artists" and personnel involved; in the former, to come up with the film and for the latter, to engage learners and ensure learning takes place, which is then translated into action for patients in the actual clinical care areas. Both entities have to go through a series of systematic stages. For film-making, the stages are as follows: Identification of problems and needs analysis; Setting objectives, based on educational strategies; Implementation of the simulation activity; Debriefing and evaluation; as well as fine-tuning for future use and archiving of scenarios/cases. Published version

Inosine is a prevalent RNA modification in animals and is formed when an adenosine is deaminated by the ADAR family of enzymes. Traditionally, inosines are identified indirectly as variants from Illumina RNA-sequencing data because they are interpreted as guanosines by cellular machineries. However, this indirect method performs poorly in protein-coding regions where exons are typically short, in non-model organisms with sparsely annotated single-nucleotide polymorphisms, or in disease contexts where unknown DNA mutations are pervasive. Here, we show that Oxford Nanopore direct RNA sequencing can be used to identify inosine-containing sites in native transcriptomes with high accuracy. We trained convolutional neural network models to distinguish inosine from adenosine and guanosine, and to estimate the modification rate at each editing site. Furthermore, we demonstrated their utility on the transcriptomes of human, mouse and Xenopus. Our approach expands the toolkit for studying adenosine-to-inosine editing and can be further extended to investigate other RNA modifications. Nanyang Technological University National Medical Research Council (NMRC) National Research Foundation (NRF) M.H.T. is supported by a National Research Foundation Singapore grant (NRF2017-NRF-ISF002–2673), an Open Fund - Individual Research Grant from the National Medical Research Council (NMRC/OFIRG/0017/2016), an EMBO Global Investigatorship, an ASPIRE League seed grant from Nanyang Technological University, core funds from the Genome Institute of Singapore, and funds for Final Year Project (FYP) and the International Genetically Engineering Machine (iGEM) competition from the School of Chemical and Biomedical Engineering. J.W.J.H. is supported by a Ph.D. research scholarship from the School of Chemical and Biomedical Engineering. Y.S.H. is supported by core funds from the Bioprocessing Technology Institute. We also acknowledge the funding support for this project from Nanyang Technological University under the URECA Undergraduate Research Programme.